Clinical trial NCT03978091
Conditions: Bacterial Infection
Keywords: Aztreonam Ceftazidime-Avibactam Efficacy Healthy Pharmacokinetics Population Safety
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2019-07-09; Completion date: 2020-11-23
Enrollment: 48 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase I, open-label, non-randomized, single center study in 48 healthy adult male and female subjects, aged 18 to 45 years. This study is aimed to investigate the safety and pharmacokinetics of ceftazidime-avibactam (AVYCAZ) combined with aztreonam (ATM), AVYCAZ alone, and ATM alone. The study will have 6 arms, arms 1-4 are the single drug administration treatment groups and will include AVYCAZ per label dosing, AVYCAZ as a continuous infusion (CI), ATM per label dosing, and ATM as a CI. Arms 5 and 6 are the two AVYCAZ and ATM combination drug administration treatment groups. The duration of subject participation will be up to 44 days, and the total length of the study will be 15 months. The primary objective of this study is to describe the safety of two dosing regimens of AVYCAZ combined with ATM relative to AVYCAZ alone, and ATM alone in healthy adult subjects.

Detailed description:
This is a Phase I, open-label, non-randomized, single center study in 48 healthy adult male and female subjects, aged 18 to 45 years. This study is aimed to investigate the safety and pharmacokinetics of ceftazidime-avibactam (AVYCAZ) combined with aztreonam (ATM), AVYCAZ alone, and ATM alone. The study will have 6 arms, arms 1-4 are the single drug administration treatment groups and will include AVYCAZ per label dosing, AVYCAZ as a continuous infusion (CI), ATM per label dosing, and ATM as a continuous infusion (CI). Arms 5 and 6 are the two AVYCAZ and ATM combination drug administration treatment groups. The duration of subject participation will be up to 44 days, and the total length of the study will be 15 months. The primary objective of this study is to describe the safety of two dosing regimens of AVYCAZ combined with ATM relative to AVYCAZ alone, and ATM alone in healthy adult subjects. The secondary objectives of this study are to; 1) Characterize the PK profiles of two dosing regimens of AVYCAZ combined with ATM, AVYCAZ alone, and ATM alone at the population level in healthy adult subjects; 2) Characterize the PK profiles of two dosing regimens of AVYCAZ combined with ATM, AVYCAZ alone, and ATM alone following initiation of dosing on day 1 in healthy adult subjects; and 3) Characterize the PK profiles of two dosing regimens of AVYCAZ combined with ATM, AVYCAZ alone, and ATM alone following multiple daily dosing in healthy adult subjects.

Arms: arm 1: 2.5g dose of ceftazidime-avibactam (AVYCAZ) administered intravenously as a 2-hour infusion, every 8 hours for 7 days. N=8 arm 2: 2.5g dose of AVYCAZ administered intravenously as a 2-hour infusion once, then 0.32g dose per hour daily as a continuous infusion (7.5 g/day) for 7 days. N=8 arm 3: 2g dose of aztreonam (ATM) administered intravenously as a 2-hour infusion, every 6 hours for 7 days. N=8 arm 4: 2g of ATM administered intravenously as a 2-hour infusion once, then 0.33g dose administered intravenously per hour, daily as a continuous infusion (8 g/day) for 7 days. N=8 arm 5: 2.5g dose of AVYCAZ administered intravenously as a 2-hour infusion, every 8 hours for 7 days, and a 1.5g dose of ATM administered intravenously as a 2-hour infusion, every 6 hours for 7 days. N=8 arm 6: 2.5 g dose of AVYCAZ administered intravenously as a 2-hour infusion every 8 hours for 7 days, and a 2g dose of ATM as a 2-hour infusion every 6 hours for 7 days. N=8
Interventions: intervention 1: AZACTAM intervention 2: Ceftazidime-Avibactam
Intervention descriptions: intervention 1: A synthetic monobactam antibiotic originally isolated from Chromobacterium violaceum intervention 2: An antibacterial combination product containing ceftazidime and avibactam

Protocol documents:
ICF_000.pdf: 
A Phase I, Open Label Study in Healthy Adults to Evaluate 
the Safety and Pharmacokinetics of AVYCAZ® in 
Combination with Aztreonam (COMBINE)
DEPRU# NJ07
Consent to Participate in a Research Study
Page 1 of 17
Subject Initials ________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
You are being asked to take part in this research study to help develop better antibiotic treatment plans 
for patients with serious Gram-negative bacteria (GNB) infections.  Research studies are voluntary and 
include only people who choose to take part.  Please read this consent form carefully and take your time 
making your decision. When your study doctor or the study staff discusses this consent form with you, 
please ask him/her to explain any words or information that you do not clearly understand.  We 
encourage you to talk with your family and friends before you decide to take part in this research study.  
The nature of the study, risks, inconveniences, discomforts, and other important information about the 
study are listed below.
Please tell the study doctor or study staff if you are taking part in another research study.
This study is being conducted by the Antibiotic Resistance Leadership Group (ARLG) (coordinated by 
Duke University).  The ARLG is funded by a grant from the National Institutes of Health (NIH). 
Portions of Dr. Guptill’s and his research team’s salaries will be paid by this grant.
CONCISE SUMMARY
The purpose of this study is to find out if ceftazidime-avibactam (AVYCAZ®) given in combination 
with aztreonam (ATM) is safe and to determine the concentration (amount) of the drugs in the body 
in healthy adults. AVYCAZ and ATM are both currently Federal Drug Administration (FDA) 
approved as individual antibiotics for the treatment of patients with various infections due to gram-
negative bacteria, but giving both drugs at the same time requires further testing. 
Healthy adults ages 18-45 are able to participate in this the study. AVYCAZ and ATM will be given 
by a catheter through a vein in your arm in the clinic at Duke. If you qualify for this study, your 
participation will last approximately 2 months. The study includes 2-3 outpatient visits and an 
8-night inpatient visit during which you will have an intravenous catheter placed. Prior to receiving 
the study antibiotic(s), you will be evaluated at the Duke Early Phase Clinical Research Unit 
(DEPRU).  If you qualify to continue participating in the study, you will receive the study 
antibiotic(s) assigned to you by the staff at the DEPRU. You may be able to continue in the study if 
you have no bad reactions(s) to the study drug(s). Tests, exams and procedures will be performed on 
you as part of the study.  
The greatest risks of this study are side effects of the study drug including allergic reactions. Please 
notify the study team if you are allergic to medicines like penicillin. There is no anticipated direct 
benefit to you for participation in the study.
If you are interested in learning more about this study, please continue reading below.
DUHS IRB
IRB NUMBER: Pro00094792
IRB REFERENCE DATE: 04/13/2020
IRB EXPIRATION DATE: 04/25/2021


A Phase I, Open Label Study in Healthy Adults to Evaluate 
the Safety and Pharmacokinetics of AVYCAZ® in 
Combination with Aztreonam (COMBINE)
DEPRU# NJ07
Consent to Participate in a Research Study
Page 2 of 17
Subject Initials ________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
WHO WILL BE MY DOCTOR ON THIS STUDY?
If you decide to participate, Dr. Jeffrey Guptill will be your doctor for the study.  If needed, Dr. Guptill 
will be in contact with your regular health care provider during the time that you are in the study and 
afterwards.
WHY IS THIS STUDY BEING DONE?
Treatment of patients with serious infections due to highly resistant GNB is a worldwide problem and is 
a major public health concern.  Also, there are increases in resistance to certain antibiotics and 
combinations of antibiotics among patients with certain GNB infections.  New antibiotics are being 
developed to treat these GNB infections that are resistant to multiple antibiotics, but they are not likely 
to be available for several years.  Until new antibiotics are available, one way to treat patients with these 
antibiotic resistant GNB infections is to give ceftazidime-avibactam (AVYCAZ) in combination with 
aztreonam (ATM). AVYCAZ and ATM are both currently FDA approved to treat patients with various 
infections due to GNB. Although AVYCAZ and ATM appear to be safe, there are limited data on the 
safety of these antibiotics when they are given together. The purpose of this study is to evaluate the 
safety and the concentration (amount) of the drugs in the body when each antibiotic is given alone and 
when the antibiotics are given together in healthy adults ages 18-45. The antibiotics will be given by a 
catheter through a vein in your arm in the clinic at Duke.  A catheter will stay in your arm until you have 
completed the study. You may receive only one antibiotic or you may be given the two antibiotics at the 
same time. You will have tests, exams and procedures to determine the safety of the antibiotics.  Blood 
and urine will also be collected to measure the levels of the antibiotics as part of this study.  
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
Participants who are 18-45 years old will be enrolled into the study. Approximately 120 participants will 
be screened to enroll 48 people will participate at Duke. 
WHAT IS INVOLVED IN THE STUDY?
You will come to the Duke Early Phase Clinical Research Unit (DEPRU) at least three times over the 
next two months. The visits include the screening visit, an inpatient visit  for 8 nights and 9 days in the 
DEPRU’s confinement (research) unit when you are enrolled into the study and the study drug(s) are 
being administered, and for one follow-up visit. If you have side effects from the drug(s), you will be 
asked to return to the clinic for additional visits to be sure the side effect has resolved or has stabilized. 
You will not be allowed to leave the DEPRU confinement unit during your inpatient visit. The research 
staff will explain each visit to you. You will be able to ask questions to make sure that you understand 
what will happen. 
Visit 1:  Screening Visits (Days -30 to Day -2)
If you agree to be in this study, you will be asked to sign and date this consent form. You will then have 
the following tests and procedures to make sure that you are eligible: 

Sign this informed consent form before any tests or procedures will be completed
DUHS IRB
IRB NUMBER: Pro00094792
IRB REFERENCE DATE: 04/13/2020
IRB EXPIRATION DATE: 04/25/2021


A Phase I, Open Label Study in Healthy Adults to Evaluate 
the Safety and Pharmacokinetics of AVYCAZ® in 
Combination with Aztreonam (COMBINE)
DEPRU# NJ07
Consent to Participate in a Research Study
Page 3 of 17
Subject Initials ________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345

Ask you questions about your age, race, sex, and ethnic group

Ask you about any past or present illnesses and medications and supplements you are taking

Complete physical examination

Collect vital signs (height, weight, blood pressure, heart rate, respiratory rate, temperature)

12-lead electrocardiogram (ECG) in triplicate, which is a test used to measure the electrical 
activity of the heart

Blood collection (approximately 2 tablespoons/30mL) to test the following: 
o
Routine lab tests to check your health
o
Hepatitis B and C
o
HIV infection*
*Note: As part of this protocol, you will be tested for HIV (human immunodeficiency virus, which 
is the virus that causes the acquired immunodeficiency syndrome [AIDS]). You will be notified of 
the results of the testing, and counseled as to the meaning of the results, whether they are positive 
or negative. If the test indicates that you are infected with HIV, you will receive additional 
counseling about the significance of your care and possible risks to other people. We are required 
to report all positive results to the North Carolina Division of Public Health. The test results will 
be kept confidential to the extent permissible under the law. If you do not want to be tested for HIV, 
then you should not agree to participate in this study.

Collect urine for drug screening, nicotine use and routine lab test

If you are a female of child bearing potential, we will test your blood to make sure you are not 
pregnant 

Alcohol screen breathalyzer
Visit 2:  Admission to Research Unit Visit (Enrollment) (Day -1-Day 8)
Day -1
If you qualify and agree to participate in the study, you will be asked to return to the clinical unit 
(DEPRU) on Day -1 (one day before drug dosing starts). After you complete the following tests and are 
confirmed eligible to participate, you will stay at the DEPRU for 9 days and 8 nights. 

You will be asked about any past or present illnesses and medications or supplements you are 
taking

Complete physical examination

Collect vital signs (height, weight, blood pressure, heart rate, respiratory rate, temperature)  

12-lead electrocardiogram (ECG) 

Blood collection (approximately 1 tablespoons/15mL) for routine lab tests 

Collect urine for drug screen, nicotine use and routine lab tests

If you are a female of child bearing potential, we will test your blood, if not already performed 
within the past 48 hours to make sure you are not pregnant 

Alcohol screen breathalyzer
DUHS IRB
IRB NUMBER: Pro00094792
IRB REFERENCE DATE: 04/13/2020
IRB EXPIRATION DATE: 04/25/2021


A Phase I, Open Label Study in Healthy Adults to Evaluate 
the Safety and Pharmacokinetics of AVYCAZ® in 
Combination with Aztreonam (COMBINE)
DEPRU# NJ07
Consent to Participate in a Research Study
Page 4 of 17
Subject Initials ________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
If you are enrolled you will be assigned into one of the following groups (cohorts) depending on when 
you are screened.  You will know which group you are being assigned at the time of your screening 
visit. 
Cohort 1:  AVYCAZ 2.5 g IV as a 2-hour infusion every 8 hours for 7 days 
Cohort 2:  AVYCAZ 2.5 g IV as a 2-hour infusion x 1, then 0.32 g per hour IV daily as a continuous 
infusion (CI) (7.5 g/day) for 7 days
Cohort 3:  ATM 2 g IV as a 2-hour infusion every 6 hours for 7 days 
Cohort 4:  ATM 2 g IV as a 2-hour infusion x 1, then 0.33 g per hour IV daily as a CI (8 g/day) for 
7 days 
Cohort 5:  AVYCAZ 2.5 g IV as a 2-hour infusion every 8 hours for 7 days combined with ATM 1.5 g 
IV as a 2-hour infusion every 6 hours for 7 days
Cohort 6:  AVYCAZ 2.5 g IV as a 2-hour infusion every 8 hours for 7 days combined with ATM 2 g 
IV as a 2-hour infusion every 6 hours for 7 days 
Day 1 (Study Drug)
On Day 1, you will be administered your first dose of the study antibiotic(s).  The antibiotic(s) you will 
receive will be based on which cohort you are enrolled. The following will be performed:

Symptom-directed physical exam

Vital signs (pre-am dose and 1-hour after starting first am dose administration)

Review of any adverse events (side effects) and any new medications or supplements you may be 
taking 

Study drug administration

Blood collection to determine the amount of the study drug(s) in your body (Plasma PK sample) as 
follows: 
o
All cohorts:  Pre-dose (10 minutes prior to the start of giving you the study drug(s) (infusion)) 
and the following times after the start of study antibiotic(s) infusion(s):, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 
6, 7, 8, hours (approximately 5 tablespoons/72 mL)

Urine collection to determine the amount of the study drug(s) in your body (Urine PK sample) >0 to 
4, >4 to 8, >8 to 12, and >12 to 24 hours after the morning dose of antibiotic(s) administration
Day 2 (Study Drug)
The following will be performed:

Symptom-directed physical exam

Vital signs (morning)

Review of adverse events and any new medications or supplements you may be taking

Study drug(s) administration

Safety labs (approximately 1 tablespoon/15mL)
DUHS IRB
IRB NUMBER: Pro00094792
IRB REFERENCE DATE: 04/13/2020
IRB EXPIRATION DATE: 04/25/2021


A Phase I, Open Label Study in Healthy Adults to Evaluate 
the Safety and Pharmacokinetics of AVYCAZ® in 
Combination with Aztreonam (COMBINE)
DEPRU# NJ07
Consent to Participate in a Research Study
Page 5 of 17
Subject Initials ________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
Days 3 (Study Drug)
The following will be performed:

Symptom-directed physical exam

Vital signs (morning)

Review of adverse events and any new medications or supplements you may be taking

Study drug(s) administration

Plasma PK sample (approximately 1 teaspoon/6ml each day)
Day 4 (Study Drug)
The following will be performed:

Symptom-directed physical exam

Vital signs (morning)

Review of adverse events and any new medications or supplements you may be taking

Study drug(s) administration

Safety labs (approximately 1 tablespoon/15mL)

Urine collection for routine lab tests
Day 5(Study Drug)
The following will be performed:

Symptom-directed physical exam

Vital signs ( morning)

Review of adverse events and any new medications or supplements you may be taking

Study drug(s) administration

Safety labs( approximately 1 teaspoon/ 5mL)

Plasma PK sample ( approximately 1 teaspoon/ 6ml each day)
Day 6 (Study Drug)
The following will be performed:

Symptom-directed physical exam

Vital signs (morning)

Review of adverse events and any new medications or supplements you may be taking 

Study drug(s) administration

Safety labs (approximately 1 tablespoon/15mL)

Urine collection to determine the amount of the study drug(s) in your body (Urine PK sample):
o
>0 to 4, >4 to 8, >8 to 12, and >12 to 24 hours after the start of the morning dose administration
DUHS IRB
IRB NUMBER: Pro00094792
IRB REFERENCE DATE: 04/13/2020
IRB EXPIRATION DATE: 04/25/2021


A Phase I, Open Label Study in Healthy Adults to Evaluate 
the Safety and Pharmacokinetics of AVYCAZ® in 
Combination with Aztreonam (COMBINE)
DEPRU# NJ07
Consent to Participate in a Research Study
Page 6 of 17
Subject Initials ________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
Day 7 (Study Drug)
The following will be performed:

Symptom-directed physical exam

Vital signs (morning)

Review of adverse events and any new medications or supplements you may be taking 

Study drug(s) administration – the study drug(s) will be stopped after the morning dose is 
administered on Day 7.

Safety labs ( approximately 1 teaspoon/6ml each day)

Blood collection to determine the amount of the study drug(s) in your body (Plasma PK sample) as 
follows: 
o
All cohorts:  Pre-dose and the following times after the start of study antibiotic(s) 
infusion(s): 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, 12, 18 and 24 hours (approximately 
6 tablespoons/96 mL)
Day 8 (Day of Discharge)
The following will be performed:

Complete physical exam, review of medications or supplements you are taking and review of 
changes in medical history

Vital signs (morning)

Review of adverse events 

Single 12-lead ECG

Blood collection for routine lab tests and plasma PK (approximately 1 tablespoons/15 mL)

Urine collection for routine lab tests
Visit 3:  Final Study Visit Day 11 +3 days (Outpatient)
The following will be performed:

Complete physical exam

Vital signs 

Review of adverse events and concomitant medications and supplements

Single 12-lead ECG

Blood collection for routine lab tests (approximately 1 tablespoon/15mL)

Urine collection for routine lab tests
Early Termination Visit (if needed)
The following will be performed:

Complete physical exam, review of medications or supplements you are taking and review of 
changes in medical history

Vital signs 

Single 12-lead ECG
DUHS IRB
IRB NUMBER: Pro00094792
IRB REFERENCE DATE: 04/13/2020
IRB EXPIRATION DATE: 04/25/2021


A Phase I, Open Label Study in Healthy Adults to Evaluate 
the Safety and Pharmacokinetics of AVYCAZ® in 
Combination with Aztreonam (COMBINE)
DEPRU# NJ07
Consent to Participate in a Research Study
Page 7 of 17
Subject Initials ________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345

Review of adverse events 

Blood collection for routine lab tests and plasma PK (approximately 1 tablespoons/15 mL)

Urine collection for routine lab tests
Unscheduled Visit (if needed)
The following will be performed:

Complete physical exam

Vital signs 

Review of adverse events and concomitant medications and supplements

Single 12-lead ECG 

Blood collection for routine lab tests and plasma PK (approximately 1 tablespoons/15 mL)

Urine collection for routine lab tests
HOW LONG WILL I BE IN THIS STUDY?
If you qualify for this study, your participation will last approximately 2 months and will include about 
11 study visits. The screening period will last up to 30 days and there will be 7 days of study drug 
administration and about 7 days of follow-up. The follow-up period will be longer than 7 days if you 
continue to have side effects from the drug. You will be followed until your side effects resolve or 
stabilize.
You can choose to stop participating at any time without penalty or loss of any benefits to which you are 
entitled, and you will continue to receive care, but not as a part of this study. However, if you decide to 
stop participating in the study, we encourage you to talk to your doctor or the study doctor Jeffrey 
Guptill first.
WHAT ARE THE RISKS OF THE STUDY?
As a result of your participation in this study, you are at risk for the following side effects. In addition, 
there may be uncommon or previously unknown problems that might occur. You should discuss these 
with the study doctor and your regular health care provider if you choose. 
Ceftazidime-avibactam (AVYCAZ) may cause some, all or none of the side-effects listed below.

Hypersensitivity reactions:  Serious and occasionally fatal allergic (anaphylactic) reactions and 
serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. 
Please notify study staff if you are allergic to antibiotics (cephalosporins, penicillins, or 
carbapenems).

Clostridium difficile-associated diarrhea has been reported for nearly all antibiotics, including 
AVYCAZ, and may range in severity from mild diarrhea to deadly inflammation of the colon.  The 
diarrhea may start during or after the AVYCAZ is administered.  C. difficile occurs naturally in the 
DUHS IRB
IRB NUMBER: Pro00094792
IRB REFERENCE DATE: 04/13/2020
IRB EXPIRATION DATE: 04/25/2021


A Phase I, Open Label Study in Healthy Adults to Evaluate 
the Safety and Pharmacokinetics of AVYCAZ® in 
Combination with Aztreonam (COMBINE)
DEPRU# NJ07
Consent to Participate in a Research Study
Page 8 of 17
Subject Initials ________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
colon.  Treatment with antibiotics alters the normal flora (microorganisms that live in the colon) and 
may permit overgrowth of C. difficile.  

Central Nervous System Reactions:  Seizures, non-convulsive status epilepticus (NCSE) (a seizure 
that causes primarily altered mental status), encephalopathy (altered mental state that is sometimes 
accompanied by physical changes), coma, asterixis (tremor of the hand when the wrist is extended), 
neuromuscular excitability (tingling in muscles), and myoclonia (twitching of muscles) have been 
reported in patients treated with ceftazidime, particularly in the setting of kidney impairment.

Nervous system:  headache, dizziness

Gastrointestinal:  abdominal pain, nausea, vomiting, and diarrhea
The following selected adverse reactions were reported in ceftazidime-avibactam treated patients at a 
rate of less than 1% in the Phase 3 trials.

Decrease in level of platelets in the blood (the part of your blood that is involved with clotting)

Irritation at drug administration site

Yeast infection (candidiasis)

Decreased potassium levels in the blood and changes in enzymes that diagnose liver function

Altered sense of taste 

Acute renal failure, renal impairment, nephrolithiasis (or kidney stone)

Rashes (including red raised or hives), itching

Anxiety
Additionally, adverse reactions reported with ceftazidime alone that were not reported in AVYCAZ 
treated patients in the Phase 3 trials are listed below:

Blood and lymphatic disorders – 
o
Agranulocytosis - Lack of one major class of infection fighting white blood cells
-
hemolytic anemia – type of decreased red blood cells caused by improper breakdown of 
red blood cells. 
-
leukopenia – low level of white blood cells in the blood
-
lymphocytosis – increase in the number of lymphocytes in the blood. Lymphocytes are a 
part of the blood involved with fighting infection
-
neutropenia – Decrease in the number of neutrophils in the blood.  Neutrophils help the 
body fight infection.  
-
thrombocytosis – High platelet count in the blood. Platelets are involved with blood 
clotting. 
-
eosinophilia – a high level of white blood cells in the blood.  Eosinophils help fight 
diseases

General disorders and administration site conditions – 
o
Inflammation at the infusion site.
o
blood collecting at the site of the injection
o
bruise at the site of infection
DUHS IRB
IRB NUMBER: Pro00094792
IRB REFERENCE DATE: 04/13/2020
IRB EXPIRATION DATE: 04/25/2021


A Phase I, Open Label Study in Healthy Adults to Evaluate 
the Safety and Pharmacokinetics of AVYCAZ® in 
Combination with Aztreonam (COMBINE)
DEPRU# NJ07
Consent to Participate in a Research Study
Page 9 of 17
Subject Initials ________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345

Jaundice (yellow discoloring of the skin)

Increased blood lactate dehydrogenase (an enzyme that frequently indicates tissue damage)

Prolonged prothrombin time (time required to clot blood)

Paresthesia (prickly or tingling sensation usually in the hands, arms, legs or feet)

Tubulointerstitial nephritis (injury to the renal tubules or interstitium of the kidney) which can 
lead to decreased kidney function

Vaginal Inflammation

Skin and subcutaneous tissue disorders
o
Angioedema –swelling under the skin
o
Erythema multiforme – skin lesions that look like bulls eyes
o
Stevens-Johnson syndrome – rare disorder of skin leading to painful red or purplish rash that 
spreads and blisters
o
Toxic epidermal necrolysis – widespread swelling, redness and necrosis of the skin. 
Laboratory Changes
Coombs test – a test to determine if your body has antibodies.  Antibodies help your body protect itself.  
However, the body can develop antibodies against itself.  The Coombs test measures if you have 
antibodies to your own body’s red blood cells.  Rarely, people who have taken this drug have changed 
from not having these antibodies to having these antibodies. 
Aztreonam (ATM) may cause some, all or none of the side-effects listed below.

Local reactions (e.g., inflammation, bruising, discomfort/swelling) following intravenous 
administration. Systemic reactions (considered to be related to therapy or of uncertain cause), 
occurring in up to 1.3% of people on this medication, include diarrhea, nausea and/or vomiting, 
and rash.

Reactions occurring at an incidence of less than 1% are listed within each body system in order 
of decreasing severity:
o
Hypersensitivity – severe allergic reaction
o
Changes in kidney function.
o
Hematologic – changes in levels of various components of your blood. 
o
Gastrointestinal – abdominal cramps and Clostridium difficile-associated diarrhea. 
Clostridium difficile-associated diarrhea has been reported for nearly all antibiotics, including 
ATM, and may range in severity from mild diarrhea to deadly inflammation of the colon.  
The diarrhea may start during or after the ATM is administered.  C. difficile occurs naturally 
in the colon.  Treatment with antibiotics alters the normal flora (microorganisms that live in 
the colon) and may permit overgrowth of C. difficile. 
o
Onset of diarrhea, bloating, nausea, pus in stool, cramps, etc. may occur during or after 
antibiotic treatment.
DUHS IRB
IRB NUMBER: Pro00094792
IRB REFERENCE DATE: 04/13/2020
IRB EXPIRATION DATE: 04/25/2021


A Phase I, Open Label Study in Healthy Adults to Evaluate 
the Safety and Pharmacokinetics of AVYCAZ® in 
Combination with Aztreonam (COMBINE)
DEPRU# NJ07
Consent to Participate in a Research Study
Page 10 of 17
Subject Initials ________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
o
Dermatologic – toxic epidermal necrolysis (widespread swelling, redness and necrosis of the 
skin), purpura (patches of purplish discoloration on the skin), erythema multiforme (skin 
lesions that look like bulls eyes), exfoliative dermatitis (intense and usually widespread 
reddening of the skin), urticaria (hives), petechiae (Pinpoint flat round red spots under the 
skin), pruritus (localized or generalized itching), diaphoresis (sweating)
o
Cardiovascular – low blood pressure, changes in the ECG that are not permanent ECG 
changes, flushing
o
Respiratory – wheezing, shortness of breath, chest pain
o
Hepatobiliary – inflammation of the liver and yellow discoloration of the skin.
o
Nervous System – seizure, confusion, balance issues, tingling or numbness, changes in sleep 
pattern, dizziness
o
Musculoskeletal – muscle aches
o
Special Senses – ringing in the ears, double vision, mouth ulcer, altered taste, numb tongue, 
sneezing, nasal congestion, bad breath
o
Other – vaginal cyst infection, inflammation of the vagina, breast tenderness
o
Body as a Whole – weakness, headache, fever, general fatigue
Studies indicate that increase in liver enzymes in the blood due to mild inflammation of the liver can 
occur in 10 to 38% of individuals who receive aztreonam. The enzyme abnormalities typically occur 
after several days of therapy. Among patients who experience liver enzyme increase while receiving 
aztreonam, the increases in liver enzymes are mild-to-moderate in nature and nearly all patients have no 
symptoms. For patients who have increase in liver enzymes, liver enzymes typically go back to normal 
once aztreonam is stopped. No individual cases of major liver injury or failure due to aztreonam therapy 
have been reported in studies. 
Laboratory Changes:  Adverse laboratory changes without regard to drug relationship that were reported 
during clinical trials were:

Liver- Increases in liver enzymes; signs or symptoms of liver dysfunction occurred in less than 
1% of recipients

Blood-increases in prothrombin and partial thromboplastin times, positive Coombs' test (see 
laboratory changes for AVYCAZ®.

Renal-increases in serum creatinine.
The side effects of AVYCAZ combined with ATM are expected to be similar to the side effects of 
AVYCAZ alone and ATM alone. However, there is a possible chance for more side effects with 
AVYCAZ combined with ATM because of taking the two drugs together.
Female
The effects of the study drug on a developing pregnancy or breastfeeding infant are not known.  Women 
who are pregnant, planning a pregnancy or breastfeeding are not allowed to participate in studies of the 
drug.
DUHS IRB
IRB NUMBER: Pro00094792
IRB REFERENCE DATE: 04/13/2020
IRB EXPIRATION DATE: 04/25/2021


A Phase I, Open Label Study in Healthy Adults to Evaluate 
the Safety and Pharmacokinetics of AVYCAZ® in 
Combination with Aztreonam (COMBINE)
DEPRU# NJ07
Consent to Participate in a Research Study
Page 11 of 17
Subject Initials ________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
 
If you are a woman who could possibly become pregnant (you have not completed menopause, or you 
have not had a hysterectomy and/or both tubes and/or both ovaries removed) and you have a partner 
who is able to father children, a blood pregnancy test will be done, and it must be negative to continue in 
the study.  In women 40 years old and older, blood pregnancy tests can sometimes give a false positive 
or indeterminate result, and additional testing may be required.
 
You and your partner must agree to either abstain completely from vaginal intercourse for 30 days to 
taking the study drug, the duration of the study, and for 30 days afterwards, or use one of the following 
methods of contraception for the same length of time: (a) partner vasectomy, (b) bilateral tubal ligation, 
(c) intrauterine device (IUD), (d) hormonal methods (birth control pills, implants, injections, patches, 
vaginal rings),.  If you are not currently using one of these methods, your study doctor will discuss 
options with you, given your personal preferences and the level of protection required for this study.   
Because no method of birth control is 100% effective, you should notify your study doctor immediately 
if you think there is any chance you could be pregnant during the 30 days after the study. Females who 
become pregnant during the study will be taken off the study drug and will be followed until the 
outcome of the pregnancy is known.
Male
The effects of the study drug on a pregnancy which began while the father was taking the drug are not 
known.  If you have a partner who could possibly become pregnant (she has not completed menopause, 
or she has not had a hysterectomy and/or both tubes and/or both ovaries removed), you must agree to 
either abstain completely from vaginal intercourse for the duration of the study and for 30 days 
afterwards, or, if you have not had a vasectomy, use a condom with spermicide every time you have 
vaginal intercourse for the same length of time.  You should inform your partner about your 
participation in this study; if she becomes pregnant within 30 days after completion of the study, you 
should inform your study doctor immediately.
Risks of Drawing Blood: 
Risks associated with drawing blood from your arm or a catheter in your vein include momentary 
discomfort and/or bruising.  Infection, excess bleeding, clotting, or fainting are also possible, although 
unlikely.
Risks of placement of IV catheter and study product administration through the IV: 
The study drug is administered through an IV catheter which is a small, flexible hollow tube inserted 
into a vein in your arm. Inserting an IV requires a needle and can cause localized discomfort. During IV 
infusion you are unlikely to feel discomfort. The vein the catheter is inserted in may become inflamed 
with signs of redness and warmth at or near the IV insertion site. Inflammation in a vein due to a blood 
clot is also a potential risk. This would be a hard area the study doctor could feel near the IV insertion 
site. In some instances the vein may develop a small rupture causing the Study Drug to leak out of the 
DUHS IRB
IRB NUMBER: Pro00094792
IRB REFERENCE DATE: 04/13/2020
IRB EXPIRATION DATE: 04/25/2021


A Phase I, Open Label Study in Healthy Adults to Evaluate 
the Safety and Pharmacokinetics of AVYCAZ® in 
Combination with Aztreonam (COMBINE)
DEPRU# NJ07
Consent to Participate in a Research Study
Page 12 of 17
Subject Initials ________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
vein.  This is generally not dangerous, but can cause discomfort and bruising. There is a risk of 
infection; however, this is a small risk as aseptic technique will be used.
Risks of Electrocardiogram (ECG):
Possible side effects of the ECG are skin irritation, itching and redness from the ECG electrode pads. 
Drug and Food Interactions: 
For your safety, you must tell the study doctor or nurse about all the prescribed medical foods and drugs, 
herbal products, over-the-counter (OTC) drugs, vitamins, natural remedies, and alcohol that you are 
taking before you start the study and before starting to take any of these products while you are on the 
study.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
While there are no direct benefits to you by participating in this study, we hope that in the future the 
information learned from this study will benefit other people with bacteria or other infection related 
illnesses. 
WILL MY INFORMATION BE KEPT CONFIDENTIAL?
Participation in research involves some loss of privacy. We will do our best to make sure that 
information about you is kept confidential (private), but we cannot guarantee total confidentiality. Your 
personal information may be viewed by individuals involved in this research and may be seen by people 
including those working with the DEPRU, funding, and regulating the study. We will share only the 
minimum necessary information in order to conduct the research. Your personal information may also 
be given out if required by law. 
As part of the study, results of your study-related laboratory tests, and procedures may be reported to the 
National Institutes of Health (NIH) and its representatives. In addition, your records may be reviewed in 
order to meet federal or state regulations. Reviewers may include representatives from the FDA, 
representatives and representatives of NIH, the Duke University Health System Institutional Review 
Board, and others as appropriate. If any of these groups review your research record, they may also need 
to review your entire medical record.
As part of this study, you will be asked to have certain tests and procedures performed. Some of these 
test results will be recorded in your medical record and will be reported to the representatives and 
representatives of NIH. Some of the tests will be performed solely for research purposes and could not 
be used for diagnosis or treatment.  These test results will not be available in your medical record. 
DUHS IRB
IRB NUMBER: Pro00094792
IRB REFERENCE DATE: 04/13/2020
IRB EXPIRATION DATE: 04/25/2021


A Phase I, Open Label Study in Healthy Adults to Evaluate 
the Safety and Pharmacokinetics of AVYCAZ® in 
Combination with Aztreonam (COMBINE)
DEPRU# NJ07
Consent to Participate in a Research Study
Page 13 of 17
Subject Initials ________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
The Department of Health and Human Services (HHS) has issued a Certificate of Confidentiality to 
further protect your privacy. With this Certificate, the investigators may not share research information 
that may identify you in any Federal, State, or local civil, criminal, administrative, legislative, or other 
proceedings, unless you have consented for this use. Research information protected by this Certificate 
cannot be shared with anyone else who is not connected with the research unless:  
1) there is a law that requires disclosure (such as to report child abuse or communicable diseases but 
not for legal proceedings); 
2) you have consented to the disclosure, including for your medical treatment; or 
3) the research information is used for other scientific research, as allowed by federal regulations 
protecting research subjects. 
Sharing the information from this study is required, however, for audit or program evaluation requested 
by the agency that is funding this project or for information that is required by the FDA.
You should understand that a Confidentiality Certificate does not prevent you or a member of your 
family from voluntarily releasing information about yourself or your participation in this research. If you 
want your research information released to an insurer, medical care provider, or any other person not 
connected with the research, you must provide consent to allow the researchers to release it. This means 
that you and your family must also actively protect your own privacy.
Finally, you should understand that the investigator is not prevented from taking steps, including 
reporting to authorities, to prevent serious harm to yourself or others.
Some information collected in research studies is maintained in your medical record. All of the blood 
and urine collected to determine the amount of the drugs in the body are being done only because you 
are in this study.  The study results will not be provided to you OR sent to your physician, but may be 
available in your DUHS medical record.
The study results will be retained in your research record for at least two years after the study is 
completed and the FDA is notified. At that time either the research information not already in your 
medical record may be destroyed or information identifying you will be removed from such study 
results at DUHS.  Any research information in your medical record will be kept indefinitely. Your 
permission to access your medical records expires at the end of the study, however your permission to 
use research information collected about you does not expire.
This information may be further shared by the sponsor of this study.  If shared by the sponsor, the 
information is no longer covered by federal privacy regulations. If this information is shared with 
outside reviewers for audit purposes, it may be further shared by them and may not be covered by 
federal privacy regulations.
DUHS IRB
IRB NUMBER: Pro00094792
IRB REFERENCE DATE: 04/13/2020
IRB EXPIRATION DATE: 04/25/2021


A Phase I, Open Label Study in Healthy Adults to Evaluate 
the Safety and Pharmacokinetics of AVYCAZ® in 
Combination with Aztreonam (COMBINE)
DEPRU# NJ07
Consent to Participate in a Research Study
Page 14 of 17
Subject Initials ________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
While the information and data resulting from this study may be presented at scientific meetings or 
published in a scientific journal, your name or other personal information will not be revealed.
Some people or groups who receive your health information might not have to follow the same privacy 
rules. Once your information is shared outside of DUHS, we cannot guarantee that it will remain private. 
If you decide to share private information with anyone not involved in the study, the federal law 
designed to protect your health information privacy may no longer apply to the information you have 
shared.  Other laws may or may not protect sharing of private health information.
WHAT ARE THE COSTS TO YOU?
There are no costs for you to participate in the study. The study drug(s) will be provided to you free of 
charge. You will not be charged for any procedure performed for the purpose of this study. You or your 
insurance provider will be responsible and billed for all costs related to your routine medical care, 
including copayments and deductibles. Routine medical care services are those that you would have 
received for your condition if you were not participating in this research study. 
Your study doctor or staff will go over the reimbursement process and other patient travel management 
services available to you.
We will monitor your DUHS patient care charges to make sure that costs are directed appropriately.  If 
you have any questions or concerns about appropriate billing, contact your study team coordinator so 
that he/she can help find a resolution.
WHAT ABOUT COMPENSATION?
You will be reimbursed up to $2,600.00 for your expenses related to your participation (parking, gas, 
and time). 
Day
Compensation
Screening
$100
Inpatient visit
$300/night
Outpatient visit
$100
You will be reimbursed based upon the completion of the visits listed.  If the study team requests that 
you come in for an unscheduled visit, you will be reimbursed $50 for the completion of each of the 
unscheduled visits. 
Payment received as compensation for participation in research is considered taxable income to the 
research subject. If payment to an individual exceeds $600 in any one calendar year, Duke University is 
required to report this information to the Internal Revenue Service (IRS). Research subject payments to 
DUHS IRB
IRB NUMBER: Pro00094792
IRB REFERENCE DATE: 04/13/2020
IRB EXPIRATION DATE: 04/25/2021


A Phase I, Open Label Study in Healthy Adults to Evaluate 
the Safety and Pharmacokinetics of AVYCAZ® in 
Combination with Aztreonam (COMBINE)
DEPRU# NJ07
Consent to Participate in a Research Study
Page 15 of 17
Subject Initials ________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
a non-employee of Duke University exceeding $600 during any calendar year will result in a 1099 
(Miscellaneous Income) form being issued to the individual and a copy sent to the IRS.
WHAT ABOUT RESEARCH RELATED INJURIES?
Immediate necessary medical care is available at Duke University Medical Center in the event that you 
are injured as a result of your participation in this research study. However, there is no obligation by 
Duke University, Duke University Health System, Inc., your Duke physician’s or NIH to provide 
monetary payment or free medical care to you in the event of a study-related injury. In general, no 
long-term medical or financial payment for research-related injuries will be provided by the NIH or the 
Federal Government.
For questions about a research-related injury, contact Dr. Jeffrey Guptill at (919) 684-1672 during
regular business hours and at (919) 684-8111 after hours and on weekends and holidays.
WHAT ABOUT MY RIGHTS TO DECLINE PARTICIPATION OR WITHDRAW FROM THE 
STUDY?
You may choose not to be in the study, or, if you agree to be in the study, you may withdraw from the 
study at any time. If you withdraw from the study, no new data about you or blood and urine samples 
will be collected for study purposes unless the data concerns an adverse event (a bad effect) related to 
the study.  If such an adverse event occurs, we may need to review your entire medical record.  All data 
that have already been collected for study purposes, including blood and urine samples to determine the 
concentration (amount) of the drugs in your body, and any new information about an adverse event 
related to the study, will be sent to the study sponsor.
Your decision not to participate or to withdraw from the study will not involve any penalty or loss of 
benefits to which you are entitled, and will not affect your access to health care at Duke.  If you do 
decide to withdraw, we ask that you contact Dr. Guptill in writing and let him know that you are 
withdrawing from the study. His mailing address is: Box 3854, Duke University Medical Center, 
Durham NC 27710. The study doctor may ask you to return for a checkup before you stop your study 
drug if he thinks that stopping the drug suddenly may harm you. He may also ask you to complete the 
tests that would normally occur when a person completes the study.
We will tell you about new information that may affect your health, welfare, or willingness to stay in 
this study.
Your doctor may decide to take you off this study if you have serious side effects, or if your study 
doctor determines that it is no longer in your best interest to continue.  The sponsor or regulatory 
agencies may stop this study at any time without your consent. Reasons why this might occur include 
you no longer meet eligibility criteria or noncompliance to study procedures or safety concerns. If this 
occurs, you will be notified and your study doctor will discuss this with you.  If the doctor determines 
DUHS IRB
IRB NUMBER: Pro00094792
IRB REFERENCE DATE: 04/13/2020
IRB EXPIRATION DATE: 04/25/2021


A Phase I, Open Label Study in Healthy Adults to Evaluate 
the Safety and Pharmacokinetics of AVYCAZ® in 
Combination with Aztreonam (COMBINE)
DEPRU# NJ07
Consent to Participate in a Research Study
Page 16 of 17
Subject Initials ________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
you must not continue in the study, no new data about you or blood and urine samples will be collected 
for study purposes unless the data concerns an adverse event (a bad effect) related to the study.  If such 
an adverse event occurs, we may need to review your entire medical record.  All data that have already 
been collected for study purposes, including the results of the analysis of your blood and urine, and any 
new information about an adverse event related to the study, will be sent to the study sponsor. Your 
blood and urine samples collected during the study will not be stored for future research and will not 
result in any commercial profit. You will not be compensated for the use of your samples other than 
what is described in this consent form.
A description of this clinical trial will be available on https://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.
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study, medical emergencies or a research-related injury, or if you have 
problems, concerns, questions or suggestions about the research, contact Dr. Jeffrey Guptill at 
(919) 684-1672 during regular business hours and at (919) 684-8111 after hours and on weekends and
holidays.
For questions about your rights as a research participant, or to discuss problems, concerns or suggestions 
related to the research, or to obtain information or offer input about the research, contact the Duke 
University Health System Institutional Review Board (IRB) Office at (919) 668-5111.
DUHS IRB
IRB NUMBER: Pro00094792
IRB REFERENCE DATE: 04/13/2020
IRB EXPIRATION DATE: 04/25/2021


A Phase I, Open Label Study in Healthy Adults to Evaluate 
the Safety and Pharmacokinetics of AVYCAZ® in 
Combination with Aztreonam (COMBINE)
DEPRU# NJ07
Consent to Participate in a Research Study
Page 17 of 17
Subject Initials ________
DUKE UNIVERSITY HEALTH SYSTEM
Form
M0345
STATEMENT OF CONSENT
"The purpose of this study, procedures to be followed, risks and benefits have been explained to me. I 
have been allowed to ask questions, and my questions have been answered to my satisfaction. I have 
been told whom to contact if I have questions, to discuss problems, concerns, or suggestions related to 
the research, or to obtain information or offer input about the research. I have read this consent form and 
agree to be in this study, with the understanding that I may withdraw at any time.  I have been told that I 
will be given a signed and dated copy of this consent form."
__________________________________________
___________     ____________
Signature of Subject
Date
Time
__________________________________________
___________     ____________
Signature of Person Obtaining Consent
Date
Time
DUHS IRB
IRB NUMBER: Pro00094792
IRB REFERENCE DATE: 04/13/2020
IRB EXPIRATION DATE: 04/25/2021

SAP_002.pdf: 
CLINICAL RESEARCH IN INFECTIOUS DISEASES 
 
 
 
SAFETY STATISTICAL ANALYSIS PLAN 
for 
DMID Protocol: 17-0107 
 
Study Title: 
 
A Phase I, Open-Label Study in Health Adults to Evaluate 
the Safety and Pharmacokinetics of AVYCAZ® in 
Combination with Aztreonam (COMBINE) 
 
NCT 03978091 
 
Version 1.0 
 
DATE: 20JUL2020 
 
THIS COMMUNICATION IS PRIVILEGED AND CONFIDENTIAL  
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
- ii - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
STUDY TITLE 
Protocol Number Code: 
DMID Protocol: 17-0107 
Development Phase: 
Phase 1 
Products: 
AVYCAZ® and Aztreonam (ATM) 
Form/Route: 
Intravenous (IV) Infusion 
Indication Studied: 
Infection with MBL-producing Gram-negative bacteria 
Sponsor: 
Division of Microbiology and Infectious Diseases 
National Institute of Allergy and Infectious Diseases 
National Institutes of Health 
Clinical Trial Initiation Date: 
14JUN2019 
Clinical Trial Completion Date: 
TBD 
Date of the Analysis Plan: 
20JUL2020 
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. 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
- iii - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
TABLE OF CONTENTS 
STUDY TITLE ............................................................................................................................... II 
TABLE OF CONTENTS ...............................................................................................................III 
LIST OF ABBREVIATIONS ....................................................................................................... VI 
1. 
PREFACE .....................................................................................................................1 
2. 
INTRODUCTION ........................................................................................................2 
2.1. 
Purpose of the Analyses ................................................................................................2 
3. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................3 
3.1. 
Study Objectives ...........................................................................................................3 
3.1.1. 
Primary Objectives .......................................................................................................3 
3.1.2. 
Secondary Objectives ...................................................................................................3 
3.1.3. 
Exploratory Objectives .................................................................................................3 
3.2. 
Endpoints ......................................................................................................................3 
3.2.1. 
Primary Endpoints ........................................................................................................3 
3.2.2. 
Secondary Endpoints ....................................................................................................3 
3.2.3. 
Exploratory Endpoints ..................................................................................................4 
3.3. 
Study Definitions and Derived Variables .....................................................................4 
3.3.1. 
Cohort ...........................................................................................................................4 
3.3.2. 
Adverse Events .............................................................................................................4 
3.3.3. 
Serious Adverse Events (SAEs) ...................................................................................6 
4. 
INVESTIGATIONAL PLAN .......................................................................................7 
4.1. 
Overall Study Design and Plan .....................................................................................7 
4.2. 
Discussion of Study Design, Including the Choice of Control Groups ........................7 
4.3. 
Selection of Study Population ......................................................................................7 
4.3.1. 
Inclusion Criteria ..........................................................................................................7 
4.3.2. 
Exclusion Criteria .........................................................................................................8 
4.4. 
Treatments ..................................................................................................................10 
4.4.1. 
Treatments Administered ............................................................................................10 
4.4.2. 
Identity of Investigational Product(s) .........................................................................10 
4.4.3. 
Method of Assigning Subjects to Treatment Groups (Randomization) .....................10 
4.4.4. 
Selection of Doses in the Study ..................................................................................10 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table of Contents (continued) 
- iv - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
4.4.5. 
Selection and Timing of Dose for Each Subject .........................................................11 
4.4.6. 
Blinding ......................................................................................................................11 
4.4.7. 
Prior and Concomitant Therapy ..................................................................................11 
4.4.8. 
Treatment Compliance ................................................................................................12 
4.5. 
Safety Variables ..........................................................................................................12 
5. 
SAMPLE SIZE CONSIDERATIONS .......................................................................14 
6. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................15 
6.1. 
General Principles .......................................................................................................15 
6.2. 
Timing of Analyses .....................................................................................................15 
6.3. 
Analysis Populations ..................................................................................................15 
6.3.1. 
Safety Population ........................................................................................................15 
6.3.2. 
PK Population .............................................................................................................15 
6.4. 
Covariates and Subgroups ..........................................................................................15 
6.5. 
Missing Data ...............................................................................................................15 
6.6. 
Interim Analyses and Data Monitoring ......................................................................15 
6.7. 
Multicenter Studies .....................................................................................................15 
6.8. 
Multiple Comparisons/Multiplicity ............................................................................15 
7. 
STUDY SUBJECTS ...................................................................................................16 
7.1. 
Disposition of Subjects ...............................................................................................16 
7.2. 
Protocol Deviations ....................................................................................................16 
8. 
EFFICACY EVALUATION ......................................................................................17 
9. 
SAFETY EVALUATION ..........................................................................................18 
9.1. 
Demographic and Other Baseline Characteristics ......................................................18 
9.1.1. 
Prior and Concurrent Medical Conditions ..................................................................18 
9.1.2. 
Prior and Concomitant Medications ...........................................................................18 
9.2. 
Measurements of Treatment Compliance ...................................................................18 
9.3. 
Adverse Events ...........................................................................................................18 
9.3.1. 
Solicited Events and Symptoms .................................................................................19 
9.3.2. 
Unsolicited Adverse Events ........................................................................................19 
9.4. 
Deaths, Serious Adverse Events and other Adverse Events .......................................19 
9.5. 
Birth Control and Pregnancies ....................................................................................20 
9.6. 
Clinical Laboratory Evaluations .................................................................................20 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table of Contents (continued) 
- v - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
9.7. 
Vital Signs and Physical Evaluations .........................................................................21 
9.8. 
ECG Assessments .......................................................................................................22 
10. 
PHARMACOKINETICS ...........................................................................................23 
11. 
IMMUNOGENICITY ................................................................................................24 
12. 
OTHER ANALYSES .................................................................................................25 
13. 
REPORTING CONVENTIONS ................................................................................26 
14. 
TECHNICAL DETAILS ............................................................................................27 
15. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES ............................................................................................28 
16. 
REFERENCES ...........................................................................................................29 
17. 
LISTING OF TABLES, FIGURES, AND LISTINGS ..............................................30 
APPENDICES ...............................................................................................................................31 
APPENDIX 1. TABLE MOCK-UPS..........................................................................................32 
APPENDIX 2. FIGURE MOCK-UPS ......................................................................................173 
APPENDIX 3. LISTINGS MOCK-UPS ...................................................................................204 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
- vi - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALP 
Alkaline Phosphate 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Classification 
ATM 
Aztreonam 
AV 
Atrioventricular 
AVI 
Avibactam 
BMI 
Body Mass Index 
BP 
Blood Pressure  
BPM 
Beats Per Minute 
BUN 
Blood Urea Nitrogen 
°C 
Degrees Celsius 
CAZ 
Ceftazidime 
CI 
Continuous Infusion 
C.I. 
Confidence Interval 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
FEV1 
Forced Expiratory Volume in 1 Second 
°F 
Degrees Fahrenheit 
G 
Gram 
HBsAg 
Hepatitis B Surface Antigen 
HCV 
Hepatitis C Virus 
hCG 
Human Chorionic Gonadotropin 
HFIM 
Hollow Fiber Infection Model 
HIV 
Human Immunodeficiency Virus 
HLT 
High Level Term 
IDES 
Internet Data Entry System 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
List of Abbreviations (continued) 
- vii - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
IV 
Intravenous 
kg 
Kilogram 
L 
Liters 
LCE 
Leukocyte Esterase 
LDH 
Lactate Dehydrogenase 
LFT 
Liver Function Test 
LLN 
Lower Limit of Normal 
MBL 
Metallo-β-Lactamase 
MedDRA® 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter 
mmHg 
Millimeter of Mercury 
msec 
Millisecond 
N 
Number (typically refers to subjects) 
NCS 
Not Clinically Significant 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, DHHS 
NIH 
National Institutes of Health 
PE 
Physical Examination 
pH 
Potential of Hydrogen 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PK/PD 
Pharmacokinetics/Pharmacodynamics 
PR 
Period of ECG extending from beginning of the P wave (the onset of atrial 
depolarization) until the beginning of the QRS complex 
PT 
Preferred Term 
PTT 
Partial Thromboplastin Time 
QT 
Period of ECG extending from the beginning of the QRS complex to the end of the T 
wave 
QTcF 
QT duration corrected for heart rate by Fridericia’s formula 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SMC 
Safety Monitoring Committee 
SOC  
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 


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U 
Units 
ULN 
Upper Limit of Normal 
USP 
United States Pharmacopeia 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 


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1. 
PREFACE 
The Safety Statistical Analysis Plan (SAP) for “A Phase 1, Open-Label Study in Healthy Adults to Evaluate 
the Safety and Pharmacokinetics of AVYCAZ® in Combination with Aztreonam (COMBINE)” (DMID 
Protocol 17-0107) describes and expands upon the statistical information presented in the protocol. The main 
text of this Safety SAP discusses analyses of safety endpoints for the study. Analysis of all Pharmacokinetic 
(PK) endpoints is presented in the PK SAP. 
This document describes all planned analyses and provides reasons and justifications for these analyses. It 
also includes sample tables, figures, and listings planned for the final analyses. Regarding the final analyses 
and Clinical Study Report (CSR), this SAP follows the International Conference on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guidelines, as indicated in 
Topic E3 (Structure and Content of Clinical Study Reports), and more generally is consistent with Topic E8 
(General Considerations for Clinical Trials) and Topic E9 (Statistical Principles for Clinical Trials). The 
structure and content of the SAP provides sufficient detail to meet the requirements identified by the FDA and 
ICH, while all work planned and reported for this SAP will follow internationally accepted guidelines 
published by the American Statistical Association and the Royal Statistical Society for statistical practice. 
This document includes a review of the study design, general statistical considerations, comprehensive 
statistical analysis methods for safety outcomes, and a list of proposed tables, figures, and listings. Within the 
table, figure, and listing mock-ups (Appendices 1, 2, and 3), references to CSR sections are included. Any 
deviation from this SAP will be described and justified in protocol amendments and/or in the CSR, as 
appropriate. The reader of this SAP is encouraged to also review to study protocol for details on conduct of 
the study and the operations aspects of clinical assessments. 


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2. 
INTRODUCTION 
This is a Phase I, open-label, single center trial studying the safety and PK of ceftazidime-avibactam 
(AVYCAZ®) combined with aztreonam (ATM), AVYCAZ® alone, and ATM alone in 48 healthy adult male 
and female subjects (6 cohorts of 8 subjects). Cohorts 1-4 are the single drug administration treatment cohorts, 
including the administration of AVYCAZ® and ATM per dosing label and as a continuous infusion (CI). The 
AVYCAZ® and ATM combination treatment regimens will be administered to Cohorts 5-6. Study safety will 
be monitored using assessments of adverse events (AEs), physical examinations (PEs), vital signs, clinical 
laboratory safety tests, and electrocardiogram (ECG) tests. Subjects who received any study product (started 
the first infusion) will be included in the Safety Population and used for all safety analyses. 
2.1. 
Purpose of the Analyses 
The main text of this Safety SAP discusses analyses of the safety endpoints collected to assess the safety of 
AVYCAZ® combined with ATM, AVYCAZ® alone, and ATM alone. Analysis of all PK objectives and 
associated endpoints are described in the PK SAP. Both safety and PK endpoints will be presented in the 
clinical study report (CSR) after completion of the study. 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
3.1.1. 
Primary Objectives 
• Describe the safety of two dosing regimens of AVYCAZ® combined with ATM relative to 
AVYCAZ® alone, and ATM alone in healthy adult subjects. 
3.1.2. 
Secondary Objectives 
• Characterize the PK profiles of two dosing regimens of AVYCAZ® combined with ATM, AVYCAZ® 
alone, and ATM alone at the population level in healthy adult subjects. 
• Characterize the PK profiles of two dosing regimens of AVYCAZ® combined with ATM, AVYCAZ® 
alone, and ATM alone following initiation of dosing on day 1 in healthy adult subjects. 
• Characterize the PK profiles of two dosing regimens of AVYCAZ® combined with ATM, AVYCAZ® 
alone, and ATM alone following multiple daily dosing in healthy adult subjects. 
3.1.3. 
Exploratory Objectives 
• Predict the distribution of plasma concentration-time profiles observed with two dosing regimens of 
AVYCAZ® combined with ATM, AVYCAZ® alone, and ATM alone in health adult subjects via 
simulations. 
• Predict the distribution of urine cumulative urine amount-time profiles observed with two dosing 
regimens AVYCAZ® combined with ATM, AVYCAZ® alone, and ATM alone in healthy adult 
subjects via simulations. 
• Examine the associations between the plasma concentration-time profiles of AVYCAZ® combined 
with ATM, AVYCAZ® alone, and ATM alone and occurrence of Alanine Aminotransferase (ALT) or 
Aspartate Aminotransferase (AST) elevations. 
3.2. 
Endpoints 
3.2.1. 
Primary Endpoints 
• Number of subjects in each treatment cohort with at least one Grade 2 or higher treatment-emergent 
AE from first dose through follow-up period. 
3.2.2. 
Secondary Endpoints 
• Incidence and severity of all treatment-emergent AEs in each treatment cohort from first dose through 
follow-up period. 
• Population mean PK parameter estimates and the magnitude of the associated inter-individual 
variability for AVYCAZ® and ATM, when given alone and in combination. 
• Individual post-hoc PK parameter estimates and calculated exposure measures in plasma for 
AVYCAZ® and ATM, when given alone and in combination following initial dosing on Day 1. 


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• Individual post-hoc PK parameter estimates and calculated exposure measures in urine for AVYCAZ® 
and ATM, when given alone and in combination following initial dosing on Day 1. 
• Individual post-hoc PK parameter estimates and calculated exposure measures in plasma for 
AVYCAZ® and ATM, when given alone and in combination following multiple daily dosing. 
• Individual post-hoc PK parameter estimates and calculated exposure measures in urine for AVYCAZ® 
and ATM, when given alone and in combination following multiple daily dosing. 
3.2.3. 
Exploratory Endpoints 
• Distribution of simulated plasma concentration-time profiles associated with each treatment cohort. 
• Distribution of simulated urine concentration-time profiles associated with each treatment cohort. 
• Occurrence of ALT and AST elevations ≥ 3 times the upper limit of normal (ULN) from first dose of 
study product through follow-up period. 
• Occurrence of ALT and AST elevations ≥ 5 times the ULN from first dose of study product through 
follow-up period. 
• Changes in ALT and AST from first dose of study product through follow-up period. 
3.3. 
Study Definitions and Derived Variables 
3.3.1. 
Cohort 
Forty-eight (48) subjects will be enrolled in the study with eight (8) subjects in each of the following 6 
cohorts. In each cohort, subjects will receive either AVYCAZ® alone, ATM alone, or AVYCAZ® combined 
with ATM: 
• Cohort 1: AVYCAZ® 2.5 g IV as a 2-hour infusion every 8 hours for 7 days (19 total doses) 
• Cohort 2: AVYCAZ® 2.5 g IV as a 2-hour infusion x 1, then 0.32 g per hour IV daily as a CI (7.5 
g/day) for 7 days (20 total doses, IV bag changes every 8 hours for CI) 
• Cohort 3: ATM 2 g IV as a 2-hour infusion every 6 hours for 7 days (25 total doses) 
• Cohort 4: ATM 2 g IV as a 2-hour infusion x 1, then 0.33 g per hour IV daily as a CI (8 g/day) for 7 
days (14 total doses, IV bag changes every 12 hours for CI) 
• Cohort 5: AVYCAZ® 2.5 g IV as a 2-hour infusion every 8 hours for 7 days and ATM 1.5 g IV as a 2-
hour infusion every 6 hours for 7 days (AVYCAZ® 19 total doses; ATM 25 total doses) 
• Cohort 6*: AVYCAZ® 2.5 g IV as a 2-hour infusion every 8 hours for 7 days and ATM 2 g IV as a 2-
hour infusion every 6 hours for 7 days (AVYCAZ® 19 total doses; ATM 25 total doses) 
*A SMC meeting will be convened after completion of Cohort 5 to assess whether the study may proceed to 
Cohort 6. 
3.3.2. 
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 


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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 local (infusion site) and systemic reactions, will be captured on the appropriate data 
collection form and electronic case report form (eCRF). Information to be collected for AEs includes event 
description, date of onset, assessment of severity, relationship to study product and alternate etiology 
(assessed only by those with the training and authority to make a diagnosis and listed on the Form FDA 1572 
as an investigator), 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, return to pretreatment status or stabilization of the condition with the expectation that it will 
remain chronic. 
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 worsens, it should 
be recorded as an AE. 
All AEs (laboratory and clinical symptoms) will be graded for severity (Table 4 and Table 5) and assessed for 
relationship to study product (see definitions below). 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 data collection form and eCRF. 
Severity of Event 
AEs will be assessed by the investigator using the protocol-defined grading system. 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 (less than 48 hours) 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 
(use of non-narcotic pain reliever or over-the-counter medication). The event interferes with usual 
activities of daily living, causing discomfort but poses no significant or permanent risk of harm to the 
research participant. 
• Severe (Grade 3): Events interrupt usual activities of daily living, or significantly affects clinical 
status, or may require intensive therapeutic intervention (requires prescription medication, or IV fluids 
or medical procedure). Severe events are usually incapacitating. 
Relationship to Study Product 
The assessment of the AE’s relationship to study product will be done by the licensed study physician 
indicated on the Form FDA 1572 and the assessment will be part of the documentation process. Whether the 
AE is related or not to the study product, is not a factor in determining what is or is not recorded in the eCRF 
in this trial. If there is any doubt as to whether a clinical observation is an AE, the event should be recorded in 
the eCRF. 


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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 event. 
3.3.3. 
Serious Adverse Events (SAEs) 
An AE is considered an SAE if, in the view of either the site PI or sponsor, it results in any of the following 
outcomes: 
• Death, 
• a life-threatening AE 
o 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. 
• 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, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
All 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 the Form FDA 1572 or by the Institution as the site PI 
or Sub-Investigator. 
• Recorded on the appropriate SAE data collection form and eCRF. 
Followed through resolution or stabilization, even if this extends beyond the study-reporting period, by a 
licensed study physician (for Investigational New Drug Application (IND) studies, a physician listed on the 
Form FDA 1572 as the site PI or Sub-Investigator). 
• Reviewed and evaluated by DMID, an Independent Safety Monitor (ISM) (as deemed necessary) or 
Safety Monitoring Committee (SMC) (periodic review unless related), and the IRB/IEC. 
For additional study definitions and derived variables related to PK endpoints, refer to the PK SAP. 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
This is a Phase 1, open-label, single center study in 48 healthy adult male and female subjects age 18-45 years 
old (6 cohorts of 8 subjects) to investigate the safety and PK of AVYCAZ® combined with ATM, AVYCAZ® 
alone, and ATM alone. Following subject screening, eligible subjects will be assigned into one of the 6 dosing 
cohorts (see Table 1). Four treatment cohorts (Cohorts 1-4) are single agent dosing cohorts and will include 
AVYCAZ® per label dosing, AVYCAZ® as a CI, ATM per label dosing, and ATM as a CI. The remaining 
two cohorts (Cohorts 5-6) are two AVYCAZ® combined with ATM regimens. Cohorts 1-4 will be completed 
prior to Cohorts 5 and 6. 
Subjects will be admitted to the study site on Day -1 for evaluations to confirm they continue to meet the 
eligibility criteria, after which they will be admitted to the study site for dosing and observation. Subjects will 
stay for a minimum of 7 nights and 8 days. Study safety will be closely monitored using daily assessment of 
AEs, vital signs, and clinical laboratory safety tests. Vital signs will be collected on all study days. Clinical 
laboratory safety tests will be collected at Screening and on Day -1, Days 2, 4, 6, and Day 8 (prior to 
discharge from the study site). Liver function tests (LFTs) will be obtained daily beginning on Day 4 until a 
subject completes dosing. The Final Visit (Day 11 + 3) will be scheduled with each subject for a final safety 
evaluation and collection of clinical laboratory safety tests. A schedule of all study events can be found in 
Table 2. 
The study will run between approximately 12-15 months. 
4.2. 
Discussion of Study Design, Including the Choice of Control Groups 
As the main focus of this study is to investigate the safety and PK of AVYCAZ® combined with ATM, 
AVYCAZ® alone, and ATM alone, there is no control group and all subjects within a cohort will receive the 
same dosing regimen. The single agent dosing cohorts (Cohorts 1-4) will be completed before the 
combination dosing cohorts (Cohorts 5-6) because although AVYCAZ® and ATM appear to be safe and well-
tolerated as standalone products, there is no available data on safety when these antibiotics are used in 
combination. 
4.3. 
Selection of Study Population 
The study will be conducted using 48 healthy volunteers aged 18-45 years old enrolled into 6 cohorts to 
observe the safety and PK of the two optimal combination regimens of AVYCAZ® with ATM. Safety and PK 
of combination regimes will be compared to AVYCAZ® and ATM dosing regimens given alone. This is a 
single center study being conducted in the United States. The study site will determine the most effective 
procedures to identify potential eligible subjects from the general public for this study. 
Only subjects who meet all of the inclusion and none of the exclusion criteria will be eligible for enrollment 
into this study. No exemptions are granted on Inclusion/Exclusion Criteria in DMID-sponsored studies. 
Eligibility criteria from version 3.0 of the protocol are listed below: 
4.3.1. 
Inclusion Criteria 
A subject must meet all the following criteria to be considered eligible for inclusion in the study. 
1. Provide a signed and dated written informed consent. 


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2. Be able to understand and willing to comply with study procedures, restrictions, and requirements, as 
determined by the Principal Investigator (PI). 
3. Male and female volunteers aged 18 to 45 years inclusive. 
4. Suitable veins for cannulation or repeated venipuncture. 
5. Subject must be in good general health as judged by the investigator as determined by medical history, 
vital signs1, body mass index (BMI) and body weight2, clinical laboratory values3, and physical 
examination (PE). 
1 Oral temp <38.0°C/100.4°F; pulse 50 to 100 bpm; systolic blood pressure 90 to 140 mmHg, and diastolic blood 
pressure 55 to 90 mmHg. 
2 BMI between 19-33 kg/m2 and body weight ≥ 50 kg 
3 Clinical chemistry, hematology, coagulation and urinalysis results within the clinical laboratory reference ranges; 
clinical laboratory values outside these ranges, if considered by the site investigator to be clinically insignificant, 
are also acceptable 
6. Sexually active female subjects must be of non-childbearing potential4 or must use a highly effective 
method of birth control5. 
4 Non-childbearing potential is defined as being post-menopausal for at least 18 months or surgically sterile via 
hysterectomy, bilateral oophorectomy, or tubal sterilization. 
5 Sexually active female subjects of childbearing potential must avoid becoming pregnant by using one of the 
following acceptable methods of birth control for 30 days prior to study product dosing and must be maintained for 
30 days after last dose of the study product: 
- 
Intrauterine contraceptive device; OR 
- 
Approved hormonal contraceptives (such as birth control pills, skin patches, Implanon®, Nexplanon®, 
DepoProvera®, or NuvaRing® 
Birth control must be captured on the appropriate date collection form. 
7. Sexually active male subjects must be vasectomized or agree to use barrier contraception (condom with 
spermicide) from first dose of study product until 30 days following the dose of study product. 
8. Nonsmokers defined as abstinence from cigarette smoking or use of nicotine-containing products for 6 
months prior to enrollment into the study. 
4.3.2. 
Exclusion Criteria 
A subject must not meet any of the following criteria to be considered eligible for inclusion in the study. 
1. History of any clinically significant (CS) disease or disorder, medical/surgical procedure, or trauma within 
4 weeks prior to the first administration of study product(s)6. 
6 In opinion of the PI, may either put the volunteer at risk because of participation in the study, or influence the 
results of the volunteer’s ability to participate in the study. 
2. History or presence of gastrointestinal, hepatic, or renal disease, or any other condition known to interfere 
with absorption, distribution, metabolism, or excretion of drugs. 
3. Known history of a clinically important allergy/hypersensitivity to avibactam (AVI), any monobactam, 
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4. Receipt of probenecid or furosemide within 14 days prior to study enrollment. 
5. Receipt of any antibiotics within 14 days prior to study enrollment. 
6. Receipt of prescription medications (except birth control pills or hormone replacement in females) within 
14 days prior to study enrollment, unless in the opinion of site investigator the medication will not 
interfere with the study procedures or impact subject safety. 
7. Receipt of non-antibiotic medications that interacts with OAT37 within 14 days prior to study enrollment. 
7 Adefovir, Anagliptin, Baricitinib, Cefaclor, Cimetidine, Ciprofloxacin (Systemic), Clofarabine, Eluxadoline, 
Empagliflozin, Furosemide, Ketoprofen, Methotrexate, Mycophenolate, PEMEtrexed, Penicillin G 
(Parenteral/Aqueous), Penicillin G Benzathine, Penicillin G Procaine, Penicillin V Benzathine, Penicillin V 
Potassium, Zidovudine 
8. Receipt of herbal and dietary supplements (including St. John’s Wort) within 14 days prior to study 
enrollment. 
9. ALT or AST laboratory value above the ULN as defined in the toxicity table in Table 5. 
10. Prolonged QT duration corrected for heart rate by Fridericia’s formula (QTcF) (> 450 msec) or shortened 
QTcF (< 340 msec) or family history of long QT syndrome. Any clinically important abnormalities in 
rhythm, conduction, or morphology of resting ECG8. 
8 Abnormalities that may interfere with interruption of QTc interval changes per the medical judgement of the PI. 
11. Any positive result on screening for human immunodeficiency virus (HIV), serum hepatitis B surface 
antigen (HBsAg) and hepatitis C virus (HCV) antibody. 
12. Creatinine clearance equal or less than 80 mL/minute (measured by Cockcroft-Gault method) [1]. 
13. History of Clostridium difficile infection in past 90 days. 
14. Known or suspected history of drug or alcohol abuse within the last 5 years, as judged by the PI. 
15. Positive screen for drugs of abuse, cotinine (nicotine), or alcohol at screening and at admission to the 
study site prior to the first administration of the study product(s). 
16. Received a new chemical entity (compound not approved for marketing) or participated in a study that 
included drug treatment within 1 month of the first dose of study product(s) for study.9 
Note: subjects consented and screened, but not dosed in this study or a previous Phase I study will not be 
excluded 
9 Period of exclusion begins at the time of the last visit of the prior study. 
17. Previous participation in the present study. 
18. Involvement in the planning and/or conduct of the study. 
19. Any ongoing/recent (during screening) medical complaints that may interfere with analysis of study data 
or are considered unlikely to comply with study procedures, restrictions, and requirements.10 
10 Judgment by the PI that the subject should not participate in the study. 
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4.4. 
Treatments 
4.4.1. 
Treatments Administered 
Subjects will receive infusions of either AVYCAZ® (2.5 g IV) combined with ATM (1.5 g or 2 g IV), 
AVYCAZ® alone, or ATM alone for 7 days. The single dosing cohorts will receive the study drug per label 
dosing or as a CI. 
4.4.2. 
Identity of Investigational Product(s) 
AVYCAZ® (ceftazidime-avibactam) 
AVYCAZ® 2.5 grams (2 grams ceftazidime and 0.5 grams avibactam) for injection is a white to yellow sterile 
powder for constitution consisting of ceftazidime pentahydrate and avibactam sodium packaged in glass vials. 
The formulation also contains sodium carbonate [2]. 
Each AVYCAZ® 2.5 grams single-dose vial contains ceftazidime 2 grams (equivalent to 2.635 grams sterile 
ceftazidime pentahydrate/sodium carbonate) and avibactam 0.5 grams (equivalent to 0.551 grams sterile 
avibactam sodium). The sodium carbonate content of the mixture is 239.6 mg/vial. The total sodium content 
of the mixture is approximately 146 mg (6.4 mEq)/vial. 
AZACTAM® (aztreonam for injection, USP) 
AZACTAM® (aztreonam for injection, USP) is a sterile, non-pyrogenic, sodium-free, white powder 
containing approximately 780 mg arginine per gram of ATM. Following constitution, the product is for 
intramuscular or intravenous use. Aqueous solutions of the product have a pH in the range of 4.5 to 7.5. 
The study product vials will be labeled according to manufacturer or regulatory specifications. The dispensed 
study product (IV bags) will be labeled with the cautionary statement “For Investigational Use Only.” 
4.4.3. 
 Method of Assigning Subjects to Treatment Groups (Randomization) 
This is an open-label study and randomization procedures are not required. Subjects will be enrolled online 
though the enrollment module of Advantage eClinical®, Emmes’ Internet Data Entry System (IDES). 
4.4.4. 
Selection of Doses in the Study 
Although AVYCAZ® combined with ATM has been shown to be efficacious against MBL-producing GNB in 
pre-clinical studies and clinical case reports, optimal dosing remains unknown. Hollow fiber infection model 
(HFIM) studies using E. coli ARLG-1013 (blaNDM-1, blaCTX-M, blaCMY, blaTEM) and K. pneumoniae ARLG-
1002 (blaNDM-1, blaCTXM-15, blaDHA, blaSHV, blaTEM) were conducted to identify AVYCAZ® combined with 
ATM regimens that result in maximal bacterial kill and resistance suppression [1]. In these HFIM 
experiments, a number of FDA-approved ATM 6-8 grams/day regimens were evaluated in combination with 
FDA-approved AVYCAZ® dosing (2.5 g IV as a 2-hour infusion every 8 hours) and CI AVYCAZ® (7.5 g IV 
daily) [2 and 3]. It was anticipated that administration of AVYCAZ® as a CI combined with ATM would 
outperform FDA-approved AVYCAZ® dosing combined with ATM. Continuous infusion administration 
maximizes the pharmacokinetics/pharmacodynamics (PK/PD) of AVYCAZ® and it was anticipated that this 
would result in enhanced bacterial killing and resistance suppression [4, 5, and 6]. Since it is not practical for 
all institutions to infuse AVYCAZ® as a CI, HFIM experiments were also conducted to identify the optimal 
dosing of AVYCAZ® combined with ATM using FDA-approved dosing regimens of each antibiotic. In these 
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be optimal. Specifically, the two combination regimens that showed maximal bacterial killing and resistance 
suppression over 7 days were: 
• AVYCAZ® 2.5 g IV as a 2-hour infusion every 8 hours combined with ATM 2 g IV as a 2-hour 
infusion every six hours, and  
• AVYCAZ® combined with ATM, each administered as a CI (AVYCAZ® 7.5 g/day CI combined with 
ATM 8 g/day CI) [1]. 
While the initial intent was to examine the two optimal AVYCAZ® and ATM regimens identified in the 
HFIM experiments, two subjects who received ATM 8 g/day CI alone in Cohort 4 experienced grade 3 
AST/ALT elevations. Despite having AST/ALT elevations >10 times the ULN, the two subjects were 
asymptomatic and there were no clinical findings suggestive of liver necrosis or jaundice. 
In response to the occurrence of two grade 3 AEs that were related to study product and of the same type 
[High Level Term (HLT)], the study was halted, and a SMC meeting was convened. The SMC recommended 
to continue the study but reduce the dose of ATM in Cohort 5 to ATM 1.5 g IV as a 2-hour infusion every 6 
hours (ATM 6 g/daily) and to administer it in combination with AVYCAZ 2.5 g IV as a 2-hour infusion every 
8 hours. Furthermore, the SMC recommended that a SMC meeting be convened after completion of Cohort 5. 
If no halting rules are met and there are no other safety concerns, the SMC recommended administering ATM 
2 g IV as a 2-hour infusion every 6 hours (ATM 8 g/daily) in combination with AVYCAZ® 2.5 g IV as a 2-
hour infusion every 8 hours in Cohort 6. The SMC was in favor of escalating the ATM dose in Cohort 6 if no 
halting rules are met as the HFIM experiments showed increased bacterial killing with 8 g/day vs 6 g/day 
combination regimens. Since the safety of ATM CI was not established in this study, the SMC was opposed to 
administering ATM as a CI in any subsequent cohorts. As an additional safeguard, the SMC also 
recommended that more intensive LFT monitoring be performed. 
4.4.5. 
Selection and Timing of Dose for Each Subject 
Administration of the study products to subjects will occur over a period of 7 days, with dosing being 
completed the morning of Day 7 for all cohorts. 
Each subject will receive doses of AVYCAZ® alone, ATM alone, or a combination of AVYCAZ® and ATM 
depending on the cohort. The dosing schedules for each cohort can be found in Table 1. Refer to Section 4.4.4 
for additional details regarding the selection of the dose timing schedule. 
4.4.6. 
Blinding 
This is an open-label, unblinded study. Blinding (masking) is not needed. 
4.4.7. 
Prior and Concomitant Therapy 
Use of concomitant medications (probenecid and furosemide) that are contraindicated in the AVYCAZ® and 
ATM package inserts will be not permitted [2 and 3]. Subjects taking such medications will be not eligible for 
the study. 
Patients who received antibiotics within 14 days prior to study enrollment will not be eligible for the study. 
Patients receiving a non-antibiotic medication that interacts with OAT3 (e.g., Adefovir, Anagliptin, 
Baricitinib, Cefaclor, Cimetidine, Ciprofloxacin (Systemic), Clofarabine, Eluxadoline, Empagliflozin, 
Furosemide, Ketoprofen, Methotrexate, Mycophenolate, PEMEtrexed, Penicillin G (Parenteral/Aqueous), 
Penicillin G Benzathine, Penicillin G Procaine, Penicillin V Benzathine, Penicillin V Potassium, Zidovudine) 
will not be included [7 and 8]. 


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In addition, no prescription (except birth control pills or hormone replacement in females) or non-prescription 
drugs will be permitted, unless in the opinion of site investigator the medication will not interfere with the 
study procedures or impact subject safety. The use of herbal and dietary supplements (including St. John’s 
Wort) will not be permitted during the study. 
4.4.8. 
Treatment Compliance 
The Investigational Pharmacist or designee is responsible for the reconstitution and labeling of the study 
products. Study products will be administered via IV infusion by a member of the clinical research team who 
is licensed to administer the study products. Administration will be documented on the source document and 
entered into the eCRF. 
Study product compliance including start and stop time of infusion, volume administered, and the occurrence 
of any infusion interruptions (greater than 10 minutes) will be captured in the source documents. 
4.5. 
Safety Variables 
The following section describes the variables related to the safety endpoints, safety related variables collected 
throughout the study. For a detailed schedule of events refer to Table 2. 
The type, incidence, relatedness, and severity of AEs and SAEs will be recorded from start of infusion of the 
first dose of study product on Day 1 through the final Study Visit of Day 11 + 3. Refer to Section 3.3 for 
definitions of AEs, SAEs, severity, and relatedness. 
The following safety laboratory parameters and vital signs will be summarized for baseline and each post-
dose time point collected. For continuous parameters, change from baseline will be summarized for all post 
dose time points. Assessments at Day -1 will serve as baseline values for all laboratory parameters. 
Serum Chemistry: 
- 
Sodium, Potassium, Chloride, Bicarbonate, Blood Urea Nitrogen (BUN), Creatinine, Glucose (Fasting 
and Non-Fasting), Albumin, Total Protein, and Lactate Dehydrogenase (LDH) will be collected at 
Screening, Day -1, and Days 2, 4, 6, 8, and 11 (+3). 
- 
Liver function tests ALT, AST, Alkaline Phosphatase (ALP), and Total Bilirubin will be collected at 
Screening, Day -1, Day 2, Days 4-8, and Day 11 (+3). Days 5 and 7 are collected for Cohorts 5 and 6 
only. 
Hematology: 
- 
Hemoglobin, Hematocrit, White Blood Cell Count (WBC), WBC differential, Red Blood Cell Count 
(RBC), and Platelets will be collected at Screening, Day -1, and Days 2, 4, 6, 8, and 11 (+3). 
- 
Coombs tests will be conducted at Screening and Day 8. 
Coagulation: 
- 
Prothrombin Time and Partial Thromboplastin Time (PTT) will be collected at Screening, Day -1, and 
Days 2, 4, 6, 8, and 11 (+3). 
Urinalysis 
- 
Dipstick urinalysis, including Protein, Glucose, Ketones, Bilirubin, Blood, Nitrites, Leukocyte 
Esterase (LCE), Urobilinogen, Specific Gravity, and pH, will be collected at Screening, Day -1, and 
Days 4, 8, and 11 (+3). 


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Vital signs including Systolic Blood Pressure (BP), Diastolic BP, Pulse Rate, Respiratory Rate, and Body 
Temperature will be obtained at Screening, Day -1, prior to dosing on Day 1, 1 hour after first dose on Day 1, 
Days 2-8, and Day 11 (+3). Change from baseline will be summarized for all post dose time points. The 
measurements obtained on Day -1 will serve at the baseline measurement. 
ECGs including QTc Interval and PR Interval will be obtained at Screening and on Days -1 (baseline), 8, and 
11 (+3). ECGs will be done in triplicate at Screening only. Single ECGs will be recorded on Days -1, 8, and 
11 (+3). In case of premature discontinuation of study drug, ECG will be performed before discharge. Overall 
ECG assessment and change from baseline will be summarized for all post dose time points. 
A complete physical examination will be completed at Screening and on Days -1, 8, and 11 (+3). Height and 
Weight will be measured at Screening and Day -1, and BMI will be calculated from the Day -1 measurements. 


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5. 
SAMPLE SIZE CONSIDERATIONS 
This is a Phase 1 study to investigate the safety and PK of AVYCAZ® combined with ATM. The sample size 
was chosen to obtain reasonable evidence of safety without exposing undue numbers of healthy subjects to 
combination of AVYCAZ® and ATM at this phase of clinical evaluation. Previous experience in Phase I 
studies has shown that the sample size being proposed is sufficient to fulfil the primary and secondary 
objectives of the study. 


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6. 
GENERAL STATISTICAL CONSIDERATIONS 
6.1. 
General Principles 
All continuous variables will be summarized using the following descriptive statistics: N (non-missing sample 
size), mean, standard deviation, median, maximum, and minimum. The frequency and percentages (based on 
the non-missing sample size) of observed levels will be reported for all categorical measures. When 95% 
confidence intervals (C.I.s) are given for a percent, exact (Clopper-Pearson) C.I.s will be used unless 
otherwise noted. 
In general, all data will be listed, sorted by treatment and subject, and when appropriate by visit number 
within subject. All summary tables will be annotated with the total population size relevant to that table, 
including any missing observations. 
6.2. 
Timing of Analyses 
The final analysis will be performed after database lock. There are no planned interim analyses. 
6.3. 
Analysis Populations 
6.3.1. 
Safety Population 
All subjects who receive any amount of study product (start first infusion) will be included in the Safety 
Population. 
6.3.2. 
PK Population 
All subjects who receive at least one dose of study drug and have at least one quantifiable plasma or urine 
concentration of ceftazidime (CAZ), AVI, or ATM measurement will be included in the PK Population. 
6.4. 
Covariates and Subgroups 
The protocol does not define any formal subgroup analyses. 
6.5. 
Missing Data 
All attempts will be made to collect any data per protocol. No imputation will be performed for missing safety 
values and outliers will not be excluded from the safety analysis. The amount of missing data and reasons for 
missingness if available will be summarized in the body of the CSR. 
6.6. 
Interim Analyses and Data Monitoring 
A safety summary report will be generated for review by the SMC if a halting rule (see Protocol v3.0 Section 
8.6) is met. No formal interim analyses were planned. However, in response to the occurrence of two grade 3 
AEs of the same HLT in Cohort 4, a SMC meeting will be convened after the completion of Cohort 5 to 
assess patient profiles for subjects with elevated liver function tests from Cohorts 1-5 and determine if the 
study should proceed to Cohort 6.  
6.7. 
Multicenter Studies 
DMID Protocol 17-0107 is a single center study. 
6.8. 
Multiple Comparisons/Multiplicity 
The safety data summarized in these analyses will not be adjusted for multiple comparisons. 


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7. 
STUDY SUBJECTS 
7.1. 
Disposition of Subjects 
The disposition of subjects in the study will be tabulated for all subjects and by treatment cohort (Table 6). 
The table shows the total number of subjects who were screened, were enrolled, started treatment on Day 1, 
completed treatment on Day 7, completed discharge on Day 8, received all scheduled treatments, received 
partial dose of study product, completed all blood draws and urine collections related to the safety endpoints, 
and completed the follow-up visit on Day 11 (+3). 
A flowchart showing the disposition of study subjects will be presented in Figure 1. This figure will present 
the number of subjects screened, enrolled, lost to follow-up, and analyzed. A listing of subjects who did not 
receive all infusions or terminated from study follow-up, including the reason for treatment discontinuation or 
termination, will be included in Listing 1. 
The composition of the analysis populations, including the reason for subject exclusion, is presented in 
Table 7. Subjects who were excluded from the analysis populations will be listed along with reason for 
exclusion (Listing 4). 
Table 9 will present a summary of the reasons that subjects were screened but not enrolled summarized by 
inclusion and exclusion criteria. 
7.2. 
Protocol Deviations 
A summary of subject-specific protocol deviations will be presented by the reason for the deviations and the 
deviation category for all subjects (Table 3). 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 included in Appendix 3 as data listings (Listing 2 and Listing 3, respectively). 


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8. 
EFFICACY EVALUATION 
There are no efficacy endpoints for this protocol. 


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9. 
SAFETY EVALUATION 
All safety analyses will be presented using the Safety Population.  
When calculating the incidence of AEs (i.e., on a per subject basis), each subject will be counted once and any 
repetitions within a subject will be ignored for events coded in the same category by the Medical Dictionary 
for Regulatory Activities (MedDRA®). The denominators for percent values will be indicated within the table 
or table header and will consist of the maximal size of the Safety Population in the indicated observation 
period. All C.I.s for proportions will be computed using the exact (Clopper-Pearson) method. Toxicity 
grading scales are provided in Table 4 and Table 5. 
9.1. 
Demographic and Other Baseline Characteristics 
Summaries of age, weight, height, BMI, sex, ethnicity, and race will be presented by treatment cohort and for 
all subjects (Table 10 and Table 11). Ethnicity will be categorized as Hispanic or Latino, Not Hispanic or 
Latino, Not Reported, and Unknown. In accordance with NIH reporting policy, subjects may self-designate as 
belonging to more than one race or may refuse to identify a race, the latter reflected in the CRF as “No” to 
each racial option. 
Individual subject listings will be presented for all demographics (Listing 5). 
9.1.1. 
Prior and Concurrent Medical Conditions 
All current illnesses and past pre-existing medical conditions will be coded using MedDRA® dictionary 
version 20.1 or higher. Summaries of subjects’ pre-existing medical conditions by MedDRA® system organ 
class (SOC) will be presented by treatment cohort and overall (Table 12). Individual subject listings will be 
presented for all medical conditions (Listing 6). 
9.1.2. 
Prior and Concomitant Medications 
Prior (30 days before administration of the first dose of study product) and concomitant medications will be 
coded to the Anatomical Therapeutic Classification (ATC) using the WHO Drug Dictionary. The use of prior 
or concomitant medications during the study will be summarized by ATC1 and ATC2 codes and treatment 
cohort for the Safety Population (Table 108). Individual subject listings will be presented for all prior and 
concomitant medications (Listing 20). 
9.2. 
Measurements of Treatment Compliance 
The number of enrolled subjects who started the first infusion of study product will be reported by treatment 
cohort and time period (Table 8). 
Dates and times for the start and end of infusion, dose number, whether the dose was interrupted, start and end 
times of dose interruption, dose duration, and actual dose received are listed for subjects who did not receive 
the full dose of study product or whose dose was interrupted for one of their scheduled doses in Listing 7. 
9.3. 
Adverse Events 
AEs will be collected after starting infusion on the first dose of study product on Day 1 through the final 
Study Visit on Day 11 +3. When calculating the incidence of AEs (i.e., on a per subject basis), each subject 
will only be counted once at the highest severity recorded and any repetitions of AEs within a subject will be 
ignored. Denominators for percentages are the number of subjects in the Safety Population. All AEs reported 
will be included in the summaries and analyses. 


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Laboratory abnormalities reported as an AE will be included in summary tables together with all other AEs. 
Additionally, all laboratory abnormalities will be summarized by laboratory parameter. Refer to Protocol v3.0 
Section 8.5 for abnormal laboratory values that are reported as AEs. 
9.3.1. 
Solicited Events and Symptoms 
No solicited events or symptoms will be collected in this study. 
9.3.2. 
Unsolicited Adverse Events 
The proportion of subjects reporting at least one unsolicited AE will be summarized by MedDRA® SOC, 
preferred term (PT), and HLT. Denominators for percentages are the number of subjects in the Safety 
Population. 
A brief overall summary of AEs will be shown in Table 13, including the number of subjects with at least one 
AE of any severity, the number of subjects with at least one related and unrelated AE of each severity, the 
number of subjects with at least one SAE, the number of subjects with at least one AE leading to early 
termination, and number of subjects with at least one SUSAR. The number of AEs reported for each subject 
will be presented in Table 14 by severity and overall. 
The following summaries for unsolicited AEs will be summarized by MedDRA® SOC, MedDRA® PT, and 
MedDRA® HLT, and by treatment cohort or treatment (AVYCAZ®, ATM, or Combination): 
• Frequency (number and percent of subjects with an AE of mild severity or greater) and the number of 
events by relationship to study product and seriousness, regardless of severity, for AEs occurring in 
10% of subjects in any treatment cohort (Table 15 by treatment cohort and Table 16 by treatment); 
• Frequency and the number of events, regardless of severity or relationship to study product. 95% C.I.s 
will be presented for proportions (Table 17 by treatment cohort and Table 18 by treatment); 
• Frequency of AEs by severity and relationship to study product. 95% C.I.s will be presented for 
proportions (Table 19 by treatment cohort and Table 20 by treatment); 
• Bar chart displaying the frequency (number of events) of related AEs by severity, MedDRA® SOC, 
and treatment cohort (Figure 2 by treatment cohort and Figure 3 by treatment); 
• Bar chart displaying the incidence (number of occurrences) of related AEs by severity, MedDRA® 
SOC, and treatment cohort (Figure 4 by treatment cohort and Figure 5 by treatment). 
AEs by subject will be presented in Listing 8. A subject listing of non-serious AEs of moderate or greater 
severity will be presented in Table 22. For Listing 8 and Table 22, all related AEs will be listed before 
unrelated AEs. 
9.4. 
Deaths, Serious Adverse Events and other Adverse Events 
A listing of SAEs by subject will be presented in Table 21. The listing will include Subject ID, treatment 
cohort, AE description, dose number, duration, reason reported as an SAE, relationship to study product, 
alternate etiology if not related, action taken with study product, whether the subject discontinued due to the 
AE, outcome, whether the AE was a suspected unexpected serious adverse reaction (SUSAR), MedDRA® 
SOC, MedDRA® PT, and MedDRA® HLT. 


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9.5. 
Birth Control and Pregnancies 
For any subjects in the Safety Population who become pregnant during the study, every attempt will be made 
to follow these subjects to completion of pregnancy to document the outcome, including information 
regarding any complications with pregnancy and/or delivery. If any pregnancies occur, listings of pregnancies 
and outcomes will be presented (Listing 21, Listing 22, Listing 23, Listing 24, and Listing 25). 
Birth control method(s) will be listed for each subject with start and end dates (Listing 26). 
9.6. 
Clinical Laboratory Evaluations 
Chemistry, Hematology, Coagulation, and Urinalysis laboratory parameters will be collected as described in 
Section 4.5. Toxicity grading criteria for the clinical laboratory evaluations can be found in Table 5. 
Unscheduled tests for medical or safety reasons will be listed but excluded from tabular and graphical 
summaries, except when calculating the maximum severity post-baseline. Assessments at Day -1 will serve as 
baseline values for all laboratory parameters. 
The following laboratory parameters will be presented: 
• Chemistry: Sodium, Potassium, Chloride, Bicarbonate, BUN, Creatinine, Glucose (Fasting and Non-
Fasting), Albumin, Total Protein, LDH, ALT, AST, ALP, and Total Bilirubin 
Note: Unknown Glucose is reported as Non-Fasting Glucose 
• Hematology: Hemoglobin, Hematocrit, WBC, Neutrophils, Lymphocytes, Monocytes, Eosinophils, 
Basophils, RBC, Platelets, and Coombs test 
• Coagulation: Prothrombin Time and PTT 
• Urinalysis: Protein, Glucose, Ketones, Bilirubin, Blood, Nitrites, LCE, Urobilinogen, Specific Gravity, 
and pH 
Laboratory parameters will be summarized by treatment cohort and parameter for change in severity from 
Baseline to all post-dose time points (including early terminations and maximum severity post-baseline). Only 
laboratory parameters that have a grading listed in Table 5 will be summarized. All baseline and post-dose 
measurements will be summarized according to the grading scale in Table 5. If any post-dose measurement is 
outside the normal range but did not meet the definition for an AE based on the grading in Table 5, it will be 
categorized as “Outside Normal Range.” Laboratory measurements collected that have a mild grading but are 
not clinically significant will be included in these tables. Additionally, laboratory parameters that have 
grading criteria for both high (results higher than normal range) and low (results lower than normal range) 
will be summarized separately. 
Frequencies (numbers and percentages) of the change in severity from Baseline to all scheduled post-dose 
time points for all Chemistry parameters, not including Bicarbonate, Chloride, Albumin, and LDH, will be 
summarized in Table 27. Frequencies of individual parameters, excluding the same parameters from Table 27, 
will be summarized starting at Table 28 and continuing through Table 38. Frequencies of the change in 
severity from Baseline to all scheduled post-dose time points for all Hematology parameters, not including 
Hematocrit, Monocytes, Basophils, and RBC, will be summarized in Table 55. Frequencies of individual 
parameters, excluding the same parameters from Table 55, will be summarized starting at Table 56 and 
continuing through Table 61. Frequencies of the change in severity from Baseline to all scheduled post-dose 
time points for all Coagulation parameters will be summarized in Table 74. Frequencies of individual 
parameters will be summarized in Table 75 and Table 76. Frequencies of the change in severity from Baseline 


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to all scheduled post-dose time points for all Urinalysis parameters, not including Ketones, Bilirubin, Nitrites, 
LCE, Urobilinogen, Specific Gravity, and pH will be summarized in Table 80. Frequencies of individual 
parameters, excluding the same parameters from Table 80, will be summarized in Table 81 and Table 82. 
Abnormal laboratory results (graded mild, moderate, or severe, or outside of reference range) for Chemistry, 
Hematology, Coagulation, and Urinalysis parameters will be listed in Table 23, Table 24, Table 25, and 
Table 26, respectively. Abnormal laboratory results that are reported as AEs and are related to the study 
product will be summarized for Chemistry, Hematology, Coagulation, and Urinalysis parameters by severity 
for all post-dose time points (Table 39, Table 62, Table 77, and Table 83, respectively). Refer to Protocol v3.0 
Section 8.5 for abnormal laboratory values that are reported as AEs. 
For continuous laboratory parameters, descriptive statistics, including mean, standard deviation, median, 
minimum, and maximum values by time point and change from baseline for all post-dose measurements will 
be presented by laboratory parameter and treatment cohort. Chemistry parameters will be presented beginning 
at Table 40 and continuing through Table 54. Hematology parameters will be presented beginning at Table 63 
and continuing through Table 72. Results from Coombs tests will be presented for Screening and Day 8 by 
treatment cohort in Table 73. Coagulation parameters will be presented in Table 78 and Table 79. Urinalysis 
parameters (Specific Gravity and pH) will be presented in Table 84 and Table 85. Categorical urinalysis 
parameters (protein, glucose, ketones, bilirubin, blood, nitrites, leukocyte esterase, and urobilinogen) will be 
presented for baseline and all post-dose measurements by treatment cohort beginning at Table 86 and 
continuing through Table 93. 
Line plots showing individual subject and mean values at baseline and all scheduled post-dose time points 
will be presented by laboratory parameter and treatment cohort. Chemistry parameters will be presented in 
Figure 6 through Figure 21. Hematology parameters will be presented in Figure 37 through Figure 47. 
Coagulation parameters will be presented in Figure 58 and Figure 59. Urinalysis parameters will be presented 
in Figure 62 and Figure 63. Line plots with standard error bars showing the mean change from baseline at 
each scheduled post-dose time point will be presented by laboratory parameter and treatment cohort. 
Chemistry parameters will be presented beginning at Figure 22 and continuing through Figure 36. 
Hematology parameters will be presented beginning at Figure 48 and continuing through Figure 57. 
Coagulation parameters will be presented in Figure 60 and Figure 61. Urinalysis parameters will be presented 
in Figure 64 and Figure 65. Laboratory parameters that have grading criteria for both males and females will 
be presented separately. 
Listing 9, Listing 10, Listing 11, and Listing 12 will provide a complete listing of individual clinical 
laboratory results with applicable reference ranges. Serology screening, Coombs test, urine cotinine, urine 
toxicology and alcohol screening, and pregnancy test results will be provided in Listing 13, Listing 14, 
Listing 15, and Listing 16, respectively. 
9.7. 
Vital Signs and Physical Evaluations 
Vital sign measurements include pulse rate, systolic BP, diastolic BP, oral temperature, and respiratory rate. 
Vital signs will be assessed at Screening, Day -1, prior to dosing and 1 hour after starting the first dose on 
Day 1, and on Days 2-8. Assessments at Day -1 will serve as baseline values for all vital sign measurements. 
The grading scale for vital sign evaluations is presented in Table 5. Summaries of vital signs by severity will 
be tabulated by time point and treatment cohort and presented for all parameters in Table 94 and by parameter 
in Table 95, Table 96, Table 97, Table 98, and Table 99. Vital signs that have grading criteria for both 
decreases (results lower than normal range) and increases (result higher than normal range) will be 
summarized separately. 


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Descriptive statistics including mean, standard deviation, median, minimum, and maximum values by time 
point and change from baseline for all post-dose measurements (including early terminations and max severity 
post-baseline) will be presented in Table 100, Table 101, Table 102, Table 103, and Table 104. 
Line plots showing individual subject and mean values at baseline and all scheduled post-dose time points 
will be presented by vital sign and treatment cohort (Figure 66, Figure 67, Figure 68, Figure 69, and 
Figure 70). Line plots with standard error bars showing the mean change from baseline at each scheduled 
post-dose time point will be presented by vital sign and treatment cohort (Figure 71, Figure 72, Figure 73, 
Figure 74, and Figure 75). 
Vital signs will be listed (Listing 17). Unplanned vital signs measurements will be included in the listing, but 
excluded from tabular and graphic summaries, except when calculating the maximum severity post-baseline. 
A physical exam will be performed at Screening and on Days -1, 8, and 11 (+3) as described in Section 4.5, as 
well as SAE follow-up as needed. Results of physical examinations, scheduled and unscheduled, will be 
presented in Listing 18. 
9.8. 
ECG Assessments 
ECG measurements include QTcF Interval and PR Interval. ECGs will be performed at Screening and on 
Days -1 (baseline), 8, and 11 (+3). The grading scale for ECG evaluations is presented in Table 4. 
ECG change in overall interpretation from Baseline to all scheduled post-dose time points by treatment cohort 
will be shown in Table 105. Summaries of ECG results will be tabulated by treatment cohort, severity 
grading, and time point (Table 106). 
Descriptive statistics including mean, standard deviation, median, minimum, and maximum values by time 
point and change from baseline will be tabulated and presented for baseline and each scheduled post-dose 
time point in Table 107. The baseline measurement used for all post-dose time points will be the 
measurements taken on Day -1. 
Line plots showing individual subject and mean values at baseline and all scheduled post-dose time points 
will be presented by ECG measurement and treatment cohort (Figure 76 and Figure 78). Line plots with 
standard error bars showing the mean change from baseline at each scheduled post-dose time point will be 
presented by ECG measurement and treatment cohort (Figure 77 and Figure 79). 
Individual data listings of ECG results will be listed (Listing 19). ECGs will be done in triplicate at Screening, 
and the individual results along with the mean of the three measurements will be included in the listing. 


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10. 
PHARMACOKINETICS 
PK analysis will be described in the PK SAP. 
Listings of subject level concentrations of CAZ, AVI, and ATM in plasma and urine will be presented in 
Listing 27 and Listing 28, respectively. Listings of subject-specific PK parameters from non-compartmental 
plasma and urine PK analyses will be presented for CAZ, AVI, and ATM in Listing 29 and Listing 30. 
Subject-specific PK parameters from the population PK analysis will be listed in Listing 31. 


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11. 
IMMUNOGENICITY 
There are no immunogenicity endpoints for this protocol. 


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12. 
OTHER ANALYSES 
There are no other analyses. 


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13. 
REPORTING CONVENTIONS 
The mean, standard deviation, and other statistics will be reported to 1 decimal place greater than the original 
data. The minimum and maximum will use the same number of decimal places as the original data. 
Proportions will be presented as 2 decimal places; values greater than zero but <0.01 will be presented as 
“<0.01”. Percentages will be reported to the nearest whole number; values greater than zero but <1% will be 
presented as “<1”; values greater than 99% but less than 100% will be reported as >99%. Estimated 
parameters, not on the same scale as raw observations (e.g. regression coefficients) will be reported to 3 
significant figures. 
Listings of individual subject data include a Subject ID column. The subject identifiers assigned by site staff 
are replaced throughout this report with the 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 
eClinical platform code followed by a numeric identifier assigned chronologically to enrolled subjects as well 
as screening failures across all sites and protocol in the eClinical platform. Any data sharing activities will 
include the USUBJID and not the subject identifiers assigned at the site. 


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14. 
TECHNICAL DETAILS 
SAS version 9.4 or above will be used to generate all tables, figures, and listings. 


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15. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES 
In response to the occurrence of two grade 3 AEs that were related to study product and of the same HLT in 
Cohort 4, the dose of ATM in Cohort 5 was reduced to 1.5 g IV as a 2-hour infusion every 6 hours (ATM 6 
g/daily) and will be administered in combination with AVYCAZ® 2.5 g IV as a 2-hour infusion every 8 hours. 
A SMC meeting will be convened after the completion of Cohort 5, and if no halting rules are met or there are 
no other safety concerns, the dose of ATM in Cohort 6 will be 2 g IV as a 2-hour infusion every 6 hours 
(ATM 8 g/daily) and administered in combination with AVYCAZ® 2.5 g IV as a 2-hour infusion every 8 
hours. 
More intensive LFT monitoring will be performed in Cohorts 5 and 6 with additional collection of LFTs on 
Days 5 and 7. 


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16. 
REFERENCES 
1. Lodise TP, Smith NM, Holden PN, T Berard, O’Donnell N, Bonomo RA, Tsuji BT. Efficacy of 
Ceftazidime-Avibactam in Combination with Aztreonam (COMBINE): Solutions for Metallo-β-lactamase 
producing-Enterobacteriaceae (MBL). Abstract # 1385. Poster presentation at IDweek2018™. San 
Francisco, CA. October 3-7, 2018.  
2. AVYCAZ® (ceftazidime and avibactam) for Injection, for intravenous use. Package insert. 
https://www.allergan.com/assets/pdf/avycaz_pi. 
3. AZACTAM® (aztreonam for injection, USP), Bristol-Myers Squibb, Package Insert.  
https://packageinserts.bms.com/pi/pi_azactam.pdf. 
4. Abdul-Aziz MH, Sulaiman H, Mat-Nor MB, et al. Beta-Lactam Infusion in Severe Sepsis (BLISS): a 
prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-
lactam infusion in critically ill patients with severe sepsis. Intensive Care Med 2016; 42(10): 1535-45. 
5. Ambrose PG, Bhavnani SM, Rubino CM, et al. Pharmacokinetics-pharmacodynamics of antimicrobial 
therapy: it's not just for mice anymore. Clin Infect Dis 2007; 44(1): 79-86. 
6. Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and 
men. Clin Infect Dis 1998; 26(1): 1-10; quiz 1-2. 
7. Lexicomp Online, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2013; April 15, 2013, 
Date accessed: December, 20, 2018. 
8. Ueo, H., et al., Human organic anion transporter hOAT3 is a potent transporter of cephalosporin 
antibiotics, in comparison with hOAT1. Biochem Pharmacol, 2005. 70(7): p. 1104-13. 
 


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17. 
LISTING OF TABLES, FIGURES, AND LISTINGS 
Table, figure, and listing shells are presented in Appendices 1, 2, and 3. 


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APPENDICES 


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APPENDIX 1. TABLE MOCK-UPS 
 
LIST OF TABLES 
Table 1: 
Treatment Cohorts ......................................................................................................38 
Table 2: 
Schedule of Study Procedures ....................................................................................39 
Table 3: 
Distribution of Protocol Deviations by Category, Type, and Treatment 
Cohort .........................................................................................................................40 
Table 4: 
Adverse Event Definitions ..........................................................................................42 
Table 5: 
Laboratory and Vital Signs Reference Ranges, Eligibility Ranges, and 
Toxicity Grading .........................................................................................................43 
Table 6: 
Subject Disposition by Treatment Cohort – All Enrolled Subjects ............................44 
Table 7: 
Analysis Population Exclusions by Treatment Cohort – All Enrolled 
Subjects .......................................................................................................................45 
Table 8: 
Dates of First Treatment by Treatment Cohort ...........................................................46 
Table 9: 
Ineligibility Summary of Screen Failures ...................................................................47 
Table 10: Summary of Categorical Demographic and Baseline Characteristics by 
Treatment Cohort ........................................................................................................49 
Table 11: Summary of Continuous Demographic and Baseline Characteristics by 
Treatment Cohort ........................................................................................................50 
Table 12: Summary of Subjects with Pre-Existing Medical Conditions by MedDRA 
System Organ Class and Treatment Cohort................................................................51 
Table 13: Overall Summary of Adverse Events .........................................................................52 
Table 14: Number of Adverse Events Experienced by Subject and Severity .............................53 
Table 15: Adverse Events Occurring in 10% of Subjects in Any Treatment Cohort by 
MedDRA System Organ Class, Preferred Term, High Level Term, 
Relationship and Treatment Cohort ............................................................................54 
Table 16: Adverse Events Occurring in 10% of Subjects in Any Treatment Cohort by 
MedDRA System Organ Class, Preferred Term, High Level Term, 
Relationship and Treatment ........................................................................................56 
Table 17: Number and Percentage of Subjects Experiencing Unsolicited Events with 
95% Confidence Intervals by MedDRA System Organ Class, Preferred 
Term, High Level Term, and Treatment Cohort .........................................................58 
Table 18: Number and Percentage of Subjects Experiencing Unsolicited Events with 
95% Confidence Intervals by MedDRA System Organ Class, Preferred 
Term, High Level Term, and Treatment .....................................................................60 


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Table 19: Unsolicited Adverse Events by MedDRA System Organ Class, Preferred 
Term, and High Level Term, Maximum Severity, Relationship, and 
Treatment Cohort ........................................................................................................61 
Table 20: Unsolicited Adverse Events by MedDRA System Organ Class, Preferred 
Term, and High Level Term, Maximum Severity, Relationship, and 
Treatment ....................................................................................................................64 
Table 21: Listing of Serious Adverse Events .............................................................................66 
Table 22: Listing of Non-Serious, Unsolicited, Moderate or Severe Adverse Events ...............67 
Table 23: Listing of Abnormal Laboratory Results – Chemistry ...............................................69 
Table 24: Listing of Abnormal Laboratory Results – Hematology ............................................70 
Table 25: Listing of Abnormal Laboratory Results – Coagulation ............................................71 
Table 26: Listing of Abnormal Laboratory Results – Urinalysis ...............................................72 
Table 27: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Cohort – Chemistry – Any Chemistry Parameter .....................................73 
Table 28: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Cohort – Chemistry – Sodium ...................................................................82 
Table 29: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Cohort – Chemistry – Potassium ...............................................................85 
Table 30: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Cohort – Chemistry – Fasting Glucose .....................................................85 
Table 31: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Cohort – Chemistry – Non-Fasting Glucose .............................................86 
Table 32: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Cohort – Chemistry – Blood Urea Nitrogen .............................................89 
Table 33: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Cohort – Chemistry – Serum Creatinine ...................................................91 
Table 34: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Cohort – Chemistry – Total Bilirubin .......................................................91 
Table 35: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Cohort – Chemistry – Aspartate Aminotransferase ..................................91 
Table 36: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Cohort – Chemistry – Alkaline Phosphatase.............................................91 
Table 37: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Cohort – Chemistry – Alanine Aminotransferase .....................................92 
Table 38: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Cohort – Chemistry – Total Protein ..........................................................95 


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Table 39: Abnormal Laboratory Results Related to Study Treatment by Parameter, 
Maximum Severity, Time Point, and Treatment Cohort – Any Chemistry 
Parameter ....................................................................................................................98 
Table 40: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Cohort – Chemistry – Sodium (mEq/L) ...................................................................100 
Table 41: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Cohort – Chemistry – Potassium (mEq/L) ...............................................................102 
Table 42: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Cohort – Chemistry – Chloride (mmol/L) ................................................................102 
Table 43: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Cohort – Chemistry – Bicarbonate (mmol/L) ...........................................................102 
Table 44: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Cohort – Chemistry – Blood Urea Nitrogen (mg/dL) ..............................................102 
Table 45: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Cohort – Chemistry – Serum Creatinine (mg/dL) ....................................................102 
Table 46: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Cohort – Chemistry – Fasting Glucose (mg/dL) ......................................................102 
Table 47: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Cohort – Chemistry – Non-Fasting Glucose (mg/dL) ..............................................102 
Table 48: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Cohort – Chemistry – Total Protein (g/dL) ..............................................................102 
Table 49: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Cohort – Chemistry – Lactate Dehydrogenase (U/L) ...............................................102 
Table 50: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Cohort – Chemistry – Albumin (g/dL) .....................................................................102 
Table 51: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Cohort – Chemistry – Total Bilirubin (mg/dL) ........................................................102 
Table 52: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Cohort – Chemistry – Aspartate Aminotransferase (U/L) ........................................102 
Table 53: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Cohort – Chemistry – Alkaline Phosphatase (U/L) ..................................................102 
Table 54: Laboratory Summary Statistics by Parameter, Time Point, Gender, and 
Treatment Cohort – Chemistry – Alanine Aminotransferase (U/L) .........................103 
Table 55: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Cohort – Hematology – Any Hematology Parameter .............................106 
Table 56: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Cohort – Hematology – White Blood Cell Count ...................................111 


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Table 57: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Cohort – Hematology – Eosinophils .......................................................114 
Table 58: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Cohort – Hematology – Neutrophils .......................................................117 
Table 59: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Cohort – Hematology – Lymphocytes ....................................................119 
Table 60: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Cohort – Hematology – Platelets ............................................................119 
Table 61: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Cohort – Hematology – Hemoglobin ......................................................120 
Table 62: Abnormal Laboratory Results Related to Study Treatment by Parameter, 
Maximum Severity, Time Point, and  Treatment Cohort – Any Hematology 
Parameter ..................................................................................................................123 
Table 63: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Cohort – Hematology – Hematocrit (%) ..................................................................125 
Table 64: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Cohort – Hematology – White Blood Cell Count (10^9/L) .....................................127 
Table 65: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Cohort – Hematology – Neutrophils (10^9/L) .........................................................127 
Table 66: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Cohort – Hematology – Lymphocytes (10^9/L) .......................................................127 
Table 67: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Cohort – Hematology – Monocytes (10^9/L) ...........................................................127 
Table 68: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Cohort – Hematology – Eosinophils (10^9/L) .........................................................127 
Table 69: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Cohort – Hematology – Basophils (10^9/L) .............................................................127 
Table 70: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Cohort – Hematology – Red Blood Cell Count (10^12/L) .......................................127 
Table 71: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Cohort – Hematology – Platelets (10^9/L) ...............................................................127 
Table 72: Laboratory Summary Statistics by Parameter, Time Point, Gender, and 
Treatment Cohort – Hematology – Hemoglobin (g/dL) ...........................................128 
Table 73: Laboratory Results by Parameter, Time Point, and Treatment Cohort – 
Hematology – Coombs Test .....................................................................................130 
Table 74: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Cohort – Coagulation – Any Coagulation Parameter ..............................131 


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Table 75: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Cohort – Coagulation – Prothrombin Time .............................................135 
Table 76: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Cohort – Coagulation – Partial Thromboplastin Time ............................135 
Table 77: Abnormal Laboratory Results Related to Study Treatment by Parameter, 
Maximum Severity, Time Point, and Treatment Cohort – Any Coagulation 
Parameter ..................................................................................................................136 
Table 78: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Cohort – Coagulation – Prothrombin Time (seconds) ..............................................138 
Table 79: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Cohort – Coagulation – Partial Thromboplastin Time (seconds) .............................139 
Table 80: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Cohort – Urinalysis – Any Urinalysis Parameter ....................................140 
Table 81: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Cohort – Urinalysis – Protein ..................................................................143 
Table 82: Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Cohort – Urinalysis – Glucose ................................................................143 
Table 83: Abnormal Laboratory Results Related to Study Treatment by Parameter, 
Maximum Severity, Time Point, and Treatment Cohort – Any Urinalysis 
Parameter ..................................................................................................................144 
Table 84: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Cohort – Urinalysis – Specific Gravity ....................................................................145 
Table 85: Laboratory Summary Statistics by Parameter, Time Point, and Treatment 
Cohort – Urinalysis – pH ..........................................................................................146 
Table 86: Laboratory Results by Parameter, Time Point, and Treatment Cohort – 
Urinalysis – Protein ..................................................................................................147 
Table 87: Laboratory Results by Parameter, Time Point, and Treatment Cohort – 
Urinalysis – Glucose .................................................................................................148 
Table 88: Laboratory Results by Parameter, Time Point, and Treatment Cohort – 
Urinalysis – Ketones .................................................................................................148 
Table 89: Laboratory Results by Parameter, Time Point, and Treatment Cohort – 
Urinalysis – Bilirubin ...............................................................................................148 
Table 90: Laboratory Results by Parameter, Time Point, and Treatment Cohort – 
Urinalysis – Blood ....................................................................................................148 
Table 91: Laboratory Results by Parameter, Time Point, and Treatment Cohort – 
Urinalysis – Nitrites ..................................................................................................148 
Table 92: Laboratory Results by Parameter, Time Point, and Treatment Cohort – 
Urinalysis – Leukocyte Esterase ...............................................................................148 


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Table 93: Laboratory Results by Parameter, Time Point, and Treatment Cohort – 
Urinalysis – Urobilinogen .........................................................................................149 
Table 94: Vital Signs by Assessment, Maximum Severity, Time Point, and Treatment 
Cohort – Any Assessment ........................................................................................150 
Table 95: Vital Signs by Assessment, Maximum Severity, Time Point, and Treatment 
Cohort – Pulse Rate ..................................................................................................154 
Table 96: Vital Signs by Assessment, Maximum Severity, Time Point, and Treatment 
Cohort – Systolic Blood Pressure .............................................................................156 
Table 97: Vital Signs by Assessment, Maximum Severity, Time Point, and Treatment 
Cohort – Diastolic Blood Pressure ...........................................................................157 
Table 98: Vital Signs by Assessment, Maximum Severity, Time Point, and Treatment 
Cohort – Oral Temperature .......................................................................................159 
Table 99: Vital Signs by Assessment, Maximum Severity, Time Point, and Treatment 
Cohort – Respiratory Rate ........................................................................................160 
Table 100: Vital Signs Summary Statistics by Assessment, Time Point, and Treatment 
Cohort – Pulse Rate (beats/minute) ..........................................................................162 
Table 101: Vital Signs Summary Statistics by Assessment, Time Point, and Treatment 
Cohort – Systolic Blood Pressure (mmHg) ..............................................................165 
Table 102: Vital Signs Summary Statistics by Assessment, Time Point, and Treatment 
Cohort – Diastolic Blood Pressure (mmHg) .............................................................165 
Table 103: Vital Signs Summary Statistics by Assessment, Time Point, and Treatment 
Cohort – Oral Temperature (°C) ...............................................................................165 
Table 104: Vital Signs Summary Statistics by Assessment, Time Point, and Treatment 
Cohort – Respiratory Rate (breaths/minute) .............................................................165 
Table 105: ECG Overall Interpretations Compared to Baseline by Post-Baseline Time 
Point and Treatment Cohort ......................................................................................166 
Table 106: ECG Results by Parameter, Severity, Time Point, and Treatment Cohort – 
QTcF/PR Interval ......................................................................................................167 
Table 107: ECG Summary Statistics by Parameter, Time Point, and Treatment Cohort ...........170 
Table 108: Number and Percentage of Subjects with Prior and Concurrent Medications 
by WHO Drug Classification and Treatment Cohort ...............................................172 
 


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9.1 
Overall Study Design and Plan Description 
Table 1: 
Treatment Cohorts 
Cohort 
Number 
Cohort Name 
No. of 
Subjects 
Treatment 
Cohort 1 
AVYCAZ IV 
8 
AVYCAZ® 2.5 g IV as 2-hour infusion every 8 hours for 7 days  
(19 total doses) 
Cohort 2 
AVYCAZ CI 
8 
AVYCAZ® 2.5 g IV as a 2-hour infusion x 1, then 0.32 g per hour IV daily as 
a Continuous Infusion (CI) (7.5 g/day) for 7 days (20 total doses, IV bag 
changes every 8 hours for CI) 
Cohort 3 
ATM IV 
8 
ATM 2 g IV as 2-hour infusion every 6 hours for 7 days  
(25 total doses) 
Cohort 4 
ATM CI 
8 
ATM 2 g IV as a 2-hour infusion x 1, then 0.33 g per hour IV daily as a CI 
(8 g/day) for 7 days (14 total doses, IV bag changes every 12 hours for CI) 
Cohort 5 
AVYCAZ IV 
+ ATM (1.5) 
IV 
8 
AVYCAZ® 2.5 g IV as 2-hour infusion every 8 hours for 7 days and ATM 
1.5 g IV as a 2-hour infusion every 6 hours for 7 days  
(AVYCAZ® 19 total doses; ATM 25 total doses) 
Cohort 6 
AVYCAZ IV 
+ ATM (2.0) 
IV 
8 
AVYCAZ® 2.5 g IV as a 2-hour infusion every 8 hours for 7 days and ATM 
2 g IV as a 2-hour infusion every 6 hours for 7 days  
(AVYCAZ® 19 total doses; ATM 25 total doses) 
 
 


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9.5.1 Efficacy/Immunogenicity and Safety Measurements Assessed and Flow Chart 
Table 2: 
Schedule of Study Procedures 
[Note: This table will be taken from the current version of the protocol at the time of the CSR.] 
 


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10.2 
Protocol Deviations 
Table 3: 
Distribution of Protocol Deviations by Category, Type, and Treatment Cohort 
Category 
Deviation Type 
Cohort 1 
(N=X) 
Cohort 2 
(N=X) 
Cohort 3 
(N=X) 
Cohort 4 
(N=X) 
Cohort 5 
(N=X) 
Cohort 6 
(N=X) 
All Subjects 
(N=X) 
No. of 
Subj. 
No. of 
Dev. 
No. of 
Subj. 
No. of 
Dev. 
No. of 
Subj. 
No. of 
Dev. 
No. of 
Subj. 
No. of 
Dev. 
No. of 
Subj. 
No. of 
Dev. 
No. of 
Subj. 
No. of 
Dev. 
No. of 
Subj. 
No. of 
Dev. 
Eligibility/enrollment 
Any type 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Did not meet inclusion criterion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Met exclusion criterion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Incorrect version of ICF signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ICF not signed prior to study 
procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment administration 
schedule 
Any type 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Out of window visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Missed visit/visit not conducted 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Missed treatment administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Delayed treatment administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Follow-up visit schedule 
Any type 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Out of window visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Missed visit/visit not conducted 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol procedure/assessment 
Any type 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood not collected 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine not collected 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Too few aliquots obtained 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Specimen result not obtained 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 3: Distribution of Protocol Deviations by Category, Type, and Treatment Cohort (continued) 
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Category 
Deviation Type 
Cohort 1 
(N=X) 
Cohort 2 
(N=X) 
Cohort 3 
(N=X) 
Cohort 4 
(N=X) 
Cohort 5 
(N=X) 
Cohort 6 
(N=X) 
All Subjects 
(N=X) 
No. of 
Subj. 
No. of 
Dev. 
No. of 
Subj. 
No. of 
Dev. 
No. of 
Subj. 
No. of 
Dev. 
No. of 
Subj. 
No. of 
Dev. 
No. of 
Subj. 
No. of 
Dev. 
No. of 
Subj. 
No. of 
Dev. 
No. of 
Subj. 
No. of 
Dev. 
 
Required procedure not conducted 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Required procedure done incorrectly 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study product temperature excursion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Specimen temperature excursion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment administration 
Any type 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Missed treatment administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Delayed treatment administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Required procedure done incorrectly 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study product temperature excursion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: N = Number of Subjects Enrolled 
 
 


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12.2.2 
Displays of Adverse Events 
Table 4: 
Adverse Event Definitions 
[Note: This table will be taken from the current version of the protocol at the time of the CSR.] 
 


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12.4.1 Individual Laboratory Measurements and Abnormal Laboratory Values 
Table 5: 
Laboratory and Vital Signs Reference Ranges, Eligibility Ranges, and Toxicity Grading 
[Note: This table will be taken from the current version of the protocol at the time of the CSR.] 
 


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14.1 
Description of Study Subjects 
14.1.1 Disposition of Subjects 
Table 6: 
Subject Disposition by Treatment Cohort – All Enrolled Subjects 
[Implementation Note: Blood Draws include hematology, chemistry, coagulation measurements that relate to the safety endpoints. Urine Collections 
include urine dipstick that relate to the safety endpoints.] 
Subject Disposition 
Cohort 1 
(N=X) 
Cohort 2 
(N=X) 
Cohort 3 
(N=X) 
Cohort 4 
(N=X) 
Cohort 5 
(N=X) 
Cohort 6 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Screened 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
x 
- 
Enrolled 
x 
100 
x 
100 
x 
100 
x 
100 
x 
100 
x 
100 
x 
100 
Started Treatment on Day 1 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Completed Treatment on Day 7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Completed Discharge on Day 8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Received All Scheduled Treatmentsa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Received Partial Dose of Study Product  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Completed All Safety Blood Drawsb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Completed All Safety Urine Collectionsb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Completed Follow-up (Study Day 11)a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: N = Number of Subjects Enrolled. n = Number of Subjects who fall into each category. 
a Refer to Listing 1 for reasons subjects discontinued or terminated early 
b Blood Draws and Urine Collections include all measurements that are related to the safety endpoints. 
 
 


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Table 7: 
Analysis Population Exclusions by Treatment Cohort – All Enrolled Subjects 
Analysis Populations 
Reason Subjects Excluded 
Cohort 1 
(N=X) 
Cohort 2 
(N=X) 
Cohort 3 
(N=X) 
Cohort 4 
(N=X) 
Cohort 5 
(N=X) 
Cohort 6 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Safety Population 
 Any Reason 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
 Did not receive any dose of study product(s) 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
PK Population 
Any Reason 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Did not receive any dose of study product(s) 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Did not have any quantifiable plasma or urine 
concentration of CAZ, AVI, or ATM 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Note: N = Number of Subjects Enrolled. n = Number of Subjects who were excluded for each reason. 
 
 


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Table 8: 
Dates of First Treatment by Treatment Cohort 
[Implementation Note: Dosing dates should be categorized monthly. For June 2019, month should start on 14JUN2019 instead of 01JUN2019 to account 
for study start date.] 
Dates of Dosing 
Cohort 1 
(N=X) 
Cohort 2 
(N=X) 
Cohort 3 
(N=X) 
Cohort 4 
(N=X) 
Cohort 5 
(N=X) 
Cohort 6 
(N=X) 
All Subjects 
(N=X) 
Total (Entire period of enrollment) 
x 
x 
x 
x 
x 
x 
x 
14JUN2019 – 30JUN2019 
x 
x 
x 
x 
x 
x 
x 
01JUL2019 – 31JUL2019 
 
 
 
 
 
 
 
01AUG2019 – 31AUG2019 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
Note: N = Number of Subjects in Safety Population 
 


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Table 9: 
Ineligibility Summary of Screen Failures 
[Implementation Note: Although all I/E criteria are included in the shell, only criteria that are reported as reasons for screen failures will be included.] 
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 
xx 
 
Provide a signed and dated written informed consent 
x 
xx 
 
Be able to understand and willing to comply with study procedures, restriction, and requirements, as determined by the PI 
x 
xx 
 
Males and females volunteer aged 18 to 45 inclusion 
x 
xx 
 
Suitable veins for cannulation or repeated venipuncture 
x 
xx 
 
Subject must be in good general health as judged by the investigator as determined by medical history, vital signs, body mass index (BMI) 
and body weight, clinical laboratory values, and physical examination (PE) 
x 
xx 
 
Sexually active female subjects must be of non-childbearing potential or must use a highly effective method of birth control 
x 
xx 
 
Sexually active male subjects must be vasectomized or agree to use barrier contraception (condom with spermicide) from first dose of study 
product until 30 days following last dose of study product 
x 
xx 
 
Nonsmokers defined as abstinence from cigarette smoking or use of nicotine-containing products for 6 months prior to enrollment into the 
study 
x 
xx 
Exclusion 
Any exclusion criterion 
x 
xx 
 
History of any clinically significant (CS) disease or disorder, medical/surgical procedure, or trauma within 4 weeks prior to the first 
administration of study product(s) 
x 
xx 
 
History or presence of gastrointestinal, hepatic, or renal disease, or any other condition known to interfere with absorption, distribution, 
metabolism, or excretion of drugs 
x 
xx 
 
Known history of a clinically important allergy/hypersensitivity to avibactam (AVI), any monobactam, any beta-lactam and/or L-arginine 
x 
xx 
 
Receipt of probenecid or furosemide within 14 days prior to study enrollment 
x 
xx 
 
Receipt of any antibiotics within 14 days prior to study enrollment 
x 
xx 
 
Receipt of prescription medication (except birth control pills or hormone replacement in females) within 14 days prior to study enrollment, 
unless in the opinion of site investigator the medication will not interfere with the study procedures or impact study safety 
x 
xx 
 
Receipt of non-antibiotic medications that interacts with OAT3 within 14 days prior to study enrollment 
x 
xx 
 
Receipt of herbal and dietary supplements (including St. John’s Wort) within 14 days prior to study enrollment 
x 
xx 
 
Alkaline transaminase (ALT) or aspartate aminotransferase (AST) laboratory value above the ULN as defined in Table 5 
x 
xx 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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Table 9: Ineligibility Summary of Screen Failures (continued) 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Inclusion/Exclusion Category 
Inclusion/Exclusion Criterion 
na 
%b 
 
Prolonged QTcF (> 450 msec) or shortened QTcF (< 340 msec) or family history of long QT syndrome.  Any clinically important 
abnormalities in rhythm, conduction, or morphology of resting ECG 
x 
xx 
 
Any positive result on screening for human immunodeficiency virus (HIV) serum hepatitis B surface antigen (HBsAg) and hepatitis C virus 
(HCV) antibody 
x 
xx 
 
Creatinine clearance equal or less than 80 mL/minute (measured by Cockcroft-Gault method) 
x 
xx 
 
History of Clostridium difficile infection in past 90 days 
x 
xx 
 
Known or suspected history of drug or alcohol abuse within the last 5 years, as judged by the PI 
x 
xx 
 
Positive screen for drugs of abuse, cotinine (nicotine), or alcohol at screening and at admission to the study site prior to the first 
administration of the study products(s) 
x 
xx 
 
Received a new chemical entity (compound not approved for marketing) or participated in a study that included drug treatment within 1 
month of the first dose of study product(s) for study 
x 
xx 
 
Previous participation in the present study 
x 
xx 
 
Involvement in the planning and/or conduct of the study 
x 
xx 
 
Any ongoing/recent (during screening) medical complaints that may interfere with analysis of study data or are considered unlikely to comply 
with study procedures, restrictions, and requirements 
x 
xx 
 
Known history of past or current epilepsy or seizure disorders, excluding febrile seizures of childhood 
x 
xx 
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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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
14.1.2 Demographic Data by Study Group 
Table 10: 
Summary of Categorical Demographic and Baseline Characteristics by Treatment Cohort 
Demographic 
Category 
Characteristic 
Cohort 1 
(N=X) 
Cohort 2 
(N=X) 
Cohort 3 
(N=X) 
Cohort 4 
(N=X) 
Cohort 5 
(N=X) 
Cohort 6 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Sex  
Male 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Female 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ethnicity  
Not Hispanic or Latino 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Hispanic or Latino 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Not Reported 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unknown 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Race  
American Indian or Alaska Native 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Asian 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Native Hawaiian or Other Pacific Islander 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Black or African American 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
White 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Multi-Racial 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unknown 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: N = Number of Subjects in Safety Population 
 
 


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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 11: 
Summary of Continuous Demographic and Baseline Characteristics by Treatment Cohort 
[Implementation Note: Use height and weight measurements from Day -1.] 
Variable 
Statistic 
Cohort 1 
(N=X) 
Cohort 2 
(N=X) 
Cohort 3 
(N=X) 
Cohort 4 
(N=X) 
Cohort 5 
(N=X) 
Cohort 6 
(N=X) 
All Subjects 
(N=X) 
Age 
Mean 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Standard Deviation 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
x 
x 
x 
x 
 
Maximum 
x 
x 
x 
x 
x 
x 
x 
BMI (kg/m2) 
Mean 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Standard Deviation 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Median 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Minimum 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Maximum 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Height (cm)a 
Mean 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Standard Deviation 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Median 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Minimum 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Maximum 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Weight (kg)a 
Mean 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Standard Deviation 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Median 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Minimum 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Maximum 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Notes: N = Number of Subjects in Safety Population; Age is rounded down to the nearest whole number; BMI = Weight (kg) / Height (m)2 
a The height and weight measurements from Day -1 were used for each subject. 
 


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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
14.1.3 Prior and Concurrent Medical Conditions 
Table 12: 
Summary of Subjects with Pre-Existing Medical Conditions by MedDRA System Organ Class and Treatment Cohort 
[Implementation Note: SOC will be ordered alphabetically.] 
MedDRA System Organ Class 
Cohort 1 
(N=X) 
Cohort 2 
(N=X) 
Cohort 3 
(N=X) 
Cohort 4 
(N=X) 
Cohort 5 
(N=X) 
Cohort 6 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any SOC 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[SOC 2] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: N = Number of Subjects in Safety Population; n = Number of Subjects reporting medical history within the specified SOC. A subject is only counted once per SOC; SOC = System Organ Class. 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
14.3 
Safety Data 
14.3.1 Displays of Adverse Events 
Table 13: 
Overall Summary of Adverse Events 
 
Cohort 1 
(N=X) 
Cohort 2 
(N=X) 
Cohort 3 
(N=X) 
Cohort 4 
(N=X) 
Cohort 5 
(N=X) 
Cohort 6 
(N=X) 
All Subjects 
(N=X) 
Subjectsa with 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
At least one AE 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
At least one related AE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At least one related Mild (Grade 1) AE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At least one related Moderate (Grade 2) AE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At least one related Severe (Grade 3) AE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At least one unrelated AE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At least one unrelated Mild (Grade 1) AE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At least one unrelated Moderate (Grade 2) AE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At least one unrelated Severe (Grade 3) AE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At least one AE leading to early termination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At least one SAEb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At least one related SAE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At least one SUSAR 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: N = Number of Subjects in Safety Population; SAE = Serious Adverse Event (Unsolicited); SUSAR = Suspected Unexpected Severe Adverse Reaction. 
a Subjects are counted once for each category regardless of the number of events. 
b A listing of SAEs is included in Table 18. 
 


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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 14: 
Number of Adverse Events Experienced by Subject and Severity 
[Implementation Note: Order by treatment cohort and descending total number of AEs reported.] 
Treatment Cohort 
Subject ID 
Number of Mild AEs 
Number of Moderate AEs 
Number of Severe AEs 
Total Number of AEs 
Cohort 1 
XX 
2 
0 
1 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 15: 
Adverse Events Occurring in 10% of Subjects in Any Treatment Cohort by MedDRA System Organ Class, Preferred Term, High 
Level Term, Relationship and Treatment Cohort 
[Implementation Note: SOC, PT, and HLT will be ordered alphabetically.] 
MedDRA 
System Organ 
Class 
MedDRA 
Preferred 
Term 
MedDRA High 
Level Term 
Cohort 1 
(N=X) 
Cohort 2 
(N=X) 
Cohort 3 
(N=X) 
Cohort 4 
(N=X) 
Cohort 5 
(N=X) 
Cohort 6 
(N=X) 
All Subjects 
(N=X) 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
Related 
Serious Adverse Events 
Any SOC 
Any PT 
Any HLT 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
[SOC 1] 
Any PT 
Any HLT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
Any HLT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[HLT 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc. 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other (Non-serious) Adverse Events 
Any SOC 
Any PT 
Any HLT 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
[SOC 1] 
Any PT 
Any HLT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
Any HLT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[HLT 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc. 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unrelated 
Serious Adverse Events 
Any SOC 
Any PT 
Any HLT 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
[SOC 1] 
Any PT 
Any HLT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
Any HLT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[HLT 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc. 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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Table 15: Adverse Events Occurring in 10% of Subjects in Any Treatment Cohort by MedDRA System Organ Class, Preferred Term, High Level Term, 
Relationship and Treatment Cohort (continued) 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
MedDRA 
System Organ 
Class 
MedDRA 
Preferred 
Term 
MedDRA High 
Level Term 
Cohort 1 
(N=X) 
Cohort 2 
(N=X) 
Cohort 3 
(N=X) 
Cohort 4 
(N=X) 
Cohort 5 
(N=X) 
Cohort 6 
(N=X) 
All Subjects 
(N=X) 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
Other (Non-serious) Adverse Events 
Any SOC 
Any PT 
Any HLT 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
[SOC 1] 
Any PT 
Any HLT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
Any HLT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[HLT 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc. 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: N = Number of Subjects in Safety Population. n = Number of Subjects Reporting Event. Events = Total Frequency of Events Reported. SOC = System Organ Class. PT = Preferred Term. HLT = 
High Level Term. 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 16: 
Adverse Events Occurring in 10% of Subjects in Any Treatment Cohort by MedDRA System Organ Class, Preferred Term, High 
Level Term, Relationship and Treatment 
[Implementation Note: SOC, PT, and HLT will be ordered alphabetically.] 
MedDRA 
System Organ Class 
MedDRA 
Preferred Term 
MedDRA 
High Level Term 
AVYCAZ 
(N=X) 
ATM 
(N=X) 
Combination 
(N=X) 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
Related 
Serious Adverse Events 
Any SOC 
Any PT 
Any HLT 
x 
x 
x 
x 
x 
x 
x 
x 
x 
[SOC 1] 
Any PT 
Any HLT 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
Any HLT 
 
 
 
 
 
 
 
 
 
 
 
[HLT 1] 
 
 
 
 
 
 
 
 
 
Etc. 
Etc. 
 
 
 
 
 
 
 
 
 
 
Other (Non-serious) Adverse Events 
Any SOC 
Any PT 
Any HLT 
x 
x 
x 
x 
x 
x 
x 
x 
x 
[SOC 1] 
Any PT 
Any HLT 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
Any HLT 
 
 
 
 
 
 
 
 
 
 
 
[HLT 1] 
 
 
 
 
 
 
 
 
 
Etc. 
Etc. 
 
 
 
 
 
 
 
 
 
 
Unrelated 
Serious Adverse Events 
Any SOC 
Any PT 
Any HLT 
x 
x 
x 
x 
x 
x 
x 
x 
x 
[SOC 1] 
Any PT 
Any HLT 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
Any HLT 
 
 
 
 
 
 
 
 
 
 
 
[HLT 1] 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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20JUL2020 
Table 16: Adverse Events Occurring in 10% of Subjects in Any Treatment Cohort by MedDRA System Organ Class, Preferred Term, High Level Term, 
Relationship and Treatment (continued) 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
MedDRA 
System Organ Class 
MedDRA 
Preferred Term 
MedDRA 
High Level Term 
AVYCAZ 
(N=X) 
ATM 
(N=X) 
Combination 
(N=X) 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
Other (Non-serious) Adverse Events 
Etc. 
Etc. 
 
 
 
 
 
 
 
 
 
 
Any SOC 
Any PT 
Any HLT 
x 
x 
x 
x 
x 
x 
x 
x 
x 
[SOC 1] 
Any PT 
Any HLT 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
Any HLT 
 
 
 
 
 
 
 
 
 
 
 
[HLT 1] 
 
 
 
 
 
 
 
 
 
Etc. 
Etc. 
 
 
 
 
 
 
 
 
 
 
Notes: N = Number of Subjects in Safety Population. n = Number of Subjects Reporting Event. Events = Total Frequency of Events Reported. SOC = System Organ Class. PT = Preferred Term. HLT = 
High Level Term. AVYCAZ = Cohort 1 and Cohort 2. ATM = Cohort 3 and Cohort 4. Combination = Cohort 5 and Cohort 6. 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
14.3.1.2 
Unsolicited Adverse Events 
Table 17: 
Number and Percentage of Subjects Experiencing Unsolicited Events with 95% 
Confidence Intervals by MedDRA System Organ Class, Preferred Term, High Level 
Term, and Treatment Cohort 
[Implementation Note: SOC, PT, and HLT will be ordered alphabetically.] 
MedDRA System Organ Class 
MedDRA Preferred Term 
 
Any Time Post Dose 
MedDRA High Level Term 
n 
% 
95% C.I.a 
Events 
All Subjects (N=X) 
Any SOC 
Any PT 
Any HLT 
x 
x 
(x, x) 
x 
[SOC 1] 
Any PT 
Any HLT 
x 
x 
(x, x) 
x 
 
[PT 1] 
Any HLT 
 
 
 
 
 
[PT 1] 
[HLT 1] 
 
 
 
 
Cohort 1 (N=X) 
Any SOC 
Any PT 
Any HLT 
x 
x 
(x, x) 
x 
[SOC 1] 
Any PT 
Any HLT 
x 
x 
(x, x) 
x 
 
[PT 1] 
Any HLT 
 
 
 
 
 
[PT 1] 
[HLT 1] 
 
 
 
 
Cohort 2 (N=X) 
Any SOC 
Any PT 
Any HLT 
x 
x 
(x, x) 
x 
[SOC 1] 
Any PT 
Any HLT 
x 
x 
(x, x) 
x 
 
[PT 1] 
Any HLT 
 
 
 
 
 
[PT 1] 
[HLT 1] 
 
 
 
 
Cohort 3 (N=X) 
Any SOC 
Any PT 
Any HLT 
x 
x 
(x, x) 
x 
[SOC 1] 
Any PT 
Any HLT 
x 
x 
(x, x) 
x 
 
[PT 1] 
Any HLT 
 
 
 
 
 
[PT 1] 
[HLT 1] 
 
 
 
 
Cohort 4 (N=X) 
Any SOC 
Any PT 
Any HLT 
x 
x 
(x, x) 
x 
[SOC 1] 
Any PT 
Any HLT 
x 
x 
(x, x) 
x 
 
[PT 1] 
Any HLT 
 
 
 
 
 
[PT 1] 
[HLT 1] 
 
 
 
 
Cohort 5 (N=X) 
Any SOC 
Any PT 
Any HLT 
x 
x 
(x, x) 
x 
[SOC 1] 
Any PT 
Any HLT 
x 
x 
(x, x) 
x 
 
[PT 1] 
Any HLT 
 
 
 
 
 
[PT 1] 
[HLT 1] 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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Table 17: Number and Percentage of Subjects Experiencing Unsolicited Events with 95% Confidence Intervals 
by MedDRA System Organ Class, Preferred Term, High Level Term, and Treatment Cohort (continued) 
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MedDRA System Organ Class 
MedDRA Preferred Term 
 
Any Time Post Dose 
MedDRA High Level Term 
n 
% 
95% C.I.a 
Events 
Cohort 6 (N=X) 
Any SOC 
Any PT 
Any HLT 
x 
x 
(x, x) 
x 
[SOC 1] 
Any PT 
Any HLT 
x 
x 
(x, x) 
x 
 
[PT 1] 
Any HLT 
 
 
 
 
 
[PT 1] 
[HLT 1] 
 
 
 
 
Notes: N = Number of Subjects in Safety Population; n = Number of Subjects Reporting Event; Events = Total Frequency of Events Reported; 
SOC = System Organ Class; PT = Preferred Term; HLT = High Level Term. 
This table presents number and percentages of subjects, as well as the number of events. A subject is only counted once per PT. 
a Calculated using the exact (Clopper-Pearson) method. 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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Table 18: 
Number and Percentage of Subjects Experiencing Unsolicited Events with 95% 
Confidence Intervals by MedDRA System Organ Class, Preferred Term, High Level 
Term, and Treatment 
[Implementation Note: SOC, PT, and HLT will be ordered alphabetically.] 
MedDRA System Organ Class 
MedDRA Preferred Term 
 
Any Time Post Dose 
MedDRA High Level Term 
n 
% 
95% C.I.a 
Events 
All Subjects (N=X) 
Any SOC 
Any PT 
Any HLT 
x 
x 
(x, x) 
x 
[SOC 1] 
Any PT 
Any HLT 
x 
x 
(x, x) 
x 
 
[PT 1] 
Any HLT 
 
 
 
 
 
[PT 1] 
[HLT 1] 
 
 
 
 
AVYCAZ (N=X) 
Any SOC 
Any PT 
Any HLT 
x 
x 
(x, x) 
x 
[SOC 1] 
Any PT 
Any HLT 
x 
x 
(x, x) 
x 
 
[PT 1] 
Any HLT 
 
 
 
 
 
[PT 1] 
[HLT 1] 
 
 
 
 
ATM (N=X) 
Any SOC 
Any PT 
Any HLT 
x 
x 
(x, x) 
x 
[SOC 1] 
Any PT 
Any HLT 
x 
x 
(x, x) 
x 
 
[PT 1] 
Any HLT 
 
 
 
 
 
[PT 1] 
[HLT 1] 
 
 
 
 
Combination (N=X) 
Any SOC 
Any PT 
Any HLT 
x 
x 
(x, x) 
x 
[SOC 1] 
Any PT 
Any HLT 
x 
x 
(x, x) 
x 
 
[PT 1] 
Any HLT 
 
 
 
 
 
[PT 1] 
[HLT 1] 
 
 
 
 
Notes: N = Number of Subjects in Safety Population; n = Number of Subjects Reporting Event; Events = Total Frequency of Events Reported; 
SOC = System Organ Class; PT = Preferred Term; HLT = High Level Term. AVYCAZ = Cohort 1 and Cohort 2. ATM = Cohort 3 and Cohort 
4. Combination = Cohort 5 and Cohort 6. 
This table presents number and percentages of subjects, as well as the number of events. A subject is only counted once per PT. 
a Calculated using the exact (Clopper-Pearson) method. 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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Table 19: 
Unsolicited Adverse Events by MedDRA System Organ Class, Preferred Term, and High 
Level Term, Maximum Severity, Relationship, and Treatment Cohort 
[Implementation Note: SOC, PT, and HLT will be ordered alphabetically. Rows for Mild, Moderate, and 
Severe will only be shown for non-zero counts.] 
MedDRA System 
Organ Class 
MedDRA Preferred 
Term 
MedDRA High 
Level Term 
Severity 
Related 
Not Related 
Total 
n 
% 
n 
% 
n 
% 
All Subjects (N=X) 
Any SOC 
Any PT 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
[SOC 1] 
Any PT 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
 
[PT 1] 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
Cohort 1 (N=X) 
Any SOC 
Any PT 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
[SOC 1] 
Any PT 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
 
[PT 1] 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
Cohort 2 (N=X) 
Any SOC 
Any PT 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 17: Unsolicited Adverse Events by MedDRA System Organ Class, Preferred Term, and High Level Term, 
Maximum Severity, Relationship, and Treatment Cohort (continued) 
- 62 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
MedDRA System 
Organ Class 
MedDRA Preferred 
Term 
MedDRA High 
Level Term 
Severity 
Related 
Not Related 
Total 
n 
% 
n 
% 
n 
% 
[SOC 1] 
Any PT 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
 
[PT 1] 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
Cohort 3 (N=X) 
Any SOC 
Any PT 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
[SOC 1] 
Any PT 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
 
[PT 1] 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
Cohort 4 (N=X) 
Any SOC 
Any PT 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
[SOC 1] 
Any PT 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
 
[PT 1] 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 17: Unsolicited Adverse Events by MedDRA System Organ Class, Preferred Term, and High Level Term, 
Maximum Severity, Relationship, and Treatment Cohort (continued) 
- 63 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
MedDRA System 
Organ Class 
MedDRA Preferred 
Term 
MedDRA High 
Level Term 
Severity 
Related 
Not Related 
Total 
n 
% 
n 
% 
n 
% 
Cohort 5 (N=X) 
Any SOC 
Any PT 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
[SOC 1] 
Any PT 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
 
[PT 1] 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
Cohort 6 (N=X) 
Any SOC 
Any PT 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
[SOC 1] 
Any PT 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
 
[PT 1] 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
Notes: N = Number of Subjects in Safety Population; SOC = System Organ Class; PT = Preferred Term; HLT = High Level Term. A subject is 
only counted once per PT/severity. 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 20: 
Unsolicited Adverse Events by MedDRA System Organ Class, Preferred Term, and High 
Level Term, Maximum Severity, Relationship, and Treatment 
[Implementation Note: SOC, PT, and HLT will be ordered alphabetically. Rows for Mild, Moderate, and 
Severe will only be shown for non-zero counts.] 
MedDRA System 
Organ Class 
MedDRA Preferred 
Term 
MedDRA High 
Level Term 
Severity 
Related 
Not Related 
Total 
n 
% 
n 
% 
n 
% 
All Subjects (N=X) 
Any SOC 
Any PT 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
[SOC 1] 
Any PT 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
 
[PT 1] 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
AVYCAZ (N=X) 
Any SOC 
Any PT 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
[SOC 1] 
Any PT 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
 
[PT 1] 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
ATM (N=X) 
Any SOC 
Any PT 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 20: Unsolicited Adverse Events by MedDRA System Organ Class, Preferred Term, and High Level Term, 
Maximum Severity, Relationship, and Treatment (continued) 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
MedDRA System 
Organ Class 
MedDRA Preferred 
Term 
MedDRA High 
Level Term 
Severity 
Related 
Not Related 
Total 
n 
% 
n 
% 
n 
% 
[SOC 1] 
Any PT 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
 
[PT 1] 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
Combination (N=X) 
Any SOC 
Any PT 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
[SOC 1] 
Any PT 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
 
[PT 1] 
Any HLT 
Any Severity 
x 
x 
x 
x 
x 
x 
 
 
Mild 
x 
x 
x 
x 
x 
x 
 
 
Moderate 
x 
x 
x 
x 
x 
x 
 
 
Severe 
x 
x 
x 
x 
x 
x 
Notes: N = Number of Subjects in Safety Population; SOC = System Organ Class; PT = Preferred Term; HLT = High Level Term. A subject is 
only counted once per PT/severity. AVYCAZ = Cohort 1 and Cohort 2. ATM = Cohort 3 and Cohort 4. Combination = Cohort 5 and Cohort 6. 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
14.3.2 Listing of Deaths and Other Serious Adverse Events 
Table 21: 
Listing of Serious Adverse Events 
Adverse 
Event 
MedDRA 
System 
Organ 
Class 
MedDRA 
Preferred 
Term 
MedDRA 
High 
Level 
Term 
Associated 
with Dose 
No. 
No. of Days 
Post 
Associated 
Dose 
(Duration) 
No. of 
Days 
Post 
Dose the 
Event 
Became 
Serious 
Reason 
Reported 
as an 
SAE 
Severity 
Relationship 
to Study 
Treatment 
If Not 
Related, 
Alternative 
Etiology 
Action 
Taken with 
Study 
Treatment 
Subject 
Discontinued 
Due to AE 
Outcome 
Is the 
Event a 
SUSAR? 
Subject ID: , Treatment Cohort: , AE Number: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
Subject ID: , Treatment Cohort: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 22: 
Listing of Non-Serious, Unsolicited, Moderate or Severe Adverse Events 
[Implementation Note: Sort by Relatedness (related then unrelated), Treatment Cohort, Subject ID.] 
Adverse 
Event 
MedDRA 
System 
Organ Class 
MedDRA 
Preferred 
Term 
MedDRA 
High Level 
Term 
Associated 
with Dose 
No. 
No. of Days 
Post 
Associated 
Dose 
(Duration) 
Severity 
Relationship 
to Study 
Treatment 
If Not 
Related, 
Alternative 
Etiology 
Action 
Taken with 
Study 
Treatment 
Subject 
Discontinued 
Due to AE 
Outcome 
Subject ID: , Treatment Cohort: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
Subject ID: , Treatment Cohort: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
14.3.3 Narratives of Deaths and Other Serious Adverse Events 
Not included in SAP, but this is a placeholder for the CSR. 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
14.3.4 Abnormal Laboratory Value Listings (by Subject) 
Table 23: 
Listing of Abnormal Laboratory Results – Chemistry 
[Implementation Note: This table will report all lab results that are outside the reference range, including results that are not graded.] 
Subject 
ID 
Treatment Cohort 
Sex 
Age (years) 
Planned Study Day 
Actual Study Day 
Laboratory 
Parameter 
(Units) 
Result (Severity) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 24: 
Listing of Abnormal Laboratory Results – Hematology 
[Implementation Note: This table will report all lab results that are outside the reference range, including results that are not graded.] 
Subject 
ID 
Treatment Cohort 
Sex 
Age (years) 
Planned Study Day 
Actual Study Day 
Laboratory 
Parameter 
(Units) 
Result (Severity) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 25: 
Listing of Abnormal Laboratory Results – Coagulation 
[Implementation Note: This table will report all lab results that are outside the reference range, including results that are not graded.] 
Subject 
ID 
Treatment Cohort 
Sex 
Age (years) 
Planned Study Day 
Actual Study Day 
Laboratory 
Parameter 
(Units) 
Result (Severity) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 26: 
Listing of Abnormal Laboratory Results – Urinalysis 
[Implementation Note: This table will report all lab results that are outside the reference range, including results that are not graded.] 
Subject 
ID 
Treatment Cohort 
Sex 
Age (years) 
Planned Study Day 
Actual Study Day 
Laboratory 
Parameter 
(Units) 
Result (Severity) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
14.3.5 Displays of Laboratory Results 
14.3.5.1 
Chemistry Results 
Table 27: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Any Chemistry 
Parameter 
[Implementation Note: Only includes chemistry parameters that have gradings (Sodium, Potassium, BUN, Serum Creatinine, Fasting Glucose, Non-
Fasting (Unknown) Glucose, Total Protein, Total Bilirubin, ALT, AST, and ALP). If no results are missing for any time point, then this column can be 
removed from the table. If there are no results that meet the criteria for “Outside Normal Range”, then this column and corresponding footnote can be 
removed from the table. Day 5 and 7 are only applicable to Cohorts 5 and 6; ALT, AST, ALP, and total bilirubin.] 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 2 
All Subjects (N=X) 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Missing 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Missing 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 27: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Any Chemistry Parameter (continued) 
- 74 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Missing 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Missing 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Missing 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Missing 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 27: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Any Chemistry Parameter (continued) 
- 75 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Missing 
 
 
 
 
 
 
 
 
 
 
 
 
Day 4 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 27: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Any Chemistry Parameter (continued) 
- 76 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Day 5 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Day 6 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 27: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Any Chemistry Parameter (continued) 
- 77 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Day 7 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Day 8 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 27: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Any Chemistry Parameter (continued) 
- 78 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
Cohort 4 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Day 11 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 27: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Any Chemistry Parameter (continued) 
- 79 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Early Termination Visit 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 27: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Any Chemistry Parameter (continued) 
- 80 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Max Severity Post Baseline All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 27: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Any Chemistry Parameter (continued) 
- 81 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outside Normal Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: N = Number of Subjects in Safety Population. n = Number of Subjects who experience each AE grading. Baseline = Measurements from Day -1. The “Max Post Baseline” rows indicate the 
maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments. Only includes Chemistry parameters that have a grading provided: sodium, potassium, 
BUN, serum creatinine, fasting glucose, non-fasting (unknown) glucose, total protein, total bilirubin, ALT, AST, and ALP 
a Measurements that were outside the normal range but did not meet the definition for an AE will be categorized as “Outside Normal Range”. 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
- 82 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 28: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Sodium 
[Implementation Note: If no results are missing for any subject at any time point, then this column can be removed from the table.] 
Time Point 
Treatment Cohort 
Baseline 
Severity 
Post-Baseline Severity 
None 
Mild/ 
Grade 1 
(Low) 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 2 
All Subjects (N=X) 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
 
Mild (Low) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild (High) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate (Low) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate (High) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe (Low) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe (High) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Missing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild (Low) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild (Low) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 4 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild (Low) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild (Low) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 28: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Sodium (continued) 
- 83 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
Baseline 
Severity 
Post-Baseline Severity 
None 
Mild/ 
Grade 1 
(Low) 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild (Low) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 6 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild (Low) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild (Low) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild (Low) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 8 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild (Low) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild (Low) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild (Low) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 28: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Sodium (continued) 
- 84 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
Baseline 
Severity 
Post-Baseline Severity 
None 
Mild/ 
Grade 1 
(Low) 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 11 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild (Low) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild (Low) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild (Low) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Early Termination Visit 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild (Low) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild (Low) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild (Low) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 28: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Sodium (continued) 
- 85 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
Baseline 
Severity 
Post-Baseline Severity 
None 
Mild/ 
Grade 1 
(Low) 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Max Severity Post Baseline 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild (Low) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild (Low) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild (Low) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: N = Number of Subjects in Safety Population. n = Number of Subjects who experience each AE grading. Baseline = Measurement from Day -1. The “Max Post Baseline” rows indicate the 
maximum severity experienced by each subject at any time point past baseline, including unscheduled assessments. 
 
Tables with similar format: 
Table 29: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Potassium 
Table 30: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Fasting Glucose 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 31: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Non-Fasting Glucose 
[Implementation Note: If no results are missing for any subject at any time point, then this column can be removed from the table.] 
Time Point 
Treatment Cohort 
Baseline 
Severity 
Post-Baseline Severity 
None 
Mild/ 
Grade 1 
(Low) 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 2 
All Subjects (N=X) 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 4 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 6 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 31: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Non-Fasting Glucose (continued) 
- 87 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
Baseline 
Severity 
Post-Baseline Severity 
None 
Mild/ 
Grade 1 
(Low) 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 8 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 11 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Early Termination Visit 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Max Severity Post 
Baseline 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 31: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Non-Fasting Glucose (continued) 
- 88 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
Baseline 
Severity 
Post-Baseline Severity 
None 
Mild/ 
Grade 1 
(Low) 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: N = Number of Subjects in Safety Population. n = Number of Subjects who experience each AE grading. Baseline = Measurements from Day -1. The “Max Post Baseline” rows indicate the 
maximum severity experienced by each subject at any time point past baseline, including unscheduled assessments. Unknown Glucose status was reported as Non-Fasting Glucose. 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
- 89 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 32: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Blood Urea Nitrogen 
[If no results are missing for any subjects at any time point, then this column can be removed from the table. If there are no results that meet the criteria 
for “Outside Normal Range”, then this column and corresponding footnote can be removed from the table. Tables 34, 35, and 36 will have entries for 
Day 5 and 7 for cohorts 5 and 6.] 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 2 
All Subjects (N=X) 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 4 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 6 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 32: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Blood Urea Nitrogen (continued) 
- 90 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 8 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 11 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Early Termination Visit 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Max Severity Post Baseline 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 32: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Blood Urea Nitrogen (continued) 
- 91 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: N = Number of Subjects in Safety Population. n = Number of Subjects who experience each AE grading. Baseline = Measurements from Day -1. The “Max Post Baseline” rows indicate the 
maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments. 
a Measurements that were outside the normal range but did not meet the definition for an AE will be categorized as “Outside Normal Range”. 
 
Tables with similar format: 
Table 33: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Serum Creatinine 
Table 34: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Total Bilirubin 
Table 35: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Aspartate 
Aminotransferase 
Table 36: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Alkaline Phosphatase 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
- 92 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 37: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Alanine 
Aminotransferase 
[If no results are missing for any subjects at any time point, then this column can be removed from the table. If there are no results that meet the criteria 
for “Outside Normal Range”, then this column and corresponding footnote can be removed from the table. Days 5 and 7 are only applicable to cohorts 5 
and 6.] 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1  
(High) 
Moderate/ 
Grade 2  
(High) 
Severe/ 
Grade 3  
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 2 
All Subjects (N=X) 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 4 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 5 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 37: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Alanine Aminotransferase (continued) 
- 93 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1  
(High) 
Moderate/ 
Grade 2  
(High) 
Severe/ 
Grade 3  
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 6 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 7 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Day 8 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 11 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 37: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Alanine Aminotransferase (continued) 
- 94 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1  
(High) 
Moderate/ 
Grade 2  
(High) 
Severe/ 
Grade 3  
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Early Termination Visit 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Max Severity Post 
Baseline 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: N = Number of Subjects in Safety Population. n = Number of Subjects who experience each AE grading. Baseline = Measurements from Day -1. The “Max Post Baseline” rows indicate the 
maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments. 
a Measurements that were outside the normal range but did not meet the definition for an AE will be categorized as “Outside Normal Range”. 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 38: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Total Protein 
[If no results are missing for any subjects at any time point, then this column can be removed from the table. If there are no results that meet the criteria 
for “Outside Normal Range”, then this column and corresponding footnote can be removed from the table.] 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
(Low) 
Moderate/ 
Grade 2 
(Low) 
Severe/ 
Grade 3 
(Low) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 2 
All Subjects (N=X) 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 4 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 6 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 38: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Total Protein (continued) 
- 96 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
(Low) 
Moderate/ 
Grade 2 
(Low) 
Severe/ 
Grade 3 
(Low) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 8 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 11 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Early Termination Visit 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 38: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Chemistry – Total Protein (continued) 
- 97 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
(Low) 
Moderate/ 
Grade 2 
(Low) 
Severe/ 
Grade 3 
(Low) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Max Severity Post Baseline 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: N = Number of Subjects in Safety Population. n = Number of Subjects who experience each AE grading. Baseline = Measurements from Day -1. The “Max Post Baseline” rows indicate the 
maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments. 
a Measurements that were outside the normal range but did not meet the definition for an AE will be categorized as “Outside Normal Range”. 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
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Table 39: 
Abnormal Laboratory Results Related to Study Treatment by Parameter, Maximum Severity, Time Point, and Treatment Cohort 
– Any Chemistry Parameter 
[Implementation Note: Only includes chemistry parameters that have gradings (Sodium, Potassium, BUN, Serum Creatinine, Fasting Glucose, Non-
Fasting (Unknown) Glucose, Total Protein, Total Bilirubin, ALT, AST, and ALP). If there are no results that meet the criteria for “Outside Normal 
Range”, then this column and corresponding footnote can be removed from the table. Days 5 and 7 are only applicable to Cohorts 5 and 6.] 
Time Point 
Treatment Cohort 
N 
Outside Normal Rangea 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
n 
% 
n 
% 
n 
% 
n 
% 
Day 2 
All Subjects 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Day 4 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Day 5 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
Day 6 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Day 7 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
Day 8 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
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Table 39: Abnormal Laboratory Results Related to Study Treatment by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Any 
Chemistry Parameter (continued) 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
N 
Outside Normal Rangea 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
n 
% 
n 
% 
n 
% 
n 
% 
Day 11 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Early Termination Visit 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Max Severity Post Baseline 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Notes: N = Number of Subjects in Safety Population. n = Number of Subjects who experience each AE grading. The “Max Post Baseline” rows indicate the maximum severity of abnormal laboratory 
results related to study treatment experienced by each subject at any time point post baseline, including unscheduled assessments. Only includes Chemistry parameters that have a grading provided: 
sodium, potassium, BUN, serum creatinine, fasting glucose, non-fasting (unknown) glucose, total protein, total bilirubin, ALT, AST, and ALP. 
a Measurements that were outside the normal range but did not meet the definition for an AE will be categorized as “Outside Normal Range”. 
 
 
 


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Table 40: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Chemistry – Sodium (mEq/L) 
[Implementation Note: Min and Max will be reported using the minimum number of significant figures of what is collected. Mean, Std. Dev., and 
Median will be reported using the maximum number of significant figures + 1 of what is collected. For example, sodium is reported as XX, so the Min 
and Max will be reported as XX, and Mean, Std. Dev., and Median will be reported as XX.X. This applies to all the lab tables (Chemistry, Hematology, 
Coagulation, and Urinalysis). Tables 51, 52, and 53 will have rows for Days 5 and 7 applicable to Cohorts 5 and 6 only.] 
 
 
 
Measurement 
Change from Baseline 
Time Point 
Treatment Cohort 
N 
Mean 
Std. Dev. 
Median 
Min, Max 
Mean 
Std. Dev. 
Median 
Min, Max 
Baseline 
All Subjects 
x 
xx.x 
xx.x 
xx.x 
xx, xx 
- 
- 
- 
- 
 
Cohort 1 
x 
xx.x 
xx.x 
xx.x 
xx, xx 
- 
- 
- 
- 
 
Cohort 2 
x 
xx.x 
xx.x 
xx.x 
xx, xx 
- 
- 
- 
- 
 
Cohort 3 
x 
xx.x 
xx.x 
xx.x 
xx, xx 
- 
- 
- 
- 
 
Cohort 4 
x 
xx.x 
xx.x 
xx.x 
xx, xx 
- 
- 
- 
- 
 
Cohort 5 
x 
xx.x 
xx.x 
xx.x 
xx, xx 
- 
- 
- 
- 
 
Cohort 6 
x 
xx.x 
xx.x 
xx.x 
xx, xx 
- 
- 
- 
- 
Day 2 
All Subjects 
x 
xx.x 
xx.x 
xx.x 
xx, xx 
xx.x 
xx.x 
xx.x 
xx, xx 
 
Cohort 1 
x 
xx.x 
xx.x 
xx.x 
xx, xx 
xx.x 
xx.x 
xx.x 
xx, xx 
 
Cohort 2 
x 
xx.x 
xx.x 
xx.x 
xx, xx 
xx.x 
xx.x 
xx.x 
xx, xx 
 
Cohort 3 
x 
xx.x 
xx.x 
xx.x 
xx, xx 
xx.x 
xx.x 
xx.x 
xx, xx 
 
Cohort 4 
x 
xx.x 
xx.x 
xx.x 
xx, xx 
xx.x 
xx.x 
xx.x 
xx, xx 
 
Cohort 5 
x 
xx.x 
xx.x 
xx.x 
xx, xx 
xx.x 
xx.x 
xx.x 
xx, xx 
 
Cohort 6 
x 
xx.x 
xx.x 
xx.x 
xx, xx 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
Day 4 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 40: Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Chemistry – Sodium (mEq/L) (continued) 
- 101 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
 
 
 
Measurement 
Change from Baseline 
Time Point 
Treatment Cohort 
N 
Mean 
Std. Dev. 
Median 
Min, Max 
Mean 
Std. Dev. 
Median 
Min, Max 
Day 6 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
Day 8 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
Day 11 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
Note: N = Number of Subjects in Safety Population with the laboratory result assessed at the respective time point. Baseline = Measurements from Day -1. 
 
 


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Tables with similar format: 
Table 41: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Chemistry – Potassium (mEq/L) 
Table 42: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Chemistry – Chloride (mmol/L) 
Table 43: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Chemistry – Bicarbonate (mmol/L) 
Table 44: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Chemistry – Blood Urea Nitrogen (mg/dL) 
Table 45: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Chemistry – Serum Creatinine (mg/dL) 
Table 46: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Chemistry – Fasting Glucose (mg/dL) 
Table 47: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Chemistry – Non-Fasting Glucose (mg/dL) 
Table 48: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Chemistry – Total Protein (g/dL) 
Table 49: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Chemistry – Lactate Dehydrogenase (U/L) 
Table 50: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Chemistry – Albumin (g/dL) 
Table 51: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Chemistry – Total Bilirubin (mg/dL) 
Table 52: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Chemistry – Aspartate Aminotransferase 
(U/L) 
Table 53: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Chemistry – Alkaline Phosphatase (U/L) 
 
 


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Table 54: 
Laboratory Summary Statistics by Parameter, Time Point, Gender, and Treatment Cohort – Chemistry – Alanine 
Aminotransferase (U/L) 
[Implementation Note: Days 5 and 7 are applicable to Cohorts 5 and 6 only.] 
 
 
 
 
Measurement 
Change from Baseline 
Time Point 
Gender 
Treatment Cohort 
N 
Mean 
Std. Dev. 
Median 
Min, Max 
Mean 
Std. Dev. 
Median 
Min, Max 
Baseline 
Male 
All Subjects 
x 
xx.x 
xx.x 
xx.x 
xx, xx 
- 
- 
- 
- 
 
 
Cohort 1 
x 
xx.x 
xx.x 
xx.x 
xx, xx 
- 
- 
- 
- 
 
 
Cohort 2 
 
 
 
 
 
- 
- 
- 
- 
 
 
… 
 
 
 
 
 
- 
- 
- 
- 
 
Female 
All Subjects 
x 
xx.x 
xx.x 
xx.x 
xx, xx 
- 
- 
- 
- 
 
 
Cohort 1 
x 
xx.x 
xx.x 
xx.x 
xx, xx 
- 
- 
- 
- 
 
 
Cohort 2 
 
 
 
 
 
- 
- 
- 
- 
 
 
… 
 
 
 
 
 
- 
- 
- 
- 
Day 2 
Male 
All Subjects 
x 
xx.x 
xx.x 
xx.x 
xx, xx 
xx.x 
xx.x 
xx.x 
xx, xx 
 
 
Cohort 1 
x 
xx.x 
xx.x 
xx.x 
xx, xx 
xx.x 
xx.x 
xx.x 
xx, xx 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
Female 
All Subjects 
x 
xx.x 
xx.x 
xx.x 
xx, xx 
xx.x 
xx.x 
xx.x 
xx, xx 
 
 
Cohort 1 
x 
xx.x 
xx.x 
xx.x 
xx, xx 
xx.x 
xx.x 
xx.x 
xx, xx 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Day 4 
Male 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
Female 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 54: Laboratory Summary Statistics by Parameter, Time Point, Gender, and Treatment Cohort – Chemistry – Alanine Aminotransferase (U/L) 
(continued) 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
 
 
 
 
Measurement 
Change from Baseline 
Time Point 
Gender 
Treatment Cohort 
N 
Mean 
Std. Dev. 
Median 
Min, Max 
Mean 
Std. Dev. 
Median 
Min, Max 
Day 5 
Male 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
 
Female 
All subjects 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
Day 6 
Male 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
Female 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Day 7 
Male 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
 
Female 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
Day 8 
Male 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 54: Laboratory Summary Statistics by Parameter, Time Point, Gender, and Treatment Cohort – Chemistry – Alanine Aminotransferase (U/L) 
(continued) 
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Measurement 
Change from Baseline 
Time Point 
Gender 
Treatment Cohort 
N 
Mean 
Std. Dev. 
Median 
Min, Max 
Mean 
Std. Dev. 
Median 
Min, Max 
 
Female 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Day 11 
Male 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
Female 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Note: N = Number of Subjects in Safety Population with the laboratory result assessed at the respective time point. Baseline = Measurements from Day -1. 
 
 


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14.3.5.2 
Hematology Results 
Table 55: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Hematology – Any Hematology 
Parameter 
[Implementation Note: Only include hematology parameters that are graded (hemoglobin, WBC, neutrophils, lymphocytes, eosinophils, and platelets). If 
no results are missing for any time point, then this column can be removed from the table. If there are no results that meet the criteria for “Outside 
Normal Range”, then this column and corresponding footnote can be removed from the table.] 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 2 
All Subjects (N=X) 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Day 4 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
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Table 55: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Hematology – Any Hematology Parameter (U/L) 
(continued) 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Day 6 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
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Table 55: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Hematology – Any Hematology Parameter (U/L) 
(continued) 
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Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Day 8 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Day 11 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
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Table 55: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Hematology – Any Hematology Parameter (U/L) 
(continued) 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
Cohort 3 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Early Termination Visit 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 55: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Hematology – Any Hematology Parameter (U/L) 
(continued) 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Max Severity Post Baseline 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: N = Number of Subjects in Safety Population. n = Number of Subjects who experience each AE grading. Baseline = Measurements from Day -1. The “Max Post Baseline” rows indicate the 
maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments. Only includes Hematology parameters that have a grading provided: hemoglobin, 
WBC, neutrophils, lymphocytes, eosinophils, and platelets. 
a Measurements that were outside the normal range but did not meet the definition for an AE will be categorized as “Outside Normal Range”. 
 


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Table 56: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Hematology – White Blood Cell 
Count 
[Implementation Note: If no results are missing for any time point, then this column can be removed from the table.] 
Time Point 
Treatment Cohort 
Baseline 
Severity 
Post-Baseline Severity 
None 
Mild/ 
Grade 1 
(Low) 
Mild 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 2 
All Subjects (N=X) 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 4 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 6 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 56: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Hematology – White Blood Cell Count (continued) 
- 112 - 
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Time Point 
Treatment Cohort 
Baseline 
Severity 
Post-Baseline Severity 
None 
Mild/ 
Grade 1 
(Low) 
Mild 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 8 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 11 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Early Termination Visit 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 56: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Hematology – White Blood Cell Count (continued) 
- 113 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
Baseline 
Severity 
Post-Baseline Severity 
None 
Mild/ 
Grade 1 
(Low) 
Mild 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Max Severity Post Baseline All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: N = Number of Subjects in Safety Population. n = Number of Subjects who experience each AE grading. Baseline = Measurements from Day -1. The “Max Post Baseline” rows indicate the 
maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments. 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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Table 57: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Hematology – Eosinophils 
[Implementation Note: If no results are missing for any time point, then this column can be removed from the table. If there are no results that meet the 
criteria for “Outside Normal Range”, then this column and corresponding footnote can be removed from the table.] 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 2 
All Subjects (N=X) 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 4 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 6 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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Table 57: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Hematology – Eosinophils (continued) 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 8 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 11 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Early Termination Visit 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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20JUL2020 
Table 57: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Hematology – Eosinophils (continued) 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Max Severity Post Baseline 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: N = Number of Subjects in Safety Population. n = Number of Subjects who experience each AE grading. Baseline = Measurements from Day -1. The “Max Post Baseline” rows indicate the 
maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments. 
a Measurements that were outside the normal range but did not meet the definition for an AE will be categorized as “Outside Normal Range”. 
 
 


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Table 58: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Hematology – Neutrophils 
[Implementation Note: If no results are missing for any time point, then this column can be removed from the table. If there are no results that meet the 
criteria for “Outside Normal Range”, then this column and corresponding footnote can be removed from the table.] 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
(Low) 
Moderate/ 
Grade 2 
(Low) 
Severe/ 
Grade 3 
(Low) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 2 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 4 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 6 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 58: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Hematology – Neutrophils (continued) 
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Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
(Low) 
Moderate/ 
Grade 2 
(Low) 
Severe/ 
Grade 3 
(Low) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 8 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 11 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Early Termination Visit 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 58: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Hematology – Neutrophils (continued) 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
(Low) 
Moderate/ 
Grade 2 
(Low) 
Severe/ 
Grade 3 
(Low) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Max Severity Post Baseline 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: N = Number of Subjects in Safety Population. n = Number of Subjects who experience each AE grading. Baseline = Measurements from Day -1. The “Max Post Baseline” rows indicate the 
maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments. 
a Measurements that were outside the normal range but did not meet the definition for an AE will be categorized as “Outside Normal Range”. 
 
Tables with similar format: 
Table 59: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Hematology – Lymphocytes 
Table 60: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Hematology – Platelets 
 
 


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Table 61: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Hematology – Hemoglobin 
[Implementation Note: If no results are missing for any time point, then this column can be removed from the table. If there are no results that meet the 
criteria for “Outside Normal Range”, then these columns and corresponding footnote can be removed from the table.] 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1  
(Low) 
Moderate/ 
Grade 2  
(Low) 
Severe/ 
Grade 3 
(Low) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 2 
All Subjects (N=X) 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 4 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 6 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 61: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Hematology – Hemoglobin (continued) 
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Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1  
(Low) 
Moderate/ 
Grade 2  
(Low) 
Severe/ 
Grade 3 
(Low) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 8 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 11 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Early Termination Visit 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 61: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Hematology – Hemoglobin (continued) 
- 122 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1  
(Low) 
Moderate/ 
Grade 2  
(Low) 
Severe/ 
Grade 3 
(Low) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Max Severity Post Baseline 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: N = Number of Subjects in Safety Population. n = Number of Subjects who experience each AE grading. Baseline = Measurements from Day -1. The “Max Post Baseline” rows indicate the 
maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments. 
a Measurements that were outside the normal range but did not meet the definition for an AE will be categorized as “Outside Normal Range”. 
 
 


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Table 62: 
Abnormal Laboratory Results Related to Study Treatment by Parameter, Maximum Severity, Time Point, and  
Treatment Cohort – Any Hematology Parameter 
[Implementation Note: Only include hematology parameters that are graded (hemoglobin, WBC, neutrophils, lymphocytes, eosinophils, and platelets). If 
there are no results that meet the criteria for “Outside Normal Range”, then this column and corresponding footnote can be removed from the table.] 
Time Point 
Treatment Cohort 
N 
Outside Normal Rangea 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
n 
% 
n 
% 
n 
% 
n 
% 
Day 2 
All Subjects 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Day 4 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Day 6 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Day 8 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Day 11 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Early Termination Visit 
All Subjects 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
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Table 62: Abnormal Laboratory Results Related to Study Treatment by Parameter, Maximum Severity, Time Point, and Treatment Cohort – 
Any Hematology Parameter (continued) 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
N 
Outside Normal Rangea 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
n 
% 
n 
% 
n 
% 
n 
% 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Max Severity Post Baseline 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Notes: N = Number of Subjects in Safety Population. n = Number of Subjects who experience each AE grading. The “Max Post Baseline” rows indicate the maximum severity of abnormal laboratory 
results related to study treatment experienced by each subject at any time point post baseline, including unscheduled assessments. Only includes Hematology parameters that have a grading provided: 
hemoglobin, WBC, neutrophils, lymphocytes, eosinophils, and platelets. 
a Measurements that were outside the normal range but did not meet the definition for an AE will be categorized as “Outside Normal Range”. 
 
 


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Table 63: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Hematology – Hematocrit (%) 
 
 
 
Measurement 
Change from Baseline 
Time Point 
Treatment Cohort 
N 
Mean 
Std. Dev. 
Median 
Min, Max 
Mean 
Std. Dev. 
Median 
Min, Max 
Baseline 
All Subjects 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
 
Cohort 1 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
 
Cohort 2 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
 
Cohort 3 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
 
Cohort 4 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
 
Cohort 5 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
 
Cohort 6 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
Day 2 
All Subjects 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
 
Cohort 1 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
 
Cohort 2 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
 
Cohort 3 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
 
Cohort 4 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
 
Cohort 5 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
 
Cohort 6 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
Day 4 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
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Table 63: Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Hematology – Hematocrit (%) (continued) 
- 126 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
 
 
 
Measurement 
Change from Baseline 
Time Point 
Treatment Cohort 
N 
Mean 
Std. Dev. 
Median 
Min, Max 
Mean 
Std. Dev. 
Median 
Min, Max 
Day 6 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
Day 8 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
Day 11 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
Note: N = Number of Subjects in Safety Population with the laboratory result assessed at the respective time point. Baseline = Measurements from Day -1. 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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Tables with similar format: 
Table 64: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Hematology – White Blood Cell Count 
(10^9/L) 
Table 65: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Hematology – Neutrophils (10^9/L) 
Table 66: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Hematology – Lymphocytes (10^9/L) 
Table 67: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Hematology – Monocytes (10^9/L) 
Table 68: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Hematology – Eosinophils (10^9/L) 
Table 69: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Hematology – Basophils (10^9/L) 
Table 70: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Hematology – Red Blood Cell Count 
(10^12/L) 
Table 71: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Hematology – Platelets (10^9/L) 
 
 


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Table 72: 
Laboratory Summary Statistics by Parameter, Time Point, Gender, and Treatment Cohort – Hematology – Hemoglobin (g/dL) 
 
 
 
 
Measurement 
Change from Baseline 
Time Point 
Gender 
Treatment Cohort 
N 
Mean 
Std. Dev. 
Median 
Min, Max 
Mean 
Std. Dev. 
Median 
Min, Max 
Baseline 
Male 
All Subjects 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
 
 
Cohort 1 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
 
 
Cohort 2 
 
 
 
 
 
- 
- 
- 
- 
 
 
… 
 
 
 
 
 
- 
- 
- 
- 
 
Female 
All Subjects 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
 
 
Cohort 1 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
 
 
Cohort 2 
 
 
 
 
 
- 
- 
- 
- 
 
 
… 
 
 
 
 
 
- 
- 
- 
- 
Day 2 
Male 
All Subjects 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
 
 
Cohort 1 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
Female 
All Subjects 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
 
 
Cohort 1 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Day 4 
Male 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
Female 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Day 6 
Male 
All Subjects 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 72: Laboratory Summary Statistics by Parameter, Time Point, Gender, and Treatment Cohort – Hematology – Hemoglobin (g/dL) (continued) 
- 129 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
 
 
 
 
Measurement 
Change from Baseline 
Time Point 
Gender 
Treatment Cohort 
N 
Mean 
Std. Dev. 
Median 
Min, Max 
Mean 
Std. Dev. 
Median 
Min, Max 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
Female 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Day 8 
Male 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
Female 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Day 11 
Male 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
Female 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Note: N = Number of Subjects in Safety Population with the laboratory result assessed at the respective time point. Baseline = Measurements from Day -1. 
 


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Table 73: 
Laboratory Results by Parameter, Time Point, and Treatment Cohort – Hematology – 
Coombs Test 
Time Point 
Treatment Cohort 
 
Positive 
Negative 
N 
n 
% 
n 
% 
Screening 
All Subjects 
x 
x 
xx 
x 
xx 
 
Cohort 1 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
… 
 
 
 
 
 
Day 8 
All Subjects 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
… 
 
 
 
 
 
Note: N = Number of Subject in Safety Population. n = Number of Subjects with each result. 
 


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14.3.5.3 
Coagulation Results 
Table 74: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Coagulation – Any Coagulation 
Parameter 
[Implementation Note: If no results are missing for any time point, then this column can be removed from the table. If there are no results that meet the 
criteria for “Outside Normal Range”, then this column and corresponding footnote can be removed from the table.] 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 2 
All Subjects (N=X) 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Day 4 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 74: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Coagulation – Any Coagulation Parameter (continued) 
- 132 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Day 6 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 74: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Coagulation – Any Coagulation Parameter (continued) 
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Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Day 8 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Day 11 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 74: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Coagulation – Any Coagulation Parameter (continued) 
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Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
Cohort 3 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Early Termination Visit 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 74: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Coagulation – Any Coagulation Parameter (continued) 
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Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Outside Normal 
Rangea 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Max Severity Post Baseline 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: N = Number of Subjects in Safety Population. n = Number of Subjects who experience each AE grading. Baseline = Measurements from Day -1. The “Max Post Baseline” rows indicate the 
maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments. 
a Measurements that were outside the normal range but did not meet the definition for an AE will be categorized as “Outside Normal Range”. 
 
Tables with similar format: 
Table 75: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Coagulation – Prothrombin Time 
Table 76: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Coagulation – Partial 
Thromboplastin Time 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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Table 77: 
Abnormal Laboratory Results Related to Study Treatment by Parameter, Maximum Severity, Time Point, and Treatment Cohort 
– Any Coagulation Parameter 
[Implementation Note: If there are no results that meet the criteria for “Outside Normal Range”, then this column and corresponding footnote can be 
removed from the table.] 
Time Point 
Treatment Cohort 
N 
Outside Normal Rangea 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(High) 
n 
% 
n 
% 
n 
% 
n 
% 
Day 2 
All Subjects 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Day 4 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Day 6 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Day 8 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Day 11 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
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Table 77: Abnormal Laboratory Results Related to Study Treatment by Parameter, Maximum Severity, Time Point, and Treatment Cohort – 
Any Coagulation Parameter (continued) 
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Time Point 
Treatment Cohort 
N 
Outside Normal Rangea 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(High) 
n 
% 
n 
% 
n 
% 
n 
% 
Early Termination Visit 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Max Severity Post Baseline 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Notes: N = Number of Subjects in Safety Population. n = Number of Subjects who experience each AE grading. The “Max Post Baseline” rows indicate the maximum severity of abnormal laboratory 
results related to study treatment experienced by each subject at any time point, including unscheduled assessments.  
a Measurements that were outside the normal range but did not meet the definition for an AE will be categorized as “Outside Normal Range”. 
 
 


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Table 78: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Coagulation – Prothrombin Time (seconds) 
 
 
 
Measurement 
Change from Baseline 
Time Point 
Treatment Cohort 
N 
Mean 
Std. Dev. 
Median 
Min, Max 
Mean 
Std. Dev. 
Median 
Min, Max 
Baseline 
All Subjects 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
 
Cohort 1 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
 
Cohort 2 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
 
Cohort 3 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
 
Cohort 4 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
 
Cohort 5 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
 
Cohort 6 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
Day 2 
All Subjects 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
 
Cohort 1 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
 
Cohort 2 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
 
Cohort 3 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
 
Cohort 4 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
 
Cohort 5 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
 
Cohort 6 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
Day 4 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
Day 6 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 78: Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Coagulation – Prothrombin Time (seconds) (continued) 
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Measurement 
Change from Baseline 
Time Point 
Treatment Cohort 
N 
Mean 
Std. Dev. 
Median 
Min, Max 
Mean 
Std. Dev. 
Median 
Min, Max 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
Day 8 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
Day 11 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
Note: N = Number of Subjects in Safety Population with the laboratory result assessed at the respective time point. Baseline = Measurements from Day -1. 
 
 
Table with similar format: 
Table 79: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Coagulation – Partial Thromboplastin Time 
(seconds) 
 


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14.3.5.4 
Urinalysis Results 
Table 80: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Urinalysis – Any Urinalysis 
Parameter 
[Implementation Note: Only include urinalysis variables that are graded (Protein, Glucose). If no results are missing for any time point, then the column 
can be removed from the table.] 
Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 4 
All Subjects (N=X) 
None 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
Day 8 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
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Table 80: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Urinalysis – Any Urinalysis Parameter (continued) 
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Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
Day 11 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 80: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Urinalysis – Any Urinalysis Parameter (continued) 
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Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
Early Termination Visit 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
Max Severity Post Baseline 
All Subjects (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 80: Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Urinalysis – Any Urinalysis Parameter (continued) 
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Time Point 
Treatment Cohort 
Baseline Severity 
Post-Baseline Severity 
None 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
Cohort 3 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 (N=X) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
Notes: N = Number of Subjects in Safety Population. n = Number of Subjects who experience each AE grading. Baseline = Measurements from Day -1. The “Max Post Baseline” rows indicate the 
maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments. Only includes Urinalysis parameters that have a grading provided: protein and 
glucose. 
 
Tables with similar format: 
Table 81: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Urinalysis – Protein 
Table 82: 
Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Cohort – Urinalysis – Glucose 
 
 


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Table 83: 
Abnormal Laboratory Results Related to Study Treatment by Parameter, Maximum 
Severity, Time Point, and Treatment Cohort – Any Urinalysis Parameter 
Time Point 
Treatment Cohort 
N 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(High) 
n 
% 
n 
% 
n 
% 
Day 4 
All Subjects 
x 
x 
xx 
x 
xx 
x 
xx 
 
Cohort 1 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
Day 8 
All Subjects 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
Day 11 
All Subjects 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
Early Termination Visit 
All Subjects 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
Max Severity Post Baseline 
All Subjects 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
Notes: N = Number of Subjects in Safety Population. n = Number of Subjects who experience each AE grading. The “Max Post Baseline” rows 
indicate the maximum severity of abnormal laboratory results related to study treatment experienced by each subject at any time point, including 
unscheduled assessments. Only includes Urinalysis parameters that have a grading provided: protein and glucose. 
 
 


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Table 84: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Urinalysis – Specific Gravity 
 
 
 
Measurement 
Change from Baseline 
Time Point 
Treatment Cohort 
N 
Mean 
Std. Dev. 
Median 
Min, Max 
Mean 
Std. Dev. 
Median 
Min, Max 
Baseline 
All Subjects 
x 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxx, x.xxx 
- 
- 
- 
- 
 
Cohort 1 
x 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxx, x.xxx 
- 
- 
- 
- 
 
Cohort 2 
x 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxx, x.xxx 
- 
- 
- 
- 
 
Cohort 3 
x 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxx, x.xxx 
- 
- 
- 
- 
 
Cohort 4 
x 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxx, x.xxx 
- 
- 
- 
- 
 
Cohort 5 
x 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxx, x.xxx 
- 
- 
- 
- 
 
Cohort 6 
x 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxx, x.xxx 
- 
- 
- 
- 
Day 4 
All Subjects 
x 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxx, x.xxx 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxx, x.xxx 
 
Cohort 1 
x 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxx, x.xxx 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxx, x.xxx 
 
Cohort 2 
x 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxx, x.xxx 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxx, x.xxx 
 
Cohort 3 
x 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxx, x.xxx 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxx, x.xxx 
 
Cohort 4 
x 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxx, x.xxx 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxx, x.xxx 
 
Cohort 5 
x 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxx, x.xxx 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxx, x.xxx 
 
Cohort 6 
x 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxx, x.xxx 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxx, x.xxx 
Day 8 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
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Table 84: Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Urinalysis – Specific Gravity (continued) 
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Measurement 
Change from Baseline 
Time Point 
Treatment Cohort 
N 
Mean 
Std. Dev. 
Median 
Min, Max 
Mean 
Std. Dev. 
Median 
Min, Max 
Day 11 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
Note: N = Number of Subjects in Safety Population with the laboratory result assessed at the respective time point 
 
 
Table with similar format: 
Table 85: 
Laboratory Summary Statistics by Parameter, Time Point, and Treatment Cohort – Urinalysis – pH 
 


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Table 86: 
Laboratory Results by Parameter, Time Point, and Treatment Cohort – Urinalysis – Protein 
Time Point 
Treatment Cohort 
 
Negative 
Trace 
1+ 
2+ 
3+ 
4+ 
N 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
All Subjects 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 4 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 8 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 11 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: N = Number of subjects in Safety Population. Baseline = Measurements from Day -1. 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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Tables with similar format: 
Table 87: 
Laboratory Results by Parameter, Time Point, and Treatment Cohort – Urinalysis – 
Glucose 
Table 88: 
Laboratory Results by Parameter, Time Point, and Treatment Cohort – Urinalysis – 
Ketones 
Table 89: 
Laboratory Results by Parameter, Time Point, and Treatment Cohort – Urinalysis – 
Bilirubin 
Table 90: 
Laboratory Results by Parameter, Time Point, and Treatment Cohort – Urinalysis – 
Blood 
Table 91: 
Laboratory Results by Parameter, Time Point, and Treatment Cohort – Urinalysis – 
Nitrites 
Table 92: 
Laboratory Results by Parameter, Time Point, and Treatment Cohort – Urinalysis – 
Leukocyte Esterase 
 
 


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Table 93: 
Laboratory Results by Parameter, Time Point, and Treatment Cohort – Urinalysis – 
Urobilinogen 
Time Point 
Treatment Cohort 
 
Positive 
Negative 
N 
n 
% 
n 
% 
Baseline 
All Subjects 
x 
x 
xx 
x 
xx 
 
Cohort 1 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
… 
 
 
 
 
 
Day 4 
All Subjects 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
… 
 
 
 
 
 
Day 8 
All Subjects 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
… 
 
 
 
 
 
Day 11 
All Subjects 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
… 
 
 
 
 
 
Notes: N = Number of Subjects in Safety Population. Baseline = Measurements from Day -1. 
 
 


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14.3.6 Displays of Vital Signs 
Table 94: 
Vital Signs by Assessment, Maximum Severity, Time Point, and Treatment Cohort – Any Assessment 
[If no results are missing for any subject at any time point, then is column can be removed from the table.] 
Time Point 
Treatment Cohort 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
All Subjects 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
 
 
Day 1 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
 
 
Day 2 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 94: Vital Signs by Assessment, Maximum Severity, Time Point, and Treatment Cohort – Any Assessment (continued) 
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Time Point 
Treatment Cohort 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 3 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
 
 
Day 4 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
 
 
Day 5 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
 
 
Day 6 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 


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Table 94: Vital Signs by Assessment, Maximum Severity, Time Point, and Treatment Cohort – Any Assessment (continued) 
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Time Point 
Treatment Cohort 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
 
 
Day 7 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
 
 
Day 8 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
 
 
Day 11 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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Table 94: Vital Signs by Assessment, Maximum Severity, Time Point, and Treatment Cohort – Any Assessment (continued) 
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Time Point 
Treatment Cohort 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Early Termination Visit 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
 
 
Max Severity Post Baseline 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
 
 
Notes: N = Number of Subjects in Safety Population. Baseline = Measurements from Day -1. The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point 
post baseline, including unscheduled assessments.  
 
 


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Table 95: 
Vital Signs by Assessment, Maximum Severity, Time Point, and Treatment Cohort – Pulse Rate 
[If no results are missing for any subject at any time point, then the column can be removed from the table.] 
Time Point 
Treatment 
Cohort 
N 
None 
Mild/ 
Grade 1 
(Low) 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
All Subjects 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
Xx 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 1 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 2 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 3 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 4 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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Table 95: Vital Signs by Assessment, Maximum Severity, Time Point, and Treatment Cohort – Pulse Rate (continued) 
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Time Point 
Treatment 
Cohort 
N 
None 
Mild/ 
Grade 1 
(Low) 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 5 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 6 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 7 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 8 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 11 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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Table 95: Vital Signs by Assessment, Maximum Severity, Time Point, and Treatment Cohort – Pulse Rate (continued) 
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Time Point 
Treatment 
Cohort 
N 
None 
Mild/ 
Grade 1 
(Low) 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Early Termination Visit 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Max Severity Post Baseline 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: N = Number of Subjects in Safety Population. Baseline = Measurements from Day -1. The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point 
post baseline, including unscheduled assessments. 
 
 
Table with similar format: 
Table 96: 
Vital Signs by Assessment, Maximum Severity, Time Point, and Treatment Cohort – Systolic Blood Pressure 
 


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Table 97: 
Vital Signs by Assessment, Maximum Severity, Time Point, and Treatment Cohort – Diastolic Blood Pressure 
[If no results are missing for any subject at any time point, then this column can be removed from the table.] 
Time Point 
Treatment Cohort 
N 
None 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
All Subjects 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Day 1 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Day 2 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Day 3 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Day 4 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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Table 97: Vital Signs by Assessment, Maximum Severity, Time Point, and Treatment Cohort – Diastolic Blood Pressure (continued) 
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Time Point 
Treatment Cohort 
N 
None 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 5 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Day 6 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Day 7 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Day 8 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Day 11 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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Table 97: Vital Signs by Assessment, Maximum Severity, Time Point, and Treatment Cohort – Diastolic Blood Pressure (continued) 
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Time Point 
Treatment Cohort 
N 
None 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Early Termination Visit 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Max Severity Post Baseline 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Notes: N = Number of Subjects in Safety Population. Baseline = Measurements from Day -1. The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point 
post baseline, including unscheduled assessments.  
 
 
Table with similar format: 
Table 98: 
Vital Signs by Assessment, Maximum Severity, Time Point, and Treatment Cohort – Oral Temperature 
 
 


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Table 99: 
Vital Signs by Assessment, Maximum Severity, Time Point, and Treatment Cohort – Respiratory Rate 
[If no results are missing for any subject at any time point, then this column can be removed from the table.] 
Time Point 
Treatment Cohort 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
All Subjects 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Day 1 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Day 2 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Day 3 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Day 4 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Day 5 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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Table 99: Vital Signs by Assessment, Maximum Severity, Time Point, and Treatment Cohort – Respiratory Rate (continued) 
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Time Point 
Treatment Cohort 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 6 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Day 7 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Day 8 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Day 11 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Early Termination Visit 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Max Severity Post Baseline 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Notes: N = Number of Subjects in Safety Population. Baseline = Measurements from Day -1. The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point 
post baseline, including unscheduled assessments. 
 


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Table 100: 
Vital Signs Summary Statistics by Assessment, Time Point, and Treatment Cohort – Pulse Rate (beats/minute) 
[Implementation Note: Min and Max will be reported using the minimum number of significant figures of what is collected. Mean, Std. Dev., and 
Median will be reported using the maximum number of significant figures + 1 of what is collected. For example, Pulse Rate is reported as XX, so the 
Min and Max will be reported as XX, and Mean, Std. Dev., and Median will be reported as XX.X. This applies to all the vital signs tables.] 
 
 
 
Measurement 
Change from Baseline 
Time Point 
Treatment Cohort 
N 
Mean 
Std. Dev. 
Median 
Min, Max 
Mean 
Std. Dev. 
Median 
Min, Max 
Baseline 
All Subjects 
x 
xx.x 
xx.x 
xx.x 
xxx, xxx 
- 
- 
- 
- 
 
Cohort 1 
x 
xx.x 
xx.x 
xx.x 
xxx, xxx 
- 
- 
- 
- 
 
Cohort 2 
 
 
 
 
 
- 
- 
- 
- 
 
Cohort 3 
 
 
 
 
 
- 
- 
- 
- 
 
Cohort 4 
 
 
 
 
 
- 
- 
- 
- 
 
Cohort 5 
 
 
 
 
 
- 
- 
- 
- 
 
Cohort 6 
 
 
 
 
 
- 
- 
- 
- 
Day 1 
All Subjects 
x 
xx.x 
xx.x 
xx.x 
xxx, xxx 
xxx 
xxx 
xxx 
xxx, xxx 
 
Cohort 1 
x 
xx.x 
xx.x 
xx.x 
xxx, xxx 
xxx 
xxx 
xxx 
xxx, xxx 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
Day 2 
All Subjects 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
xxx 
xxx 
xxx 
xxx, xxx 
 
Cohort 1 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
xxx 
xxx 
xxx 
xxx, xxx 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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Table 100: Vital Signs Summary Statistics by Assessment, Time Point, and Treatment Cohort – Pulse Rate (beats/minute) (continued) 
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Measurement 
Change from Baseline 
Time Point 
Treatment Cohort 
N 
Mean 
Std. Dev. 
Median 
Min, Max 
Mean 
Std. Dev. 
Median 
Min, Max 
Day 3 
All Subjects 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
xxx 
xxx 
xxx 
xxx, xxx 
 
Cohort 1 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
xxx 
xxx 
xxx 
xxx, xxx 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
Day 4 
All Subjects 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
xxx 
xxx 
xxx 
xxx, xxx 
 
Cohort 1 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
xxx 
xxx 
xxx 
xxx, xxx 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
Day 5 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
Day 6 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
20JUL2020 
Table 100: Vital Signs Summary Statistics by Assessment, Time Point, and Treatment Cohort – Pulse Rate (beats/minute) (continued) 
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Measurement 
Change from Baseline 
Time Point 
Treatment Cohort 
N 
Mean 
Std. Dev. 
Median 
Min, Max 
Mean 
Std. Dev. 
Median 
Min, Max 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
Day 7 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
Day 8 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
Day 11 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
Note: N = Number of Subjects in Safety Population with the laboratory result assessed at the respective time point. Baseline = Measurements from Day -1. 
 


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Tables with similar format: 
Table 101: 
Vital Signs Summary Statistics by Assessment, Time Point, and Treatment Cohort – Systolic Blood Pressure (mmHg) 
Table 102: 
Vital Signs Summary Statistics by Assessment, Time Point, and Treatment Cohort – Diastolic Blood Pressure (mmHg) 
Table 103: 
Vital Signs Summary Statistics by Assessment, Time Point, and Treatment Cohort – Oral Temperature (°C) 
Table 104: 
Vital Signs Summary Statistics by Assessment, Time Point, and Treatment Cohort – Respiratory Rate (breaths/minute) 
 
 


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14.3.7 Displays of ECG Measurements 
Table 105: 
ECG Overall Interpretations Compared to Baseline by Post-Baseline Time Point and Treatment Cohort 
 
ECG Interpretation Compared to Baseline (N = X) 
Time Point 
Treatment Cohort 
Normal at 
Both Times 
n (%) 
Normal to 
Abnormal, NCS 
n (%) 
Normal to 
Abnormal, CS 
n (%) 
Normal to 
Othera 
n (%) 
Abnormal, NCS 
at Both Times 
n (%) 
Abnormal, NCS 
to Abnormal, CS 
n (%) 
Abnormal, 
NCS to Normal 
n (%) 
Abnormal, 
NCS to Othera 
n (%) 
Missing 
n (%) 
Day 8 
All Subjects 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Cohort 1 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
Day 11 
All Subjects 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
Notes: N = Number of Subjects in Safety Population with the ECG measurement at the visit indicated above. CS = Clinically Significant. NCS = Not Clinically Significant. 
a See Listing 18 for details about ECG Overall Interpretations classified as “Other” 
 
 


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Table 106: 
ECG Results by Parameter, Severity, Time Point, and Treatment Cohort – QTcF/PR 
Interval 
[If no results are missing for any subject at any time point, then this column can be removed from the table.] 
Time Point 
Treatment 
Cohort 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
QTcF Interval (msec) 
Baseline 
All Subjects 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
 
 
Day 8 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
 
 
Day 11 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
 
 
Early Termination Visit 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
Version 1.0 
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Table 106: ECG Results by Parameter, Severity, Time Point, and Treatment Cohort – QTcF/PR Interval 
(continued) 
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Time Point 
Treatment 
Cohort 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Max Severity Post Baseline All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
 
 
PR Interval (msec) 
Baseline 
All Subjects 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
 
 
Day 8 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
 
 
Day 11 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
 
 
Early Termination Visit 
All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 17-0107 
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Table 106: ECG Results by Parameter, Severity, Time Point, and Treatment Cohort – QTcF/PR Interval 
(continued) 
- 169 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time Point 
Treatment 
Cohort 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
 
 
Max Severity Post Baseline All Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
 
 
Notes: N = Number of Subjects in Safety Population. Baseline = Measurements from Day -1. The “Max Post Baseline” rows indicate the 
maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments. 
 
 
 


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Table 107: 
ECG Summary Statistics by Parameter, Time Point, and Treatment Cohort 
[Implementation Note: Use the QTcF and PR Intervals from the most recent measurement prior to first study product administration. If using 
measurements from Screening Visit (visit 00), use the average of the measurements taken.] 
 
 
 
Measurement 
Change from Baseline 
Time Point 
Treatment Cohort 
N 
Mean 
Std. Dev. 
Median 
Min, Max 
Mean 
Std. Dev. 
Median 
Min, Max 
QTcF Interval (msec) 
Baseline 
All Subjects 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
- 
- 
- 
- 
 
Cohort 1 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
- 
- 
- 
- 
 
Cohort 2 
 
 
 
 
 
- 
- 
- 
- 
 
Cohort 3 
 
 
 
 
 
- 
- 
- 
- 
 
Cohort 4 
 
 
 
 
 
- 
- 
- 
- 
 
Cohort 5 
 
 
 
 
 
- 
- 
- 
- 
 
Cohort 6 
 
 
 
 
 
- 
- 
- 
- 
Day 8 
All Subjects 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
 
Cohort 1 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
Day 11 
All Subjects 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
 
Cohort 1 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 


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Table 107: ECG Summary Statistics by Parameter, Time Point, and Treatment Cohort (continued) 
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Measurement 
Change from Baseline 
Time Point 
Treatment Cohort 
N 
Mean 
Std. Dev. 
Median 
Min, Max 
Mean 
Std. Dev. 
Median 
Min, Max 
PR Interval (msec) 
Baseline 
All Subjects 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
- 
- 
- 
- 
 
Cohort 1 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
- 
- 
- 
- 
 
Cohort 2 
 
 
 
 
 
- 
- 
- 
- 
 
Cohort 3 
 
 
 
 
 
- 
- 
- 
- 
 
Cohort 4 
 
 
 
 
 
- 
- 
- 
- 
 
Cohort 5 
 
 
 
 
 
- 
- 
- 
- 
 
Cohort 6 
 
 
 
 
 
- 
- 
- 
- 
Day 8 
All Subjects 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
 
Cohort 1 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
Day 11 
All Subjects 
 
 
 
 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
Cohort 2 
 
 
 
 
 
 
 
 
 
 
Cohort 3 
 
 
 
 
 
 
 
 
 
 
Cohort 4 
 
 
 
 
 
 
 
 
 
 
Cohort 5 
 
 
 
 
 
 
 
 
 
 
Cohort 6 
 
 
 
 
 
 
 
 
 
Notes: N = Number of Subjects in Safety Population. Baseline = Measurements from Day -1. 
 
 


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14.4 
Summary of Prior and Concomitant Medications 
Table 108: 
Number and Percentage of Subjects with Prior and Concurrent Medications by WHO Drug Classification and Treatment Cohort 
WHO Drug Code 
Level 1, Anatomic 
Group 
WHO Drug Code 
Level 2, Therapeutic 
Subgroup 
Cohort 1 
(N=X) 
Cohort 2 
(N=X) 
Cohort 3 
(N=X) 
Cohort 4 
(N=X) 
Cohort 5 
(N=X) 
Cohort 6 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
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. N = Number of Subjects reporting taking at least one medication in the specific WHO Drug Class. 
 
 


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APPENDIX 2.  FIGURE MOCK-UPS 
 
LIST OF FIGURES 
Figure 1: 
CONSORT Flow Diagram .......................................................................................179 
Figure 2: 
Frequency of Related Adverse Events by MedDRA System Organ Class, 
Severity, and Treatment Cohort ................................................................................180 
Figure 3: 
Frequency of Related Adverse Events by MedDRA System Organ Class, 
Severity, and Treatment ............................................................................................181 
Figure 4: 
Incidence of Related Adverse Events by MedDRA System Organ Class, 
Maximum Severity, and Treatment Cohort ..............................................................182 
Figure 5: 
Incidence of Related Adverse Events by MedDRA System Organ Class, 
Maximum Severity, and Treatment ..........................................................................183 
Figure 6: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Sodium (mEq/L) .......184 
Figure 7: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Potassium 
(mEq/L) .....................................................................................................................185 
Figure 8: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Chloride 
(mmol/L) ...................................................................................................................185 
Figure 9: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Bicarbonate 
(mmol/L) ...................................................................................................................185 
Figure 10: Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Blood Urea 
Nitrogen (mg/dL) ......................................................................................................185 
Figure 11: Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Creatinine 
(mg/dL) .....................................................................................................................185 
Figure 12: Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Fasting Glucose 
(mg/dL) .....................................................................................................................185 
Figure 13: Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Non-Fasting 
Glucose (mg/dL) .......................................................................................................185 
Figure 14: Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Albumin (g/dL) .........185 


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Figure 15: Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Total Protein 
(g/dL) ........................................................................................................................185 
Figure 16: Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Total Bilirubin 
(mg/dL) .....................................................................................................................185 
Figure 17: Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Alkaline 
Aminotransferase, Male (U/L) ..................................................................................185 
Figure 18: Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Alkaline 
Aminotransferase, Female (U/L) ..............................................................................185 
Figure 19: Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Aspartate 
Aminotransferase (U/L) ............................................................................................185 
Figure 20: Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Alkaline 
Phosphate (U/L) ........................................................................................................185 
Figure 21: Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Lactate 
Dehydrogenase (U/L) ...............................................................................................185 
Figure 22: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Chemistry – Sodium (mEq/L) .......186 
Figure 23: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Chemistry – Potassium 
(mEq/L) .....................................................................................................................187 
Figure 24: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Chemistry – Chloride 
(mmol/L) ...................................................................................................................187 
Figure 25: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Chemistry – Bicarbonate 
(mmol/L) ...................................................................................................................187 
Figure 26: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Chemistry – Blood Urea 
Nitrogen (mg/dL) ......................................................................................................187 
Figure 27: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Chemistry – Serum 
Creatinine (mg/dL) ...................................................................................................187 


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Figure 28: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Chemistry – Fasting Glucose 
(mg/dL) .....................................................................................................................187 
Figure 29: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Chemistry – Non-Fasting 
Glucose (mg/dL) .......................................................................................................187 
Figure 30: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Chemistry – Albumin (g/dL) .........187 
Figure 31: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Chemistry – Total Protein 
(g/dL) ........................................................................................................................187 
Figure 32: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Chemistry – Total Bilirubin 
(mg/dL) .....................................................................................................................187 
Figure 33: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Chemistry – Alkaline 
Aminotransferase (U/L) ............................................................................................187 
Figure 34: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Chemistry – Aspartate 
Aminotransferase (U/L) ............................................................................................187 
Figure 35: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Chemistry – Alkaline 
Phosphate (U/L) ........................................................................................................187 
Figure 36: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Chemistry – Lactate 
Dehydrogenase (U/L) ...............................................................................................187 
Figure 37: Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Hematology – Hemoglobin, 
Male (g/dL) ...............................................................................................................188 
Figure 38: Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Hematology – Hemoglobin, 
Female (g/dL) ...........................................................................................................189 
Figure 39: Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Hematology – Hematocrit 
(%) ............................................................................................................................189 
Figure 40: Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Hematology – White Blood 
Cells (10^9/L) ...........................................................................................................189 


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Figure 41: Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Hematology – Neutrophils 
(10^9/L) ....................................................................................................................189 
Figure 42: Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Hematology – Lymphocytes 
(10^9/L) ....................................................................................................................189 
Figure 43: Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Hematology – Monocytes 
(10^9/L) ....................................................................................................................189 
Figure 44: Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Hematology – Eosinophils 
(10^9/L) ....................................................................................................................189 
Figure 45: Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Hematology – Basophils 
(10^9/L) ....................................................................................................................189 
Figure 46: Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Hematology – Red Blood 
Cells (10^12/L) .........................................................................................................189 
Figure 47: Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Hematology – Platelets 
(10^9/L) ....................................................................................................................189 
Figure 48: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Hematology – Hemoglobin 
(g/dL) ........................................................................................................................190 
Figure 49: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Hematology – Hematocrit 
(%) ............................................................................................................................191 
Figure 50: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Hematology – White Blood 
Cells (10^9/L) ...........................................................................................................191 
Figure 51: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Hematology – Neutrophils 
(10^9/L) ....................................................................................................................191 
Figure 52: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Hematology – Lymphocytes 
(10^9/L) ....................................................................................................................191 
Figure 53: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Hematology – Monocytes 
(10^9/L) ....................................................................................................................191 


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Figure 54: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Hematology – Eosinophils 
(10^9/L) ....................................................................................................................191 
Figure 55: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Hematology – Basophils 
(10^9/L) ....................................................................................................................191 
Figure 56: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Hematology – Red Blood 
Cells (10^12/L) .........................................................................................................191 
Figure 57: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Hematology – Platelets 
(10^9/L) ....................................................................................................................191 
Figure 58: Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Coagulation – Prothrombin 
Time (seconds) ..........................................................................................................192 
Figure 59: Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Coagulation – Partial 
Thromboplastin Time (seconds) ...............................................................................193 
Figure 60: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Coagulation – Prothrombin 
Time (sec) .................................................................................................................194 
Figure 61: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Coagulation – Partial 
Thromboplastin Time (sec).......................................................................................194 
Figure 62: Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Urinalysis – Specific Gravity ........195 
Figure 63: Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Urinalysis – pH ..............................196 
Figure 64: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Urinalysis – Specific Gravity ........197 
Figure 65: Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Urinalysis – pH ..............................197 
Figure 66: Vital Signs by Scheduled Visits: Individual and Mean Values by Assessment 
and Treatment Cohort – Systolic Blood Pressure (mmHg) ......................................198 
Figure 67: Vital Signs by Scheduled Visits: Individual and Mean Values by Assessment 
and Treatment Cohort – Diastolic Blood Pressure (mmHg) ....................................199 
Figure 68: Vital Signs by Scheduled Visits: Individual and Mean Values by Assessment 
and Treatment Cohort – Pulse Rate (beats/minute) ..................................................199 


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Figure 69: Vital Signs by Scheduled Visits: Individual and Mean Values by Assessment 
and Treatment Cohort – Respiratory Rate (breaths/minute) .....................................199 
Figure 70: Vital Signs by Scheduled Visits: Individual and Mean Values by Assessment 
and Treatment Cohort – Oral Temperature (°C) .......................................................199 
Figure 71: Vital Signs by Scheduled Visits: Mean Changes from Baseline by 
Assessment and Treatment Cohort – Systolic Blood Pressure (mmHg) ..................200 
Figure 72: Vital Signs by Scheduled Visits: Mean Changes from Baseline by 
Assessment and Treatment Cohort – Diastolic Blood Pressure (mmHg) .................201 
Figure 73: Vital Signs by Scheduled Visits: Mean Changes from Baseline by 
Assessment and Treatment Cohort – Pulse Rate (beats/minute) ..............................201 
Figure 74: Vital Signs by Scheduled Visits: Mean Changes from Baseline by 
Assessment and Treatment Cohort – Respiratory Rate (breaths/minute) .................201 
Figure 75: Vital Signs by Scheduled Visits: Mean Changes from Baseline by 
Assessment and Treatment Cohort – Oral Temperature (°C) ...................................201 
Figure 76: ECG by Scheduled Visits: Individual and Mean Values by Parameter and 
Treatment Cohort – QTcF Interval (msec) ...............................................................202 
Figure 77: ECG by Scheduled Visits: Mean Changes from Baseline by Parameter and 
Treatment Cohort – QTcF Interval (msec) ...............................................................203 
Figure 78: ECG by Scheduled Visits: Individual and Mean Values by Parameter and 
Treatment Cohort – PR Interval (msec) ....................................................................203 
Figure 79: ECG by Scheduled Visits: Mean Changes from Baseline by Parameter and 
Treatment Cohort – PR Interval (msec) ....................................................................203 
 


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10.1 
Disposition of Subjects 
Figure 1: 
CONSORT Flow Diagram 
 
 


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14.3.1.2 Unsolicited Adverse Events 
Figure 2: 
Frequency of Related Adverse Events by MedDRA System Organ Class, Severity, and 
Treatment Cohort 
[Implementation Note: A generic figure is shown below. This figure includes all unsolicited events across all 
treatment cohorts. A horizontal bar chart should be presented in 1 image file with separate panels for each 
study arm (6 panels in total – Top Row: Cohort 1, Cohort 2, Cohort 3; Bottom Row: Cohort 4, Cohort 5, 
Cohort 6(2.0) IV). The study arms should be indicated in panel headers including “(N=X)”, where N=Number 
of Subjects in the Safety Population. Axes should be labeled as follows – y-axis: “System Organ Class”; x-
axis: “Number of Events”. The y-axis should present all SOCs reported by at least one subject as well as an 
“Any SOC” category. The Y-axis should be sorted with “Any SOC” first, then in decreasing order of total 
frequency.] 
 
 


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Figure with Similar Format: 
Figure 3: 
Frequency of Related Adverse Events by MedDRA System Organ Class, Severity, and 
Treatment 
[Implementation Note: A horizontal bar chart should be presented in 1 image file with separate panels for 
each study treatment (3 panels in total – AVYCAZ, ATM, and Combination (2.0) IV). The treatments should 
be indicated in panel headers including “(N=X)”, where N=Number of Subjects in the Safety Population. 
Axes should be labeled as follows – y-axis: “System Organ Class”; x-axis: “Number of Events”. The y-axis 
should present all SOCs reported by at least one subject as well as an “Any SOC” category. The Y-axis 
should be sorted with “Any SOC” first, then in decreasing order of total frequency.] 
 


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Figure 4: 
Incidence of Related Adverse Events by MedDRA System Organ Class, Maximum 
Severity, and Treatment Cohort 
[Implementation Note: A generic figure is shown below. This figure includes all unsolicited events across all 
treatment cohorts. A horizontal bar chart should be presented in 1 image file with separate panels for each 
study arm (6 panels in total – Top Row: Cohort 1, Cohort 2, Cohort 3; Bottom Row: Cohort 4, Cohort 5, 
Cohort 6). The study arms should be indicated in panel headers including “(N=X)”, where N=Number of 
Subjects in the Safety Population in each group. Axes should be labeled as follows – y-axis: “System Organ 
Class”; x-axis: “Incidence of Events”. The y-axis should present all SOCs reported by at least one subject as 
well as an “Any SOC” category. The Y-axis should be sorted with “Any SOC” first, then in decreasing order 
of total incidence.] 
 
 
 
 


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Figure with Similar Format: 
Figure 5: 
Incidence of Related Adverse Events by MedDRA System Organ Class, Maximum 
Severity, and Treatment 
[Implementation Note: A horizontal bar chart should be presented in 1 image file with separate panels for 
each study treatment (3 panels in total – AVYCAZ, ATM, and Combination). The treatments should be 
indicated in panel headers including “(N=X)”, where N=Number of Subjects in the Safety Population in each 
group. Axes should be labeled as follows – y-axis: “System Organ Class”; x-axis: “Incidence of Events”. The 
y-axis should present all SOCs reported by at least one subject as well as an “Any SOC” category. The Y-axis 
should be sorted with “Any SOC” first, then in decreasing order of total incidence.] 
 


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14.3.5 
Displays of Laboratory Results 
Figure 6: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Sodium (mEq/L) 
[Implementation Note: For all individual and mean value figures, the y-axis should match for all cohorts. 
Additionally, different lines types and markers should be used for each line in each sub-plot. 
 
 
 


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Figures with Similar Formats: 
Figure 7: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Potassium (mEq/L) 
Figure 8: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Chloride (mmol/L) 
Figure 9: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Bicarbonate (mmol/L) 
Figure 10: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Blood Urea Nitrogen 
(mg/dL) 
Figure 11: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Creatinine (mg/dL) 
Figure 12: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Fasting Glucose (mg/dL) 
Figure 13: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Non-Fasting Glucose 
(mg/dL) 
Figure 14: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Albumin (g/dL) 
Figure 15: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Total Protein (g/dL) 
Figure 16: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Total Bilirubin (mg/dL) 
Figure 17: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Alkaline Aminotransferase, 
Male (U/L) 
Figure 18: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Alkaline Aminotransferase, 
Female (U/L) 
Figure 19: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Aspartate 
Aminotransferase (U/L) 
Figure 20: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Alkaline Phosphate (U/L) 
Figure 21: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by 
Laboratory Parameter and Treatment Cohort – Chemistry – Lactate Dehydrogenase 
(U/L) 


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Figure 22: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Laboratory Parameter and Treatment Cohort – Chemistry – Sodium (mEq/L) 
[Implementation Note: All change from baseline figures should include the parameter name with units in the 
figure header. For liver function tests (ALT, AST, ALP, and total bilirubin) that have additional collections in 
Cohorts 5 and 6, create one image file that contains a panel for cohorts 1-4 (left) and cohorts 5-6 (right). For 
lab parameters that have gradings that are broken up by gender (Chemistry – ALT and Hematology – 
Hemoglobin only), create one image file that contains a panel for each gender (Males on top and Females on 
bottom). ALT will have four panels broken up by gender and cohort based on the above separations.] 
 
 
 


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Figures with similar format: 
Figure 23: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Treatment Cohort – Chemistry – Potassium (mEq/L) 
Figure 24: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Treatment Cohort – Chemistry – Chloride (mmol/L) 
Figure 25: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Treatment Cohort – Chemistry – Bicarbonate (mmol/L) 
Figure 26: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Treatment Cohort – Chemistry – Blood Urea Nitrogen (mg/dL) 
Figure 27: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Treatment Cohort – Chemistry – Serum Creatinine (mg/dL) 
Figure 28: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Treatment Cohort – Chemistry – Fasting Glucose (mg/dL) 
Figure 29: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Treatment Cohort – Chemistry – Non-Fasting Glucose (mg/dL) 
Figure 30: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Treatment Cohort – Chemistry – Albumin (g/dL) 
Figure 31: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Treatment Cohort – Chemistry – Total Protein (g/dL) 
Figure 32: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Treatment Cohort – Chemistry – Total Bilirubin (mg/dL) 
Figure 33: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Treatment Cohort – Chemistry – Alkaline Aminotransferase (U/L) 
Figure 34: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Treatment Cohort – Chemistry – Aspartate Aminotransferase (U/L) 
Figure 35: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Treatment Cohort – Chemistry – Alkaline Phosphate (U/L) 
Figure 36: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Treatment Cohort – Chemistry – Lactate Dehydrogenase (U/L) 
 


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Figure 37: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by Laboratory 
Parameter and Treatment Cohort – Hematology – Hemoglobin, Male (g/dL) 
 
 
 


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Figures with similar format: 
Figure 38: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by Laboratory 
Parameter and Treatment Cohort – Hematology – Hemoglobin, Female (g/dL) 
Figure 39: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by Laboratory 
Parameter and Treatment Cohort – Hematology – Hematocrit (%) 
Figure 40: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by Laboratory 
Parameter and Treatment Cohort – Hematology – White Blood Cells (10^9/L) 
Figure 41: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by Laboratory 
Parameter and Treatment Cohort – Hematology – Neutrophils (10^9/L) 
Figure 42: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by Laboratory 
Parameter and Treatment Cohort – Hematology – Lymphocytes (10^9/L) 
Figure 43: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by Laboratory 
Parameter and Treatment Cohort – Hematology – Monocytes (10^9/L) 
Figure 44: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by Laboratory 
Parameter and Treatment Cohort – Hematology – Eosinophils (10^9/L) 
Figure 45: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by Laboratory 
Parameter and Treatment Cohort – Hematology – Basophils (10^9/L) 
Figure 46: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by Laboratory 
Parameter and Treatment Cohort – Hematology – Red Blood Cells (10^12/L) 
Figure 47: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by Laboratory 
Parameter and Treatment Cohort – Hematology – Platelets (10^9/L) 
 


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Figure 48: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Treatment Cohort – Hematology – Hemoglobin (g/dL) 
 
 
 


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Figures with similar format: 
Figure 49: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Treatment Cohort – Hematology – Hematocrit (%) 
Figure 50: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Treatment Cohort – Hematology – White Blood Cells (10^9/L) 
Figure 51: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Treatment Cohort – Hematology – Neutrophils (10^9/L) 
Figure 52: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Treatment Cohort – Hematology – Lymphocytes (10^9/L) 
Figure 53: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Treatment Cohort – Hematology – Monocytes (10^9/L) 
Figure 54: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Treatment Cohort – Hematology – Eosinophils (10^9/L) 
Figure 55: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Treatment Cohort – Hematology – Basophils (10^9/L) 
Figure 56: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Treatment Cohort – Hematology – Red Blood Cells (10^12/L) 
Figure 57: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Treatment Cohort – Hematology – Platelets (10^9/L) 
 


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Figure 58: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by Laboratory 
Parameter and Treatment Cohort – Coagulation – Prothrombin Time (seconds) 
 
 
 


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Figure with similar format: 
Figure 59: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by Laboratory 
Parameter and Treatment Cohort – Coagulation – Partial Thromboplastin Time 
(seconds) 
 


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Figure 60: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Treatment Cohort – Coagulation – Prothrombin Time (sec) 
 
 
 
Figure with similar format: 
Figure 61: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Treatment Cohort – Coagulation – Partial Thromboplastin Time (sec) 
 


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Figure 62: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by Laboratory 
Parameter and Treatment Cohort – Urinalysis – Specific Gravity 
 
 
 


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Figure with similar format: 
Figure 63: 
Laboratory Results by Scheduled Visits: Individual and Mean Values by Laboratory 
Parameter and Treatment Cohort – Urinalysis – pH 
 
 


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Figure 64: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Treatment Cohort – Urinalysis – Specific Gravity 
 
 
 
Figure with similar format: 
Figure 65: 
Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Laboratory 
Parameter and Treatment Cohort – Urinalysis – pH 
 


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14.3.6 
Displays of Vital Signs 
Figure 66: 
Vital Signs by Scheduled Visits: Individual and Mean Values by Assessment and 
Treatment Cohort – Systolic Blood Pressure (mmHg) 
 
 
 


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Figures with similar format: 
Figure 67: 
Vital Signs by Scheduled Visits: Individual and Mean Values by Assessment and 
Treatment Cohort – Diastolic Blood Pressure (mmHg) 
Figure 68: 
Vital Signs by Scheduled Visits: Individual and Mean Values by Assessment and 
Treatment Cohort – Pulse Rate (beats/minute) 
Figure 69: 
Vital Signs by Scheduled Visits: Individual and Mean Values by Assessment and 
Treatment Cohort – Respiratory Rate (breaths/minute) 
Figure 70: 
Vital Signs by Scheduled Visits: Individual and Mean Values by Assessment and 
Treatment Cohort – Oral Temperature (°C) 
 
 


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Figure 71: 
Vital Signs by Scheduled Visits: Mean Changes from Baseline by Assessment and 
Treatment Cohort – Systolic Blood Pressure (mmHg) 
 
 
 


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Figures with similar format: 
Figure 72: 
Vital Signs by Scheduled Visits: Mean Changes from Baseline by Assessment and 
Treatment Cohort – Diastolic Blood Pressure (mmHg) 
Figure 73: 
Vital Signs by Scheduled Visits: Mean Changes from Baseline by Assessment and 
Treatment Cohort – Pulse Rate (beats/minute) 
Figure 74: 
Vital Signs by Scheduled Visits: Mean Changes from Baseline by Assessment and 
Treatment Cohort – Respiratory Rate (breaths/minute) 
Figure 75: 
Vital Signs by Scheduled Visits: Mean Changes from Baseline by Assessment and 
Treatment Cohort – Oral Temperature (°C) 
 


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14.3.7 
Displays of ECG Measurements 
Figure 76: 
ECG by Scheduled Visits: Individual and Mean Values by Parameter and Treatment 
Cohort – QTcF Interval (msec) 
 


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Figure 77: 
ECG by Scheduled Visits: Mean Changes from Baseline by Parameter and Treatment 
Cohort – QTcF Interval (msec) 
 
 
 
Figures with similar format: 
Figure 78: 
ECG by Scheduled Visits: Individual and Mean Values by Parameter and Treatment 
Cohort – PR Interval (msec) 
[Implementation Note: Similar format to Figure 76.] 
Figure 79: 
ECG by Scheduled Visits: Mean Changes from Baseline by Parameter and Treatment 
Cohort – PR Interval (msec) 
[Implementation Note: Similar format to Figure 77.] 
 


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APPENDIX 3. LISTINGS MOCK-UPS 
LISTINGS 
Listing 1: 16.2.1: Early Terminations or Discontinued Subjects ..............................................207 
Listing 2: 16.2.2.1: Subject-Specific Protocol Deviations ........................................................208 
Listing 3: 16.2.2.2: Non-Subject-Specific Protocol Deviations ................................................209 
Listing 4: 16.2.3: Subjects Excluded from Analysis Populations .............................................210 
Listing 5: 16.2.4.1: Demographic Data .....................................................................................211 
Listing 6: 16.2.4.2: Pre-Existing and Concurrent Medical Conditions .....................................212 
Listing 7: 16.2.5: Drug Concentration Data for Subjects with an Incomplete or 
Interrupted Infusion ..................................................................................................213 
Listing 8: 16.2.7: Unsolicited Adverse Events ..........................................................................214 
Listing 9: 16.2.8.1: Clinical Laboratory Results – Chemistry ..................................................215 
Listing 10: 16.2.8.2: Clinical Laboratory Results – Hematology ...............................................216 
Listing 11: 16.2.8.3: Clinical Laboratory Results – Coagulation ...............................................217 
Listing 12: 16.2.8.4: Clinical Laboratory Results – Urinalysis...................................................218 
Listing 13: 16.2.8.5: Screening Laboratory Results – Serology .................................................219 
Listing 14: 16.2.8.6: Laboratory Results – Coombs Test ...........................................................220 
Listing 15: 16.2.8.7: Laboratory Results – Urine Cotinine, Urine Toxicology, and 
Alcohol Testing ........................................................................................................221 
Listing 16: 16.2.8.8: Laboratory Results – Pregnancy Testing ...................................................222 
Listing 17: 16.2.9.1: Vital Signs .................................................................................................223 
Listing 18: 16.2.9.2: Physical Exam Findings ............................................................................224 
Listing 19: 16.2.9.3: Listing of ECG Interval Measurements and Overall Interpretation ..........225 
Listing 20: 16.2.10: Concomitant Medications ...........................................................................226 
Listing 21: 16.2.11.1: Pregnancy Reports – Maternal Information ............................................227 
Listing 22: 16.2.11.2: Pregnancy Reports – Gravida and Para ...................................................227 
Listing 23: 16.2.11.3: Pregnancy Reports – Live Birth Outcomes .............................................228 
Listing 24: 16.2.11.4: Pregnancy Reports – Still Birth Outcomes ..............................................228 
Listing 25: 16.2.11.5: Pregnancy Reports – Spontaneous, Elective, or Therapeutic 
Abortion Outcomes ...................................................................................................228 
Listing 26: Birth Control Listing.................................................................................................229 
Listing 27: Subject Level CAZ, AVI, and ATM Concentrations in Plasma ...............................230 


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Listing 28: Subject Level CAZ, AVI, and ATM Concentrations in Urine .................................230 
Listing 29: Subject-Specific Pharmacokinetic Parameters from Non-Compartmental 
Plasma Pharmacokinetic Analysis ............................................................................231 
Listing 30: Subject-Specific Pharmacokinetic Parameters from Non-Compartmental 
Urine Pharmacokinetic Analysis ..............................................................................231 
Listing 31: Subject-Specific Pharmacokinetic Parameters from Population 
Pharmacokinetic Analysis (Final Model) .................................................................231 
 


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16.1.6 Listing of Subjects Receiving Investigational Product 
Not included in SAP, but this is a placeholder for the CSR. 
 


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16.2 
Database Listings by Subject 
16.2.1 Discontinued Subjects 
Listing 1: 
16.2.1: Early Terminations or Discontinued Subjects 
Treatment Cohort 
Subject ID 
Category 
Reason for Early Termination or Treatment Discontinuation 
Study Day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.2 Protocol Deviations 
Listing 2: 
16.2.2.1: Subject-Specific Protocol Deviations 
Treatment 
Cohort 
Subject 
ID 
DV Number 
Deviation 
Deviation 
Category 
Study 
Day 
Reason for 
Deviation 
Deviation 
Resulted in AE? 
Deviation Resulted in 
Subject Termination? 
Deviation Affected 
Product Stability? 
Deviation 
Resolution 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 3: 
16.2.2.2: Non-Subject-Specific Protocol Deviations 
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 Analysis Populations 
Listing 4: 
16.2.3: Subjects Excluded from Analysis Populations 
Treatment Cohort 
Subject ID 
Analyses from which  
Subject is Included 
Analyses from which  
Subject is Excluded 
Results Available? 
Reason Subject Excluded 
 
 
[e.g., Safety, PK] 
[e.g., Safety, PK] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 5: 
16.2.4.1: Demographic Data 
Treatment Cohort 
Subject ID 
Sex 
Age at Enrollment (years) 
Ethnicity 
Race 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 6: 
16.2.4.2: Pre-Existing and Concurrent Medical Conditions 
Treatment Cohort 
Subject ID 
MH Number 
Medical History Term 
MedDRA System Organ Class 
MedDRA Preferred Term 
Condition Start Day  
Condition End Day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.5 Compliance and/or Drug Concentration Data 
Listing 7: 
16.2.5: Drug Concentration Data for Subjects with an Incomplete or Interrupted Infusion 
[Implementation Note: Only include subjects who did not receive the full dose of study product or dose was interrupted for one of their scheduled doses.] 
Treatment 
Cohort 
Subject ID 
Dose 
Number 
Study Product 
Administered 
Dose Start 
Date 
Dose 
Taken? 
Dose 
Interrupted? 
Dose Start 
Time 
Dose 
End 
Time 
Interruption 
Start Time 
Interruption 
End Time 
Dose 
Duration 
(min) 
Actual Dosage 
Administered 
(mL) 
Cohort 1 
XX 
XX 
AVYCAZ or ATM ddMMMyyyy Yes/No 
Yes/No 
hh:mm 
hh:mm 
hh:mm 
hh:mm 
XXX 
XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.7 Adverse Events 
Listing 8: 
16.2.7: Unsolicited Adverse Events 
[Implementation Note: Sort by relatedness (related then unrelated), Treatment Cohort, Subject ID.] 
Adverse 
Event 
MedDRA 
System 
Organ 
Class 
MedDRA 
Preferred Term 
MedDRA 
High 
Level 
Term 
Associated 
with Dose 
No. 
No. of Days 
Post 
Associated 
Dose 
(Duration) 
Severity 
SAE? 
Relationship 
to Study 
Treatment 
In Not 
Related, 
Alternative 
Etiology 
Action 
Taken with 
Study 
Treatment 
Subject 
Discontinued 
Due to AE 
Outcome 
Treatment Cohort: , Subject ID: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Cohort: , Subject ID: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
Note: For additional details about SAEs, see Table 18. 
 


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16.2.8 Individual Laboratory Measurements 
Listing 9: 
16.2.8.1: Clinical Laboratory Results – Chemistry 
[Implementation Note: If laboratory result is Outside of Normal Range, use ‘ONR’ as Severity Grade.] 
Treatment 
Cohort 
Subject ID Study Day 
Actual 
Study Day  
Sex  
Age 
(years) 
Laboratory Parameter 
(Units) 
Result (Severity Grade) 
Change from Baselinea 
Reference 
Range Low 
Reference 
Range High 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Baseline = Measurement from Day -1. 
 
 


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Listing 10: 
16.2.8.2: Clinical Laboratory Results – Hematology 
[Implementation Note: If laboratory result is Outside of Normal Range, use ‘ONR’ as Severity Grade.] 
Treatment 
Cohort 
Subject ID 
Study Day 
Actual 
Study Day  
Sex  
Age (years) 
Laboratory Parameter 
(Units) 
Result (Severity 
Grade) 
Change from 
Baselinea 
Reference Range 
Low 
Reference Range 
High 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Baseline = Measurement from Day -1. 
 
 


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Listing 11: 
16.2.8.3: Clinical Laboratory Results – Coagulation 
[Implementation Note: If laboratory result is Outside of Normal Range, use ‘ONR’ as Severity Grade.] 
Treatment 
Cohort 
Subject ID 
Study Day 
Actual Study 
Day  
Sex 
Age (years) 
Laboratory 
Parameter 
(Units) 
Result (Severity 
Grade) 
Change from 
Baselinea 
Reference Range 
High 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Baseline = Measurement from Day -1. 
 
 


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Listing 12: 
16.2.8.4: Clinical Laboratory Results – Urinalysis 
[Implementation Note: Change from Baseline row will be N/A for urinalysis parameters that are recorded as Negative/Trace/1+/2+/3+/4+. If laboratory 
result is Outside of Normal Range, use ‘ONR’ as Severity Grade.] 
Treatment Cohort 
Subject ID 
Study Day 
Actual Study Day  
Sex  
Age (years) 
Laboratory 
Parameter (Units) 
Result (Severity 
Grade) 
Change from 
Baselinea 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Baseline = Measurement from Day -1. 
 
 


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Listing 13: 
16.2.8.5: Screening Laboratory Results – Serology 
Treatment Cohort 
Subject ID 
Study Day 
Actual Study Day 
HIV Antibodies 
HBsAg 
HCV Antibodies 
Cohort 1 
XXXX 
Screening 
-15 
Positive/Negative 
Positive/Negative 
Positive/Negative 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 14: 
16.2.8.6: Laboratory Results – Coombs Test 
Treatment Cohort 
Subject ID 
Study Day 
Actual Study Day 
Coombs Test Result 
Cohort 1 
XXXX 
Screening 
-15 
Positive/Negative 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 15: 
16.2.8.7: Laboratory Results – Urine Cotinine, Urine Toxicology, and Alcohol Testing 
[Implementation Notes: Listing will include results from urine cotinine, urine toxicology, and alcohol breathalyzer testing.] 
Treatment Cohort 
Subject ID 
Study Day 
Actual Study Day 
Test 
Result 
Cohort 1 
XXXX 
Screening 
-15 
Barbiturates 
Positive/Negative 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 16: 
16.2.8.8: Laboratory Results – Pregnancy Testing 
Treatment Cohort 
Subject ID 
Study Day 
Actual Study Day 
Result 
Cohort 1 
XXXX 
Screening 
-15 
Positive/Negative 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.9 Vital Signs and Physical Exam Findings 
Listing 17: 
16.2.9.1: Vital Signs 
Treatment 
Cohort 
Subject ID 
Study Day 
Actual Study 
Day 
Oral 
Temperature 
(°C) 
Systolic Blood 
Pressure 
(mmHg) 
Diastolic Blood 
Pressure 
(mmHg) 
Pulse Rate 
(beats per 
minute) 
Respiratory 
Rate (breaths 
per minute) 
Weight (kg) 
Height (cm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 18: 
16.2.9.2: Physical Exam Findings 
Treatment 
Cohort 
Subject ID 
Study Day 
Actual Study 
Day 
Body System 
Abnormal Finding 
Reported as an AE? 
(AE Description; Number) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 19: 
16.2.9.3: Listing of ECG Interval Measurements and Overall Interpretation 
 
Interval Measurement 
 
Treatment 
Cohort 
Subject 
ID 
Study 
Day 
Actual 
Study Day 
Date of 
Assessment 
Time of 
Assessment 
(hh:mm) 
QTcF 
Interval 
(msec) 
PR Interval 
(msec) 
Replicate 
Number 
Change from 
Baselinea 
Overall Assessment 
Comments 
Cohort 1 
XX 
Screening 
-15 
ddMMMyyyy 
hh:mm 
395 
130 
1 
- 
- 
 
Cohort 1 
XX 
Screening 
-15 
ddMMMyyyy 
hh:mm 
400 
135 
2 
- 
- 
 
Cohort 1 
XX 
Screening 
-15 
ddMMMyyyy 
hh:mm 
405 
140 
3 
- 
- 
 
Cohort 1 
XX 
Screening 
-15 
ddMMMyyyy 
Mean 
400 
135 
- 
- 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Baseline = Measurement from Day -1. 
 
 


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16.2.10 Concomitant Medications 
Listing 20: 
16.2.10: Concomitant Medications 
Treatment 
Cohort 
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) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.11 Pregnancy Reports 
Listing 21: 
16.2.11.1: Pregnancy Reports – Maternal Information 
Treatment 
Cohort 
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 AE listing. Medications taken during pregnancy are included in the Concomitant Medications Listing. 
 
Listing 22: 
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. Extremely PB = <25 weeks; Very Early PB = 25 0/7 - 31 6/7 weeks; Early PB = 32 0/7 – 33 6/7 weeks; Late PB = 34 0/7 – 36 6/7 
weeks; Early TB = 37 0/7 – 38 6/7 weeks; Full TB = 39 0/7 – 40 6/7 weeks; Late TB = 41 0/7 – 41 6/7 weeks; Post TB = >= 42 0/7 weeks. 
a Preterm Birth 
b Term Birth 
 
 


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Listing 23: 
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 AE listing. 
 
Listing 24: 
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 25: 
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 26: 
Birth Control Listing 
Treatment 
Cohort 
Subject ID 
Sex 
Child Bearing 
Potential 
(if Female) 
Sexually Active 
(if Male) 
Birth Control 
Method 
Start Date 
Start Date 
Certainty 
End Date 
End Date 
Certainty 
Ongoing? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 27: 
Subject Level CAZ, AVI, and ATM Concentrations in Plasma 
[Implementation Note: Out of window blood draws will be marked with an asterisk. If CEF, AVI, or ATM concentration levels are below LLQQ, report 
as BQL and include footnote “BQL = Below Quantitative Limit”. If no levels are BQL, footnote does not need to be included in table.] 
Treatment Cohort 
Subject ID 
Date of Blood Draw 
(ddMMMyyyy) 
Time of Blood Draw 
(hh:mm) 
Nominal Timea 
(hr) 
Actual Timea 
(hr) 
CEF Concentration 
in Plasma 
(µg/mL) 
AVI Concentration 
in Plasma 
(µg/mL) 
ATM Concentration 
in Plasma 
(µg/mL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: BQL = Below Quantitative Limit 
a Times relative to start of study product infusion. For actual time, out of window times are indicated by an asterisk.  
 
Listing 28: 
Subject Level CAZ, AVI, and ATM Concentrations in Urine 
[Implementation Note: Out of window urine collections will be marked with an asterisk.] 
Drug 
Treatment 
Cohort 
Subject ID 
Study Day 
Date of Urine 
Collection 
(ddMMMyyyy) 
Time of Urine 
Collection 
(hh:mm) 
Nominal Time a 
(hr) 
Actual Time a 
(hr) 
Volume of 
Urine 
(mL) 
Drug 
Concentration 
in Urine 
(µg/mL) 
Amount of 
Drug in 
Urineb 
(µg) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Times relative to start of study product infusion. For actual time, out of window times are indicated by an asterisk. 
b Amount of Drug in Urine = Volume * Drug Concentration 
 


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Listing 29: 
Subject-Specific Pharmacokinetic Parameters from Non-Compartmental Plasma Pharmacokinetic Analysis 
Drug 
Treatment 
Cohort 
Subject ID 
Cmax 
(µg/mL) 
Tmax 
(hr) 
AUC0-Tau,1  
(µg·hr/mL) 
AUC0-Tau,ss 
(µg·hr/mL) 
Cmin 
(µg/mL) 
Kel 
(1/hr) 
T1/2,kel 
(hr) 
CLss 
(L/h) 
Vz 
(L) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 30: 
Subject-Specific Pharmacokinetic Parameters from Non-Compartmental Urine Pharmacokinetic Analysis 
Drug 
Treatment 
Cohort 
Subject ID 
Day 1 
Ae0-4 
(µg) 
Day 1 
Ae0-8 
(µg) 
Day 1 
Ae0-12 
(µg) 
Day 1 
Ae0-24 
(µg) 
Day 1 
Fe0-24 
Day 6 
Ae0-4 
(µg) 
Day 6 
Ae0-8 
(µg) 
Day 6 
Ae0-12 
(µg) 
Day 6 
Ae0-24 
(µg) 
Day 6 
Fe0-24 
CLR 
(L/h) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 31: 
Subject-Specific Pharmacokinetic Parameters from Population Pharmacokinetic Analysis (Final Model) 
[Implementation Note: Other Parameters may be added depending on the final model.] 
Drug 
Treatment 
Cohort 
Subject ID 
V 
(L) 
Vp 
(L) 
CL 
(L/h) 
Q 
(L/h) 
Cmax, ss 
(µg/mL) 
Cmin, ss 
(µg/mL) 
AUC0-24,ss 
(µg·hr/mL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Prot_001.pdf: 
A Phase I, Open-Label Study in Healthy Adults to Evaluate the 
Safety and Pharmacokinetics of AVYCAZ® in Combination with 
Aztreonam (COMBINE) 
DMID Protocol Number: 17-0107 
DMID Funding Mechanism: UM1AI104681 
IND Sponsor: National Institutes of Health (NIH)/National Institute of Allergy and Infectious 
Diseases (NIAID)/Division of Microbiology and Infectious Diseases (DMID) 
Site Principal Investigator: Jeff Guptill, M.D., MA, MHS 
ARLG Principal Investigator: Thomas Lodise, Pharm.D., Ph.D. 
DMID Clinical Project Manager: Chidi Obasi, MBBS, PhD 
Draft or Version Number:  v3.0 
24 January 2020 
 
 
 


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STATEMENT OF ASSURANCE 
Each Institution will hold a current Federal Wide Assurance (FWA) issued by the Office of 
Human Research Protections (OHRP) for federally-funded human subject’s 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 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. 
 


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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with Good Clinical Practice (GCP) and as required by 
the following: 
• 
United States Code of Federal Regulations (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 (Institutional Review Boards), 21 CFR Part 11, and 21 CFR Part 312 
(Investigational New Drug Application) 
• 
International Conference on Harmonisation: Good Clinical Practice (ICH E6); 62 Federal 
Register 25691 (1997); and future 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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SIGNATURE PAGE 
The signature below provides the necessary assurance that this trial will be conducted according 
to all stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal regulations and 
ICH E6 Good Clinical Practice (GCP) guidelines. 
I agree to conduct the study in compliance with GCP and applicable regulatory requirements. 
I agree to conduct the study in accordance with the current protocol and will not make changes to 
the protocol without obtaining the sponsor’s approval and IRB/IEC approval, except when 
necessary to protect the safety, rights, or welfare of subjects. 
Site Investigator Signature:* 
 
Signed: 
 
Date: 
 
 
Jeff Guptill, M.D., MA, MHS 
Associate Professor, Duke Clinical Research Institute 
(DCRI) 
 
 
 
 
 


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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 .........................................................................................................................10 
LIST OF FIGURES .......................................................................................................................11 
LIST OF ABBREVIATIONS ........................................................................................................12 
PROTOCOL SUMMARY .............................................................................................................18 
 
KEY ROLES.........................................................................................................................21 
 
BACKGROUND AND SCIENTIFIC RATIONALE ..........................................................23 
 
Background .................................................................................................................23 
 
Scientific Rationale .....................................................................................................25 
2.2.1 Purpose of Study ............................................................................................25 
2.2.2 Study Population ............................................................................................26 
 
Potential Risks and Benefits .......................................................................................26 
2.3.1 Potential Risks ...............................................................................................27 
2.3.2 Potential Benefits ...........................................................................................30 
 
STUDY DESIGN, OBJECTIVES AND ENDPOINTS OR OUTCOME MEASURES .....31 
 
Study Design Description ...........................................................................................31 
 
Study Objectives .........................................................................................................32 
3.2.1 Primary ...........................................................................................................32 
3.2.2 Secondary .......................................................................................................32 
3.2.3 Exploratory ....................................................................................................32 
 
Study Endpoints or Outcome Measures .....................................................................32 
3.3.1 Primary ...........................................................................................................32 
3.3.2 Secondary .......................................................................................................32 
3.3.3 Exploratory ....................................................................................................33 
 
STUDY INTERVENTION/STUDY PRODUCT ................................................................34 


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Study Product Description ..........................................................................................34 
4.1.1 Formulation, Packaging, and Labeling ..........................................................35 
4.1.2 Product Storage and Stability .........................................................................36 
 
Acquisition/Distribution .............................................................................................37 
 
Dosage/Regimen, Preparation, Dispensing and Administration of Study 
Intervention/Study Product .......................................................................................38 
 
Accountability Procedures for the Study Intervention/Study Product(s) ...................39 
 
SELECTION OF SUBJECTS AND STUDY ENROLLMENT AND WITHDRAWAL ....40 
 
Eligibility Criteria .......................................................................................................40 
5.1.1 Subject Inclusion Criteria...............................................................................40 
5.1.2 Subject Exclusion Criteria .............................................................................41 
 
Withdrawal from the Study, Discontinuation of Study Product, or Study Termination
 ..................................................................................................................................43 
5.2.1 Withdrawal from the Study or Discontinuation of the Study Product ...........43 
5.2.2 Subject Replacement ......................................................................................44 
5.2.3 Study Termination .........................................................................................44 
 
STUDY PROCEDURES ......................................................................................................45 
 
Screening (Days -30 to Day -2) ..................................................................................45 
 
Enrollment (Day -1) ....................................................................................................46 
 
Planned Study Visits (Days 1 – 8) ..............................................................................47 
6.3.1 Treatment (Day 1) ..........................................................................................47 
6.3.2 Treatment (Day 2) ..........................................................................................47 
6.3.3 Treatment (Day 4, 6) ......................................................................................48 
6.3.4 Treatment (Day 3, 5, 7) ..................................................................................48 
6.3.5 Discharge (Day 8) ..........................................................................................48 
6.3.6 Final Study Visit (Day 11 +3) ........................................................................49 
 
Early Termination Visit ..............................................................................................50 
 
Unscheduled Study Visits ...........................................................................................50 
 
Protocol Deviations ....................................................................................................51 
 
DESCRIPTION OF CLINICAL AND LABORATORY EVALUATIONS .......................52 


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Clinical Evaluations ....................................................................................................52 
7.1.1 Research Procedures ......................................................................................52 
7.1.2 Assessment of Concomitant Medications/Treatments other than Study 
Product ...........................................................................................................53 
7.1.3 Assessment of Subject Compliance with the Study Visit Schedule ..............53 
 
Laboratory Evaluations ...............................................................................................54 
7.2.1 Clinical Laboratory Evaluations ....................................................................54 
7.2.2 Research Assays .............................................................................................55 
 
ASSESSMENT OF SAFETY ...............................................................................................58 
 
Assessing and Recording Safety Parameters ..............................................................58 
8.1.1 Adverse Events (AEs) ....................................................................................58 
8.1.2 Serious Adverse Events (SAEs) .....................................................................60 
 
Specification of Safety Parameters .............................................................................61 
8.2.1 Solicited Events .............................................................................................61 
8.2.2 Unsolicited Events .........................................................................................61 
 
Reporting Procedures ..................................................................................................61 
8.3.1 Reporting Serious Adverse Events ................................................................61 
8.3.2 Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND
 ........................................................................................................................62 
8.3.3 Reporting of Pregnancy .................................................................................62 
 
Type and Duration of Follow-up of Subjects after Adverse Events ...........................63 
 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings......................................................................................63 
 
Halting Rules ..............................................................................................................63 
8.6.1 Study Halting Criteria ....................................................................................63 
8.6.2 Individual Halting Criteria .............................................................................64 
 
Safety Oversight .........................................................................................................64 
8.7.1 Independent Safety Monitor (ISM) ................................................................64 
8.7.2 Safety Monitoring Committee (SMC) ...........................................................64 
 
HUMAN SUBJECTS PROTECTION .................................................................................66 
 
Institutional Review Board/Independent Ethics Committee ......................................66 


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Informed Consent Process ..........................................................................................66 
 
Exclusion of Women, Minorities, and Children (Special Populations) ......................68 
 
Subject Confidentiality ...............................................................................................68 
 
Certificate of Confidentiality ......................................................................................69 
 
Costs, Subject Compensation, and Research Related Injuries ...................................69 
 
STATISTICAL CONSIDERATIONS .................................................................................70 
 Study Hypotheses .......................................................................................................70 
 Sample Size Considerations .......................................................................................70 
 Treatment Assignment Procedures .............................................................................70 
 Final Analysis Plan .....................................................................................................71 
10.4.1 Safety 71 
10.4.2 Pharmacokinetic Analyses .............................................................................72 
10.4.3 Initial Exploratory Analysis ...........................................................................72 
10.4.4 Non-compartmental pharmacokinetic analysis ..............................................72 
10.4.5 Population Pharmacokinetic Analysis ...........................................................72 
10.4.6 Monte Carlo Simulation .................................................................................73 
10.4.7 Exposure-response relationship analysis .......................................................73 
 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ..............74 
 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................75 
 
DATA HANDLING AND RECORD KEEPING ................................................................76 
 Data Management Responsibilities ............................................................................76 
 Data Coordinating Center/Biostatistician Responsibilities ........................................76 
 Data Capture Methods ................................................................................................76 
 Types of Data ..............................................................................................................77 
 Study Records Retention ............................................................................................77 
 
CLINICAL MONITORING .................................................................................................78 
 
PUBLICATION POLICY ....................................................................................................79 
 
LITERATURE REFERENCES ............................................................................................80 
 
APPENDICES ......................................................................................................................84 
 
Schedule of Events............................................................................85 


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Toxicity Table ...................................................................................87 
 
 


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LIST OF TABLES 
Table 1: Treatment Cohorts (8 subjects/cohort) ............................................................................38 
 
 


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LIST OF FIGURES 
Figure 1: Chemical structure of ceftazidime pentahydrate ............................................................34 
Figure 2: Chemical structure of avibactam sodium .......................................................................34 
Figure 3: Chemical structure of ATM injection ............................................................................35 
 
 
 


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LIST OF ABBREVIATIONS 
α 
Alpha 
AE 
Adverse Event/Adverse Experience 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
AM 
Ante Meridiem 
AST 
Aspartate Aminotransferase 
ARLG 
Antibacterial Resistance Leadership Group 
ATM 
Aztreonam 
AUC 
Area Under the Curve 
AUC(0-Tau) 
Area under the plasma concentration-time curve during the 
dosing interval on Day 1 
AUC0-Tau,ss 
Area under the plasma concentration-time curve during the 
dosing interval at steady state  
AV 
Atrioventricular 
AVI 
Avibactam 
BMI 
Body Mass Index 
BPM 
Beats Per Minute 
BUN 
Blood Urea Nitrogen 
°C 
Degrees Celsius 
Cmax 
Maximum Plasma Concentration 
Css,max 
Maximum Plasma Concentration at Steady State 
Css,max(tss,max) 
Time to Maximum Plasma Concentration at Steady State 
Css,min 
Minimum Plasma Concentration at Steady State 
C(tmax) 
Time to Maximum Plasma Concentration 


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CAZ 
Ceftazidime 
CFR 
Code of Federal Regulations 
CFU 
Colony Forming Unit 
CI 
Continuous Infusion 
cIAI 
Complicated Intraabdominal Infection 
Cl 
Chloride 
CL 
Systemic Plasma Clearance 
cm 
Centimeters 
CRF 
Case Report Form 
CROMS 
Clinical Research Operations and Management Support 
CS 
Clinically Significant 
cUTI 
Complicated Urinary Tract Infection 
DCRI 
Duke Clinical Research Institute 
DEPRU 
Duke Early Phase Research Unit 
DHHS 
Department of Health and Human Services 
dL 
Deciliter  
DMID 
Division of Microbiology and Infectious Diseases, NIAID, 
NIH, DHHS 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ESBL 
Extended-spectrum β-lactamases 
°F 
Degrees Fahrenheit 
FDA 
Food and Drug Administration 
FEV1 
Forced Expiratory Volume in 1 Second 
FWA 
Federal Wide Assurance 
g 
Gram 


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GCP 
Good Clinical Practice 
GNB 
Gram Negative Bacteria 
HBsAg 
Hepatitis B Surface Antigen 
HCO3 
Bicarbonate 
HCV 
Hepatitis C Virus 
hCG 
Human Chorionic Gonadotropin 
HEENT 
Head, Eye, Ear, Nose, Throat 
HFIM 
Hollow Fiber Infection Model 
HLT 
High Level Term 
HIV 
Human Immunodeficiency Virus 
hpf 
High Power Field 
IATA 
International Air Transport Association 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDS 
Investigational Drug Services 
IEC 
Independent or Institutional Ethics Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
IV 
Intravenous 
K/CUMM 
Liters/mm3 
K 
Potassium 
kg 
Kilogram 
KPC 
Klebsiella pneumoniae Carbapenemase 
L 
Liters 


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LCE 
Leukocyte Esterase 
LDH 
Lactate Dehydrogenase 
LFT 
Liver Function Test 
LLC 
Limited Liability Company 
m2 
Meters Squared 
MBL 
Metallo-β-Lactamase 
MD 
Maryland 
M.D. 
Medical Doctor 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mEq 
Milliequivalent 
mL 
Milliliter 
MM 
Medical Monitor 
mmHg 
Millimeter of Mercury 
MOP 
Manual of Procedures 
msec 
Millisecond 
Na 
Sodium 
NC 
North Carolina 
NCA 
Non-compartmental Analysis 
NCS 
Not Clinically Significant 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, 
DHHS 
NIH 
National Institutes of Health 
OER 
Office of Extramural Research 
OHRP 
Office of Human Research Protection 


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PD 
Pharmacodynamic 
pH 
Potential of Hydrogen 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PMC 
Pharmacometrics Center 
PR 
Period on ECG extending from beginning of the P wave (the 
onset of atrial depolarization) until the beginning of the QRS 
complex 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
PubMed 
Public/Publisher MEDLINE 
PVC 
Premature Ventricular Contraction 
QA 
Quality Assurance 
QC 
Quality Control 
QT 
Period on ECG extending from the beginning of the QRS 
complex to the end of the T wave 
QTc 
QT interval, corrected for Heart Rate 
QTcF 
QT duration corrected for heart rate by Fridericia’s formula 
RAUC(0-Tau) 
Accumulation ratio for AUC(0-Tau)  
RBC 
Red Blood Cell 
RCmax 
Accumulation ratio for Cmax 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SDCC 
Statistical and Data Coordinating Center 
SMC 
Safety Monitoring Committee 
tmax 
Time for Maximum Concentration of Drug 
U 
Units 


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ULN 
Upper Limit of Normal 
USA 
United States of America 
US 
United States 
USP 
United States Pharmacopeia 
Vss 
Volume of Distribution at Steady-State 
Vz 
Volume of Distribution at the Terminal Phase 
WBC 
White Blood Cell 
w/v 
Weight/Volume 
 
 
 


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PROTOCOL SUMMARY 
Title: 
A Phase I, Open-Label Study in Healthy Adults to Evaluate the 
Safety and Pharmacokinetics of AVYCAZ® in Combination with 
Aztreonam (COMBINE) 
Design of the Study: 
This is a Phase I, open-label, single center study in 48 healthy 
adult male and female subjects to investigate the safety and 
pharmacokinetics of ceftazidime-avibactam (AVYCAZ) 
combined with aztreonam (ATM), AVYCAZ alone, and ATM 
alone. Cohorts 1-4 are the single drug administration treatment 
cohorts and will include AVYCAZ per label dosing, AVYCAZ 
as a continuous infusion (CI), ATM per label dosing, and ATM 
as a CI.  Cohorts 5 and 6 are the two AVYCAZ and ATM 
combination drug administration treatment cohorts.  Study safety 
will be monitored using assessments of adverse events (AE’s), 
vital signs, and clinical laboratory safety tests. Serial blood and 
urine samples will be collected for pharmacokinetic (PK) 
evaluation. 
Study Phase: 
1 
Study Population: 
Forty-eight (48) healthy, adult male and female subjects ages 18-
45.  The study will be conducted in the United States. 
Number of Sites: 
1 
Description of Study 
Product or Intervention: 
Eight (8) subjects/cohort.   
• 
Cohort 1:  AVYCAZ 2.5 g IV as a 2-hour infusion every 
8 hours for 7 days  
• 
Cohort 2:  AVYCAZ 2.5 g IV as a 2-hour infusion x 1, then 
0.32 g per hour IV daily as a CI (7.5 g/day) for 7 days 
• 
Cohort 3:  ATM 2 g IV as a 2-hour infusion every 6 hours for 
7 days 
• 
Cohort 4:  ATM 2 g IV as a 2-hour infusion x 1, then 0.33 g 
per hour IV daily as a CI (8 g/day) for 7 days  


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• 
Cohort 5:  AVYCAZ 2.5 g IV as a 2-hour infusion every 
8 hours for 7 days and ATM 1.5 g IV as a 2-hour infusion 
every 6 hours for 7 days 
• 
Cohort 6:  AVYCAZ 2.5 g IV as a 2-hour infusion every 8 
hours for 7 days and ATM 2 g as a 2-hour infusion every 6 
hours for 7 days 
Study Objectives: 
 
Primary:  
• 
Describe the safety of two dosing regimens of AVYCAZ 
combined with ATM relative to AVYCAZ alone and ATM 
alone in healthy adult subjects. 
Secondary: 
• 
Characterize the PK profiles of two dosing regimens of 
AVYCAZ combined with ATM, AVYCAZ alone, and ATM 
alone at the population level in healthy adult subjects. 
• 
Characterize the PK profiles of two dosing regimens of 
AVYCAZ combined with ATM, AVYCAZ alone, and ATM 
alone following initiation of dosing on Day 1 in healthy adult 
subjects. 
• 
Characterize the PK profiles of two dosing regimens of 
AVYCAZ combined with ATM, AVYCAZ alone, and ATM 
alone following multiple daily dosing in healthy adult 
subjects. 
Exploratory: 
• 
Predict the distribution of plasma concentration-time profiles 
observed with two dosing regimens AVYCAZ combined 
with ATM, AVYCAZ alone, and ATM alone in healthy adult 
subjects via simulations. 
• 
Predict the distribution of cumulative urine amount-time 
profiles observed with two dosing regimens AVYCAZ 
combined with ATM, AVYCAZ alone, and ATM alone in 
healthy adult subjects via simulations. 
• 
Examine the associations between the plasma concentration-
time profiles of AVYCAZ combined with ATM, AVYCAZ 


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alone, and ATM alone and occurrence of ALT or AST 
elevations. 
Duration of Individual 
Subject Participation: 
Up to 44 days (Screening: within 30 days of Day 1 of study 
product administration; study product administration: 7 days; 
outpatient follow-up visit: Day 11 +3 days post Day 1 of study 
product administration). 
Estimated Time to Last 
Subject/Last Study Day: 
The study will run between approximately 12-15 months. 
 
 


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KEY ROLES 
Antibacterial Resistance 
Leadership Group 
(ARLG) Lead Principal 
Investigator: 
Thomas Lodise, PharmD, PhD 
Professor, Pharmacy Practice 
Albany College of Pharmacy and Health Sciences 
Telephone: 1 (518) 694-7292 
Thomas.Lodise@acphs.edu  
ARLG Co-Investigator 
J Nicholas O’Donnell, PharmD, MSc 
Assistant Professor, Pharmacy Practice 
Albany College of Pharmacy and Health Sciences 
Telephone:  1 (518) 694-7203 
Nick.Odonnell@acphs.edu  
ARLG Project Leader 
Smitha Zaharoff, PhD 
Clinical Trials Project Leader 
Duke Clinical Research Institute (DCRI) 
Telephone: 1 (919) 668-8607 
smitha.zaharoff@duke.edu  
Study Site Principal 
Investigator: 
Jeffrey Guptill, M.D 
Associate Professor 
Duke University 
Telephone:  1 (919) 668-6373 
jeffrey.guptill@duke.edu  
Study Site: 
Duke Early Phase Research Unit (DEPRU) 
40 Medicine Circle 
Room 14214, Red Zone, Duke South 
Durham, NC  27710 
 
Debbie Freeman 
Nurse Manager, Operations 
Telephone:  1 (919) 684-1780   
debra.h.freeman@duke.edu  
DMID Clinical Project 
Manager: 
Chidi Obasi, MBBS, PhD 
5601 Fishers Lane, 7E17 
Rockville MD 20852 
Telephone: 1 (301) 761-6899 
chidi.obasi@nih.gov  


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Safety and 
Pharmacovigilance 
Contractor: 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support 
(CROMS) 
6500 Rock Spring Dr., Suite 650 
Bethesda, MD 20817 
SAE Hot Line: 1-800-537-9979 (US) 
SAE Fax: 1-800-275-7619 (US) 
SAE Email: PVG@dmidcroms.com  
Pharmacokinetic Analysis 
Group 
DCRI Pharmacometrics Center 
300 West Morgan Street, Suite 800 
Durham, NC 27701 
DCRI-PMC@duke.edu  
Statistical and Data 
Coordinating Center: 
The Emmes Company 
401 N. Washington St. Suite 700 
Rockville, MD  20850 
Study Agent Repository: 
Duke Investigational Drug Services (IDS) 
Duke University Hospital 
pharmacy-grp_ids@dm.duke.edu  
DMID Clinical Materials 
Services: 
Fisher BioServices  
c/o DMID Clinical Materials Services (CMS) 
20439 Seneca Meadows Parkway 
Germantown, MD 20876 
Telephone: 1 (240) 477-1350 
Fax: 1 (240) 477-1360 
DMID.CMS@ThermoFisher.com 
Laboratory: 
Keystone Bioanalytical, Inc. 
501 Dickerson Rd 
North Wales, PA 19454 


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BACKGROUND AND SCIENTIFIC RATIONALE 
 
Background  
Treatment of patients with serious infections due to highly resistant Gram-negative bacteria 
(GNB) remains problematic and is a major public health concern.  Not only is there increased 
resistance among frequently encountered GNB like Pseudomonas aeruginosa and Klebsiella 
pneumoniae, but there is also a rise in the number of multidrug-resistant strains [1-3].  This 
change is driven in large part by the increasing prevalence and complexity of a variety of β-
lactamases [4]. The most important of these are the extended-spectrum β-lactamases (ESBLs) 
and carbapenemases, such as Klebsiella pneumoniae carbapenemase (KPC) [1,3,4]. The metallo-
β-lactamases (MBLs), which have the ability to hydrolyze all β-lactams except aztreonam 
(ATM), have emerged recently as problematic carbapenemases [5-10].  While there has been an 
impressive drug development response to combat ESBL- and KPC-producing GNB infections, 
none of the recently approved antibiotics have reliable activity against MBL-producing GNB 
[11,12].  Several antibiotics with activity against MBL-producing GNB are being developed, but 
none are anticipated to be available until at least 2021 [11,13]. 
Previous studies have demonstrated that while ATM is not hydrolyzed by MBLs, many MBL-
bearing GNB co-harbor ESBLs that hydrolyze ATM [6,7,9,13,15].  Combination with avibactam 
(AVI), a beta-lactamase inhibitor, protects ATM from hydrolysis by ESBLs and KPCs and 
results in effective killing of bacteria harboring a broad range of beta-lactamase enzymes [5-
8,10,13,15].  The ATM-AVI combination is currently being tested in clinical trials; however, it 
will be several years before this new treatment option will be considered for approval by the 
Food and Drug Administration (FDA) for treating patients infected with MBL-producing GNB.   
This underscores the exigency of redeploying our existing agents in innovative ways to meet the 
needs of patients today [14]. 
One strategy that may serve as a “bridge” treatment for MBL-producing GNB infections is 
ceftazidime-avibactam (AVYCAZ®) combined with ATM [5,13,16,17].  In the combination of 
ATM with AVYCAZ, AVI inhibits the ESBL and KPC beta-lactamases that are often present in 
MBL-producing GNB, allowing ATM, which is unaffected by MBLs, to effectively bind to 
bacterial penicillin binding proteins.  Limited data to date suggest that AVYCAZ combined with 
ATM is a promising treatment for patients with MBL-producing GNB infections [5,10,13,17].  
In a MBL-producing K. pneumoniae time-kill assay, AVYCAZ combined with ATM resulted in 
a ≥ 3-log10-colony forming unit (CFU)/mL decrease compared to AVYCAZ alone [13].  In a 
murine neutropenic thigh infection model with the same strain, an almost 4-log10-CFU/mL 
greater reduction was noted with AVYCAZ combined with ATM vs. AVYCAZ alone [13].  
Although the precise mechanism of improved bacterial killing activity with AVYCAZ combined 
with ATM is not completely understood, it is likely attributable to maximal saturation of the 


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diverse penicillin binding proteins present in GNB, flooding of periplasm with β-lactams, and 
maximal binding of available β-lactamases [5,14]. 
The combination of AVYCAZ with ATM has been employed clinically.  To date, four published 
case reports have documented successful use of this combination in 14 patients with serious 
infections due to MBL-producing GNB [5,13,16,17]. Patients have received this combination for 
infections due to MBL-bearing strains of Klebsiella pneumoniae, Enterobacter cloacae, 
Pseudomonas aeruginosa, and Stenotrophomonas maltophilia.  While there are theoretical safety 
concerns with dual beta-lactam use, no adverse events (AEs) were attributed to receipt of 
AVYCAZ combined with ATM across the published patient reports [5,13,14, 16,17].  This is 
notable as at least two of the patients described in these case reports received AVYCAZ 
combined with ATM for greater than one month [13,17]. 
Although AVYCAZ combined with ATM has been shown to be efficacious against MBL-
producing GNB in pre-clinical studies and clinical case reports, optimal dosing remains 
unknown. Hollow fiber infection model (HFIM) studies using E. coli ARLG-1013 (blaNDM-1, 
blaCTX-M, blaCMY, blaTEM) and K. pneumoniae ARLG-1002 (blaNDM-1, blaCTXM-15, blaDHA, blaSHV, 
blaTEM were conducted to identify AVYCAZ combined with ATM regimens that result in 
maximal bacterial kill and resistance suppression [23].  In these HFIM experiments, a number of 
FDA-approved ATM 6-8 grams (g)/day regimens were evaluated in combination with FDA-
approved AVYCAZ dosing (2.5 g IV as a 2-hour infusion every 8 hours) and continuous 
infusion (CI) AVYCAZ (7.5 g IV daily) [18,19].  It was anticipated that administration of 
AVYCAZ as a CI combined with ATM would outperform FDA-approved AVYCAZ dosing 
combined with ATM.  Continuous infusion administration maximizes the pharmacokinetics/ 
pharmacodynamics (PK/PD) of AVYCAZ and it was anticipated that this would result in 
enhanced bacterial killing and resistance suppression [20-22]. Since it is not practical for all 
institutions to infuse AVYCAZ as a CI, HFIM experiments were also conducted to identify the 
optimal dosing of AVYCAZ combined with ATM using FDA-approved dosing regimens of each 
antibiotic. In these HFIM experiments, maximal daily dose of AVYCAZ combined with 8g/day 
ATM regimens were found to be optimal.  Specifically, the two combination regimens that 
showed maximal bacterial killing and resistance suppression over 7 days were: 
• 
AVYCAZ 2.5 g IV as a 2-hour infusion every 8 hours combined with ATM 2 g IV as a 2-
hour infusion every six hours, and 
• 
AVYCAZ combined with ATM, each administered as a CI (AVYCAZ 7.5 g/day CI 
combined with ATM 8g/day CI) [23]. 
While the initial intent was to examine the two optimal AVYCAZ with ATM regimens identified 
in the HFIM experiments, two subjects who received ATM 8g/day CI alone in cohort 4 
experienced grade 3 AST/ALT elevations.  Despite having AST/ALT elevations >10 ULN, the 
two subjects were asymptomatic and there were no clinical findings suggestive of liver necrosis 


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or jaundice.  There were also no elevations in ALP and bilirubin and there were no clinically 
significant elevations in all other serum chemistries and blood counts.  The two subjects’ in 
cohort 4 continued to experience elevations in AST/ALT for 1 to 2 days after discontinuation of 
ATM but the AST/ALT values then trended down 2 to 4 days after study product 
discontinuation.  For both subjects, AST/ALT values returned to baseline within 25 days after 
discontinuation of ATM.  Please note that for both subjects, daily AST/ALT monitoring was not 
performed as subjects had been discharged from the study unit and only returned for two 
additional AE follow up visits 5-9 and 25 days after discontinuation of ATM.          
Asymptomatic serum aminotransferase elevations are common during high dose, intravenous 
ATM therapy (10% to 38%) [24].  Liver enzyme elevations occur slightly more commonly 
during aztreonam therapy than with other comparative antibiotics. As observed in the two 
subjects in cohort 4 with grade 3 AST/ALT elevations, aztreonam induced liver injury appears to 
be transient, mild and asymptomatic, marked only by serum enzyme elevations. Data indicate 
that aztreonam is an unlikely cause of clinically apparent liver injury (likelihood score of E) and 
no individual case of frank liver injury and jaundice attributable to aztreonam have been 
reported.   
In response to the occurrence of two grade 3 AEs that were related to study product and of the 
same type [High Level Term (HLT)], the study was halted and a Safety Monitoring Committee 
(SMC) meeting was convened.  The SMC recommended to continue the study but reduce the 
dose of ATM in cohort 5 to ATM 1.5 g IV as a 2-hour infusion every 6 hours (ATM 6 g/daily) 
and to administer it in combination with AVYCAZ 2.5 g IV as a 2-hour infusion every 8 hours.    
The HFIM study indicated that this was an effective combination regimen and SMC 
recommended administering it in cohort 5.  Furthermore, the SMC recommended that a SMC 
meeting be convened after completion of cohort 5.  If no halting rules are met and there are no 
other safety concerns, the SMC recommended administering ATM 2 g IV as a 2-hour infusion 
every 6 hours (ATM 8 g/daily) in combination with AVYCAZ 2.5 g IV as a 2-hour infusion 
every 8 hours in cohort 6.  The SMC was in favor of escalating the ATM dose in cohort 6 if no 
halting rules are met as the HFIM experiments showed increased bacterial killing with 8 g/day vs 
6 g/day combination regimens.  Since the safety of ATM CI was not established in this study, the 
SMC was opposed to administering ATM as a CI in any subsequent cohorts.  As an additional 
safeguard, the SMC also recommended that more intensive Liver Function Test (LFT) 
monitoring be performed.    
 
Scientific Rationale 
2.2.1 Purpose of Study 
Before uniform adoption of AVYCAZ with ATM combination regimens that were found to be 
effective in the aforementioned HFIM studies into clinical practice, it is important to establish 


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the safety and PK of these regimens in humans [23]. This is critically important as two subjects 
in the ATM 8g/daily CI treatment cohort (cohort 4) experienced asymptomatic grade 3 
AST/ALT elevations.  Therefore, this phase 1 study in healthy adults will evaluate the safety and 
PK of AVYCAZ combined with ATM.  AVYCAZ and ATM are both currently approved as 
standalone products for the treatment of patients with various infections due to GNB. Both 
antibiotics are generally safe and well-tolerated, although mild-to-moderate asymptomatic serum 
aminotransferase elevations are common with ATM [18, 19, 24].  These elevations are usually 
self-limiting and do not require ATM discontinuation [18, 24].  Although AVYCAZ and ATM 
appear to be safe and well-tolerated, there are no available data on safety when these antibiotics 
are used in combination. It is unclear if AVYCAZ combined with ATM will further exacerbate 
liver enzyme elevations or lead to other AEs due to the potential of cumulative toxicity from 
dual-β-lactam treatment [14].  There are also no published PK data of these antibiotics when 
administered concurrently, and it is therefore unknown if use of these agents in combination will 
lead to an altered PK profile of each agent due to inhibition of renal or other compensatory 
clearance mechanisms. Therefore, it is important to assess the safety and pharmacokinetic profile 
of AVYCAZ combined with ATM relative to its standalone counterparts before widespread 
adoption into clinical practice.   
2.2.2 Study Population 
The study will be conducted using healthy volunteers to observe the safety and PK of 
combination regimens of AVYCAZ with ATM that were found to be effective in previous HFIM 
experiments [23].  Safety and PK of combination regimes will be compared to the AVYCAZ and 
ATM dosing regimens given alone [23].  This is a single center study being conducted in the 
United States.  The study site will determine the most efficient procedures to identify potentially 
eligible subjects from the general public for the study.  Women of child-bearing potential will 
not be excluded from the study.  In addition, special populations, e.g., non-English speakers, 
illiterate or non-writing individuals will not be excluded from this study. 
Children and vulnerable populations will be excluded from this study as there is insufficient 
safety data and this is the first time AVYCAZ combined with ATM will be administered in a 
systematic manner and as there is insufficient safety data to support the inclusion of these 
vulnerable populations. 
 
Potential Risks and Benefits 
AVYCAZ and ATM are both currently FDA-approved and the package inserts are the primary 
source of risk information for AVYCAZ and ATM [18,19]. 


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2.3.1 Potential Risks 
2.3.1.1 AVYCAZ 
Hypersensitivity Reactions:  Serious and occasionally fatal hypersensitivity (anaphylactic) 
reactions and serious skin reactions have been reported in patients receiving beta-lactam 
antibacterial drugs.  Before therapy with AVYCAZ is instituted, careful inquiry about previous 
hypersensitivity reactions to other cephalosporins, penicillins, or carbapenems should be made.  
Exercise caution if this product is to be given to a penicillin or other beta-lactam-allergic patient 
because cross-sensitivity among beta-lactam antibacterial drugs has been established.  
Discontinue the drug if an allergic reaction to AVYCAZ occurs. 
Clostridium difficle-Associated Diarrhea: Clostridium difficile-associated diarrhea has been 
reported for nearly all antibiotics, including AVYCAZ, and may range in severity from mild 
diarrhea to fatal colitis.  The diarrhea may start during or after the AVYCAZ is administered.  
C. difficle occurs naturally in the colon.  Treatment with antibiotic drugs alters the normal flora 
(microorganisms that live in the colon) and may permit overgrowth of C. difficle. 
Central Nervous System Reactions:  Seizures, non-convulsive status epilepticus, encephalopathy, 
coma, asterixis, neuromuscular excitability, and myoclonia have been reported in patients treated 
with ceftazidime, particularly in the setting of renal impairment.  
Nervous System:  headache, dizziness 
Gastrointestinal:  abdominal pain, nausea, vomiting, diarrhea 
The following selected adverse reactions were reported in AVYCAZ treated patients at a rate of 
less than 1% in the Phase 3 clinical trials and are not described elsewhere in the labeling. 
• 
Blood and lymphatic disorders - thrombocytopenia 
• 
General disorders and administration site conditions - injection site phlebitis 
• 
Infections and infestations - candidiasis 
• 
Investigations - increased aspartate aminotransferase (AST), increased alanine 
aminotransferase (ALT), increased gamma-glutamyltransferase 
• 
Metabolism and nutrition disorders - hypokalemia 
• 
Nervous system disorders - dysgeusia 
• 
Renal and urinary disorders - acute renal failure, renal impairment, nephrolithiasis 
• 
Skin and subcutaneous tissue disorders - rash, rash maculo-papular, urticaria, pruritus 
• 
Psychiatric disorders - anxiety 


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Additionally, adverse reactions reported with ceftazidime alone that were not reported in 
AVYCAZ treated patients in the Phase 3 clinical trials are listed below: 
• 
Blood and lymphatic disorders - agranulocytosis, hemolytic anemia, leukopenia, 
lymphocytosis, neutropenia, thrombocytosis, eosinophilia 
• 
General disorders and administration site conditions - infusion site inflammation, injection 
site hematoma, injection site thrombosis 
• 
Hepatobiliary disorders - jaundice 
• 
Investigations - increased blood lactate dehydrogenase, prolonged prothrombin time (PT) 
• 
Nervous system disorders - paresthesia 
• 
Renal and urinary disorders - tubulointerstitial nephritis 
• 
Reproductive and breast disorders - vaginal inflammation 
• 
Skin and subcutaneous tissue disorders - angioedema, erythema multiforme, Stevens-Johnson 
syndrome, toxic epidermal necrolysis 
Laboratory Changes:  Seroconversion from a negative to a positive direct Coombs test result at 
any time up to the last visit occurred in 31/240 (12.9%) of patients receiving AVYCAZ plus 
metronidazole with initial negative Coombs test and at least one follow-up test and in 7/235 
(3.0%) of patients receiving meropenem in the Phase 3 cIAI trial. 
Seroconversion from a negative to a positive direct Coombs test result at any time up to the last 
visit occurred in 7/216 (3.2%) of patients receiving AVYCAZ with initial negative Coombs test 
and at least one follow-up test and 2/214 (0.9%) of patients receiving doripenem in the Phase 3 
cUTI trial. No adverse reactions representing hemolytic anemia were reported in any treatment 
group. 
Ceftazidime is excreted in human milk in low concentrations. It is not known whether AVI is 
excreted into human milk, although AVI was shown to be excreted in the milk of rats. No 
information is available on the effects of CAZ and AVI on the breast-fed child or on milk 
production. 
2.3.1.2 Aztreonam  
Asymptomatic serum aminotransferase elevations have been reported with ATM therapy (10% 
to 38%) [24].  The enzyme abnormalities are usually mild-to-moderate, asymptomatic, self-
limited and not requiring drug discontinuation.  Instances of marked aminotransferase elevations 
within 3 to 5 days of starting ATM have been reported, but these cases were without jaundice 
and resolved over time once the drug was stopped.  ATM is an unlikely cause of clinically 


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apparent liver injury and no individual cases of frank liver injury and jaundice attributable to 
ATM have been reported. 
Local reactions such as phlebitis/thrombophlebitis following intravenous (IV) administration; 
and discomfort/swelling at the injection site following intramuscular administration occurred at 
rates of approximately 1.9% and 2.4% respectively. 
Systemic reactions (considered to be related to therapy or of uncertain etiology) occurring at an 
incidence of 1% to 1.3% include diarrhea, nausea and/or vomiting, and rash.  Reactions 
occurring at an incidence of less than 1% are listed within each body system in order of 
decreasing severity: 
• 
Hypersensitivity - anaphylaxis, angioedema, bronchospasm 
• 
Renal - Prolonged serum levels of ATM may occur in patients with transient or persistent 
renal insufficiency. 
• 
Hematologic - pancytopenia, neutropenia, thrombocytopenia, anemia, eosinophilia, 
leukocytosis, thrombocytosis 
• 
Gastrointestinal - abdominal cramps; rare cases of Clostridium difficile-associated diarrhea, 
including pseudomembranous colitis, or gastrointestinal bleeding have been reported.   
• 
Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment. 
• 
Dermatologic - toxic epidermal necrolysis, purpura, erythema multiforme, exfoliative 
dermatitis, urticaria, petechiae, pruritus, diaphoresis 
• 
Cardiovascular - hypotension, transient electrocardiogram (ECG) changes (ventricular 
bigeminy and premature ventricular contraction (PVC), flushing 
• 
Respiratory - wheezing, dyspnea, chest pain 
• 
Hepatobiliary - hepatitis, jaundice 
• 
Nervous System - seizure, confusion, vertigo, paresthesia, insomnia, dizziness 
• 
Musculoskeletal - muscular aches 
• 
Special Senses - tinnitus, diplopia, mouth ulcer, altered taste, numb tongue, sneezing, nasal 
congestion, halitosis 
• 
Other - vaginal candidiasis, vaginitis, breast tenderness 
• 
Body as a Whole - weakness, headache, fever, malaise 


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Laboratory Changes:  Adverse laboratory changes without regard to drug relationship that were 
reported during clinical trials were: 
• 
Hepatic - elevations of AST, Serum Glutamic Oxaloacetic Transaminase, ALT, Serum 
Glutamic-Pyruvic Transaminase, and alkaline phosphatase (ALP); signs or symptoms of 
hepatobiliary dysfunction occurred in less than 1% of recipients 
• 
Hematologic - increases in prothrombin and partial thromboplastin times, positive Coombs 
test. 
• 
Renal - increases in serum creatinine. 
In pregnant women, ATM crosses the placenta and enters the fetal circulation.  ATM is excreted 
in human milk in concentrations that are less than 1% of concentrations determined in 
simultaneously obtained maternal serum. 
2.3.1.3 AVYCAZ Combined with ATM 
The risks associated with AVYCAZ combined with ATM are expected to be similar to those 
associated with AVYCAZ alone and ATM alone.  However, there is a theoretical risk for 
increased adverse reactions with AVYCAZ combined with ATM relative to that observed with 
receipt of AVYCAZ alone and ATM alone due to the potential of cumulative or additive toxicity 
from receiving two beta-lactams simultaneously relative to receiving just one beta-lactam [14].  
To date, published reports have described the use of AVYCAZ combined with ATM in 14 
patients [5,13,16,17].  No adverse reactions were attributed to receipt of AVYCAZ combined 
with ATM in these reports.  Four of the 14 patients (28.6%) were reported to have died but none 
of the deaths were considered related to the patient’s infection or receipt of the AVYCAZ 
combined with ATM. 
2.3.1.4 Risks of Drawing Blood and Intravenous Infusions 
Risks associated with drawing blood from the subjects’ arm or administering IV fluids include 
momentary discomfort and/or bruising.  Infection, excess bleeding, clotting, or fainting are also 
possible, although unlikely. 
2.3.2 Potential Benefits 
There are no benefits to healthy subjects for their inclusion in this protocol.  However, data from 
this study may be helpful in determining safe treatment doses in patients with serious antibiotic 
resistant GNB infections. 


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STUDY DESIGN, OBJECTIVES AND ENDPOINTS OR 
OUTCOME MEASURES 
 
Study Design Description 
This is a Phase I, open-label, single center study in 48 healthy adult male and female subjects age 
18-45 years old (6 cohorts of 8 subjects) to investigate the safety and PK of AVYCAZ combined 
with ATM, AVYCAZ alone, and ATM alone. 
Following subject screening, eligible subjects will be assigned into one of the dosing cohorts. 
Subjects will be admitted to the study site on Day -1 for evaluations to confirm they continue to 
meet eligibility criteria, after which they will be admitted to the study site for dosing and 
observation.  Subjects will stay for a minimum of 7 nights and 8 days.  Cohorts 1-4 will be 
completed prior to Cohorts 5 and 6. 
Six dosing cohorts will be evaluated (see Section 4.3).  Four treatment cohorts are single agent 
dosing cohorts and will include AVYCAZ per label dosing, AVYCAZ as a CI, ATM per label 
dosing, and ATM as a CI.  Single drug treatment cohorts are being conducted to collect baseline 
safety and pharmacokinetic data.  The remaining two cohorts are two AVYCAZ combined with 
ATM regimens that were found to be effective in the aforementioned HFIM studies (see 
Section 2.1).  In the treatment cohorts in which the antibiotics are administered as a CI, an initial 
loading dose will be administered prior to starting the CI.  Since the maximum concentration of 
antibiotic (Cmax) is lower and the time for maximum concentration of drug (tmax) is delayed with 
CI, the initial loading dose is included to shorten the time it takes to achieve critical PK/PD 
associated with maximal response [20,25,26].  The use of initial loading doses is also congruent 
with clinical practice guideline recommendations to use PK/PD data to optimize dosing early in 
the course of therapy for patients with serious, life threatening infections [27, 28]. 
Study safety will be closely monitored using daily assessments of AE’s, vital signs and clinical 
laboratory safety tests.  Clinical laboratory safety tests will be collected on Day -1, Days 2, 4, 6 
and Day 8 (prior to discharge from the study site).  LFTs will be obtained daily beginning on 
Day 4 until a subject completes dosing.  The Final Visit (Day 11 + 3) will be scheduled with 
each subject for a final safety evaluation and collection of clinical laboratory safety tests. 
Plasma and urine concentrations of AVYCAZ and ATM will be quantified, when each antibiotic 
is given alone (AVYCAZ or ATM), and in combination (AVYCAZ combined with ATM) 
following the first dose and after multiple administrations.   
 
The study will run between approximately 12-15 months. 


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Study Objectives 
3.2.1 Primary 
• 
Describe the safety of two dosing regimens of AVYCAZ combined with ATM relative to 
AVYCAZ alone, and ATM alone in healthy adult subjects. 
3.2.2 Secondary 
• 
Characterize the PK profiles of two dosing regimens of AVYCAZ combined with ATM, 
AVYCAZ alone, and ATM alone at the population level in healthy adult subjects. 
• 
Characterize the PK profiles of two dosing regimens of AVYCAZ combined with ATM, 
AVYCAZ alone, and ATM alone following initiation of dosing on day 1 in healthy adult 
subjects. 
• 
Characterize the PK profiles of two dosing regimens of AVYCAZ combined with ATM, 
AVYCAZ alone, and ATM alone following multiple daily dosing in healthy adult subjects. 
3.2.3 Exploratory  
• 
Predict the distribution of plasma concentration-time profiles observed with two dosing 
regimens AVYCAZ combined with ATM, AVYCAZ alone, and ATM alone in healthy adult 
subjects via simulations. 
• 
Predict the distribution of urine cumulative urine amount-time profiles observed with two 
dosing regimens AVYCAZ combined with ATM, AVYCAZ alone, and ATM alone in 
healthy adult subjects via simulations. 
• 
Examine the associations between the plasma concentration-time profiles of AVYCAZ 
combined with ATM, AVYCAZ alone, and ATM alone and occurrence of ALT or AST 
elevations. 
 
Study Endpoints or Outcome Measures 
3.3.1 Primary  
• 
Number of subjects in each treatment cohort with at least one Grade 2 or higher treatment-
emergent AE from first dose through follow-up period. 
3.3.2 Secondary  
• 
Incidence and severity of all treatment-emergent AEs in each treatment cohort from first dose 
through follow-up period. 


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• 
Population mean PK parameter estimates and the magnitude of the associated 
inter-individual variability for AVYCAZ and ATM, when given alone and in combination. 
• 
Individual post-hoc PK parameter estimates and calculated exposure measures in plasma for 
AVYCAZ and ATM, when given alone and in combination following initial dosing on  
Day 1. 
• 
Individual post-hoc PK parameters estimates and calculated exposure measures in urine for 
AVYCAZ and ATM, when given alone and in combination following initial dosing on  
Day 1. 
• 
Individual post-hoc PK parameter estimates and calculated exposure measures in plasma for 
AVYCAZ and ATM, when given alone and in combination following multiple daily dosing. 
• 
Individual post-hoc PK parameters estimates and calculated exposure measures in urine for 
AVYCAZ and ATM, when given alone and in combination following multiple daily dosing.  
3.3.3 Exploratory  
• 
Distribution of simulated plasma concentration-time profiles associated with each treatment 
cohort. 
• 
Distribution of simulated urine concentration-time profiles associated with each treatment 
cohort. 
• 
Occurrence of ALT or AST elevations ≥ 3 times upper limit of normal (ULN) from first dose 
of study product through follow-up period. 
• 
Occurrence of ALT or AST elevations ≥ 5 times ULN from first dose of study product 
through follow-up period. 
• 
Changes in ALT or AST from first dose of study product through follow-up period. 


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STUDY INTERVENTION/STUDY PRODUCT 
 
Study Product Description 
AVYCAZ: 
AVYCAZ is an antibacterial combination product for intravenous administration consisting of 
the semisynthetic cephalosporin ceftazidime pentahydrate and the beta-lactamase inhibitor 
avibactam sodium at a fixed ratio of 4:1 [19]. 
• 
Ceftazidime 
Ceftazidime is a semisynthetic, beta-lactam antibacterial drug. It is the pentahydrate of 
(6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(2-carboxypropan-2-yloxyimino)acetamido)-8-oxo-3-
(pyridinium-1-ylmethyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate.  Its molecular 
weight is 636.6.  The empirical formula is C22H32N6O12S2. 
Figure 1: Chemical Structure of Ceftazidime Pentahydrate 
 
• 
Avibactam 
Avibactam sodium chemical name is sodium [(2S,5R)-2-carbamoyl-7-oxo-1,6-
diazabicyclo[3.2.1]octan-6-yl] sulfate.  Its molecular weight is 287.23. The empirical formula is 
C7H10N3O6SNa. 
Figure 2: Chemical Structure of Avibactam Sodium 
 


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AZACTAM® (aztreonam for injection, USP): 
AZACTAM® (aztreonam for injection, USP) injection contains the active ingredient ATM, a 
monobactam. It was originally isolated from Chromobacterium violaceum. It is a synthetic 
bactericidal antibiotic [18]. 
The monobactams, having a unique monocyclic beta-lactam nucleus, are structurally different 
from other beta-lactam antibiotics (e.g., penicillins, cephalosporins, cephamycins). The sulfonic 
acid substituent in the 1-position of the ring activates the beta-lactam moiety; an aminothiazolyl 
oxime side chain in the 3-position and a methyl group in the 4-position confer the specific 
antibacterial spectrum and beta-lactamase stability. Aztreonam is designated chemically as (Z)-
2-[[[(2-amino-4-thiazolyl)[[(2S,3S)-2-methyl-4-oxo-1-sulfo-3-
azetidinyl]carbamoyl]methylene]amino]oxy]-2-methylpropionic acid. 
Figure 3: Chemical Structure of ATM Injection 
 
4.1.1 Formulation, Packaging, and Labeling 
AVYCAZ (ceftazidime-avibactam) 
AVYCAZ 2.5 grams (2 grams ceftazidime and 0.5 grams avibactam) for injection is a white to 
yellow sterile powder for constitution consisting of ceftazidime pentahydrate and avibactam 
sodium packaged in glass vials.  The formulation also contains sodium carbonate [19]. 
Each AVYCAZ 2.5 grams single-dose vial contains ceftazidime 2 grams (equivalent to 2.635 
grams sterile ceftazidime pentahydrate/sodium carbonate) and avibactam 0.5 grams (equivalent 
to 0.551 grams sterile avibactam sodium). The sodium carbonate content of the mixture is 239.6 
mg/vial.  The total sodium content of the mixture is approximately 146 mg (6.4 mEq)/vial. 
AZACTAM® (aztreonam for injection, USP) 
AZACTAM (aztreonam for injection, USP) is a sterile, non-pyrogenic, sodium-free, white 
powder containing approximately 780 mg arginine per gram of ATM.  Following constitution, 
the product is for intramuscular or intravenous use.  Aqueous solutions of the product have a pH 
in the range of 4.5 to 7.5.   


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The study product vials will be labeled according to manufacturer or regulatory specifications.  
The dispensed study product (IV bags) will be labeled with the cautionary statement “For 
Investigational Use Only.” 
4.1.2 Product Storage and Stability 
AVYCAZ (ceftazidime-avibactam) 
Storage of AVYCAZ vials: 
• 
AVYCAZ vials should be stored at 20° to 25°C (68° to 77°F); excursions permitted between 
15°C and 30°C (59°F and 86°F) [See USP Controlled Room Temperature]. Protect from 
light. Store in carton until time of use [19]. 
Stability of AVYCAZ: 
• 
Upon constitution with appropriate diluent, the constituted AVYCAZ solution may be held at 
room temperature for no longer than 30 minutes prior to transfer and dilution in a suitable 
infusion bag. 
• 
Following dilution of the constituted solutions with the appropriate diluents, AVYCAZ 
solutions in the infusion bags are stable for 12 hours when stored at room temperature. 
• 
Following dilution of the constituted solutions with the appropriate diluents, AVYCAZ 
solutions in the infusion bags may also be refrigerated at 2 to 8°C (36 to 46°F) for up to 
24 hours; and then should be used within 12 hours of subsequent storage at room 
temperature. 
AZACTAM® (aztreonam for injection, USP): 
Storage of AZACTAM® (aztreonam for injection, USP): 
• 
Store AZACTAM® vials in original packages at room temperature; avoid excessive heat 
(above 40°C (104° F)). 
Stability of Intravenous AZACTAM®: 
• 
AZACTAM solutions for intravenous infusion at concentrations not exceeding 2% weight/ 
volume (w/v) must be used within 48 hours following constitution if kept at controlled room 
temperature 15° to 30°C (59° to 86°F) or within 7 days if refrigerated (2° to 8°C/ 36° to 
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Acquisition/Distribution 
AVYCAZ (ceftazidime-avibactam) 
AVYCAZ vials manufactured by Allergan will be purchased by the study site’s Investigational 
Pharmacy. 
AZACTAM® (aztreonam for injection, USP): 
AZACTAM® vials manufactured by Bristol-Myers Squibb will be obtained by the DMID 
Clinical Materials Services (CMS) and shipped to the following address at Fisher BioServices 
for storage and site distribution: 
DMID-CMS 
20439 Seneca Meadows Parkway 
Germantown, MD 20876 
Tel: 1 (240) 477-1350 
Fax: 1 (240) 477-1360 
E-mail: DMID.CMS@ThermoFisher.com 
AZACTAM® will be shipped to Duke IDS upon request by the study site and approval by 
DMID. 
Sterile Water for Injection (WFI), USP 
The sterile water for injection (WFI), USP is nonpyrogenic and contains no bacteriostatic, 
antimicrobial agent, or added buffer.  Each gram of ATM should be initially reconstituted with at 
least 3 mL WFI, USP.  Single-dose container WFI will be purchased by the study sites 
Investigational Pharmacy. 
0.9% Sodium Chloride, USP (Normal Saline) 
0.9% Sodium Chloride Injection, USP is a sterile, nonpyrogenic, isotonic solution of sodium 
chloride and water for injection.  Each mL contains 9 mg of sodium chloride and contains no 
preservatives, bacteriostatic, antimicrobial agent, or added buffer.  The solution is clear in 
appearance and may contain hydrochloric acid and/or sodium hydroxide for pH adjustment (pH 
5.3 [4.5 to 7.0]).  Normal saline in single use and IV bags will be purchased by the 
Investigational Pharmacy for dilution of AVYCAZ, preparation of IV administration bags for 
both study products and flushing of IV lines.  The appropriate size IV bag will be determined by 
the Investigational Pharmacy to ensure the correct amount of study product is being infused. 


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Dosage/Regimen, Preparation, Dispensing and Administration of Study 
Intervention/Study Product 
Both AVYCAZ and ATM will be prepared in separate IV bags according to the products’ IV 
infusion directions in the package insert. Complete instructions for dosage, preparation, labeling, 
storage, stability, and administration is detailed in protocol-specific Manual of Procedures 
(MOP).  Dosing will be completed the morning of Day 7 for all cohorts. 
For cohorts 5 and 6, both drugs will be administered either via a double lumen catheter 
connected to separate ports, or via a single lumen Y-site injection port.  Stability data in both the 
AVYCAZ and ATM package insert and protocol-specific Y-site stability studies support CI 
administration outlined in Table 1. 
The infusion times listed in the table below are approximate (refer to the MOP for infusion time 
windows).  Dose modifications will not be permitted. 
Table 1: Treatment Cohorts (8 subjects/cohort) 
Cohort 1: 
AVYCAZ 2.5 g IV as a 2-hour infusion every 8 hours for 7 days  
(19 total doses) 
Cohort 2: 
AVYCAZ 2.5 g IV as a 2-hour infusion x 1, then 0.32 g per hour IV daily as a 
CI (7.5 g/day) for 7 days (20 total doses, IV bag changes every 8 hours for CI) 
Cohort 3: 
ATM 2 g IV as a 2-hour infusion every 6 hours for 7 days  
(25 total doses) 
Cohort 4: 
ATM 2 g IV as a 2-hour infusion x 1, then 0.33 g per hour IV daily as a CI 
(8 g/day) for 7 days (14 total doses, IV bag changes every 12 hours for CI) 
Cohort 5: 
AVYCAZ 2.5 g IV as a 2-hour infusion every 8 hours for 7 days and ATM 
1.5 g IV as a 2-hour infusion every 6 hours for 7 days  
(AVYCAZ 19 total doses; ATM 25 total doses) 
Cohort 6*: 
AVYCAZ 2.5 g IV as a 2-hour infusion  every 8 hours for 7 days and ATM 2 g 
IV as a 2-hour infusion  every 6 hours for 7 days  
(AVYCAZ 19 total doses; ATM 25 total doses) 
*A SMC meeting will be convened after completion of cohort 5 to assess whether the study may 
proceed to cohort 6.   
 
 


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Accountability Procedures for the Study Intervention/Study Product(s) 
AVYCAZ will be purchased by the study site’s Investigational Pharmacy. ATM will be obtained 
by the DMID CMS and shipped to Duke IDS upon request by the study site and approval by 
DMID. Once received, AVYCAZ and ATM will be stored in and dispensed by the 
Investigational Pharmacy. Unused product will be destroyed and documented per institutional 
procedures. 
The FDA requires accounting for the disposition of all study products. The Investigator is 
responsible for ensuring that a current record of product disposition is maintained and product is 
dispensed only at an official study site by authorized personnel as required by applicable 
regulations and guidelines. Records of study product disposition, as required by federal law, 
consist of the date received at the Investigational Pharmacy, lot number(s), each subject assigned 
study number, date, lot number(s) and quantity administered to each subject and final disposition 
for unused study product.  
The Investigational Pharmacist will be responsible for maintaining accurate records of the 
shipment and dispensing of the study product. The pharmacy records must be available for 
inspection by the Division of Microbiology and Infectious Diseases (DMID) monitoring 
contractors and is subject to inspection by a regulatory agency (e.g., FDA) at any time. An 
assigned Study Monitor will review the pharmacy records. 


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SELECTION OF SUBJECTS AND STUDY ENROLLMENT 
AND WITHDRAWAL 
Subject inclusion and exclusion criteria must be confirmed by a study clinician licensed to make 
medical diagnoses. 
No exemptions are granted on subject Inclusion/Exclusion Criteria in DMID-sponsored studies. 
Questions about eligibility will be directed toward the DMID Medical Officer. 
The study site will determine the most efficient procedures to identify potentially eligible 
subjects from the general public for the study.   
 
Eligibility Criteria 
5.1.1 Subject Inclusion Criteria 
A subject must meet all the following criteria to be considered eligible for inclusion in this study: 
1. Provide a signed and dated written informed consent. 
2. Be able to understand and willing to comply with study procedures, restrictions, and 
requirements, as determined by the Principal Investigator (PI). 
3. Male and female volunteers aged 18 to 45 years inclusive.  
4. Suitable veins for cannulation or repeated venipuncture. 
5. Subject must be in good general health as judged by the investigator as determined by 
medical history, vital signs1, body mass index (BMI) and body weight2, clinical laboratory 
values3, and physical examination (PE). 
 
1 Oral temp <38.0°C/100.4°F; pulse 50 to 100 bpm; systolic blood pressure 90 to 140 mm Hg, and diastolic blood 
pressure 55 to 90 mmHg. 
2 BMI between 19-33 kg/m2 and body weight ≥ 50 kg 
3 Clinical chemistry, hematology, coagulation and urinalysis results within the clinical laboratory reference ranges; 
clinical laboratory values outside these ranges, if considered by the site investigator to be clinically insignificant, are 
also acceptable 


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6. Sexually active female subjects must be of non-childbearing potential4 or must use a highly 
effective method of birth control5. 
7. Sexually active male subjects must be vasectomized or agree to use barrier contraception 
(condom with spermicide) from first dose of study product until 30 days following the last 
dose of study product. 
8. Nonsmokers defined as abstinence from cigarette smoking or use of nicotine-containing 
products for 6 months prior to enrollment into the study. 
5.1.2 Subject Exclusion Criteria 
A subject must not meet any of the following criteria to be considered eligible for inclusion in 
this study: 
1. History of any clinically significant (CS) disease or disorder, medical/surgical procedure, or 
trauma within 4 weeks prior to the first administration of study product(s)6. 
2. History or presence of gastrointestinal, hepatic, or renal disease, or any other condition 
known to interfere with absorption, distribution, metabolism, or excretion of drugs. 
3. Known history of a clinically important allergy/hypersensitivity to AVI, any monobactam, 
any beta-lactam and/or L-arginine. 
4. Receipt of probenecid or furosemide within 14 days prior to study enrollment 
5. Receipt of any antibiotics within 14 days prior to study enrollment. 
6. Receipt of prescription medications (except birth control pills or hormone replacement in 
females) within 14 days prior to study enrollment, unless in the opinion of site investigator 
the medication will not interfere with the study procedures or impact subject safety. 
 
4 Non-childbearing potential is defined as being post-menopausal for at least 18 months or surgically sterile via 
hysterectomy, bilateral oophorectomy, or tubal sterilization. 
5 Sexually active female subjects of childbearing potential must avoid becoming pregnant by using one of the 
following acceptable methods of birth control for 30 days prior to study product dosing and must be maintained for 
30 days after last dose of study product: 
- 
Intrauterine contraceptive device; OR 
- 
Approved hormonal contraceptives (such as birth control pills, skin patches, Implanon®, Nexplanon®, 
DepoProvera®, or NuvaRing®); OR 
Birth control must be captured on the appropriate data collection form. 
6 In the opinion of the PI, may either put the volunteer at risk because of participation in the study, or influence the 
results or the volunteer's ability to participate in the study. 


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7.   Receipt of non-antibiotic medications that interacts with OAT37 within 14 days prior to 
study enrollment. 
8.   Receipt of herbal and dietary supplements (including St. John’s Wort) within 14 days prior 
to study enrollment. 
9.   ALT or AST laboratory value above the ULN as defined in the toxicity table in Appendix 
B. 
10. Prolonged QTcF (> 450 msec) or shortened QTcF (< 340 msec) or family history of long QT 
syndrome.  Any clinically important abnormalities in rhythm, conduction, or morphology of 
resting ECG.8 
11. Any positive result on screening for human immunodeficiency virus (HIV) serum hepatitis B 
surface antigen (HBsAg) and hepatitis C virus (HCV) antibody. 
12. Creatinine clearance equal or less than 80 mL/minute (measured by Cockcroft-Gault  
method) [23]. 
13. History of Clostridium difficile infection in past 90 days. 
14. Known or suspected history of drug or alcohol abuse within the last 5 years, as judged by the 
PI.  
15. Positive screen for drugs of abuse, cotinine (nicotine), or alcohol at screening and at 
admission to the study site prior to the first administration of the study products(s). 
16. Received a new chemical entity (compound not approved for marketing) or participated in a 
study that included drug treatment within 1 month of the first dose of study product(s) for 
study.9 
Note:  subjects consented and screened, but not dosed in this study or a previous Phase I 
study will not be excluded. 
17. Previous participation in the present study. 
18. Involvement in the planning and/or conduct of the study. 
 
7 Adefovir, Anagliptin,  Baricitinib, Cefaclor, Cimetidine, Ciprofloxacin (Systemic), Clofarabine, Eluxadoline, 
Empagliflozin, Furosemide, Ketoprofen, Methotrexate, Mycophenolate, PEMEtrexed, Penicillin G 
(Parenteral/Aqueous), Penicillin G Benzathine, Penicillin G Procaine, Penicillin V Benzathine, Penicillin V 
Potassium, Zidovudine 
8 Abnormalities that may interfere with interpretation of QTc interval changes per the medical judgment of the PI. 
9 Period of exclusion begins at the time of the last visit of the prior study. 


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19. Any ongoing/recent (during screening) medical complaints that may interfere with analysis 
of study data or are considered unlikely to comply with study procedures, restrictions, and 
requirements.10 
20. Known history of past or current epilepsy or seizure disorders, excluding febrile seizures of 
childhood. 
 
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 voluntarily withdraw their consent for study participation at any time without 
penalty or loss of benefits to which they are otherwise entitled.   
An investigator may also withdraw a subject from receiving the study product for any reason. If 
the subject agrees, follow-up safety evaluations will be conducted.  If a subject withdraws or is 
withdrawn prior to completion of the study, the reason for this decision must be recorded in the 
case report forms (CRFs).  
The reasons, might include, but are not limited to the following: 
• 
Subject withdraws consent 
• 
Subject no longer meets eligibility criteria 
• 
Subject meets individual halting criteria (see Section 8.6.2) 
• 
Subject becomes noncompliant 
• 
Medical disease or condition or new clinical finding(s) for which continued participation, in 
the opinion of the investigator might compromise the safety of the subject, interfere with the 
subject’s successful completion of this study, or interfere with the evaluation of responses 
• 
Subject lost to follow-up 
The investigator should be explicit regarding study follow-up (e.g. safety follow-up) that might 
be carried out despite the fact the subject will not receive further study product.  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 must be inclusive in the original informed consent 
 
10 Judgment by the PI that the subject should not participate in the study. 


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or the investigator may seek subsequent informed consent using an IRB/IEC-approved consent 
form with the revised procedures. 
Every attempt should be made to complete a physical examination and all Day 8 procedures for 
all subjects who withdraw from the study or discontinue study product. 
The investigator will inform the subject that any data already collected will be retained and 
analyzed even if the subject withdraws from this study.  
5.2.2 Subject Replacement 
Subjects who are enrolled but drop out before receiving study product(s) will be replaced.  If two 
or more subjects in a dosing cohort have an incomplete PK profile, subjects will be replaced in 
that dosing cohort to ensure there are at least seven subjects with complete PK profiles in each 
dosing cohort.  A subject will be considered to have a complete PK profile if  ≥70% of plasma 
PK samples are collected.  For participants who have incomplete PK profiles, their available PK 
data will be considered in the PK analyses. 
5.2.3 Study Termination  
If the study is prematurely terminated by the sponsor, any regulatory authority, or the 
investigator for any reason, the investigator will promptly inform the study subjects and assure 
appropriate therapy or follow-up for the subjects, as necessary (see Section 6.4 and 8.3). The 
investigator will provide a detailed written explanation of the termination to the IRB/IEC. 


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STUDY PROCEDURES 
The study schedule is outlined below and in the Schedule of Events (Appendix A).  Protocol 
waivers or exemptions are not allowed. Therefore, adherence to the study design requirements, 
including those specified in the Schedule of Events, is required. 
Amendments or changes to the protocol require the approval of the sponsor and the Institution 
Review Board (IRB). 
 
Screening (Days -30 to Day -2) 
The study site will determine the most efficient procedures to identify potentially eligible 
subjects for the study. Subjects will report to the study site between Days -30 to Day -2. The 
study will be explained to each potential subject.  A signed and dated IRB-approved informed 
consent form (ICF) must be properly obtained from each subject before any study-specific test or 
evaluation is administered.  Approximately 75 subjects will be screened to enroll 48 evaluable 
subjects.  Individuals who agree to participate and sign the informed consent will undergo the 
following procedures [also see Schedule of Events (Appendix A)].   
• 
Obtain informed consent 
• 
Review and obtain medical history, concomitant medication(s), demographics, height, and 
weight.  Ensure review of any history of hypersensitivity to drugs with a similar chemical 
structure or class to ATM, AVI or CAZ. 
• 
Complete physical examination 
• 
Vital signs:  Systolic and diastolic blood pressures (mmHg), pulse rate (BPM), respiratory 
rate, and body temperature (oral measurement) 
• 
12-lead ECG in triplicate (mean value of ECGs will be used to determine study eligibility) 
• 
Clinical chemistry:  sodium (Na), potassium (K), chloride (Cl), bicarbonate (HCO3), blood 
urea nitrogen (BUN), serum creatinine, glucose, albumin, total protein, total bilirubin, ALT, 
AST, ALP and lactate dehydrogenase (LDH) 
• 
Hematology:  Hemoglobin, hematocrit, white blood cell count (WBC), WBC differential, red 
blood cell count (RBC), platelets  
• 
Coagulation:  PT and Partial thromboplastin time (PTT) 
• 
Viral serology:  HIV, HBsAg, HCV antibody 
• 
Coombs test 


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• 
Urinalysis: dipstick urinalysis, including protein, glucose, ketones, bilirubin, blood, nitrites, 
leukocyte esterase (LCE), urobilinogen, specific gravity, and pH. 
NOTE: The administration of ceftazidime may result in a false-positive reaction for glucose 
in the urine with certain methods.  The clinical laboratory equipment will measure glucose 
via glucose oxidase reactions, which is not affected by ceftazidime administration. [17] 
• 
Urine drug screening 
• 
Pregnancy testing (females of child bearing potential only): Serum human chorionic 
gonadotropin (hCG) 
• 
Alcohol Screen Breathalyzer 
• 
Cotinine Test 
 
Enrollment (Day -1) 
Subjects will report to the study site on Day -1 for the procedures listed below and in the 
Schedule of Events (Appendix A).  Once eligibility has been confirmed, subjects will be enrolled 
into the study and assigned to a treatment cohort. Assessments at Day -1 will serve as baseline 
values.  Subjects will remain at the study site until discharge on Day 8 or until withdrawal from 
the study (see Section 5.2). 
• 
Complete physical examination, height and weight, concomitant medication review and 
review for changes in medical history 
• 
Vital signs:  Systolic and diastolic blood pressures (mmHg), pulse rate (BPM), respiratory 
rate, and body temperature (oral measurement) 
• 
Single 12-lead ECG 
• 
Clinical chemistry:  Na, K, Cl, HCO3, BUN, serum creatinine, glucose, albumin, total 
protein, total bilirubin, ALT, AST, ALP and LDH 
• 
Hematology:  Hemoglobin, hematocrit, WBC, WBC differential, RBC, platelets 
• 
Coagulation:  PT and PTT 
• 
Urinalysis and urine drug screening 
• 
Pregnancy testing (females of child bearing potential only): Serum hCG if not already 
performed within 48 hours of Day -1. Results must be available prior to administration of 
study product. 


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• 
Alcohol Screen Breathalyzer 
• 
Cotinine Test 
 
Planned Study Visits (Days 1 – 8) 
6.3.1 Treatment (Day 1) 
The following procedures will be completed as listed below and in the Schedule of Events 
(Appendix A): 
• 
Symptom directed physical exam 
• 
Vital signs will be obtained prior to dosing on Day 1 and 1 hour after starting AM dose 
• 
Monitoring for AEs will begin after the first dose of study product 
• 
Review for any new medication 
• 
Study product administration as outlined in Section 4 
• 
Plasma and urine PK as outlined in Sections 7.2.2. 
6.3.2 Treatment (Day 2) 
The following procedures will be completed as listed below and in the Schedule of Events 
(Appendix A): 
• 
Symptom directed physical exam 
• 
Vital signs will be obtained in the morning 
• 
Monitor for AEs. 
• 
Review for any new medication 
• 
Study product administration as outlined in Section 4. 
• 
Clinical chemistry:  Na, K, Cl, HCO3, BUN, serum creatinine, glucose, albumin, total 
protein, total bilirubin, ALT, AST, ALP and LDH 
• 
Hematology:  hemoglobin, hematocrit, WBC, WBC differential, RBC, platelets 
• 
Coagulation:  PT and PTT 


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6.3.3 Treatment (Day 4, 6) 
The following procedures will be completed as listed below and in the Schedule of Events 
(Appendix A): 
• 
Symptom directed physical exam 
• 
Vital signs will be obtained in the morning 
• 
Monitor for AEs. 
• 
Review for any new medication 
• 
Study product administration as outlined in Section 4. 
• 
Clinical chemistry:  Na, K, Cl, HCO3, BUN, serum creatinine, glucose, albumin, total 
protein, total bilirubin, ALT, AST, ALP and LDH 
• 
Hematology:  hemoglobin, hematocrit, WBC, WBC differential, RBC, platelets 
• 
Coagulation:  PT and PTT 
• 
Day 4 only: Urinalysis 
• 
Day 6 only: Urine PK as outlined in Section 7.2.2.2 
6.3.4 Treatment (Day 3, 5, 7) 
The following procedures will be completed as listed below and in the Schedule of Events 
(Appendix A): 
• 
Symptom directed physical exam 
• 
Vital signs will be obtained in the morning 
• 
Monitor for AEs 
• 
Review for any new medication 
• 
Study product administration as outlined in Section 4. 
• 
Plasma PK as outlined in Section 7.2.2.1 
• 
Day 5 and 7 only: LFTs: ALT, AST, ALP, and total bilirubin 
6.3.5 Discharge (Day 8) 
The following procedures will be completed as listed below and in the Schedule of Events 
(Appendix A): 


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• 
Complete physical examination, concomitant medication review and review for changes in 
medical history 
• 
Vital signs will be obtained in the morning 
• 
Single 12-lead ECG 
• 
Assessment of AEs 
• 
Clinical chemistry:  Na, K, Cl, HCO3, BUN, serum creatinine, glucose, albumin, total 
protein, total bilirubin, ALT, AST, ALP and LDH 
• 
Hematology:  Hemoglobin, hematocrit, WBC, WBC differential, RBC, platelets 
• 
Coagulation:  PT and PTT 
• 
Coombs Test 
• 
Urinalysis 
• 
Plasma PK as outlined in Section 7.2.2.1 
• 
Schedule Day 11 Final Study Visit 
6.3.6 Final Study Visit (Day 11 +3) 
Subjects will report to the study site on Day 11 + 3 for the final study visit and completion of the 
assessments as listed below and in the Schedule of Events (Appendix A): 
• 
Complete physical examination and concomitant medication review 
• 
Vital signs 
• 
Single 12-lead ECG 
• 
Assessment of AEs 
• 
Clinical chemistry:  Na, K, Cl, HCO3, BUN, serum creatinine, glucose, albumin, total 
protein, total bilirubin, ALT, AST, ALP and LDH 
• 
Hematology:  Hemoglobin, hematocrit, WBC, WBC differential, RBC, platelets 
• 
Coagulation:  PT and PTT 
• 
Urinalysis 


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Early Termination Visit  
• 
In circumstances where a subject discontinues the study early, an early termination visit will 
be performed. Every attempt should be made to complete a physical examination and all 
other Day 8 procedures for all subjects who withdraw from the study or discontinue study 
product.  The reason(s) for early termination should be reflected in the source documentation 
and the Study Termination electronic case report form (eCRF).  Complete physical 
examination, concomitant medication review and review for changes in medical history 
• 
Vital signs 
• 
Single 12-lead EGC 
• 
Assessment of AEs 
• 
Clinical chemistry:  Na, K, Cl, HCO3, BUN, serum creatinine, glucose, albumin, total 
protein, total bilirubin, ALT, AST, ALP and LDH 
• 
Hematology:  Hemoglobin, hematocrit, WBC, WBC differential, RBC, platelets  
• 
Coagulation:  PT and PTT 
• 
Coombs Test 
• 
Urinalysis 
• 
Sample for a single plasma PK level 
 
Unscheduled Study Visits 
The PI may decide a subject requires an unscheduled visit outside the normal schedule. At a 
minimum this visit will include a physical exam, clinical chemistry, hematology, coagulation 
test, and AE assessment.  However the following may be included based on the judgement of  
the PI. 
• 
Complete physical examination, concomitant medication review and review for changes in 
medical history 
• 
Vital signs 
• 
Single 12-lead ECG 
• 
Assessment of AEs 
• 
Clinical chemistry:  Na, K, Cl, HCO3, BUN, serum creatinine, glucose, albumin, total 
protein, total bilirubin, ALT, AST, ALP and LDH 


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• 
Hematology:  Hemoglobin, hematocrit, WBC, WBC differential, RBC, platelets 
• 
Coagulation:  PT and PTT 
• 
Coombs Test 
• 
Urinalysis 
• 
Sample for a single plasma PK level (optional) 
Unscheduled study visits will be assigned a trailing alpha letter after the study day number.  For 
example, if a subject has an unscheduled study day that occurs between study day 1 and study 
day 2, the study visit day would be numbered as study day 1S. 
 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial 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 are to 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 five working days of identification of the protocol deviation, or within 
five 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 study subject data collection 
forms.  A completed copy of the DMID Protocol Deviation Form must be maintained in the 
Regulatory File, as well as in the subject’s chart.  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 Research Procedures 
The following will be obtained: 
• 
Complete medical history – subjects will be queried regarding a history of significant 
medical disorders and any allergies.  Specifically querying if the subject has a history of 
hypersensitivity to drugs with a similar chemical structure or class to ATM, AVI or CAZ. 
• 
Complete medications history – subjects will be queried regarding all prescription and over-
the-counter medications and supplements taken within 24 hours and any study products taken 
within 90 days prior to start of study products. 
• 
A complete physical examination should include general appearance, neurological, head, eye, 
ear, nose, throat (HEENT), cardiovascular, lungs, abdomen, musculoskeletal, and skin 
examinations.  The physical examination performed at Day -1 will serve as the baseline for 
clinical assessments.  
• 
A targeted or focused physical examination is symptom directed and includes neurological, 
HEENT, and musculoskeletal examinations and is specifically related to reported AEs during 
the study (e.g., abdomen for AEs of vomiting or diarrhea). 
• 
Height and weight will be measured at Screening and Day -1 to calculate the BMI. 
• 
Vital signs should be collected after resting in supine position.  Vital signs include systolic 
and diastolic blood pressures (mmHg), pulse rate (BPM), respiratory rate, and body 
temperature. 
• 
The PI or his designee will interpret ECGs in real time during inpatient dosing periods and 
within 12 hours for late-night tracings. If a CS abnormality is detected, an appointed 
cardiologist at the study site will immediately interpret the ECG. A licensed physician listed 
on Form FDA 1572 will review the final results. Subjects with CS findings will be referred 
either to the emergency department or to their primary care physician for follow-up. 
An ECG will be recorded in triplicate approximately 2 minutes apart at the Screening visit. 
Single ECGs will be recorded on Days -1, 8, and 11 (+3).  Subjects must be lying supine or 
sitting for 10 minutes before recording the ECG tracings. 


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The ECGs will be printed and evaluated by an appropriately qualified physician at the study 
site. The reader will sign and date the safety ECGs and provide a global interpretation using 
the following categories: 
• 
Normal ECG 
• 
Abnormal ECG-not clinically significant (NCS) 
• 
Abnormal ECG-CS 
• 
Unable to evaluate 
• 
Other -details will be noted in the source document and eCRF 
7.1.2 Assessment of Concomitant Medications/Treatments Other Than Study Product 
Use of concomitant medications (probenecid and furosemide) that are contraindicated in the 
AVYCAZ and ATM package inserts will not be permitted [18,19].  Subjects taking such 
medications will not be eligible for the study.   
Patients who received antibiotics within the 14 days prior to study enrollment will not be eligible 
for the study.  
Patients receiving a non-antibiotic medication that interacts with OAT3 (e.g., Adefovir, 
Anagliptin, Baricitinib, Cefaclor, Cimetidine, Ciprofloxacin (Systemic), Clofarabine, 
Eluxadoline, Empagliflozin, Furosemide, Ketoprofen, Methotrexate, Mycophenolate, 
PEMEtrexed, Penicillin G (Parenteral/Aqueous), Penicillin G Benzathine, Penicillin G Procaine, 
Penicillin V Benzathine, Penicillin V Potassium, Zidovudine) will not be included [30,31]. 
In addition, no prescription (except birth control pills or hormone replacement in females) or 
non-prescription drugs will be permitted, unless in the opinion of site investigator the medication 
will not interfere with the study procedures or impact subject safety.  The use of herbal and 
dietary supplements (including St. John’s Wort) will not be permitted during the study. 
7.1.3 Assessment of Subject Compliance With the Study Visit Schedule 
The Investigational Pharmacist or designee is responsible for the reconstitution and labeling of 
the study products. Study products will be administered via IV infusion by a member of the 
clinical research team who is licensed to administer the study products. Administration will be 
documented on the source document and entered into the eCRF. 
Study product compliance including start and stop time of infusion, volume administered, and 
the occurrence of any infusion interruptions (greater than 10 minutes) will be captured in the 
source documents. 


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Laboratory Evaluations 
Subjects will have up to approximately 135 mL of blood drawn for safety laboratory tests in each 
of the study cohorts.   
Safety laboratory monitoring will include:  hematology, clinical chemistry, LFTs, coagulation, 
viral serology and urinalysis. 
7.2.1 Clinical Laboratory Evaluations 
• 
Clinical chemistry:  Na, K, Cl, HCO3, BUN, serum creatinine, glucose, albumin, total 
protein, total bilirubin, ALT, AST, ALP and LDH 
• 
LFTs: ALT, AST, ALP, and total bilirubin 
• 
Hematology:  Hemoglobin, hematocrit, WBC, WBC differential, RBC, platelets 
• 
Coombs Test 
• 
Coagulation:  PT, PTT 
• 
Serology: HIV, HBsAg, HCV 
• 
Urinalysis:  dipstick urinalysis, including protein, glucose, ketones, bilirubin, blood, nitrites, 
LCE, urobilinogen, specific gravity, and pH.  The administration of ceftazidime may result in 
a false-positive reaction for glucose in the urine with certain methods.  The clinical 
laboratory equipment will measure glucose via glucose oxidase reactions, which is not 
affected by ceftazidime administration. 
• 
Pregnancy testing (females of child bearing potential only): Serum human chorionic 
gonadotropin (hCG).  
• 
Alcohol screen breathalyzer 
• 
Cotinine Test 
• 
Urine drug screen:  amphetamines, barbiturates, benzodiazepines, cocaine metabolites, 
opiates, cannabinoids and phencyclidine 


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7.2.2 Research Assays 
7.2.2.1 Plasma Pharmacokinetic Sample Collection 
Venous plasma samples for pharmacokinetic analyses of AVYCAZ and ATM will be collected 
at the following time points ±5 minutes for pre-dose, during, and end of short infusion samples 
and then ±15 minutes for other samples.  The actual date and time of each blood sample 
collection will be recorded in the subjects’ source document and the eCRF.  The timing of the 
study assessments should allow the blood draw to occur at the exact nominal time. 
Approximately 192 mL of blood will be obtained from each subject for determining plasma 
AVYCAZ and ATM for each dosing regimen.  Blood collected will be processed at the study 
site’s laboratory. 
Cohort 1 (AVYCAZ Q8 hours treatment cohort) 
• 
Day 1: blood samples will be collected pre-dose (10 minutes prior to the start of 1st infusion), 
0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, and 8 hours after the start of the 1st infusion (8 hour sample 
must be collected prior to the start of the 2nd dose of AVYCAZ). 
• 
Day 3: Blood samples will be collected 10 minutes prior to the start of the 1st infusion on 
Day 3. 
• 
Day 5: Blood samples will be collected 10 minutes prior to the start of the 1st infusion on 
Day 5. 
• 
Day 7, blood samples will be collected pre-dose (10 minutes prior to the start of the morning 
infusion on Day 7, which is the last infusion of the study), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 
10, 12, 18, and 24 hours after the start of the Day 7 infusion. 
Cohorts 2, 4 (CI treatment cohort) 
• 
Day 1: blood samples will be collected at pre-dose (10 minutes prior to the start of 
1st infusion), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, and 8 hours after the start of the 1st infusion of 
Day 1.  
• 
Day 3: Blood samples will be collected 10 minutes prior to the start of the 1st infusion on 
Day 3. 
• 
Day 5: Blood samples will be collected 10 minutes prior to the start of the 1st infusion on 
Day 5. 
• 
Day 7: Blood samples will be collected 10 minutes prior to the start of the 1st infusion(s) on 
Day 7 (last infusion(s) of the study), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, 12, 18, and 
24 hours after the start of the Day 7 infusion(s). 


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Cohort 3 (ATM Q6 hours treatment cohort) 
• 
Day 1: blood samples will be collected pre-dose (10 minutes prior to the start of 1st infusion), 
0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6 (6 hour sample must be collected prior to the start of the 2nd dose 
of ATM), 7, and 8 hours after the start of the 1st infusion.  
• 
Day 3: Blood samples will be collected 10 minutes prior to the start of the 1st infusion on 
Day 3. 
• 
Day 5: Blood samples will be collected 10 minutes prior to the start of the 1st infusion on 
Day 5. 
• 
Day 7: blood samples will be collected pre-dose (10 minutes prior to the start of the morning 
infusion on Day 7, which is the last infusion of the study), 0.5, 1, 1.5, 2 , 2.5, 3, 4, 5, 6, 7, 8, 
10, 12, 18, and 24 hours after the start of the Day 7 infusion. 
Cohort 5, 6 (AVYCAZ Q8 hours + ATM Q6 hours treatment cohort) 
• 
Day 1: blood samples will be collected pre-dose (10 minutes prior to the start of 1st infusion), 
0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6 (6 hour sample must be collected prior to the start of the 2nd dose 
of ATM), 7, and 8 hours after the start of the 1st infusion (8 hour sample must be collected 
prior to the start of the 2nd dose of AVYCAZ).  
• 
Day 3: Blood samples will be collected 10 minutes prior to the start of the 1st infusion on 
Day 3. 
• 
Day 5: Blood samples will be collected 10 minutes prior to the start of the 1st infusion on 
Day 5. 
• 
Day 7: blood samples will be collected pre-dose (10 minutes prior to the start of the morning 
infusion on Day 7, which is the last infusion of the study), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 
10, 12, 18, and 24 hours after the start of the Day 7 infusion. 
7.2.2.2 Urine Pharmacokinetic Sample Collection 
Each study subject will have serial urine samples collected on Day 1 and Day 6 to determine 
urine concentrations of AVYCAZ and ATM alone and in combination.  The actual date and time 
of each urine sample collection will be recorded in the subjects’ source document and the eCRF.  
The total volume of urine for each collection interval will be recorded. After measuring total 
volume of urine for each collection interval, aliquots of urine samples will be taken from the 
collected urine sample and transferred into suitably labeled polypropylene cryogenic sample 
storage vials and maintain being chilled before being transferred to freezer. 


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Days 1 and 6: 
Serial urine samples will be collected for all cohorts at the following intervals:  >0 to 4, >4 to 8, 
>8 to 12, and >12 to 24 hours after the start of the morning dose administration(s) of the day. 
7.2.2.3 Laboratory Specimen Preparation, Handling, and Storage 
Plasma and urine PK specimens will be processed and stored in a -80oC freezer until time of 
shipment to Keystone Bioanalytical laboratory for analysis. 
Detailed instructions for the preparation, handling, and storage of plasma and urine PK 
specimens are detailed in the study MOP including aliquots of specimens, temperature 
requirements, where they will be stored, and how they will be labeled. 
7.2.2.4 Laboratory Specimen Shipping 
After the completion of each dosing cohort, both plasma and urine PK samples for all subjects in 
each cohort will be shipped on dry ice to Keystone Bioanalytical laboratory for analysis.  
Samples will be shipped in compliance with the International Air Transport Association (IATA) 
regulations.  Plasma and urine PK samples will be shipped in separate shipping containers.  
Instructions for the shipment of specimens are outlined in the study MOP. 


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ASSESSMENT OF SAFETY 
 
Assessing and Recording Safety Parameters 
This study will assist in determining the safety profile for the combination of AVYCAZ with 
ATM, AVYCAZ alone and ATM alone.  The same safety data will be collected across all 
treatment cohorts.  AVYCAZ and ATM both are approved drugs with established safety profiles.  
However, the AVYCAZ CI regimens examined as part of this study are not FDA approved.  
There is also limited published safety data on ATM alone. 
To ensure a clear comparison of safety between the single dose cohorts and the combination 
dosing cohorts for this study, AEs will be collected for all study cohorts.   
8.1.1 Adverse Events (AEs) 
Monitoring for AEs will begin after starting infusion of the first dose of study product on Day 1 
through the final Study Visit on Day 11 +3.   
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 local (infusion site) and systemic reactions, will be captured on the 
appropriate data collection form and eCRF.  Information to be collected for AEs includes event 
description, date of onset, assessment of severity, relationship to study product and alternate 
etiology (assessed only by those with the training and authority to make a diagnosis and listed on 
the Form FDA 1572 as an investigator), 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, return to pretreatment status 
or stabilization of the condition with the expectation that it will remain chronic. 
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 worsens, it should be recorded as an AE. 


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8.1.1.1 Adverse Events Grading 
All AEs (laboratory and clinical symptoms) will be graded for severity (Appendix B) and 
assessed for relationship to study product (see definitions below). 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 data collection form and eCRF. Changes 
in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of intensity. 
Severity of Event:   
AEs will be assessed by the investigator using a protocol-defined grading system (Laboratory 
and Vital Signs Reference Ranges, Eligibility Ranges, and Toxicity Grading information in 
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 (less than 48 hours) 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 (use of non-narcotic pain reliever or over-the-counter medication).  The event 
interferes with usual activities of daily living, causing discomfort but poses no significant or 
permanent risk of harm to the research participant. 
• 
Severe (Grade 3):  Events interrupt usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention (requires prescription 
medication, or IV fluids or medical procedure).  Severe events are usually incapacitating. 
Relationship to Study Product: The assessment of the AE’s relationship to study product will 
be done by the licensed study physician indicated on the Form FDA 1572 and the assessment 
will be part of the documentation process.  Whether the AE is related or not to the study product, 
is not a factor in determining what is or is not recorded in the eCRF in this trial.  If there is any 
doubt as to whether a clinical observation is an AE, the event should be recorded in the eCRF. 
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 event. 


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8.1.2 Serious Adverse Events (SAEs) 
An AE is considered an SAE if, in the view of either the site PI or sponsor, it results in any of the 
following outcomes:  
• 
Death, 
• 
a life-threatening AE11, 
• 
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, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
All 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 the Form FDA 1572 or by the 
Institution as the site PI or Sub-Investigator. 
• 
Recorded on the appropriate SAE data collection form and eCRF. 
Followed through resolution or stabilization, even if this extends beyond the study-reporting 
period, by a licensed study physician (for Investigational New Drug Application (IND) studies, a 
physician listed on the Form FDA 1572 as the site PI or Sub-Investigator). 
• 
Reviewed and evaluated by DMID, an Independent Safety Monitor (ISM) (as deemed 
necessary) or SMC (periodic review unless related), and the IRB/IEC. 
 
11 Life-threatening adverse event. 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 


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Specification of Safety Parameters 
8.2.1 Solicited Events 
Solicited events will not be collected as part of this study. 
8.2.2 Unsolicited Events 
Unsolicited events are AEs that occur following administration of study product.  Subjects can 
be queried as needed to evaluate occurrence of any AEs. 
 
Reporting Procedures 
8.3.1 Reporting Serious Adverse Events 
For this study, all AE/SAEs occurring from first dose of study product on Day 1 through Day 
11 + 3 days after last dose of study product(s) will be collected in the eCRF.   
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 the SDCC system 
that must match the data on the SAE Report form. 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.  
The site will send a copy of the SAE report(s) to the ISM when they are provided to the DMID 
Pharmacovigilance Group.  The DMID Medical Monitor (MM) 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 PI 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. 
8.3.2 Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND 
Following notification from the site PI or appropriate sub-investigator, DMID, as the IND 
sponsor, will report any suspected unexpected serious adverse event (SUSAR).  DMID will 
report an SAE as a SUSAR only if there is evidence to suggest a causal relationship between the 
study intervention and the SAE.  DMID will submit an IND safety report to the FDA and will 
notify all participating site PIs (i.e., all PIs to whom the sponsor is providing drug under its 
IND(s) or under any PI’s IND(s)of potential serious risks from clinical studies or any other 
source, as soon as possible.  DMID will report to the FDA any unexpected fatal or life-
threatening suspected adverse reaction as soon as possible, but in no case later than seven (7) 
calendar days after the sponsor’s initial receipt of the information.  If the event is not fatal or life-
threatening the IND safety report will be submitted within 15 calendar days after the sponsor 
determines that the information qualifies for reporting as specified in 21 CFR Part 312.32.  
Relevant follow up information to an IND safety report will be submitted as soon as the 
information is available.  Upon request from FDA, DMID will submit to the 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 SAEs designated as “not related” to study product(s), will be reported to the FDA at least 
annually in a summary format. 
8.3.3 Reporting of Pregnancy 
Female subjects of childbearing age who become pregnant during the study will be discontinued 
from study medication and will be followed for pregnancy outcome.  Pregnancy occurring during 
a clinical investigation, although not considered a SAE, must be reported within the same 
timelines as a SAE. The positive pregnancy test will be recorded in the database within 5 days of 
site awareness, on the Pregnancy Report form.  The report will include pregnancy outcome (e.g., 
any premature terminations, elective or therapeutic, any spontaneous abortions or stillbirths), as 
well as the health status of the mother and child, including date of delivery and infant’s sex and 
weight.  Any subject with a positive pregnancy test, who has received study product(s), will be 
followed through eight (8) weeks post-live delivery or elective or natural termination of the 
pregnancy, whichever occurs first.  If the database is locked at time of pregnancy, a supplemental 
report will be generated and completed after birth, which will be appended to the database.  Any 
occurring AEs or SAEs that occur to the mother or fetus will be recorded in the eCRF in the 
database and on the SAE Report form.  


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The site is responsible for notifying their local IRB of any pregnancies in accordance with local 
policies. 
 
Type and Duration of Follow-up of Subjects after Adverse Events 
Adverse events, including serious AEs, will be assessed and collected from initial recognition of 
the AE occurring from first dose of study product on Day 1 through end of the protocol defined 
follow-up period (Day 11 + 3). 
All AEs and serious AEs occurring from first dose of study product on Day 1 through Day 11 + 
3 days will be followed up through resolution even if duration of follow-up goes beyond the 
protocol-defined follow-up period. 
Resolution of an AE is defined as the return to pre-treatment 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 
Mild abnormal laboratory values (Grade 1) that are not, in the investigator's opinion, medically 
significant should not be reported as AEs. Any Grade 2 or higher abnormal laboratory value (see 
Appendix B) will be reported as an AE regardless of the relationship to the study product.  
Laboratory abnormalities reported as AEs will be followed until the abnormality stabilizes or 
normalizes. 
 
Halting Rules 
8.6.1 Study Halting Criteria 
If any of the following events occur, enrollment and dosing for all subject will be suspended 
until the event is assessed by the SMC: 
• 
Any subject develops an SAE related to the study product through the last study visit. 
• 
In cohorts 2, 4, 5, and 6, two (2) or more subjects, in a single treatment cohort, experience a 
Grade 3 (severe) AE (including clinical, ECG, vital signs and laboratory AEs) that is related 
to study product and is of the same type [High Level Term (HLT)]. 
• 
In cohorts 5 and 6, three (3) or more subjects (cumulative) experience a Grade 3 (severe) AE 
(including clinical, ECG, vital, and laboratory AEs) that is related to the study products 
(combination) and is of the same type (HLT). 
• 
Any subject develops anaphylaxis within 24 hours after receiving the study product. 


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8.6.2 Individual Halting Criteria 
Further dosing of study product will be halted for any individual subject if any one of the 
following occurs:  
• 
Any SAE related to the study product. 
• 
Any Grade 3 AE event related to the study product. 
• 
Any other condition that the study site PI judges to unduly increase the risk to the subject. 
 
Safety Oversight 
8.7.1 Independent Safety Monitor (ISM) 
For this clinical trial, DMID will require an Independent Safety Monitor (ISM) to be assigned for 
each study site and the requirement for an ISM will be specified in the protocol. An ISM is a 
physician with relevant expertise whose primary responsibility is to provide to DMID an 
independent safety assessment in a timely fashion. The ISM will review all SAEs in real time 
and other AEs as needed and provide an independent assessment to DMID.   
8.7.2 Safety Monitoring Committee (SMC) 
This clinical study will utilize a SMC, which is an independent group of experts that advises the 
DMID. The primary responsibility of the SMC is to monitor subject safety. The SMC is external 
to the DMID and comprises at least 3 voting members. The SMC will consist of members with 
appropriate phase 1 study expertise to contribute to the interpretation of the data from this trial. 
Its activities will be delineated in an 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 study team. The DMID or the SMC may convene ad hoc 
meetings of the SMC according to protocol criteria or if there are concerns that arise during the 
study. 
As defined in the charter, the SMC will review data at specified times during the course of the 
study for subject and overall study progress, and may conduct ad hoc reviews as appropriate 
when a halting rule is met or for immediate concerns regarding observations during this study. 
The SMC will meet as follows: 
• 
Organization meeting (prior to start of the study). 
• 
Ad-hoc meeting when a halting rule is met or by request of the PI, ISM, or DMID MM if any 
safety concern arises. 
• 
Upon completion of cohort 5, prior to enrolling cohort 6.  


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• 
Final review meeting, to be conducted 6 to 8 months after clinical database lock to review the 
cumulative safety data for the study.  
The data will be provided in a standard summary format. The SMC may be asked to provide 
recommendations in response to questions posed by the DMID. 
Study product(s) administration data, including dose interruptions, modifications, and the 
associated reason(s), will be reported to the SMC. 
The SMC will operate under the rules of a DMID-approved charter. Data reviews may include 
enrollment and demographic information, medical history, concomitant medications, physical 
assessments, dosing compliance, protocol adherence, clinical laboratory values, PK data, and 
SAEs. Additional data may be requested by the SMC, and interim statistical reports may be 
generated as deemed necessary and appropriate by DMID. The SMC will receive data in 
aggregate and stratified by treatment cohort. The objective of the SMC is to make 
recommendations to the sponsors if the study should continue per protocol, be modified and then 
proceed, or be terminated.  After each review/meeting the SMC will make recommendations as 
to the advisability of proceeding with study (as applicable), and to continue, modify, or terminate 
this study. 
The DMID Medical Monitor or Medical Officer is empowered to stop study enrollment and 
administration if halting criteria are met or if any serious safety concerns arise. 


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HUMAN SUBJECTS PROTECTION 
 
Institutional Review Board/Independent Ethics Committee 
Each site PI will obtain IRB approval for this protocol to be conducted at his/her research site(s), 
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. The IRB/IEC must be registered with OHRP as applicable to the 
research.  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 and the IRB/IEC.  The investigator will notify the IRB/IEC of deviations 
from the protocol and reportable SAEs, as applicable to the IRB/IEC policy. 
Each institution engaged in this research will hold a current Federalwide Assurance (FWA) 
issued by the Office of Human Research Protection (OHRP) for federally funded research. 
 
Informed Consent Process 
Informed consent is a process that is initiated prior to an individual agreeing to participate in a 
clinical trial and continuing throughout the individual’s clinical trial participation.  Before any 
study 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 consent form. The explanation will be organized and presented in lay 
terminology and language that facilitates understanding why one might or might not want to 
participate. 
An investigator or designee will describe the protocol to potential subjects face-to-face. The key 
information about the purpose of the study, the procedures and experimental aspects of the study, 
risks and discomforts, any expected benefits to the subject, and alternative treatment will be 
presented first to the subject.   
Subjects will also receive an explanation that the trial involves research, and a detailed summary 
of the proposed study procedures and study interventions/products.  This will include aspects of 


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the trial that are experimental, the probability for random assignment to treatment cohort, any 
expected benefits, all possible risks (including a statement that the particular treatment or 
procedure may involve risks to the subject or to the embryo or fetus, if the subject is or may 
become pregnant, that are currently unforeseeable), the expected duration of the subject’s 
participation in the trial, alternative procedures that may be available and the important potential 
benefits and risks of these available alternative procedures.  
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 the 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 of the anticipated financial expenses, if any, to the subject 
for participating in the trial, as well as any anticipated prorated payments, if any, to the subject 
for participating in the trial. They will be informed of whom to contact (e.g., the investigator) for 
answers to any questions relating to the research project.  
Information will also include the foreseeable circumstances and/or reasons under which the 
subject’s participation in the trial may be terminated. The subjects will be informed that 
participation is voluntary and that they are free to withdraw from the study for any reason at any 
time without penalty or loss of benefits to which the subject is 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 authority(ies) 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 the trial are published, the subject’s identity will remain 
confidential. Subjects will be informed whether private information collected from this research 
will be used for additional research, even if identifiers are removed.   
Subjects will be allowed sufficient time to consider participation in this research trial, and have 
the opportunity to discuss this trial with their family, friends or legally authorized representative, 
or think about it prior to agreeing to participate. 
Informed consent forms will be IRB-approved and subjects will be asked to read and review the 
ICF. Subjects must sign the ICF prior to starting any study procedures being done specifically for 
this trial. 


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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 the 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 study. 
Study personnel may employ recruitment efforts prior to obtaining study 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 to subjects who consent to participate in 
this trial in accordance with IRB requirements.  The informed consent document 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. 
 
Exclusion of Women, Minorities, and Children (Special Populations) 
Women of child-bearing potential will not be excluded from the trial.  In addition, special 
populations, e.g., non-English speakers, illiterate or non-writing individuals will not be excluded 
from this study. 
Children and vulnerable populations will be excluded from this study as there is insufficient 
safety data and this is the first time AVYCAZ combined with ATM will be studied in a clinical 
trial. 
 
Subject Confidentiality 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and 
the sponsor(s) and their agents. This confidentiality includes documentation, investigation data, 
subject’s clinical information, and all other information generated during participation in the 
study. No information concerning the study or the data generated from the study will be released 
to any unauthorized third party without prior written approval of the DMID and the subject. 
Subject confidentiality will be maintained when study results are published or discussed in 
conferences.  The study monitor or other authorized representatives of the sponsor or 
governmental regulatory agencies may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the subjects in this study. The clinical study site will permit 
access to such records. 


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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, 
evaluation forms, reports, and other records that leave the site will be identified only by a coded 
number. 
 
Certificate of Confidentiality 
To protect privacy, a Certificate of Confidentiality will be issued.  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 United 
States Government that is used for auditing or evaluation of federally funded projects, like this 
study, 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 for other research will only occur if consent was 
obtained from the individual to whom the information or document pertains. 
 
Costs, Subject Compensation, and Research Related Injuries 
There is no cost to subjects for the research tests, procedures, and study product while taking part 
in this trial.  Subjects may be compensated for their participation in this trial.  Compensation will 
be in accordance with the local IRB’s policies and procedures, and pursuant to IRB approval. 
If it is determined by the site PI 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.  Study personnel will try to reduce, control, and treat any complications 
from this trial.  Immediate medical treatment may be provided by the participating site.  No 
financial compensation will be provided to the subject by the NIAID, NIH to the subject for any 
injury suffered due to participation in this trial. 


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STATISTICAL CONSIDERATIONS 
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a Statistical Analysis and PK Plan. The Statistical Analysis and PK Plan 
document may modify the plans outlined in the protocol; however, any major modifications of 
the primary endpoints definitions and/or their analyses will also be reflected in a protocol 
amendment. Additional statistical analyses other than those described in this section may be 
performed if deemed appropriate and included in the plan. 
This is a Phase 1 study of the safety and PK of AVYCAZ with ATM. Each subject will be 
assigned to a cohort as described in Section 4.3 and have PK samples collected at designated 
time points.  For a subject to be considered “completed” they will have received the full seven 
days of scheduled study product(s), as well as completing an in person safety follow up.   
A subject will be considered to have a complete PK profile if ≥70% of plasma PK samples are 
collected.  If two or more subjects in a dosing cohort have an incomplete PK profile, subjects 
will be replaced in that dosing cohort to ensure there at least 7 subjects with complete PK 
profiles in each dosing cohort.  For participants who have incomplete PK profile, their available 
PK data will be considered in the PK analyses. 
 Study Hypotheses 
The aim of this study is to evaluate the safety and PK of combination doses of AVYCAZ with 
ATM. As this is a Phase I study, no hypothesis will be tested. 
 Sample Size Considerations 
This is a Phase I study to investigate the safety and PK of AVYCAZ combined with ATM.  The 
sample size was chosen to obtain reasonable evidence of safety without exposing undue numbers 
of healthy subjects to combination of AVYCAZ with ATM at this phase of clinical evaluation.  
Previous experience in Phase I studies has shown that the sample size being proposed is 
sufficient to fulfil the primary and secondary objectives of the study. 
 Treatment Assignment Procedures 
This is an open-label study and randomization and masking procedures are not required. 


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 Final Analysis Plan 
10.4.1 Safety 
All subjects who receive at least one dose of study product(s) will be included in the safety 
analysis. AEs [i.e., those beginning after the first dose of study product(s)] will be summarized 
using frequency counts and percentages by treatment cohort. Graphical presentations may be 
used, as appropriate. The following summaries will be presented for AEs and SAEs: 
• 
Overall (i.e., regardless of severity or relationship to study product) 
• 
By severity grade (mild, moderate, or severe), 
• 
By relationship to study product, 
• 
By MedDRA level hierarchy (System Organ Class 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 1 or more events. If more than 1 
occurrence of an event is reported, the event of the worst severity or the worst-case relationship 
assessment will be summarized.  Furthermore, listings of deaths (if any), SAEs, and AEs that 
lead to study discontinuation will be made. The number of volunteers who have any AEs, SAEs, 
AEs that lead to withdrawal, and AEs judged causally related to study product(s) by the PI will 
be summarized.  Shifts in clinical laboratory data will be tabulated. 
For each treatment cohort, the percentage of subjects who experience the following selected 
dichotomous events will be calculated. Subjects will be counted for each event only once, at the 
highest observed grade. Event categories include: 
• 
Premature discontinuation of study product(s) 
• 
Any grade 1 or higher laboratory value 
• 
Any grade 1 or higher sign or symptom 
• 
Any grade 1 or higher AEs 
• 
Any grade 1 or higher occurrence of laboratory values, signs, symptoms and/or diagnosis 
• 
Grade 1 or higher of any specific AE that occurs in at least 10% of subjects for any regimen 
Separate tables and listings of SAEs will be generated. 
Safety laboratory parameters and vital signs will be tabulated for each treatment cohort using 
descriptive statistics. Laboratory values for hematologic, urinalysis, coagulation, and clinical 
chemistry panels will be compared to normal ranges as reported by the reference laboratory. 
Vital signs, physical examinations, clinical laboratory values, and ECG parameters will be 


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presented by treatment cohort. Continuous variables (hematology [including direct Coombs], 
clinical chemistry, coagulation, ECGs, urinalysis, and vital signs) will be summarized using 
descriptive statistics (n, mean, standard deviation, minimum, median, and maximum) by 
treatment, or scheduled time point, as appropriate. Categorical variables (e.g., urinalysis, etc.) 
will be summarized in frequency tables (frequency counts and proportion) by treatment, age 
group, or scheduled time point, as appropriate. Where applicable, data will be summarized for 
the absolute value at each scheduled assessment, and for the corresponding change from 
baseline. 
10.4.2 Pharmacokinetic Analyses 
Pharmacokinetic analyses will be completed by the DCRI Pharmacometrics Center (PMC).  The 
study population and methodology used to evaluate individual agent and combination PK 
parameters will be described in detail in the PK Plan and is reviewed briefly below. 
10.4.3 Initial Exploratory Analysis 
Concentration-time data will be visualized using box and whisker plots, with investigation of any 
outliers for erroneous time or concentration data entry. Individual concentration-time plots will 
be generated on linear and semi-log scales to inform potentially optimal structural model builds 
for analysis. 
10.4.4 Non-Compartmental Pharmacokinetic Analysis 
Non-compartmental analysis (NCA) will be used as the initial approach to generated base PK 
parameter estimates for each individual agent (i.e. CAZ, AVI and ATM). These analyses will be 
conducted using an appropriate statistical package. This descriptive analysis will allow for 
comparison to previously published data on each of the individual agents. The following PK 
parameters will be calculated as appropriate and if possible depending on actual samples 
collected: maximum plasma concentration (Cmax) after the first dose on Day 1, maximum plasma 
concentration at steady state (Css,max), time to Cmax (tmax), time to Css,max (tss,max), minimum plasma 
concentration at the end of the dosing interval on Day 1 [Cmin] and at steady state (Css,min), steady 
state concentration after CI (Css), area under the plasma concentration-time curve during the 
dosing interval on Day 1 [AUC(0-Tau)] and at steady state during the dosing interval [AUC0-Tau,ss], 
systemic plasma clearance (CL), renal clearance (CLR), volume of distribution during terminal 
phase (Vz), dose-normalized exposure parameters after the first and multiple dose, accumulation 
ratio for Cmax (RCmax) and AUC(0-Tau) [RAUC(0-Tau)]. Nominal sampling time will be used in PK 
calculations, unless it is decided that actual times are needed. 
10.4.5 Population Pharmacokinetic Analysis 
Population pharmacokinetic analysis provides a platform to identify patient covariates which can 
help explain a portion of the inter-individual variability in selected PK parameters. The non-


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linear mixed effects modeling software NONMEM® Version 7.2 (ICON Development Solutions, 
Ellicott City, MD) will be used to develop the population PK model for CAZ, AVI and ATM 
concentrations in plasma. Different structural PK models (e.g., 2 and 3 compartment) will be 
fitted to the concentration-time data of each drug. Between-subject variability on model 
parameters and different residual error models will be tested.  Model development will be guided 
by goodness of fit plots, plausibility of parameter estimates, and reduction in inter-individual 
variability for structural and residual error parameters, as well as objective function and 
shrinkage values. 
Upon selection of an appropriate base structural PK model, covariate effects (i.e., age, sex, body 
size descriptors and renal function) will be evaluated using stepwise forward selection followed 
by stepwise backward elimination processes.  Standard model diagnostic plots and procedures 
will be used to evaluate model appropriateness.  Model validation will be performed using visual 
predictive check and bootstrapping. 
10.4.6 Monte Carlo Simulation 
Monte Carlo simulations will be performed using the final population PK model with all 
statistically significant covariate effects. Simulated exposures of treatment cohorts will be 
evaluated. Simulated medians and 90% prediction intervals for each treatment cohort will be 
overlaid on the observed concentration-time data from subjects as a QC check. 
10.4.7 Exposure-Response Relationship Analysis 
Using the final population PK model, EBE PK parameters and dosing information, simulations 
will be performed to predict PK exposure of CAZ, AVI and ATM in study subjects. Multiple 
exposure parameters may be explored. The association between occurrence of ALT or AST 
elevations and PK exposure of CAZ, AVI and ATM will be explored using standard statistical 
correlation methodologies. 


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SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
Each participating 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. Each 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 study 
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 pharmacy, at the laboratories, 
and medico-technical departments involved in the clinical trial.  


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QUALITY CONTROL AND QUALITY ASSURANCE 
Following a written DMID-accepted site quality management plan, each participating site(s) and 
its subcontractors are responsible for conducting routine QA and quality control (QC) activities 
to internally monitor study progress and protocol compliance.  The site PI 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 PI will ensure all study personnel are appropriately trained and applicable documentations 
are maintained on site. 
The SDCC will implement QC procedures beginning with the data entry system and generate 
data QC 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. 
 


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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. 
All source documents and laboratory reports must be reviewed by the clinical team and data 
entry staff, who will ensure that they are accurate and complete.  Adverse events must be graded, 
assessed for severity and causality, and reviewed by the site PI or designee. 
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 PIs and other study personnel 
on making corrections to the data collection forms and eCRF. 
 Data Coordinating Center/Biostatistician Responsibilities 
Data collection is the responsibility of the study personnel at the participating clinical study site 
under the supervision of the site PI.  During the study, the site PI must maintain complete and 
accurate documentation for the study. 
The Emmes Company will serve as the SDDC for this study and will be responsible for data 
management, quality review, analysis (with the exception of the PK analyses) and reporting of 
the study data. Adverse events and concomitant medications will be coded using the MedDRA 
and World Health Organization Drug dictionaries (WHO DD) respectively.  The DCRI PMC 
will be responsible for all analysis of PK data. 
 Data Capture Methods 
Clinical data (including, but not limited to, AE/SAEs, concomitant medications, medical history, 
physical assessments, and clinical laboratory values) will be collected on data collection forms 
by study personnel then entered into eCRFs via a 21 CFR Part 11-compliant internet data entry 
system provided by the study data coordinating center.  The data system includes password 
protection and internal quality checks, such as automatic range checks, to identify data that 
appear inconsistent, incomplete, or inaccurate.   


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Data will be entered into the eCRF on an ongoing basis and will be reviewed on a continuous 
basis throughout the study. 
 Types of Data 
Data for this trial will be collected in a single database.  The data will include medical history, 
demographics, physical examination, vital signs, ECGs, concomitant medications, study product 
administration, PK collection times, bioanalytical data, PK modelling and safety (e.g., clinical 
laboratory values and AEs/SAEs).  The PK modelling will be completed at the DCRI PMC and a 
copy transferred to the SDDC database. 
 Study Records Retention 
Study records and reports including, but not limited to, eCRFs, source documents, ICFs, 
laboratory test results, and study product disposition records will be retained for 2 years after a 
marketing application is approved for the study product for the indication for which it is being 
investigated; or, if no application is to be filed or if the application is not approved for the study 
product, until 2 years after the investigation is discontinued and the FDA has been notified. 
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 is conducted to ensure that the human subjects’ protections, study and laboratory 
procedures, study intervention administration, and data collection processes are of high quality 
and meet sponsor, ICH/GCP guidelines and applicable regulations, and that this clinical trial is 
conducted in accordance with the protocol, protocol-specific MOP and applicable sponsor 
standard operating procedures.  DMID, the sponsoring agency, 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 participating site, study 
personnel, and all study documentation according to the DMID-approved site monitoring plan.  
Study monitors will meet with site PIs to discuss any problems and actions to be taken, and will 
document site visit findings and discussions. 
 


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PUBLICATION POLICY 
Following completion of the study, the lead PI is expected to publish the results of this research 
in a scientific journal.  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 
1. Antimicrobial Resistance Fact Sheet.  http://www.who.int/mediacentre/factsheets/fs194/en/ 
accessed 04/29/15. 
2. Weiner LM, Webb AK, Limbago B, et al. Antimicrobial-Resistant Pathogens Associated 
With Healthcare-Associated Infections: Summary of Data Reported to the National 
Healthcare Safety Network at the Centers for Disease Control and Prevention, 2011-2014. 
Infect Control Hosp Epidemiol 2016; 37(11): 1288-301. 
3. CDC 2013. Antibiotic resistant threats in the United States. Available at: 
http://www.cdc.gov/drugresistance/threat-report-2013/. Accessed July 6, 2015. 
4. Jacoby GA, Munoz-Price LS. The new beta-lactamases. N Engl J Med 2005; 352(4): 380-91. 
5. Davido B, Fellous L, Lawrence C, Maxime V, Rottman M, Dinh A. Ceftazidime-Avibactam 
and Aztreonam, an Interesting Strategy To Overcome beta-Lactam Resistance Conferred by 
Metallo-beta-Lactamases in Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrob 
Agents Chemother 2017; 61(9).(pii): e01008-17. doi: 10.1128/AAC.-17. Print 2017 Sep. 
6. Karlowsky JA, Kazmierczak KM, de Jonge BLM, Hackel MA, Sahm DF, Bradford PA. In 
Vitro Activity of Aztreonam-Avibactam against Enterobacteriaceae and Pseudomonas 
aeruginosa Isolated by Clinical Laboratories in 40 Countries from 2012 to 2015. Antimicrob 
Agents Chemother 2017; 61(9).(pii): e00472-17. doi: 10.1128/AAC.-17. Print 2017 Sep. 
7. Kazmierczak KM, Rabine S, Hackel M, et al. Multiyear, Multinational Survey of the 
Incidence and Global Distribution of Metallo-beta-Lactamase-Producing Enterobacteriaceae 
and Pseudomonas aeruginosa. Antimicrob Agents Chemother 2016; 60(2): 1067-78. doi: 
10.128/AAC.02379-15. Print 2016 Feb. 
8. Singh R, Kim A, Tanudra MA, et al. Pharmacokinetics/pharmacodynamics of a beta-lactam 
and beta-lactamase inhibitor combination: a novel approach for aztreonam/avibactam. J 
Antimicrob Chemother 2015; 70(9): 2618-26. doi: 10.1093/jac/dkv132. Epub 2015 May 29. 
9. Walsh TR, Toleman MA, Poirel L, Nordmann P. Metallo-beta-lactamases: the quiet before 
the storm? Clin Microbiol Rev 2005; 18(2): 306-25. 
10. Wenzler E, Deraedt MF, Harrington AT, Danizger LH. Synergistic activity of ceftazidime-
avibactam and aztreonam against serine and metallo-beta-lactamase-producing gram-
negative pathogens. Diagn Microbiol Infect Dis 2017; 88(4): 352-4. doi: 
10.1016/j.diagmicrobio.2017.05.009. Epub May 18. 


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11. Wright H, Bonomo RA, Paterson DL. New agents for the treatment of infections with Gram-
negative bacteria: Restoring the miracle or false dawn? Clin Microbiol Infect 2017 Oct; 
23(10): 704-712. doi: 10.1016/j.cmi.2017.09.001. Epub 2017 Sep 8 
12. IDSA Facts on Antibacterial Resistance.  
http://www.idsociety.org/uploadedFiles/IDSA/Policy_and_Advocacy/Current_Topics_and_I
ssues/Antimicrobial_Resistance/Strengthening_US_Efforts/Background/Antibiotic%20Resist
ance%20Fact%20Sheet.pdf.  accessed 04/29/15. 
13. Marshall S, Hujer AM, Rojas LJ, et al. Can Ceftazidime-Avibactam and Aztreonam 
Overcome beta-Lactam Resistance Conferred by Metallo-beta-Lactamases in 
Enterobacteriaceae? Antimicrob Agents Chemother 2017; 61(4).(pii): e02243-16. doi: 
10.1128/AAC.-16. Print 2017 Apr. 
14. Rahm C, Butterfield JM, Nicasio AM, Lodise TP. Dual beta-lactam therapy for serious 
Gram-negative infections: is it time to revisit? Diagn Microbiol Infect Dis 2014; 80(4): 239-
59. doi: 10.1016/j.diagmicrobio.2014.07.007. Epub  Jul 31. 
15. Monoue ML, Abbo LM, Rosa R, et al. In Vitro Discordance with In Vivo Activity: 
Humanized Exposures of Ceftazidime-Avibactam, Aztreonam, and Tigecycline Alone and in 
Combination against New Delhi Metallo-beta-Lactamase-Producing Klebsiella pneumoniae 
in a Murine Lung Infection Model. Antimicrob Agents Chemother 2017; 61(7).(pii): e00486-
17. doi: 10.1128/AAC.-17. Print 2017 Jul. 
16. Shaw E, Rombauts A, Tubau F, et al. Clinical outcomes after combination treatment with 
ceftazidime/avibactam and aztreonam for NDM-1/OXA-48/CTX-M-15-producing Klebsiella 
pneumoniae infection. J Antimicrob Chemother 2017. 
17. Mojica MF, Ouellette CP, Leber A, et al. Successful Treatment of Bloodstream Infection 
Due to Metallo-β-Lactamase-Producing Stenotrophomonas maltophilia in a Renal Transplant 
Patient. Antimicrob Agents Chemother. 2016;60(9):5130-4. Published 2016 Aug 22. 
doi:10.1128/AAC.00264-16 
18. AZACTAM® (aztreonam for injection, USP), Bristol-Myers Squibb, Package Insert.  
https://packageinserts.bms.com/pi/pi_azactam.pdf. 
19. AVYCAZ® (ceftazidime and avibactam) for Injection, for intravenous use. Package insert. 
https://www.allergan.com/assets/pdf/avycaz_pi 
20. Abdul-Aziz MH, Sulaiman H, Mat-Nor MB, et al. Beta-Lactam Infusion in Severe Sepsis 
(BLISS): a prospective, two-centre, open-labelled randomised controlled trial of continuous 
versus intermittent beta-lactam infusion in critically ill patients with severe sepsis. Intensive 
Care Med 2016; 42(10): 1535-45. 


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21. Ambrose PG, Bhavnani SM, Rubino CM, et al. Pharmacokinetics-pharmacodynamics of 
antimicrobial therapy: it's not just for mice anymore. Clin Infect Dis 2007; 44(1): 79-86. 
22. Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing 
of mice and men. Clin Infect Dis 1998; 26(1): 1-10; quiz 1-2. 
23. Lodise TP, Smith NM, Holden PN, T Berard, O’Donnell N, Bonomo RA, Tsuji BT. Efficacy 
of Ceftazidime-Avibactam in Combination with Aztreonam (COMBINE): Solutions for 
Metallo-β-lactamase producing-Enterobacteriaceae (MBL). Abstract # 1385. Poster 
presentation at IDweek2018™. San Francisco, CA. October 3-7, 2018.  
24. National Library of Medicine and National Institute of Diabetes and Digestive and Kidney 
Diseases.  https://livertox.nlm.nih.gov/Aztreonam.htm. 
25. Roberts JA, Abdul-Aziz MH, Davis JS, Dulhunty JM, Cotta MO, Myburgh J, Bellomo R, 
Lipman J. Continuous versus Intermittent β-Lactam Infusion in Severe Sepsis. A Meta-
analysis of Individual Patient Data from Randomized Trials. Am J Respir Crit Care Med. 
2016 Sep 15;194(6):681-91. doi: 10.1164/rccm.201601-0024OC. PubMed PMID: 26974879. 
26. Roberts JA, Kirkpatrick CM, Roberts MS, Dalley AJ, Lipman J. First-dose and steady-state 
population pharmacokinetics and pharmacodynamics of piperacillin by continuous or 
intermittent dosing in critically ill patients with sepsis. Int J Antimicrob Agents. 2010 
Feb;35(2):156-63. doi: 10.1016/j.ijantimicag.2009.10.008.Epub 2009 Dec 16. PubMed 
PMID: 20018492. 
27. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, 
Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M,  Marini JJ, 
Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, 
Zimmerman JL, Vincent JL; International Surviving Sepsis Campaign Guidelines 
Committee; American Association of Critical-Care Nurses; American College of Chest 
Physicians; American College of Emergency Physicians; Canadian Critical Care Society; 
European Society of Clinical Microbiology and Infectious  iseases; European Society of 
Intensive Care Medicine; European Respiratory Society; International Sepsis Forum; 
Japanese Association for Acute Medicine; Japanese Society of Intensive Care Medicine; 
Society of Critical Care Medicine; Society of Hospital Medicine; Surgical Infection Society; 
World Federation of Societies of Intensive and Critical Care Medicine. Surviving Sepsis 
Campaign: international guidelines for management of severe sepsis and septic shock: 2008.  
Crit Care Med. 2008 Jan;36(1):296-327. Erratum in: Crit Care Med. 2008 Apr;36(4):1394-6. 
PubMed PMID: 18158437. 
28. Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, Napolitano 
LM, O'Grady NP, Bartlett JG, Carratalà J, El Solh AA, Ewig S, Fey PD, File TM Jr, 


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Restrepo MI, Roberts JA, Waterer GW, Cruse P, Knight SL, Brozek JL. Management of 
Adults With Hospital-acquired and Ventilator-associated Pneumonia:  2016 Clinical Practice 
Guidelines by the Infectious Diseases Society of America and the American Thoracic 
Society. Clin Infect Dis. 2016 Sep 1;63(5):e61-e111. doi: 10.1093/cid/ciw353. Epub 2016 Jul 
14. PubMed PMID: 27418577; PubMed Central  PMCID: PMC4981759. 
29. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976; 16(1): 31-41. 
30. Lexicomp Online, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2013; 
April 15, 2013, Date accessed: December, 20, 2018. 
31. Ueo, H., et al., Human organic anion transporter hOAT3 is a potent transporter of 
cephalosporin antibiotics, in comparison with hOAT1. Biochem Pharmacol, 2005. 70(7): p. 
1104-13. 
 


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APPENDICES 
 
 


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 Schedule of Events 
Evaluation 
Screening1 
Visit 1 
Enrollment2 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Discharge 
Visit 10 / Final 
Visit 
Unscheduled / Early 
Termination Visit 
 
Day  
-30 to 
Day -2 
Day -1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 5 
Day 
6 
Day 
7 
Day 
8 
Day 11 
(+3) 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Confirmation 
of eligibility 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Medical 
history & 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Height / 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
Review of 
changes in 
medical history 
 
X 
 
 
 
 
 
 
 
X 
 
X 
Concomitant 
medications 
X 
X 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X 
X 
X 
Physical 
examination 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
Symptom 
directed 
physical 
examination 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Vital signs4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG5 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
Assessment of 
adverse events6 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assignment to 
treatment 
cohort7 
 
X 
 
 
 
 
 
 
 
 
 
 
Study product 
administration 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Clinical 
chemistry8 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
LFTs9 
 
 
 
 
 
 
X 
 
X 
 
 
 
Hematology10 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Coagulation 
test11 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Viral 
serology12 
X 
 
 
 
 
 
 
 
 
 
 
 
Coombs test 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Urinalysis13 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 


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Evaluation 
Screening1 
Visit 1 
Enrollment2 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Discharge 
Visit 10 / Final 
Visit 
Unscheduled / Early 
Termination Visit 
 
Day  
-30 to 
Day -2 
Day -1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 5 
Day 
6 
Day 
7 
Day 
8 
Day 11 
(+3) 
 
Serum hCG 
pregnancy 
test14 
X 
X 
 
 
 
 
 
 
 
 
 
 
Alcohol Screen 
breathalyzer 
X 
X 
 
 
 
 
 
 
 
 
 
 
Urine cotinine 
test 
X 
X 
 
 
 
 
 
 
 
 
 
 
Urine drug 
screen15 
X 
X 
 
 
 
 
 
 
 
 
 
 
Plasma PK16 
 
 
X 
 
X 
 
X 
 
X 
X 
 
X17 
Urine PK18 
 
 
X 
 
 
 
 
X 
 
 
 
 
1. 
Screening evaluations must be completed within 30 days prior to enrollment 
2. 
All baseline procedures should be done before study intervention 
3. 
Review for any new medication only 
4. 
Vital Signs:  collected after 10 minutes of resting in supine position and include systolic and diastolic blood pressures (mmHg), pulse rate 
(BPM), respiratory rate, and body temperature (oral measurement).  Day 1 - prior to dosing on Day 1 and 1 hour after starting AM dose.  
Days 2-8 will be obtained each morning 
5. 
Subjects must be lying supine or sitting for 10 minutes prior to ECG.  ECG will be done in triplicate 2 minutes apart at Screening only.  
Single ECGs will be recorded on Days -1, 8, and 11 (+3) 
6. 
Monitoring for adverse events will begin after the first dose of study product 
7. 
Assignment to dosing cohort:  Must occur after all inclusion and exclusion criteria have been confirmed 
8. 
Clinical Chemistry: sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, albumin, total protein, total bilirubin, ALT, AST, 
ALP and LDH 
9. 
Liver function tests (LFTs): ALT, AST, ALP, and total bilirubin 
10. Hematology: Hemoglobin, hematocrit, WBC, WBC differential, RBC, platelets 
11. Coagulation: PT and PTT 
12. Viral serology:  HIV, HBsAg, HCV antibody 
13. Urinalysis: Dipstick urinalysis, including protein, glucose, ketones, bilirubin, blood, nitrites, LCE, urobilinogen, specific gravity, and pH 
14. Serum pregnancy test on Day-1 must be completed within 48 hours prior dosing.  Results must be obtained prior to study product(s) 
administration 
15. Urine drug screen for: amphetamines, barbiturates, benzodiazepines, cocaine metabolites, opiates, cannabinoids and phencyclidine 
16. Plasma PK collection times:  See Section 7.2.2.1 
17. Unscheduled visit – plasma PK collection is optional 
18. Urine PK collection times:  See Section 7.2.2.2 
 
 


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Toxicity Table 
Clinical Adverse Events 
CARDIOVASCULAR 
TOXICITY 
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 
QTc (Fridericia’s correction)1 
 
or QTcb (Bazett’s)1 
Asymptomatic, QTc 
interval 450-479 
msec OR Increase 
in interval  
20-30 msec above 
baseline 
Asymptomatic, QTc 
interval 480-499 msec 
OR Increase in interval 
31-50 msec above 
baseline 
Asymptomatic, QTc interval ≥ 
500 msec OR Increase in 
interval ≥ 51 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 
TOXICITY 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Cough 
Transient; no 
treatment  
Persistent cough  
Interferes with daily activities 
Bronchospasm, Acute 
Transient; no 
treatment;  
71% - 80% FEV1 
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 
TOXICITY 
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 
Diarrhea  
2 - 3 loose or 
watery stools or 
<400 g24 hours 
4 - 5 loose or watery 
stools or 400 - 800 
g/24 hours 
6 or more loose or watery 
stools or >800g24 hours OR 
requires IV hydration OR 
requires medical intervention 
 
1 Inclusion dependent upon protocol requirements. 


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LOCAL REACTIONS 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Pain 
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 
Discomfort only to 
touch 
Discomfort with 
movement 
Significant discomfort at rest 
Erythema/Redness2 
2.5 - 5 cm 
5.1 - 10 cm 
>10 cm 
Induration/Swelling3 
2.5 - 5 cm and does 
not interfere with 
activity 
5.1 - 10 cm OR 
interferes with activity 
>10 cm OR prevents daily 
activity 
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 adverse 
event (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 
 
 
2 In addition to grading the measured local reaction at the greatest single diameter, the measurement should be 
recorded as a continuous variable. 
3 Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement.  


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Laboratory and Vital Signs Reference Ranges, Eligibility Ranges, and Toxicity Grading 
Blood, Serum, or Plasma Chemistries1 
Reference 
Range2 
Eligibility 
Range3 
LO/HI/N4 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Sodium (mEq/L) 
135 - 145 
135 - 145 
LO 
132 - <LLN 
130 - 131 
<130 
HI 
>ULN - 148 
149 - 150 
>150 
Potassium (mEq/L) 
3.5 – 5.0 
3.5 – 5.0 
HI 
>ULN - 5.2 
5.3 - 5.4 
>5.4 
LO 
>LLN - 3.1 
<3.1 - 3.0 
<3.0 
Blood Urea Nitrogen (BUN, mg/dL) 
7 - 20 
7 - 20 
HI 
21 - 26 
27 - 31 
>31 
Creatinine (mg/dL) 
0.5 - 1.2 
0.5 – 1.2 
HI 
>ULN - 1.7 
1.8 - 2.0 
>2.0 
Glucose (mg/dL) 
<70 
<70 
LO 
65 - 69 
55 - 64 
<55 
70 - 99 
70 - 99 
HI5 
>ULN - 120 
121 - 130 
>130 
70 - 140 
70 - 140 
HI6 
141 - 159 
160 - 200 
>200 
Total Protein (g/dL) 
5.8 - 7.8 
5.8 - 7.8 
LO 
5.2 - <LLN 
4.8 - 5.1 
<4.8 
Bilirubin, serum total (mg/dL)  
0.4 - 1.5 
0.4 - 1.5 
HI 
1.6 - 2.0 
2.1 - 2.5 
>2.5 
ALT (U/L) 
Female: 14-54 
Female: 14-54 
HI 
>ULN - 105 
106 - 175 
>175 
Male: 17-63 
Male: 17-63 
AST (U/L) 
15 - 41 
15 - 41 
HI 
42 - 105 
106 - 175 
>175 
Alkaline phosphatase (U/L) 
24 - 110 
24 - 110 
HI 
111 - 240 
241 - 360 
>360 
 
 
1 Depending upon the lab used, references ranges, eligibility ranges and grading may be split out by sex and/or age. 
2 Reference range of site laboratory 
3 Laboratory values acceptable for eligibility for enrollment 
4 High, Low, Not Graded 
5 Fasting 
6 Non-fasting 


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Hematology 
Reference 
Range7 
Eligibility 
Range8 
LO/HI/N9 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Hemoglobin (Females) (g/dL) 
Hemoglobin (Males) (g/dL) 
12.0-15.5 
12.0-15.5 
LO 
11.0 - 11.9 
9.5 - 10.9 
<9.5 
13.7-17.3 
13.7-17.3 
LO 
12.0 – 13.6 
10.0 - 11.9 
<10.0 
White Blood Cell Count (WBC, K/CUMM) 
3.2-9.8 
3.2-9.8 
HI 
9.9 – 14.99 
15.00 - 20.00 
>20.00 
LO 
2.50 - 3.19 
1.50 - 2.49 
<1.50 
Lymphocytes (K/CUMM) 
0.6-4.2 
0.6-4.2 
LO 
0.50 – 0.59 
0.40 - 0.49 
<0.4 
Neutrophils (K/CUMM) 
2.0-8.6 
2.0-8.6 
LO 
1.50 – 1.99 
1.00 - 1.49 
<1.00 
Eosinophils (K/CUMM) 
0.0-0.7 
0.0-0.7 
HI 
>ULN - 0.74 
0.75 - 1.50 
>1.50 
Platelets (K/CUMM) 
150-450 
150-450 
LO 
120 - 149 
100 - 119 
<100 
Coagulation 
 
 
 
 
 
 
Prothrombin time (PT, seconds) 
9.5-13.1 
9.5-13.1 
HI 
>ULN - 14.4 
14.5 - 15.7 
>15.7 
Partial thromboplastin time (PTT or aPTT, seconds) 
26.8-37.1 
26.8-37.1 
HI 
>ULN - 42.1 
42.2 - 50.0 
>50.0 
Urine*  
 
 
 
 
 
 
Protein (dipstick) 
0 
0 
HI 
1+ 
2+ 
>2+ 
Glucose (dipstick) 
0 
0 
HI 
1+ 
2+ 
>2+ 
 
Vital Signs 
Mild  
(Grade 1)10 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Fever (°F)  
100.4 - 101.1 
101.2 - 102.0 
≥102.1 
 
7 Reference range of site laboratory 
8 Laboratory values acceptable for eligibility for enrollment 
9 High, Low, Not Graded 
10 If initial bound of Grade 1 has gap from reference range or eligibility range, calculations based on NEJM reference ranges 


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Vital Signs 
Mild  
(Grade 1)10 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Tachycardia - beats per minute11 
101 - 115 
116 - 130 
>130 or ventricular 
dysrhythmias 
Bradycardia - beats per minute12 
50 – 54 or 45 – 49 
if baseline 50-59 bpm 
45 – 49 or 40 - 44 
if baseline 50-59 bpm 
< 45 or <40 
if baseline 50-59 bpm 
Hypertension (systolic) - mm Hg13 
141 - 150 
151 - 160 
>160 
Hypertension (diastolic) - mm Hg 
91 - 95 
96 - 100 
>100 
Hypotension (systolic) - mm Hg 
85 - 89 
80 - 84 
<80 
Tachypnea - breaths per minute 
23 - 25 
26 - 30 
>30 
 
 
11 Expanded heart rate limits can be considered with normal ECGs. 
12 Expanded heart rate limits can be considered with normal ECGs. 
13 Assuming subject is awake, resting, and supine; for AE, 3 measurements on the same arm with concordant results.