Clinical trial NCT05645757
Conditions: Bacterial Infection
Keywords: Double-blind Intravenous Ertapenem Phase 1 Safety Zidebactam (WCK 6777)
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2023-04-19; Completion date: 2023-11-03
Enrollment: 54 participants; Allocation: RANDOMIZED; Intervention model: FACTORIAL

Brief summary:
This is a Phase 1, single center study to investigate the safety, tolerability, and pharmacokinetics (PK) of three dose-level groups of WCK 6777 (ERT and ZID combination), and two dose-level groups of ERT alone and ZID (WCK 5107) alone in 52 healthy adult male and female subjects aged 18 to 45 years old (both inclusive). Seven treatment cohorts will be evaluated in this study. WCK 6777 will be evaluated in three cohorts - Cohorts 1, 4 and 7- of 8 subjects each (6 study drug combinations and 2 placebos); ERT will be evaluated alone in two cohorts - Cohorts 2 and 5- of 8 subject each (6 ERT and 2 placebos); and ZID will be evaluated in two cohorts, Cohorts 3 and 6, of 6 subjects each (all ZID). The study will be placebo-controlled and double-blinded in all cohorts except Cohorts 3 and 6. No placebo subjects are included in standalone ZID cohorts, since adequate safety data for higher doses of ZID alone in comparison with placebo are available from completed Phase 1 studies of WCK 5107 (ZID) alone and the ZID-only arms of WCK 5222 (cefepime + ZID) studies. The primary objective is to assess the safety and tolerability of three dose-escalating regimens of WCK 6777 ( ERT and ZID combination) and two-dose escalating regimens of standalone ERT or ZID following single daily doses for 7 days in healthy adult subjects.

Detailed description:
This is a Phase 1, single center study to investigate the safety, tolerability, and pharmacokinetics (PK) of three dose-level groups of WCK 6777 (ERT and ZID combination), and two dose-level groups of ERT alone and ZID (WCK 5107) alone in 52 healthy adult male and female subjects aged 18 to 45 years old (both inclusive). Seven treatment cohorts will be evaluated in this study. WCK 6777 will be evaluated in three cohorts - Cohorts 1, 4 and 7- of 8 subjects each (6 study drug combinations and 2 placebos); ERT will be evaluated alone in two cohorts - Cohorts 2 and 5- of 8 subject each (6 ERT and 2 placebos); and ZID will be evaluated in two cohorts, Cohorts 3 and 6, of 6 subjects each (all ZID). The study will be placebo-controlled and double-blinded in all cohorts except Cohorts 3 and 6. No placebo subjects are included in standalone ZID cohorts, since adequate safety data for higher doses of ZID alone in comparison with placebo are available from completed Phase 1 studies of WCK 5107 (ZID) alone and the ZID-only arms of WCK 5222 (cefepime + ZID) studies. In each cohort, either study drugs alone or their combination will be administered by a single intravenous infusion (IV) of 100 mL daily for 7 consecutive days in Cohort 1 or 250 mL daily for 7 consecutive days in Cohorts 2 to 7. For each treatment cohort, however, the dose will be progressively escalated from 1 g/daily to 2 g/daily and to 3 g/daily, and the duration of infusion time increased from 30 min to 1 h and to 2 h over the course of the study. In Cohort 1, WCK 6777 2 g (ERT 1 g/daily combined with ZID 1 g/daily) will be administered in 30 (±5) minutes (min); in Cohort 2 (ERT 2 g/daily), Cohort 3 (ZID 2 g/daily), and Cohort 4 (WCK 6777 4 g \[ERT 2 g/daily combined with ZID 2 g/daily\]) the study drug(s) will be administered in 60 (±10) min, and in Cohort 5 (ERT 3 g/daily), Cohort 6 (ZID 3 g daily) and Cohort 7 (WCK 6777 6 g \[ERT 3 g/daily combined with ZID 3 g/daily\]), the study drug(s) will be administered in 120 (±10) min. The primary objective is to assess the safety and tolerability of three dose-escalating regimens of WCK 6777 ( ERT and ZID combination) and two-dose escalating regimens of standalone ERT or ZID following single daily doses for 7 days in healthy adult subjects. The secondary objective is to characterize the PK profiles in plasma (total \& free) and in urine of three dose-escalating regimens of WCK 6777 (ERT and ZID combination) and two dose-escalating regimens of standalone ERT or ZID following a single initial dose on Day 1 and after single daily doses for 7 days in healthy adult subjects.

Arms: arm 1: WCK 6777 (Ertapenem 1 g combined with Zidebactam 1 g) or placebo administered by 100 ml of intravenous infusion (IV) for 30 (±5) minutes once daily for 7 days. N= 8 arm 2: Ertapenem 2 g or placebo administered by 250 ml of intravenous infusion (IV) for 1 hour once daily for 7 days. N=8 arm 3: Zidebactam 2 g administered by 250 ml of intravenous infusion (IV) for 1 hour,once daily,for 7 days. N=6 arm 4: WCK 6777 (Ertapenem 2 g combined with Zidebactam 2 g) or placebo administered by 250 ml of intravenous infusion (IV) for 1 hour, once daily, for 7 days. N=8 arm 5: Ertapenem 3 g or placebo administered by 250 ml of intravenous infusion (IV) for 2 hours, once daily, for 7 days. N=8 arm 6: Zidebactam 3 g administered by 250 ml of intravenous infusion (IV) for 2 hours, once daily, for 7 days. N=6 arm 7: WCK 6777 (Ertapenem 3 g combined with Zidebactam 3 g) or placebo administered by 250 ml of intravenous infusion (IV) for 2 hours, once daily, for 7 days. N=8
Interventions: intervention 1: Ertapenem intervention 2: Placebo intervention 3: WCK 6777 intervention 4: Zidebactam
Intervention descriptions: intervention 1: A 1-beta methyl-carbapenem that is structurally related to beta-lactam antibiotics intervention 2: Placebo intervention 3: A combination of ertapenem (ERT) and zidebactam (ZID) intervention 4: A betaß-lactamase inhibitor and betaß-lactam enhancer from the diazabicyclooctane (DBO) class

Protocol documents:
ICF_000.pdf: 
Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 21-0013 
ICF version 4.0  –  15 November 2022 
Page 1 of 27 
  
  
Martin Kankam, MD, PhD, MPH, FAPCR 
Advarra IRB Approved Version 18 Nov 2022 
Revised 24 Mar 2023 
 
INFORMED CONSENT TO TAKE PART IN A CLINICAL 
RESEARCH STUDY AND AUTHORIZATION TO USE AND 
DISCLOSE MEDICAL INFORMATION 
 
TITLE: 
  
A Phase 1, Randomized, Double-Blind, Placebo-Controlled, 
Dose-Escalation Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of Intravenous Ertapenem in Combination with 
Zidebactam (WCK 6777) in Healthy Adult Subjects 
PROTOCOL NO.:  
DMID 21-0013 
PURPOSE:  
Multiple drug-resistant infection 
TYPE OF STUDY:  
Phase I – HEALTHY SUBJECTS 
SPONSOR:  
Division of Microbiology and Infectious Diseases (DMID) 
  
National Institute of Allergy and Infectious Diseases (NIAID) 
  
National Institutes of Health (NIH) 
  
5601 Fishers Lane, MSC 9806 
  
Bethesda, Maryland 20892 
STUDY DOCTOR:  
Martin Kankam, MD, PhD, MPH, FAPCR 
RESEARCH SITE 
ADDRESS: 
Altasciences Clinical Kansas, Inc. 
10103 and/or 10203 and/or 10183 Metcalf Avenue 
Overland Park, KS 66212 
TELEPHONE NUMBER  913-696-1601 (24-hour number) 
 
KEY INFORMATION 
The following is a summary of the things you should know about this clinical research study: 
 
• You are invited to take part in a clinical research study of the drugs ertapenem (ERT) and 
zidebactam (ZID), which will be administered separately, or combined (ERT-ZID or WCK 
6777). This means that the study drugs are allowed to be evaluated in healthy persons like you 
in this study by the U.S. Food and Drug Administration (FDA), but not approved for use in 
people by prescription. Your participation is voluntary and your consent to participate is 
sought after you have read and understood information provided in this document and have 
your questions about the study answered before any study tests are done. If you consented and 
then change your mind, you may withdraw from the study and notify the study doctor. If you 
withdraw after you received even a dose of a study drug, you will have a medical evaluation 
and lab tests to ensure you are doing well and you will be asked to consent to remain in the 
study for more safety follow up and possibly for some more blood sampling for measuring the 
study drug concentration in your blood. 
 


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 21-0013 
ICF version 4.0  –  15 November 2022 
Page 2 of 27 
  
  
Martin Kankam, MD, PhD, MPH, FAPCR 
Advarra IRB Approved Version 18 Nov 2022 
Revised 24 Mar 2023 
 
• Zidebactam (ZID) is a compound that is being developed for use in combination with other 
antibiotics, such as with ertapenem (ERT), for the treatment of severe infections that are 
resistant to multiple available antibiotics. Ertapenem (ERT) is an antibiotic approved by the 
FDA for use in people for the treatment of various infections. In this study, ERT will be used 
in doses higher than approved by the FDA. In this study, ZID and ERT will be studied alone 
and in combination. The combination of ERT and ZID is called WCK 6777 and will be used 
in people for the first time in this study. 
  
• The purpose of this research study is to collect information about the safety of taking ZID and 
ERT alone or in combination (WCK 6777), that is, if any side-effects occur after taking them, 
and their type and how severe they are. Information will also be collected about the study drug 
pharmacokinetics (PK), that is, how the body handles the drugs after taking them at the doses 
to be used. 
   
• You will be assigned to one of 7 study treatment cohorts (groups), numbered 1 to 7. Some 
cohorts will have both study drugs (Cohorts 1, 4 and 7) and others only ERT (Cohort 2 and 
Cohort 5) or only ZID (Cohort 3 and Cohort 6). The cohorts will run sequentially in the order 
they are numbered, that is, Cohort 1 will be done before Cohort 2, etc. and the lowest dose 
will be in Cohort 1 and the highest in Cohort 7. 
 
• A total of 52 subjects will take part in the study, 8 subjects each in Cohorts 1, 2, 4, 5, and 7 
and 6 subjects each in Cohorts 3 and 6. In Cohorts 1, 2, 4, 5 and 7, you will be assigned 
randomly (like tossing a coin) to receive either the study drug (75% chance) or placebo 
(saline, salt water) (25% chance). In Cohorts 3 and 6, you will receive only the designated 
study drug. 
 
• The study drug(s) or placebo will be infused intravenously (IV; in a vein) once a day for 7 
days, and the volume and duration of each infusion will vary depending on the cohort you will 
be assigned to: 100 mL (about 3.5 ounces) over 30 minutes in Cohort 1, 250 mL (about 8.5 
ounces) over 60 minutes in Cohorts 2, 3 and 4 and 250 mL (about 8.5 ounces) over 120 
minutes in Cohorts 5, 6 and 7.  
  
• If you decide to participate, you will be in the study for up to 42 days (from Screening Visit to 
Final Visit). There is a  Screening Period of up to 27 days to determine if you meet the study 
requirements; an Inpatient Period of 9 days/8 nights, with 1 day to check-in, to confirm you 
can take part in study and be admitted in the clinical research site, 7 days with daily dosing 
with the study drug or placebo assigned to your cohort, and 1 day of evaluations before 
discharge; and an Out-patient Follow-up Period with one final visit to the research site 
between 4 to 7 days after receiving the last dose of the study drug. 
 
• Screening evaluations will start after signing this form to document your willingness to take 
part in this study. We will collect demographic information about you (age, sex, race and 
ethnicity) and social habits (smoking, alcohol use, drug use, exercise). Medical evaluations 
will include your medical and surgical history, history of medications you take, physical 
examination (PE), measurement of your body weight and height, taking your vital signs (VS; 


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 21-0013 
ICF version 4.0  –  15 November 2022 
Page 3 of 27 
  
  
Martin Kankam, MD, PhD, MPH, FAPCR 
Advarra IRB Approved Version 18 Nov 2022 
Revised 24 Mar 2023 
 
measurement of blood pressure, heart rate, breathing rate and temperature), blood and urine 
tests, test for hepatitis and HIV, a pregnancy test if you are female, a test to confirm if you are 
postmenopausal if you are female, and an electrocardiogram (ECG; paper tracing of the heart 
signals). If you meet all the requirements to take part in the study, you will be given an 
appointment to check-in in the clinical research site 1 day before starting study drug 
administration to confirm that you continue meeting the requirements to participate in the 
study. 
  
• Starting on Day 1 and until Day 7, you will receive a single IV dose of the study drug or 
placebo according to the cohort (group) you are in. The effects of the study drug on you will 
be assessed by your reports of symptoms and responses to questions by the clinical staff, 
physical exams focused on the symptoms you have, vital signs, and blood and urine 
laboratory tests at various timepoints after you received the study drug and until your last 
visit. Blood and urine samples will also be collected during these days to measure the drug 
concentration and study the drug pharmacokinetics (PK, how your body handles the drug).  
Blood will be drawn from a vein in the arm opposite the one for infusion. You will be 
discharged from the clinical site on Day 8 and return to the clinical site between Day 11 and 
14 for your final out-patient visit. 
 
• Risks that could be caused by the study drugs are: 
o Zidebactam (ZID) was safe and well-tolerated in previous studies in healthy people in 
doses the same or higher than the doses to be used in this study. The most common side 
effects thought to be related to the study drug were:  
 Mild to moderate headache 
 Injection site irritation (pain, redness) 
o Zidebactam’s potential to cause mutations and cancer needs further testing, and there are 
no long-term studies to evaluate this risk in animals and humans. However, this risk is 
considered low because the study drug will be administered only up to 7 times (doses) in 
this study.  
o Ertapenem (ERT) was safe and well-tolerated as a standalone drug by patients at the FDA 
approved dose (1 gram daily) after it was approved as a prescription drug. In this study, 
ERT will be used at higher doses than the approved dose, and these doses (2 grams and 3 
grams daily) were found to be safe and well-tolerated in research studies in healthy 
people. The most common side effects thought to be related to the drug were:  
 Mild to moderate diarrhea 
 Nausea 
 Vomiting 
 Headache 
 Somnolence (increased tendency to sleep) 
 Dizziness 
 Vein irritation at the infusion site 
 Vaginitis in females 
 Increase of liver enzymes 
 Increase of platelet counts in the blood 


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 21-0013 
ICF version 4.0  –  15 November 2022 
Page 4 of 27 
  
  
Martin Kankam, MD, PhD, MPH, FAPCR 
Advarra IRB Approved Version 18 Nov 2022 
Revised 24 Mar 2023 
 
o Potential side-effects of ertapenem are:  
 An allergic reaction 
 Muscle tremor 
 In the higher doses (2 grams and 3 grams) that will be used in this study, the 
following may occur: 
• Nausea 
• Diarrhea 
• Brief dizziness 
o WCT 6777 (ERT+ZID combination) has not been studied before in people. Side effects 
could be those of each of the study drug components or others that are not known. 
 
• Risks that could be caused by the study procedures are: 
o There may be side effects of inserting needles or a catheter in the vein to collect blood or for 
an IV infusion. Local pain, bruising, bleeding, phlebitis (inflammation or infection of the 
vein) or thrombophlebitis (clotting of blood in the vein) might occur at the site of the needle 
stick or IV catheter. There is a possibility of dizziness or fainting while your blood is being 
drawn. 
o There may be side effects of blood draws, such as dizziness standing or feeling tired, which 
may be caused by decreased blood volume or anemia (low blood counts). The amount of 
blood that will be drawn is less than the volume drawn in a blood donation. 
o There could be side effects from the ECG patches, such as a rash or minor irritation of the 
skin with itching. There could also be a need to shave a small area of the skin to place the 
patch. 
  
• The study staff will monitor your well-being during the study, evaluate you medically, and 
provide appropriate treatment as required. Precautions will be taken to minimize 
complications from blood draws or IV infusions. 
  
• The study has no direct benefit for you. Knowledge gained in the study could be of future 
benefit to public health and to individuals with infections, who might benefit if the study drug 
is licensed. You will be promptly notified of any abnormal clinical test results that may 
suggest previously unknown abnormalities that could be clinically significant, and you will be 
counseled to see your own doctor for follow up. 
 
• There are no alternatives to the research study. You are free to consent to participate in the 
study or not to participate or to withdraw after you consented initially. You will be 
compensated for the study days and procedures you complete. You will not be penalized if 
you withdraw from the study. 
 
• Your personal health information will be protected. Your study medical record, laboratory test 
results and storage tubes containing your blood (plasma) and urine specimens will be coded 
and will not identify you by name or provide any other personal information that can identify 
you. 
 
 
 


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 21-0013 
ICF version 4.0  –  15 November 2022 
Page 5 of 27 
  
  
Martin Kankam, MD, PhD, MPH, FAPCR 
Advarra IRB Approved Version 18 Nov 2022 
Revised 24 Mar 2023 
 
INTRODUCTION 
You are being asked to be a volunteer in a clinical research study. You cannot be in this study if 
you are in another research study or have been in another study within the past month. Before you 
agree to be a part of this study, it is very important that you read and understand the study plan 
and in what ways you will need to cooperate. This consent form may have words in it that you do 
not understand. You may ask the study doctor or the study staff to explain any words or 
information that you do not understand. If you sign and date this form, it means you want to be in 
this study. 
  
This form describes the reason for the study, and the way the study will be done. It also describes 
the benefits, risks, discomforts, and warnings about the study. This form will also explain how 
your medical information will be used, and who may see it. It describes your rights as a volunteer 
in the study. 
  
The study staff will ask you many questions. Your answers must be completely truthful. Your 
health history and any changes in the way you feel during the study are very important. You must 
tell the study staff about any changes in your health or the way you feel. If you are not truthful, 
you may harm yourself by being in this study. Your signature on this consent form serves as proof 
of your promise that the information you give is true and correct and that you will remain truthful 
during this research study. 
 
Altasciences Clinical Kansas, Inc., the research site, is being paid by the Division of 
Microbiology and Infectious Diseases (DMID) of the National Institute of Allergy and Infectious 
Diseases (NIAID), part of the National Institutes of Health (NIH). DMID is also referred to as the 
“study sponsor” in this document. 
 
BACKGROUND AND PURPOSE  
The study doctor and the Division of Microbiology and Infectious Diseases (DMID) and the drug 
company, Wockhardt, Ltd, are conducting this research study of WCK 6777 (ZID-ERT), an 
investigational combination of two study drugs, Zidebactam (ZID) and Ertapenem (ERT). 
Zidebactam (ZID) is an investigational drug that has been allowed by the Food and Drug 
Administration (FDA) to be used in humans in research studies only. Ertapenem (ERT) is an 
antibiotic approved by the FDA for human use in 2001. The doses of ERT to be used in this 
research study are higher than the max daily dose recommended by prescription. This research 
study is the first one where the combination of ZID with ERT, called WCT 6777, will be studied. 
 
ZID is a synthetic antibiotic that was made to combat infections against bacteria that are resistant 
to existing antibiotics. It can block some bacterial proteins that cause resistance to available 
antibiotics and enhances (boosts, makes stronger) the effect of other antibiotics, like ERT, to 
which bacteria are developing resistance. In animals, ZID increased the ability of other antibiotics 
to kill of some of the most resistant bacteria known that are the cause of severe kidney, lung and 
abdominal infections in people. ZID in combination with another antibiotic called cefepime is in 
advance testing for the treatment of urinary (kidney) infections in people. In this study, ZID will 
be evaluated in combination with ERT. 
    


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 21-0013 
ICF version 4.0  –  15 November 2022 
Page 6 of 27 
  
  
Martin Kankam, MD, PhD, MPH, FAPCR 
Advarra IRB Approved Version 18 Nov 2022 
Revised 24 Mar 2023 
 
ERT is a synthetic antibiotic that has been approved by the Food and Drug Administration (FDA) 
and has been used extensively in the last 21 years for the treatment of severe skin , kidney, lung, 
abdominal and other infections in people from age 3 months and up. ERT is considered 
investigational in this study because it will be used in doses higher than recommended by 
prescription. It is also studied in combination with ZID because it was found that bacteria that 
were no longer sensitive to ERT or to ZID alone in the laboratory were sensitive to the 
combination of the two study drugs. 
 
WCK 6777 (ERT+ZID) is a combination of these two antibiotics, ERT and ZID, that has shown 
to be effective against resistant bacteria in the lab and in animal studies. The combination is 
evaluated in healthy persons before it is tested in people with infections in order to understand the 
safety profile and the PK of the two antibiotics used together. It is expected that the combination 
will be effective in infections for which the number of existing effective antibiotics becomes 
smaller. The combination of the two study drugs could also be given in an outpatient facility as an 
IV infusion that is completed in relatively short time, something that could cut down 
hospitalization time and cost. 
 
This research study will evaluate the effects of progressively increasing doses of either ZID or 
ERT alone or WCK 6777 (ERT+ZID combination) when administered IV as single daily doses 
for 7 days. The overall goals are to determine the safety, tolerability, and pharmacokinetics (PK) 
of the study drugs and if there are interactions when given together. Pharmacokinetics is the study 
of how a drug is absorbed, distributed, metabolized, and eventually eliminated by the body. 
 
This study will be conducted in adults between 18 to 45 years of age who are in good health, do 
not take certain medications, and, for women, if they are not pregnant or breastfeeding. There will 
be a total of approximately 52 male and female subjects in this study.  This study will be done at 
one site in the United States. All subjects in this study will receive a single IV dose of either the 
study drug or the combination of the two study drugs daily for 7 days. 
 
The study will take up to 42 days to complete and is made up of the following periods: a 
Screening Period up to 27 days (Day -28 to Day -2), during which you will have screening tests if 
you consent to participate ; a Check-in day (Day -1) to confirm your eligibility and, if you still 
qualify, to admit you in the research site and enroll you in the study; an Inpatient Study Treatment 
Period lasting 9 days/8 nights, with eligibility reviewed prior to study treatment administered on 
Day 1, and once daily doses of the study drugs or placebo from Day 1 to Day 7, and discharge 
from the Research Site on Day 8; and an Outpatient Follow-up Period of up to 6 days, with a 
single, last visit to the Research Site on Day 11 (+3 days) (4 to 7 days after the last study 
treatment). 
 
A description of this research study will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This website will not include information that can identify you. At most, 
the website will include a summary of the study results. You can search this website at any time. 
 


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 21-0013 
ICF version 4.0  –  15 November 2022 
Page 7 of 27 
  
  
Martin Kankam, MD, PhD, MPH, FAPCR 
Advarra IRB Approved Version 18 Nov 2022 
Revised 24 Mar 2023 
 
INFORMATION ABOUT THE STUDY 
If you are eligible to take part in this study, you will receive either one of the study drugs or their 
combination according to the cohort (group) you were screened for. The study drug(s), doses of 
each drug, and the volume and duration of infusion in each cohort vary and are as follows: 
 
COHORT 
NUMBER 
STUDY 
DRUG 
STUDY 
DRUG DOSE 
INFUSION VOLUME 
INFUSION 
DURATION 
1 
WCK 6777 
or placebo  
1 gram ERT 
+ 1 gram ZID 
100 mL (about 3.5 ounces) 
30 minutes 
2 
ERT 
or placebo 
2 grams ERT 
250 mL (about 8.5 ounces) 
1 hour 
3 
ZID 
2 grams ZID 
250 mL (about 8.5 ounces 
1 hour 
4 
WCK 6777 
or placebo  
2 grams ERT 
+ 2 grams ZID  
 
1 hour 
5 
ERT 
or placebo 
3 grams ERT 
250 mL (about 8.5 ounces 
2 hours 
6 
ZID 
3 grams ZID 
250 mL (about 8.5 ounces 
2 hours 
7 
WCK 6777 
or placebo 
3 grams ERT 
+ 3 grams ZID 
250 mL (about 8.5 ounces 
2 hours 
 
Each subject in each cohort, except Cohort 3 and Cohort 6, will be randomized (like tossing a 
coin) to receive either study drug or placebo (salt water for infusion). The chance of receiving 
placebo is 25%. Additional subjects may also be admitted to the Research Site before dosing and 
may serve as back-up study subjects. You may be selected to participate in this research study as 
either a study subject or a back-up study subject. If you were selected as a back-up but did not 
receive a study treatment, you could be placed in the same cohort or another one if you are still 
interested in taking part in the study. 
 
On Days 1 to 7, you will have a catheter inserted into a vein in the hand or arm for taking blood 
and another catheter for infusing the study drug or study drug combination in the opposite arm. 
The infusion volume and duration of infusion will vary depending on the cohort you are in: For 
Cohort 1, the volume will be 100 mL (about 3.5 ounces) and the infusion will last 0.5 hours (30 
minutes); for Cohorts 2, 3 and 4, the volume will be 250 mL (about 8.5 ounces) and the infusion 
will last 1 hour (60 minutes); and for Cohorts 5, 6 and 7, the volume will be 250 mL (about 8.5 
ounces) and the  infusion will last 2 hours (120 minutes). After dosing with study drug, you will 
be monitored daily, and data will be collected to evaluate the effect of the study drug on you. 
After the dose on Day 1, you will have frequent blood samples taken for the next 24 hours to 
measure the concentration of study drug in the blood, and you will be asked to collect all your 
urine samples during the same period. Blood and urine collections up to 24 hours after the dose 
will also be done on Day 7. 
 
You will be asked to come to the Research Site 3 times: 2 times before receiving the study drug, 
and 1 time after receiving it. You will be admitted in the Research Site on Day -1 after you 
complete testing on the second visit and stay in the Altasciences Clinical Kansas research site for 
8 nights/9 days if you meet the requirements for receiving the study drug. 


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 21-0013 
ICF version 4.0  –  15 November 2022 
Page 8 of 27 
  
  
Martin Kankam, MD, PhD, MPH, FAPCR 
Advarra IRB Approved Version 18 Nov 2022 
Revised 24 Mar 2023 
 
  
The first visit will be a screening visit. You will be informed about the study, have your questions 
answered and, if you decide to participate in the study, as shown by signing and dating this 
consent form, you can proceed to the first part of screening to evaluate your eligibility to take part 
in the study. If you decide to participate and sign this consent form, we will collect your 
demographic information (age, sex, race, ethnicity) and social habits (smoking, alcohol and drug 
use, exercise), The medical evaluations will include your medical and surgical history, history of 
prescription and non-prescription medications you take, a physical exam (PE), measurements of 
your height and weight and of your vital signs (VS; blood pressure, heart rate, breathing rate, and 
temperature), an ECG (a paper tracing of your heart beats), standard blood tests (blood counts, 
chemistries, coagulation tests) and urine lab tests, a pregnancy test if you are female, a test to 
confirm if you are post-menopausal if you’re female, tests for hepatitis B and C and for HIV, and 
urine tests for drugs, alcohol, and cotinine. 
  
If you pass the screening tests, you will be asked to return to the Research Site for a second visit 
on (Day -1, Check-in) to complete medical and lab tests and confirm that you can be admitted. If 
you continue to be eligible to continue participating in the study, then you will stay in the 
Research Site overnight for the inpatient study treatment period. 
o If you do not pass the screening test, the study staff will tell you why and may counsel you 
to seek medical attention based on any abnormal lab tests or other findings. 
 
On the next day (Day 1), you will begin the inpatient study treatment period of the study. In 
the morning on Day 1, you will have baseline VS and collection of plasma and urine for PK. You 
will be required to have no food to eat for at least 4 hours before the IV study treatment infusion. 
Catheters will be inserted in a vein in one arm to infuse the study drug and in another vein in the 
other arm to draw blood. You will receive the study drug or placebo IV through the vein, The 
volume and duration of duration of infusion will vary depending on the cohort you are in (see the 
table on page 6). You may eat food 1 hour after the end of the infusion. In the next 24 hours, you 
will have 7-9 blood draws at scheduled times, each about 2 teaspoons, to measure the study drug 
concentration in the blood (plasma PK). You will also start collecting all the urine at intervals for 
the measurement of the study drug (urine PK) until 24 hours after the start of dosing. The last PK 
will be completed before you receive the next dose of study drug on Day 2. 
 
Recording and evaluating side-effects will start with the first dose and continue through the 
end of the study. 
 
On Days 2 to 6, you will have an IV infusion of the study drug daily, in the same volume, study 
drug dose, for the same duration and starting about the same time as on Day 1. You may eat food 
1 hour after the end of the IV infusion. You will have vital signs taken before infusion. You will 
have blood drawn for lab tests before dosing on Days 2, 4 and 6. Plasma PK blood draws will be 
collected before each dose on Days 2, 3, 4, 5 and 6 and 12 hours after the dose. The catheters in 
your veins may stay in up to 3-4 days, but they may be removed more frequently if your veins are 
irritated or the catheters do not work, and new catheters will be placed in your veins. 
 


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Page 9 of 27 
  
  
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Advarra IRB Approved Version 18 Nov 2022 
Revised 24 Mar 2023 
 
On Day 7, you will have the last dose of study drug or placebo infused IV as on Day 1. You will 
have medical assessments Plasma and urine PK will be collected at scheduled times for 24 hours 
after the study drug infusion, until the morning of Day 8, exactly as it was done on Day 1. 
 
On Day 8, you will complete required medical and lab testing. You will be counseled to avoid 
prohibited drugs, avoid pregnancy and continue contraception for 30 days after last dose of the 
study drug. If you are a male, you will be counseled not to donate sperm for 30 days after the last 
dose of study drug and, for you and your partner to use appropriate contraception for the same 
period. Then you will be discharged from the research site after you complete all your 
evaluations. 
 
On Day 11 (+3 days), that is 11 to 14 days after the first dose (4 to 7 days after the last dose), you 
will be asked to return to the research site to complete required final medical and lab evaluations. 
 
You will be asked for any new symptoms before the first dose and continue until you complete 
the study on the last visit. You will have additional physical exams and lab tests as needed for the 
evaluation of any new symptoms and findings that you may have. You may be asked to return to 
the research unit to follow up on any abnormal lab tests or other findings as necessary until they 
are no longer present, or they are not clinically significant in the judgement of study doctors. 
 
The schedule for screening, check-in / enrollment study treatment, and outpatient follow-up 
periods is shown in the table below: 
    
Outpatient 
Screening 
Inpatient 
Inpatient Study 
Treatment 
Outpatient 
Follow Up 
Screening Period 
Check-in/ 
Enrollment 
Dosing 
Discharge 
Final Visit 
Day -28 to Day -2 
Day -1 
Day 1 to Day 7 
Day 8 
Day 11 (+3 days) 
  
MEDICAL MONITORING 
The study staff will monitor you for side effects during your stay in the Research Site and provide 
medical care as needed if you have any medical problems. Guidelines have been created to 
evaluate the safety of the study drug. If you have any side effects, we will evaluate your 
symptoms and treat you as indicated according to standard medical practices. 
 
WHAT WILL HAPPEN DURING THE STUDY? 
  
SCREENING PERIOD (Day -28 to Day -2) 
 
SCREENING VISIT: 
During this visit, you will be informed about the study, have your questions answered and, if you 
decide you want to participate in the study, show your intent by signing and dating this consent 
form.  
  


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 21-0013 
ICF version 4.0  –  15 November 2022 
Page 10 of 27 
  
  
Martin Kankam, MD, PhD, MPH, FAPCR 
Advarra IRB Approved Version 18 Nov 2022 
Revised 24 Mar 2023 
 
After signing this consent and before you begin the study, you will have the following screening 
tests done to determine if you are in good health and qualify to continue participation in the study: 
• Complete medical history (including your demographic information) and medication 
review. 
• Vital signs (VS; blood pressure, heart rate, breathing rate and oral temperature) and height 
and weight measured, and Body Mass Index (BMI) calculated. 
• Complete a Physical Examination. 
• Have a 12-lead ECG (standard recording) - This will require attachment of electrodes 
from the standard ECG machine to your chest, arms, and legs. Male subjects may have to 
have their chest hair shaved for the ECG. Female subjects may not be allowed to wear a 
bra during ECG-related procedures. 
• You will have blood and urine collected for laboratory tests (you will be asked to not eat 
or drink anything other than water for at least 4 hours before blood collection). 
• You will have a urine test for alcohol, and urine drug screen for illegal drugs and cotinine 
(for detecting nicotine products). (The tests must be negative to qualify.) 
• Blood collected for serum pregnancy test if female. (The test must be negative to qualify.) 
• Blood collected for measurement of follicle-stimulating hormone (FSH) if post-
menopausal female. 
• Testing for Hepatitis B, Hepatitis C, and HIV infections: Your blood will be tested for the 
HIV antibody. HIV is a virus that causes AIDS. You will also be tested for Hepatitis B 
and C Viruses. (Test results must be negative to qualify.) 
o Note that it may take weeks or months after being infected with HIV for the test to be 
positive. If you have a positive HIV or hepatitis test, you cannot be in the study. If the 
HIV or hepatitis test are positive, you will be notified by the Research Site and given 
information on how to follow up for further medical care. As required by law, positive 
test results must be reported by the Research Site to the State Department of Health. If 
you have any questions about what information is required to be reported, please ask 
the study staff. If the Research Site becomes aware during your participation in this 
study that there is any change in the HIV or Hepatitis Virus results, you will be 
withdrawn from the study. Your test results are private (confidential); however, this 
cannot be guaranteed. For example, it is possible for a court of law to get health or 
study records without your permission.  
 
You will be told of the results of medical tests and whether you can continue participating in the 
study. 
• If you do not meet the study requirements, you will be discharged from the study. You 
will be told why you were not selected for the study. 
o If there is a medical condition or abnormal laboratory test that needs further medical 
attention, you will be counselled to follow up with your primary doctor  or contact 
community physicians or clinics where you can go for testing and follow up. You may 
sign a release form to allow the Research Site to release medical tests to you or send 
them to your own doctor or clinic. 
• If your medical tests are good and confirm your eligibility to participate in the research 
study, the study staff will ask you to return to the Research Site on Day -1 to complete the 
inpatient screening tests to confirm your eligibility to participate in the study. 


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 21-0013 
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Page 11 of 27 
  
  
Martin Kankam, MD, PhD, MPH, FAPCR 
Advarra IRB Approved Version 18 Nov 2022 
Revised 24 Mar 2023 
 
o You will be told to come prepared to stay for the inpatient study treatment if you pass 
the tests. 
o You will be counselled to avoid pregnancy, use appropriate contraception (both male 
and female), and avoid prohibited medications, tobacco and other nicotine products, 
alcohol, and marijuana and illegal drugs. 
o You should avoid strenuous physical activity. 
 
CHECK-IN VISIT (Day -1) (1 day before the study treatment period) 
On this day, you will have the same tests as you did at the Screening visit to confirm that you 
continue being in good health and meet the requirements for admission and receiving the study 
drugs. The study doctor will review the results of your tests to see if you still qualify. 
• If you do not meet the study requirements, you will be discharged on this day. You will be 
told why you were not selected for the study. If there is a medical condition or abnormal 
laboratory test that needs further medical attention, you will be counselled to follow up 
with your primary doctor or contact community physicians or clinics where you can go for 
testing and follow up. You may sign a release form to allow the Research Site to release 
medical tests to you or send them to your own doctor or clinic. 
• 
If you meet the study requirements, you will be admitted to the Research Site.  
 
After you are admitted, you will complete an orientation of the in-patient facility , and asked to 
read the House Rules that describe what you are expected to follow while you stay in this facility 
and participate in the study.  
• 
You will be told what study treatment cohort you were assigned to and review the 
procedures that will be performed during the Inpatient Study Treatment period. You will not 
be told if you are going to receive active study drug or placebo if you are assigned to a cohort 
where either one will be used (Cohorts 1, 2, 4, 5, and 7). 
• You will be counseled to avoid excessive exercise. 
• You will be encouraged to drink plenty of fluids to keep well hydrated. 
• You will receive dinner and snacks in the Research Site. 
• You will not be allowed to eat anything for 4 hours before taking the study drug the 
following morning, but you will be allowed to drink water during that period. 
 
INPATIENT STUDY TREATMENT PERIOD (Days 1 to 8) 
You will receive the study drug daily in the morning on Days 1 to Day 7 and followed as inpatient 
until Day 8. The following procedures will be done during this period: 
 
DAY 1 and DAY 7 (In-patient Dosing): 
 
Before Dosing: 
• 
You will not eat any food or drink (other than water) at least 4 hours before taking the 
study drug (dosing). That means that you may have an evening snack the night before 
dosing but no food afterwards, and you will not eat breakfast before dosing. You will be 
allowed to drink water during that time before dosing. 


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 21-0013 
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Page 12 of 27 
  
  
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Advarra IRB Approved Version 18 Nov 2022 
Revised 24 Mar 2023 
 
• 
If you have new symptoms, you will have a physical exam and any medications you took 
will be reviewed and your vital signs measured. The results of the above will be reviewed 
to see if you still qualify to receive the study drug. 
• 
You will have an IV catheter placed in a vein in your forearm to infuse study drug. You 
will have another IV catheter placed in a vein in your other arm to draw blood. 
• 
You will have blood (plasma) PK and urine PK samples collected for analysis of study 
drug before dosing starts.  
• 
You will be asked to empty the bladder as close to the start of the study drug infusion as 
possible. 
• 
You will be encouraged to keep well hydrated starting before the study drug infusion and 
continue until 24 hours after the last dose. 
Dosing: 
• 
You will receive the study drug or placebo by IV infusion (in a vein) using an infusion 
pump in a volume and duration of infusion specified for the study drug or study drug 
combination selected for your cohort (See the table on page 6). 
 
After Dosing Starts: 
• 
You should report any side effects that you may experience after infusion starts until 
the end of the study. You will also be observed for side-effects during the infusion. 
• 
You will have a physical exam done as needed for evaluation of new symptoms after 
dosing starts until the end of the study. 
• 
Any medication that you take will be recorded to the end of the study. 
• 
You will not eat solid food during the infusion and at least 1 hour after the end of the 
infusion but be able to drink water and non-carbonated beverages.  
• 
You will have your vital signs measured. 
• 
You will have blood drawn to measure the concentration of study drug approximately 7-9 
times after you started receiving the study drug, depending on the cohort (group) you were 
assigned to. 
• 
You will be asked to collect all urine for the next 24 hours in pools every 4 hours as 
follows: from the start of dosing to 4 hours, 4-8 hours, 8-12 hours, and 12-24 hours. Study 
staff will instruct you on how to collect the urine at various intervals. 
• 
You will have the infusion site and the blood drawing site checked periodically by the 
study staff. Let the study staff know if you experience any discomfort or other symptoms 
at these sites. 
• 
The study staff will let you know if they will keep the IV infusion line and blood draw line 
open to be used on the following day or removed and replaced. 
• 
You may be served a meal 1 hour after the infusion. Let the study staff know if you have 
any nausea and you cannot eat. 
• 
You will be encouraged to keep well hydrated. 
• 
You will be counseled to avoid excessive exercise until the study end. 
 
 
 


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 21-0013 
ICF version 4.0  –  15 November 2022 
Page 13 of 27 
  
  
Martin Kankam, MD, PhD, MPH, FAPCR 
Advarra IRB Approved Version 18 Nov 2022 
Revised 24 Mar 2023 
 
DAY 2 to DAY 6 (In-patient Dosing): 
 
Before Dosing: 
• You should report any side effects that you may experience. 
• Any medication that you take will be recorded to the end of the study. 
• Your infusion site and blood draw line will be examined, and new catheters inserted if 
needed. 
• Your vital signs will be measured. 
• You will have blood samples collected for clinical lab tests (Days 2, 4 and 6 only). 
• You will have blood (plasma) drawn to measure the concentration of study drug daily 
within 30 min before dosing. 
• You will be asked to finish the collection of urine for measuring the concentration of study 
drug within 30 min before dosing (Day 2 only). 
 
Dosing:  
• You will have the study drug or placebo infused IV (in a vein) as on Day 1. 
 
After Dosing Starts: 
• You should report any side effects that you may experience after infusion on each 
day.  
• You will be observed for side-effects during the infusion. 
• You will have a physical exam for evaluation of your symptoms. 
• Any medication that you take will be recorded to the end of the study. 
• You will have assessments after dosing on those days that are identical to those done on 
Day 1. 
• Your study drug infusion IV line will be removed. 
• You should continue good hydration daily. 
• You will be counseled to avoid excessive exercise. 
 
DAY 8 (Inpatient Follow-up): 
• You should report any side effects that you may experience. after infusion starts until 
the end of the study. 
• You will have vital signs and weight measured, and an ECG recorded. 
• You will have blood and urine samples collected for clinical laboratory tests. 
• You will have blood (plasma) drawn to measure the concentration of study drug at 24 
hours after last dose on Day 7. 
• You will complete the collection of urine to measure the concentration of study drug at 
12- 24 hours after last dose on Day 7. 
• You will have the IV infusion site examined and the IV blood draw catheter removed. 
You should report any discomfort you have at the infusion or blood draw site. 
• You will have a complete physical examination. 
• You will be discharged from the Research Site after review of clinical laboratory tests, 
ECGs, and other assessments by authorized clinician. 


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Page 14 of 27 
  
  
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Advarra IRB Approved Version 18 Nov 2022 
Revised 24 Mar 2023 
 
• You will be counseled to avoid pregnancy, continue contraception for 30 days after the 
last dose, avoid donating sperm for 30 days after last dose if you are a male, and avoid 
excessive exercise. 
• 
You will be provided contact information and instructions to report to the Research Site 
any side effects or new symptoms that you develop during these periods and any 
medication that you take. 
• 
You will be given an appointment to return to the Research Site to have follow-up tests on 
Day 11 (+3 days) after first dose (4 to 7 days after last dose). 
 
DAY 11 (+3 days) (Out-patient Follow-up – Final Visit): 
• You should report any side effects that you may have experienced after your 
discharge from the research site on Day 8. 
• You will be asked to report any medications that you took after your discharge from the 
research site on Day 8.  
• You will have vital signs measured, and an ECG recorded 
• You will have blood and urine samples collected for clinical laboratory tests. 
• Your IV infusion site and IV blood draw site will be examined. Report any discomfort you 
have at the infusion or blood draw site. 
• You will have a complete physical examination 
• You will be counseled to avoid pregnancy, continue contraception for 30 days after the 
last dose, if you are a male avoid donating sperm for 30 days after last dose, and avoid 
excessive exercise. 
• You should report any side effects that you may experience. You may be asked to return 
for an unscheduled visit for any symptoms that you may have. 
 
The study staff will notify you if you have completed the study or if you must return to the 
research site for any lab tests that need be followed. 
 
EARLY TERMINATION: 
If you choose to withdraw from the study or are terminated by the investigator before you 
complete the study, you may be asked to consent to remain in the study to complete safety and PK 
blood collections. If you do not consent to remain in the study, you will have the same tests and 
procedures as described for Day 11 (Final Visit). 
 
UNSCHEDULED VISIT (if needed): 
You may return to the Research Site for an unscheduled visit at any time after your discharge on 
Day 8 or after the last visit (Day 11) if you have any symptoms that you want to discuss or 
because the study staff asked you to come in for an evaluation. The following activities could be 
done according to the reason of your extra visit:  
• You will be asked to provide information on the side-effects you may experience. 
• You will be asked to document medications you take. 
• You may have the Vital Signs measured. 
• You may have a physical examination. 
• You may have a 12-lead ECG if needed. 


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 21-0013 
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Page 15 of 27 
  
  
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Advarra IRB Approved Version 18 Nov 2022 
Revised 24 Mar 2023 
 
• You may have blood drawn and/or urine collected for clinical laboratory tests, if 
applicable. 
• The study staff will give you information and tell you if you need to return for follow up 
for another visit. 
 
The study staff may also request to have procedures performed that are not listed above to ensure 
your safety throughout the study. 
 
ADDITIONAL DRUG AND ALCOHOL SCREENS 
Random urine drug and alcohol screens may be repeated at any time during the study if the study 
staff suspects alcohol or drug use. If you test positive for drug or alcohol use at any time after the 
first dose of study drug, you may be discontinued from the study. 
 
CONTROLLED SEARCH 
Designated study staff reserves the right to do a controlled search by having you put on a gown in 
order to have your clothes and person checked for disallowed items that may have been brought 
into the research site. This search involves removing all undergarments as well as putting on a 
gown so that there is no place the disallowed items could be kept. 
 
At each admission into the research site, a search of your clothing, like pockets, and bags will 
occur. You will not be required to remove your clothing or undergarments, but staff may ask you 
to turn your pockets inside out or check areas of clothing that could conceal restricted items. 
Study staff will also perform a bag check and confiscate any items not permitted to be brought 
into the research site. These belongings will be returned to you at discharge from the research 
site. 
 
BLOOD SAMPLES 
Blood samples will be drawn by single needle-sticks or through an IV catheter, as determined by 
the study staff. An IV catheter is a small plastic tube inserted into your arm vein by a needle. The 
needle is removed, but the tube temporarily remains in your vein. This tube allows the removal of 
blood without having to stick you each time. It will be removed every 3-4 days or sooner if not 
working well or if you have local pain or vein irritation. The total amount of blood drawn will be 
up to about 371 mL (about 12.5 oz, a bit over a cup) during the in-patient study treatment period 
(Days 1 to Day 8) and 425 mL (about 14.0 oz) during the entire study (from screening to the final 
visit on Day 11). For comparison, a standard blood donation at a blood collection center, once in a 
56-day period, is about 500 mL (2 cups) of blood. 
 
Additional blood samples may be drawn during the study, if the study staff considers it necessary 
for monitoring your health. 
 
Blood samples and collected data will only be used for this study. Blood samples left after all 
routine clinical laboratory testing is done will be discarded by the clinical safety laboratory. 
 


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 21-0013 
ICF version 4.0  –  15 November 2022 
Page 16 of 27 
  
  
Martin Kankam, MD, PhD, MPH, FAPCR 
Advarra IRB Approved Version 18 Nov 2022 
Revised 24 Mar 2023 
 
YOUR ROLE IN THIS STUDY 
Taking part in a research study can be an inconvenience to your daily life. Please consider the 
study time commitments and responsibilities as a research subject when you are deciding to 
participate. Your responsibilities as a subject include the following: 
• You cannot participate in this study if you have participated in a prior study within the 
past 30 days. 
• We ask you to provide accurate responses to questions about your past medical and 
surgical history (illnesses and surgeries you had including abnormal lab tests, X-rays, and 
other procedures), medications you are taking, medications you are allergic to and your 
family history. Failure to respond accurately may result in side-effects that may be 
harmful after you receive the study drug(s). 
• You must read, and agree to follow, the House Rules at the Research Site if you want to 
take part in this study. House Rules discuss proper behavior at the Research Site and are 
important to ensure your safety and make sure the study results are accurate. Failure to 
follow these rules may result in reduced compensation or involuntary discharge from this 
study. 
• You must report any side effects and medical problems to the study staff. 
• You must give true and complete answers to any questions. 
• You must be able to comply with the study procedures and visit schedule. 
• You must follow all instructions from the study staff. 
• You must inform the study staff if you decide to discontinue your participation in the 
study. If you decide to discontinue your participation in the study, you may be asked to 
consent to stay in the study and complete any remaining procedures for the most recent 
study treatment period. If you do not consent to complete any remaining procedures, you 
will be asked to complete the early termination visit procedures as described in this 
consent form. 
• You must agree to use an effective method of contraception, as defined later in this 
consent form, throughout the study and for 30 days after the last dose. If you are male, you 
must agree not to donate sperm for 30 days after dosing and, if you are sexually active, 
you and partner to use safe contraception. 
• You must not do any strenuous activity for 2 days before the dosing and at any time 
during the study until discharge on Day 8, and for 24 hours before the out-patient follow 
up visit on Day 11 (+3 days). 
• You must not consume alcohol until your discharge from the clinical site on Day 8 and 
recommended to avoid alcohol during the out-patient follow-up period until Day 11 (+3 
days) (final visit). Tell the study doctor if you consumed any alcoholic beverages during 
this time. 
• You must not use marijuana or other illegal drugs during the study. 
• You will be advised to avoid smoking after screening. Smoking is prohibited during the 
in-patient period of the study (Day -1 to Day 8) and recommended to avoid smoking 
during the follow-up out-patient period to the end of the study (Day 11). 
• You must not participate in another research study at any time during this study or 
continue participating in another study and have blood draws. This includes studies of a 
drug, biologic (such as vaccine or proteins), device, or blood product. 
  


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ICF version 4.0  –  15 November 2022 
Page 17 of 27 
  
  
Martin Kankam, MD, PhD, MPH, FAPCR 
Advarra IRB Approved Version 18 Nov 2022 
Revised 24 Mar 2023 
 
PROHIBITED MEDICATIONS, VACCINATIONS, and BLOOD DONATIONS  
Additional restrictions to ensure the health and safety of study subjects are listed below: 
• 
You must not take any prescription medications within 14 days before check-in on Day -1 
(a day before the start of study drug infusions) or during the study. Certain drugs should 
be avoided for a longer period before taking the study drug. (See Risks of study drug(s) 
below). 
• 
You will continue taking birth control medications that you were already using. Certain 
over-the counter medications may be permitted if approved by the study staff. Please 
report all prescription medications you are taking. 
• 
You must not take any non-prescription medications, herbs, vitamins, or nutritional 
supplements from the time of screening (about 14 days before dosing) to the end of the 
study (Day 11), except for single doses of acetaminophen up to 1,000 mg. Certain non-
prescription medications are prohibited if taken 14 days before dosing, and others may be 
permitted if approved by the study staff. Please report all non-prescription medications, 
herbs, vitamins, or nutritional supplements you are taking. 
• 
You must not donate any blood or blood products (red cells, white cells, platelets, plasma) 
during the course of this study. Tell the study doctor if you donated any blood or blood 
products within 3 months before dosing. If you did, we could delay your screening. 
• 
You must not receive any blood or blood products during this study unless it is medically 
necessary. 
  
RISKS OF STUDY DRUGS 
 
Observed Risks with ZID: 
There were no identified risks associated with ZID in completed human studies in 91 healthy 
subjects who were given IV single doses ranging from 250 mg to 6 grams daily. The most 
common side effects, reported by more than one subject, were:  
• Headache 
• Diarrhea 
• Infrequent bowel movements 
• Irritation at the injection site 
 
Other side effects that were reported less frequently were: 
• Muscle aches 
• Numbness around the mouth 
• Vaginal discomfort or discharge (in females) 
 
All side effects were mild. ZID was safe and well-tolerated and there were no clinically important 
changes in laboratory tests and ECGs during that study. 
 
Potential Risks with ZID: 
Until more clinical experience with ZID is available, similar undesirable effects as observed for 
other drugs should be anticipated. Special attention will be paid to signs and symptoms of allergic 
reactions. Further testing is needed to understand the potential for ZID to cause mutations and 


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Page 18 of 27 
  
  
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Advarra IRB Approved Version 18 Nov 2022 
Revised 24 Mar 2023 
 
cancer. Long-term studies in animals and humans are not available. Due to the short duration of 
study treatment with ZID, the risk of cancer is low.   
 
Observed risks with ERT: 
ERT has been licensed as an antibiotic since 2001 and has been used by patients in the 
recommended dose (1 gram daily) and by healthy people in research studies at doses (2 gram and 
3 gram) that will be used in this study. The most common side effects have been:  
• Diarrhea 
• Irritation of the infusion vein 
• Nausea 
• Headache 
• Vaginitis (in females) 
 
Rarely, ERT can cause:  
• Diarrhea 
• Dizziness 
• Increase the risk of seizures, especially in people who have a history of seizures or a 
condition that makes them more sensitive to seizures.  
 
ERT does not cause changes that increase the risk of cancer.  
 
Potential Drug Interactions: 
There are no clinical data on drug interactions with the WCK 6777 (ERT+ZID). However, based 
on the knowledge about the metabolism of the study drugs and their excretion from the urine, the 
following drugs should be avoided from 14 days before the first dose to the end of the study: 
• Lasix (Furosemide) 
• Probenecid 
• Other drugs that interact with OTA3 (Adefovir, Anagliptin, Baricitinib, Cefaclor, 
Cimetidine, Ciprofloxacin (Systemic), Clofarabine, Eluxadoline, Empagliflozin, 
Ketoprofen, Methotrexate, Mycophenolate, PEMEtrexed, Penicillin G 
(Parenteral/Aqueous), Penicillin G Benzathine, Penicillin G Procaine, Penicillin V 
Benzathine, Penicillin V Potassium, Zidovudine). 
• Valproic acid 
 
Use During Pregnancy and Lactation: 
The effects of the study drugs on the pregnant mother and the fetus have not been well studied 
Therefore, you should not participate in the study if you are pregnant or plan to become pregnant 
during the study. 
 
ERT has been reported to be detected in maternal milk. Therefore, you should not participate in 
the study if you are breastfeeding. 
 


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 21-0013 
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Page 19 of 27 
  
  
Martin Kankam, MD, PhD, MPH, FAPCR 
Advarra IRB Approved Version 18 Nov 2022 
Revised 24 Mar 2023 
 
Overdose: 
There is no specific antidote in case of overdose. The same measures as recommended for other 
antibiotics (treatment cessation, adequate hydration, and kidney dialysis) will be provided as 
medically necessary. 
 
Drug Abuse and Dependency: 
No clinical experience available. 
 
Potential Risks of WCK 6777 (ERT + ZID): 
This is the first time that ERT and ZID are used in people together and there is no information on 
their side effects; this study will provide some answers. 
 
It is anticipated that the symptoms could be the same as known for each drug separately. Testing 
before the clinical study did not show any interactions among the two drugs in standard tests of 
predicting additional side effects of drugs in humans. 
 
BLOOD SAMPLE RISKS 
There may be side effects of drawing blood with a needle and/or IV tubes and IV catheter 
placement. Local pain, bruising, bleeding, redness, swelling, or induration (palpable hard area) 
might occur at the site of the needle stick where blood is drawn. Infection at the infusion site or 
blood draw site is possible but unlikely as aseptic technique will be used. There is a possibility of 
dizziness or fainting while your blood is being drawn. Precautions will be taken to minimize the 
above side effects. There is a small risk your blood counts will decrease slightly during the course 
of the study, but not expected to cause anemia (low blood counts that cause symptoms and need 
treatment). Any symptoms that may occur are usually reversible with good nutrition and drinking 
fluids. 
 
ECG RISKS 
ECG patched may case a skin reaction such as redness or itching. You may also experience 
localized skin discomforts and/or hair loss associated with the placement of ECG patches. 
 
UNKNOWN RISKS 
You may have side effects or discomforts that are not listed in this form. Some side effects may 
not be known yet. New ones could happen to you. Tell the study staff right away if you have any 
problems. 
  
INFORMATION ON BIRTH CONTROL  
 
Females: 
The effects of study drug(s) on the unborn child are not known at this time. Therefore, it is 
important that women who are pregnant, may become pregnant or who are breastfeeding NOT 
participate in this study. If you are a woman who can get pregnant, you must use an acceptable 
form of birth control that is very effective in preventing pregnancy. You must agree to use birth 
control for at least 30 days after dosing. You agree to avoid becoming pregnant during this study. 
  


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 21-0013 
ICF version 4.0  –  15 November 2022 
Page 20 of 27 
  
  
Martin Kankam, MD, PhD, MPH, FAPCR 
Advarra IRB Approved Version 18 Nov 2022 
Revised 24 Mar 2023 
 
The following are acceptable forms of birth control for this study: 
• 
Progestin implants. 
• 
Intrauterine devices (IUD). 
• 
Surgery to prevent pregnancy in females (such as bilateral tubal ligation, salpingectomy 
[removal of the tubes], oophorectomy [removal of the ovaries], or hysterectomy [removal 
of the uterus]). 
• 
Abstinence. 
Tell the study staff if you use any other forms of birth control. 
If at any time during this study you think you may be pregnant, you are requested to contact the 
study doctor at the telephone number listed on the first page of this form. 
 
Males: 
The effect of study drug(s) on the unborn child is unknown at this time. The effect of the study 
drug on the male reproductive system is unknown. Therefore, you must agree to use an acceptable 
form of birth control from dosing with study drug through at least 30 days after the last dose.  
Acceptable birth control means not having sex (abstinence) or having a vasectomy. If you are 
sexually active, you should agree to use a condom with spermicide throughout this study and for 
at least 30 days after dosing. Tell the study staff if you use any other form of birth control. 
  
You should also not donate sperm for 30 days after the last dose. 
 
It is also recommended that you make certain that your female partner is also using an acceptable 
form of birth control if you have not had a vasectomy and are using a condom. If you think that 
your partner may be pregnant at any time during this study to 30 days after dosing, you are 
requested to contact the study doctor at the telephone number listed on the first page of this form.  
 
REPORTING PREGNANCY 
If you are a woman, you should report to the study staff if you miss your period and suspect you 
are pregnant or if you become pregnant during the 30 days after dosing. With your permission, 
you will continue to be followed for safety during this study. You are requested to provide 
pregnancy outcome to the study staff upon delivery or pregnancy termination. 
  
If you are a male and your female partner becomes pregnant during the 30 days after dosing , we 
ask you to inform study staff of the pregnancy and provide pregnancy outcome upon delivery or 
pregnancy termination. 
  
INFORMATION ON USE OF ALCOHOL, MARIJUANA OR OTHER ILLEGAL DRUGS 
You are not allowed to use alcohol, marijuana or other illegal drugs (such as cocaine, etc.) 
because they may cause you serious harm and are strictly forbidden while you are in this study. 
You will be tested for drugs and alcohol at Screening, and on Day -1. If you are found to be in 
possession of or using marijuana or other illegal drugs at the Research Site, then Altasciences 
Clinical Kansas, Inc. is obligated to report the use of marijuana or other illegal drugs to the 
appropriate legal authorities. 
 
 
 


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 21-0013 
ICF version 4.0  –  15 November 2022 
Page 21 of 27 
  
  
Martin Kankam, MD, PhD, MPH, FAPCR 
Advarra IRB Approved Version 18 Nov 2022 
Revised 24 Mar 2023 
 
INFORMATION ON ACTIVITIES TO AVOID 
You should avoid excessive exercise from at least 2 days before your admission to the Research 
Site to after the discharge on Day 8 after dosing and 24 hours before your last follow-up visit 
(Day 11). 
 
NEW INFORMATION ABOUT STUDY DRUG(S) 
The study doctor or study staff will discuss with you any important new information, findings or 
changes to the way the research will be performed that may affect your decision to remain in this 
study. If this happens, you will be asked to decide if you want to keep taking part in this study. 
You may be given an additional informed consent and will be asked to agree in writing that you 
were told about these new findings. 
 
BENEFITS TO THE STUDY SUBJECT 
The goal of this research study is to provide scientific information. You will not receive any 
medical benefits. This study may help doctors and scientists learn things about the study drug that 
will help others. 
  
ALTERNATE THERAPY 
This is a clinical research study. It is not treatment or therapy. The other choice is to not 
participate in this study. 
  
PAYMENT FOR PARTICIPATION 
If, after screening, you are enrolled in the study and complete all the study visits, you will receive 
a total of up to $4,300.00 at the completion of your participation in the study to help cover the 
costs of your participation and compensate you for your time. If after enrollment your 
participation is ended early, or if you withdraw for any reason, the amount you will be paid will 
be prorated and the payment made when your participation in the study ends. This means that you 
will receive payment only for the portion of the study that you completed and only after your 
participation in the study has been completed. Payment will be prorated as follows: 
 
Visit 1 
Screening 
$150  
Visit 2 
Day -1 Admit 
$375  
Visits 3-9 
Days 1 to Day 7 In-house 
$2,625  
Visit 10 
Day 8 Discharge 
Visit 11 
Day 11 Follow-Up Office Visit / End of 
Study 
$225  
Completion Amount 
$925  
Total 
$4,300  
 
Visit 1 will be compensated in the amount of $150 at the completion of the visit. 
Visits 2 through 10 (8 overnight stays) will be compensated in the amount of $3,000 ($375 per 
overnight stay) at discharge on Visit 10. 
 
Visit 11 will be compensated in the amount of $225 at the completion of the visit. 


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 21-0013 
ICF version 4.0  –  15 November 2022 
Page 22 of 27 
  
  
Martin Kankam, MD, PhD, MPH, FAPCR 
Advarra IRB Approved Version 18 Nov 2022 
Revised 24 Mar 2023 
 
Compensation will be issued in the form of a check, pre-loaded MasterCard, or cash. The form of 
compensation will be determined by the study staff. 
 
For any outpatient visit that occurs on a weekend, the associated compensation will be paid on the 
next business day. 
 
Unscheduled visits may be compensated up to $50 as determined by the study staff. 
 
All visits must be completed within the scheduled timeframe in order to receive the end of study 
completion amount of $925 on Visit 11. Failure to complete all visits within the allowable 
timeframe will make you ineligible to receive the completion amount. 
 
Money may be deducted from your study compensation if you do not follow the in-house rules or 
other reasonable instructions given by the study staff. For example, if illegal substances are 
brought into the research site or you are found to be using an illegal substance while in house, up 
to half of your previously earned amount may be deducted and you may be withdrawn from the 
study as determined by the study staff. 
 
If you withdraw or are withdrawn from the study early, you will only be compensated for the 
visits that you complete. 
 
If you discontinue from the in-house portion of the study early for any reason, you will be 
compensated one night’s earned stipend the same day you discharge from the study. 
 
The remainder of your earned in-house stipend will be compensated to you on the originally 
scheduled study day/date of discharge from the in-house portion of the study. 
 
You may be required to report the compensation received for this study to the Internal Revenue 
Service as taxable income. According to the IRS (Internal Revenue Service) guidelines, you will 
be responsible for paying taxes on any compensation that you receive from your study 
participation. Altasciences Clinical Kansas, Inc. will send you a 1099-form for this purpose. 
Altasciences Clinical Kansas, Inc. will also report to the IRS any compensation that you receive 
that totals $600.00 or more for the calendar year. You must tell Altasciences Clinical Kansas, Inc. 
of your new mailing address if you move after your participation in a study. This is to make sure 
you receive your 1099 for your year-end tax reporting. 
 
COMPENSATION FOR INJURY  
• 
In the event you experience an adverse reaction (side-effect), illness or injury during this 
study, you should immediately seek treatment. It is important that you tell your study 
doctor if you have experienced one of these events. You must contact the study staff at  
the telephone number listed on the first page of this form as soon as you are able. You 
may obtain medical care in the same way as you would ordinarily receive any other 
medical treatment. Immediate necessary care, emergency treatment, and professional 
services will be available to research subjects just as they are to the community generally. 
No long-term medical care or financial compensation for research-related injuries will be 
provided by the NIH or the Federal Government. 


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 21-0013 
ICF version 4.0  –  15 November 2022 
Page 23 of 27 
  
  
Martin Kankam, MD, PhD, MPH, FAPCR 
Advarra IRB Approved Version 18 Nov 2022 
Revised 24 Mar 2023 
 
• 
Medical care will be given to you at no cost if you are injured because of being in this 
study. 
• 
While you are in this study, you may be injured because of your personal conduct or 
during activities, which are not part of this study. There are no plans to pay you for these 
types of injuries. 
 
COSTS TO YOU  
There is no cost to you to participate in this study. You do not have to pay for any study-related 
medicines, procedures, or study treatment at the Research Site during this study. 
  
SOURCE OF FUNDING 
This research study is being funded by NIAID/NIH, which has a contract with a company named 
DVC to do studies like this one. Altasciences Clinical Kansas, Inc.  has signed a contract with 
IQVIA, Inc., a subcontractor of DVC, to conduct this research study under the direction of Martin 
Kankam, MD. 
  
VOLUNTARY PARTICIPATION IN THIS STUDY  
Your participation in this study is voluntary. You will be starting this study of your own free will 
and without any kind of pressure. You may quit this study any time you wish. If you withdraw 
from this study, you will not be penalized. You will not lose any benefits to which you were 
otherwise entitled. 
 
If you have health problems, you will get medical attention. You may be withdrawn from this 
study by the study staff and/or the sponsor of this study, without your consent, if it is in your best 
medical interest. It is possible that the study staff and/or sponsor may think you can stay in this 
study. You must decide what you want to do. 
 
The study staff may stop your participation in this study at any time without your consent for any 
of the following reasons: 
• 
If you don’t follow the study staff’s instructions; 
• 
Something serious happens to you which may require treatment; 
• 
The study staff decides it is in the best interest of your health, and welfare to discontinue 
further participation; 
• 
You do not later consent to any future changes that may be made in the study plan.  
 
The sponsor may stop this study for other reasons not known now. 
  
The FDA or the Institutional Review Board (IRB, see below) may also terminate this study if 
there are safety concerns. 
 
IF YOU WITHDRAW FROM THE STUDY 
If you do not complete this study for any reason, you will be asked to undergo a physical exam, 
vital signs measurement, 12-lead ECG, blood and urine laboratory tests, and tests for the 
measurement of study drug concentration in your blood if early termination occurs within 24 


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 21-0013 
ICF version 4.0  –  15 November 2022 
Page 24 of 27 
  
  
Martin Kankam, MD, PhD, MPH, FAPCR 
Advarra IRB Approved Version 18 Nov 2022 
Revised 24 Mar 2023 
 
hours of dosing. This is needed to identify any changes that may have occurred after you began to 
take the study drug and to protect your safety, health, and welfare. 
 
If you received any amount of the study drug but withdraw from the trial within 24 hours after 
dosing, you will be encouraged to continue follow-up (with your consent) for safety assessments. 
We may also ask you to provide PK blood and urine sample(s) to complete scheduled collection if 
you had received study drug on the day you withdrew from the study. 
 
CERTIFICATE OF CONFIDENTIALITY 
To help us protect your privacy, we have a Certificate of Confidentiality from NIH. The study 
staff can use this Certificate to legally refuse to give information that may identify you in any 
federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for 
example, if there is a court subpoena. The study staff will use the Certificate to resist any 
demands for information that would identify you, except for reporting of communicable diseases, 
such as Hepatitis Virus and HIV infections, to state and local health departments, or for reporting 
possession or use of marijuana or other illegal drugs while at the Research Site to the appropriate 
legal authorities. 
  
A Certificate of Confidentiality does not prevent disclosure of your information to the NIH, FDA, 
or federal funding agency. Information from this study will be given to DMID and Wockhardt 
Ltd., the pharmaceutical organization developing WCK 6777 and other drugs for the treatment of 
infectious diseases. Any persons or companies, which are contracted by the sponsor for 
conducting this study, measuring drug level in blood samples, monitoring the execution of this 
study, and analyzing the data, will have access to the research information during and after this 
study, The information will also be given to the FDA. It may be given to governmental agencies 
in other countries where the study drug may be considered for approval. 
  
Medical records which identify you and the consent form signed by you will be looked at and/or 
copied for research or regulatory purposes by: 
• 
The sponsor 
• 
An agent for the sponsor 
• 
An agent for the study doctor 
• 
The FDA 
• 
Department of Health and Human Services (DHHS) agencies 
• 
The Institutional Review Board, Advarra IRB. 
  
Absolute confidentiality cannot be guaranteed because of the need to give information to these 
parties. The results of this research study may be presented at meetings or in publications. Your 
identity will not be disclosed in those presentations. 
• 
Altasciences Clinical Kansas, Inc. will handle the medical information obtained in this 
study with the strictest confidence. It will be protected as required by laws and/or 
regulations. It will not be made publicly available. 
• 
If the results of this study are published, you will not be identified by name. 
• 
Your identity will not be disclosed to anyone else, unless required by law. 
  


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 21-0013 
ICF version 4.0  –  15 November 2022 
Page 25 of 27 
  
  
Martin Kankam, MD, PhD, MPH, FAPCR 
Advarra IRB Approved Version 18 Nov 2022 
Revised 24 Mar 2023 
 
By signing this consent, you authorize Altasciences Clinical Kansas, Inc. to verify your study 
participation history with other businesses that conduct clinical research studies. 
  
A Certificate of Confidentiality does not prevent you or a member of your family from voluntarily 
releasing information about yourself or your involvement in this research. If you give your 
consent to release information to a medical care provider, an insurer, or other person to receive 
research information, then the researchers will not withhold that information. 
 
PRIMARY CARE PHYSICIAN NOTIFICATION  
We would like your permission to contact the doctor you see regularly to let them know that you 
are taking part in this study. It is important for all your doctors to know that you may be taking an 
experimental drug. Your doctor will want to know and think about all the drugs you are taking 
before giving you any new ones. While you are in the study, the study doctor will ask about your 
symptoms. If you have symptoms after the study ends, your other doctor may want to contact the 
study personnel. 
  
If you agree, your primary care physician (regular doctor) will be informed of your participation 
in the study.  Indicate your choice below by initialing only one (1) section below. 
  
  
_______  
Initials  
  
I do not have a primary care physician.  
  
_______  
Initials  
I do not want my primary care physician notified.  
  
_______  
Initials  
  
I would like my primary care physician notified and below is my physician’s 
contact information.  
Physician’s Name: _________________________________________  
Address: _________________________________________________  
               _________________________________________________   
Phone No.: _______________________________________________  
  
 
WHOM TO CONTACT ABOUT THIS STUDY 
During the study, if you experience any medical problems, suffer a research-related injury, or 
have questions, concerns, or complaints about the study, such as: 
• Whom to contact in the case of a research-related injury or illness; 
• Payment or compensation for being in the study, if any; 
• Your responsibilities as a research subject; 
• Eligibility to participate in the study; 


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 21-0013 
ICF version 4.0  –  15 November 2022 
Page 26 of 27 
  
  
Martin Kankam, MD, PhD, MPH, FAPCR 
Advarra IRB Approved Version 18 Nov 2022 
Revised 24 Mar 2023 
 
• The study doctor’s or study site’s decision to withdraw you from participation; 
• Results of tests and/or procedures; 
 
Please contact the study doctor at the telephone number listed on the first page of this 
consent document.  
If you seek emergency care, or hospitalization is required, alert the treating physician that you are 
participating in this research study.  
 
An institutional review board (IRB) is an independent committee established to help protect the 
rights of research subjects. If you have any questions about your rights as a research subject, 
and/or concerns or complaints regarding this research study, contact: 
 
• By mail: 
 
Study Subject Adviser 
Advarra IRB 
6100 Merriweather Dr., Suite 600 
Columbia, MD 21044 
• or call toll free: 
877-992-4724 
• or by email: 
 
adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: Pro00066629  


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 21-0013 
ICF version 4.0  –  15 November 2022 
Page 27 of 27 
  
  
Martin Kankam, MD, PhD, MPH, FAPCR 
Advarra IRB Approved Version 18 Nov 2022 
Revised 24 Mar 2023 
 
CONSENT and AUTHORIZATION 
 
I have read all information in this document, and all my questions have been answered to my 
satisfaction. I voluntarily consent to participate in this study. I will be given a signed and dated 
copy of this consent form, and have been told the description of the study drug, and the name, 
address and phone number of the study doctor. My signature gives my consent to participate. I 
authorize the release of my medical records and health information related to this study, including 
my signed and dated consent form and any addendum, to the sponsor and its representatives, the 
FDA, Advarra IRB and other regulatory agencies as described above. By signing and dating this 
form, I have not given up any of my legal rights as a research subject. 
 
 
Print Subject’s Name 
 
Date 
Subject’s Signature 
 
 
Person Obtaining Informed Consent Printed Name 
 
 
Person Obtaining Informed Consent Signature  
 
Date 
Witness Printed Name 
 
 
Witness Signature 
 
Date 
Investigator's Signature* 
 
Date 
*The Investigator's signature evidences only that the Investigator has reviewed the consent form 
and the signatures of the subject, person obtaining consent, and witness, for compliance. 
 

SAP_002.pdf: 
CLINICAL RESEARCH IN INFECTIOUS DISEASES 
 
STATISTICAL ANALYSIS PLAN 
for 
 
DMID Protocol: 21-0013 
 
Study Title: 
A PHASE I, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
DOSE ESCALATION STUDY TO EVALUATE THE SAFETY, TOLERABILITY, 
AND PHARMACOKINETICS OF INTRAVENOUS ERTAPENEM IN 
COMBINATION WITH ZIDEBACTAM (WCK 6777) IN HEALTHY ADULT 
SUBJECTS 
 
NCT05645757 
 
Version 1.0 
 
DATE: 07NOV2023 
RESTRICTED 


Statistical Analysis Plan - DMID Protocol: 21-0013  
Version 1.0 
07NOV2023 
- 2 - 
RESTRICTED 
STUDY TITLE 
Protocol Number Code: 
DMID Protocol: 21-0013 
Development Phase: 
Phase 1 
Products: 
Ertapenem PLUS Zidebactam (WCK 6777) 
Ertapenem 
Zidebactam 
Placebo 
Form/Route: 
Intravenous (IV) infusion 
Indication Studied: 
Bacterial Infection 
Sponsor: 
Division of Microbiology and Infectious Diseases 
National Institute of Allergy and Infectious Diseases 
National Institutes of Health 
Clinical Trial Initiation Date: 
19APR2023 
Clinical Trial Completion Date: 
TBD 
Date of the Analysis Plan: 
07NOV2023 
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: 21-0013  
Version 1.0 
07NOV2023 
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TABLE OF CONTENTS 
STUDY TITLE ................................................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
PREFACE ...................................................................................................................10 
2. 
INTRODUCTION ......................................................................................................11 
2.1. 
Purpose of the Analyses ..............................................................................................11 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................12 
3.1. 
Study Objectives .........................................................................................................12 
3.2. 
Endpoints ....................................................................................................................12 
3.3. 
Study Definitions and Derived Variables ...................................................................12 
4. 
INVESTIGATIONAL PLAN .....................................................................................13 
4.1. 
Overall Study Design and Plan ...................................................................................13 
4.2. 
Discussion of Study Design, Including the Choice of Control Groups ......................14 
4.3. 
Selection of Study Population ....................................................................................14 
4.3.1. 
Inclusion Criteria ........................................................................................................14 
4.3.2. 
Exclusion Criteria .......................................................................................................14 
4.4. 
Treatments ..................................................................................................................15 
4.4.1. 
Treatments Administered ............................................................................................15 
4.4.2. 
Identity of Investigational Product(s) .........................................................................15 
4.4.3. 
Method of Assigning Participants to Treatment Groups (Randomization) ................16 
4.4.4. 
Selection of Doses in the Study ..................................................................................16 
4.4.5. 
Selection and Timing of Dose for Each Participant ...................................................16 
4.4.6. 
Blinding ......................................................................................................................17 
4.4.7. 
Prior and Concomitant Therapy ..................................................................................17 
4.4.8. 
Treatment Compliance ................................................................................................18 
4.5. 
Safety and Pharmacokinetic Variables .......................................................................18 
4.5.1. 
Safety Variables ..........................................................................................................18 
4.5.2. 
Pharmacokinetics Variables ........................................................................................19 
5. 
SAMPLE SIZE CONSIDERATIONS .......................................................................21 
6. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................22 
6.1. 
General Principles .......................................................................................................22 


Statistical Analysis Plan - DMID Protocol: 21-0013  
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Table of Contents (continued) 
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6.2. 
Timing of Analyses .....................................................................................................22 
6.3. 
Analysis Populations ..................................................................................................22 
6.3.1. 
Safety Population ........................................................................................................23 
6.3.2. 
PK Analysis Population ..............................................................................................23 
6.3.3. 
PK Analysis Subset Population ..................................................................................23 
6.4. 
Covariates and Subgroups ..........................................................................................23 
6.5. 
Missing Data ...............................................................................................................23 
6.6. 
Interim Analyses and Data Monitoring ......................................................................23 
6.7. 
Multicenter Studies .....................................................................................................23 
6.8. 
Multiple Comparisons/Multiplicity ............................................................................23 
7. 
STUDY PARTICIPANTS ..........................................................................................24 
7.1. 
Disposition of Participants ..........................................................................................24 
7.2. 
Protocol Deviations ....................................................................................................24 
8. 
EFFICACY EVALUATION ......................................................................................25 
9. 
SAFETY EVALUATION ..........................................................................................26 
9.1. 
Demographic and Other Baseline Characteristics ......................................................26 
9.1.1. 
Prior and Concurrent Medical Conditions ..................................................................26 
9.1.2. 
Prior and Concomitant Medications ...........................................................................26 
9.2. 
Measurements of Treatment Compliance ...................................................................27 
9.3. 
Adverse Events ...........................................................................................................27 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events ....................27 
9.5. 
Pregnancies .................................................................................................................27 
9.6. 
Clinical Laboratory Evaluations .................................................................................28 
9.7. 
Vital Signs and Physical Evaluations .........................................................................29 
9.8. 
12-Lead Standard Electrocardiogram .........................................................................30 
9.9. 
Tolerability .................................................................................................................30 
10. 
PHARMACOKINETICS ...........................................................................................31 
10.1. 
Noncompartmental Analysis ......................................................................................33 
10.1.1. 
Single-Dose Plasma PK Parameters ...........................................................................34 
10.1.2. 
Multiple-Dose Plasma PK Parameters ........................................................................36 
10.1.3. 
Urine PK Parameters ..................................................................................................37 
10.1.4. 
Assessment of Dose Proportionality ...........................................................................38 


Statistical Analysis Plan - DMID Protocol: 21-0013  
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10.1.5. 
Assessment of Drug-Drug Interactions ......................................................................39 
10.1.6. 
Assessment of Saturation and Linearity of Protein Binding ......................................40 
11. 
IMMUNOGENICITY ................................................................................................41 
12. 
OTHER ANALYSES .................................................................................................42 
13. 
REPORTING CONVENTIONS ................................................................................43 
14. 
TECHNICAL DETAILS ............................................................................................44 
15. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES ............................................................................................45 
16. 
REFERENCES ...........................................................................................................46 
17. 
LISTING OF TABLES, FIGURES, AND LISTINGS ..............................................47 
APPENDICES ...............................................................................................................................48 
APPENDIX 1. TABLE MOCK-UPS..........................................................................................49 
APPENDIX 2. FIGURE MOCK-UPS ......................................................................................140 
APPENDIX 3. LISTINGS MOCK-UPS ...................................................................................176 
 


Statistical Analysis Plan - DMID Protocol: 21-0013  
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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
Ae, urine 
Amount of unchanged drug excreted in urine during each collection 
interval 
Ae, urine(0-24) 
Cumulative amount of unchanged drug excreted in urine from time zero 
(predose) to 24 hours after Dose 1 
Ae, urine(0-24),ss  
Cumulative amount of unchanged drug excreted in urine from time zero 
(predose) to 24 hours after Dose 7 
ALT 
Alanine Aminotransferase 
AP 
Alkaline Phosphatase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under the Concentration – Time Curve 
AUC(0-24) 
Area under the concentration – time curve from time zero to 24 h 
AUC(0-24),ss 
Area under the concentration – time curve from time zero to 24 h at steady 
state 
AUC0-inf 
Area under the concentration - time curve from time zero to infinity 
AUC0-last 
Area under the concentration - time curve from time zero to the last 
concentration above the lower limit of quantitation 
AUC(0-t) 
Area under the concentration - time curve from time zero to time t 
AUC(0-tau) 
Area under the concentration – time curve to the end of the dosing interval 
AUC(0-tau),ss 
Area under the concentration – time curve to the end of the dosing interval 
at steady state 
BMI 
Body Mass Index 
BP 
Blood Pressure  
BUN 
Blood Urea Nitrogen 
C 
Celsius 
Cavg 
Calculated average concentration during the dosing interval 
CHEM 
Chemistry 
CI 
Confidence Interval 
CLCR 
Creatinine Clearance 
CLR(0-24) 
Renal clearance to 24 h following Dose 1 
CLR,ss 
Renal clearance at Steady State 


Statistical Analysis Plan - DMID Protocol: 21-0013  
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List of Abbreviations (continued) 
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CLT 
Total Clearance 
Cmax 
Maximum Concentration 
Cmax,ss 
Maximum Concentration at Steady State 
Cmin 
Minimum Concentration 
Cmin,ss 
Minimum Concentration at Steady State 
CO2 
Carbon Dioxide 
COAG 
Coagulation 
ConMeds 
Concomitant Medications 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
DBP 
Diastolic Blood Pressure 
DMID 
Division of Microbiology and Infectious Diseases 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ERT 
Ertapenem 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
fe, urine 
Fraction (%) of dose excreted unchanged in urine during each collection 
interval following Dose 1 and Dose 7 
fe, urine(0-24) 
Fraction of dose excreted unchanged in urine from time zero (predose) to 
24 hours following Dose 1 and Dose 7 
h 
Hours 
Hct 
Hematocrit 
HEENT 
Head, Eyes, Ears, Nose, and Throat 
HEM 
Hematology 
Hgb 
Hemoglobin 
HR 
Heart Rate 
ICH 
International Council for Harmonisation 
INR 
International Normalized Ratio 
IQR 
Interquartile Range 
IRB 
Institutional Review Board 
IV 
Intravenous 


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Ke 
Terminal Phase Elimination Rate Constant 
L 
Liter 
LDH 
Lactic Dehydrogenase 
LLN 
Lower Limit of Normal 
LLOQ 
Lower Limit of Quantitation 
mcg 
Microgram 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities  
mEq 
Milliequivalent 
mg 
Milligram 
mL 
Milliliter 
MM 
Medical Monitor 
MO 
Medical Officer 
MOP 
Manual of Procedures 
MPV 
Mean Platelet Volume 
N 
Number (typically refers to participants) 
NCE 
New Chemical Entity 
NIH 
National Institutes of Health 
NRBC CT 
Nucleated Red Blood Cell Count 
ONR 
Outside of Normal Range 
PE 
Physical Exam 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PT 
Preferred Term 
QD 
Administered once per day 
QTc 
Corrected QT Interval of the ECG 
QTcF 
Corrected QT interval of the ECG using Fridericia’s Formula 
RAUC 
Accumulation ratio for AUC 
RBC 
Red Blood Cell 
RCmax 
Accumulation ratio for Cmax 


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RDW 
Red Cell Distribution Width 
RR 
Respiratory Rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SDCC 
Statistical and Data Coordinating Center 
SMC 
Safety Monitoring Committee 
SOC  
System Organ Class 
t1/2 
Terminal Half-life 
TEAE 
Treatment-emergent Adverse Event 
Tmax 
Time to obtain maximum concentration 
Tmax,ss 
Time to obtain maximum concentration at steady state 
Tmin 
Time to obtain minimum concentration 
Tmin,ss 
Time to obtain minimum concentration at steady state 
UA 
Urinalysis 
ULN 
Upper Limit of Normal 
Vd 
Volume of Distribution 
Vd,ss 
Volume of Distribution at Steady State 
VS 
Vital Signs 
WBC 
White Blood Cell 
WHO 
World Health Organization 
ZID 
Zidebactam 
 


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1. 
PREFACE 
The Statistical Analysis Plan (SAP) for “A Phase I, Randomized, Double-blind, Placebo-controlled, Dose 
Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Intravenous Ertapenem in 
Combination with Zidebactam (WCK 6777) in Healthy Adult Subjects” (Division of Microbiology and 
Infectious Diseases (DMID) Protocol 21-0013) describes and expands upon the statistical information 
presented in the protocol. 
This document describes all planned analyses and provides reasons and justifications for these analyses. It 
also includes sample tables, listings, and figures planned for the final analyses. Regarding the final analyses 
and Clinical Study Report (CSR), this SAP follows the International Council for 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) [1], and more generally is consistent with Topic E8 
(General Considerations for Clinical Trials) [2] and Topic E9 (Statistical Principles for Clinical Trials) [3]. 
The structure and content of the SAP provides sufficient detail to meet the requirements identified by the 
Food and Drug Administration (FDA) and ICH, while all work planned and reported for this SAP will follow 
internationally accepted guidelines published by the American Statistical Association [4] and the Royal 
Statistical Society for statistical practice [5].  
This document contains four sections: (1) a review of the study design, (2) general statistical considerations, 
(3) comprehensive statistical analysis methods for pharmacokinetic and safety outcomes, and (4) 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 
the study protocol for details on conduct of the study and the operational aspects of clinical assessments. 


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2. 
INTRODUCTION 
This is a phase 1, randomized, double-blind, placebo-controlled, dose escalation study to evaluate the safety, 
tolerability, and pharmacokinetics (PK) of intravenous (IV) Ertapenem (ERT) in combination with 
Zidebactam (ZID) (WCK 6777) in healthy adult participants. Seven cohorts will be enrolled in the study. 
Cohorts 1, 2, 4, 5, and 7 will have 8 participants, 6 receiving the active drug and 2 receiving the placebo. All 6 
participants enrolled in cohorts 3 and 6 will receive the active drug. 
2.1. 
Purpose of the Analyses 
These analyses will assess the safety, tolerability, and PK of WCK 6777 in comparison with placebo and will 
be included in the CSR. 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
Primary 
• Assess the safety and tolerability of three dose-escalating regimens of WCK 6777 (ERT and ZID 
combination) and two dose-escalating regimens of standalone ERT or ZID following single daily 
doses for 7 days in healthy adult participants 
Secondary  
• Characterize the PK profiles in plasma (total and free) and in urine of three dose-escalating regimens 
of WCK 6777 (ERT and ZID combination) and the two dose-escalating regimens of standalone ERT 
or ZID following single daily doses for 7 days in healthy adult participants 
3.2. 
Endpoints 
Primary 
• Type, incidence, severity, and relatedness to study drug of all treatment-emergent adverse events 
(TEAEs) and serious adverse events (SAEs) in each treatment cohort from the first dose through the 
follow-up period. 
Secondary  
• PK parameter estimates and calculated exposures in plasma (total and free) and urine for ERT and 
ZID, when given alone and in combination following the single initial dosing on Day 1 and after daily 
dose administration for 7 days. 
3.3. 
Study Definitions and Derived Variables  
Baseline 
Any systemic medical condition and the last vital sign (VS), electrocardiogram (ECG) and clinical safety 
laboratory test value that are recorded prior to dosing on Day 1 will be considered a baseline finding for the 
purpose of data analysis. 
Treatment Group 
Results of safety and PK analyses will be presented by study product. All participants assigned to the placebo 
group will be presented as pooled together for the purposes of these analyses. Treatment groups will be 
presented in the following order: WCK 6777 2g, ERT 2g, ZID 2g, WCK 6777 4g, ERT 3g, ZID 3g, WCK 
6777 6g, Placebo. Results from placebo participants will not appear in the PK analyses. 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
This is a phase 1, randomized, double-blind, placebo-controlled, dose escalation study to evaluate the safety, 
tolerability, and pharmacokinetics of IV ERT in combination with Zidebactam (WCK 6777) in healthy adult 
participants. An overall schematic of study design is shown in Figure 1. This study will enroll 52 participants 
into 7 cohorts.  
WCK 6777 (ERT+ZID) will be evaluated in three cohorts - Cohorts 1, 4, and 7 will have 8 participants each 
(6 study drug combination and 2 placebos); ERT will be evaluated in two cohorts - Cohorts 2 and 5 will have 
8 participants each (6 ERT and 2 placebo); and ZID will be evaluated in two cohorts - Cohorts 3 and 6 will 
have 6 participants each (all 6 ZID). The study will be placebo-controlled and double-blinded in all cohorts 
except Cohorts 3 and 6. No placebo participants are included in standalone ZID cohorts since adequate safety 
data for higher doses of ZID are available. 
Study enrollment will proceed from Cohort 1 to Cohort 7 starting with the lowest dose and escalating to the 
next higher dose. Individual dose Cohorts 2 and 3, as well as Cohorts 5 and 6 will run in parallel. For each 
combination treatment cohort (Cohorts 1, 4 and 7), two sentinel participants will receive study treatments (one 
WCK 6777 and one placebo; drug/placebo ratio 1:1) and followed for safety for approximately 24 hours (h) 
prior to dosing of the remaining 6 participants in the cohort. If no halting rules have been met 24 h after start 
of dosing, dosing of sentinel participants will continue for the remainder of the study and the additional 6 
participants in the cohort will be dosed (5 will receive WCK 6777 and 1 will receive placebo; drug/placebo 
ratio 5:1). Sentinels will not be employed in the single treatment cohorts. 
Blood (plasma) and urine samples will be collected for measuring drug concentrations for PK analysis for 24 
h after starting the first IV infusion on Day 1, and for 24 h after starting the last IV infusion on Day 7. Plasma 
concentrations will also be measured before and 12 h after dosing on Days 2 to 6. Total and free drug 
concentrations of ERT and ZID will be measured in plasma and total drug concentration of ERT and ZID in 
the urine by validated LC-MS/MS assays. 
Safety data will be monitored from the time of infusion on Day 1 through Day 8, and at the last visit (Day 
11+3 days) and will consist of: daily assessments of TEAEs, vital signs and symptom-directed physical 
examination (PE); clinical laboratory safety tests (Day -1, Days 2, 4, 6, and Day 8 [prior to the discharge from 
the study site]), and 12-lead ECGs (Day-1, Day 8 and Day 11 [+3 days]), and a complete PE on the last visit 
(Day 11 +3 days). AEs will be assessed by the study clinicians for severity or seriousness, and relatedness to 
study drug(s) and include outcome and duration. 
Dose escalation from combination Cohort 1 (1 g ERT + 1 g ZID) to higher single dose Cohorts 2 (2 g ERT) 
and 3 (2 g ZID), and from combination Cohort 4 (2 g ERT + 2 g ZID) to higher single dose Cohorts 5 (3 g 
ERT) and 6 (3 g ZID) will be based on the safety monitoring committee (SMC) review of unblinded 
cumulative interim safety data collected through study Day 11 (+3 days) in each combination treatment cohort 
(See Protocol Section 9.6.1). The recommendation to continue to the next planned combination cohorts (i.e., 
Cohort 4 and Cohort 7), will be made by the study team (DMID medical officer (MO) and medical monitor 
(MM) and the site principal investigator (PI)) after review of blinded safety data in Cohorts 2 and 3 and 
Cohorts 5 and 6, respectively. The statistical and data coordinating center (SDCC) will provide a report of 
number of participants meeting dose escalation halting criteria. The decision to continue dose escalation to the 
next single or combination dose cohorts will be made by DMID after review of the SMC or the study team 
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4.2. 
Discussion of Study Design, Including the Choice of Control Groups 
The treatment regimen for the first combination cohort (Cohort 1), WCK 6777 2 g (ERT 1 g with ZID 1 g 
daily; 30-minute infusion), was selected because there are no human safety and PK data available with these 
agents in combination. The second combination cohort (Cohort 4) will evaluate the safety and PK of the 
anticipated therapeutic combination regimen of WCK 6777 4 g (ERT 2 g with ZID 2 g daily; 1-h infusion). 
The third combination-treatment cohort (Cohort 7) will evaluate the safety and PK of higher daily doses of 
WCK 6777 6 g (ERT 3 g + ZID 3 g daily; 2-h infusion). The primary purpose of the ERT 3 g with ZID 3 g 
combination treatment cohort is to ensure maximal flexibility in the clinical development program in the 
event there is a need to evaluate more intensive combination daily dosing regimens and different infusion 
strategies in future clinical trials. Moreover, 3 + 3 g/daily combination regimen will provide critical 
information on dose proportionality, PK linearity, and plasma protein binding linearity. As it is well-
established that healthy participants do not fully reflect the real-world inter-participant variability observed in 
patients [6], the higher daily dosing regimen will also provide data on the safety, tolerability, and PK of upper 
range exposures likely to be encountered in clinical practice with ERT 2 g + ZID 2 g. To mitigate the risk of 
higher osmolality-linked infusion reactions, the volume of each infusion in the 2-g and 3-g dose standalone 
and combined groups (Cohorts 2-7) will be increased to 250 mL. The duration of infusions in the 2 g and 3-g 
cohorts were chosen to mitigate infusion duration-related AEs (nausea, vomiting) with ERT doses >2 g [7]. In 
four of the seven cohorts (Cohorts 2, 3, 5 and 6) single 2-g and 3 g ERT or ZID infusions 
will be administered. ERT 1 g daily and ZID 1 g daily will not be evaluated as single drug treatment cohorts 
as there are sufficient safety, tolerability, and PK data with these standalone regimens [7, 8, 9]. 
In all cohorts, 6 participants will receive study drug product. Two additional participants will receive placebo 
in the 2 g/daily and 3 g/daily ERT single treatment cohorts to maximize interpretation of the safety and 
tolerability of the observed results. The single drug treatment cohorts are being conducted to collect the 
baseline safety and pharmacokinetic data. Specifically, the single treatment arms of ERT and ZID are 
necessary to assess for the presence of any PK interactions between the two constituents and to deduce the 
role of each, in the event of any safety or tolerability signals in the combination cohorts. In conjunction with 
the escalating dose combination regimens, the single treatment drug cohorts will also provide information on 
dose PK proportionality, which is necessary for building robust individual population PK models for ERT and 
ZID, which, supplemented with PK/PD studies, will help justify the dose regimen for advanced clinical trials. 
4.3. 
Selection of Study Population 
Only participants who meet all inclusion criteria and no exclusion criteria will be eligible for 
enrollment into the trial. Eligibility criteria can be found in v5.0 of the Protocol. 
4.3.1. 
Inclusion Criteria 
For a list of inclusion criteria, see Section 5.1 of Protocol v5.0. 
4.3.2. 
Exclusion Criteria 
For a list of exclusion criteria, see Section 5.2 of Protocol v5.0. 
 


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4.4. 
Treatments 
4.4.1. 
Treatments Administered  
In each cohort, either study drug alone or in combination will be administered as an intravenous infusion (IV) 
of 100 mL daily for 7 consecutive days in Cohort 1 or 250 mL daily for 7 consecutive days in Cohorts 2 to 7. 
For each successive treatment cohort, however, the dose will be progressively escalated from 1 g/daily to 2 
g/daily and to 3 g/daily, and the duration of infusion time increased from 30 min to 1 h and to 2 h over the 
course of the study. In Cohort 1, WCK 6777 2 g (ERT 1 g/daily combined with ZID 1 g/daily) will be 
administered in 30 (±5) minutes (min); in Cohort 2 (ERT 2 g/daily), Cohort 3 (ZID 2 g/daily), and Cohort 4 
(WCK 6777 4 g [ERT 2 g/daily combined with ZID 2 g/daily] the study drug(s) will be administered in 60 
(±10) min, and in Cohort 5 (ERT 3 g/daily), Cohort 6 (ZID 3 g daily) and Cohort 7 (WCK 6777 6 g [ERT 3 
g/daily combined with ZID 3g/daily]), the study drug(s) will be administered in 120 (±10) min. 
4.4.2. 
Identity of Investigational Product(s) 
Zidebactam for Injection, 1 g/vial 
Zidebactam dihydrate (CAS No. 1996664-59-5) is a proprietary New Chemical Entity (NCE) of Wockhardt 
coded as WCK 5107. It is a bicyclo-acyl-hydrazide (DBO pharmacophore) chemically identified as (2S, 5R)-
7-Oxo-6-sulphooxy-2-[N'-(©-piperidin-3-carbonyl)-hydrazinocarbonyl]-1, 6-diaza-bicyclo [3.2.1] octane 
dihydrate. ZID has a molecular formula of C13H21N5O7S·2H2O and a molecular weight of 427.45 daltons 
(includes two water molecules). ZID exists as pale yellow to white crystalline powder. It is slightly 
hygroscopic and is freely soluble in water and insoluble in dichloromethane [9]. 
Ertapenem Sodium for Injection, 1 g/vial (ERT) 
ERT is generally available as ertapenem sodium (CAS No. 153773-82-1), and chemically identified as [4R-
[3(3S*,5S*),4α,5β,6β(R*)]]-3-[[5-[[(3-carboxyphenyl)amino] carbonyl]-3-pyrrolidinyl]thio]-6-(1-
hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0] hept-2-ene-2-carboxylic acid monosodium salt. It has a 
molecular formula C22H24N3O7SNa and a molecular weight of 497.50 daltons. ERT sodium is a white to off-
white hygroscopic, weakly crystalline powder. It is soluble in water and 0.9% sodium chloride solution, 
practically insoluble in ethanol, and insoluble in isopropyl acetate and tetrahydrofuran [8]. 
WCK 6777 (ERT-ZID) 
WCK 6777 is a combination of equal amounts of ERT, a carbapenem antibiotic, and ZID, a non-β-lactam 
entity which acts as a β-lactam enhancer. It is being developed as once-a day parenteral therapy for the 
treatment of Gram-negative infections. The indications described for ERT would be targeted for WCK 6777 
in clinical settings. 
Placebo 
0.9% Sodium Chloride Injection, USP will be used as the placebo for this study. 
Sterile Water for Injection, USP is sterile, nonpyrogenic, distilled water for intravenous administration after 
addition of a suitable solute. No antimicrobial or other substance has been added. The pH is 5.5 (5.0 to 7.0). 
The osmolarity is 0 mOsmol/L. It will be used for reconstituting ERT and ZID separately or combined (for 
WCK 6777) prior to dilution with sterile 0.9% Sodium Chloride Injection, USP. 
0.9% Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution. Each 100 mL contains 900 mg 
sodium chloride in water for injection. It contains sodium (Na+) 154 mEq/L and chloride (Cl–) 154 mEq/L. 
The osmolarity is 308 mOsmol/L (calc.). The solution may contain hydrochloric acid and/or sodium 
hydroxide for pH adjustment (pH 5.6, range 4.5 to 7.0). This solution contains no bacteriostatic, antimicrobial 
agent or added buffer. It will be used as the diluent for ERT and ZID and as the placebo in this study. 


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4.4.3. 
Method of Assigning Participants to Treatment Groups (Randomization) 
For the drug combination cohorts (Cohorts 1, 4, and 7) and standalone ERT cohorts (Cohorts 2 and 5), the 
trial will be double-blinded, placebo controlled, with eight participants randomized to receive either active 
drug(s) or placebo (normal saline) in an overall 3:1 ratio (6 participants study drug and 2 participants 
placebo). For each drug combination dosing cohort, two sentinel participants will be randomized in a 1:1 
fashion to active drug and placebo and will be followed for 24 h. If there are no safety events, the remaining 
six participants in each cohort will be randomized in a 5:1 ratio to active drug and placebo. Sentinel 
participants will not be used for the randomized, standalone ERT cohorts and for the ZID cohorts.  
Randomized treatment assignments for these cohorts will be generated centrally at the SDCC through the 
Advantage eClinical® application by the unblinded study biostatistician, and a list will be transferred to the 
unblinded study personnel (i.e., research pharmacists and a verifier) at the research site prior to start of the 
study for the purpose of an emergency back-up, which will be kept up in a secure place. The research 
pharmacists will perform dose preparation; the unblinded verifier is a member of the pharmacy team who will 
not participate in dose preparation. 
4.4.4. 
Selection of Doses in the Study 
In vivo pharmacokinetic/pharmacodynamic (PK/PD) studies involving neutropenic mouse lung 
infection models have demonstrated that the ERT-ZID combination exerts significant bactericidal action 
against KPC, OXA-48-like and MBL-expressing Enterobacterales at mouse exposures that correspond to 2 g 
q24h clinical exposures of ERT and 2 g q24h exposures of ZID obtained when dosed individually [9]. 
The IV No Observed Adverse Effect Level (NOAEL) doses, based on a 28-day repeat dose toxicity study for 
ZID in rat and dog, are 800 and 750 mg/kg/day, respectively, and the corresponding exposure in terms of 24-
hour (h) area under the plasma drug concentration-time curves (AUCs) are 1950 and 1962 µg·h/mL, 
respectively. On the basis of ZID NOAEL dose exposures in dog (750 mg/kg/day) and rat (800 mg/kg/day) 
and anticipated ZID clinical exposure of 300 µg·h/mL at 2 g/day, a safety window of approximately six times 
is estimated [9]. 
Extrapolation of the dog IV NOAEL dose of 750 mg/kg to a human dose (based on body surface area) would 
lead to a human equivalent dose for ZID of 416 mg/kg, corresponding to 29 g for a 70- kg human. Likewise, 
considering the NOAEL dose (800 mg/kg) in rat, the human equivalent dose for ZID would be 64 mg/kg, 
corresponding to 9 g for a 70 kg human [9]. 
4.4.5. 
Selection and Timing of Dose for Each Participant 
Study product for each participant will be assigned by randomization and will not be further adjusted. A list of 
study products by cohort is available in Table 1. 
A Phase 1 study is required given that human safety and PK data are not available for ERT and ZID 
administered in combination. The following observations support conduct of this study: (a) Non-clinical 
mechanism of action (MOA) and PK/PD studies establish ERT/ZID 2 g/2 g QD as a potential treatment of 
patients with CRE infections; (b) Multiple Phase 1 studies conducted for ZID alone or in combination with 
FEP demonstrated safety and tolerability of ZID at multiple daily doses up to 6 g (2 g q8h) administered over 
7 to 10 days; (c) Higher IV ERT doses of 2 g and 3 g QD have been studied in previous phase 1 and 2 studies 
(n = 101) [7, 8]; (d) The preclinical toxicity studies of WCK 6777 in rats and dogs employing doses that 
generated exposures higher than the clinical exposures reported for ERT 2 g and ZID 2 g suggest that the 
combination would be safe and tolerable. 


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4.4.6. 
Blinding 
All investigative site personnel, study volunteers, DMID, Wockhardt and DVC personnel will remain blinded 
through database lock, with the exception of an unblinded pharmacist/verifier at the research site, an 
unblinded SDCC biostatistician, and a DMID/CMS manager responsible for PK sample storage. The 
randomization scheme will be provided to the unblinded research pharmacist at the site, who will perform 
dose preparation, and a pharmacy verifier who will not participate in dose preparation. These pharmacy 
personnel at the site will not be involved in study-related assessments or have participant contact for data 
collection following study drug administration. The study staff participating in the administration of study 
product and assessment of the participants will not be aware of the administered contents of the IV infusion in 
the randomized arms of the study. Study drugs will be diluted in normal saline, and they will look identical to 
placebo in the IV infusion bag so the study staff and the participant will not be able to determine whether 
placebo or active drug are being administered. The label on the IV infusion bag will not have information that 
can identify the contents. Only plasma and urine PK samples collected from participants who received active 
drug(s) will be sent to the bioanalytical laboratory, KCAS, for testing. To select these samples, an SDCC 
Unblinded Biostatistics Team will determine which volunteers received active drug and will provide the list 
of samples from those volunteers to DMID-CMS. DMID-CMS repository employees will identify those 
samples and ship to KCAS. KCAS personnel are blinded regarding participant, study day, and timepoint 
sequence within a study day. Individual samples are barcoded, and the barcode includes information that can 
match the sample to the volunteer identification number, aliquot number, treatment cohort and collection 
timepoint. Data from KCAS will be received by the SDCC Unblinded Biostatistics Team and entered into the 
database after the safety analysis was completed by the SDCC Blinded Biostatistics team. The SMC will 
receive blinded data in aggregate and presented by cohort. The SMC may review unblinded data prepared by 
an unblinded biostatistician in the closed session only. 
4.4.7. 
Prior and Concomitant Therapy  
Medications include the following: prescription drugs, birth control hormonal preparations, nonprescription 
medication, herbs, vitamins, nutritional supplements, and illicit and recreational substances. Medications 
taken before or after dosing will be reported as Prior Medications or Concomitant Medications (ConMeds), 
respectively. 
Prior prescription medications will be recorded at Screening Visit. All prior medications are not allowed 
during the study period with the exception of oral contraceptives, which are permitted throughout the study if 
already used. 
The following medications are prohibited for the indicated periods prior to dosing: 
• Receipt of probenecid or furosemide within 14 days prior to study enrollment. 
• Receipt of any antibiotics within 14 days prior to study enrollment. 
• 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 participant safety). 
• Receipt of the following medications that interact with human OAT3 within 14 days prior to study 
enrollment: 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. 
• Receipt of herbal and dietary supplements (including St. John’s Wort) within 14 days prior to study 


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enrollment. 
• Receipt of valproic acid within 14 days prior to study enrollment. 
Non-prescription medications, herbs, vitamins, and nutritional supplements will not be taken within 14 
days before dosing and during the trial. Exceptions: vitamins and OTC medications, taken for <48 h for the 
treatment of common symptoms (e.g., headache, indigestion, muscle pain), including solitary doses of up to 
1,000 mg acetaminophen (paracetamol), may be allowed if approved by the Site PI or authorized clinician(s). 
Blood/blood products (RBCs, WBCs, platelets, and plasma) donation of 500 mL within 3 months or more 
than 100 mL within 30 days before signing informed consent to this trial is not allowed, and it is prohibited 
during the course of this trial.  
Following dosing, each new ConMed and changes to existing medications will be recorded. Participants will 
be required not to utilize non-study medications during the trial except those deemed necessary by the Site PI 
or authorized clinician(s). 
Any drug (e.g., non-prescription medications, herbal supplements, vitamins, or prescription medications) or 
vaccines or blood/blood products used by the participant during the trial will be recorded in the participant’s 
source documents and on the appropriate electronic case report form (eCRF), and the PI or authorized 
clinician(s) will note whether the use was medically indicated and immediately necessary. Any use of 
medications not authorized by the Site PI or authorized clinician(s) will be recorded as a deviation. 
4.4.8. 
Treatment Compliance 
Since each dose of study drug(s) will be administered by site personnel, participant compliance is not 
anticipated to be an issue. Complete information regarding any partial or interrupted dosing will be 
documented. Participants withdrawn prior to dosing or without at least one PK blood draw will be excluded 
from PK data analysis. All PK samples prior to participant withdrawal or treatment discontinuation will be 
included in summaries of drug concentrations. Participants who receive any amount of study product will be 
followed up with their consent for safety assessments until Final Visit (Day 11+3) and for completion of 
scheduled plasma PK sample collection following the last dose of study drug they received.  
4.5. 
Safety and Pharmacokinetic Variables 
The following section describes the safety and PK endpoints of the study. As this study is a Phase 1 clinical 
trial in healthy adult participants, there will be no assessment of drug efficacy. For a detailed schedule of 
study procedures refer to Table 2. 
4.5.1. 
Safety Variables 
The following safety endpoints will be assessed:  
• Chemistry (CHEM), Hematology (HEM), Urinalysis (UA), and Coagulation (COAG) clinical 
laboratory result safety parameters will be collected according to the schedule of study procedures in 
Table 2: 
- 
The following parameters will be measured:  
o CHEM parameters: electrolytes (sodium, potassium, chloride, total carbon dioxide [CO2]), 
creatinine with estimation of creatinine clearance (CLCR) by the Cockcroft-Gault method, 
blood urea nitrogen (BUN), glucose (fasting), total bilirubin, direct bilirubin, alanine 


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aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP), lactic 
dehydrogenase (LDH), total protein, and albumin. 
o HEM parameters: Hemoglobin (Hgb), Hematocrit (Hct), red blood cell (RBC), platelet count, 
and white blood cell (WBC) count with absolute differential count. 
o COAG parameters: international normalized ratio (INR) with prothrombin time (PT), activated 
partial thromboplastin time (APTT). 
o UA parameters: Routine dipstick testing of clean-catch urine for occult blood, protein, glucose, 
ketones, nitrate, bilirubin, leucocyte esterase, specific gravity, and pH. 
 If urine dipstick is abnormal for blood, protein, glucose and leukocyte esterase, urine 
microscopy will be performed (for WBC, RBC, bacteria, and other cell counts), and the 
results will supersede those of the dipstick UA. 
• VS parameters will be collected according to the schedule in Table 2: 
- 
The following parameters will be measured: 
o resting (measured after supine for at least 5 min) systolic blood pressure (SBP) and diastolic 
BP (DBP), heart rate (HR), respiratory rate (RR), and oral temperature (T).  
• ECG parameters will be collected according to the schedule in Table 2: 
- 
ECG measurements will be conducted in triplicate, and the mean of triplicate values will be used 
for analysis, including analyses of change from baseline. 
- 
The following parameters will be measured:  
o PR interval, QRS duration, QT interval, QTcF interval, RR interval, and ventricular rate 
• Physical exams:  
- 
Complete physical exams will be collected according to the schedule in Table 2 and include the 
following parameters:  
o General appearance, HEENT, heart, lungs, abdomen, skin, musculoskeletal system, lymph 
nodes, and a standard neurological exam. 
- 
A symptom-directed physical exam may be performed before dosing on Day 1, at any time after 
dosing on Days 1 to 7, and at Unscheduled visit for evaluation of TEAEs. 
Incidence, relatedness, and severity of TEAEs and SAEs will be recorded from the time of dosing to the final 
visit on the appropriate eCRF. All AEs will be graded for severity and the relationship to the study product by 
a trained and qualified member of the study team as described in Sections 9.2.2 and 9.2.3 of the study 
protocol v5.0. AEs and SAEs are defined in Section 9 of the protocol. Clinical VS and systemic AEs will be 
graded using the toxicity grading scales in Protocol Appendix B, Table 2. Clinical laboratory, and ECG 
results will be assessed using the toxicity grading scales in Protocol Appendix B, Table 3 and Table 4, 
respectively. 
4.5.2. 
Pharmacokinetics Variables 
Blood (plasma) samples and urine samples for PK analysis will be collected according to the schedule of 
study procedures listed in Table 2. Total and free ERT and ZID concentrations will be measured in plasma 
samples, and total ERT and ZID concentrations will be measured in urine samples. Plasma and urine 


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concentrations of ERT and ZID will be quantitated using validated Study drug concentration data in plasma 
and urine will be transferred to SDCC (Emmes) from the bioanalytical lab, KCAS, for reporting and 
pharmacokinetic analysis.   
PK parameters to be estimated for single dose and multiple dose plasma samples and urine samples are 
detailed in Section 10.1. 


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5. 
SAMPLE SIZE CONSIDERATIONS 
The sample size of 52 participants assigned into 7 treatment cohorts with 8 participants per cohort (6 
participants randomized to receive active drug(s) and 2 placebo), with the exception of Cohorts 3 and 6, 
where 6 participants will receive active ZID only, was chosen to obtain reasonable evidence of safety without 
exposing undue numbers of healthy participants to ERT combined with ZID, ERT alone, and ZID alone at 
this phase of clinical evaluation. Previous experience in Phase 1 studies has shown that the sample size being 
proposed is sufficient to fulfill the primary and secondary objectives of the study. Power calculations have not 
been performed. 
Participants who are withdrawn before dosing or who do not have at least 1 PK blood draw will be replaced 
with a participant assigned to the same treatment cohort. Additionally, participants will be replaced in each 
cohort to ensure there are at least 7 participants with complete PK profiles in each cohort with 8 participants 
each and at least 5 participants in each standalone ZID cohort. A participant will be considered to have a 
complete PK profile if at least 70% of planned plasma PK samples are collected.  
The SDCC (Emmes) will monitor the number of participants in each cohort with a complete PK profile. Due 
to the potential for 2 of the 7 participants in each cohort with complete PK profiles to be placebo participants 
it is expected there will be at least 5 participants with evaluable PK data in each cohort with 8 participants 
(Cohorts 1, 2, 4, 5, and 7). It is expected that 5 participants in each cohort with 6 participants (Cohorts 3 and 
6) will have evaluable PK data since this cohort enrolls no placebo participants.  
 


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6. 
GENERAL STATISTICAL CONSIDERATIONS 
6.1. 
General Principles 
Summary statistics for continuous data will include the number of participants included in analysis (N), mean, 
standard deviation (SD), median, minimum value (min), and maximum value (max). Summary statistics for 
discrete data will include frequencies and proportions and may include confidence intervals (CIs) for the 
proportion. When 95% CIs are given for a proportion, exact (Clopper-Pearson) CIs will be used, unless 
otherwise specified. All randomized participants will be included in the summaries of participant 
demographics. The Safety Population will be used for summaries of safety endpoints and the PK Analysis 
Population or the PK Analysis Subset will be used for summaries of PK endpoints. 
Denominators for safety endpoints will be the number of participants in the Safety Population. Denominators 
for clinical, clinical laboratory, VS, and ECG results at planned study timepoints will be the number of 
participants in the Safety Population with available results at the specified timepoint for that parameter. 
Denominators for the conceptual “Maximum Severity Post Baseline” timepoint for clinical, clinical 
laboratory, VS, and ECG results will be the number of participants with an observed result for the parameter 
obtained post dose.  
The sort order for listings is indicated in the implementation note for each listing shell. The sort order of 
clinical, clinical laboratory tests, VS, and ECG parameters is described in Section 9.  
6.2. 
Timing of Analyses 
A final CSR will be prepared after all safety, 12-lead standard ECG, and plasma and urine PK data are 
available.  
Interim cumulative safety data to determine escalation to higher dose will be presented to the SMC after 
completion of Cohort 1 and Cohort 4.  
Blinded safety and tolerability data will be periodically reviewed by the DMID medical team (medical 
monitor and medical officer) and the site PI or authorized study clinician (listed on FDA Form 1572) to assess 
whether rules for halting progression to the next study cohort have been met (see Protocol Section 9.5 for a 
list of halting criteria) and specifically to recommend dose escalation to Cohort 4 following Cohorts 2 and 3, 
and to Cohort 7 following Cohorts 5 and 6. SMC meetings are scheduled to review cumulative interim safety 
data after completion of all participants in Cohort 1 before dose escalation to Cohorts 2 and 3, and after 
completion of all participants in Cohorts 1 through 4 before dose escalation to Cohorts 5 and 6. An ad hoc 
SMC meeting will review safety data if halting criteria have been met for dose escalation to Cohorts 4 and 7. 
The SMC will receive data in aggregate. The SMC may request to receive data by study product vs. placebo 
in a closed session. The SMC may also request that the blind be broken for individual participants, as needed, 
to assess safety issues. 
The SMC will review final safety data in all cohorts when available after database lock. 
6.3. 
Analysis Populations 
All analysis populations to be used in the final analysis are described in this section. A tabular listing of all 
randomized and enrolled participants excluded from an analysis population (Safety Population, PK Analysis 
Population, or PK Analysis Subset) will be included in the CSR (Listing 5). Reasons for exclusion from 
analysis populations will be summarized in Table 9. 


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6.3.1. 
Safety Population 
The safety population will include all participants who received any amount of study drug(s). 
6.3.2. 
PK Analysis Population 
The PK analysis population will consist of all participants who received at least a single dose of study drug  
and have at least one quantifiable post-dosing plasma drug concentration measured. 
6.3.3. 
PK Analysis Subset Population 
The PK Analysis Subset is defined as the subset of the PK Analysis Population that received the intended 
doses of study drug(s) and have sufficient data that permit estimation of PK parameters. Any participant with 
at least one estimable PK parameter will be included in this subset, however, only estimable parameters will 
be summarized. Participants will be analyzed by dose as treated. 
To assess the impact of missing data, a sensitivity analysis will be conducted using the PK Analysis Subset 
Subgroup. PK data from participants that were compliant with dosing and had all planned PK samples 
collected on either Day 1 or Day 7 will be included from the respective complete day(s) for this subset. 
6.4. 
Covariates and Subgroups 
The protocol does not define any formal subgroup analyses; however, a sensitivity analysis of the PK 
Analysis Subset will be conducted using the PK Analysis Subset Subgroup. 
6.5. 
Missing Data 
All attempts will be made to collect all data per protocol. No imputation will be performed for missing values.  
Outliers will not be excluded from the safety and PK analyses. Outliers identified during the PK analysis will 
be discussed in the CSR text. Outliers will be defined as any values of plasma or urine concentration for a 
given Treatment Group that fall outside the interquartile fences of their respective distribution. Given an 
interquartile range (IQR) of Q3-Q1, where Q3 is the 75th percentile and Q1 is the 25th percentile, outliers will 
be those that are greater than Q3 + (1.5 x IQR) or those that are less than Q1 - (1.5 x IQR). 
6.6. 
Interim Analyses and Data Monitoring 
An SMC meeting to review safety data is planned after the completion of Cohort 1 before dose escalation to 
Cohorts 2 and 3, and after the completion of Cohort 4 before dose escalation to Cohorts 5 and 6. Safety data, 
including AEs; SAEs; clinical assessments; VS; clinical laboratory results (CHEM, HEM, COAG, and UA); 
and 12 lead ECGs will be presented by cohort. Reasons for participants who terminate the study early or 
discontinue treatment will be presented for all cohorts. The SMC may also review safety data by Treatment 
Group in the closed session or ad hoc meetings as requested. 
6.7. 
Multicenter Studies 
This is a single-site study. 
6.8. 
Multiple Comparisons/Multiplicity 
The analysis of the primary endpoint in this study is descriptive rather than a hypothesis test, therefore no 
adjustments for multiple testing are planned. 


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7. 
STUDY PARTICIPANTS 
7.1. 
Disposition of Participants 
Screened participants who were ineligible for enrollment in the study (screen failures) or eligible but not 
enrolled will be summarized by inclusion and exclusion criteria (Table 10). Enrolled participants who were 
ineligible for inclusion in analysis populations will be summarized by reason for participant exclusion and 
Treatment Group (Table 9). Individual listings of participants who were excluded from the Safety Population, 
the PK Analysis Population, or the PK Analysis Subset will be listed (Listing 5).  
Participant disposition will be summarized (Table 8), showing the number of participants who were screened, 
enrolled and randomized, received study product, had at least one quantifiable post-dosing plasma drug 
concentration measured, completed all planned PK blood draws, completed all planned PK urine samples, 
have complete PK profiles, completed final study visit, and terminated early. Participants who discontinued 
dosing or terminated early from the study will be listed (Listing 2). A flowchart displaying the disposition of 
study participants will be included (Figure 2). This figure will present the number of participants screened, 
enrolled, lost to follow-up, and analyzed by Treatment Group. 
7.2. 
Protocol Deviations 
A summary of participant-specific protocol deviations will be presented by deviation category, deviation type, 
and Treatment Group (Table 7). This table will provide both the number of participants and the number of 
deviations for each deviation category and deviation type. All participant-specific protocol deviations and 
non-participant-specific protocol deviations will be listed in Listing 3 and Listing 4 respectively. 


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


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9. 
SAFETY EVALUATION 
All safety analyses will be performed using the Safety Population and will be presented by Treatment Group. 
Placebo participants from each cohort that enrolled placebos (Cohorts 1, 2, 4, 5, and 7) will be pooled together 
for the purposes of the safety analyses. 
TEAEs and SAEs will be coded using the latest version of the Medical Dictionary for Regulatory Activities® 
(MedDRA). All AEs occurring after study drug dosing will be summarized using frequency counts and 
percentages. The following summaries will be presented for TEAEs and SAEs: 
• Overall (i.e., regardless of severity or relationship to treatment). 
• By severity grade (mild, moderate, or severe). 
• By relationship to study drug. 
• By MedDRA level hierarchy (system organ class [SOC], higher level group term [HLGT] and 
preferred term [PT]). 
Unless otherwise specified, at each level of participant summarization in reporting the incidence of TEAEs, a 
participant will be counted once if the participant reported one or more TEAEs. If more than one occurrence 
of a TEAE is reported, the TEAE of the worst severity or the worst-case relationship assessment will be 
summarized. 
If a participant was accepted into the trial with a laboratory value of an analyte that overlaps with values used 
for grading Grade 1 laboratory abnormalities, a TEAE will be reported if the on-study value of the same 
analyte is graded Grade 2 or higher. 
9.1. 
Demographic and Other Baseline Characteristics 
Sex, ethnicity, and race of all participants will be summarized by Treatment Group (Table 11). Ethnicity will 
be categorized “Hispanic or Latino,” or “Not Hispanic or Latino,” “Unknown,” or “Not Reported.” In 
accordance with National Institutes of Health (NIH) reporting policies, participants may self-designate as 
belonging to more than one race or may refuse to identify a race, the latter reflected in the case report form 
(CRF) as “No” to each race option. Age at enrollment, height, weight, and body mass index (BMI) at 
Screening will be summarized by Treatment Group (Table 12). Individual participant listings will be 
presented for all demographic and baseline characteristics (Listing 6).  
9.1.1. 
Prior and Concurrent Medical Conditions 
All current illnesses and past pre-existing medical conditions will be MedDRA coded using MedDRA 
dictionary version 24.1 or higher. Summaries of participants’ pre-existing medical conditions by MedDRA 
SOC will be presented by Treatment Group (Table 13). Individual participant listings will be presented for all 
medical conditions (Listing 7). 
9.1.2. 
Prior and Concomitant Medications  
All medications will be coded to the Anatomical Therapeutic Classification (ATC) using the current version 
of the WHO Drug Dictionary. The use of prior and concomitant medications taken during the study will be 
summarized by ATC 1 and ATC 2 (separately, in Table 215 for prior medications and Table 216 for 
ConMeds). Individual participant listings will be presented for all prior medication (Listing 37) and ConMeds 
(Listing 38).  


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Regardless of the certainty of the date entered, drugs will be listed and summarized as prior medications when 
the end date for the medication is before study product administration and listed and summarized as 
concomitant medications otherwise. If a medication has no recorded end date it will be considered a 
concomitant medication. 
9.2. 
Measurements of Treatment Compliance 
Date and time of study product administration, along with information on whether the participant was dosed 
according to protocol will be included in Listing 8. A listing of infusion interruptions will be presented in 
Listing 9. Participant level ERT/ZID concentrations at each timepoint will be included in Listing 10 for total 
ERT and/or ZID concentrations in plasma, Listing 11 for free ERT and/or ZID concentrations in plasma, and 
Listing 20 for total ERT and/or ZID concentrations in urine.  
9.3. 
Adverse Events 
An overall summary of adverse events by Treatment Group will be presented in Table 192 including the 
number of participants with at least one AE, number of participants with at least one related AE, and number 
of participants with at least one SAE.  
All AEs will be presented in Listing 25. A participant listing of non-serious AEs of moderate or greater 
severity will also be reported (Table 196).  
The following summaries for AEs will be presented by Treatment Group, SOC, HLGT, and PT:  
• The number of AEs and number and proportion of participants reporting an AE or SAE that occurred 
in 5% of participants in any treatment group will be presented (Table 193). 
• The number of AEs and number and proportion of participants reporting an AE will be presented. The 
95% CI for the proportion of participants experiencing each SOC/HLGT/PT will also be presented 
(Table 194).  
• The number and proportion of participants reporting a related or unrelated AE will be presented by 
severity and relationship to study product (Table 195). 
Summaries of AEs will be presented graphically in bar charts by Treatment Group and SOC. For summaries 
of proportions of participants reporting an AE, denominators will be the number of participants in the Safety 
Population for each Treatment Group:  
• The total number of related AEs reported will be presented (Figure 65). 
• The proportion of participants reporting a related AE will be presented by the maximum severity 
reported per SOC (Figure 66). 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events 
Individual data listings of deaths and other SAEs will be provided (Table 197). The listing will include 
participant ID, Treatment Group, AE description, SOC, HLGT, PT, duration of AE, reason reported as an 
SAE, severity, relationship to treatment, alternate etiology if not related, action taken with study treatment, 
whether the participant discontinued due to the AE, and AE outcome.  
9.5. 
Pregnancies 
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• Maternal information will be presented in Listing 39. 
• Gravida and para information will be presented in Listing 40. 
• Live birth outcomes will be presented in Listing 41, and still birth outcomes will be presented in 
Listing 42. 
• Spontaneous, elective, or therapeutic abortion outcomes will be presented in Listing 43. 
9.6. 
Clinical Laboratory Evaluations 
Toxicity grading criteria for clinical laboratory results can be found in Table 5. Unscheduled clinical 
laboratory evaluations will be included in listings of all clinical laboratory results, but excluded from tabular 
and graphical summaries by timepoint, except when calculating the maximum severity post baseline. All 
clinical laboratory results will be listed for each participant from time of screening to last study visit. Any 
abnormal lab results at Screening or Baseline with values in the Grade 1 range but deemed acceptable for 
enrollment per protocol Section 5.1, inclusion criterion #5, will be presented in listings but will only be 
reported as TEAEs if the severity increases to Grade 2 or higher. Clinical laboratory parameters that have 
grading criteria for both decreases (result lower than normal range) and increases (result higher than normal 
range) will be summarized separately by direction. 
All safety laboratory results, severity, and change from baseline will be listed for each participant by 
Treatment Group and timepoint. Abnormal laboratory results (laboratory results outside the normal range 
defined in the protocol) will be presented. Abnormal laboratory results that do not have toxicity grading 
ranges defined in the protocol will not have severity indicated in tables and listings of abnormal laboratory 
results, except as “ONR” (out of normal range). Results that have toxicity grading ranges defined in the 
protocol and are outside the normal range, but not mild, moderate, or severe, will have (ONR) as the severity 
included after the result.  
The sort order for chemistry parameters will be as follows: sodium, potassium, calcium, chloride, CO2, 
creatinine, CLCR, BUN, glucose (fasting), total bilirubin, direct bilirubin, ALT, AST, AP, LDH, total protein, 
and albumin. 
The sort order for hematology parameters will be as follows: Hgb, Hct, RBC, platelet count, Total WBC 
count, and absolute counts for neutrophils, monocytes, lymphocytes, eosinophils, and basophils. 
The sort order for coagulation parameters will be as follows: INR, PT, and APTT. 
The sort order for urinalysis parameters will be as follows: occult blood, protein, glucose, bilirubin, ketones, 
nitrate, leucocyte esterase, specific gravity, and pH. 
• All CHEM results, including at unscheduled visits, will be presented in Listing 26. Abnormal results 
will be presented in Table 198. 
• All HEM results, including at unscheduled visits, will be presented in Listing 27. Abnormal results 
will be presented in Table 199. 
• All COAG results, including at unscheduled visits, will be presented in Listing 28. Abnormal results 
will be presented in Table 200. 
• All UA results (dipstick and microscopic), including at unscheduled visits, will be presented in 
Listing 29. Abnormal results will be presented in Table 201. 
All Screening results will be listed for each participant by Treatment Group and visit: 


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• Serology results (Listing 30). 
• Serum human chorionic gonadotropin (hCG) and FSH pregnancy testing results (Listing 31). 
• Urine toxicology and alcohol urine results (Listing 32). 
Laboratory results will be summarized in tables and figures:  
• Proportion of participants with mild, moderate, or severe laboratory results by parameter, Treatment 
Group, and timepoint for CHEM (Table 202), HEM (Table 204), COAG (Table 206), and UA 
(Table 208). 
• Summary statistics of measurements and change from baseline are presented by parameter, Treatment 
Group, and timepoint for CHEM (Table 203), HEM (Table 205), COAG (Table 207), and UA 
(Table 209).  
• Graphical presentation of change from baseline at scheduled visits by Treatment Group, and timepoint 
for each parameter as a series of box plots.  
o CHEM parameters will be presented beginning at Figure 66 and continuing through Figure 82. 
o HEM parameters will be presented beginning at Figure 83 and continuing through Figure 91. 
o COAG parameters will be presented for INR (Figure 92), PT (Figure 93) and APTT (Figure 94). 
o UA parameters presented include specific gravity (Figure 95) and pH (Figure 96). 
9.7. 
Vital Signs and Physical Evaluations 
Toxicity grading criteria for VS results can be found in Table 3. Unscheduled VS measurements will be listed, 
but excluded from tabular and graphical summaries by timepoint, except when calculating the maximum 
severity post baseline. Baseline is defined as the VS measurement taken 30min before dosing on Day 1. If VS 
measurements are repeated due to technical errors, the initial measurements made in error will not be used for 
analysis but will be listed. The following rules will be used to determine which VS measurement to use for 
analyses if repeat measurements occur: 
1. If the first replicate is normal, then it will be used for analysis. 
2. If the first and second replicates are both abnormal, then the replicate with the higher severity will be 
used for analysis. 
3. If the first replicate is abnormal, the second replicate is normal, and the third replicate was not 
performed, then the first replicate will be used in the analysis. 
4. If the first replicate is abnormal, the second replicate is normal, and the third replicate is normal, then 
the second replicate will be used in the analysis. 
5. If the first replicate is abnormal, the second replicate is normal, and the third replicate is abnormal, 
then the abnormal replicate with the higher severity will be used for analysis. 
VS parameters that have grading criteria for both decreases (result lower than normal range) and increases 
(result higher than normal range) will be summarized separately by direction. The sort order for VS 
parameters will be as follows: SBP, DBP, HR, RR, and T. 
VS results will be summarized in tables and figures:  


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• Proportion of participants with mild, moderate, or severe VS results by parameter, Treatment Group, 
and timepoint (Table 210). 
• Summary statistics of measurements and change from baseline are presented by parameter, Treatment 
Group, and timepoint (Table 211).  
• Graphical presentation of change from baseline by parameter, Treatment Group, and timepoint 
(beginning at Figure 97 and continuing through Figure 101). 
All VS measurements, including height, weight, and BMI, will be presented in Listing 33.  
Abnormal physical exam findings will be presented in Listing 34.  
9.8. 
12-Lead Standard Electrocardiogram 
Toxicity grade criteria for 12-lead standard ECG parameters (mean of PR and QTcF intervals only from 
single ECG recordings on Day 8 and Day 11 (+3 days)) can be found in Table 6. Unscheduled 12-lead 
standard ECG measurements will be listed but excluded from tabular and graphical summaries by timepoint, 
except when calculating maximum severity post baseline. Individual interval measurements and overall 
interpretations will be presented in Listing 35 and Listing 36, respectively. The parameter order will be as 
follows: PR Interval, QRS Duration, QT Interval, QTcF Interval, RR Interval, Mean Ventricular Heart Rate 
(based on RR interval). 
12-lead standard ECG results will be summarized in tables and figures:  
• Summary of 12-lead standard ECG change in overall interpretation from baseline will be shown by 
Treatment Group and timepoint (Table 212) 
• Proportion of participants with mild, moderate, or severe 12-lead standard ECG results will be 
presented for QTcF interval by Treatment Group, timepoint, and severity (Table 213).  
• Summary statistics of 12-lead standard ECG change from baseline results will be shown by parameter, 
Treatment Group, and timepoint (Table 214). 
• Graphically, 12-lead standard ECG change from baseline results will be presented by parameter, 
Treatment Group, and timepoint. PR interval will be presented in Figure 102, QRS interval will be 
presented in Figure 103, QT interval will be presented in Figure 104, QTcF interval will be presented 
in Figure 105, RR interval will be presented in Figure 106, and mean ventricular heart rate (based on 
RR interval) will be presented in Figure 107.  
9.9. 
Tolerability 
Tolerability to study product will be summarized by Treatment Group in Table 14 and include number and 
incidence of participants who: 1) discontinued study drug due to an AE, 2) chose to withdraw from the study 
due to an AE at any time from start of dosing until end of study, or 3) were withdrawn from the study by the 
investigator due to an AE at any time from start of dosing until end of study. 


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10. 
PHARMACOKINETICS 
The PK Analysis Population will be used when summarizing plasma and urine drug concentrations, and the 
PK Analysis Subset will be used to conduct noncompartmental analysis (NCA). For both measured analytes 
in each specimen type, concentrations below the limit of quantification (BQL) collected before the first 
measurable PK concentration above the lower limit of quantification (LLOQ) will be treated as 0 for plotting 
and for all calculations including NCA and concentration summary statistics. All other BQL values, for each 
analyte within each specimen type, observed after the first measurable concentration will be treated as 
missing. There will be no imputation of missing concentrations. The geometric mean (GM) of concentrations 
will be treated as missing for sets of data points containing a BQL value.  
Collection of plasma or urine samples outside of the protocol defined time window for the timepoint, 
determined by exact rather than nominal time of collection, will not result in exclusion of the sample result 
from NCA. Plasma or urine samples collected out of window will be evaluated on a case-by-case basis. 
Results from PK plasma samples that were collected substantially outside of the protocol defined time 
window will be excluded from concentration summary statistics by nominal timepoints and plots of mean 
concentration by nominal timepoint. Substantially out-of-window samples are defined to be twice the size of 
the protocol required windows. For plasma samples these substantially out-of-window samples will be 
defined as those collected:  
• Greater than ± 10 minutes outside of the nominal timepoint for the 0.25 h, 0.5 h, 1 h, and 2 h post-dose 
samples for Dose 1 and Dose 7 as well as the 12 h post-dose samples for Dose 2 through Dose 6  
• greater than ± 20 minutes outside of the nominal timepoint for the 3 h and 4 h post-dose samples for 
Dose 1 and Dose 7  
• greater than ± 30 minutes outside of the nominal timepoint for the 8 h, 12 h, and 18 h post-dose 
samples for Dose 1 and Dose 7  
• greater than ± 1 h for the 24 h post-dose sample for Dose 1 and Dose 7  
For urine samples these will be defined as:  
• greater than ± 20 minutes for the 0-4 h timepoints 
• greater than ± 30 minutes for the 4-8 h and 8-12 h timepoints 
• greater than ± 1 h for the 12-24 h timepoint for Dose 1 and Dose 7 
If the exact time of plasma PK sample collection is not recorded then the collection time will be imputed as 
the planned time for analysis, as long as it is not known that the sample was collected outside of the protocol 
defined window. If the start and/or end time of a urine PK sample is unknown, then the missing time(s) will 
be assumed to be the planned sample collection time (start or end), as long as it is not known that the sample 
was collected outside of the protocol defined window. If the exact collection time is not known for either 
sample type, but it is known that the sample was collected outside of the protocol defined time window, then 
the timepoint may be excluded from analysis at the discretion of the PK analyst. Rationale for excluding 
results from analysis will be described in the CSR. Results from samples with imputed collection times will 
be indicated in listings of PK sample concentrations. 
All participants who have at least one quantifiable plasma concentration of ERT or ZID will be included in 
the PK Analysis Population. Drug concentrations in plasma (µg/mL) and urine (mg) will be summarized by 
Treatment Group and listed by participant: 


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• Participant level concentrations of ERT and ZID in plasma (total concentrations in Listing 10 and free 
concentrations in Listing 11) and in urine (Listing 20). 
Participant level concentration listings will include separate columns for concentrations reported by the lab 
and concentrations used for analysis. The lab reported concentrations may include codes, such as: “BQL” or 
“QNS” (Quantity not Sufficient), while the analysis concentrations will contain numeric data only, including 
imputed values such as 0 for pre-dose timepoints and BQL samples prior to the first quantifiable sample. 
Listings will also indicate the nominal time (i.e., the planned time) and actual post dose time in hours 
associated with the sample and will note sample times which were collected out of window, substantially out 
of window, or imputed. 
Individual concentrations will be presented in tables and figures by Treatment Group and nominal timepoint: 
• The GM and coefficient of variation (CV%) of individual total and free concentrations in plasma will 
be presented tabularly by Treatment Group for ERT (Table 15 for Dose 1, Table 16 for Doses 2-6, and 
Table 17 for Dose 7) and ZID (Table 48 for Dose 1, Table 49 for Doses 2-6, and Table 50 for Dose 7).  
• Individual concentrations in plasma and summary statistics will be presented tabularly for each 
Treatment Group for ERT (total concentrations beginning at Table 18 and continuing through 
Table 32 and free concentrations beginning at Table 33 and continuing through Table 47) and for ZID 
(total concentrations beginning at Table 51 and continuing through Table 65 and free concentrations 
beginning at Table 66 and continuing through Table 80).  
• Individual total concentrations in plasma will be presented graphically for ERT at Dose 1 (Figure 3) 
and Dose 7 (Figure 4). Trough concentrations for Doses 2-8 (Figure 5) and concentrations 12h after 
dosing on Doses 1-7 (Figure 6) will also be presented. These figures will also be presented for total 
ZID concentrations in plasma (Figure 11 through Figure 14, respectively). 
• Individual free concentrations in plasma will be presented graphically for ERT at Dose 1 (Figure 7) 
and Dose 7 (Figure 8). Trough concentrations for Doses 2-8 (Figure 9) and concentrations 12h after 
dosing on Days 1-7 (Figure 10) will also be presented. These figures will also be presented for free 
ZID concentrations in plasma (Figure 15 through Figure 18, respectively). 
• Semi-log plots of individual total concentration-time profiles in plasma will be presented graphically 
for ERT at Dose 1 (Figure 19) and Dose 7 (Figure 20) and for ZID at Dose 1 (Figure 23) and Dose 7 
(Figure 24). 
• Semi-log plots of individual free concentration-time profiles in plasma will be presented graphically 
for ERT at Dose 1 (Figure 21) and Dose 7 (Figure 22) and for ZID at Dose 1 (Figure 25) and Dose 7 
(Figure 26). 
• Graphically, plots of mean concentration in plasma profiles will be presented with error bars 
representing ± 1 SD around each sample timepoint for total and free concentrations of both ERT 
(Figure 27 and Figure 28) and ZID (Figure 31 and Figure 32). Mean trough concentrations will be 
presented for Doses 1-7 for total and free ERT (Figure 29) and ZID (Figure 33). Mean concentrations 
in plasma 12h after dosing will be presented for total and free ERT (Figure 30) and ZID (Figure 34). 
• Semi-log plots of mean concentration in plasma profiles will be presented with ± 1 SD around each 
sample timepoint for total and free concentrations of ERT (Figure 35 and Figure 36) and ZID (Figure 
39 and Figure 40). Semi-log plots of mean trough concentrations will be presented for Doses 1-7 for 
total and free ERT (Figure 37) and ZID (Figure 41). Semi-log plots of mean concentrations in plasma 
12h after dosing will be presented for total and free ERT (Figure 38) and ZID (Figure 42). 


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• Summary statistics for percent protein binding at each collection timepoint will be presented by 
Treatment Group in Table 129 through Table 133 for ERT and Table 134 through Table 138 for ZID. 
Percent binding will be calculated as ((Ctotal-Cfree)/Ctotal) x 100%, where Ctotal is the total concentration 
of ERT/ZID in plasma and Cfree is the free concentration of ERT/ZID in plasma. Percent protein 
binding will be presented graphically for ERT in Figure 43 for Dose 1 and Dose 7 and Figure 44 for 
Doses 1-7, and for ZID in Figure 45 for Dose 1 and Dose 7 and Figure 46 for Doses 1-7. 
• The GM and CV% of urine concentrations are reported by Treatment Group for ERT (Table 139 for 
Dose 1 and Table 140 for Dose 7) and ZID (Table 141 for Dose 1 and Table 142 for Dose 7). 
• Individual concentrations in urine and summary statistics will be presented tabularly for each 
Treatment Group for ERT (beginning at Table 143 and continuing through Table 152) and for ZID 
(beginning at Table 153 and continuing through Table 162).  
• Individual cumulative amount of ERT excreted into urine will be presented graphically (Dose 1 in 
Figure 53 and Dose 7 in Figure 54). Individual cumulative amount of ZID excreted into urine will be 
presented in Figure 45 for Dose 1 and Figure 56 for Dose 7. 
• Plots of mean cumulative amount excreted into urine will be presented by Treatment Group for ERT 
(Figure 57) and ZID (Figure 58). 
10.1. 
Noncompartmental Analysis 
PK parameters from plasma PK data will be estimated through NCA using version 8.3.4 or higher of Phoenix 
WinNonlin®. Actual post dose time will be used for the estimation of plasma PK parameters instead of 
nominal time. In the case of imputed sample collection times, the imputed time will be included in NCA. PK 
parameters derived from urine concentration data will be calculated using a combination of Phoenix 
WinNonlin and SAS version 9.4 or above. Any outliers identified in the PK analysis will be discussed in the 
analysis report. Outliers will not be excluded from the PK analysis. 
Summary statistics of PK parameter estimates by Treatment Group will be presented in tables. Summary 
statistics will include the mean, SD, min, max, CV% and GM: 
• Single-dose plasma PK parameters (defined in Section 10.1.1) will be summarized and presented 
tabularly for all Treatment Groups for total concentrations of ERT (Table 81) and ZID (Table 83) and 
for free concentrations of ERT (Table 82) and ZID (Table 84). 
• Multiple-dose plasma PK parameters (defined in Section 10.1.2) will be summarized and presented 
tabularly for all Treatment Groups for total concentrations of ERT (Table 85) and ZID (Table 87) and 
for free concentrations of ERT (Table 86) and ZID (Table 88). 
• Detailed summary statistics of each single-dose plasma PK parameter will be presented tabularly for 
each Treatment Group for concentrations of total ERT in plasma (beginning at Table 89 and 
continuing through Table 93) and concentrations of total ZID in plasma (beginning at Table 99 and 
continuing through Table 103). PK parameters will be presented for concentrations of free ERT in 
plasma (beginning at Table 94 and continuing through Table 98) and for concentrations of free ZID in 
plasma (beginning at Table 104 and continuing through Table 108). 
• Detailed summary statistics of each multiple-dose plasma PK parameter will be presented tabularly for 
each Treatment Group for concentrations of total ERT in plasma (beginning at Table 109 and 
continuing through Table 113) and concentrations of total ZID in plasma (beginning at Table 119 and 
continuing through Table 123). PK parameters will be presented for concentrations of free ERT in 


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plasma (beginning at Table 114 and continuing through Table 118) and for concentrations of free ZID 
in plasma (beginning at Table 124 and continuing through Table 128). 
• Urine PK parameters will be summarized and presented tabularly for all Treatment Groups for ERT 
(Table 163 for Dose 1 and Table 164 for Dose 7) and ZID (Table 165 for Dose 1 and Table 166 for 
Dose 7). 
• Detailed summary statistics of each urine PK parameter will be presented tabularly for each Treatment 
Group for ERT (beginning at Table 167 and continuing through Table 175) and ZID (beginning at 
Table 176 and continuing through Table 185). 
• Participant specific single-dose PK parameters for total and free concentrations of ERT in plasma 
(total concentrations in Listing 12 and free concentrations in Listing 13) and for total and free 
concentrations of ZID in plasma (total concentrations in Listing 14 and free concentrations in 
Listing 15). 
• Participant specific multiple-dose PK parameters for total and free concentrations of ERT in plasma 
(total concentrations in Listing 16 and free concentrations in Listing 17) and for total and free 
concentrations of ZID in plasma (total concentrations in Listing 18 and free concentrations in 
Listing 19). 
• Participant specific urine PK parameters for ERT (Listing 21 for Dose 1 and Listing 22 for Dose 7) 
and for ZID (Listing 23 for Dose 1 and Listing 24 for Dose 7). 
The definition of CV% is described below: 
For an independent identically distributed random sample {x1, x2,…, xn} from a log-normal distribution, let s2 
be the sample variance statistic of the natural log-transformed values of the sample. The CV% will be defined 
as: 
CV% = ඥexp(s2) −1 × 100% 
Phoenix WinNonlin NCA will use the following settings to compute parameters from plasma PK data:  
• Linear Up Log Down calculation method 
• Uniform weighting 
• Ke Acceptance Criteria 
o Rsq_adjusted > 0.90 
o Includes at least 3 timepoints after Tmax 
10.1.1. 
Single-Dose Plasma PK Parameters 
These parameters will be computed (if estimable) from the plasma total and free concentration-time data over 
the 24-hour following Dose 1 for each study drug: 
Cmax  
Cmax is defined as the maximum drug or metabolite concentration observed in plasma over all PK sample 
concentrations. It will be obtained from the Cmax parameter calculated by WinNonlin. If there is no 
measurable concentration in the participant’s PK profile, then Cmax will be missing for that participant. Cmax 
will be reported in units of µg/mL. The dose-normalized parameter Cmax/Dose will also be reported from 
Cmax_D in WinNonlin. 


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Cmin 
Cmin is defined as the observed minimum concentration at the end of the dosing interval. It will be obtained 
from the Cmin parameter calculated by WinNonlin. 
Tmax  
Time of maximum concentration (Tmax) is defined as the time at which the Cmax occurs. It will be obtained 
from the Tmax parameter calculated by WinNonlin. If there is no measurable Cmax in the participant’s PK 
profile, then Tmax will be missing for that participant. Tmax will be reported in units of h. 
Ke 
The terminal phase elimination rate constant (Ke or λz) is defined as the first-order rate constant describing 
the rate of decrease of drug or metabolite concentration in the terminal phase (defined as the terminal region 
of the PK curve where drug or metabolite concentration follows first-order elimination kinetics). Ke will be 
computed as the slope of a terminal region consisting of > 3 successive points in the plot of log-transformed 
concentration data versus time. Ke will be estimated using uniform weighting.  
Timepoints used in the estimation of Ke will be initially selected using the WinNonlin automatic algorithm. 
Manually chosen timepoints may be used at the discretion of the PK analyst after examination of the 
automatically chosen points in the context of the semi-log profile to improve estimation of Ke on a case-by-
case basis. The set of points chosen must contain only timepoints after Tmax, include at least 3 timepoints, and 
satisfy the Ke Acceptance Criteria described above. Otherwise, the elimination rate constant and all derived 
parameters (apparent terminal elimination half-life [t1/2], AUC Extrapolated to Infinity [AUC0-inf], total 
clearance [CL], and apparent volume of distribution during terminal phase [Vd]) will be treated as missing.  
This parameter will be obtained from the Lambda_z parameter calculated by WinNonlin. Ke will be reported 
in units of 1/h.  
t1/2 
The t1/2 is defined as the time required for the drug or metabolite concentration to decrease by a factor of one-
half in the terminal phase. The t1/2 can be estimated as ln(2)/ Ke. It will be obtained from the HL_Lambda_z 
parameter calculated by WinNonlin. Half-life will be reported in units of h.  
AUC 
AUC0-last is defined as the area under the concentration-time curve from dosing (time 0) to the time of the last 
measured concentration. AUC0-last will be estimated using the Linear Up Log Down calculation method and 
obtained from the AUClast parameter calculated by WinNonlin. 
AUC0-inf is defined as the total area under the concentration-time curve from dosing (time 0) taken to the limit 
as the end time becomes arbitrarily large. AUC0-inf can be calculated by adding AUC0-last to an extrapolated 
value equal to the last measured concentration greater than the LLOQ divided by Ke: 
AUC0-inf = AUC0-last + Clast
 Ke  
Where Clast is the last measured concentration > LLOQ. AUC0-inf will be obtained from the AUCINF_obs 
parameter calculated by WinNonlin®.  
%AUCex is defined as percentage of AUC0-inf obtained by extrapolation from time of the last measured 
concentration to infinity. %AUCex can be calculated by dividing AUC from time of the last measured 
concentration to infinity by AUC0-inf:  


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%AUC𝑒𝑒𝑒𝑒= AUC0−inf −AUC0−last
AUC0−inf
, 
If %AUCex is >20%, the estimated AUC0-inf will be excluded from statistical summaries of PK parameter 
estimates and downstream calculations. %AUCex will be obtained from the AUC_%Extrap_obs parameter 
calculated by WinNonlin.  
AUC0-24 will be calculated as the AUC extrapolated to 24 h after dosing. This will be obtained from the 
WinNonlin AUC0_24 parameter. 
AUC0-tau will be calculated as the AUC to the end of the dosing interval. The dose-normalized parameter 
AUC0-tau/Dose will also be reported. These parameters will be obtained from the AUC_tau and AUC_tau_D 
parameters in WinNonlin, respectively. 
All AUCs will be reported in units of µg*h/mL. 
CLT 
Total clearance (CLT) will be obtained from Dose/AUCinf. If %AUCex is >20%, the estimated CLT value will 
be excluded from statistical summaries of parameter estimates and downstream calculations. CLT will be 
obtained from the CL_obs parameter calculated by WinNonlin. Clearance will be reported in units of L/h.  
Vd 
Apparent volume of distribution (Vd) will be calculated as (CLT)/ Ke. If %AUCex is >20%, the estimated Vd 
value will be excluded from statistical summaries of parameter estimates and downstream calculations. Vd 
will be obtained from Vz_obs calculated by WinNonlin. Volume will be reported in units of L.  
10.1.2. 
Multiple-Dose Plasma PK Parameters 
These parameters will be computed (if estimable) from the drug total and free concentration-time data over 
the 24-hour dosing interval following Dose 7 for each study drug. Note that these parameter estimates assume 
that steady state has been achieved. 
Cmax,ss 
Cmax,ss is the observed maximum concentration at steady state. This will be obtained from the Cmax parameter 
calculated by WinNonlin for Dose 7. 
Cmin,ss 
Cmin,ss is the observed minimum concentration at the end of the dosing interval at steady state. This will be 
obtained from the Cmin parameter calculated by WinNonlin for Dose 7. 
Cavg 
Cavg is the calculated average concentration during the dosing interval. It is calculated as AUC0-tau,ss/tau. This 
will be obtained from the Cavg parameter calculated by WinNonlin for Dose 7. 
Tmax,ss 
Tmax,ss is the time of maximum concentration (Cmax) at steady state. This will be obtained from the Tmax 
parameter calculated by WinNonlin for Dose 7. 
Tmin 


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Tmin is the time to minimum concentration (Cmin). This will be obtained from the Tmin parameter calculated 
by WinNonlin for Dose 7. 
AUC(0-24),ss 
AUC(0-24),ss is calculated as the area under the plasma concentration - time curve extrapolated to 24 h after 
dosing (see Section 10.1.1 for additional details). 
AUC(0-tau),ss 
AUC(0-tau),ss is calculated as the area under the plasma concentration - time curve to the end of the dosing 
interval at steady state. 
t1/2 
t1/2 will be obtained from the HL_Lambda_z parameter calculated by WinNonlin for Dose 7. 
CLss 
CLss will be obtained from the CLss_F parameter calculated by WinNonlin. 
Vd,ss 
Vd,ss is the volume of distribution at steady state. It will be obtained from Vz_obs in WinNonlin. 
Linearity Index 
The Linearity Index is calculated as AUC(0-tau),ss (Dose 7) / AUC(0-∞) (Dose 1). 
RAUC 
RAUC is the accumulation ratio for AUC, which is estimated as AUC(0-tau),ss (Dose 7) / AUC(0-24) (Dose 1) 
where AUC(0-tau),ss (Dose 7) and AUC(0-24) (Dose 1) are both taken from the 0-24h interval on their respective 
days. 
RCmax 
RCmax is the accumulation ratio for Cmax, which is estimated as Cmax (Dose 7) / Cmax (Dose 1). 
10.1.3. 
Urine PK Parameters 
Ae,urine 
Ae,urine is defined as the amount of unchanged drug excreted in urine during each collection interval 
following Dose 1 and Dose 7 (i.e., at 0-4, 4-8, 8-12, 12-24 h after initiation of infusion). 
Ae,urine(0-24) is the cumulative amount of unchanged drug excreted in urine from zero (predose) to 24 h 
following Dose 1. 
Ae,urine(0-24),ss is the cumulative amount of unchanged drug excreted in urine from zero (predose) to 24 h after 
Dose 7.  
fe,urine 
fe,urine is defined as the fraction (%) of dose excreted unchanged in urine during each collection interval 
following Dose 1 and Dose 7 (i.e., at 0-4, 4-8, 8-12, 12-24 h after initiation of infusion). 
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fe,urine(0-24),ss is the fraction (%) of dose excreted unchanged in urine from zero (predose) to 24 h following 
Dose 7. 
CLR 
CLR is defined as the renal clearance of drug or metabolite and will be calculated as Aelast/AUC0-t1. Where 
AUC0-t1 is defined as AUC from dosing (time 0) to collection time (t1) based on the last collected 
concentration in urine.  
CLr(0-24) will be calculated as the renal clearance until the last collected concentration for Dose 1 (24h) and 
CLr,ss will be calculated as the renal clearance until the last collected concentration for Dose 7.  
AUC0-t1 will be converted to mg*min/mL for calculations of CLR. CLR will be treated a missing if AUC0-t1 or 
Aelast is not estimable. Renal clearance of ERT or ZID will be reported in units of mL/min.  
10.1.4. 
Assessment of Dose Proportionality 
The presence of dose proportionality in plasma in terms of exposure parameters (Cmax, AUC0-last, and AUC0-inf 
for Dose 1 and Cmax,ss, AUC(0-24),ss, and AUC(0-tau),ss for Dose 7) over the range of studied doses will be 
assessed for ERT and ZID for the WCK 6777 cohorts using a power model approach with methods described 
by Smith et al. [10]. The PK Analysis Subset will be used for this analysis.  
The power model for the specific case of AUC0-last may be specified with model parameters α and β to be 
estimated as: 
𝐴𝐴𝐴𝐴𝐴𝐴0−𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙= 𝑒𝑒α × 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑β 
Let ρ be the highest dose studied / lowest dose studied and let (L, U) represent the 90% CI for β෠. In the 
presence of dose proportionality,  ρβ෡/ρ = ρβ෡−1 = 1. Note that normality of β ෡is assumed, and this 
assumption implies that ρβ෡−1 has an assumed log-normal distribution. Accordingly, dose proportionality 
across the studied dose range is concluded using methodology analogous to that commonly used for an 
assessment of bioequivalence when:  
Θl = 0.8 ≤ ρ𝐿𝐿−1 < ρ𝑈𝑈−1  ≤ 1.25 = Θh. 
Or, equivalently,  
1 + 
log 0.8
log ρ ≤L <  𝑈𝑈 ≤1 + 
log 1.25
log ρ . 
The analysis may be inconclusive if the CI (ρ𝐿𝐿−1, ρ𝑈𝑈−1) overlaps partially with the interval (0.80, 1.25) or if 
the (ρ𝐿𝐿−1, ρ𝑈𝑈−1) contains the interval (0.80, 1.25). Dose proportionality assessments will be presented 
graphically and tabularly for Dose 1 and Dose 7 exposure parameters of ERT and ZID using the WCK 6777 
dose groups: 
• Tabular results of statistics and parameters from the plasma dose proportionality power model will be 
presented for total and free plasma concentrations of both ERT and ZID in Table 186 and Table 187 
for Dose 1 and for total and free plasma concentrations of ERT and ZID in Table 188 and Table 189 
for Dose 7. 
• Predicted values from a power model, including 90% pointwise prediction bands, will be overlaid on 
plots of the single-dose exposure parameter parameters (Cmax, AUC0-last, or AUC0-inf) versus dose. 
Pointwise prediction bands will be defined by lower and upper limits of 90% pointwise prediction 
intervals computed from the power model at each planned dose level.  


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• Figures will be presented for all exposure parameters. For total and free ERT and ZID in plasma, Cmax 
will be presented in Figure 59, AUC0-last in Figure 60, AUC0-inf in Figure 61, Cmax,ss in Figure 62, 
AUC(0-24),ss in Figure 63, and AUC(0-tau),ss in Figure 64.  
10.1.5. 
Assessment of Drug-Drug Interactions 
The presence of drug-drug interactions for ZID and ERT in the WCK 6777 cohorts will be assessed using an 
analysis of variance (ANOVA) approach for the log-transformed dose-normalized exposure parameters (Cmax, 
AUC0-last, AUC0-tau, AUC0-inf, Cmax,ss, and AUC0-tau,ss) and protein binding parameters (% Bound Day 1, % 
Bound Day 7, Amount Bound Day 1, and Amount Bound Day 7). For 2 g ERT and 2 g ZID dose groups, the 
exposure parameters will be compared to those for 4 g WCK 6777 (2 g ERT + 2 g ZID). For 3 g ERT and 3 g 
ZID dose groups, the exposure parameters will be compared to those for 6 g WCK 6777 (3 g ERT + 3 g ZID). 
The PK Analysis Subset will be used for this analysis.   
ANOVA models will be fit for exposure parameters estimated for total ERT in plasma, free ERT in plasma, 
total ZID in plasma, and free ZID in plasma. Assuming kinetics are linear, the mixed effects model for the 
ANOVA analysis of AUC0-last for total ERT in plasma, for example, may be specified as 
log (
𝐴𝐴𝐴𝐴𝐴𝐴0−𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙
𝜌𝜌𝑗𝑗
)𝑖𝑖𝑖𝑖= 𝜇𝜇+ 𝑎𝑎𝑖𝑖(𝑗𝑗) + 𝛾𝛾𝑗𝑗+ 𝜀𝜀𝑖𝑖𝑖𝑖, 
where µ is the overall mean of the log-transformed dose-normalized AUC0-last, 𝑎𝑎𝑖𝑖(𝑗𝑗) (𝑖𝑖= 1, … ,5) is a random 
participant-specific intercept, γj (𝑗𝑗= 1,2,3,4) represents the fixed dose cohort effect, ρj is the jth dose / lowest 
dose studied in monotherapy (i.e., 2 g), and the errors εij are assumed independent and identically distributed 
from the standard normal distribution.  
The linearity of the kinetics assumption for the above models will be assessed via comparisons of the 
estimated GM of the dose-normalized PK exposure parameters for the comparison groupings listed above. If 
the linearity of kinetics assumption does not hold, dose-specific ANOVA models will be fit with only two 
fixed dose cohort effects, including ERT or ZID alone and ERT + ZID in combination at the specific dose (2 
g or 3 g).  
The GMs of dose-normalized exposure parameters and ratios of geometric least-squares means of exposure 
parameters after their transformation from the log-transformed analysis back to their original scale, as well as 
their corresponding 95% and 90% confidence intervals, respectively, will be presented in Table 190 for the 
PK Analysis Subset and Table 191 for the PK Analysis Subset Subgroup. 
For the drug-drug interaction ANOVA analysis, the following pseudocode will be used to estimate the dose-
normalized GMs of exposure parameters and ratios of the geometric least-squares means with their 
corresponding confidence intervals. 
/* Get data only for specific drug (free or total) and PK parameter */ 
data drug_conc_param; 
set dataset; where trt in ("drug 2 g", "drug 3 g", "WCK 6777 4 g", "WCK 6777 6 g"); 
if param="Parameter Name" and pkconc="Free/Total drug"; 
run; 
 
/* Fit Mixed-Effects ANOVA model and estimate log-transformed PK parameter estimates and 
ratios*/ 
proc mixed data=drug_conc_param; *Update to correct parameter, such as Cmax; 
class subject trt; 
model log_dose_norm_param = trt / ddfm=kr2; 
random intercept / subject=subjid; 


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estimate '2 g standalone drug vs combination' trt 1 0 -1 0 / cl alpha=0.1; *log-
transformed GLSM ratios and 90% CIs; 
estimate '3 g standalone drug vs combination' trt 0 1 0 -1 / cl alpha=0.1; 
lsmeans trt / cl alpha=0.05; *log-transformed mean estimates of parameter and 95% CIs, 
adjusting for all model parameters; 
odds output estimates=estimate_param; *output log transformed GLCM ratios; 
lsmeans lsm_param; *output estimates from lsmeans statement; 
run; 
10.1.6. 
 Assessment of Saturation and Linearity of Protein Binding 
Percent protein binding vs total concentration of ERT in plasma will be presented separately for both 
ERT/ZID monotherapy and WCK combination therapy cohorts. Linear regressions will be fit for each cohort 
for Dose 1 and Dose 7 and presented alongside R-squared values for ERT in Figure 47 and for ZID Figure 48. 
Percent protein binding vs log-transformed total concentration is presented for ERT in Figure 49 and for ZID 
in Figure 50. Protein binding saturation of ERT will be presented separately for both ERT and WCK cohorts 
in Figure 51 and for ZID Figure 52.  
 


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11. 
IMMUNOGENICITY 
Not applicable. 


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12. 
OTHER ANALYSES 
Not applicable. 


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13. 
REPORTING CONVENTIONS 
P-values ≥0.001 and ≤0.999 will be reported to 3 decimal places; p-values less than 0.001 will be reported as 
“<0.001” 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. 
For PK parameters, AUCs will be reported using 3 significant digits. t1/2, Tmax, CLT, and Vd values will be 
reported using 2 significant digits. Ke values will be reported to 3 significant digits. Cmax will be reported with 
the same number of significant digits as the measurement.  
 


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14. 
TECHNICAL DETAILS 
SAS version 9.4 or above and R versions 3.2 or above will be used to generate tables, figures, and listings. PK 
parameters will be estimated through NCA using Phoenix® WinNonlin version 8.3.4 or later. 


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15. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES 
If there are any changes to the planned analyses prior to final data lock and after finalization of the SAP, they 
may be added to the SAP as an addendum. The SAP will not be amended after final data lock. 


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16. 
REFERENCES 
1. ICH Harmonised Tripartite Guideline. Structure and Content of Clinical Study Reports E3. 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. 1995. Retrieved from: 
https://database.ich.org/sites/default/files/E3_Guideline.pdf. 
2. ICH Harmonised Tripartite Guideline. General Considerations for Clinical Trials E8. International 
Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for 
Human Use. 1997. Retrieved from: https://database.ich.org/sites/default/files/E8_Guideline.pdf 
3. ICH Harmonised Tripartite Guideline. Statistical Principles for Clinical Trials E9. International 
Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for 
Human Use. 1998. Retrieved from: https://database.ich.org/sites/default/files/E9_Guideline.pdf. 
4. American Statistical Association Guideline. Ethical Guidelines for Statistical Practice. American 
Statistical Association. 2022. Retrieved from: https://www.amstat.org/docs/default-source/amstat-
documents/ethicalguidelines.pdf?sfvrsn=bdeeafdd_3. 
5. Royal Statistical Association Guideline. Code of Conduct. The Royal Statistical Association. 2014. 
Retrieved from: https://rss.org.uk/RSS/media/File-library/About/2019/RSS-Code-of-Conduct-2014.pdf. 
6. Ambrose PG, Bhavnani SM, Ellis-Grosse EJ, Drusano GL. Pharmacokinetic-pharmacodynamic 
considerations in the design of hospital-acquired or ventilator-associated bacterial pneumonia studies: 
look before you leap! Clin Infect Dis. 2010;51 Suppl 1:S103-S110. doi:10.1086/653057 
7. Teppler H, Gesser RM, Friedland IR, et al. Safety and tolerability of ertapenem. J Antimicrob 
Chemother. 2004;53 Suppl 2:ii75-ii81. doi:10.1093/jac/dkh209 
8. INVANZ® (ertapenem sodium injection. Prescribing information, Merck Sharpe and Dohme LLC. 
Available from:  https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021337s038lbl. pdf   
9. Investigator’s Brochure, WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)], Edition: 7.0, 11 November 
2022, Wockhardt 
10. Smith, Brian P., et al. Confidence interval criteria for assessment of dose proportionality. 
Pharmaceutical Research 17.10 (2000): 1278-1283. 
 


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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 
 
 


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LIST OF TABLES 
Table 1: 
Study Design ...............................................................................................................61 
Table 2: 
Schedule of Study Procedures ....................................................................................62 
Table 3: 
Clinical Vital Signs Adverse Event Toxicity Grading Scale ......................................65 
Table 4: 
Clinical Adverse Event Toxicity Grading Scale .........................................................66 
Table 5: 
Clinical Laboratory Reference Ranges and Toxicity Grading Scale ..........................69 
Table 6: 
ECG Toxicity Grading Scale ......................................................................................73 
Table 7: 
Distribution of Protocol Deviations by Category, Type, and Treatment 
Group ..........................................................................................................................74 
Table 8: 
Participant Disposition by Treatment Group ..............................................................76 
Table 9: 
Analysis Population Exclusions by Treatment Group ................................................77 
Table 10: Ineligibility Summary of Screen Failures ...................................................................78 
Table 11: Summary of Categorical Demographic and Baseline Characteristics by 
Treatment Group .........................................................................................................81 
Table 12: Summary of Continuous Demographic and Baseline Characteristics by 
Treatment Group .........................................................................................................82 
Table 13: Summary of Participants with Pre-Existing Medical Conditions by MedDRA 
System Organ Class and Treatment Group ................................................................83 
Table 14: Tolerability by Treatment Group ................................................................................84 
Table 15: ERT Concentrations in Plasma by Treatment Group – Dose 1 ..................................85 
Table 16: ERT Concentrations in Plasma by Treatment Group – Doses 2-6 .............................86 
Table 17: ERT Concentrations in Plasma by Treatment Group – Dose 7 ..................................86 
Table 18: Summary Statistics for Total ERT Concentrations in Plasma – WCK 6777 
2g, Dose 1 ...................................................................................................................87 
Table 19: Summary Statistics for Total ERT Concentrations in Plasma – WCK 6777 
2g, Doses 2-6 ..............................................................................................................88 
Table 20: Summary Statistics for Total ERT Concentrations in Plasma – WCK 6777 
2g, Dose 7 ...................................................................................................................89 
Table 21: Summary Statistics for Total ERT Concentrations in Plasma – ERT 2g, Dose 
1 ..................................................................................................................................89 
Table 22: Summary Statistics for Total ERT Concentrations in Plasma – ERT 2g, 
Doses 2-6 ....................................................................................................................89 
Table 23: Summary Statistics for Total ERT Concentrations in Plasma – ERT 2g, Dose 
7 ..................................................................................................................................89 


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Table 24: Summary Statistics for Total ERT Concentrations in Plasma – WCK 6777 
4g, Dose 1 ...................................................................................................................89 
Table 25: Summary Statistics for Total ERT Concentrations in Plasma – WCK 6777 
4g, Doses 2-6 ..............................................................................................................89 
Table 26: Summary Statistics for Total ERT Concentrations in Plasma – WCK 6777 
4g, Dose 7 ...................................................................................................................89 
Table 27: Summary Statistics for Total ERT Concentrations in Plasma – ERT 3g, Dose 
1 ..................................................................................................................................89 
Table 28: Summary Statistics for Total ERT Concentrations in Plasma – ERT 3g, 
Doses 2-6 ....................................................................................................................89 
Table 29: Summary Statistics for Total ERT Concentrations in Plasma – ERT 3g, Dose 
7 ..................................................................................................................................89 
Table 30: Summary Statistics for Total ERT Concentrations in Plasma – WCK 6777 
6g, Dose 1 ...................................................................................................................89 
Table 31: Summary Statistics for Total ERT Concentrations in Plasma – WCK 6777 
6g, Doses 2-6 ..............................................................................................................89 
Table 32: Summary Statistics for Total ERT Concentrations in Plasma – WCK 6777 
6g, Dose 7 ...................................................................................................................89 
Table 33: Summary Statistics for Free ERT Concentrations in Plasma – WCK 6777 2g, 
Dose 1 .........................................................................................................................90 
Table 34: Summary Statistics for Free ERT Concentrations in Plasma – WCK 6777 2g, 
Doses 2-6 ....................................................................................................................90 
Table 35: Summary Statistics for Free ERT Concentrations in Plasma – WCK 6777 2g, 
Dose 7 .........................................................................................................................90 
Table 36: Summary Statistics for Free ERT Concentrations in Plasma – ERT 2g, Dose 
1 ..................................................................................................................................90 
Table 37: Summary Statistics for Free ERT Concentrations in Plasma – ERT 2g, Doses 
2-6 ...............................................................................................................................90 
Table 38: Summary Statistics for Free ERT Concentrations in Plasma – ERT 2g, Dose 
7 ..................................................................................................................................90 
Table 39: Summary Statistics for Free ERT Concentrations in Plasma – WCK 6777 4g, 
Dose 1 .........................................................................................................................90 
Table 40: Summary Statistics for Free ERT Concentrations in Plasma – WCK 6777 4g, 
Doses 2-6 ....................................................................................................................90 
Table 41: Summary Statistics for Free ERT Concentrations in Plasma – WCK 6777 4g, 
Dose 7 .........................................................................................................................90 
Table 42: Summary Statistics for Free ERT Concentrations in Plasma – ERT 3g, Dose 
1 ..................................................................................................................................90 


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Table 43: Summary Statistics for Free ERT Concentrations in Plasma – ERT 3g, Doses 
2-6 ...............................................................................................................................90 
Table 44: Summary Statistics for Free ERT Concentrations in Plasma – ERT 3g, Dose 
7 ..................................................................................................................................90 
Table 45: Summary Statistics for Free ERT Concentrations in Plasma – WCK 6777 6g, 
Dose 1 .........................................................................................................................90 
Table 46: Summary Statistics for Free ERT Concentrations in Plasma – WCK 6777 6g, 
Doses 2-6 ....................................................................................................................90 
Table 47: Summary Statistics for Free ERT Concentrations in Plasma – WCK 6777 6g, 
Dose 7 .........................................................................................................................90 
Table 48: ZID Concentrations in Plasma by Treatment Group – Dose 1 ...................................91 
Table 49: ZID Concentrations in Plasma by Treatment Group – Doses 2-6 ..............................91 
Table 50: ZID Concentrations in Plasma by Treatment Group – Dose 7 ...................................91 
Table 51: Summary Statistics for Total ZID Concentrations in Plasma – WCK 6777 
2g, Dose 1 ...................................................................................................................92 
Table 52: Summary Statistics for Total ZID Concentrations in Plasma – WCK 6777 
2g, Doses 2-6 ..............................................................................................................92 
Table 53: Summary Statistics for Total ZID Concentrations in Plasma – WCK 6777 
2g, Dose 7 ...................................................................................................................92 
Table 54: Summary Statistics for Total ZID Concentrations in Plasma – ZID 2g, Dose 
1 ..................................................................................................................................92 
Table 55: Summary Statistics for Total ZID Concentrations in Plasma – ZID 2g, Doses 
2-6 ...............................................................................................................................92 
Table 56: Summary Statistics for Total ZID Concentrations in Plasma – ZID 2g, Dose 
7 ..................................................................................................................................92 
Table 57: Summary Statistics for Total ZID Concentrations in Plasma – WCK 6777 
4g, Dose 1 ...................................................................................................................92 
Table 58: Summary Statistics for Total ZID Concentrations in Plasma – WCK 6777 
4g, Doses 2-6 ..............................................................................................................92 
Table 59: Summary Statistics for Total ZID Concentrations in Plasma – WCK 6777 
4g, Dose 7 ...................................................................................................................92 
Table 60: Summary Statistics for Total ZID Concentrations in Plasma – ZID 3g, Dose 
1 ..................................................................................................................................92 
Table 61: Summary Statistics for Total ZID Concentrations in Plasma – ZID 3g, Doses 
2-6 ...............................................................................................................................92 
Table 62: Summary Statistics for Total ZID Concentrations in Plasma – ZID 3g, Dose 
7 ..................................................................................................................................92 


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Table 63: Summary Statistics for Total ZID Concentrations in Plasma – WCK 6777 
6g, Dose 1 ...................................................................................................................92 
Table 64: Summary Statistics for Total ZID Concentrations in Plasma – WCK 6777 
6g, Doses 2-6 ..............................................................................................................92 
Table 65: Summary Statistics for Total ZID Concentrations in Plasma – WCK 6777 
6g, Dose 7 ...................................................................................................................92 
Table 66: Summary Statistics for Free ZID Concentrations in Plasma – WCK 6777 2g, 
Dose 1 .........................................................................................................................93 
Table 67: Summary Statistics for Free ZID Concentrations in Plasma – WCK 6777 2g, 
Doses 2-6 ....................................................................................................................93 
Table 68: Summary Statistics for Free ZID Concentrations in Plasma – WCK 6777 2g, 
Dose 7 .........................................................................................................................93 
Table 69: Summary Statistics for Free ZID Concentrations in Plasma – ZID 2g, Dose 1 .........93 
Table 70: Summary Statistics for Free ZID Concentrations in Plasma – ZID 2g, Doses 
2-6 ...............................................................................................................................93 
Table 71: Summary Statistics for Free ZID Concentrations in Plasma – ZID 2g, Dose 7 .........93 
Table 72: Summary Statistics for Free ZID Concentrations in Plasma – WCK 6777 4g, 
Dose 1 .........................................................................................................................93 
Table 73: Summary Statistics for Free ZID Concentrations in Plasma – WCK 6777 4g, 
Doses 2-6 ....................................................................................................................93 
Table 74: Summary Statistics for Free ZID Concentrations in Plasma – WCK 6777 4g, 
Dose 7 .........................................................................................................................93 
Table 75: Summary Statistics for Free ZID Concentrations in Plasma – ZID 3g, Dose 1 .........93 
Table 76: Summary Statistics for Free ZID Concentrations in Plasma – ZID 3g Doses 
2-6 ...............................................................................................................................93 
Table 77: Summary Statistics for Free ZID Concentrations in Plasma – ZID 3g, Dose 7 .........93 
Table 78: Summary Statistics for Free ZID Concentrations in Plasma – WCK 6777 6g, 
Dose 1 .........................................................................................................................93 
Table 79: Summary Statistics for Free ZID Concentrations in Plasma – WCK 6777 6g, 
Doses 2-6 ....................................................................................................................93 
Table 80: Summary Statistics for Free ZID Concentrations in Plasma – WCK 6777 6g, 
Dose 7 .........................................................................................................................93 
Table 81: Summary Statistics for Total ERT Single-Dose PK Parameters in Plasma by 
Treatment Group .........................................................................................................94 
Table 82: Summary Statistics for Free ERT Single-Dose PK Parameters in Plasma by 
Treatment Group .........................................................................................................94 


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Table 83: Summary Statistics for Total ZID Single-Dose PK Parameters in Plasma by 
Treatment Group .........................................................................................................94 
Table 84: Summary Statistics for Free ZID Single-Dose PK Parameters in Plasma by 
Treatment Group .........................................................................................................94 
Table 85: Summary Statistics for Total ERT Multiple-Dose PK Parameters in Plasma 
by Treatment Group ....................................................................................................95 
Table 86: Summary Statistics for Free ERT Multiple-Dose PK Parameters in Plasma 
by Treatment Group ....................................................................................................96 
Table 87: Summary Statistics for Total ZID Multiple-Dose PK Parameters in Plasma 
by Treatment Group ....................................................................................................96 
Table 88: Summary Statistics for Free ZID Multiple-Dose PK Parameters in Plasma by 
Treatment Group .........................................................................................................96 
Table 89: Summary Statistics for Total ERT Single-Dose PK Parameters in Plasma – 
WCK 6777 2g .............................................................................................................97 
Table 90: Summary Statistics for Total ERT Single-Dose PK Parameters in Plasma – 
ERT 2g ........................................................................................................................98 
Table 91: Summary Statistics for Total ERT Single-Dose PK Parameters in Plasma – 
WCK 6777 4g .............................................................................................................98 
Table 92: Summary Statistics for Total ERT Single-Dose PK Parameters in Plasma – 
ERT 3g ........................................................................................................................98 
Table 93: Summary Statistics for Total ERT Single-Dose PK Parameters in Plasma – 
WCK 6777 6g .............................................................................................................98 
Table 94: Summary Statistics for Free ERT Single-Dose PK Parameters in Plasma – 
WCK 6777 2g .............................................................................................................98 
Table 95: Summary Statistics for Free ERT Single-Dose PK Parameters in Plasma – 
ERT 2g ........................................................................................................................98 
Table 96: Summary Statistics for Free ERT Single-Dose PK Parameters in Plasma – 
WCK 6777 4g .............................................................................................................98 
Table 97: Summary Statistics for Free ERT Single-Dose PK Parameters in Plasma – 
ERT 3g ........................................................................................................................98 
Table 98: Summary Statistics for Free ERT Single-Dose PK Parameters in Plasma – 
WCK 6777 6g .............................................................................................................98 
Table 99: Summary Statistics for Total ZID Single-Dose PK Parameters in Plasma – 
WCK 6777 2g .............................................................................................................98 
Table 100: Summary Statistics for Total ZID Single-Dose PK Parameters in Plasma – 
ZID 2g .........................................................................................................................98 
Table 101: Summary Statistics for Total ZID Single-Dose PK Parameters in Plasma – 
WCK 6777 4g .............................................................................................................98 


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Table 102: Summary Statistics for Total ZID Single-Dose PK Parameters in Plasma – 
ZID 3g .........................................................................................................................98 
Table 103: Summary Statistics for Total ZID Single-Dose PK Parameters in Plasma – 
WCK 6777 6g .............................................................................................................98 
Table 104: Summary Statistics for Free ZID Single-Dose PK Parameters in Plasma – 
WCK 6777 2g .............................................................................................................98 
Table 105: Summary Statistics for Free ZID Single-Dose PK Parameters in Plasma – 
ZID 2g .........................................................................................................................98 
Table 106: Summary Statistics for Free ZID Single-Dose PK Parameters in Plasma – 
WCK 6777 4g .............................................................................................................98 
Table 107: Summary Statistics for Free ZID Single-Dose PK Parameters in Plasma – 
ZID 3g .........................................................................................................................98 
Table 108: Summary Statistics for Free ZID Single-Dose PK Parameters in Plasma – 
WCK 6777 6g .............................................................................................................98 
Table 109: Summary Statistics for Total ERT Multiple-Dose PK Parameters in Plasma – 
WCK 6777 2g .............................................................................................................99 
Table 110: Summary Statistics for Total ERT Multiple-Dose PK Parameters in Plasma – 
ERT 2g ......................................................................................................................100 
Table 111: Summary Statistics for Total ERT Multiple-Dose PK Parameters in Plasma – 
WCK 6777 4g ...........................................................................................................100 
Table 112: Summary Statistics for Total ERT Multiple-Dose PK Parameters in Plasma – 
ERT 3g ......................................................................................................................100 
Table 113: Summary Statistics for Total ERT Multiple-Dose PK Parameters in Plasma – 
WCK 6777 6g ...........................................................................................................100 
Table 114: Summary Statistics for Free ERT Multiple-Dose PK Parameters in Plasma – 
WCK 6777 2g ...........................................................................................................100 
Table 115: Summary Statistics for Free ERT Multiple-Dose PK Parameters in Plasma – 
ERT 2g ......................................................................................................................100 
Table 116: Summary Statistics for Free ERT Multiple-Dose PK Parameters in Plasma – 
WCK 6777 4g ...........................................................................................................100 
Table 117: Summary Statistics for Free ERT Multiple-Dose PK Parameters in Plasma – 
ERT 3g ......................................................................................................................100 
Table 118: Summary Statistics for Free ERT Multiple-Dose PK Parameters in Plasma – 
WCK 6777 6g ...........................................................................................................100 
Table 119: Summary Statistics for Total ZID Multiple-Dose PK Parameters in Plasma – 
WCK 6777 2g ...........................................................................................................100 
Table 120: Summary Statistics for Total ZID Multiple-Dose PK Parameters in Plasma – 
ZID 2g .......................................................................................................................100 


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Table 121: Summary Statistics for Total ZID Multiple-Dose PK Parameters in Plasma – 
WCK 6777 4g ...........................................................................................................100 
Table 122: Summary Statistics for Total ZID Multiple-Dose PK Parameters in Plasma – 
ZID 3g .......................................................................................................................100 
Table 123: Summary Statistics for Total ZID Multiple-Dose PK Parameters in Plasma – 
WCK 6777 6g ...........................................................................................................100 
Table 124: Summary Statistics for Free ZID Multiple-Dose PK Parameters in Plasma – 
WCK 6777 2g ...........................................................................................................100 
Table 125: Summary Statistics for Free ZID Multiple-Dose PK Parameters in Plasma – 
ZID 2g .......................................................................................................................100 
Table 126: Summary Statistics for Free ZID Multiple-Dose PK Parameters in Plasma – 
WCK 6777 4g ...........................................................................................................100 
Table 127: Summary Statistics for Free ZID Multiple-Dose PK Parameters in Plasma – 
ZID 3g .......................................................................................................................100 
Table 128: Summary Statistics for Free ZID Multiple-Dose PK Parameters in Plasma – 
WCK 6777 6g ...........................................................................................................100 
Table 129: Amount and Percent ERT Protein Binding – WCK 6777 2g ...................................101 
Table 130: Amount and Percent ERT Protein Binding – ERT 2g ..............................................102 
Table 131: Amount and Percent ERT Protein Binding – WCK 6777 4g ...................................102 
Table 132: Amount and Percent ERT Protein Binding – ERT 3g ..............................................102 
Table 133: Amount and Percent ERT Protein Binding – WCK 6777 6g ...................................102 
Table 134: Amount and Percent ZID Protein Binding – WCK 6777 2g ....................................102 
Table 135: Amount and Percent ZID Protein Binding – WCK ZID 2g .....................................102 
Table 136: Amount and Percent ZID Protein Binding – WCK 6777 4g ....................................102 
Table 137: Amount and Percent ZID Protein Binding – WCK ZID 3g .....................................102 
Table 138: Amount and Percent ZID Protein Binding – WCK 6777 6g ....................................102 
Table 139: ERT Concentrations in Urine by Treatment Group – Dose 1 ..................................103 
Table 140: ERT Concentrations in Urine by Treatment Group – Dose 7 ..................................103 
Table 141: ZID Concentrations in Urine by Treatment Group – Dose 1 ...................................103 
Table 142: ZID Concentrations in Urine by Treatment Group – Dose 7 ...................................103 
Table 143: ERT Summary Statistics for Concentrations in Urine – WCK 6777 2g, Dose 
1 ................................................................................................................................104 
Table 144: ERT Summary Statistics for Concentrations in Urine – WCK 6777 2g, Dose 
7 ................................................................................................................................105 
Table 145: ERT Summary Statistics for Concentrations in Urine – ERT 2g, Dose 1 ................105 


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Table 146: ERT Summary Statistics for Concentrations in Urine – ERT 2g, Dose 7 ................105 
Table 147: ERT Summary Statistics for Concentrations in Urine – WCK 6777 4g, Dose 
1 ................................................................................................................................105 
Table 148: ERT Summary Statistics for Concentrations in Urine – WCK 6777 4g, Dose 
7 ................................................................................................................................105 
Table 149: ERT Summary Statistics for Concentrations in Urine – ERT 3g, Dose 1 ................105 
Table 150: ERT Summary Statistics for Concentrations in Urine – ERT 3g, Dose 7 ................105 
Table 151: ERT Summary Statistics for Concentrations in Urine – WCK 6777 6g, Dose 
1 ................................................................................................................................105 
Table 152: ERT Summary Statistics for Concentrations in Urine – WCK 6777 6g, Dose 
7 ................................................................................................................................105 
Table 153: ZID Summary Statistics for Concentrations in Urine – WCK 6777 2g, Dose 
1 ................................................................................................................................105 
Table 154: ZID Summary Statistics for Concentrations in Urine – WCK 6777 2g, Dose 
7 ................................................................................................................................105 
Table 155: ZID Summary Statistics for Concentrations in Urine – ZID 2g, Dose 1 ..................105 
Table 156: ZID Summary Statistics for Concentrations in Urine – ZID 2g, Dose 7 ..................105 
Table 157: ZID Summary Statistics for Concentrations in Urine – WCK 6777 4g, Dose 
1 ................................................................................................................................105 
Table 158: ZID Summary Statistics for Concentrations in Urine – WCK 6777 4g, Dose 
7 ................................................................................................................................105 
Table 159: ZID Summary Statistics for Concentrations in Urine – ZID 3g, Dose 1 ..................105 
Table 160: ZID Summary Statistics for Concentrations in Urine – ZID 3g, Dose 7 ..................105 
Table 161: ZID Summary Statistics for Concentrations in Urine – WCK 6777 6g, Dose 
1 ................................................................................................................................105 
Table 162: ZID Summary Statistics for Concentrations in Urine – WCK 6777 6g, Dose 
7 ................................................................................................................................105 
Table 163: Summary Statistics for ERT PK Parameters in Urine by Treatment Group, 
Dose 1 .......................................................................................................................106 
Table 164: Summary Statistics for ERT PK Parameters in Urine by Treatment Group, 
Dose 7 .......................................................................................................................107 
Table 165: Summary Statistics for ZID PK Parameters in Urine by Treatment Group, 
Dose 1 .......................................................................................................................107 
Table 166: Summary Statistics for ZID PK Parameters in Urine by Treatment Group, 
Dose 7 .......................................................................................................................107 
Table 167: Summary Statistics for ERT PK Parameters in Urine – WCK 6777 2g, Dose 
1 ................................................................................................................................108 


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Table 168: Summary Statistics for ERT PK Parameters in Urine – ERT 2g, Dose 1 ................108 
Table 169: Summary Statistics for ERT PK Parameters in Urine – WCK 6777 4g, Dose 
1 ................................................................................................................................108 
Table 170: Summary Statistics for ERT PK Parameters in Urine – ERT 3g, Dose 1 ................108 
Table 171: Summary Statistics for ERT PK Parameters in Urine – WCK 6777 6g, Dose 
1 ................................................................................................................................108 
Table 172: Summary Statistics for ERT PK Parameters in Urine – ERT 2g, Dose 7 ................109 
Table 173: Summary Statistics for ERT PK Parameters in Urine – WCK 6777 4g, Dose 
7 ................................................................................................................................110 
Table 174: Summary Statistics for ERT PK Parameters in Urine – ERT 3g, Dose 7 ................110 
Table 175: Summary Statistics for ERT PK Parameters in Urine – WCK 6777 6g, Dose 
7 ................................................................................................................................110 
Table 176: Summary Statistics for ZID PK Parameters in Urine – WCK 6777 2g, Dose 
1 ................................................................................................................................110 
Table 177: Summary Statistics for ZID PK Parameters in Urine – ZID 2g, Dose 1 ..................110 
Table 178: Summary Statistics for ZID PK Parameters in Urine – WCK 6777 4g, Dose 
1 ................................................................................................................................110 
Table 179: Summary Statistics for ZID PK Parameters in Urine – ZID 3g, Dose 1 ..................110 
Table 180: Summary Statistics for ZID PK Parameters in Urine – WCK 6777 6g, Dose 
1 ................................................................................................................................110 
Table 181: Summary Statistics for ZID PK Parameters in Urine – WCK 6777 2g, Dose 
7 ................................................................................................................................110 
Table 182: Summary Statistics for ZID PK Parameters in Urine – ZID 2g, Dose 7 ..................110 
Table 183: Summary Statistics for ZID PK Parameters in Urine – WCK 6777 4g, Dose 
7 ................................................................................................................................110 
Table 184: Summary Statistics for ZID PK Parameters in Urine – ZID 3g, Dose 7 ..................110 
Table 185: Summary Statistics for ZID PK Parameters in Urine – WCK 6777 6g, Dose 
7 ................................................................................................................................110 
Table 186: Assessment of Dose Proportionality of WCK 6777 in Plasma – Dose 1, PK 
Analysis Subset .........................................................................................................111 
Table 187: Assessment of Dose Proportionality of WCK 6777 in Plasma – Dose 1, PK 
Analysis Subset Subgroup ........................................................................................111 
Table 188: Assessment of Dose Proportionality of WCK 6777 in Plasma – Dose 7, PK 
Analysis Subset .........................................................................................................111 
Table 189: Assessment of Dose Proportionality of WCK 6777 in Plasma – Dose 7, PK 
Analysis Subset Subgroup ........................................................................................111 


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Table 190: Assessment of Drug-Drug Interactions of ERT and ZID for Concentrations 
of WCK 6777 in Plasma – PK Analysis Subset .......................................................112 
Table 191: Assessment of Drug-Drug Interactions of ERT and ZID for Concentrations 
of WCK 6777 in Plasma – PK Analysis Subset Subgroup .......................................115 
Table 192: Overall Summary of Adverse Events .......................................................................116 
Table 193: Adverse Events Occurring in 5% of Participants in Any Treatment Group by 
MedDRA System Organ Class and Preferred Term, and Treatment Group - 
Safety Population ......................................................................................................117 
Table 194: Summary of Adverse Events by MedDRA System Organ Class, High Level 
Group Term, Preferred Term, and Treatment Group ...............................................118 
Table 195: Adverse Events by MedDRA System Organ Class and Preferred Term, 
Maximum Severity, Relationship, and Treatment Group .........................................119 
Table 196: Listing of Non-Serious Moderate or Severe Adverse Events ...................................120 
Table 197: Listing of Serious Adverse Events ...........................................................................121 
Table 198: Listing of Abnormal Laboratory Results - Chemistry ..............................................123 
Table 199: Listing of Abnormal Laboratory Results - Hematology ...........................................124 
Table 200: Listing of Abnormal Laboratory Results - Coagulation ...........................................125 
Table 201: Listing of Abnormal Laboratory Results - Urinalysis ..............................................126 
Table 202: Chemistry Laboratory Toxicity Grade by Parameter, Treatment Group, 
Timepoint, and Severity ............................................................................................127 
Table 203: Chemistry Summary Statistics Measurement and Change from Baseline by 
Parameter, Treatment Group, and Timepoint ...........................................................128 
Table 204: Hematology Laboratory Toxicity Grade by Parameter, Treatment Group, 
Timepoint, and Severity ............................................................................................129 
Table 205: Hematology Summary Statistics Measurement and Change from Baseline by 
Parameter, Treatment Group, and Timepoint ...........................................................129 
Table 206: Coagulation Laboratory Toxicity Grade by Parameter, Treatment Group, 
Timepoint, and Severity ............................................................................................130 
Table 207: Coagulation Summary Statistics Measurement and Change from Baseline by 
Parameter, Treatment Group, and Timepoint ...........................................................130 
Table 208: Urinalysis Laboratory Toxicity Grade by Parameter, Treatment Group, 
Timepoint, and Severity ............................................................................................131 
Table 209: Urinalysis Summary Statistics Measurement and Change from Baseline by 
Parameter, Treatment Group, and Timepoint ...........................................................131 
Table 210: Vital Sign Toxicity Grade by Parameter, Treatment Group, Timepoint, and 
Severity .....................................................................................................................132 


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Table 211: Vital Sign Summary Statistics Measurement and Change from Baseline by 
Parameter, Treatment Group, and Timepoint ...........................................................133 
Table 212: Summary of Post Dose ECG Change in Overall Interpretations from 
Baseline by Treatment Group and Timepoint ..........................................................135 
Table 213: ECG Toxicity Grade by Parameter, Severity, Treatment Group, and 
Timepoint ..................................................................................................................136 
Table 214: ECG Summary Statistics Measurement and Change from Baseline by 
Parameter, Severity, Treatment Group, and Timepoint ............................................137 
Table 215: Number and Percentage of Participants with Prior Medications by WHO 
Drug Classification and Treatment Group ................................................................138 
Table 216: Number and Percentage of Participants with Concomitant Medications by 
WHO Drug Classification and Treatment Group .....................................................139 
 


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9.1 
Overall Study Design and Plan Description 
Table 1: 
Study Design 
Cohort No. 
Study Drug-Dose 
Infusion time - frequency 
Participants 
Cohort 1 
WCK 6777 2 g 
(ERT 1 g + ZID 1 g)  
or placebo 
30 (±5) minutes - once daily-for 7 days 
8 (6 drug combination, 2 placebo) 
Cohort 2 
ERT 2 g  
or placebo 
60 (±10) minutes - once daily-for 7 days 
8 (6 drug, 2 placebo) 
Cohort 3 
ZID 2 g 
60 (±10) minutes - once daily-for 7 days 
6 (all drug) 
Cohort 4 
WCK 6777 4 g 
(ERT 2 g + ZID 2 g) 
 or placebo 
60 (±10) minutes - once daily-for 7 days 
8 (6 drug combination, 2 placebo) 
Cohort 5 
ERT 3 g  
or placebo 
120 (±10) minutes - once daily-for 7 
days 
8 (6 drug, 2 placebo) 
Cohort 6 
ZID 3 g 
120 (±10) minutes - once daily-for 7 
days 
6 (all drug)  
Cohort 7 
WCK 6777 6 g 
(ERT 3 g + ZID 3 g) 
or placebo 
120 (±10) minutes - once daily-for 7 
days 
8 (6 drug combination, 2 placebo) 
 


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Table 2: 
Schedule of Study Procedures 
Evaluation (↓) 
Screening 1 
Check-in/ Enrollment 
In-patient Treatment 
Out-
patient 
follow-up 
Unscheduled /  
Early 
Termination 
Visit (V) 
1 
2 
 
 
 
 
 
 
 
 
3 
 
Study Day (D) 
-28 to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
11 (+3) 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of eligibility criteria 
X 
X 2 
X 2 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Height, Weight and BMI 3  
X 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 2 
 
 
 
 
 
 
 
X 
 
 
MH update 
 
X 2 
X 2 
 
 
 
 
 
 
 
 
 
Prior and Concomitant medications 4 
X 
X 
X 4 
X 4 
X 4 
X 4 
X 4 
X 4 
X 4 
X 4 
X 4 
X 4 
Physical examination (PE) 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
Symptom directed (focused) PE 5  
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Vital signs 6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 7 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
Clinical Laboratory testing (HEM, CHEM, and 
COAG) 8 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Urinalysis 9 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Viral serology 10 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum HCG pregnancy test (all females) and FSH 
(post-menopausal females only) 11 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (all females) 11 
 
X 
 
 
 
 
 
 
 
 
 
 
Urine drug screen 12 
X 
X 
 
 
 
 
 
 
 
 
 
 
Urine alcohol test 
X 
X 
 
 
 
 
 
 
 
 
 
 
Urine cotinine test 
X 
X 
 
 
 
 
 
 
 
 
 
 


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Evaluation (↓) 
Screening 1 
Check-in/ Enrollment 
In-patient Treatment 
Out-
patient 
follow-up 
Unscheduled /  
Early 
Termination 
Admission of eligible participants /Assignment to 
treatment cohort / Randomization 13 
 
X 
 
 
 
 
 
 
 
 
 
 
Study drug administration 14 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Assessment of adverse events 15 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of infusion and blood drawing sites 16 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma PK 17 
 
 
X 17 
X 17 
X 17 
X 17 
X 17 
X 17 
X 17 
X 17 
 
X 18 
Urine PK 19 
 
 
X 19 
 
 
 
 
 
X 19 
 
 
 
Discharge from in-patient site 
 
 
 
 
 
 
 
 
 
X 
 
 
Final visit / Discharge from study 
 
 
 
 
 
 
 
 
 
 
X 
 
Counseling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 Screening evaluations must be completed within 28 days prior to administration of study drug(s). 
2 Confirmation of eligibility for admission and enrollment and randomization on Day -1, and for dosing on Day 1 after completion of all baseline procedures before study intervention  
   Baselines are: Complete PE, weight, Clinical labs and ECG on Day-1; VS (within 30 min before dosing on Day 1), MH and Prior Medications updates, and Focused PE (as needed for new symptoms) predose on Day 1 
3 BMI ≥18-32 kg/m2  and Weight ≥ 100 lbs  (At Screening). Weight also measured on Day 8.   
4 Concomitant medications include any new medications taken only after initiation of first dose on Day 1. 
5 Symptoms directed (focused) PE for evaluation of new symptoms prior to dosing on Day 1, and for evaluation of TEAEs after dosing on Day 1 to the end of the study, or ET  
6 Vital Signs: collected after 5 minutes of resting in supine position and include SBP, DBP, HR and T (oral measurement). Recorded at Screening, Day -1, Days 1 to 7 (within 30 min prior to dosing, at the end of infusion (+10 
min) and 1 hour (±5 min) after the end of infusion), Day 8, and Day 11 (+3), or ET.  
7 Participants 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). 
8 Clinical Laboratory testing for Hematology (HEM: Hemoglobin, hematocrit, RBC, WBC, WBC differential count, platelet count), Clinical Chemistry (CHEM: sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
estimated CLCR (by the Cockcroft-Gault method), calcium, glucose, albumin, total protein, total bilirubin, direct bilirubin, ALT, AST, ALP and LDH) and Coagulation (COAG: PT and AP). – Lab values on Day -1 are considered 
baseline. 
9 Urinalysis: Dipstick urinalysis, including protein, glucose, ketones, bilirubin, occult blood, nitrate, leukocyte esterase, specific gravity, and pH. If dipstick UA is abnormal for blood, protein, glucose and leukocyte esterase, a 
microscopic UA will be done (for WBC, RBC, bacteria, and other cell counts), and results will supersede those of the dipstick UA. Lab values on Day -1 are considered baseline. 
10 Viral serology: HIV antibody, HBsAg, HCV antibody 
11 Serum pregnancy at Screening and Urine pregnancy test on Day-1 from all females; FSH at Screening only from post-menopausal females. 
12 Urine drug screen panel for: amphetamines, barbiturates, benzodiazepines, cocaine metabolites, cannabinoids (THC), opiates, phencyclidine, and tri-cyclic antidepressants – At Screening and Day -1  
13 Assignment to dosing cohort and randomization: Must occur after all inclusion and exclusion criteria have been confirmed on Day -1 and participant was admitted to the in-patient site.  
14 Study drug or placebo administered IV according to cohort and randomization assignment. Withhold solid food at least 4 h before starting the infusion and 1 h after completion of infusion. Oral liquids are allowed.   
15 Monitoring for treatment-emergent AEs and SAEs will begin upon initiation of the first dose of study product(s) and continue until the last visit, or ET. 
16 Assess and replace IV catheters no more frequently than every 72 to 96 h or as clinically indicated. 
17 Plasma PK collection times:   
DAY 1 and DAY 7:  
  For the 30 min infusion (Cohort 1): Predose (within 30 min; t=0) and at 0.25 h (±5 min), 0.5 h (±5 min) (immediately at end of infusion), 1 h (±5 min), 2 h (±5 min), 3 (±10 min), 4 h (±10 min), 8 h (±15 min), 12 h (±15 min), 
18 (±15 min) and 24 h (±30 min) after start of infusion 
For the 60 min infusion (Cohorts 2, 3 and 4): Predose (within 30 min; t=0) and at 0.5 h (±5 min), 1 h (±5 min) (immediately at end of infusion), 2 h (±5 min), 3 h (±10 min), 4 h (±10 min), 8 h (±15 min), 12 h (±15 min), 18 h 
(±15 min) and 24 h (±30 min) after start of infusion 


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Evaluation (↓) 
Screening 1 
Check-in/ Enrollment 
In-patient Treatment 
Out-
patient 
follow-up 
Unscheduled /  
Early 
Termination 
For the 120 min infusion (Cohorts 5, 6 and 7): Predose (within 30 min; t=0) and at 1 h (±5 min), 2 h (±5 min) (immediately end of infusion), 3 h (±10 min), 4 h (±10 min), 8 h (±15 min), 12 h (±15 min), 18 (±15 min) and 24 
(±30 min) after start of infusion 
DAY 2 to DAY 6:  
Predose (within 30 min) and 12 (±5 min) h after start of infusion. 
18 Unscheduled visit – plasma PK collection is optional 
19 Urine PK collection times: 
DAY 1 and DAY 7:  
Before the start of infusion (within 60 min), and at the following intervals after the start of the infusion: 0 to 4 h (±10 min), 4 to 8 h (±15 min), 8 to 12 h (±15 min), and 12 to 24 h (±30 min). 


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12.2.2 Displays of Adverse Events 
Table 3: 
Clinical Vital Signs Adverse Event Toxicity Grading Scale 
Clinical AEs 
Reference range 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
VITAL SIGNS a 
 
 
 
 
Fever -°C 
Fever -°F 
36.1 - 37.2 a 
97.0 - 99.0 a 
37.3 - 38.4 
99.1 - 101.1 
38.5 - 38.9 
101.2 - 102.0 
>38.9 
>102.0 
Tachycardia - bpm 
50 - 100 b,c,d 
 
101 - 115 
 
116 - 130 
>130 or ventricular 
dysrhythmias 
Bradycardia – bpm 
45 - 49 
40 - 44 
<40 
Hypertension (systolic) 
- mmHg 
130/89 
b,c,d 
131 - 150 
151 - 160 
>160 
Hypertension (diastolic) 
- mmHg 
90 - 95 
96 - 100 
>100 
Hypotension (systolic) - 
mmHg 
85 - 88 
80 - 84 
<80 
Tachypnea – breaths 
per min 
10 - 20 b,c,d 
21 - 25 
26 - 30 
>30 
Notes:   aNo recent hot or cold beverages or smoking. A protocol should select either 0C or 0F for inclusion 
bAssume awake and in supine position for 5 min at rest. Abnormal HR and BP on first measurement due to a technical (procedural) error may 
be repeated twice more with the participant resting between measurements for at least 5 min (See Protocol Section 8.1.6).  
cExceptions to screening BP and HR reference range are: 
Participants with baseline HR ≥ 45 to 50 bpm may be accepted if otherwise healthy adults with known history of asymptomatic bradycardia 
Participants with baseline SBP up to 140 mmHg and DBP up to 90 mmHg may be accepted if otherwise healthy.  
dIsolated/individual abnormalities of VS would not be considered toward halting criteria. Abnormalities of VS will be described as “increased 
X” or “decreased X” (X = HR, BP, RR, temperature) if asymptomatic, transient and not associated with a systemic or organ-specific disorder 
and coded by MedDRA within the System Organ Class (SOC) “Investigations.” These abnormalities will be graded per criteria in this table, but 
not considered in determining whether study stopping criteria have been met. On the other hand, abnormalities of VS that are either secondary 
to systemic or organ-specific clinical syndrome or primary disorders will be coded in the appropriate SOC (e.g., “cardiac disorders”, 
“respiratory disorders”, “immunological disorders”, etc.). These abnormalities will be considered in determining whether stopping criteria have 
been met. 
 


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Table 4: 
Clinical Adverse Event Toxicity Grading Scale 
Clinical AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
CARDIOVASCULAR DISORDERS 
Arrhythmia (except Sinus 
tachycardia) 
 
Asymptomatic or transient signs; 
no medical intervention required. 
 
Recurrent and/or persistent signs; 
symptomatic medical intervention 
required. 
Hemorrhage 
Estimated blood loss <100 mL. 
Estimated blood loss >100 mL; no 
transfusion required. 
 
Blood transfusion required. 
RESPIRATORY DISORDERS 
Cough  
Transient cough; no treatment 
required. 
 
Persistent cough; treatment 
required. 
Interferes with daily activities. 
Bronchospasm, Acute 
Transient bronchospasm; no 
treatment required; FEV1 71-80% 
of predicted peak flow. 
Requires treatment; 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 usual and social activities 
OR requires treatment. 
EAR AND LABYRINTH DISORDERS  
Tinnitus 
Mild symptoms: intervention not 
indicated. 
Moderate symptoms; limiting 
instrumental ADL. 
Severe symptoms; limiting self-care 
ADL. 
Vertigo  
Mild symptoms. 
Moderate symptoms; limiting 
instrumental ADL. 
Severe symptoms; limiting self-care 
ADL. 
GASTROINTESTINAL DISORDERS 
Nausea  
No interference with normal 
activity. 
Some interference with normal 
activity. 
Prevents daily activities. 
Vomiting  
No interference with activity OR 
1-2 episodes in a 24-h period. 
Some interference with activity OR 
>2 episodes in a 24-h period. 
Prevents daily activity OR requires 
medical intervention. 
Diarrhea  
2-3 loose OR watery stools in a 
24-h period. 
4-5 loose OR watery stools in a 24-
h period. 
6 or more loose or watery stools in a 
24-h period OR requires IV hydration 
OR requires medical intervention. 
Oral Discomfort / 
Dysphagia 
Mild discomfort; no difficulty 
swallowing. 
Some limits on eating /drinking. 
Eating/talking very limited; unable to 
swallow solid foods. 
NEUROLOGICAL DISORDERS 
Dizziness 
Mild unsteadiness or  
sensation of movement 
Moderate unsteadiness or  
sensation of movement;  
limiting instrumental activities of 
daily life (ADL) 
Severe unsteadiness or  
sensation of movement;  
limiting self-care ADL; medical 
intervention required  
Headache  
Mild pain; No interference with 
activity. 
Moderate pain; repeated use of 
non-narcotic pain reliever for more 
than 24 h OR some interference 
with activity. 
Significant pain; any use of narcotic 
pain reliever OR prevents daily 
activity OR requires triptans. 


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Table 4: Clinical Adverse Event Toxicity Grading Scale (continued) 
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Clinical AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Hypersomnia 
Mild increased need for sleep 
Moderate increased need for  
sleep 
Severe increased need for  
sleep including excessive daytime 
sleepiness 
Seizure 
Brief partial seizure and no  
loss of consciousness 
Brief generalized seizure 
New onset seizures (partial or  
generalized); multiple seizures  
despite medical intervention 
Somnolence 
Mild but more than usual  
drowsiness or sleepiness 
Moderate sedation; limiting  
instrumental ADL 
Obtundation or stupor 
Syncope 
- 
- 
Fainting; orthostatic collapse 
Tremor 
Mild symptoms 
Moderate symptoms; limiting 
instrumental ADL 
Severe symptoms; limiting self-care  
Other 
Asymptomatic or mild  
symptoms; clinical or  
diagnostic observations only;  
intervention not indicated 
Moderate; minimal, local or  
noninvasive intervention  
indicated, limiting age-appropriate 
instrumental ADL 
Severe or medically significant  
but not immediately life threatening; 
hospitalization or prolongation of 
existing  
hospitalization indicated;  
limiting self-care  
PSYCHIATRIC DISORDERS 
Altered Mental Status: Includes agitation, confusion, disorientation, decreased mental acuity, changed mental status, somnolence, stupor 
Agitation  
Mild mood alteration  
Moderate mood alteration  
Severe agitation; hospitalization 
not indicated  
Confusion  
Mild disorientation  
Moderate disorientation; 
limiting instrumental ADL  
Severe disorientation; limiting 
self-care   
Insomnia  
Mild difficulty falling asleep, 
staying asleep or waking up 
early  
Moderate difficulty falling 
asleep, staying asleep or waking 
up early  
Severe difficulty in falling asleep, 
staying asleep or waking up early; 
medical intervention required  
Psychiatric disorders - 
Other, specify  
Asymptomatic or mild 
symptoms; clinical or 
diagnostic observations only; 
intervention not indicated  
Moderate; minimal, local or 
noninvasive intervention 
indicated; limiting age-
appropriate instrumental ADL  
Severe or medically significant 
but not immediately life-
threatening; limiting self-care; 
psychiatric intervention required  
LOCAL IV CATHETER REACTION 
IV site reaction 
Not applicable. 
Erythema with associated 
symptoms (e.g., edema, pain, 
induration, phlebitis). 
Ulceration or necrosis; severe tissue 
damage; operative intervention 
indicated. 


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Table 4: Clinical Adverse Event Toxicity Grading Scale (continued) 
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Clinical AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
SYSTEMIC REACTIONS 
Anaphylaxis ** 
-- 
-- 
Symptomatic bronchospasm, with or 
without urticaria; parenteral 
intervention indicated; allergy-related 
edema or angioedema; 
hypotension. 
**Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of histamine and histamine-like substances 
from mast cells, causing a hypersensitivity immune response. Clinically, it presents with breathing difficulty, dizziness, hypotension, cyanosis, 
and loss of consciousness, and may lead to death. 
Allergic Reaction  
Pruritus without rash. 
Localized urticaria OR requires 
oral therapy. 
Generalized urticaria OR angioedema 
OR anaphylaxis OR requires 
epinephrine 
Hypersensitivity 
(including drug fever) 
Transient flushing or rash; 
temperature 38.0 – 38.4°C (100.4 
– 101.1°F). 
Rash; flushing; urticaria; dyspnea; 
temperature 38.5 – 38.9°C (101.2 – 
102.0°F). 
Symptomatic bronchospasm with or 
without urticaria; parenteral 
medication indicated; 
allergy-related edema or angioedema; 
hypotension; temperature >38.9°C 
(>102.0°F).  
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. 
SKIN 
Mucocutaneous 
Erythema, pruritus. 
Diffuse, maculo-papular rash, dry 
desquamation. 
Vesiculation OR moist desquamation 
OR ulceration. 
Pruritus 
No or minimal interference with 
usual social and functional 
activities.  
Greater than minimal interference 
with usual social and functional 
activities.  
Inability to perform usual social and 
functional daily activities. 
ALL OTHER CONDITIONS 
Illness or clinical AE (as 
defined according to 
applicable regulations) 
Require minimal or no treatment; 
does not interfere with the 
participant’s daily activities. 
 
Result in a low level of 
inconvenience or concern with 
therapeutic measures; may cause 
some interference with functioning. 
Interrupt a participants’s usual daily 
activity and may require systemic 
drug therapy or other treatment; are 
usually incapacitating. 
 


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12.4.1 Individual Laboratory Measurements and Abnormal Laboratory Values 
Table 5: 
Clinical Laboratory Reference Ranges and Toxicity Grading Scale 
Laboratory AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Blood, serum, or plasma * 
HEMATOLOGY 
Hemoglobin decrease,  
Female, 18Y – g/dL 
9.5 – 11.4 
7.9 – 9.4 
<7.9 
Hemoglobin decrease,  
Female, >18Y – g/dL 
9.7 – 11.6 
8.1 – 9.6 
<8.1 
Hemoglobin decrease,  
Male, 18Y – g/dL 
10.0 – 11.9 
8.0 – 9.9 
<8.0 
Hemoglobin decrease,  
Male, >18Y – g/dL 
11.2 – 13.1 
9.2 – 11.1 
<9.2 
WBC increase  
18Y – x103/ µL 
13.1 – 15.0 
15.1 – 20.0 
>20.0 
WBC increase  
>18Y – x103/ µL 
10.9 – 15.0 
15.1 – 20.0 
>20.0 
WBC decrease 
18Y – x103/ µL 
3.0 – 4.4 
1.5 – 2.9 
<1.5 
WBC decrease 
>18Y – x103/ µL  
2.3 – 3.7 
1.1 – 2.2 
<1.1 
Neutrophils decrease  
18Y – cells/ µL 
1,200 – 1,799 
750 – 1,199 
<750  
Neutrophils decrease  
>18Y – cells/ µL 
1,000 – 1,499 
750 – 999 
<750  
Lymphocytes decrease  
18Y– cells/ µL 
850 – 1,199 
400 – 849 
<400 
Lymphocytes decrease  
>18Y – cells/ µL 
500 - 849 
300 - 499 
<300 
Monocytes increase –  
18Y – cells/ µL 
901 – 2,000 
2,001 – 3,000 
>3,000 
Monocytes increase  
>18Y – cells/ µL 
951 – 2,000 
2,001 – 3,000 
>3,000 
Eosinophils increase  
>6Y– cells/ µL 
501 – 750 
751 – 1,000 
>1,000 
Basophils increase  
>6Y– cells/ µL 
201 – 500 
501 – 800 
>800 
Platelets decrease – x103/ µL 
90 – <140 
55 – <90 
<55 
COAGULATION 
PT INR 
>1.1 – 1.8 
>1.8 – 2.1 
>2.1 


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Table 5: Clinical Laboratory Reference Ranges and Toxicity Grading Scale (continued) 
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Laboratory AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Prothrombin Time - sec 
>11.5 – 15.0 
>15.0 – 18.6 
>18.6 
Activated Partial Thromboplastin Time (APTT) - sec 
>32 – 54 
>54 – 75 
>75 
CHEMISTRY 
Sodium decrease – mmol/L 
130 - 134 
124 –129 
<124 
Sodium increase – mmol/L 
147 - 150 
 151 – 156 
>156 
Potassium increase, 
19Y - mmol;/L 
5.2 – 6.0 
6.1 – 6.5 
>6.5 
Potassium increase,  
>19Y - mmol/L 
5.4 – 6.0 
6.1 – 6.5 
>6.5 
Potassium decrease,  
19Y – mmol/L 
3.2 – 3.7 
2.6 – 3.1 
<2.6 
Potassium decrease,   
>19Y - mmol/L 
3.0 – 3.4  
2.5 – 2.9 
<2.5 
Carbon dioxide increase – mmol/L 
33 – 36 
37 – 40 
>40 
Carbon dioxide decrease – mmol/L 
17 – 19 
14 – 16 
<14 
Calcium increase,  
Male,  4 -19Y – mg/dL   
10.5 – 11.2 
11.3 – 12.3 
>12.3 
Calcium increase,  
Male, 20 - 49Y – mg/dL 
10.4 – 11.4 
11.5 – 12.5 
>12.5 
Calcium increase,  
Female, 4 -19Y – mg/dL 
10.5 – 11.4 
11.5 – 12.5 
>12.5 
Calcium increase,  
Female 20 - 49Y – mg/dL 
10.3 – 11.4 
11.5 – 12.5 
>12.5 
Calcium decrease,  
Male, 4 -19Y – mg/dL 
8.1 – 8.8 
7.3 – 8.0 
<7.3 
Calcium decrease,  
Male, 20 - 49Y – mg/dL 
8.1 – 8.5 
7.3 – 8.0 
<7.3 
Calcium decrease,  
Female, 4 -19Y – mg/dL 
8.1 – 8.8 
7.3 – 8.0 
<7.3 
Calcium decrease, 
Female, 20-49Y – mg/dL 
8.1 – 8.5 
7.3 – 8.0 
<7.3 
Blood urea nitrogen (BUN) increase,  
19Y - mg/dL 
21 – 58 
59 – 120 
>120 
Blood urea nitrogen (BUN) increase, 
>19Y- mg/dL  
26 – 58 
59 – 120 
>120 
Glucose decrease, fasting – mg/dL 
47 – 64 
40 – 46 
<40 
Glucose increase, fasting – mg/dL 
100 – 160 
161 – 250 
>250 
Glucose increase, non-fasting – mg/dL 
140 – 200 
201 – 250 
>250 


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Table 5: Clinical Laboratory Reference Ranges and Toxicity Grading Scale (continued) 
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Laboratory AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Creatinine increase,  
Male, 18 - 29Y – mg/dL 
1.25 – 1.62 
1.63 – 2.24 
>2.24 
Creatinine increase,  
Male, 30 – 39 Y – mg/dL 
1.27 – 1.64 
1.65 – 2.27 
>2.27 
Creatinine increase,  
Male, 40 - 49Y – mg/dL 
1.30 – 1.68 
1.69 – 2.32 
>2.32 
Creatinine increase,  
Female, 18 - 29Y – mg/dL 
0.97 – 1.25  
1.26 – 1.73 
>1.73 
Creatinine increase,  
Female, 30 - 39Y – mg/dL 
0.98 – 1.26 
1.27 – 1.75 
>1.75 
Creatinine increase,  
Female, 40 - 49Y – mg/dL 
1.00 – 1.29 
1.30 – 1.78 
>1.78 
Direct bilirubin 
0.3 – 0.6 
0.7 – 1.2 
>1.2 
Total bilirubin (serum) increase 
(with other LFTs in the normal range), 19Y – mg/dL 
1.2 – 1.7 
1.8 – 2.5 
>2.5 
Total bilirubin (serum) increase  
(with other LFTs in the normal range), >19Y – mg/dL 
1.3 – 1.8 
1.9 – 2.6 
>2.6 
Total bilirubin (serum) increase (accompanied by a >3 x ULN 
increase in ALT or AST), 19Y – mg/dL 
1.2 – 2.0 
2.1 – 2.8 
>2.8 
Total bilirubin (serum) increase  
(accompanied by a >3 x ULN increase in ALT or AST), >19Y – 
mg/dL 
1.3 – 2.1 
2.2 – 3.0 
>3.0 
Total protein decrease, 
19Y – g/dL 
5.3 – 6.2 
4.5 – 5.2 
<4.5 
Total protein decrease, 
>19Y – g/dL 
5.1 – 6.0 
4.3 – 5.0 
<4.3 
Albumin, decrease - g/dL 
3.0 – 3.5 
2.0– 2.9 
<2.0 
AST increase,  
19Y – U/L 
33 – 64 
65 – 96 
>96 
AST increase,  
20-49Y – U/L 
41 – 80 
81 – 120 
>120 
ALT increase,   
Male, 19Y – U/L 
47 – 92 
93 – 138 
>138 
ALT increase,   
Male, >19Y – U/L 
47 – 92 
93 – 138 
>138 
ALT increase,   
Female, 19Y – U/L 
33 – 64 
65 – 96 
>96 
ALT increase,   
Female, >19Y – U/L 
30 – 58 
59 – 87 
>87 


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Table 5: Clinical Laboratory Reference Ranges and Toxicity Grading Scale (continued) 
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Laboratory AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Alkaline phosphatase (AP) increase, 
Male, 19Y – U/L 
170 – 338 
339 – 507 
>507 
Alkaline phosphatase (AP) increase,  
Male, ≤49Y – U/L 
131 – 260 
261 – 345 
>345 
Alkaline phosphatase (AP) increase,   
Female, 19Y – U/L 
129 – 256 
257 – 384 
>384 
Alkaline phosphatase (AP) increase,   
Female, ≤49Y – U/L 
126 – 250 
251 – 375 
>375 
Urine  
URINALYSIS by Dipstick 
Protein 
1+ 
2+ 
>2+ 
Blood (occult) 
1+ 
2+ 
>2+ 
Glucose 
1+ 
2+ 
>2+ 
Leukocyte esterase 
1+ 
2+ 
>2+ 
URINE MICROSCOPY 
Red blood cells (RBC) per HPF 
3 – 10 
11 – 40 
>40 and/or gross blood 
WBC (microscopic) – WBC per HPF 
6 – 10 
11 – 40 
>40 and/or symptomatic 
urogenital infection 
Bacteria (microscopic) 
few 
moderate 
Many 
Note 1: With the exception of AST, ALT, AP, total and direct  bilirubin, BUN, creatinine, CLCR (by the Cockcroft-Gault method), and urine 
protein, which should be within reference range, lab values of other analytes in the grade 1 range are acceptable for enrollment if (a) they are 
not considered to be clinically significant by the investigator and (b) there is no cluster of abnormal labs that combined are suggestive of an 
underlying disorder. 
Note 2: Other Exceptions to screening laboratory tests’ normal reference ranges are: 
a. 
Racially based low total WBC or neutrophil counts up to toxicity Grade 1 are allowed, but toxicity Grades 2 or 3 are exclusionary. 
b. 
Labs performed as part of a panel but not listed above are to be recorded in the database. If abnormal, they are not exclusionary and are 
not to be graded per Toxicity table, however, the investigator would make a clinical decision about their clinical significance and, if clinically 
significant, they will be graded according to the criteria in Protocol Section 9.2.1. (Examples include mean corpuscular volume (MCV), mean 
corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW), mean platelet 
volume (MPV), and nucleated red blood cell count (NRBC CT), which are included in a CBC with differential.)  
Note 3: If a subject was accepted into the trial with a laboratory value of an analyte that overlaps with values used for grading Grade 1 
laboratory abnormalities, a TEAE will be reported if the on-study value of the same analyte increases in severity to Grade 2 or higher compared 
to the baseline. 
Note 4: If the dipstick UA is abnormal for blood, protein, glucose and leukocyte esterase, a microscopic UA will be performed, and the results 
will supersede the results of the dipstick UA. 
Note 5: Menstruating females with a positive dipstick UA or microscopic UA may be retested following cessation of menses. Gross blood in 
urine that is confirmed due to menses is not a TEAE (but is for all other reasons. 
Note 6: Isolated laboratory values that are outside the range of eligibility but are thought to be due to an acute condition or due to collection or 
laboratory error may be repeated once. 
Note 7: For the microscopic UA, Lab-reported ranges 3 -10 for RBC and 6-10 for WBC would be Grade 1; 10-20 and 20-40 for both RBC and 
WBC would be Grade 2; and > 40 for both RBC and WBC would be Grade 3. 


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Table 6: 
ECG Toxicity Grading Scale 
ECG interval 
abnormality 
Reference 
range 
Grade 1 
Grade 2 
Grade 3 
QTcF interval 
prolonged (msec): 
• 
Male 
• 
Female 
• 
≤450 msec 
• 
≤470 msec 
Asymptomatic, 
QTcF 
• 
451 - 479 msec 
• 
471 - 479 msec 
Asymptomatic, QTcF 
480-500 msec OR 
increase in interval 30-59 
msec above baseline 
Asymptomatic, 
QTcF >500 msec  
OR 
increase in interval 
≥60 msec above baseline 
PR interval 
prolonged (msec) 
≤ 210 msec 
211-250 msec 
>250 msec 
Type II 2nd degree AV block 
OR 
ventricular pause >3.0 sec 
Note 1: Events will be coded as treatment-emergent SAEs if there are life-threatening associated symptoms or signs (arrhythmia, CHF, 
hypotension, syncope, TdP, etc.). 
Note 2: If a male participant was accepted into the trial with a QTcF value that overlaps with values used for grading Grade 1 QTcF prolongation, 
a TEAE will be reported if the QTcF value is higher than the baseline value. 


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10.2 
Protocol Deviations 
Table 7: 
Distribution of Protocol Deviations by Category, Type, and Treatment Group 
Category 
Deviation Type 
Number of Participants (Number of Deviations) 
WCK 6777 2g 
(N=X) 
ERT 2g 
(N=X) 
ZID 2g 
(N=X) 
WCK 
6777 4g 
(N=X) 
ERT 3g 
(N=X) 
ZID 3g 
(N=X) 
WCK 
6777 6g 
(N=X) 
Placebo 
(N=X) 
All 
Participants 
(N=X) 
Eligibility/enrollment 
Any type 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Did not meet inclusion criterion 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Met exclusion criterion 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
ICF not signed prior to study procedures 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Other 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Treatment administration 
schedule 
Any type 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Out of window visit 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Missed visit/visit not conducted 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Missed treatment administration 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Delayed treatment administration 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Other 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Follow-up visit schedule 
Any type 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Out of window visit 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Missed visit/visit not conducted 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Other 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Protocol procedure/assessment 
Any type 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x 
Incorrect version of ICF signed 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Blood not collected 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Urine not collected 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Other specimen not collected 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 


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Table 7: Distribution of Protocol Deviations by Category, Type, and Treatment Group (continued) 
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Category 
Deviation Type 
Number of Participants (Number of Deviations) 
WCK 6777 2g 
(N=X) 
ERT 2g 
(N=X) 
ZID 2g 
(N=X) 
WCK 
6777 4g 
(N=X) 
ERT 3g 
(N=X) 
ZID 3g 
(N=X) 
WCK 
6777 6g 
(N=X) 
Placebo 
(N=X) 
All 
Participants 
(N=X) 
Too few aliquots obtained 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Specimen result not obtained 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Required procedure not conducted 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Required procedure done incorrectly 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Study product temperature excursion 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Specimen temperature excursion 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Other 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Treatment administration 
Any type 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Required procedure done incorrectly 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Study product temperature excursion 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Other 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Blinding policy/procedure 
Any type 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Treatment unblinded 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Other 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Note: N= Number of participants randomized. 
 
 


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14.1 
Description of Study Participants 
14.1.1 Disposition of Participants 
Table 8: 
Participant Disposition by Treatment Group 
Participant Disposition 
WCK 
6777 2g 
(N=X) 
ERT 2g 
(N=X) 
ZID 2g 
(N=X) 
WCK 
6777 4g 
(N=X) 
ERT 3g 
(N=X) 
ZID 3g 
(N=X) 
WCK 
6777 6g 
(N=X) 
Placebo 
(N=X) 
All 
Participants 
(N=X) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Screened 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
x 
Enrolled/Randomized 
x (100) 
x (100) 
x (100) 
x (100) 
x (100) 
x (100) 
x (100) 
x (100) 
x (100) 
Included in the Safety Population 
(Received at least One Dose of 
Study Product) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Received All Planned Doses of 
Study Product 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Included in the PK Analysis 
Population 
(Had at least One Quantifiable 
Post-Dosing Plasma Drug 
Concentration Measured) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Included in the PK Analysis 
Subset 
(Had at least one estimable PK 
parameter) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Completed all PK Blood Draws 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Completed all PK Urine Samples 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Completed Final Study Visit 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Early Termination 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Note: N= Number of participants randomized. 
 
 
 
 


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Table 9: 
Analysis Population Exclusions by Treatment Group 
Analysis Populations 
Reason Participants Excluded 
WCK 
6777 2g 
(N=X) 
ERT 2g 
(N=X) 
ZID 2g 
(N=X) 
WCK 
6777 4g 
(N=X) 
ERT 3g 
(N=X) 
ZID 3g 
(N=X) 
WCK 
6777 6g 
(N=X) 
Placebo 
(N=X) 
All 
Participants 
(N=X) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Safety Population 
No study product received 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
PK Analysis Population 
Any Reason 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Participant received placebo  
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Did not receive at least one dose of study drug 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Participant has no measurable concentration of drug in 
plasma at any timepoint 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
PK Analysis Subset 
Any Reason 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Exclusion from PK Analysis Population 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
No estimable PK parameters 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
PK Analysis Subset 
Subgroup 
Any Reason 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Excluded from PK Analysis Subset 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Missing at least one planned PK sample on both Day 1 and 
Day 7 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Note: N= Number of participants randomized. 
 


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Table 10: 
Ineligibility Summary of Screen Failures 
Inclusion/Exclusion Category 
Inclusion/Exclusion Criterion 
na 
%b 
Total number of screen failures 
 
x 
100 
Eligible but not Enrolled 
Any reason 
x 
xx 
 
[Reason 1] 
x 
xx 
 
[Reason 2] 
x 
xx 
Inclusion and Exclusion 
Number of participants failing any eligibility criterion 
x 
xx 
Inclusion 
Any inclusion criterion 
x 
xx 
 
Provide a signed and dated written informed consent and agrees to 
comply with the study procedures and length of confinement to the 
research site. 
x 
xx 
 
Be able to understand and willing to comply with study 
procedures, restrictions, and requirements, as determined by the 
Site Principal Investigator (PI) or authorized clinician(s) (listed 
on FDA Form 1572). 
x 
xx 
 
Adults 18 to 45 years of age inclusive, including non-pregnant, non-
lactating females. 
x 
xx 
 
Have suitable veins for cannulation or repeated venipuncture. 
x 
xx 
 
Be in good general health at the time of enrollment. 
x 
xx 
 
Sexually active females must be of non-childbearing potential or 
must use a highly effective method of birth control from 
screening to 30 days following the last dose of study product. 
x 
xx 
 
Sexually active males must be vasectomized or agree to use barrier 
contraception and not donate sperm from first dose of study product 
until 30 days following the last dose. 
x 
xx 
 
Participants must be willing to avoid excessive physical exercise 
within 48 h prior to dosing until discharge from the CTU on Day 8, 
and 24 h before the last visit (Day 11 +3 days). 
x 
xx 
 
No history of acute febrile or infectious illness for at 
least 7 days prior to the administration of study drug(s). 
x 
xx 
Exclusion 
Any exclusion criterion 
x 
xx 


Statistical Analysis Plan - DMID Protocol: 21-0013  
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Table 10: 
Ineligibility Summary of Screen Failures (continued) 
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Inclusion/Exclusion Category 
Inclusion/Exclusion Criterion 
na 
%b 
Total number of screen failures 
 
x 
100 
 
Known history of a clinically significant food or drug 
allergy/hypersensitivity including known allergy/hypersensitivity to 
ERT, any β-lactam drugs or other related drugs. 
x 
xx 
 
Current seasonal allergies with ongoing symptoms for more than a 
week prior to dosing requiring glucocorticoids and/or frequent use of 
antihistamines for treatment. 
x 
xx 
 
Any history of a chronic condition including renal failure that 
may increase risk to participant or interfere with endpoint 
assessment, or any unstable chronic disease. 
x 
xx 
 
History of any psychiatric condition that has required 
hospitalization in the last 12 months or participant is 
considered psychologically unstable by the investigator. 
 
 
 
History of any clinically significant (CS) disease or disorder, 
medical/surgical procedure, or trauma within 4 weeks prior to 
initiation of administration of study product(s). 
 
 
 
History of Clostridium difficile induced diarrhea within 1 year 
before screening 
 
 
 
Known history of past or current epilepsy or seizure disorders, 
excluding febrile seizures of childhood. 
 
 
 
Prior exposure to Zidebactam. 
 
 
 
Use of any prohibited prescription or non-prescription medication 
within 14 days prior to the first dose of study drug(s) as described in 
Protocol Section 6.6. 
 
 
 
Use of any investigational drug product within 30 days or 5 
half-lives (whichever is longer) before investigational product 
administration in this study. 
 
 
 
Planned participation in a clinical research study that requires 
treatment with a study drug, blood draws or other invasive 
assessments during the study period (screening until final visit). 
 
 


Statistical Analysis Plan - DMID Protocol: 21-0013  
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Table 10: 
Ineligibility Summary of Screen Failures (continued) 
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Inclusion/Exclusion Category 
Inclusion/Exclusion Criterion 
na 
%b 
Total number of screen failures 
 
x 
100 
 
Blood or plasma donation of 500 mL within 3 months or more 
than 100 mL within 30 days before signing informed consent or 
planned donation prior to completion of this trial. 
 
 
 
Positive serum pregnancy test for women at screening and urine 
pregnancy test at check- in. 
 
 
 
Positive urine alcohol test or urine drug screen test at screening or check-in 
(Day -1). 
 
 
 
Positive test for HIV antibodies, hepatitis B-virus surface 
antigen (HBsAg), or anti-hepatitis C-virus antibodies 
(anti-HCV) at screening. 
 
 
 
History of ≥10 pack-years smoking in the 5-year period before 
screening, or positive urine cotinine screen at check-in. 
 
 
 
History of binge drinking or heavy drinking of alcohol at any time in 
the 6 months before study product administration. 
 
 
a More than one criterion may be marked per participant. 
b Denominator for percentages is the total number of screen failures. 
 
 


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14.1.2 Demographic Data by Study Group 
Table 11: 
Summary of Categorical Demographic and Baseline Characteristics by Treatment Group 
Variable 
Characteristic 
WCK 6777 
2g 
(N=X) 
ERT 2g 
(N=X) 
ZID 2g 
(N=X) 
WCK 6777 
4g 
(N=X) 
ERT 3g 
(N=X) 
ZID 3g 
(N=X) 
WCK 6777 
6g 
(N=X) 
Placebo 
(N=X) 
All 
Participants 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Sex  
Male 
x 
xx 
x 
xx 
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 
x 
xx 
x 
xx 
Hispanic or Latino 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Not Reported 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unknowns 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Race  
American Indian or Alaska Native 
x 
xx 
x 
xx 
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 participants in the Safety Population 
 


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Table 12: 
Summary of Continuous Demographic and Baseline Characteristics by Treatment Group 
Variable 
Statistic 
WCK 6777 2g 
(N=X) 
ERT 2g 
(N=X) 
ZID 2g 
(N=X) 
WCK 6777 4g 
(N=X) 
ERT 3g 
(N=X) 
ZID 3g 
(N=X) 
WCK 6777 6g 
(N=X) 
Placebo 
(N=X) 
All 
Participants 
(N=X) 
Age (years) 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Standard 
Deviation 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Minimum 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Maximum 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Height (cm) 
Mean 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Standard 
Deviation 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Weight (kg) 
Mean 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Standard 
Deviation 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
BMI (kg/m2) 
Mean 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Standard 
Deviation 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Note: N=Number of participants in the Safety Population 
 


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14.1.3 Prior and Concurrent Medical Conditions 
Table 13: 
Summary of Participants with Pre-Existing Medical Conditions by MedDRA System Organ Class and Treatment Group 
MedDRA System 
Organ Class 
WCK 6777 2g 
(N=X) 
ERT 2g 
(N=X) 
ZID 2g 
(N=X) 
WCK 6777 4g 
(N=X) 
ERT 3g 
(N=X) 
ZID 3g 
(N=X) 
WCK 6777 6g 
(N=X) 
Placebo 
(N=X) 
All 
Participants 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any SOC 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[SOC 2] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: N=Number of participants in the Safety Population; n = Number of participants reporting medical history within the specified SOC. A participant is only counted once per SOC. 
 
 


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14.2 
Tolerability Data 
Table 14: 
Tolerability by Treatment Group 
Participants who: 
WCK 6777 
2g 
(N=X) 
ERT 2g 
(N=X) 
ZID 2g 
(N=X) 
WCK 6777 
4g 
(N=X) 
ERT 3g 
(N=X) 
ZID 3g 
(N=X) 
WCK 6777 
6g 
(N=X) 
Placebo 
(N=X) 
All 
Participants 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Discontinued study drug due to an AE 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chose to withdraw from the study due  to an AE 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Were withdrawn from the study by the 
investigator due to an AE 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Note: N=Number of participants in the Safety Population; n=number of participants meeting each tolerability category criteria. 


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14.3 
Pharmacokinetic Data 
Table 15: 
ERT Concentrations in Plasma by Treatment Group – Dose 1 
  
Nominal Timea (h) 
Treatment 
Group 
0 
0.25 
0.5 
1 
2 
3 
4 
8 
12 
18 
24 
Total ERT 
WCK 6777 2g 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
ERT 2g 
x (x) 
- 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
WCK 6777 4g 
x (x) 
- 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
ERT 3g 
x (x) 
- 
- 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
WCK 6777 6g 
x (x) 
- 
- 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Free ERT 
… 
 
 
 
 
 
 
 
 
 
 
 
Notes: Concentrations are reported in units of µg/mL. Timepoints where data was not collected are denoted by “-“. Timepoints where data was not estimable are denoted by “NE”. 
Values of GM (CV %) are shown. 
a Times are relative to time of dosing. Time 0 concentrations are drawn within 30 minutes prior to dosing. 
 


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Table 16: 
ERT Concentrations in Plasma by Treatment Group – Doses 2-6 
  
Nominal Timea (h) 
 
Dose 2 
Dose 3 
Dose 4 
Dose 5 
Dose 6 
Treatment 
Group 
0 
12 
0 
12 
0 
12 
0 
12 
0 
12 
Total ERT 
WCK 6777 2g 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
ERT 2g 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
WCK 6777 4g 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
ERT 3g 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
WCK 6777 6g 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Free ERT 
… 
 
 
 
 
 
 
 
 
 
 
Notes: Concentrations are reported in units of µg/mL. Timepoints where data was not estimable are denoted by “NE”. 
Values of GM (CV %) are shown. 
a Times are relative to time of dosing. Time 0 concentrations are drawn within 30 minutes prior to dosing on the given day. 
Tables with similar format: 
Table 17: 
ERT Concentrations in Plasma by Treatment Group – Dose 7 
[Repeat Table 15 for Dose 7]


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Table 18: 
Summary Statistics for Total ERT Concentrations in Plasma – WCK 6777 2g, Dose 1 
  
Nominal Timea (h) 
Participant ID 
0 
0.25 
0.5 
1 
2 
3 
4 
8 
12 
18 
24 
99ZZZ001 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
99ZZZ002 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
99ZZZ003 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
… 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Statistics 
 
 
 
 
 
 
 
 
 
 
 
Nb 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mean 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SD 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CV% 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GM 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Median 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(Min, Max) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Notes: Timepoints where data was not estimable are denoted by “NE“. 
a Times are relative to time of first dosing. Time 0 concentrations are drawn within 30 minutes prior to dosing. 
b Number of data points used to compute the summary statistics. BQL values were imputed as 0 if they did not come after a PK sample concentration that is above the LLOQ and treated as missing 
otherwise. 


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Table 19: 
Summary Statistics for Total ERT Concentrations in Plasma – WCK 6777 2g, Doses 2-6 
  
Nominal Timea (h) 
 
Dose 2 
Dose 3 
Dose 4 
Dose 5 
Dose 6 
Participant ID 
0 
12 
0 
12 
0 
12 
0 
12 
0 
12 
99ZZZ001 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
99ZZZ002 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
99ZZZ003 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
… 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Statistics 
 
 
 
 
 
 
 
 
 
 
Nb 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mean 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SD 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CV% 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GM 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Median 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(Min, Max) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Notes: Concentrations are reported in units of µg/mL. Timepoints where data was not estimable are denoted by “NE“. 
a Times are relative to time of dosing. Time 0 concentrations are drawn within 30 minutes prior to dosing on the given day. 
b Number of data points used to compute the summary statistics. BQL values were imputed as 0 if they did not come after a PK sample concentration that is above the LLOQ and treated as missing 
otherwise. 


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Tables with similar format: 
Table 20: 
Summary Statistics for Total ERT Concentrations in Plasma – WCK 6777 2g, Dose 7 
Table 21: 
Summary Statistics for Total ERT Concentrations in Plasma – ERT 2g, Dose 1 
Table 22: 
Summary Statistics for Total ERT Concentrations in Plasma – ERT 2g, Doses 2-6 
Table 23: 
Summary Statistics for Total ERT Concentrations in Plasma – ERT 2g, Dose 7 
Table 24: 
Summary Statistics for Total ERT Concentrations in Plasma – WCK 6777 4g, Dose 1 
Table 25: 
Summary Statistics for Total ERT Concentrations in Plasma – WCK 6777 4g, Doses 2-6 
Table 26: 
Summary Statistics for Total ERT Concentrations in Plasma – WCK 6777 4g, Dose 7 
Table 27: 
Summary Statistics for Total ERT Concentrations in Plasma – ERT 3g, Dose 1 
Table 28: 
Summary Statistics for Total ERT Concentrations in Plasma – ERT 3g, Doses 2-6 
Table 29: 
Summary Statistics for Total ERT Concentrations in Plasma – ERT 3g, Dose 7 
Table 30: 
Summary Statistics for Total ERT Concentrations in Plasma – WCK 6777 6g, Dose 1 
Table 31: 
Summary Statistics for Total ERT Concentrations in Plasma – WCK 6777 6g, Doses 2-6 
Table 32: 
Summary Statistics for Total ERT Concentrations in Plasma – WCK 6777 6g, Dose 7 
 


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Table 33: 
Summary Statistics for Free ERT Concentrations in Plasma – WCK 6777 2g, Dose 1 
Table 34: 
Summary Statistics for Free ERT Concentrations in Plasma – WCK 6777 2g, Doses 2-6 
Table 35: 
Summary Statistics for Free ERT Concentrations in Plasma – WCK 6777 2g, Dose 7 
Table 36: 
Summary Statistics for Free ERT Concentrations in Plasma – ERT 2g, Dose 1 
Table 37: 
Summary Statistics for Free ERT Concentrations in Plasma – ERT 2g, Doses 2-6 
Table 38: 
Summary Statistics for Free ERT Concentrations in Plasma – ERT 2g, Dose 7 
Table 39: 
Summary Statistics for Free ERT Concentrations in Plasma – WCK 6777 4g, Dose 1 
Table 40: 
Summary Statistics for Free ERT Concentrations in Plasma – WCK 6777 4g, Doses 2-6 
Table 41: 
Summary Statistics for Free ERT Concentrations in Plasma – WCK 6777 4g, Dose 7 
Table 42: 
Summary Statistics for Free ERT Concentrations in Plasma – ERT 3g, Dose 1 
Table 43: 
Summary Statistics for Free ERT Concentrations in Plasma – ERT 3g, Doses 2-6 
Table 44: 
Summary Statistics for Free ERT Concentrations in Plasma – ERT 3g, Dose 7 
Table 45: 
Summary Statistics for Free ERT Concentrations in Plasma – WCK 6777 6g, Dose 1 
Table 46: 
Summary Statistics for Free ERT Concentrations in Plasma – WCK 6777 6g, Doses 2-6 
Table 47: 
Summary Statistics for Free ERT Concentrations in Plasma – WCK 6777 6g, Dose 7 
 


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Table 48: 
ZID Concentrations in Plasma by Treatment Group – Dose 1 
  
Nominal Timea (h) 
Treatment Group 
0 
0.25 
0.5 
1 
2 
3 
4 
8 
12 
18 
24 
Total ZID 
WCK 6777 2g 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
ZID 2g 
x (x) 
- 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
WCK 6777 4g 
x (x) 
- 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
ZID 3g 
x (x) 
- 
- 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
WCK 6777 6g 
x (x) 
- 
- 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Free ZID 
… 
 
 
 
 
 
 
 
 
 
 
 
Notes: Concentrations are reported in units of µg/mL. Timepoints where data was not collected are denoted by “-“. Timepoints where data was not estimable are denoted by “NE”. 
Values of GM (CV %) are shown. 
a Times are relative to time of dosing. Time 0 concentrations are drawn within 30 minutes prior to dosing. 
Tables with similar format: 
Table 49: 
ZID Concentrations in Plasma by Treatment Group – Doses 2-6 
[This Table will be similar to Table 16 for total ERT.] 
Table 50: 
ZID Concentrations in Plasma by Treatment Group – Dose 7   
 [This Table will be similar to Table 17 for total ERT.] 
 


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Tables with similar format to Table 18/19: 
Table 51: 
Summary Statistics for Total ZID Concentrations in Plasma – WCK 6777 2g, Dose 1 
Table 52: 
Summary Statistics for Total ZID Concentrations in Plasma – WCK 6777 2g, Doses 2-6 
Table 53: 
Summary Statistics for Total ZID Concentrations in Plasma – WCK 6777 2g, Dose 7 
Table 54: 
Summary Statistics for Total ZID Concentrations in Plasma – ZID 2g, Dose 1 
Table 55: 
Summary Statistics for Total ZID Concentrations in Plasma – ZID 2g, Doses 2-6 
Table 56: 
Summary Statistics for Total ZID Concentrations in Plasma – ZID 2g, Dose 7 
Table 57: 
Summary Statistics for Total ZID Concentrations in Plasma – WCK 6777 4g, Dose 1 
Table 58: 
Summary Statistics for Total ZID Concentrations in Plasma – WCK 6777 4g, Doses 2-6 
Table 59: 
Summary Statistics for Total ZID Concentrations in Plasma – WCK 6777 4g, Dose 7 
Table 60: 
Summary Statistics for Total ZID Concentrations in Plasma – ZID 3g, Dose 1 
Table 61: 
Summary Statistics for Total ZID Concentrations in Plasma – ZID 3g, Doses 2-6 
Table 62: 
Summary Statistics for Total ZID Concentrations in Plasma – ZID 3g, Dose 7 
Table 63: 
Summary Statistics for Total ZID Concentrations in Plasma – WCK 6777 6g, Dose 1 
Table 64: 
Summary Statistics for Total ZID Concentrations in Plasma – WCK 6777 6g, Doses 2-6 
Table 65: 
Summary Statistics for Total ZID Concentrations in Plasma – WCK 6777 6g, Dose 7 
 


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Table 66: 
Summary Statistics for Free ZID Concentrations in Plasma – WCK 6777 2g, Dose 1 
Table 67: 
Summary Statistics for Free ZID Concentrations in Plasma – WCK 6777 2g, Doses 2-6 
Table 68: 
Summary Statistics for Free ZID Concentrations in Plasma – WCK 6777 2g, Dose 7 
Table 69: 
Summary Statistics for Free ZID Concentrations in Plasma – ZID 2g, Dose 1 
Table 70: 
Summary Statistics for Free ZID Concentrations in Plasma – ZID 2g, Doses 2-6 
Table 71: 
Summary Statistics for Free ZID Concentrations in Plasma – ZID 2g, Dose 7 
Table 72: 
Summary Statistics for Free ZID Concentrations in Plasma – WCK 6777 4g, Dose 1 
Table 73: 
Summary Statistics for Free ZID Concentrations in Plasma – WCK 6777 4g, Doses 2-6 
Table 74: 
Summary Statistics for Free ZID Concentrations in Plasma – WCK 6777 4g, Dose 7 
Table 75: 
Summary Statistics for Free ZID Concentrations in Plasma – ZID 3g, Dose 1 
Table 76: 
Summary Statistics for Free ZID Concentrations in Plasma – ZID 3g Doses 2-6 
Table 77: 
Summary Statistics for Free ZID Concentrations in Plasma – ZID 3g, Dose 7 
Table 78: 
Summary Statistics for Free ZID Concentrations in Plasma – WCK 6777 6g, Dose 1 
Table 79: 
Summary Statistics for Free ZID Concentrations in Plasma – WCK 6777 6g, Doses 2-6 
Table 80: 
Summary Statistics for Free ZID Concentrations in Plasma – WCK 6777 6g, Dose 7


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Table 81: 
Summary Statistics for Total ERT Single-Dose PK Parameters in Plasma by Treatment Group 
PK Parameter (Units) 
WCK 6777 2g 
ERT 2g 
WCK 6777 4g 
ERT 3g 
WCK 6777 6g 
PK Analysis Subgroup 
Cmax, (µg/mL) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Cmax/Dose, ((µg/mL)/mg) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Cmin, (µg/mL) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Tmax, (h) 
x (x - x) 
x (x - x) 
x (x - x) 
x (x - x) 
x (x - x) 
AUC(0-t), (µg*h/mL) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
AUC(0-inf), (µg*h/mL) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
AUC(0-24), (µg*h/mL) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
AUC(0-last), (µg*h/mL) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
AUC(0-tau), (µg*h/mL) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
AUC(0-tau)/Dose, ((µg*h/mL)/mg) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
t1/2, (h) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
CLT, (L/h) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Ke, (1/h) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Vd, (L) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
PK Analysis Subgroup Subset 
… 
 
 
 
 
 
Note: Single-dose parameters are calculated over the 24-hour period following Dose 1. 
Values of GM (CV %) are shown, except for Tmax for which values of median (min-max) are shown. 
Tables with similar format: 
Table 82: 
Summary Statistics for Free ERT Single-Dose PK Parameters in Plasma by Treatment Group 
Table 83: 
Summary Statistics for Total ZID Single-Dose PK Parameters in Plasma by Treatment Group 
Table 84: 
Summary Statistics for Free ZID Single-Dose PK Parameters in Plasma by Treatment Group 


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Table 85: 
Summary Statistics for Total ERT Multiple-Dose PK Parameters in Plasma by Treatment Group 
PK Parameter (Units) 
WCK 6777 2g 
ERT 2g 
WCK 6777 4g 
ERT 3g 
WCK 6777 6g 
PK Analysis Subgroup 
Cmax,ss, (µg/mL) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Cmax,ss/Dose, ((µg/mL)/mg) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Cmin,ss, (µg/mL) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Cavg, (µg/mL) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Tmax,ss, (h) 
x (x - x) 
x (x - x) 
x (x - x) 
x (x - x) 
x (x - x) 
Tmin, (h) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
AUC(0-24),ss, (µg*h/mL) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
AUC(0-tau),ss, (µg*h/mL) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
AUC(0-tau),ss/Dose, ((µg*h/mL)/mg) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
t1/2, (h) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
CLT, (L/h) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Vd,ss, (L) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Linearity Indexa 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
RAUCb 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
RCmaxc 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
PK Analysis Subgroup Subset 
… 
 
 
 
 
 
Note: Multi-dose parameters are calculated over the 24-hour period following Dose 7. Values of GM (CV %) are shown, except for Tmax for which values of median (min-max) are shown. 
aLinearity Index is defined as AUC(0-tau),ss (Dose 7) / AUC(0-∞) (Dose 1) 
bRAUC is defined as AUC(0-tau) (Dose 7) / AUC(0-24) (Dose 1) 
cRCmaz is defined as Cmax (Dose 7) / Cmax (Dose 1) 
 
 


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Tables with similar format: 
Table 86: 
Summary Statistics for Free ERT Multiple-Dose PK Parameters in Plasma by Treatment Group 
Table 87: 
Summary Statistics for Total ZID Multiple-Dose PK Parameters in Plasma by Treatment Group 
Table 88: 
Summary Statistics for Free ZID Multiple-Dose PK Parameters in Plasma by Treatment Group 


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Table 89: 
Summary Statistics for Total ERT Single-Dose PK Parameters in Plasma – WCK 6777 2g 
PK Parameter (Units) 
N 
Mean (SD) 
Minimum, Maximum 
Geometric Mean (CV%) 
PK Analysis Subgroup 
Cmax, (µg/mL) 
x 
x (x.x) 
x, x 
x (x.x) 
Cmax/Dose, ((µg/mL)/mg) 
x 
x (x.x) 
x, x 
x (x.x) 
Cmin, (µg/mL) 
x 
x (x.x) 
x, x 
x (x.x) 
Tmax, (h) 
x 
x (x.x) 
x, x 
x (x.x) 
AUC(0-t), (µg*h/mL) 
x 
x (x.x) 
x, x 
x (x.x) 
AUC(0-inf), (µg*h/mL) 
x 
x (x.x) 
x, x 
x (x.x) 
AUC(0-24), (µg*h/mL) 
x 
x (x.x) 
x, x 
x (x.x) 
AUC(0-last), (µg*h/mL) 
x 
x (x.x) 
x, x 
x (x.x) 
AUC(0-tau), (µg*h/mL) 
x 
x (x.x) 
x, x 
x (x.x) 
AUC(0-tau)/Dose, ((µg*h/mL)/mg) 
x 
x (x.x) 
x, x 
x (x.x) 
t1/2, (h) 
x 
x (x.x) 
x, x 
x (x.x) 
CLT, (L/h) 
x 
x (x.x) 
x, x 
x (x.x) 
Ke, (1/h) 
x 
x (x.x) 
x, x 
x (x.x) 
Vd, (L) 
x 
x (x.x) 
x, x 
x (x.x) 
PK Analysis Subgroup Subset 
… 
 
 
 
 
 
 


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Tables with similar format: 
Table 90: 
Summary Statistics for Total ERT Single-Dose PK Parameters in Plasma – ERT 2g 
Table 91: 
Summary Statistics for Total ERT Single-Dose PK Parameters in Plasma – WCK 6777 4g 
Table 92: 
Summary Statistics for Total ERT Single-Dose PK Parameters in Plasma – ERT 3g 
Table 93: 
Summary Statistics for Total ERT Single-Dose PK Parameters in Plasma – WCK 6777 6g 
Table 94: 
Summary Statistics for Free ERT Single-Dose PK Parameters in Plasma – WCK 6777 2g 
Table 95: 
Summary Statistics for Free ERT Single-Dose PK Parameters in Plasma – ERT 2g 
Table 96: 
Summary Statistics for Free ERT Single-Dose PK Parameters in Plasma – WCK 6777 4g 
Table 97: 
Summary Statistics for Free ERT Single-Dose PK Parameters in Plasma – ERT 3g 
Table 98: 
Summary Statistics for Free ERT Single-Dose PK Parameters in Plasma – WCK 6777 6g 
Table 99: 
Summary Statistics for Total ZID Single-Dose PK Parameters in Plasma – WCK 6777 2g 
Table 100: 
Summary Statistics for Total ZID Single-Dose PK Parameters in Plasma – ZID 2g 
Table 101: 
Summary Statistics for Total ZID Single-Dose PK Parameters in Plasma – WCK 6777 4g 
Table 102: 
Summary Statistics for Total ZID Single-Dose PK Parameters in Plasma – ZID 3g 
Table 103: 
Summary Statistics for Total ZID Single-Dose PK Parameters in Plasma – WCK 6777 6g 
Table 104: 
Summary Statistics for Free ZID Single-Dose PK Parameters in Plasma – WCK 6777 2g 
Table 105: 
Summary Statistics for Free ZID Single-Dose PK Parameters in Plasma – ZID 2g 
Table 106: 
Summary Statistics for Free ZID Single-Dose PK Parameters in Plasma – WCK 6777 4g 
Table 107: 
Summary Statistics for Free ZID Single-Dose PK Parameters in Plasma – ZID 3g 
Table 108: 
Summary Statistics for Free ZID Single-Dose PK Parameters in Plasma – WCK 6777 6g 
 
 


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Table 109: 
Summary Statistics for Total ERT Multiple-Dose PK Parameters in Plasma – WCK 6777 2g 
PK Parameter (Units) 
N 
Mean (SD) 
Minimum, Maximum 
Geometric Mean 
(CV%) 
PK Analysis Subgroup 
Cmax,ss, (µg/mL) 
x (x) 
x (x) 
x (x) 
x (x) 
Cmax,ss/Dose, ((µg/mL)/mg) 
x (x) 
x (x) 
x (x) 
x (x) 
Cmin,ss, (µg/mL) 
x (x) 
x (x) 
x (x) 
x (x) 
Cavg, (µg/mL) 
x (x) 
x (x) 
x (x) 
x (x) 
Tmax,ss, (h) 
x (x - x) 
x (x - x) 
x (x - x) 
x (x - x) 
Tmin, (h) 
x (x) 
x (x) 
x (x) 
x (x) 
AUC(0-24),ss, (µg*h/mL) 
x (x) 
x (x) 
x (x) 
x (x) 
AUC(0-tau),ss, (µg*h/mL) 
x (x) 
x (x) 
x (x) 
x (x) 
AUC(0-tau),ss/Dose, ((µg*h/mL)/mg) 
x (x) 
x (x) 
x (x) 
x (x) 
t1/2, (h) 
x (x) 
x (x) 
x (x) 
x (x) 
CLT, (L/h) 
x (x) 
x (x) 
x (x) 
x (x) 
Vd,ss, (L) 
x (x) 
x (x) 
x (x) 
x (x) 
Linearity Indexa 
x (x) 
x (x) 
x (x) 
x (x) 
RAUCb 
x (x) 
x (x) 
x (x) 
x (x) 
RCmaxc 
x (x) 
x (x) 
x (x) 
x (x) 
PK Analysis Subgroup Subset 
… 
 
 
 
 
Note: Values of GM (CV %) are shown, except for Tmax for which values of median (min-max) are shown. 
aLinearity Index is defined as AUC(0-tau),ss (Dose 7) / AUC(0-∞) (Dose 1) 
 bRAUC is defined as AUC(0-tau) (Dose 7) / AUC(0-24) (Dose 1) 
cRCmaz is defined as Cmax (Dose 7) / Cmax (Dose 1) 


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Tables with similar format: 
Table 110: 
Summary Statistics for Total ERT Multiple-Dose PK Parameters in Plasma – ERT 2g 
Table 111: 
Summary Statistics for Total ERT Multiple-Dose PK Parameters in Plasma – WCK 6777 4g 
Table 112: 
Summary Statistics for Total ERT Multiple-Dose PK Parameters in Plasma – ERT 3g 
Table 113: 
Summary Statistics for Total ERT Multiple-Dose PK Parameters in Plasma – WCK 6777 6g 
Table 114: 
Summary Statistics for Free ERT Multiple-Dose PK Parameters in Plasma – WCK 6777 2g 
Table 115: 
Summary Statistics for Free ERT Multiple-Dose PK Parameters in Plasma – ERT 2g 
Table 116: 
Summary Statistics for Free ERT Multiple-Dose PK Parameters in Plasma – WCK 6777 4g 
Table 117: 
Summary Statistics for Free ERT Multiple-Dose PK Parameters in Plasma – ERT 3g 
Table 118: 
Summary Statistics for Free ERT Multiple-Dose PK Parameters in Plasma – WCK 6777 6g 
Table 119: 
Summary Statistics for Total ZID Multiple-Dose PK Parameters in Plasma – WCK 6777 2g 
Table 120: 
Summary Statistics for Total ZID Multiple-Dose PK Parameters in Plasma – ZID 2g 
Table 121: 
Summary Statistics for Total ZID Multiple-Dose PK Parameters in Plasma – WCK 6777 4g 
Table 122: 
Summary Statistics for Total ZID Multiple-Dose PK Parameters in Plasma – ZID 3g 
Table 123: 
Summary Statistics for Total ZID Multiple-Dose PK Parameters in Plasma – WCK 6777 6g 
Table 124: 
Summary Statistics for Free ZID Multiple-Dose PK Parameters in Plasma – WCK 6777 2g 
Table 125: 
Summary Statistics for Free ZID Multiple-Dose PK Parameters in Plasma – ZID 2g 
Table 126: 
Summary Statistics for Free ZID Multiple-Dose PK Parameters in Plasma – WCK 6777 4g 
Table 127: 
Summary Statistics for Free ZID Multiple-Dose PK Parameters in Plasma – ZID 3g 
Table 128: 
Summary Statistics for Free ZID Multiple-Dose PK Parameters in Plasma – WCK 6777 6g 
 
 


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Table 129: 
Amount and Percent ERT Protein Binding – WCK 6777 2g 
 
 
Amount Bound 
Percent Bound 
Nominal Timea (h) 
n 
Mean (SD) 
Min, Max 
Mean (SD) 
Min, Max 
Dose 1 
0 
x  
x  
x.x 
x.x 
x.x 
0.25 
x 
x 
- 
- 
- 
0.5 
x 
x 
x.x 
x.x 
- 
1 
x 
x 
x.x 
x.x 
x.x 
2 
x 
x 
x.x 
x.x 
x.x 
3 
x 
x 
x.x 
x.x 
x.x 
4 
x 
x 
x.x 
x.x 
x.x 
8 
x 
x 
x.x 
x.x 
x.x 
12 
x 
x 
x.x 
x.x 
x.x 
18 
x 
x 
x.x 
x.x 
x.x 
24 
x 
x 
x.x 
x.x 
x.x 
Dose 2 
0 
x 
x 
x.x 
x.x 
x.x 
12 
x 
x 
x.x 
x.x 
x.x 
Dose 3 
… 
 
 
 
 
 
Dose 4 
… 
 
 
 
 
 
Dose 5 
… 
 
 
 
 
 
Dose 6 
… 
 
 
 
 
 
Dose 7 
… 
 
 
 
 
 


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Notes: Timepoints where data was not collected are denoted by “-“. Timepoints where data was not estimable are denoted by “NE”.  
n= Number of participants with estimable amount/percent binding at the given timepoint. 
Values of GM (CV %) are shown. 
Amount bound will be calculated as Ctotal-Cfree. Percent bound will be calculated as ((Ctotal-Cfree)/Ctotal) x 100%. 
a Times are relative to time of dosing. 
Tables with similar format: 
Table 130: 
Amount and Percent ERT Protein Binding – ERT 2g 
Table 131: 
Amount and Percent ERT Protein Binding – WCK 6777 4g 
Table 132: 
Amount and Percent ERT Protein Binding – ERT 3g 
Table 133: 
Amount and Percent ERT Protein Binding – WCK 6777 6g 
Table 134: 
Amount and Percent ZID Protein Binding – WCK 6777 2g 
Table 135: 
Amount and Percent ZID Protein Binding – WCK ZID 2g 
Table 136: 
Amount and Percent ZID Protein Binding – WCK 6777 4g 
Table 137: 
Amount and Percent ZID Protein Binding – WCK ZID 3g 
Table 138: 
Amount and Percent ZID Protein Binding – WCK 6777 6g 
 


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Table 139: 
ERT Concentrations in Urine by Treatment Group – Dose 1 
  
Nominal Timea (h) 
Treatment Group 
-1 - 0 
0 - 4 
4 - 8 
8 - 12 
12 - 24 
WCK 6777 2g 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
ERT 2g 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
WCK 6777 4g 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
ERT 3g 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
WCK 6777 6g 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Notes: Concentrations are reported in units of µg/mL. Timepoints where data was not collected are denoted by “-“. Timepoints where data was not estimable are denoted by “NE”. 
Values of GM (CV %) are shown. 
a Times are relative to time of dosing. 
Tables with similar format: 
Table 140: 
ERT Concentrations in Urine by Treatment Group – Dose 7 
Table 141: 
ZID Concentrations in Urine by Treatment Group – Dose 1 
Table 142: 
ZID Concentrations in Urine by Treatment Group – Dose 7 
 
 
 


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Table 143: 
ERT Summary Statistics for Concentrations in Urine – WCK 6777 2g, Dose 1 
  
Nominal Timea (h) 
Participant ID 
-1 - 0 
0 - 4 
 4 - 8 
8 - 12 
12 - 24 
99ZZZ001 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
99ZZZ002 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
99ZZZ003 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
… 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Statistics 
 
 
 
 
 
Nb 
x 
x 
x 
x 
x 
Mean 
x 
x 
x 
x 
x 
SD 
x 
x 
x 
x 
x 
CV% 
x 
x 
x 
x 
x 
GM 
x 
x 
x 
x 
x 
Median 
x 
x 
x 
x 
x 
Min, Max 
x, x 
x, x  
x, x  
x, x  
x, x  
Notes: Timepoints where data was not estimable are denoted by “NE”. 
a Times are relative to time of first dosing. 
b Number of data points used to compute the summary statistics. BQL values were imputed as 0 if they did not come after a PK sample concentration that is above the LLOQ and treated as missing 
otherwise. 
 
 


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Tables with similar format: 
Table 144: 
ERT Summary Statistics for Concentrations in Urine – WCK 6777 2g, Dose 7 
Table 145: 
ERT Summary Statistics for Concentrations in Urine – ERT 2g, Dose 1 
Table 146: 
ERT Summary Statistics for Concentrations in Urine – ERT 2g, Dose 7 
Table 147: 
ERT Summary Statistics for Concentrations in Urine – WCK 6777 4g, Dose 1 
Table 148: 
ERT Summary Statistics for Concentrations in Urine – WCK 6777 4g, Dose 7 
Table 149: 
ERT Summary Statistics for Concentrations in Urine – ERT 3g, Dose 1 
Table 150: 
ERT Summary Statistics for Concentrations in Urine – ERT 3g, Dose 7 
Table 151: 
ERT Summary Statistics for Concentrations in Urine – WCK 6777 6g, Dose 1 
Table 152: 
ERT Summary Statistics for Concentrations in Urine – WCK 6777 6g, Dose 7 
Table 153: 
ZID Summary Statistics for Concentrations in Urine – WCK 6777 2g, Dose 1 
Table 154: 
ZID Summary Statistics for Concentrations in Urine – WCK 6777 2g, Dose 7 
Table 155: 
ZID Summary Statistics for Concentrations in Urine – ZID 2g, Dose 1 
Table 156: 
ZID Summary Statistics for Concentrations in Urine – ZID 2g, Dose 7 
Table 157: 
ZID Summary Statistics for Concentrations in Urine – WCK 6777 4g, Dose 1 
Table 158: 
ZID Summary Statistics for Concentrations in Urine – WCK 6777 4g, Dose 7 
Table 159: 
ZID Summary Statistics for Concentrations in Urine – ZID 3g, Dose 1 
Table 160: 
ZID Summary Statistics for Concentrations in Urine – ZID 3g, Dose 7 
Table 161: 
ZID Summary Statistics for Concentrations in Urine – WCK 6777 6g, Dose 1 
Table 162: 
ZID Summary Statistics for Concentrations in Urine – WCK 6777 6g, Dose 7 
 


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Table 163: 
Summary Statistics for ERT PK Parameters in Urine by Treatment Group, Dose 1 
  
WCK 6777 2g 
ERT 2g 
WCK 6777 4g 
ERT 3g 
WCK 6777 6g 
PK Analysis Subgroup 
Ae,urine (mg) 0-4 h 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
Ae,urine (mg) 4-8 h 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
Ae,urine (mg) 8-12 h 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
Ae,urine (mg) 12-24 h 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
Ae,urine(0-24) (mg) 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
fe,urine 0-4 h 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
fe,urine 4-8 h 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
fe,urine 8-12 h 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
fe,urine 12-24 h 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
fe,urine(0-24) 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
CLR(0-24) 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
x (xx, xx) 
PK Analysis Subgroup Subset 
… 
 
 
 
 
 
Note: Values of Mean (Min, Max) are shown, except for CLR, for which values of GM (CV %) are shown.  
a Times are relative to time of dosing. 
 
 


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Tables with similar format: 
Table 164: 
Summary Statistics for ERT PK Parameters in Urine by Treatment Group, Dose 7 
[Implementation Note: Repeat Table 163 for Dose 7 with rows for AE,urine(0-24),ss (mg), fe,urine(0-24),ss, and CLR,ss instead of AE,urine(0-24) (mg), 
fe,urine(0-24), and CLR(0-24).]   
Table 165: 
Summary Statistics for ZID PK Parameters in Urine by Treatment Group, Dose 1 
Table 166: 
Summary Statistics for ZID PK Parameters in Urine by Treatment Group, Dose 7 
[Implementation Note: Repeat Table 165 for Dose 7 with rows for AE,urine(0-24),ss (mg), fe,urine(0-24),ss, and CLR,ss instead of AE,urine(0-24) (mg), 
fe,urine(0-24), and CLR(0-24).]   
 
 


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Table 167: 
Summary Statistics for ERT PK Parameters in Urine – WCK 6777 2g, Dose 1 
Statistics 
Ae,urine 0-4 h 
(mg) 
Ae,urine 4-8 h 
(mg) 
Ae,urine 8-12 h 
(mg) 
Ae,urine 12-
24 h 
(mg) 
Ae,urine(0-24)  
(mg) 
fe,urine 0-4 
h 
(%) 
fe,urine 4-
8 h 
(%) 
fe,urine 8-
12 h 
(%) 
fe,urine12-
24 h 
(%) 
fe,urine(0-
24)  
(%) 
CLR(0-24) 
PK Analysis Subgroup 
N 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mean 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SD 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Median 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Min 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Max 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GM 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CV % 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PK Analysis Subgroup Subset 
… 
 
 
 
 
 
 
 
 
 
 
 
Tables with similar format: 
Table 168: 
Summary Statistics for ERT PK Parameters in Urine – ERT 2g, Dose 1 
Table 169: 
Summary Statistics for ERT PK Parameters in Urine – WCK 6777 4g, Dose 1 
Table 170: 
Summary Statistics for ERT PK Parameters in Urine – ERT 3g, Dose 1 
Table 171: 
Summary Statistics for ERT PK Parameters in Urine – WCK 6777 6g, Dose 1 
 
 


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Table 172: 
Summary Statistics for ERT PK Parameters in Urine – ERT 2g, Dose 7 
Statistics 
Ae,urine 0-4 h 
(mg) 
Ae,urine 4-8 h 
(mg) 
Ae,urine 8-12 h 
(mg) 
Ae,urine 12-
24 h 
(mg) 
Ae,urine(0-
24),ss  
(mg) 
fe,urine 
0-4 h 
(%) 
fe,urine 4-8 
h 
(%) 
fe,urine 8-12 
h 
(%) 
fe,urine12-
24 h 
(%) 
fe,urine(0-
24),ss  
(%) 
CLR,ss 
PK Analysis Subgroup 
N 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mean 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SD 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Median 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Min 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Max 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GM 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CV % 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PK Analysis Subgroup Subset 
… 
 
 
 
 
 
 
 
 
 
 
 


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Tables with similar format: 
Table 173: 
Summary Statistics for ERT PK Parameters in Urine – WCK 6777 4g, Dose 7 
Table 174: 
Summary Statistics for ERT PK Parameters in Urine – ERT 3g, Dose 7 
Table 175: 
Summary Statistics for ERT PK Parameters in Urine – WCK 6777 6g, Dose 7 
Tables with similar format to Table 173/178: 
Table 176: 
Summary Statistics for ZID PK Parameters in Urine – WCK 6777 2g, Dose 1 
Table 177: 
Summary Statistics for ZID PK Parameters in Urine – ZID 2g, Dose 1 
Table 178: 
Summary Statistics for ZID PK Parameters in Urine – WCK 6777 4g, Dose 1 
Table 179: 
Summary Statistics for ZID PK Parameters in Urine – ZID 3g, Dose 1 
Table 180: 
Summary Statistics for ZID PK Parameters in Urine – WCK 6777 6g, Dose 1 
Table 181: 
Summary Statistics for ZID PK Parameters in Urine – WCK 6777 2g, Dose 7 
Table 182: 
Summary Statistics for ZID PK Parameters in Urine – ZID 2g, Dose 7 
Table 183: 
Summary Statistics for ZID PK Parameters in Urine – WCK 6777 4g, Dose 7 
Table 184: 
Summary Statistics for ZID PK Parameters in Urine – ZID 3g, Dose 7 
Table 185: 
Summary Statistics for ZID PK Parameters in Urine – WCK 6777 6g, Dose 7 
 
 
 


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Table 186: 
Assessment of Dose Proportionality of WCK 6777 in Plasma – Dose 1, PK Analysis Subset 
Statistic 
ERT 
ZID 
Cmax 
AUC0-last 
AUC0-inf 
Cmax 
AUC0-last 
AUC0-inf 
(µg/mL) 
(µg*h/mL) 
(µg*h/mL) 
(µg/mL) 
(µg*h/mL) 
(µg*h/mL) 
Total 
Lowest Dose Included (mg) 
x 
x 
x 
x 
x 
x 
Highest Dose Included (mg) 
x 
x 
x 
x 
x 
x 
ρ  
x 
x 
x 
x 
x 
x 
β-hat 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
Standard Error (β-hat) 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
ρ β-hat-1 90% CI 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
Conclude parameter shows dose proportionality? 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Free 
… 
 
 
 
 
 
 
Note: β-hat is an estimate obtained using the linear model log(Param) = α + dose × β, where Param is AUC0-last, AUC0-inf , or Cmax. Perfect dose proportionality is equivalent to β = 1. The value ρ is 
equivalent to the ratio of the highest dose included in the analysis divided by the lowest dose included in the analysis. Presence of dose proportionality is concluded when the 90% confidence interval 
for ρ β-hat-1 is contained within the interval (0.80,1.25). 
Tables with similar format: 
Table 187: 
Assessment of Dose Proportionality of WCK 6777 in Plasma – Dose 1, PK Analysis Subset Subgroup 
Table 188: 
Assessment of Dose Proportionality of WCK 6777 in Plasma – Dose 7, PK Analysis Subset 
[Implementation note: this table will contain Cmax,ss AUC(0-24),ss and AUC(0-tau),ss instead of the above parameters] 
Table 189: 
Assessment of Dose Proportionality of WCK 6777 in Plasma – Dose 7, PK Analysis Subset Subgroup 
[Implementation note: this table will contain Cmax,ss AUC(0-24),ss and AUC(0-tau),ss instead of the above parameters] 


Statistical Analysis Plan - DMID Protocol: 21-0013  
Version 1.0 
07NOV2023 
- 112 - 
RESTRICTED 
Table 190: 
Assessment of Drug-Drug Interactions of ERT and ZID for Concentrations of WCK 6777 in Plasma – PK Analysis Subset 
Treat
ment 
Group 
Cmax/Dose 
(µg/mL) 
AUC0-last/Dose 
(µg/mL) 
AUC0-tau/Dose 
(µg/mL) 
AUC0-inf/Dose 
(µg/mL) 
Cmax,ss/Dose 
(µg/mL) 
AUC0-
tau,ss/Dose 
(µg/mL) 
% Bound  
Day 1 
% Bound  
Day 7 
Amount 
Bound Day 1 
Amount 
Bound Day 7 
GM 
(95% 
CI) 
GLS
MR 
(90% 
CI) 
GM 
(95% 
CI) 
GLS
MR 
(90% 
CI) 
GM 
(95% 
CI) 
GLS
MR 
(90% 
CI) 
GM 
(95% 
CI) 
GLS
MR 
(90% 
CI) 
GM 
(95% 
CI) 
GLS
MR 
(90% 
CI) 
GM 
(95% 
CI) 
GLS
MR 
(90% 
CI) 
GM 
(95% 
CI) 
GLS
MR 
(90% 
CI) 
GM 
(95% 
CI) 
GLS
MR 
(90% 
CI) 
GM 
(95% 
CI) 
GLS
MR 
(90% 
CI) 
GM 
(95% 
CI) 
GLS
MR 
(90% 
CI) 
Total ERT 
2 g 
ERT 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
4 g 
WCK 
6777 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
3 g 
ERT 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
6 g 
WCK 
6777 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
Total ZID 
2 g 
ZID 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx)\ 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
4 g 
WCK 
6777 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 


Statistical Analysis Plan - DMID Protocol: 21-0013  
Version 1.0 
07NOV2023 
Table 190: Assessment of Drug-Drug Interactions of ERT and ZID for Concentrations of WCK 6777 in Plasma – PK Analysis Subset 
(continued) 
- 113 - 
RESTRICTED 
3 g 
ZID 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
6 g 
WCK 
6777 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
Free ERT 
2 g 
ERT 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
4 g 
WCK 
6777 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
3 g 
ERT 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
6 g 
WCK 
6777 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
Free ZID 
2 g 
ZID 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
4 g 
WCK 
6777 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 


Statistical Analysis Plan - DMID Protocol: 21-0013  
Version 1.0 
07NOV2023 
Table 190: Assessment of Drug-Drug Interactions of ERT and ZID for Concentrations of WCK 6777 in Plasma – PK Analysis Subset 
(continued) 
- 114 - 
RESTRICTED 
3 g 
ZID 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
x.xx 
(x.xx,
x.xx) 
6 g 
WCK 
6777 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
x.xx 
(x.xx,
x.xx) 
- 
Notes: DN = Dose-Normalized. CI = Confidence Interval. GM = Geometric Mean. GLSMR = Geometric Least-Squares Mean Ratio.  
Estimates and CIs are obtained using an ANOVA model for the log-transformed dose-normalized exposure parameter with the lowest dose studied in standalone, 2 g, as the reference dose. Dose-
normalized GLSMRs are calculated using the relevant WCK 6777 dose group as the denominator. 


Statistical Analysis Plan - DMID Protocol: 21-0013  
Version 1.0 
07NOV2023 
- 115 - 
RESTRICTED 
Tables with similar format: 
Table 191: 
Assessment of Drug-Drug Interactions of ERT and ZID for Concentrations of WCK 6777 in Plasma – PK Analysis Subset 
Subgroup 
 


Statistical Analysis Plan - DMID Protocol: 21-0013  
Version 1.0 
07NOV2023 
- 116 - 
RESTRICTED 
14.3 
Safety Data 
14.3.1 Displays of Adverse Events 
Table 192: 
Overall Summary of Adverse Events 
Participantsa with 
WCK 6777 
2g 
(N=X) 
ERT 2g 
(N=X) 
ZID 2g 
(N=X) 
WCK 6777 
4g 
(N=X) 
ERT 3g 
(N=X) 
ZID 3g 
(N=X) 
WCK 6777 
6g 
(N=X) 
Placebo 
(N=X) 
All 
Participants 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
At least one adverse event 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
At least one related adverse event 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
     Mild (Grade 1) 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
     Moderate (Grade 2)  
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
     Severe (Grade 3)  
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
At least one severe (Grade 3) unsolicited 
adverse event 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
     Related  
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
     Unrelated 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
At least one serious adverse event 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
At least one related, serious adverse event 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
At least one adverse event leading to early 
terminationb  
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
N = Number of participants in the Safety Population 
a Participants are counted once for each category regardless of the number of events. 
b As reported on the Adverse Event eCRF. 


Statistical Analysis Plan - DMID Protocol: 21-0013  
Version 1.0 
07NOV2023 
- 117 - 
RESTRICTED 
Table 193: 
Adverse Events Occurring in 5% of Participants in Any Treatment Group by MedDRA System Organ Class and Preferred Term, 
and Treatment Group - Safety Population 
MedDRA 
System 
Organ 
Class 
MedDRA 
Preferred 
Term 
WCK 6777 2g 
(N=X) 
ERT 2g 
(N=X) 
ZID 2g 
(N=X) 
WCK 6777 4g 
(N=X) 
ERT 3g 
(N=X) 
ZID 3g 
(N=X) 
WCK 6777 6g 
(N=X) 
Placebo 
(N=X) 
All Participants 
(N=X) 
 
 
n 
% Events
n 
% 
Event
s 
n 
% 
Event
s 
n 
% 
Event
s 
n 
% 
Event
s 
n 
% 
Event
s 
n 
% 
Event
s 
n 
% 
Event
s 
n 
% Event
s 
Serious Adverse Events 
All  
All 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PT1 
SOC1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Etc. 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other (Non-serious) Adverse Events 
All  
All 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PT1 
SOC1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Etc 
Etc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N = number of participants in the Safety Population (number of participants at risk).  
n = number of participants reporting event.  
Events = total frequency of events reported. 


Statistical Analysis Plan - DMID Protocol: 21-0013  
Version 1.0 
07NOV2023 
- 118 - 
RESTRICTED 
14.3.1.1 
Adverse Events 
Table 194: 
Summary of Adverse Events by MedDRA System Organ Class, High Level Group Term, 
Preferred Term, and Treatment Group 
[Implementation Note: If there is only 1 PT for an SOC and HLGT, there will be no “Any PT” row. 
Repeat for the following treatment groups: WCK 6777 2g, ERT 2g, ZID 2g, WCK 6777 4g, ERT 3g, ZID 3g, 
WCK 6777 6g, Placebo] 
Treatment Group 
MedDRA System 
Organ Class 
MedDRA High Level 
Group Term 
MedDRA Preferred 
Term 
n (%) 
95% CIa 
Number of 
Events 
All Participants 
(N=X) 
Any SOC 
Any HLGT 
Any PT 
x (x) 
xx, xx 
x 
 
[SOC 1] 
Any HLGT 
Any PT 
x (x) 
xx, xx 
x 
 
 
HLGT1 
Any PT 
x (x) 
xx, xx 
x 
 
 
 
[PT 1] 
x (x) 
xx, xx 
x 
 
[SOC 2] 
Any HLGT 
Any PT 
x (x) 
xx, xx 
x 
 
 
HLGT1 
Any PT 
x (x) 
xx, xx 
x 
 
 
 
[PT 1] 
x (x) 
xx, xx 
x 
WCK 6777 2g 
(N=X) 
… 
 
… 
x (x) 
xx, xx 
x 
… 
… 
 
… 
x (x) 
xx, xx 
x 
Placebo (N=X) 
… 
 
… 
x (x) 
xx, xx 
x 
Notes: N=Number of participants in the Safety Population in the specified treatment group. 
n=number of participants reporting adverse events within each SOC/HLGT/PT. 
A participant is only counted once per PT per treatment group. 
a Exact Clopper-Pearson Confidence Interval. 
 


Statistical Analysis Plan - DMID Protocol: 21-0013  
Version 1.0 
07NOV2023 
- 119 - 
RESTRICTED 
Table 195: 
Adverse Events by MedDRA System Organ Class and Preferred Term, Maximum 
Severity, Relationship, and Treatment Group 
[Implementation Note: If there is only 1 PT for an SOC and HLGT, there will be no “Any PT” row. 
Repeat for the following treatment groups: WCK 6777 2g, ERT 2g, ZID 2g, WCK 6777 4g, ERT 3g, ZID 3g, 
WCK 6777 6g, Placebo] 
Treatment 
Group 
MedDRA System 
Organ Class 
MedDRA High Level 
Group Term 
MedDRA 
Preferred Term  
Severity 
Related  
n (%) 
Not Related  
n (%) 
Total  
n (%) 
All 
Participants 
(N=X) 
Any SOC 
Any HLGT 
Any PT 
Any Severity 
x (%) 
x (%) 
x (%) 
  
  
 
  
Mild 
x (%) 
x (%) 
x (%) 
  
  
 
  
Moderate 
x (%) 
x (%) 
x (%) 
  
  
 
  
Severe 
x (%) 
x (%) 
x (%) 
  
[SOC 1] 
Any HLGT 
Any PT 
Any Severity 
x (%) 
x (%) 
x (%) 
  
  
 
  
… 
x (%) 
x (%) 
x (%) 
  
  
HLGT1 
Any PT 
Any Severity 
x (%) 
x (%) 
x (%) 
  
  
 
  
… 
x (%) 
x (%) 
x (%) 
 
  
HLGT1 
[PT1] 
Any Severity 
x (%) 
x (%) 
x (%) 
 
  
 
  
… 
x (%) 
x (%) 
x (%) 
WCK 6777 
2g (N=X) 
Any SOC 
 
Any PT 
Any Severity 
x (%) 
x (%) 
x (%) 
… 
… 
 
… 
… 
x (%) 
x (%) 
x (%) 
Placebo 
(N=X) 
… 
 
… 
… 
x (%) 
x (%) 
x (%) 
Notes: N=Number of participants in the Safety Population in each treatment group. 
Participants are only counted once per PT and treatment group, in the highest reported severity. 
 


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14.3.2 Listing of Deaths, Other Serious and Significant Adverse Events 
Table 196: 
Listing of Non-Serious Moderate or Severe Adverse Events 
[Implementation Note: This listing is included in the table shells document, as it is included in the body of the CSR. If the event is ongoing (no stop 
date), indicate “ongoing” for the “Duration of AE in Days”. Listing should be sorted by Treatment Group, Participant ID, and AE Number. 
Treatment Group order: WCK 6777 2g, ERT 2g, ZID 2g, WCK 6777 4g, ERT 3g, ZID 3g, WCK 6777 6g, Placebo] 
Adverse 
Event 
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 
Participant 
Discontinued 
Due to AE 
Outcome 
MedDRA 
System 
Organ 
Class 
MedDRA High 
Level Group 
Term 
MedDRA 
Preferred Term 
Participant ID: , Treatment Group: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
Participant ID: , Treatment Group: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 


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Table 197: 
Listing of Serious Adverse Events 
[Implementation Note: This listing is included in the table shells document, as it is included in the body of the CSR. If the event is ongoing (no stop 
date), indicate “ongoing” for the “Duration of AE in Days”. If more than one reason is selected for the reason reported as an SAE, list all reasons in the 
column separated by a comma. In the “If Not Related, Alternate Etiology” column, merge the 2 data fields for collecting alternate etiology, separate by a 
colon. Listing should be sorted by Treatment Group, Participant ID, and AE Number. 
Treatment Group order: WCK 6777 2g, ERT 2g, ZID 2g, WCK 6777 4g, ERT 3g, ZID 3g, WCK 6777 6g, Placebo] 
Adverse 
Event 
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 
Participant 
Discontinued 
Due to AE 
Outcome 
MedDRA 
System 
Organ 
Class 
MedDRA 
High Level 
Group 
Term 
MedDRA 
Preferred 
Term 
Participant ID: , Treatment Group: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
Participant ID: , Treatment Group: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 


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


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14.3.4 Abnormal Laboratory Value Listings (by Participant) 
Table 198: 
Listing of Abnormal Laboratory Results - Chemistry 
[Implementation Note: This listing is included in the table shells document, as it is included in the body of the CSR. This listing includes all abnormal 
Chemistry results (laboratory results outside of the normal range defined in the protocol). Normal chemistry results for other parameters that occurred on 
the same visit as the abnormal result will not be listed. There is a separate, complete listing of all Chemistry results in Appendix 3. In the Laboratory 
Parameter column, indicate the units in parentheses after the parameter, e.g., Sodium (mEq/L). This listing is not color-coded, but the severity should be 
included in parentheses after the result, e.g., 133 (Mild). Results that are outside the normal range but not mild, moderate, or severe will have (ONR) as 
the severity included after the result. Results that meet grading criteria of mild, moderate, or severe but which are not treatment emergent (not worse than 
baseline, as described in Section 9.6) will be shown as “ONR”. 
Sort order: Treatment Group, Participant ID, Timepoint, and Parameter. 
Treatment Group order: WCK 6777 2g, ERT 2g, ZID 2g, WCK 6777 4g, ERT 3g, ZID 3g, WCK 6777 6g, Placebo] 
Participant 
ID 
Treatment 
Group 
Sex 
Age 
(years) 
Planned 
Timepoint 
Actual 
Study Day 
Laboratory 
Parameter 
(Units) 
Result 
(Severity) 
Relationship to 
Treatment 
If Not Related, 
Alternate 
Etiology 
Action Taken 
with Study 
Treatment 
Participant 
Discontinued Due 
to Result? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 199: 
Listing of Abnormal Laboratory Results - Hematology 
[Implementation Note: This listing is included in the table shells document, as it is included in the body of the CSR. This listing includes all abnormal 
Hematology results (laboratory results outside of the normal range defined in the protocol). Normal hematology results for other parameters that 
occurred on the same visit as the abnormal result will not be listed. There is a separate, complete listing of all Hematology results in Appendix 3. In the 
Laboratory Parameter column, indicate the units in parentheses after the parameter, e.g., Hemoglobin (g/dL). This listing is not color-coded, but the 
severity should be included in parentheses after the result, e.g., 10.5 (Moderate). Results that are outside the normal range but not mild, moderate, or 
severe will have (ONR) as the severity included after the result. Results that meet grading criteria of mild, moderate, or severe but which are not 
treatment emergent (not worse than baseline, as described in Section 9.6) will be shown as “ONR”. 
Sort order: Treatment Group, Participant ID, Timepoint, and Parameter 
Treatment Group order: WCK 6777 2g, ERT 2g, ZID 2g, WCK 6777 4g, ERT 3g, ZID 3g, WCK 6777 6g, Placebo] 
Participant 
ID 
Treatment 
Group 
Sex 
Age 
(years) 
Planned 
Timepoint 
Actual 
Study Day 
Laboratory 
Parameter 
(Units) 
Result 
(Severity) 
Relationship to 
Treatment 
If Not Related, 
Alternate 
Etiology 
Action Taken 
with Study 
Treatment 
Participant 
Discontinued Due 
to Result? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 200: 
Listing of Abnormal Laboratory Results - Coagulation 
[Implementation Note: This listing is included in the table shells document, as it is included in the body of the CSR. This listing includes all abnormal 
Coagulation results (laboratory results outside of the normal range defined in the protocol). Normal coagulation results for other parameters that occurred 
on the same visit as the abnormal result will not be listed. There is a separate, complete listing of all Coagulation results in Appendix 3. In the Laboratory 
Parameter column, indicate the units in parentheses after the parameter, e.g., Prothrombin Time (s). This listing is not color-coded, but the severity 
should be included in parentheses after the result, e.g., 10.5 (Moderate). Results that are outside the normal range but not mild, moderate, or severe will 
have (ONR) as the severity included after the result. Results that meet grading criteria of mild, moderate, or severe but which are not treatment emergent 
(not worse than baseline, as described in Section 9.6) will be shown as “ONR”. 
Sort order: Treatment Group, Participant ID, Timepoint, and Parameter. 
Treatment Group order: WCK 6777 2g, ERT 2g, ZID 2g, WCK 6777 4g, ERT 3g, ZID 3g, WCK 6777 6g, Placebo] 
Participant 
ID 
Treatment 
Group 
Sex 
Age 
(years) 
Planned 
Timepoint 
Actual 
Study Day 
Laboratory 
Parameter 
(Units) 
Result 
(Severity) 
Relationship to 
Treatment 
If Not Related, 
Alternate 
Etiology 
Action Taken 
with Study 
Treatment 
Participant 
Discontinued Due 
to Result? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 201: 
Listing of Abnormal Laboratory Results - Urinalysis 
[Implementation Note: This listing is included in the table shells document, as it is included in the body of the CSR. This listing includes all abnormal 
Urinalysis results (laboratory results outside of the normal range defined in the protocol). Normal urinalysis results for other parameters that occurred on 
the same visit as the abnormal result will not be listed. There is a separate, complete listing of all Urinalysis results. In the Laboratory Parameter column, 
indicate the units in parentheses after the parameter, e.g., Red Blood Cells by Microscopy (/HPF). The test type used to obtain the results will also be 
indicated in the Laboratory Parameter column (e.g., Bilirubin by Dipstick, Red Blood Cells by Microscopy, etc.). This listing is not color-coded, but the 
severity should be included in parentheses after the result, e.g., 10.5 (Moderate). Results that are outside the normal range but not mild, moderate, or 
severe will have (ONR) as the severity included after the result. Results that meet grading criteria of mild, moderate, or severe but which are not 
treatment emergent (not worse than baseline, as described in Section 9.6) will be shown as “ONR”. Method should describe the type of urinalysis done, 
dipstick or microscopic test. 
Sort order: Treatment Group, Participant ID, Timepoint, and Parameter. 
Treatment Group order: WCK 6777 2g, ERT 2g, ZID 2g, WCK 6777 4g, ERT 3g, ZID 3g, WCK 6777 6g, Placebo] 
Participant 
ID 
Treatment 
Group 
Sex 
Age 
(years) 
Planned 
Timepoint 
Actual 
Study Day 
Laboratory 
Parameter 
(Units) 
Result 
(Severity) 
Relationship to 
Treatment 
If Not Related, 
Alternate 
Etiology 
Action Taken 
with Study 
Treatment 
Participant 
Discontinued Due 
to Result? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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14.3.5 Displays of Laboratory Results 
14.3.5.1 
Chemistry Results 
Table 202: 
Chemistry Laboratory Toxicity Grade by Parameter, Treatment Group, Timepoint, and 
Severity 
[Implementation Note: If there is not at least one Mild, Moderate, or Severe event for a Treatment Group 
within a parameter, then only the Maximum Severity Post Baseline row will be shown for that parameter. 
Only include chemistry parameters with grading criteria in the protocol. Toxicities representing an increase in 
the laboratory result will be summarized separately from decreases. For example, there will be one row for 
“Sodium, Decrease” and another for “Sodium, Increase”.] 
Treatment 
Group 
Timepoint 
N 
Mild 
Moderate 
Severe 
n (%) 
n (%) 
n (%) 
Chemistry - Any Parameter 
All Participants 
Baseline 
x 
x (x) 
x (x) 
x (x) 
 
Maximum Severity Post Baseline 
x 
x (x) 
x (x) 
x (x) 
 
Day 2 
x 
x (x) 
x (x) 
x (x) 
  
Day 4 
x 
x (x) 
x (x) 
x (x) 
  
Day 6 
x 
x (x) 
x (x) 
x (x) 
  
Day 8 
x 
x (x) 
x (x) 
x (x) 
 
Day 11 
x 
x (x) 
x (x) 
x (x) 
WCK 6777 2g 
Baseline 
x 
x (x) 
x (x) 
x (x) 
  
… 
x 
x (x) 
x (x) 
x (x) 
ERT 2g 
Baseline 
x 
x (x) 
x (x) 
x (x) 
  
… 
x 
x (x) 
x (x) 
x (x) 
ZID 2g 
Baseline 
x 
x (x) 
x (x) 
x (x) 
  
… 
x 
x (x) 
x (x) 
x (x) 
WCK 6777 4g 
Baseline 
x 
x (x) 
x (x) 
x (x) 
  
… 
x 
x (x) 
x (x) 
x (x) 
ERT 3g 
Baseline 
x 
x (x) 
x (x) 
x (x) 
  
… 
x 
x (x) 
x (x) 
x (x) 
ZID 3g 
Baseline 
x 
x (x) 
x (x) 
x (x) 
  
… 
x 
x (x) 
x (x) 
x (x) 
WCK 6777 6g 
Baseline 
x 
x (x) 
x (x) 
x (x) 
 
… 
x 
x (x) 
x (x) 
x (x) 
Placebo 
Baseline 
x 
x (x) 
x (x) 
x (x) 
  
… 
x 
x (x) 
x (x) 
x (x) 
Albumin, Decrease  
Any Dose 
Baseline 
x 
x (x) 
x (x) 
x (x) 
… 
… 
x 
x (x) 
x (x) 
x (x) 
Notes: The “Maximum Severity Post Baseline” rows indicate the maximum severity experienced by each participant at any timepoint post 
baseline, including unscheduled assessments. 
N=Number of participants in the Safety Population with the laboratory result assessed at the respective timepoint. 
 


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Table 203: 
Chemistry Summary Statistics Measurement and Change from Baseline by Parameter, Treatment Group, and Timepoint 
Treatment Group 
Timepoint 
N 
Measurement 
Change from Baseline 
Mean 
SD 
Median 
Min, Max 
Mean 
SD 
Median 
Min, Max 
Sodium (mmol/L) 
All Participants 
Baseline 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
 
Day 2 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
 
Day 4 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
 
Day 6 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
 
Day 8 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
 
Day 11 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
WCK 6777 2g 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
… 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
ERT 2g 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
… 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
ZID 2g 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
… 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
WCK 6777 4g 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
… 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
ERT 3g 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
… 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
ZID 3g 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
… 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
WCK 6777 6g 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
… 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
Placebo 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
… 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
[Repeat for all parameters] 
Note: N=Number of participants in the Safety Population with the laboratory result assessed at the respective timepoint. 


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14.3.5.2 
Hematology Results 
Table 204: 
Hematology Laboratory Toxicity Grade by Parameter, Treatment Group, Timepoint, and Severity 
[This table will repeat Table 199 for Hematology Parameters] 
Table 205: 
Hematology Summary Statistics Measurement and Change from Baseline by Parameter, Treatment Group, and Timepoint 
[This table will repeat Table 200 for Hematology Parameters] 


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14.3.5.3 
Coagulation Results 
Table 206: 
Coagulation Laboratory Toxicity Grade by Parameter, Treatment Group, Timepoint, and Severity 
[This table will repeat Table 199 for Coagulation Parameters] 
Table 207: 
Coagulation Summary Statistics Measurement and Change from Baseline by Parameter, Treatment Group, and Timepoint 
[This table will repeat Table 200 for Coagulation Parameters] 


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14.3.5.4 
Urinalysis Results 
Table 208: 
Urinalysis Laboratory Toxicity Grade by Parameter, Treatment Group, Timepoint, and Severity 
[This table will repeat Table 199 for Urinalysis Parameters with timepoints baseline, day 4, day 8, day 11] 
Table 209: 
Urinalysis Summary Statistics Measurement and Change from Baseline by Parameter, Treatment Group, and Timepoint 
[This table will repeat Table 200 for Urinalysis Parameters with timepoints baseline, day 4, day 8, day 11] 
 


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14.3.5 Displays of Vital Signs 
Table 210: 
Vital Sign Toxicity Grade by Parameter, Treatment Group, Timepoint, and Severity 
[Implementation Note: If there is not at least one Mild, Moderate, or Severe event for a Treatment Group 
within a parameter, then only the Maximum Severity Post Baseline row will be shown for that parameter. 
Summarize increase results separately from decrease results. For example, there will be one row for “Pulse, 
Decrease” and another for “Pulse, Increase”.] 
Treatment Group 
Timepoint 
N 
Mild 
Moderate 
Severe 
n (%) 
n (%) 
n (%) 
Any Parameter 
All Participants 
Baseline 
x 
x (x) 
x (x) 
x (x) 
 
Maximum Severity Post Baseline 
x 
x (x) 
x (x) 
x (x) 
  
Day 1 
x 
x (x) 
x (x) 
x (x) 
  
Day 2 
x 
x (x) 
x (x) 
x (x) 
  
Day 3 
x 
x (x) 
x (x) 
x (x) 
  
Day 4 
x 
x (x) 
x (x) 
x (x) 
  
Day 5 
x 
x (x) 
x (x) 
x (x) 
  
Day 6 
x 
x (x) 
x (x) 
x (x) 
  
Day 7 
x 
x (x) 
x (x) 
x (x) 
  
Day 8 
x 
x (x) 
x (x) 
x (x) 
  
Day 11 
x 
x (x) 
x (x) 
x (x) 
WCK 6777 2g 
Baseline 
x 
x (x) 
x (x) 
x (x) 
  
… 
x 
x (x) 
x (x) 
x (x) 
ERT 2g 
Baseline 
x 
x (x) 
x (x) 
x (x) 
  
… 
x 
x (x) 
x (x) 
x (x) 
ZID 2g 
Baseline 
x 
x (x) 
x (x) 
x (x) 
  
… 
x 
x (x) 
x (x) 
x (x) 
WCK 6777 4g 
Baseline 
x 
x (x) 
x (x) 
x (x) 
  
… 
x 
x (x) 
x (x) 
x (x) 
ERT 3g 
Baseline 
x 
x (x) 
x (x) 
x (x) 
  
… 
x 
x (x) 
x (x) 
x (x) 
ZID 3g 
Baseline 
x 
x (x) 
x (x) 
x (x) 
  
… 
x 
x (x) 
x (x) 
x (x) 
WCK 6777 6g 
Baseline 
x 
x (x) 
x (x) 
x (x) 
 
… 
x 
x (x) 
x (x) 
x (x) 
Placebo 
Baseline 
x 
x (x) 
x (x) 
x (x) 
  
… 
x 
x (x) 
x (x) 
x (x) 
Pulse, Decrease (bpm) 
All Participants 
Baseline 
x 
x (x) 
x (x) 
x (x) 
… 
… 
x 
x (x) 
x (x) 
x (x) 
… 
Notes: The “Maximum Severity Post Baseline” rows indicate the maximum severity experienced by each participant at any timepoint post 
baseline, including unscheduled assessments. 
N=Number of participants in the Safety Population with the vital sign assessed at the respective timepoint. 
 


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Table 211: 
Vital Sign Summary Statistics Measurement and Change from Baseline by Parameter, Treatment Group, and Timepoint  
Treatment Group 
Timepoint 
N 
Measurement 
Change from Baseline 
Mean 
SD 
Median 
Min, Max 
Mean 
SD 
Median 
Min, Max 
Systolic Blood Pressure 
All Participants 
Baseline 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
 
Day 1 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
 
Day 2 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
 
Day 3 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
 
Day 4 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
 
Day 5 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
 
Day 6 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
 
Day 7 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
 
Day 8 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
 
Day 11 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
WCK 6777 2g 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
… 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
ERT 2g 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
… 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
ZID 2g 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
… 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
WCK 6777 4g 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
… 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
ERT 3g 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
… 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
ZID 3g 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
… 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
WCK 6777 6g 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
… 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 


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Table 211: 
Vital Sign Summary Statistics Measurement and Change from Baseline by Parameter, Treatment Group, and Timepoint 
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Treatment Group 
Timepoint 
N 
Measurement 
Change from Baseline 
Mean 
SD 
Median 
Min, Max 
Mean 
SD 
Median 
Min, Max 
Systolic Blood Pressure 
Placebo 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
… 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
[Repeat for all parameters] 
Note: N=Number of participants in the Safety Population with the vital sign assessed at the respective timepoint. 


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Table 212: 
Summary of Post Dose ECG Change in Overall Interpretations from Baseline by Treatment Group and Timepoint   
Change from Baseline in ECG 
Interpretation 
WCK 6777 
2g 
n (%) 
ERT 2g 
n (%) 
ZID 2g 
n (%) 
WCK 6777 
4g 
n (%) 
ERT 3g 
n (%) 
ZID 3g 
n (%) 
WCK 6777 
6g 
n (%) 
Placebo 
n (%) 
All 
Participants 
n (%) 
Day 8 
N 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Normal at Both Times 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Normal to Abnormal, NCS 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Normal to Abnormal, CS 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Day 11 
N 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Normal at Both Times 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Normal to Abnormal, NCS 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Normal to Abnormal, CS 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Notes: N=Number of participants in the Safety Population with ECG measurements at the timepoints indicated.  
NCS = Not clinically significant, CS = Clinically significant. 
 


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Table 213: 
ECG Toxicity Grade by Parameter, Severity, Treatment Group, and Timepoint 
[Implementation Note: If there is not at least one Mild, Moderate, or Severe event for a Treatment Group 
within a parameter, then only the Maximum Severity Post Baseline row will be shown for that parameter.] 
Treatment Group 
Timepoint 
N 
Mild 
Moderate 
Severe 
n (%) 
n (%) 
n (%) 
QTcF Interval (msec) 
All Participants 
Baseline 
x 
x (x) 
x (x) 
x (x) 
  
Maximum Severity Post Baseline 
x 
x (x) 
x (x) 
x (x) 
  
Day 8 
x 
x (x) 
x (x) 
x (x) 
  
Day 11 
x 
x (x) 
x (x) 
x (x) 
WCK 6777 2g 
Baseline 
x 
x (x) 
x (x) 
x (x) 
  
… 
x 
x (x) 
x (x) 
x (x) 
ERT 2g 
Baseline 
x 
x (x) 
x (x) 
x (x) 
  
… 
x 
x (x) 
x (x) 
x (x) 
ZID 2g 
Baseline 
x 
x (x) 
x (x) 
x (x) 
  
… 
x 
x (x) 
x (x) 
x (x) 
WCK 6777 4g 
Baseline 
x 
x (x) 
x (x) 
x (x) 
  
… 
x 
x (x) 
x (x) 
x (x) 
ERT 3g 
Baseline 
x 
x (x) 
x (x) 
x (x) 
  
… 
x 
x (x) 
x (x) 
x (x) 
ZID 3g 
Baseline 
x 
x (x) 
x (x) 
x (x) 
  
… 
x 
x (x) 
x (x) 
x (x) 
WCK 6777 6g 
Baseline 
x 
x (x) 
x (x) 
x (x) 
 
… 
x 
x (x) 
x (x) 
x (x) 
Placebo 
Baseline 
x 
x (x) 
x (x) 
x (x) 
  
… 
x 
x (x) 
x (x) 
x (x) 
Notes: The "Maximum Severity Post Baseline" row indicates the maximum severity of ECG results experienced across all participants at any 
timepoint post baseline, including unscheduled assessments.  
N=Number of participants in the Safety Population with ECG results assessed at the respective timepoint. 
 
 


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Table 214: 
ECG Summary Statistics Measurement and Change from Baseline by Parameter, Severity, Treatment Group, and Timepoint  
Treatment Group 
Timepoint 
N 
Measurement 
Change from Baseline 
Mean 
SD 
Median 
Min, Max 
Mean 
SD 
Median 
Min, Max 
PR Interval (msec) 
All Participants 
Baseline 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
 
Day 8 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
 
Day 11 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
WCK 6777 2g 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
… 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
ERT 2g 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
… 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
ZID 2g 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
… 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
WCK 6777 4g 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
… 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
ERT 3g 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
… 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
ZID 3g 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
… 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
WCK 6777 6g 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
… 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
Placebo 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
- 
- 
- 
- 
… 
 
x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
xx.xx 
xx.xx 
xx.xx 
xx.x, xx.x 
[Repeat for all parameters] 
Note: N=Number of participants in the Safety Population with ECG measurements at the respective timepoint. 
 


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14.4 
Summary of Prior and Concomitant Medications 
Table 215: 
Number and Percentage of Participants with Prior Medications by WHO Drug Classification and Treatment Group 
WHO Drug Code 
Level 1, Anatomic 
Group 
WHO Drug Code 
Level 2, 
Therapeutic 
Subgroup 
WCK 6777 2g 
(N=X) 
ERT 2g 
(N=X) 
ZID 2g 
(N=X) 
WCK 6777 4g 
(N=X) 
ERT 3g 
(N=X) 
ZID 3g 
(N=X) 
WCK 6777 6g 
(N=X) 
Placebo 
(N=X) 
All 
Participants 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any Level 1 Codes Any Level 2 Codes 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[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] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N = Number of participants in the Safety Population. n=Number of participants reporting taking at least one medication in the specific WHO Drug Class. 
 
 
 
 


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Table 216: 
Number and Percentage of Participants with Concomitant Medications by WHO Drug Classification and Treatment Group 
WHO Drug Code 
Level 1, Anatomic 
Group 
WHO Drug Code 
Level 2, 
Therapeutic 
Subgroup 
WCK 6777 2g 
(N=X) 
ERT 2g 
(N=X) 
ZID 2g 
(N=X) 
WCK 6777 4g 
(N=X) 
ERT 3g 
(N=X) 
ZID 3g 
(N=X) 
WCK 6777 6g 
(N=X) 
Placebo 
(N=X) 
All 
Participants 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any Level 1 Codes Any Level 2 Codes 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
[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] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N = Number of participants in the Safety Population. n=Number of participants 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: 
Schematic of Study Design .......................................................................................145 
Figure 2: 
CONSORT Flow Diagram .......................................................................................146 
Figure 3: 
Individual Total ERT Concentration in Plasma Profiles, Dose 1 .............................147 
Figure 4: 
Individual Total ERT Concentration in Plasma Profiles, Dose 7 .............................148 
Figure 5: 
Individual Total Trough ERT Concentration in Plasma Profiles, Doses 1 - 7 .........148 
Figure 6: 
Individual Total ERT Concentration in Plasma Profiles 12h After Dosing, 
Doses 1-7 ..................................................................................................................148 
Figure 7: 
Individual Free ERT Concentration in Plasma Profiles, Dose 1 ..............................148 
Figure 8: 
Individual Free ERT Concentration in Plasma Profiles, Dose 7 ..............................148 
Figure 9: 
Individual Free ERT Trough Concentration in Plasma Profiles, Doses 1-7 .............148 
Figure 10: Individual Free ERT Concentration in Plasma Profiles 12h After Dosing, 
Doses 1-7 ..................................................................................................................148 
Figure 11: Individual Total ZID Concentration in Plasma Profiles, Dose 1 ..............................148 
Figure 12: Individual Total ZID Concentration in Plasma Profiles, Dose 7 ..............................148 
Figure 13: Individual Total Trough ZID Concentration in Plasma Profiles, Doses 1-7 ............148 
Figure 14: Individual Total ZID Concentration in Plasma Profiles 12h After Dosing, 
Doses 1-7 ..................................................................................................................149 
Figure 15: Individual Free ZID Concentration in Plasma Profiles, Dose 1 ...............................149 
Figure 16: Individual Free ZID Concentration in Plasma Profiles, Dose 7 ...............................149 
Figure 17: Individual Free ZID Trough Concentration in Plasma Profiles, Doses 1-7 .............149 
Figure 18: Individual Free ZID Concentration in Plasma Profiles 12h After Dosing, 
Doses 1-7 ..................................................................................................................149 
Figure 19: Semi-Log Individual Total ERT Concentration in Plasma Profiles, Dose 1 ............150 
Figure 20: Semi-Log Individual Total ERT Concentration in Plasma Profiles, Dose 7 ............151 
Figure 21: Semi-Log Individual Free ERT Concentration in Plasma Profiles, Dose 1 .............151 
Figure 22: Semi-Log Individual Free ERT Concentration in Plasma Profiles, Dose 7 .............151 
Figure 23: Semi-Log Individual Total ZID Concentration in Plasma Profiles, Dose 1 .............151 
Figure 24: Semi-Log Individual Total ZID Concentration in Plasma Profiles, Dose 7 .............151 
Figure 25: Semi-Log Individual Free ZID Concentration in Plasma Profiles, Dose 1 ..............151 
Figure 26: Semi-Log Individual Free ZID Concentration in Plasma Profiles, Dose 7 ..............151 


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Figure 27: Mean ERT Concentration in Plasma Profiles by Treatment Group, Dose 1 ............152 
Figure 28: Mean ERT Concentration in Plasma Profiles by Treatment Group, Dose 7 ............153 
Figure 29: Mean Trough ERT Concentration in Plasma Profiles by Treatment Group, 
Doses 1-7 ..................................................................................................................153 
Figure 30: Mean ERT Concentration in Plasma Profiles by Treatment Group 12h After 
Dosing, Doses 1-7 .....................................................................................................153 
Figure 31: Mean ZID Concentration in Plasma Profiles by Treatment Group, Dose 1 .............153 
Figure 32: Mean ZID Concentration in Plasma Profiles by Treatment Group, Dose 7 .............153 
Figure 33: Mean Trough ZID Concentration in Plasma Profiles by Treatment Group, 
Doses 1-7 ..................................................................................................................153 
Figure 34: Mean ZID Concentration in Plasma Profiles by Treatment Group 12h After 
Dosing, Doses 1-7 .....................................................................................................153 
Figure 35: Semi-Log Mean ERT Concentration in Plasma Profiles by Treatment Group, 
Dose 1 .......................................................................................................................154 
Figure 36: Semi-Log Mean ERT Concentration in Plasma Profiles by Treatment Group, 
Dose 7 .......................................................................................................................154 
Figure 37: Semi-Log Mean Trough ERT Concentration in Plasma Profiles by 
Treatment Group, Doses 2-8 .....................................................................................154 
Figure 38: Semi-Log Mean ERT Concentration in Plasma Profiles by Treatment Group 
12h After Dosing, Doses 1-7 ....................................................................................154 
Figure 39: Semi-Log Mean ZID Concentration in Plasma Profiles by Treatment Group, 
Dose 1 .......................................................................................................................154 
Figure 40: Semi-Log Mean ZID Concentration in Plasma Profiles by Treatment Group, 
Dose 7 .......................................................................................................................154 
Figure 41: Semi-Log Mean Trough ZID Concentration in Plasma Profiles by Treatment 
Group, Doses 2-8 ......................................................................................................154 
Figure 42: Semi-Log Mean ZID Concentration in Plasma Profiles by Treatment Group 
12h After Dosing, Doses 1-7 ....................................................................................154 
Figure 43: Mean Percent ERT Protein Binding, Dose 1 and Dose 7 .........................................155 
Figure 44: Mean Percent ERT Protein Binding, Doses 1-7 .......................................................156 
Figure 45: Mean Percent ZID Protein Binding, Dose 1 and Dose 7 ..........................................156 
Figure 46: Mean Percent ZID Protein Binding, Doses 1-7 ........................................................156 
Figure 47: Percent ERT Protein Binding vs Total Concentration, Dose 1 and Dose 7 .............157 
Figure 48: Percent ZID Protein Binding vs Total Concentration, Dose 1 and Dose 7 ..............158 
Figure 49: Percent ERT Protein Binding vs log10 Total Concentration, Dose 1 and 
Dose 7 .......................................................................................................................158 


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Figure 50: Percent ZID Protein Binding vs log10 Total Concentration, Dose 1 and Dose 
7 ................................................................................................................................158 
Figure 51: Amount ERT Bound vs Total Concentration, Dose 1 and Dose 7 ...........................158 
Figure 52: Amount ZID Bound vs Total Concentration, Dose 1 and Dose 7 ............................158 
Figure 53: Individual Cumulative Amount of ERT Excreted into Urine, Dose 1 .....................159 
Figure 54: Individual Cumulative Amount of ERT Excreted into Urine, Dose 7 .....................160 
Figure 55: Individual Cumulative Amount of ZID Excreted into Urine, Dose 1 ......................160 
Figure 56: Individual Cumulative Amount of ZID Excreted into Urine, Dose 7 ......................160 
Figure 57: Mean Cumulative Amount of ERT Excreted into Urine by Treatment Group ........161 
Figure 58: Mean Cumulative Amount of ZID Excreted into Urine by Treatment Group .........162 
Figure 59: Dose Proportionality, ERT and ZID Concentrations in Plasma - Cmax ....................163 
Figure 60: Dose Proportionality, ERT and ZID Concentrations in Plasma – AUC0-last .............163 
Figure 61: Dose Proportionality, ERT and ZID Concentrations in Plasma – AUC0-inf .............163 
Figure 62: Dose Proportionality, ERT and ZID Concentrations in Plasma - Cmax,ss ..................163 
Figure 63: Dose Proportionality, ERT and ZID Concentrations in Plasma – AUC(0-24),ss .........163 
Figure 64: Dose Proportionality, ERT and ZID Concentrations in Plasma – AUC(0-tau),ss.........163 
Figure 65: Frequency of Related Adverse Events by MedDRA System Organ Class and 
Severity .....................................................................................................................164 
Figure 66: Incidence of Related Adverse Events by MedDRA System Organ Class and 
Maximum Severity ...................................................................................................165 
Figure 67: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – Albumin ....................................166 
Figure 68: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – Sodium ......................................167 
Figure 69: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – Potassium ..................................167 
Figure 70: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – Calcium ....................................167 
Figure 71: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – Chloride ....................................167 
Figure 72: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – Total Carbon Dioxide ...............167 
Figure 73: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – Creatinine .................................167 
Figure 74: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – Blood Urea Nitrogen ................167 


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Figure 75: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – Glucose .....................................167 
Figure 76: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – Total Bilirubin ..........................167 
Figure 77: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – Direct Bilirubin .........................167 
Figure 78: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – Alanine Aminotransferase ........167 
Figure 79: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – Aspartate 
Aminotransferase ......................................................................................................168 
Figure 80: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – Alkaline Phosphatase ...............168 
Figure 81: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – Lactic Dehydrogenase ..............168 
Figure 82: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – Total Protein .............................168 
Figure 83: Hematology Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – Hemoglobin ..............................169 
Figure 84: Hematology Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – Hematocrit ................................169 
Figure 85: Hematology Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – RBC ..........................................169 
Figure 86: Hematology Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – Platelet Count ...........................169 
Figure 87: Hematology Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – WBC Count ..............................169 
Figure 88: Hematology Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – Neutrophils ...............................169 
Figure 89: Hematology Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – Lymphocytes ............................169 
Figure 90: Hematology Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – Eosinophils ...............................169 
Figure 91: Hematology Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – Basophils ..................................169 
Figure 92: Hematology Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – Monocytes ................................169 


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Figure 93: Coagulation Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – INR ...........................................170 
Figure 94: Coagulation Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – Prothrombin Time ....................170 
Figure 95: Coagulation Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – Activated Partial 
Thromboplastin Time ...............................................................................................170 
Figure 96: Urinalysis Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – Specific Gravity ........................171 
Figure 97: Urinalysis Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter, Treatment Group, and Timepoint – pH .............................................171 
Figure 98: Vital Signs by Scheduled Visits: Change from Baseline by Parameter, 
Timepoint, and Treatment Group – Systolic Blood Pressure ...................................172 
Figure 99: Vital Signs by Scheduled Visits: Change from Baseline by Parameter, 
Timepoint, and Treatment Group – Diastolic Blood Pressure .................................173 
Figure 100: Vital Signs by Scheduled Visits: Change from Baseline by Parameter, 
Timepoint, and Treatment Group – Heart Rate ........................................................173 
Figure 101: Vital Signs by Scheduled Visits: Change from Baseline by Parameter, 
Timepoint, and Treatment Group – Oral Temperature .............................................173 
Figure 102: Vital Signs by Scheduled Visits: Change from Baseline by Parameter, 
Timepoint, and Treatment Group – Respiratory Rate ..............................................173 
Figure 103: ECG by Scheduled Visits: Change from Baseline by Parameter and 
Treatment Group – PR Interval ................................................................................174 
Figure 104: ECG by Scheduled Visits: Change from Baseline by Parameter and 
Treatment Group – QRS Interval .............................................................................175 
Figure 105: ECG by Scheduled Visits: Change from Baseline by Parameter and 
Treatment Group – QT Interval ................................................................................175 
Figure 106: ECG by Scheduled Visits: Change from Baseline by Parameter and 
Treatment Group – QTcF Interval ............................................................................175 
Figure 107: ECG by Scheduled Visits: Change from Baseline by Parameter and 
Treatment Group – RR Interval ................................................................................175 
Figure 108: ECG by Scheduled Visits: Change from Baseline by Parameter and 
Treatment Group – Mean Ventricular Heart Rate ....................................................175 
 


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9.5.1 Safety Measurements Assessed and Flow Chart 
Figure 1: 
Schematic of Study Design 
 
 
 


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10.1 
Disposition of Participants 
Figure 2: 
CONSORT Flow Diagram 
 


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14.2.2 
Displays of PK Results 
Figure 3: 
Individual Total ERT Concentration in Plasma Profiles, Dose 1 
 


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Similar figures: 
Figure 4: 
Individual Total ERT Concentration in Plasma Profiles, Dose 7 
[Repeat above figure for Dose 7] 
Figure 5: 
Individual Total Trough ERT Concentration in Plasma Profiles, Doses 1 - 7   
[This will repeat the above figure for the t=0 pre-dose time point for Doses 1-7 and the 24 h post-dose time point for Dose 7. (The x-axis label will be 
replaced with ‘Doses’ and tick marks will be (1,2,3,4,5,6,7)] 
Figure 6: 
Individual Total ERT Concentration in Plasma Profiles 12h After Dosing, Doses 1-7 
[This will repeat the above figure for time=12h for Doses 1-7. The x-axis label will be replaced with ‘Doses’ and tick marks will be (1,2,3,4,5,6,7)] 
 
Figure 7: 
Individual Free ERT Concentration in Plasma Profiles, Dose 1 
[This will repeat the above figure for Dose 1 free concentrations] 
Figure 8: 
Individual Free ERT Concentration in Plasma Profiles, Dose 7 
[Repeat above figure for Dose 7 free concentrations] 
Figure 9: 
Individual Free ERT Trough Concentration in Plasma Profiles, Doses 1-7 
[This will repeat the above figure for the t=0 pre-dose time point for Doses 1-7 and the 24 h post-dose time point for Dose 7. (The x-axis label will be 
replaced with ‘Doses’ and tick marks will be (1,2,3,4,5,6,7)] 
Figure 10: 
Individual Free ERT Concentration in Plasma Profiles 12h After Dosing, Doses 1-7 
[This will repeat the above figure for time=12h for Doses 1-7. The x-axis label will be replaced with ‘Doses’ and tick marks will be (1,2,3,4,5,6,7)] 
Figure 11: 
Individual Total ZID Concentration in Plasma Profiles, Dose 1 
[Repeat ERT figure for ZID] 
Figure 12: 
Individual Total ZID Concentration in Plasma Profiles, Dose 7 
[Repeat ERT figure for ZID] 
Figure 13: 
Individual Total Trough ZID Concentration in Plasma Profiles, Doses 1-7 
[Repeat ERT figure for ZID] 


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Figure 14: 
Individual Total ZID Concentration in Plasma Profiles 12h After Dosing, Doses 1-7 
[Repeat ERT figure for ZID] 
Figure 15: 
Individual Free ZID Concentration in Plasma Profiles, Dose 1 
[Repeat ERT figure for ZID] 
Figure 16: 
Individual Free ZID Concentration in Plasma Profiles, Dose 7 
[Repeat ERT figure for ZID] 
Figure 17: 
Individual Free ZID Trough Concentration in Plasma Profiles, Doses 1-7 
[Repeat ERT figure for ZID] 
Figure 18: 
Individual Free ZID Concentration in Plasma Profiles 12h After Dosing, Doses 1-7 
[Repeat ERT figure for ZID] 


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Figure 19: 
Semi-Log Individual Total ERT Concentration in Plasma Profiles, Dose 1 
 
Similar figures: 


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Figure 20: 
Semi-Log Individual Total ERT Concentration in Plasma Profiles, Dose 7 
[Repeat above figure for Dose 7] 
Figure 21: 
Semi-Log Individual Free ERT Concentration in Plasma Profiles, Dose 1 
[Repeat above figure for free concentrations] 
Figure 22: 
Semi-Log Individual Free ERT Concentration in Plasma Profiles, Dose 7 
[Repeat above figure for Dose 7] 
Figure 23: 
Semi-Log Individual Total ZID Concentration in Plasma Profiles, Dose 1 
[Repeat figure above for ZID] 
Figure 24: 
Semi-Log Individual Total ZID Concentration in Plasma Profiles, Dose 7 
[Repeat figure above for ZID] 
Figure 25: 
Semi-Log Individual Free ZID Concentration in Plasma Profiles, Dose 1 
[Repeat figure above for ZID] 
Figure 26: 
Semi-Log Individual Free ZID Concentration in Plasma Profiles, Dose 7 
[Repeat figure above for ZID] 
 
 


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Figure 27: 
Mean ERT Concentration in Plasma Profiles by Treatment Group, Dose 1 


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Similar figures: 
Figure 28: 
Mean ERT Concentration in Plasma Profiles by Treatment Group, Dose 7 
[Repeat above figure for Dose 7] 
Figure 29: 
Mean Trough ERT Concentration in Plasma Profiles by Treatment Group, Doses 1-7 
[This will repeat the above figure for the t=0 pre-dose time point for Doses 1-7 and the 24 h post-dose time point for Dose 7. (The x-axis label will be 
replaced with ‘Doses’ and tick marks will be (1,2,3,4,5,6,7)] 
Figure 30: 
Mean ERT Concentration in Plasma Profiles by Treatment Group 12h After Dosing, Doses 1-7 
[This will repeat the above figure for time=12h for Doses 1-7. The x-axis label will be replaced with ‘Doses’ and tick marks will be (1,2,3,4,5,6,7)] 
Figure 31: 
Mean ZID Concentration in Plasma Profiles by Treatment Group, Dose 1 
[Repeat Figure 27 for ZID] 
Figure 32: 
Mean ZID Concentration in Plasma Profiles by Treatment Group, Dose 7 
[Repeat above figure for Dose 7] 
Figure 33: 
Mean Trough ZID Concentration in Plasma Profiles by Treatment Group, Doses 1-7 
[This will repeat the above figure for the t=0 pre-dose time point for Doses 1-7 and the 24 h post-dose time point for Dose 7. (The x-axis label will be 
replaced with ‘Doses’ and tick marks will be (1,2,3,4,5,6,7)] 
Figure 34: 
Mean ZID Concentration in Plasma Profiles by Treatment Group 12h After Dosing, Doses 1-7 
[This will repeat the above figure for time=12h for Doses 1-7. The x-axis label will be replaced with ‘Doses’ and tick marks will be (1,2,3,4,5,6,7)] 
 
 


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Figure 35: 
Semi-Log Mean ERT Concentration in Plasma Profiles by Treatment Group, Dose 1 
Figure 36: 
Semi-Log Mean ERT Concentration in Plasma Profiles by Treatment Group, Dose 7 
[Repeat above figure for Dose 7] 
Figure 37: 
Semi-Log Mean Trough ERT Concentration in Plasma Profiles by Treatment Group, Doses 2-8 
[This will repeat the above figure for the t=0 pre-dose time point for Doses 1-7 and the 24 h post-dose time point for Dose 7. (The x-axis label will be 
replaced with ‘Doses’ and tick marks will be (1,2,3,4,5,6,7)] 
Figure 38: 
Semi-Log Mean ERT Concentration in Plasma Profiles by Treatment Group 12h After Dosing, Doses 1-7 
[This will repeat the above figure for time=12h for Doses 1-7. The x-axis label will be replaced with ‘Doses’ and tick marks will be (1,2,3,4,5,6,7)] 
Figure 39: 
Semi-Log Mean ZID Concentration in Plasma Profiles by Treatment Group, Dose 1 
[Repeat Figure 27 for ZID] 
Figure 40: 
Semi-Log Mean ZID Concentration in Plasma Profiles by Treatment Group, Dose 7 
[Repeat above figure for Dose 7] 
Figure 41: 
Semi-Log Mean Trough ZID Concentration in Plasma Profiles by Treatment Group, Doses 2-8 
[This will repeat the above figure for the t=0 pre-dose time point for Doses 1-7 and the 24 h post-dose time point for Dose 7. (The x-axis label will be 
replaced with ‘Doses’ and tick marks will be (1,2,3,4,5,6,7)] 
Figure 42: 
Semi-Log Mean ZID Concentration in Plasma Profiles by Treatment Group 12h After Dosing, Doses 1-7 
[This will repeat the above figure for time=12h for Doses 1-7. The x-axis label will be replaced with ‘Doses’ and tick marks will be (1,2,3,4,5,6,7)] 
 
 


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Figure 43: 
Mean Percent ERT Protein Binding, Dose 1 and Dose 7 
 
 


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Similar figures: 
Figure 44: 
Mean Percent ERT Protein Binding, Doses 1-7 
[Implementation note: replace ‘Time (h)’ with ‘Doses’ and tick marks with 1:7. Times 0 h and 12 h will be shown for each dose. Only one panel will be 
shown.] 
Figure 45: 
Mean Percent ZID Protein Binding, Dose 1 and Dose 7 
Figure 46: 
Mean Percent ZID Protein Binding, Doses 1-7 
[Implementation note: replace ‘Time (h)’ with ‘Doses’ and tick marks with 1:7. Times 0 h and 12 h will be shown for each dose. Only one panel will be 
shown.] 
 
 


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Figure 47: 
Percent ERT Protein Binding vs Total Concentration, Dose 1 and Dose 7 
 
 
 


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Similar figures: 
Figure 48: 
Percent ZID Protein Binding vs Total Concentration, Dose 1 and Dose 7 
Figure 49: 
Percent ERT Protein Binding vs log10 Total Concentration, Dose 1 and Dose 7 
[Implementation note: x-axis label will be updated to ‘log10 Total Concentration in Plasma (µg)’] 
Figure 50: 
Percent ZID Protein Binding vs log10 Total Concentration, Dose 1 and Dose 7 
[Implementation note: x-axis label will be updated to ‘log10 Total Concentration in Plasma (µg)’] 
Figure 51: 
Amount ERT Bound vs Total Concentration, Dose 1 and Dose 7 
[Implementation note: The y-axis will be replaced with ‘Amount Bound (µg)’] 
Figure 52: 
Amount ZID Bound vs Total Concentration, Dose 1 and Dose 7 
[Implementation note: The y-axis will be replaced with ‘Amount Bound (µg)’] 
 
 
 
 
 


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Figure 53: 
Individual Cumulative Amount of ERT Excreted into Urine, Dose 1 
 


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Similar figures: 
Figure 54: 
Individual Cumulative Amount of ERT Excreted into Urine, Dose 7 
Figure 55: 
Individual Cumulative Amount of ZID Excreted into Urine, Dose 1 
Figure 56: 
Individual Cumulative Amount of ZID Excreted into Urine, Dose 7


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Figure 57: 
Mean Cumulative Amount of ERT Excreted into Urine by Treatment Group 
 


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Similar figure: 
Figure 58: 
Mean Cumulative Amount of ZID Excreted into Urine by Treatment Group 
 


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Figure 59: 
Dose Proportionality, ERT and ZID Concentrations in Plasma - Cmax 
 
Similar figures: 
Figure 60: 
Dose Proportionality, ERT and ZID Concentrations in Plasma – AUC0-last 
Figure 61: 
Dose Proportionality, ERT and ZID Concentrations in Plasma – AUC0-inf 
Figure 62: 
Dose Proportionality, ERT and ZID Concentrations in Plasma - Cmax,ss 
Figure 63: 
Dose Proportionality, ERT and ZID Concentrations in Plasma – AUC(0-24),ss 
Figure 64: 
Dose Proportionality, ERT and ZID Concentrations in Plasma – AUC(0-tau),ss


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14.3.1.2 Adverse Events 
Figure 65: 
Frequency of Related Adverse Events by MedDRA System Organ Class and Severity 
[Implementation Note: This figure includes serious and non-serious unsolicited adverse events related to the 
study product. Note that this figure will present the number of participants with each type of SOC. A 
participant will only be counted once for the same SOC for the maximum severity reported. 
There will be one panel for each of the following groups: 
All Participants, WCK 6777 2g, ERT 2g, ZID 2g, WCK 6777 4g, ERT 3g, ZID 3g, WCK 6777 6g, Placebo 
Order SOCs alphabetically.] 
 
 


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Figure 66: 
Incidence of Related Adverse Events by MedDRA System Organ Class and Maximum 
Severity  
[Implementation Note: This figure includes serious and non-serious unsolicited adverse events related to the 
study product. Note that this figure will present the number of participants with each type of SOC. A 
participant will only be counted once for the same SOC for the maximum severity reported. 
There will be one panel for each of the following groups: 
All Participants, WCK 6777 2g, ERT 2g, ZID 2g, WCK 6777 4g, ERT 3g, ZID 3g, WCK 6777 6g, Placebo 
Order SOCs alphabetically.] 
 
 


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14.3.5 
Displays of Laboratory Results 
14.3.5.1  
Chemistry Results 
Figure 67: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by Parameter, 
Treatment Group, and Timepoint – Albumin 
 
 
 


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Similar Figures: 
Figure 68: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by Parameter, 
Treatment Group, and Timepoint – Sodium 
[Repeat Figure 61 for Sodium] 
Figure 69: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by Parameter, 
Treatment Group, and Timepoint – Potassium 
[Repeat Figure 61 for Potassium] 
Figure 70: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by Parameter, 
Treatment Group, and Timepoint – Calcium 
[Repeat Figure 61 for Calcium] 
Figure 71: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by Parameter, 
Treatment Group, and Timepoint – Chloride 
[Repeat Figure 61 for Chloride] 
Figure 72: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by Parameter, 
Treatment Group, and Timepoint – Total Carbon Dioxide 
[Repeat Figure 61 for CO2] 
Figure 73: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by Parameter, 
Treatment Group, and Timepoint – Creatinine 
[Repeat Figure 61 for Creatinine] 
Figure 74: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by Parameter, 
Treatment Group, and Timepoint – Blood Urea Nitrogen 
[Repeat Figure 61 for BUN] 
Figure 75: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by Parameter, 
Treatment Group, and Timepoint – Glucose 
[Repeat Figure 61 for Glucose] 
Figure 76: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by Parameter, 
Treatment Group, and Timepoint – Total Bilirubin 
[Repeat Figure 61 for Total Bilirubin] 
Figure 77: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by Parameter, 
Treatment Group, and Timepoint – Direct Bilirubin 
[Repeat Figure 61 for Direct Bilirubin] 
Figure 78: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by Parameter, 
Treatment Group, and Timepoint – Alanine Aminotransferase 
[Repeat Figure 61 for ALT] 


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Figure 79: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by Parameter, 
Treatment Group, and Timepoint – Aspartate Aminotransferase 
[Repeat Figure 61 for AST] 
Figure 80: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by Parameter, 
Treatment Group, and Timepoint – Alkaline Phosphatase 
[Repeat Figure 61 for AP] 
Figure 81: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by Parameter, 
Treatment Group, and Timepoint – Lactic Dehydrogenase 
[Repeat Figure 61 for LDH] 
Figure 82: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by Parameter, 
Treatment Group, and Timepoint – Total Protein 
[Repeat Figure 61 for Total Protein] 
 
 
 


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14.3.5.2  
Hematology Results 
Figure 83: 
Hematology Laboratory Results by Scheduled Visits: Change from Baseline by 
Parameter, Treatment Group, and Timepoint – Hemoglobin 
[Repeat Figure 61 for Hgb] 
Figure 84: 
Hematology Laboratory Results by Scheduled Visits: Change from Baseline by 
Parameter, Treatment Group, and Timepoint – Hematocrit 
[Repeat Figure 61 for Hct] 
Figure 85: 
Hematology Laboratory Results by Scheduled Visits: Change from Baseline by 
Parameter, Treatment Group, and Timepoint – RBC 
[Repeat Figure 61 for RBC] 
Figure 86: 
Hematology Laboratory Results by Scheduled Visits: Change from Baseline by 
Parameter, Treatment Group, and Timepoint – Platelet Count 
[Repeat Figure 61 for Platelet Count] 
Figure 87: 
Hematology Laboratory Results by Scheduled Visits: Change from Baseline by 
Parameter, Treatment Group, and Timepoint – WBC Count 
[Repeat Figure 61 for WBC Count] 
Figure 88: 
Hematology Laboratory Results by Scheduled Visits: Change from Baseline by 
Parameter, Treatment Group, and Timepoint – Neutrophils 
[Repeat Figure 61 for Neutrophils] 
Figure 89: 
Hematology Laboratory Results by Scheduled Visits: Change from Baseline by 
Parameter, Treatment Group, and Timepoint – Lymphocytes 
[Repeat Figure 61 for Lymphocytes] 
Figure 90: 
Hematology Laboratory Results by Scheduled Visits: Change from Baseline by 
Parameter, Treatment Group, and Timepoint – Eosinophils 
[Repeat Figure 61 for Eosinophils] 
Figure 91: 
Hematology Laboratory Results by Scheduled Visits: Change from Baseline by 
Parameter, Treatment Group, and Timepoint – Basophils 
[Repeat Figure 61 for Basophils] 
Figure 92: 
Hematology Laboratory Results by Scheduled Visits: Change from Baseline by 
Parameter, Treatment Group, and Timepoint – Monocytes 
[Repeat Figure 61 for Monocytes] 
 
 


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14.3.5.3  
Coagulation Results 
Figure 93: 
Coagulation Laboratory Results by Scheduled Visits: Change from Baseline by 
Parameter, Treatment Group, and Timepoint – INR 
[Repeat Figure 61 for INR] 
Figure 94: 
Coagulation Laboratory Results by Scheduled Visits: Change from Baseline by 
Parameter, Treatment Group, and Timepoint – Prothrombin Time  
[Repeat Figure 61 for PT] 
Figure 95: 
Coagulation Laboratory Results by Scheduled Visits: Change from Baseline by 
Parameter, Treatment Group, and Timepoint – Activated Partial Thromboplastin Time  
[Repeat Figure 61 for APTT] 
 
 
 


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14.3.5.4  
Urinalysis Results 
Figure 96: 
Urinalysis Laboratory Results by Scheduled Visits: Change from Baseline by Parameter, 
Treatment Group, and Timepoint – Specific Gravity 
[Repeat Figure 61 for Specific Gravity with timepoints d4, d8, d11] 
Figure 97: 
Urinalysis Laboratory Results by Scheduled Visits: Change from Baseline by Parameter, 
Treatment Group, and Timepoint – pH 
[Repeat Figure 61 for pH with timepoints d4, d8, d11] 
 
 
 


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14.3.5.5  
Displays of Vital Signs 
Figure 98: 
Vital Signs by Scheduled Visits: Change from Baseline by Parameter, Timepoint, and Treatment Group – Systolic Blood Pressure  
 


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Figure 99: 
Vital Signs by Scheduled Visits: Change from Baseline by Parameter, Timepoint, and Treatment Group – Diastolic Blood 
Pressure  
[Repeat Figure 91 for DBP] 
Figure 100: 
Vital Signs by Scheduled Visits: Change from Baseline by Parameter, Timepoint, and Treatment Group – Heart Rate 
[Repeat Figure 91 for Heart rate] 
Figure 101: 
Vital Signs by Scheduled Visits: Change from Baseline by Parameter, Timepoint, and Treatment Group – Oral Temperature 
[Repeat Figure 91 for Temperature] 
Figure 102: 
Vital Signs by Scheduled Visits: Change from Baseline by Parameter, Timepoint, and Treatment Group – Respiratory Rate 
[Repeat Figure 91 for Respiratory rate] 
 


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14.3.5.7  
Displays of ECG Measurements 
Figure 103: 
ECG by Scheduled Visits: Change from Baseline by Parameter and Treatment Group – 
PR Interval  
 
 


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Similar figures: 
Figure 104: 
ECG by Scheduled Visits: Change from Baseline by Parameter and Treatment Group – 
QRS Interval  
Figure 105: 
ECG by Scheduled Visits: Change from Baseline by Parameter and Treatment Group – 
QT Interval  
Figure 106: 
ECG by Scheduled Visits: Change from Baseline by Parameter and Treatment Group – 
QTcF Interval  
Figure 107: 
ECG by Scheduled Visits: Change from Baseline by Parameter and Treatment Group – 
RR Interval  
Figure 108: 
ECG by Scheduled Visits: Change from Baseline by Parameter and Treatment Group – 
Mean Ventricular Heart Rate  
 


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APPENDIX 3. LISTINGS MOCK-UPS 
 
 


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LISTINGS 
Listing 1: 16.1.6: Listing of Participants Receiving Investigational Product ...........................179 
Listing 2: 16.2.1: Early Terminations or Discontinued Participants .........................................180 
Listing 3: 16.2.2.1: Participant-Specific Protocol Deviations ...................................................181 
Listing 4: 16.2.2.2: Non-Participant-Specific Protocol Deviations ..........................................182 
Listing 5: 16.2.3: Participants Excluded from Analysis Populations ........................................183 
Listing 6: 16.2.4.1: Demographic Data .....................................................................................184 
Listing 7: 16.2.4.2: Pre-Existing and Concurrent Medical Conditions .....................................185 
Listing 8: 16.2.5: Compliance Data ..........................................................................................186 
Listing 9: 16.2.5: Infusion Interruptions ...................................................................................187 
Listing 10: Participant Level Total ERT and ZID Concentrations – Plasma ..............................188 
Listing 11: Participant Level Free ERT and ZID Concentrations – Plasma ...............................188 
Listing 12: Participant Specific Single-Dose ERT Plasma PK Parameters - Total ....................189 
Listing 13: Participant Specific Single-Dose ERT Plasma PK Parameters - Free ......................189 
Listing 14: Participant Specific Single-Dose ZID Plasma PK Parameters – Total .....................189 
Listing 15: Participant Specific Single-Dose ZID Plasma PK Parameters - Free .......................189 
Listing 16: Participant Specific Multiple-Dose ERT Plasma PK Parameters - Total .................190 
Listing 17: Participant Specific Multiple-Dose ERT Plasma PK Parameters - Free ..................190 
Listing 18: Participant Specific Multiple-Dose ZID Plasma PK Parameters – Total .................190 
Listing 19: Participant Specific Multiple-Dose ZID Plasma PK Parameters - Free ...................190 
Listing 20: Participant Level Total ERT and ZID Concentrations in Urine ...............................191 
Listing 21: Participant Specific ERT Urine PK Parameters, Dose 1 ..........................................192 
Listing 22: Participant Specific ERT Urine PK Parameters, Dose 7 ..........................................192 
Listing 23: Participant Specific ZID Urine PK Parameters, Dose 1 ...........................................192 
Listing 24: Participant Specific ZID Urine PK Parameters, Dose 7 ...........................................192 
Listing 25: 16.2.7.3: Adverse Events ..........................................................................................193 
Listing 26: 16.2.8.1: Clinical Laboratory Results – Chemistry ..................................................194 
Listing 27: 16.2.8.2: Clinical Laboratory Results – Hematology ...............................................195 
Listing 28: 16.2.8.3: Clinical Laboratory Results – Coagulation ...............................................196 
Listing 29: 16.2.8.4: Clinical Laboratory Results – Urinalysis...................................................197 
Listing 30: 16.2.9.1: Screening Laboratory Results – Serology .................................................198 
Listing 31: 16.2.9.1: Screening Laboratory Results – hCG and Serum FSH Tests ....................199 


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Listing 32: 16.2.9.1: Screening Laboratory Results – Urine Toxicology ...................................200 
Listing 33: 16.2.9.2: Vital Signs .................................................................................................201 
Listing 34: 16.2.9.3: Physical Exam Findings ............................................................................202 
Listing 35: 16.2.9.4: Listing of ECG Interval Measurements .....................................................203 
Listing 36: 16.2.9.4: Listing of ECG Overall Interpretation and Comments ..............................204 
Listing 37: Prior Medications ......................................................................................................205 
Listing 38: 16.2.10: Concomitant Medications ...........................................................................206 
Listing 39: 16.2.11.1: Pregnancy Reports – Maternal Information ............................................207 
Listing 40: 16.2.11.2: Pregnancy Reports – Gravida and Para ...................................................208 
Listing 41: 16.2.11.3: Pregnancy Reports – Live Birth Outcomes .............................................209 
Listing 42: 16.2.11.4: Pregnancy Reports – Still Birth Outcomes ..............................................210 
Listing 43: 16.2.11.5: Pregnancy Reports – Spontaneous, Elective, or Therapeutic 
Abortion Outcomes ...................................................................................................211 
 


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Listing 1: 
16.1.6: Listing of Participants Receiving Investigational Product 
(not included in SAP, but this is a placeholder for the CSR) 


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16.2 
Database Listings by Participant 
16.2.1 Discontinued Participants 
Listing 2: 
16.2.1: Early Terminations or Discontinued Participants 
[Implementation Note: Category will either be “Early Termination” or “Treatment Discontinuation”. In the “Reason” column, concatenate any “specify” 
fields, including AE number and DV number.  
Sort order: Treatment Group, Participant ID, Category (in the case that a participant both terminates early and discontinues treatment).] 
Treatment Group 
 Participant ID 
Category 
Reason for Early Termination or Treatment Discontinuation 
Study Day 
 
 
 
 
 
 
 
 


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16.2.2 Protocol Deviations 
Listing 3: 
16.2.2.1: Participant-Specific Protocol Deviations 
[Implementation Note: In the “Deviation” column, concatenate any and all “specify” fields (including visit number, etc.). If  “Reason for Deviation is 
“Other,” concatenate the “specify” fields, separated by a colon, e.g., “Other: Participant refusal.” If deviation resulted in AE or participant termination, 
or affected product stability, indicate which of those events occurred in the listing row since those 3 columns were concatenated. 
Review the site comments carefully. Replace any occurrences of the PATID in the comments with the USUBJID.  
Sort order: Treatment Group, Participant ID, DV Number.] 
Treatment 
Group 
Participant 
ID 
DV Number 
Deviation 
Deviation 
Category 
Study Day 
Reason for 
Deviation 
Deviation 
Resulted 
in AE? 
Deviation Resulted 
in Participant 
Termination? 
Deviation 
Affected 
Product 
Stability? 
Deviation 
Resolution 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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


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16.2.3 Participants Excluded from the Safety and/or PK Analysis 
Listing 5: 
16.2.3: Participants Excluded from Analysis Populations 
[Implementation Note: This data in this listing should be congruent with the “Analysis Populations by Treatment Group” table. If a participant was not 
excluded from any analysis population, the participant will not appear in the listing. If the participant was excluded from multiple analysis populations, 
they will have one row per analysis population excluded from in the listing. 
If no specifications are required for a reason for exclusion, then exclude the last column “Reason Participant Excluded Specification”. 
Sort order: Treatment Group, Participant ID, Analysis from which Participant is Excluded (order: Safety, PK Analysis Population, PK Analysis Subset).] 
Treatment Group 
Participant ID 
Analyses in which 
Participant is Included 
Analyses from which  
Participant is Excluded 
Results Available? 
Reason Participant Excluded 
 
 
[e.g., Safety, PK Analysis, PK 
Analysis Subset] 
[e.g., Safety, PK Analysis, PK 
Analysis Subset] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: “Yes” in the “Results available” column indicates that available data were removed from the analysis. “No” indicates that no data were available for inclusion in the analysis. 
 
 


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16.2.4 Demographic Data 
Listing 6: 
16.2.4.1: Demographic Data 
[Implementation Note: If a participant is multi-racial, in “Race” column, note “Multiple: (list races, separated by a comma).” 
Sort order: Treatment Group, Participant ID.] 
Treatment Group 
 Participant ID 
Sex 
Age at Enrollment (years) 
Ethnicity 
Race 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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


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16.2.5 Compliance and/or Drug Concentration Data (if available) 
Listing 8: 
16.2.5: Compliance Data 
[Implementation Note: For planned doses that did not occur, the date and time columns for those doses will be “not dosed.” 
Sort Order: Treatment Group, Participant ID] 
Treatment Group 
Participant ID 
Dose Number 
Planned Volume Administered? 
Dose Date 
Infusion Start Time 
Infusion End Time 
WCK 6777 2g 
PHU.0123 
x 
Yes/No 
ddMMMyyyy 
hh:mm 
hh:mm 
… 
  
 
  
  
  
 
  
  
 
  
  
  
 
  
  
 
  
  
  
 
 
 
 
 


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Listing 9: 
16.2.5: Infusion Interruptions 
[Implementation Note: If multiple interruptions occur, they will be listed sequentially by ‘Interruption Number’. 
Sort Order: Treatment Group, Participant ID, Dose Number] 
Treatment 
Group 
Participant 
ID 
Dose 
Number 
Interruption 
Number 
Reason Infusion 
Interrupted 
If Safety Related, 
Volume Received 
Prior to Interruption 
Action Taken 
Infusion 
Restarted? 
Duration of 
Interruption 
Comments 
 
 
 
 
 
 


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16.2.6 Participant Level PK Concentrations 
Listing 10: 
Participant Level Total ERT and ZID Concentrations – Plasma 
[Implementation Note: Units of nominal time and actual timepoint vary by timepoint and will be provided for each time rather than in the column 
heading. Laboratory Reported Concentration will give verbatim value reported by lab (with minimal formatting, as needed) and will use a character 
value such as PC.PCORRES. Analysis Concentration will report the value actually used for analysis and will use a numeric variable such as 
ADNCA.AVAL. If one or more samples are excluded from NCA, two additional columns will be provided in the PK report listing: Excluded from NCA 
(Yes/No) and Reason for Exclusion from NCA.  
In the actual time column, mark out of window times with one asterisk (*), mark substantially out of window times with two asterisks (**), and mark 
imputed times with three asterisks (***).Sort order: Treatment Group, Participant ID, Analyte (ERT then ZID, if both are available), Study Day, and 
Actual Time.] 
Treatment 
Group 
Participant 
ID 
Analyte 
Study 
Day 
Nominal 
Timea 
Actual Timea  
Laboratory Reported Concentrations 
(µg/mL) 
Analysis Concentrations (µg/mL) 
WCK 6777 2g 
PHU.00123 
ERT 
Day 1 
0 h 
0 h 
0 
0 
WCK 6777 2g 
PHU.00123 
ZID 
Day 1 
0 h 
0 h 
0 
0 
 
 
 
 
 
 
 
 
Similar listing: 
Listing 11: 
Participant Level Free ERT and ZID Concentrations – Plasma 


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Listing 12: 
Participant Specific Single-Dose ERT Plasma PK Parameters - Total 
[Implementation Note: Sort order: Treatment Group, Participant ID.] 
Treatment 
Group 
Participant 
ID 
Study 
Day 
Cmax 
(µg/mL) 
Cmax/Dose 
((µg/mL)/mg) 
Cmin 
(µg/mL) 
Tmax 
(h) 
Tmin 
(h) 
AUC0-t 
(µg*h/mL) 
AUC0-inf 
(µg*h/mL) 
AUC0-24 
(µg*h/mL) 
AUC0-last 
(µg*h/mL) 
AUC0-tau 
(µg*h/mL) 
AUC0-tau/Dose 
((µg*h/mL)/mg) 
t1/2 
(h) 
CLT 
(L/h) 
Ke 
(1/h) 
Vd 
(L) 
  
  
 
  
  
  
 
 
  
  
 
 
 
 
  
  
  
  
  
  
 
  
  
  
 
 
  
  
 
 
 
 
  
  
  
  
  
  
 
  
  
  
 
 
  
  
 
 
 
 
  
  
  
  
  
  
 
  
  
  
 
 
  
  
 
 
 
 
  
  
  
  
Similar listings: 
Listing 13: 
Participant Specific Single-Dose ERT Plasma PK Parameters - Free 
Listing 14: 
Participant Specific Single-Dose ZID Plasma PK Parameters – Total 
Listing 15: 
Participant Specific Single-Dose ZID Plasma PK Parameters - Free 
 
 
 


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Listing 16: 
Participant Specific Multiple-Dose ERT Plasma PK Parameters - Total 
[Implementation Note: Sort order: Treatment Group, Participant ID.] 
Treatment 
Group 
Participant 
ID 
Cmax,ss 
(µg/mL) 
Cmax,ss/Dose 
((µg/mL)/mg) 
Cmin,ss 
(µg/mL) 
Cavg 
(µg/mL) 
Tmax,ss 
(h) 
Tmin 
(h) 
AUC0-24,ss 
(µg*h/mL) 
AUC0-tau,ss 
(µg*h/mL) 
AUC0-tau,ss/Dose 
((µg*h/mL)/mg) 
t1/2 
(h) 
CLss 
(L/h) 
Vd,ss 
(L) 
Linearity 
Index 
RAUC 
RCmax 
  
  
  
  
  
 
  
  
 
 
 
 
  
  
  
 
  
  
  
  
  
  
 
  
  
 
 
 
 
  
  
  
 
  
  
  
  
  
  
 
  
  
 
 
 
 
  
  
  
 
  
  
  
  
  
  
 
  
  
 
 
 
 
  
  
  
 
  
Similar listings: 
Listing 17: 
Participant Specific Multiple-Dose ERT Plasma PK Parameters - Free 
Listing 18: 
Participant Specific Multiple-Dose ZID Plasma PK Parameters – Total 
Listing 19: 
Participant Specific Multiple-Dose ZID Plasma PK Parameters - Free 


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Listing 20: 
Participant Level Total ERT and ZID Concentrations in Urine 
[Implementation Note: Units of nominal time and actual timepoint vary by timepoint and will be provided for each time rather than in the column 
heading. Laboratory Reported Concentration will give verbatim value reported by lab (with minimal formatting, as needed) and will use a character 
value such as PC.PCORRES. Analysis Drug Concentration will report the value actually used for analysis and will use a numeric variable such as 
ADNCA.AVAL. If one or more samples are excluded from NCA, two additional columns will be provided in the PK report listing: Excluded from NCA 
(Yes/No) and Reason for Exclusion from NCA.  
In the actual time column, mark out of window times with one asterisk (*) and mark imputed times with three asterisks (***) Sort order: Treatment 
Group, Analyte (ERT then ZID, if both are available), Participant ID, Study Day, and Actual Time.] 
Treatment 
Group 
Analyte 
Participant ID 
Study Day 
Nominal 
Collection 
Intervala 
Actual 
Collection 
Intervala 
Laboratory Reported 
Concentration (ng/mL) 
Urine Volume 
(mL) 
Analysis Concentrations 
(ng/mL) 
WCK 6777 2g 
ERT 
PHU.00123 
Day 1 
0-6 h 
0-6 h 
0 
100 
0 
WCK 6777 2g 
ZID 
PHU.00123 
Day 1 
0-6 h 
0-6 h 
0 
100 
0 
aTimes are relative to time of dose. For actual time, out of window times are indicated by an asterisk (*) and imputed times are indicated by three asterisks (***). 
BQL=Below Quantitative Limit 
 
 
 


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Listing 21: 
Participant Specific ERT Urine PK Parameters, Dose 1 
[Sort Order: Treatment Group (WCK 6777 2g, ERT 2g, ZID 2g, WCK 6777 4g, ERT 3g, ZID 3g, WCK 6777 6g), Participant ID.] 
Treatment 
Group 
Participant 
ID 
Ae,urine  
0-4 h 
(mg) 
Ae,urine  
4-8 h 
(mg) 
Ae,urine  
8-12 h 
(mg) 
Ae,urine 
12-24 h 
(mg) 
Ae,urine
(0-24)  
(mg) 
Ae,urine
(0-24),ss  
(mg) 
fe,urine  
0-4 h 
(mg) 
fe,urine  
4-8 h 
(mg) 
fe,urine  
8-12 h 
(mg) 
fe,urine  
12-24 h 
(mg) 
fe,urine(
0-24)  
(mg) 
fe,urine(
0-24),ss  
(mg) 
CLR(0-24) 
CLR,ss 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Similar listings: 
Listing 22: 
Participant Specific ERT Urine PK Parameters, Dose 7 
Listing 23: 
Participant Specific ZID Urine PK Parameters, Dose 1 
Listing 24: 
Participant Specific ZID Urine PK Parameters, Dose 7 


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16.2.7 Adverse Events 
Listing 25: 
16.2.7.3: Adverse Events 
[Implementation Note: If the event is ongoing (no stop date), indicate “ongoing” in the duration column. In the “Relationship to Study Treatment 
(Alternate Etiology)” column, merge the data fields for relationship to study treatment and alternate etiology, separated by a colon. This listing includes 
all unsolicited adverse events.  
Sort Order: Treatment Group, Participant ID, AE Number.] 
Adverse 
Event 
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 
Participant 
Discontinued 
Due to AE 
Outcome 
MedDRA 
System 
Organ 
Class 
MedDRA 
High Level 
Group 
Term 
MedDRA 
Preferred 
Term 
Treatment Group: , Participant ID: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Group: , Participant ID: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
 


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16.2.8 Individual Laboratory Measurements 
Listing 26: 
16.2.8.1: Clinical Laboratory Results – Chemistry 
[Implementation Note: These listings (for hematology, chemistry, coagulation, and urinalysis) include all laboratory results, scheduled and unscheduled. 
These listings are not color-coded, but the severity should be included in parentheses after the result for abnormal results, e.g., 16.2 (Mild). The “extra” 
fields that are completed for abnormal results are not included in this listing; they are included in the listing of abnormal laboratory results that is 
included in the table shells document. Results outside of the reference range but not graded as Mild, Moderate, or Severe, should have ONR shown as 
the Severity Grade. Change from Baseline column will be blank for parameters that are not numeric. 
Sort order: Parameter, Treatment Group, Participant ID, and Timepoint.] 
Treatment 
Group 
Participant ID 
Sex  
Age (years) 
Actual 
Study Day 
Planned 
Timepoint  
Laboratory 
Parameter (Units) 
Result (Severity 
Grade) 
Reference 
Range Low 
Reference Range 
High 
Change from 
Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 27: 
16.2.8.2: Clinical Laboratory Results – Hematology 
Treatment 
Group 
Participant ID 
Sex  
Age (years) 
Actual 
Study Day 
Planned 
Timepoint  
Laboratory 
Parameter (Units) 
Result (Severity 
Grade) 
Reference 
Range Low 
Reference Range 
High 
Change from 
Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 28: 
16.2.8.3: Clinical Laboratory Results – Coagulation 
Treatment 
Group 
Participant ID 
Sex  
Age (years) 
Actual 
Study Day 
Planned 
Timepoint 
Laboratory Parameter (Units) 
Result 
(Severity 
Grade) 
Reference 
Range 
Low 
Reference 
Range 
High 
Change 
from 
Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 29: 
16.2.8.4: Clinical Laboratory Results – Urinalysis 
[Implementation Note: The test type used to obtain the results will be indicated in the Laboratory Parameter column (e.g., Bilirubin by Dipstick, Red 
Blood Cells by Microscopy, etc.).] 
Treatment 
Group 
Participant ID 
Sex  
Age (years) 
Actual 
Study Day 
Planned 
Timepoint  
Laboratory 
Parameter (Units) 
Result (Severity 
Grade) 
Reference 
Range Low 
Reference Range 
High 
Change from 
Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.9 Individual Screening Measurements 
Listing 30: 
16.2.9.1: Screening Laboratory Results – Serology 
[Sort Order: Treatment Group, Participant ID, Visit (visit order: Screening, Admission, Unscheduled).] 
Treatment Group 
Participant ID 
Visit 
HIV Antibodies 
HCV Antibodies  
HBsAg 
ERT 2g 
PHU.00123 
Screening 
Negative 
Negative 
Negative 
ERT 2g 
PHU.00123 
Unscheduled (Day 4) 
Negative 
Negative 
Negative 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 


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Listing 31: 
16.2.9.1: Screening Laboratory Results – hCG and Serum FSH Tests 
[Implementation Note: If there are results for serum hCG on an Unscheduled visit, then the Study Day will be included in parentheses for the Visit. Type 
of hCG test will be given in parentheses after the hCG result, e.g..., Negative (serum) or Negative (urine). If obtained, FSH testing results will be shown 
in this listing.] 
Sort order: Treatment Group, Participant ID, Visit (visit order: Screening, Admission, Unscheduled).] 
Treatment Group 
Participant ID 
Visit 
HCG Result 
FSH Test Result 
ERT 2g 
PHU.00123 
Screening 
Negative (serum) 
ND 
ERT 2g  
PHU.00123  
Baseline  
Negative (urine)  
ND 
  
  
  
  
 
Note: ND=Test not performed 
 


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Listing 32: 
16.2.9.1: Screening Laboratory Results – Urine Toxicology  
[Implementation Note: If there are results for urine toxicology on an Unscheduled visit, then the Study Day will be included in parentheses for the Visit. 
Sort order: Dose Group, Participant ID, Visit (visit order: Screening, Admission, Unscheduled).] 
Treatment 
Group 
Participant 
ID 
Visit 
Amphetamines 
Cocaine 
Barbiturates 
Benzodiazepines 
Opiates 
Cannabinoids 
TCAs 
Phencyclidine 
Alcohol 
Cotinine 
ERT 2g 
PHU.00123 
Screening 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
ERT 2g 
PHU.00123 
Admission 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.9 Vital Signs and Physical Exam Findings 
Listing 33: 
16.2.9.2: Vital Signs 
[Implementation Note: This listing includes all vital sign assessments, scheduled and unscheduled. All height, weight, and BMI measurements will also 
be included in this listing. These listings are not color-coded, but the severity should be included in parentheses after the result for abnormal assessments, 
e.g., 100.7 (Mild).  
Sort order: Treatment Group, Participant ID, Parameter (order: Height, Weight, BMI, Systolic Blood Pressure, Diastolic Blood Pressure, Pulse, 
Respiratory Rate, Temperature), Timepoint, Date of Assessment, Time of Assessment.] 
Treatment Group 
Participant ID 
Actual Study Day  
Planned Timepoint 
Date of Assessment 
Time of Assessment 
Result (Severity) 
Change from Baseline 
 
 
 
 
ddMMMyyyy 
hh:mm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 34: 
16.2.9.3: Physical Exam Findings 
[Implementation Note: This listing includes all physical exam findings, scheduled and unscheduled. If a participant does not have any findings upon 
examination, they will not be included in this listing. If reported as an AE, display “Yes” with the AE description and number in parentheses, e.g., “Yes 
(AE Description; 007)”.  
Sort order: Treatment Group, Participant ID, Date of Assessment, Timepoint, Time of Assessment, Body System, and Finding.] 
Treatment 
Group 
Participant ID 
Actual Study 
Day 
Planned 
Timepoint 
Body System 
Abnormal Finding 
Reported as an AE? 
(AE Description; Number) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.9 Individual ECG Results 
Listing 35: 
16.2.9.4: Listing of ECG Interval Measurements 
[Implementation Note: This listing includes all ECG assessments, scheduled and unscheduled. These listings are not color-coded, but the severity should 
be included in parentheses after the result for abnormal assessments, e.g., 100.7 (Mild). For the mean of triplicate readings, no assessment time should be 
presented and the replicate number should specify “Mean”.  
Sort order: Treatment Group, Participant ID, Parameter, Date of Assessment, Time of Assessment.] 
Treatment 
Group 
Participant 
ID 
Sex 
Parameter 
Timepoint 
Assessment Date 
Assessment Time 
Result 
(Severity) 
Change from 
Baseline 
Replicate 
Number 
WCK 6777 
2g 
PHU.00123 
Male 
PR Interval 
Baseline 
ddMMMyyy  
hh:mm 
210 
- 
1 
WCK 6777 
2g 
PHU.00123 
Male 
PR Interval 
Day 4 
ddMMMyyy  
hh:mm 
250 (Mild) 
40 
1 
  
  
  
  
 
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
 
 
 
 


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Listing 36: 
16.2.9.4: Listing of ECG Overall Interpretation and Comments 
[Implementation Note: This listing includes all ECG assessments, scheduled and unscheduled.  
Sort order: Treatment Group, Participant ID, Date of Assessment, Time of Assessment.] 
Treatment 
Group 
Participant 
ID 
Sex 
Timepoint 
Assessment Date 
Interpretation 
Change from 
Baseline 
Morphological 
Abnormalities 
Present? 
Long QT? 
Comments 
WCK 6777 
2g 
PHU.00123 
Male 
Baseline 
ddMMMyyy 
Normal NCS 
- 
N 
N 
Sinus Bradycardia 
WCK 6777 
2g 
PHU.00123 
Male 
Day 4 
ddMMMyyy 
Abnormal NCS 
NCB 
Y 
N 
Sinus Bradycardia 
  
  
  
  
  
  
 
 
 
  
  
  
  
  
  
  
 
 
 
  
  
  
  
  
  
  
 
 
 
  
Notes: NCB= No change from baseline. NSB= Not clinically significant, change from baseline. CSB= Clinically significant change from baseline. 
 
 
 


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16.2.10 Prior and Concomitant Medications 
Listing 37: 
Prior Medications 
[Implementation Note: Include prior medications (medications with an end date prior to dosing) only. If the medication was taken for a Medical History 
condition, then include the MH description and the MH number in parentheses in the “Taken for a condition on the Medical History” column. If the start 
or end date is more than 30 days before enrollment, then categorize Medication Start/End Day as follows:  
• 5 years prior to enrollment 
• 1-5 years prior to enrollment 
• 1-12 months prior to enrollment 
Sort order: Treatment Group, Participant ID, and CM Number]. 
Treatment 
Group 
Participant 
ID 
CM 
Number 
Medication 
Medication 
Start Day 
Medication 
End Day 
Indication 
Taken for a condition on Medical 
History? (MH Description; MH 
Number) 
ATC Level 1  
(ATC Level 2) 
WCK 
6777 2g 
PHU.00123 
001 
BENADRYL 
1-12 months 
prior to 
enrollment 
1-12 months 
prior to 
enrollment 
ITCHING 
No 
DERMATOLOGICALS (ANTIPRURITICS, 
INCL. ANTIHISTAMINES, ANESTHETICS, 
ETC.) 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 


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Listing 38: 
16.2.10: Concomitant Medications 
[Implementation Note: “Medication Start Day” and “Medication End Day” are relative to enrollment (which is Day 1, day before enrollment is Day -1).  
If ongoing, display “Ongoing” in the “Medication End Day” column. If taken for an AE or MH, display “Yes” with the AE or MH description and 
number in parentheses, e.g., “Yes (AE/MH Description; 007)”. In the CSR, Participant ID should be USUBJID (not PATID) for purposes of de-
identification.  
Sort order: Treatment Group, Participant ID, and CM Number.] 
Treatment 
Group 
Participant 
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 39: 
16.2.11.1: Pregnancy Reports – Maternal Information 
[Implementation Note: Only include the “Pregnancy Number” column if a participant has more than 1 pregnancy. Date of Conception will be calculated 
based on estimated delivery date. BMI will be calculated based on pre-pregnancy height and weight. Mother’s weight gain will be calculated based on 
pre-pregnancy weight and end of pregnancy weight. If a major congenital anomaly with previous pregnancy, display “Yes” and the text from the 
“specify” field, separated by a colon. If any substance use is reported, include a listing of substance use. If autopsy revealed an alternate etiology, display 
“Yes” and the text from the “specify” field, separated by a colon. If abnormality in product of conception, display “Yes” and the text from the “specify” 
field, separated by a colon. In the CSR, Participant ID should be USUBJID (not PATID) for purposes of de-identification. Sort order: Treatment Group, 
Participant ID, Pregnancy Number.] 
Treatment 
Group 
Participant 
ID 
Pregnancy 
Number 
Study Day 
Corresponding 
to Estimated 
Date of 
Conception 
Source of 
Maternal 
Information 
Pregnancy 
Status 
Mother’s 
Pre-
Pregnancy 
BMI 
Mother’s 
Weight 
Gain 
During 
Pregnancy 
Tobacco, 
Alcohol, or 
Drug Use 
During 
Pregnancy? 
Medications 
During 
Pregnancy? 
Maternal 
Complications 
During 
Pregnancy? 
Maternal 
Complications 
During Labor, 
Delivery, or 
Post-Partum? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Maternal Complications are included in the Adverse Event listing. Medications taken during pregnancy are included in the Concomitant Medications Listing. 
 
 


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16.2.11.2: Pregnancy Reports – Gravida and Para 
 
 
 
Live Births 
 
 
 
 
 
Participant 
ID 
Pregnancy 
Number 
Gravida 
Extremely 
PBa 
Very 
Early 
PBa 
Early 
PBa 
Late 
PBa 
Early 
TBb 
Full 
TBb 
Late 
TBb 
Post 
TBb 
Still 
Births 
Spontaneous 
Abortion/ 
Miscarriage 
Elective 
Abortions 
Therapeutic 
Abortions 
Major 
Congenital 
Anomaly 
with 
Previous 
Pregnancy? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Gravida includes the current pregnancy, para events do not. 
a Preterm Birth 
b Term Birth 
 
 
 


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16.2.11.3: Pregnancy Reports – Live Birth Outcomes 
Participant 
ID 
Pregnancy 
Number 
Fetus 
Number 
Pregnancy 
Outcome 
(for this 
Fetus) 
Fetal 
Distress 
During 
Labor and 
Delivery? 
Delivery 
Method 
Gestational 
Age at Live 
Birth  
Size for 
Gestational 
Age 
Apgar 
Score, 1 
minute 
Apgar 
Score, 5 
minutes 
Cord pH 
Congenital 
Anomalies? 
Illnesses/ 
Hospitalizations 
within 1 Month 
of Birth? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Congenital Anomalies are included in the Adverse Event listing. 
 
 


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16.2.11.4: Pregnancy Reports – Still Birth Outcomes 
Participant 
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? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.11.5: Pregnancy Reports – Spontaneous, Elective, or Therapeutic Abortion Outcomes 
Participant 
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 
 
 
 
 
 
 
 
 

Prot_001.pdf: 
DMID Protocol 21-0013 
Version 5.0 
WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)] 
                             
15 June 2023 
 
 
DMID/NIAID/NIH 
CONFIDENTIAL 
 
 
 
1 
A PHASE I, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, DOSE ESCALATION STUDY TO EVALUATE 
THE SAFETY, TOLERABILITY, AND PHARMACOKINETICS 
OF INTRAVENOUS ERTAPENEM IN COMBINATION WITH 
ZIDEBACTAM (WCK 6777) IN HEALTHY ADULT SUBJECTS 
 
DMID Protocol Number: 21-0013 
 
 
DMID Funding Mechanism: Phase 1 Clinical Trial Units 
 
 
Pharmaceutical Support: Wockhardt Bio AG 
 
 
IND Sponsor: Division of Microbiology and Infectious Diseases (DMID), 
National Institute of Allergy and Infectious Diseases (NIAID),  
National Institutes of Health (NIH) 
 
 
Site Principal Investigator: Martin Kankam, MD, PhD, MPH, FAPCR 
 
 
DMID Clinical Project Manager: Maureen Mehigan, RN 
 
Version Number: 5.0 
 
 
15 June 2023 
 


DMID Protocol 21-0013 
Version 5.0 
WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)] 
                             
15 June 2023 
 
 
DMID/NIAID/NIH 
CONFIDENTIAL 
 
 
 
2 
STATEMENT OF COMPLIANCE 
The clinical trial will be carried out in accordance with Good Clinical Practice (GCP) and as 
required by the following: 
• United States (U.S.) Code of Federal Regulations (CFR) applicable to clinical trials 
(45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 54, 21 CFR Part 56, and 21 CFR Part 312). 
• International Council for Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use E6(R2) Good Clinical Practice (ICH E6 GCP): Integrated 
Addendum to ICH E6(R1) Guidance for Industry, published in the Federal Register (83 
Federal Register 8882 (2018)), including the latest finalized National Institutes of Health 
(NIH) Clinical Terms of Award, as applicable. 
Compliance with these standards provides public assurance that the rights, safety, and well-being 
of the subjects are protected and, consistent with principles that originate in the Declaration of 
Helsinki. 
All key personnel (all individuals responsible for the design and conduct of the trial) have 
completed Human Subjects Protection Training. 
 
 


DMID Protocol 21-0013 
Version 5.0 
WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)] 
                             
15 June 2023 
 
 
DMID/NIAID/NIH 
CONFIDENTIAL 
 
 
 
3 
SIGNATURE PAGE 
The signature below constitutes the approval of the protocol and its attachments and provides the 
necessary assurances that the trial will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory 
requirements as well as applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Site Investigator: 
 
 
Martin Kankam, MD, PhD, MPH, FAPCR 
_________________________________________________ 
Name/Title (Print) 
 
 
Signature: 
 
_________________________________________________ 
 
Date:  
 
_________________________________________________ 
 
 


DMID Protocol 21-0013 
Version 5.0 
WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)] 
                             
15 June 2023 
 
 
DMID/NIAID/NIH 
CONFIDENTIAL 
 
 
 
4 
TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE .................................................................................................2 
SIGNATURE PAGE .......................................................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF ABBREVIATIONS ........................................................................................................10 
PROTOCOL SUMMARY .............................................................................................................16 
1 
Key Roles ..............................................................................................................................22 
2 
Background Information and Scientific Rationale ...............................................................23 
2.1 
Background Information ...........................................................................................23 
2.2 
Ertapenem and Zidebactam (WCK 6777).................................................................24 
2.2.1 Zidebactam (WCK 5107) .........................................................................25 
2.2.1.1 Physicochemical properties ..........................................................25 
2.2.1.2 Mechanism of Action ...................................................................26 
2.2.1.3 Antibacterial activity ....................................................................26 
2.2.1.4 In Vitro Drug Interaction Studies .................................................26 
2.2.1.5 Genetic Toxicity ...........................................................................26 
2.2.1.6 Preclinical In Vivo Safety Profile .................................................27 
2.2.2 Ertapenem .................................................................................................27 
2.2.2.1 Physicochemical Properties ..........................................................27 
2.2.2.2 Mechanism of Action ...................................................................27 
2.2.2.3 Antibacterial Activity ...................................................................28 
2.2.2.4 In Vitro Drug Interaction Studies .................................................28 
2.2.2.5 Genetic Toxicity ...........................................................................28 
2.2.2.6 Preclinical and Clinical Safety Profile ..........................................28 
2.2.2.7 Clinical Indication ........................................................................29 
2.2.3 WCK 6777 (Combination of ERT and ZID) ............................................29 
2.2.3.1 Mechanism of Action ...................................................................29 
2.2.3.2 Antibacterial activity – In Vitro ....................................................29 
2.2.3.3 Antibacterial activity – In Vivo .....................................................30 
2.2.3.4 Safety Pharmacology – In Vitro ...................................................30 
2.2.3.5 Preclinical Safety – In Vivo ..........................................................31 
2.3 
Clinical Experience ...................................................................................................31 
2.3.1 Human Studies with Zidebactam .............................................................31 
2.3.1.1 Safety and Tolerability .................................................................31 
2.3.1.2 Pharmacokinetics ..........................................................................32 
2.3.2 Human Studies with Ertapenem ...............................................................33 
2.3.2.1 Safety and Tolerability .................................................................33 
2.3.2.2 Pharmacokinetics ..........................................................................34 


DMID Protocol 21-0013 
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WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)] 
                             
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5 
2.3.3 Human Studies with WCK 6777 ..............................................................34 
2.4 
Rationale ...................................................................................................................34 
2.4.1 Study Rationale ........................................................................................34 
2.4.2 Rationale for Dose Selection ....................................................................35 
2.5 
Identified and Potential Risks and Benefits Associated with the Study ...................35 
2.5.1 Risks with ZID .........................................................................................35 
2.5.2 Risks with ERT ........................................................................................36 
2.5.3 Risks with WCK 6777 ..............................................................................36 
2.5.4 Venipuncture and IV Catheter Risks ........................................................36 
2.5.5 Additional Risks .......................................................................................37 
2.6 
Known Potential Benefits .........................................................................................37 
2.7 
Risk/Benefit Ratio .....................................................................................................37 
3 
Objectives and Outcome Measures .......................................................................................39 
3.1 
Study Objectives .......................................................................................................39 
3.2 
Study Outcome Measures .........................................................................................39 
4 
Study Design .........................................................................................................................40 
4.1 
Sub-studies ................................................................................................................43 
5 
Study Enrollment and Withdrawal .......................................................................................44 
5.1 
Subject Inclusion Criteria .........................................................................................44 
5.2 
Subject Exclusion Criteria ........................................................................................45 
5.3 
Treatment Assignment Procedures ...........................................................................46 
5.3.1 Enrollment and Randomization Procedures .............................................46 
5.3.2 Masking Procedures .................................................................................47 
5.3.3 Reasons for Withdrawal and Discontinuation of Study Drug 
Administration ..........................................................................................48 
5.3.4 Handling of Withdrawals and Discontinuation of Study Drug 
Administration ..........................................................................................48 
5.3.5 Lost to Follow-up .....................................................................................49 
5.3.6 Termination of Study ................................................................................49 
6 
Study Intervention/investigational products .........................................................................50 
6.1 
Description of Study Products ..................................................................................50 
6.1.1 Zidebactam for Injection, 1 g/vial ............................................................50 
6.1.2 Ertapenem Sodium for Injection, 1 g/vial (ERT) .....................................50 
6.1.3 WCK 6777 (ERT-ZID) ............................................................................50 
6.1.4 Placebo .....................................................................................................51 
6.1.5 Acquisition ...............................................................................................51 
6.1.6 Formulation, Packaging, and Labeling .....................................................51 
6.1.7 Product Storage and Stability ...................................................................52 
6.1.7.1 Stability in Storage Prior to Reconstitution ..................................52 


DMID Protocol 21-0013 
Version 5.0 
WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)] 
                             
15 June 2023 
 
 
DMID/NIAID/NIH 
CONFIDENTIAL 
 
 
 
6 
6.1.7.2 Stability of ERT or ZID after Reconstitution in Sterile Water for 
Injection ........................................................................................53 
6.1.7.3 Stability of ERT or ZID after Dilution in 0.9% Sodium Chloride
 ......................................................................................................53 
6.1.7.4 Photostability ................................................................................53 
6.2 
Dosage, Preparation, and Administration of Study Intervention/ Investigational 
Products.....................................................................................................................54 
6.3 
Modification of the Study Intervention/ Investigational Products ............................54 
6.3.1 Overdose ...................................................................................................54 
6.4 
Accountability Procedures for the Study Intervention/ Investigational Products .....55 
6.5 
Assessment of Subject Compliance with the Study Intervention/ Investigational 
Products.....................................................................................................................56 
6.6 
Prior and  Concomitant Medications/Treatments .....................................................56 
6.7 
Subject Restrictions  and Precautions .......................................................................57 
6.7.1 Smoking ....................................................................................................57 
6.7.2 Physical Activity ......................................................................................57 
6.7.3 Food and Fluid intake ...............................................................................57 
6.7.4 Alcohol, Marijuana and Illicit Drugs .......................................................58 
7 
Study Schedule .....................................................................................................................59 
7.1 
Recruitment ...............................................................................................................59 
7.2 
Screening Visit (Day -28 to Day -2) .........................................................................59 
7.3 
Baseline / Check-in (Day -1) ....................................................................................60 
7.4 
Inpatient Treatment Period (Days 1 to 8) .................................................................61 
7.4.1 DAY 1 ......................................................................................................61 
7.4.2 DAY 2 ......................................................................................................62 
7.4.3 DAY 3 ......................................................................................................63 
7.4.4 DAY 4 ......................................................................................................64 
7.4.5 DAY 5 ......................................................................................................65 
7.4.6 DAY 6 ......................................................................................................66 
7.4.7 DAY 7 ......................................................................................................66 
7.4.8 DAY 8 ......................................................................................................68 
7.5 
Outpatient Follow-up Period / Last Visit (Day 11 + 3 days) ....................................68 
7.6 
Early Termination (if needed) ...................................................................................69 
7.7 
Unscheduled Visit (if needed) ..................................................................................69 
8 
Clinical Procedures / Evaluations .........................................................................................70 
8.1 
Clinical Procedures and Evaluations ........................................................................70 
8.1.1 Informed Consent .....................................................................................70 
8.1.2 Demographics ...........................................................................................70 
8.1.3 Inclusion/Exclusion Criteria .....................................................................70 


DMID Protocol 21-0013 
Version 5.0 
WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)] 
                             
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CONFIDENTIAL 
 
 
 
7 
8.1.4 Medical History ........................................................................................70 
8.1.5 Physical Examination ...............................................................................71 
8.1.6 Vital Signs ................................................................................................71 
8.1.6.1 Screening to Predose on Day 1 .....................................................71 
8.1.6.2 Post Dosing on Day 1 through Day 11 (+ 3days) or ET ...............72 
8.1.7 12-lead Standard Electrocardiogram (ECG) ............................................72 
8.2 
Laboratory Evaluations .............................................................................................72 
8.2.1 Clinical Laboratory Evaluations (Hematology, Coagulation, 
Chemistry and Urinalysis) ........................................................................72 
8.2.2 Viral Serology Testing .............................................................................73 
8.2.3 Pregnancy Testing ....................................................................................73 
8.2.4 Serum FSH Testing ..................................................................................74 
8.2.5 Urine Toxicology Screening ....................................................................74 
8.2.6 Urine Alcohol and Cotinine Testing ........................................................74 
8.3 
Blood and Urine Sampling and Bioanalytical Assays for Pharmacokinetics (PK) ..74 
8.3.1 Blood Sampling for Plasma Total and Free ERT and ZID Assay ............74 
8.3.2 Collection of Urine for Total ERT and ZID Assay ..................................75 
8.3.3 Specimen Preparation, Handling and Shipping ........................................75 
8.3.3.1 Instructions for Specimens Preparation, Handling, and Storage ..75 
8.3.3.2 Specimen Shipment ......................................................................76 
8.4 
Disposition of Plasma and Urine Samples ................................................................77 
9 
Assessment of Safety ............................................................................................................78 
9.1 
Specification of Safety Parameters ...........................................................................78 
9.2 
Methods and Timing for Assessing, Recording and Analyzing Safety Parameters .78 
9.2.1 Adverse Events .........................................................................................78 
9.2.2 Severity of Events ....................................................................................79 
9.2.3 Relationship to Study Products ................................................................79 
9.2.4 Reporting Adverse Events ........................................................................80 
9.2.5 Serious Adverse Events ............................................................................80 
9.2.6 Procedures to be Followed in the Event of Abnormal Laboratory Test 
Values or Abnormal Clinical Findings .....................................................81 
9.3 
Reporting Procedures ................................................................................................81 
9.3.1 Serious Adverse Events ............................................................................81 
9.3.2 SUSAR Regulatory Reporting for Studies Conducted under DMID 
Sponsored IND .........................................................................................82 
9.3.3 Other Adverse Events (if applicable) .......................................................83 
9.3.3.1 Reporting of Overdose ..................................................................83 
9.3.3.2 Reporting of Pregnancy ................................................................83 
9.4 
Type and Duration of Follow-up of Subjects after Adverse Events .........................84 


DMID Protocol 21-0013 
Version 5.0 
WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)] 
                             
15 June 2023 
 
 
DMID/NIAID/NIH 
CONFIDENTIAL 
 
 
 
8 
9.5 
Halting Rules ............................................................................................................84 
9.5.1 Study Halting Criteria ..............................................................................84 
9.5.2 Individual Subject Halting Criteria ..........................................................84 
9.5.3 Dose Escalation Halting Criteria ..............................................................85 
9.6 
Safety Oversight........................................................................................................86 
9.6.1 Safety Monitoring Committee (SMC) ......................................................86 
10 
Clinical Monitoring...............................................................................................................87 
10.1 
Site Monitoring Plan .................................................................................................87 
11 
Statistical Considerations ......................................................................................................88 
11.1 
Study Hypotheses......................................................................................................88 
11.2 
Sample Size Considerations ......................................................................................88 
11.3 
Safety Review ...........................................................................................................88 
11.4 
Final Analysis Plan ...................................................................................................88 
11.4.1 Analysis Populations ................................................................................89 
11.4.2 Demographics and Baseline Characteristics ............................................89 
11.4.3 Safety Analysis .........................................................................................89 
11.4.3.1 Adverse and Serious Adverse Events ...........................................89 
11.4.3.2 Additional Safety Analyses ..........................................................90 
11.4.3.3 Tolerability Assessment ................................................................90 
11.4.4 PK Analysis ..............................................................................................90 
11.4.5 Plasma PK parameters: .............................................................................91 
11.4.6 Urine PK parameters: ...............................................................................92 
11.4.7 Missing Values and Outliers ....................................................................92 
11.4.8 Multiple Comparisons / Multiplicity ........................................................93 
11.4.9 Interim Reports .........................................................................................93 
12 
Source Documents and Access to Source Data/Documents .................................................94 
13 
Quality Control and Quality Assurance ................................................................................95 
14 
Ethics/Protection of Human Subjects ...................................................................................96 
14.1 
Ethical Standard ........................................................................................................96 
14.2 
Institutional Review Board .......................................................................................96 
14.3 
Informed Consent Process ........................................................................................96 
14.4 
Exclusion of Women, Minorities and Children (Special Populations) .....................97 
14.5 
Subject Confidentiality .............................................................................................98 
14.6 
Certificate of Confidentiality ....................................................................................98 
14.7 
Study Discontinuation ...............................................................................................99 
15 
Data Handling and Record Keeping ...................................................................................100 
15.1 
Data Management Responsibilities.........................................................................100 
15.2 
Data Capture Methods ............................................................................................100 
15.3 
Types of Data ..........................................................................................................100 


DMID Protocol 21-0013 
Version 5.0 
WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)] 
                             
15 June 2023 
 
 
DMID/NIAID/NIH 
CONFIDENTIAL 
 
 
 
9 
15.4 
Timing/Reports .......................................................................................................101 
15.5 
Study Records Retention .........................................................................................101 
15.6 
Protocol Deviations .................................................................................................101 
16 
Publication Policy ...............................................................................................................102 
17 
Literature References ..........................................................................................................103 
18 
Appendices..........................................................................................................................106 
Appendix A: Schedule of Study Procedures and Evaluations .....................................................107 
Appendix B: Adverse Events Toxicity Grading Criteria .............................................................109 
Appendix C: Blood Volume Withdrawn During the Trial ..........................................................119 
 
 
 
LIST OF TABLES 
Table 1 Study Treatment Cohort................................................................................................... 40 
Table 2 Toxicity Grading Tables – CLINICAL AEs .................................................................. 110 
Table 3 Toxicity Grading Tables – LABORATORY AEs ......................................................... 114 
Table 4 Toxicity Grading Tables – ECG .................................................................................... 118 
Table 5: Laboratory Samples and Estimated Total Blood Volume (mL) ................................... 119 
 
 
LIST OF FIGURES 
Figure 1 Description Schematic of Study Design ......................................................................... 21 
 


DMID Protocol 21-0013 
Version 5.0 
WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)] 
                             
15 June 2023 
 
 
DMID/NIAID/NIH 
CONFIDENTIAL 
 
 
 
10 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
Ae, urine 
Amount of unchanged drug excreted in urine during each collection 
interval 
Ae,urine(0-24) 
Cumulative amount of unchanged drug excreted in urine from zero 
(predose) to 24 hours 
Ae,urine(0-36) 
Cumulative amount of unchanged drug excreted in urine from zero 
(predose) to 36 hours 
ALT 
Alanine Aminotransferase 
AP 
Alkaline Phosphatase 
APTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Concentration – Time Curve 
AUC (0-t) 
Area under the concentration - time curve from time zero to time t 
AUC(0-24) 
Area under the concentration – time curve from time zero to 24 h 
AUC(0-∞) 
Area under the concentration - time curve from time zero to infinity 
AUC(0-last) 
Area under the concentration - time curve from time zero to the last 
concentration above the lower limit of quantitation 
AUC(0-tau) 
Area under the concentration – time curve to the end of the dosing interval  
β-HCG 
Beta Human Chorionic Gonadotropin 
BL 
β-lactamase 
BLI 
β-lactamase inhibitor 
BMI 
Body Mass Index 
BP 
Blood Pressure 
bpm 
Beats per Minute 
BUN 
Blood Urea Nitrogen 
CAP 
Community-acquired Pneumonia 
CBC 
Complete Blood Count 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CHEM 
Chemistry Panel 
CI 
Confidence Interval 


DMID Protocol 21-0013 
Version 5.0 
WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)] 
                             
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CONFIDENTIAL 
 
 
 
11 
cIAI 
Complicated Intra-abdominal Infections 
Cavg 
Calculated average concentration during the dosing interval 
Cmax 
Maximum Concentration 
Cmin 
Minimum Concentration 
CLCR 
Creatinine Clearance 
CLr(0-24) 
Renal clearance to 24 h after initial dose 
CLr, ss 
Renal clearance following multiple dosing 
CLT 
Total Clearance 
CMS 
Clinical Materials Services 
ConMed(s) 
Concomitant Medication(s) 
COAG 
Coagulation 
CPM 
Clinical Project Manager 
CRE 
Carbapenem-Resistant Enterobacterales 
CROMS 
Clinical Research Operations and Management Support 
CSR 
Clinical Study Report 
CTU 
Clinical Trial Unit 
cUTI 
Complicated Urinary Tract Infection 
DBP 
Diastolic Blood Pressure 
DVC 
Dynport Vaccine Company, LLC, a GDIT company 
dL 
Deciliter 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, NIH 
eCRF 
Electronic Case Report Form 
EC 
Ethics Committee 
ECG  
Electrocardiogram 
EDC 
Electronic Data Capture 
ERT 
Ertapenem 
ESBL 
Extended-Spectrum β-lactamases 
ET 
Early Termination 
fe,urine(0-24) 
Fraction of dose excreted unchanged in urine from zero (predose) to 24 
hours 


DMID Protocol 21-0013 
Version 5.0 
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12 
fe,urine(0-36) 
Fraction of dose excreted unchanged in urine from zero (predose) to 36 
hours 
FEP 
Cefepime 
FDA 
Food and Drug Administration 
FH 
Family History 
FSH 
Follicle-Stimulating Hormone 
FWA 
Federalwide Assurance 
g 
Gram(s) 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
eGFR 
Estimated GFR 
h 
Hour(s) 
HBsAg 
Hepatitis B Surface Antigen 
Hct 
Hematocrit 
HCV 
Hepatitis C Virus 
HEENT 
Head, Eyes, Ears, Nose, and Throat 
HEM 
Hematology Panel 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
HLGT 
High Level Group Term 
HPF 
High-Powered Field 
HR 
Heart Rate 
IATA 
International Air Transport Association 
IB 
Investigator’s Brochure 
IC50 
Half Maximal Inhibitory Concentration 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
IMP 
Imipenemase  
IND 
Investigational New Drug  
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 


DMID Protocol 21-0013 
Version 5.0 
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IUD 
Intrauterine Device 
IV 
Intravenous(ly) 
kg 
Kilogram(s) 
LC-MS/MS 
Liquid Chromatography with Tandem Mass Spectrometry 
LLN 
Lower Limit of Normal 
MAD 
Multiple Ascending Dose 
MBL 
Metallo-β-lactamases 
MDR 
Multiple Drug Resistant 
MedDRA 
Medical Dictionary for Regulatory Activities 
µg 
Microgram(s) 
mg 
Milligram(s) 
MH 
Medical History 
MIC 
Minimum Inhibitory Concentration 
min 
Minute(s) 
mL 
Milliliter(s) 
MM 
Medical Monitor 
mmHg 
Millimeters of Mercury 
mmol 
Millimole(s) 
MO 
Medical Officer 
MOP 
Manual of Procedures 
msec 
Milliseconds(s) 
N 
Number (typically refers to the total number of subjects) 
n 
Number (typically refers to a subset of the total number of subjects) 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH 
NIH 
National Institutes of Health 
NOAEL 
No Observable Adverse Effect Level 
NSAID 
Nonsteroidal Anti-Inflammatory Drug 
OAT 
Organic Anion Transporter  
OPAT 
Out-Patient Parenteral Antibiotic Therapy 
OER 
Office of Extramural Research, NIH 
OTC 
Over the Counter 


DMID Protocol 21-0013 
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PD 
Pharmacodynamic(s) 
PE 
Physical Examination 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
POC 
Point of Contact 
Protime 
Prothrombin time 
PVG 
Pharmacovigilance Group 
QID 
Four times a day 
QTc 
Corrected QT Interval of the ECG 
QTcF  
Corrected QT interval of the ECG using Fridericia’s Formula 
RAUC 
Accumulation ratio for AUC 
RBC 
Red Blood Cell 
RCAUC 
Accumulation ratio for AUC 
RCmax 
Accumulation ratio for Cmax 
RP 
Research Pharmacist 
RR 
Respiratory Rate 
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SDCC 
Statistical and Data Coordinating Center 
sec 
Second(s) 
SMC 
Safety Monitoring Committee 
SOC 
System Organ Class 
T 
Temperature 
t1/2 
Terminal Elimination Half-life 
Tmax 
Time of Maximum Concentration 
Tmin 
Time of Minimum Concentration 
TEAE 
Treatment-emergent Adverse Event 
TID 
Three times a day 


DMID Protocol 21-0013 
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15 
TLF 
Tables, Listing and Figures 
UA 
Urinalysis 
ULN 
Upper Limit of Normal 
US 
United States 
Vd 
Volume of Distribution 
VS 
Vital Signs 
Vd,ss 
Volume of distribution at steady state  
WBC 
White Blood Cell 
WCK 5107 
Zidebactam 
WCK 5222 
Combination of Cefepime with Zidebactam 
WCK 6777 
Combination of Ertapenem with Zidebactam 
WHO 
World Health Organization 
ZID 
Zidebactam 
 
 


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PROTOCOL SUMMARY 
Title: 
A Phase I, Randomized, Double-blind, Placebo-controlled, Dose 
Escalation Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of Intravenous Ertapenem in Combination with 
Zidebactam (WCK 6777) in Healthy Adult Subjects 
Phase: 
1 
Population: 
Approximately 52 evaluable healthy male or female subjects 18 to 
45 years of age (both inclusive) at the time of dosing 
Number of Sites: 
One (Altasciences Clinical Kansas, Inc.)  
Study Duration:  
Approximately 11 months from study activation to last subject last 
visit 
Subject Participation 
Duration: 
Each subject will participate in the study for up to 42 days. The trial 
will consist of a Screening Period of up to 27 days as outpatient  
(Day -28 to Day -2); a Check-in/Baseline/Enrollment Day (Day -1); 
a Treatment Period of minimum of 7 nights/8 days (Days 1 to 8) as 
inpatient, with daily dosing on Days 1 to 7 and discharge on Day 8; 
and an out-patient Follow-up Period of 3 to 6 days (Days 9 to 14) 
with one site visit on Day 11 (+3 days) (Final Visit). 
Description of 
Agents: 
WCK 6777 is the designation for the combined preparation 
containing Ertapenem (ERT) and Zidebactam (ZID; WCK 5107) in 
equal amounts, ranging from 2 g (1 g of each compound) to 6 g (3 g 
of each compound). 
 
ERT is an approved antibacterial drug that belongs to the class of 
carbapenem antibiotics. ERT is provided as lyophilized powder of 
ERT sodium in a glass vial containing ERT 1 g/vial. The doses to be 
used range from 1 g to 3 g per injection daily for 7 days, depending 
on the study cohort. Sterile Water for Injection, USP will be used to 
reconstitute the drug and sterile 0.9% Sodium Chloride, USP to 
further dilute the reconstituted solution to the desired volume for IV 
infusion, which is 100  mL for the ERT 1-g combination with 1-g 
ZID, as the 2-g WCK 6777 (1-g ERT + 1-g ZID), and 250 mL either 


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for the 2-g or 3-g standalone ERT or for the combination with 2-g or 
3-g ZID, respectively as the 4-g WCK 6777 (2-g ERT + 2-g ZID) or 
the 6-g WCK 6777 (3-g ERT + 3-g ZID). ERT will be administered 
by IV infusion over a period from 30 min to 2 hours, depending on 
the drug amount delivered following study design. 
 
ZID is a synthetic compound that belongs to a novel class of bicyclic 
diazabicyclooctane (DBO) with dual functions as β-lactamase 
inhibitor and β-lactam enhancer. It is under investigation as an 
antibacterial agent in combination with cefepime (WCK 5222). ZID 
dihydrate is provided in lyophilized powder in a glass vial containing 
1 g/vial. The doses to be used range from 1 g to 3 g per infusion 
daily for 7 days depending on the study cohort. Sterile Water for 
Injection, USP will be used to reconstitute the drug and sterile 0.9% 
Sodium Chloride, USP to further dilute it to the desired volume for 
IV infusion, which is 100 mL for the ZID 1-g combination with 
ERT, as the 2 g WCK 6777 (1 g ZID + 1 g ERT), and 250 mL either 
for the 2 g or 3 g standalone ZID or for the combination with 2 g or 
3 g ERT, respectively for the 4 g WCK 6777 (2 g ZID + 2 g ERT) or 
the 6 g WCK 6777 (3 g ZID + 3 g ERT). ZID will be administered 
by IV infusion over a period from 30 min to 2 h, depending on the 
drug amount delivered following study design. 
Objectives: 
Primary 
Assess the safety and tolerability of three dose-escalating regimens 
of WCK 6777 (ERT and ZID combination) and two-dose escalating 
regimens of standalone ERT or ZID following single daily doses for 
7 days in healthy adult subjects 
Secondary 
Characterize the PK profiles in plasma (total & free) and in urine of 
three dose-escalating regimens of WCK 6777 (ERT and ZID 
combination) and two dose-escalating regimens of standalone ERT 
or ZID following a single initial dose on Day 1 and after single daily 
doses for 7 days in healthy adult subjects 
Outcome Measures:  
Primary 
Type, incidence, severity, and relatedness to study drug of all 
treatment-emergent adverse events (AEs) and serious adverse events 


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(SAEs) in each treatment cohort from the first dose through the 
follow-up period 
Secondary  
PK parameter estimates and calculated exposure measures in plasma 
(total and free) and urine for ERT and ZID, when given alone and in 
combination following a single initial dose on Day 1 and after single 
daily dose administration for 7 days 
Description of Study 
Design: 
This is a Phase 1, single center study to investigate the safety, 
tolerability, and pharmacokinetics (PK) of three dose-level groups of 
WCK 6777 (ERT and ZID combination), and two dose-level groups 
of ERT alone and ZID (WCK 5107) alone in 52 healthy adult male 
and female subjects aged 18 to 45 years old (both inclusive). 
Seven treatment cohorts will be evaluated in this study (Table 1 and 
Figure 1). WCK 6777 will be evaluated in three cohorts - Cohorts 1, 
4 and 7- of 8 subjects each (6 study drug combinations and 2 
placebos); ERT will be evaluated alone in two cohorts – Cohorts 2 
and 5- of 8 subject each (6 ERT and 2 placebos); and ZID will be 
evaluated in two cohorts, Cohorts 3 and 6, of 6 subjects each (all 
ZID). The study will be placebo-controlled and double-blinded in all 
cohorts except Cohorts 3 and 6. No placebo subjects are included in 
standalone ZID cohorts, since adequate safety data for higher doses 
of ZID alone in comparison with placebo are available from 
completed Phase 1 studies of WCK 5107 (ZID) alone and the ZID-
only arms of WCK 5222 (cefepime + ZID) studies. 
In each cohort, either study drugs alone or their combination will be 
administered by a single intravenous infusion (IV) of 100 mL daily 
for 7 consecutive days in Cohort 1 or 250 mL daily for 7 consecutive 
days in Cohorts 2 to 7. For each treatment cohort, however, the dose 
will be progressively escalated from 1 g/daily to 2 g/daily and to 
3 g/daily, and the duration of infusion time increased from 30 min to 
1 h and to 2 h over the course of the study. In Cohort 1, WCK 6777 
2 g (ERT 1 g/daily combined with ZID 1 g/daily) will be 
administered in 30 (±5) minutes (min); in Cohort 2 (ERT 2 g/daily), 
Cohort 3 (ZID 2 g/daily), and Cohort 4 (WCK 6777 4 g [ERT 
2 g/daily combined with ZID 2 g/daily]) the study drug(s) will be 
administered in 60 (±10) min, and in Cohort 5 (ERT 3 g/daily), 


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Cohort 6 (ZID 3 g daily) and Cohort 7 (WCK 6777 6 g [ERT 3 
g/daily combined with ZID 3 g/daily]), the study drug(s) will be 
administered in 120 (±10) min. (See Table 1). 
Study enrollment will proceed from Cohort 1 to Cohort 7 starting 
with the lowest dose and escalating to the next higher dose. 
Individual dose Cohorts 2 and 3 and 5 and 6 will run in parallel. For 
each combination treatment cohort (Cohorts 1, 4 and 7), two sentinel 
subjects will receive study treatments (one WCK 6777 and one 
placebo; drug/ placebo ratio 1:1) and followed for safety for 
approximately 24 h prior to dosing of the remaining 6 subjects in the 
cohort. If no halting rules have been met 24 hours after start of 
dosing, dosing of sentinel subjects will continue for the remainder of 
the study and the additional 6 subjects in the cohort will be dosed (5 
will receive WCK 6777 and 1 will receive placebo; drug/placebo 
ratio 5:1).  Sentinels will not be employed in the single treatment 
cohorts. 
Blood (plasma) and urine samples will be collected for measuring 
drug concentrations for PK analysis for 24 h after starting the first IV 
infusion on Day 1, and for 24 h after starting the last IV infusion on 
Day 7. Plasma concentrations of study drugs will also be measured 
before and 12 h after dosing on Days 2 to 6. Total and free drug 
concentrations of ERT and ZID will be measured in plasma and total 
drug concentration of ERT and ZID in the urine by validated LC-
MS/MS assays. 
Safety data will be monitored from the time of infusion on Day 1 to 
the last visit (Day 11+3 days) and will consist of: daily assessments 
of treatment-emergent AEs, vital signs and symptom-directed 
physical examination (PE);  clinical laboratory safety tests (Day -1, 
Days 2, 4, 6 and Day 8 (prior to the discharge from the study site]), 
and 12-lead ECGs, and a complete PE on the last visit 
(Day 11 +3 days). AEs will be assessed by the study clinicians for 
severity or seriousness, and relatedness to study drug(s) and include 
outcome and duration. 
The decision for dose escalation from combination Cohort 1 (1 g 
ERT + 1 g ZID) to the next planned higher single dose Cohorts 2 
(2 g ERT) and 3 (2 g ZID), and from combination Cohort 4 (2 g ERT 


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+ 2 g ZID) to single dose Cohorts 5 (3 g ERT) and 6 (3 g ERT) will 
be based on unblinded review of cumulative interim safety data to 
Day 11 (+3 days) of each combination cohort by the Safety 
Monitoring Committee (SMC). The recommendation to continue to 
combination Cohort 4 and to combination Cohort 7 (3 g ERT + 3 g 
ZID) will be made by the study team (DMID Medical Officer [MO] 
and Medical Monitor [MM] and Site PI) after review of blinded 
safety data in Cohorts 2 and 3 and Cohorts 5 and 6, respectively, to 
determine if halting rules are met. The SMC will review all interim 
safety data, not only those that meet pre-specified halting rules. after 
completion of Cohort 1 and Cohorts 1-4, and all final safety data 
after database lock. 
If no halting criteria are met, the decision to continue dose escalation 
will be made and announced by DMID. If halting criteria are met, an 
ad hoc meeting of the SMC will convene to review the unblinded 
data and make recommendations about dose escalation and the 
continuation of the trial. 
The SMC will also review the aggregate data in the first 4 cohorts, 
before dosing the remaining cohorts, and the cumulative safety data 
at the end of the trial after the database lock. 
Estimated Time to 
Complete Enrollment 
Up to 10 months (from dosing of first subject to final visit of last 
subject). 
 
 


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Figure 1 Description Schematic of Study Design  
 
 


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1 
KEY ROLES 
Site Principal Investigator: 
Martin Kankam, MD, PhD, MPH, FAPCR  
Altasciences Clinical Kansas, Inc. 
10103 Metcalf Avenue 
Overland Park, KS 66212 
Office: 913-696-1601 
Email: mkankam@altasciences.com 
DMID Clinical Project Manager: 
Maureen Mehigan, RN 
DMID/NIAID/NIH/HHS 
5601 Fishers Lane, Room 7E19  
Bethesda, MD 20892-9826 
Office: 240-627-3317 
Email: mmehigan@niaid.nih.gov  
Statistical and Data Coordinating 
Center (SDCC): 
The Emmes Company, LLC 
401 N. Washington Street, Suite 700 
Rockville, MD 20850 
Phone: 301-251-1161 
Fax: 301-576-3558 
Email: phase1@emmes.com  
Bioanalytical Laboratory: 
KCAS Bioanalytical and Biomarker Services 
Test Materials Management 
10830 South Clay Blair Boulevard 
Olathe, KS 66061 
Phone: 913-248-3106 
Fax: 913-248-3106 
Email: TMM@kcasbio.com 


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2 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background Information 
Antibiotics were one of the significant medical discoveries in the 20th century and they save 
200,000 American lives annually, extend life expectancy, and facilitate major advances in 
medicine and surgery [1]. Despite best efforts, our ability to use antibiotics safely and effectively 
has been compromised by the emergence of antibiotic resistance. Antimicrobial resistance is an 
ongoing public-health problem of critical importance and is considered as one of the top ten 
threats to global health by the World Health Organization (WHO) [2]. Among the various 
emerging resistant bacterial pathogens, carbapenem-resistant bacteria are particularly worrisome 
given that carbapenems have long been considered the most reliable last-resort treatment for 
infections caused by Gram-negative pathogens. Carbapenem resistance predominately manifests 
in various Gram-negative organisms including Enterobacterales, which have been recognized as 
an urgent threat by both the CDC and WHO that require aggressive action [3, 4]. While a variety 
of mechanisms contribute to carbapenem resistance among Enterobacterales, it is driven in a 
large part by the increasing prevalence and complexity of a variety of β-lactamases. The most 
important of these are the class A serine carbapenemases, such as KPC, class B metallo-β-
lactamases (MBLs), such as Verona integron Metallo β-lactamase (VIM), imipenemase (IMP) 
and New Delhi Metallo β-lactamase (NDM) and class D carbapenemases, such as OXA-48 types 
[5]. 
 
Evidence shows that the only way to stay ahead of the resistance curve is to follow the best 
infection control practices, use antibiotics prudently, and bring new agents to the market [6]. 
There has been an impressive antibiotic drug development response in recent years to combat the 
rise in antibiotic resistant pathogens and several intravenous (IV) antibiotics with activity against 
certain carbapenem- resistant Enterobacterales (CREs) encountered in clinical practice have been 
approved by both the FDA and EMA [7, 8]. While these recently approved agents are welcomed 
additions to our antibiotic armamentarium, nearly all are required to be administered by IV, 
multiple times-a-day with infusion times ranging from 1 to 3 hours. The dosing and 
administration requirements of these newer agents are associated with some logistical challenges, 
but they are largely manageable in hospitalized patients. However, infections due to CREs are of 
substantial concern across all clinical settings, including the community setting, and none of 
newer agents with enhanced CRE activity are conducive for outpatient use. Plazomicin is the 
only recently approved agent against CREs that is dosed once daily but it lacks comprehensive 
coverage of CREs (such as strains producing NDM due to co-expression of 16S rRNA methyl 
transferases) and does not possess a safety profile commensurate for outpatient parenteral 


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antimicrobial therapies (OPAT) [9]. Among epidemiologic studies that identified the occurrence 
of community-onset CRE infections, the prevalence ranged from 8 to 30% globally and from 5 to 
11% in the United States [10]. 
 
The rise in community-onset CRE infections highlights the critical need for effective OPAT [11]. 
OPAT has the potential to be the ‘standard-of-care’ for the management of many infections 
requiring IV antimicrobial therapy like CRE infections. For some conditions, initiation of OPAT 
in the outpatient or emergency department setting may allow avoidance of hospitalization 
entirely [12]. Avoidable hospitalizations impose a significant burden on already stressed health-
care systems which could be mitigated to a large extent if an effective OPAT is available. The 
availability of an effective OPAT also facilitates early discharge of clinically stable patients. 
Data shows that patients often remain in the hospital after their acute infection resolves, and it is 
possible to discharge these patients with OPAT without compromising the clinical outcomes 
[13]. Beyond the potential cost benefits, early discharge of suitable patients with OPAT has been 
shown to improve patient satisfaction, reduce healthcare-associated infections, and allow 
resources to be reallocated to increase patient care throughput. A potential OPAT solution for 
patients with CRE infections in development is the combination of ERT with ZID (WCK 6777, 
ERT-ZID), which will be evaluated in this study as a once-daily intravenous infusion (IV) 
administered over 0.5 to 2 hours. 
2.2 
Ertapenem and Zidebactam (WCK 6777) 
WCK 6777 is the code name for Wockhardt’s proprietary combination of ertapenem (ERT) and 
zidebactam (ZID). 
 
ERT is a once-daily IV carbapenem antibiotic that is FDA-approved for multiple indications in 
the United States. It is a well-established OPAT drug with robust activity against infections due 
to extended-spectrum β-lactamase (ESBL) producing-Enterobacterales [14]. However, ERT has 
no activity against CRE. Moreover, strains harboring multiple ESBLs and AmpC and decreased 
expression of porins also tend to show reduced susceptibility to ERT owing to hampered uptake 
of ERT [15]. ZID is a novel diazabicyclooctane (DBO) [16]. In addition to β-lactamase 
inhibition like other DBOs, such as avibactam and relebactam, ZID forms a strong covalent 
interaction with the penicillin binding protein 2 (PBP2) present in all the clinically important, 
carbapenem-resistant Gram-negative pathogens [17-19]. This feature, termed as β-lactam 
enhancer action, is maximized when ZID is combined with β-lactams like ERT and cefepime 
that bind to PBPs other than PBP2. The antibacterial effects of the PBP-optimized ZID/β-lactam 
combinations are (1) enhanced microbiologic activity against MBL-expressing Gram-negative 
bacteria albeit ZID lacks β-lactamase inhibitory activity against MBLs [20] and (2) substantial 
reductions in % f T>MIC requirements for the partner β-lactam [21-22]. Both these advantages 


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were demonstrated in vitro and in vivo with ZID combined with cefepime (FEP) (WCK 5222, 
Wockhardt’s three times a day [TID] drug) [21, 23]. WCK 5222 is active against Gram-negative 
organisms expressing all four Ambler classes of β- lactamases and has pharmacokinetic/ 
pharmacodynamics (PK/PD) susceptibility breakpoint of 64 µg/mL as compared to 8 µg/mL for 
cefepime alone [23-26]. Presently, cefepime/ZID is pending evaluation in Phase 3 trials for 
complicated urinary tract infections (cUTI) and ventilated-nosocomial pneumonia. 
 
This proposed Phase 1 healthy subject study is aimed to evaluate the safety, tolerability, and 
pharmacokinetics (PK) of the once-daily IV combination of ERT with ZID (WCK 6777). To 
date, pre-clinical animal PK/PD studies that simulated clinical exposure profiles of ERT 2 g and 
ZID 2 g, IV once- daily demonstrated bactericidal activity against KPC-, OXA-48, and MBL-
producing Enterobacterales with ERT/ZID MIC values up to 8 µg/mL [27]. Although the FDA-
approved dosing regimen for ERT in human is 1 g IV daily [28], the safety of IV ERT doses up 
to 3 g once-daily have been evaluated in Phase 1 and 2 studies [29]. Clinical studies with ZID 
have established safety for a single highest dose of 3 g and total divided daily dose of 6 g/day 
[30, 31], with some clinical studies characterizing the PK of ZID in pulmonary tissues of healthy 
subjects [32] as well as in plasma of subjects with impaired renal function [33] 
(ClinicalTrials.gov Identifiers: NCT02532140, NCT02674347, NCT02707107, NCT03630094, 
NCT02942810, NCT03554304). However, no human safety and PK data are available with these 
agents when they are used in combination as a once-daily dosing regimen. Therefore, the 
proposed Phase 1 studies will assess the safety, tolerability, and PK of escalating regimens of 
ERT in combination with ZID to determine its suitability for continued clinical development. 
2.2.1 
Zidebactam (WCK 5107)  
2.2.1.1 
Physicochemical properties  
Zidebactam dihydrate (CAS No. 1996664-59-5) is a proprietary New Chemical Entity (NCE) of 
Wockhardt coded as WCK 5107. It is a bicyclo-acyl-hydrazide (DBO pharmacophore) 
chemically identified as (2S, 5R)-7-Oxo-6-sulphooxy-2-[N'-((R)-piperidin-3-carbonyl)-
hydrazinocarbonyl]-1, 6-diaza-bicyclo [3.2.1] octane dihydrate. The structure and absolute 
stereochemistry of ZID has been confirmed though various instrumental methods of analysis 
such as elemental analysis, NMR spectrometry, mass spectrometry, and single crystal X-ray 
analysis. ZID has a molecular formula of C13H21N5O7S.2H2O and a molecular weight of 
427.45 daltons (includes two water molecules). ZID exists as pale yellow to white crystalline 
powder. It is slightly hygroscopic and is freely soluble in water and insoluble in dichloromethane 
[34]. 


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2.2.1.2 
Mechanism of Action 
ZID has a novel, dual mechanism of action, involving broad-spectrum inhibition of various 
serine β-lactamases including Class A, C and certain Class D β-lactamases, and as β-lactam 
enhancer due to selective, high-affinity binding (IC50 0.01 to 0.26 μM ) to Gram-negative PBP2, 
(a key enzyme involved in cell wall synthesis and maintenance of the rod shape), of in all the 
four clinically significant Gram-negative pathogens, namely, E. coli, K. pneumoniae, 
P. aeruginosa and A. baumannii [17-19, 34]. 
2.2.1.3 
Antibacterial activity 
By virtue of strong affinity towards Gram-negative PBP2 and also pan-β-lactamase stability, ZID 
exhibits antibacterial activity against certain pathogens on standalone basis. For example, ZID 
MIC50/90 for Enterobacterales and P. aeruginosa were 0.12/>64 µg/mL and 0.5/>64 µg/mL, 
respectively. It should be noted that though standalone ZID shows impressive in vitro activity, it 
does not translate into adequate in vivo efficacy due to single PBP2 binding action [20, 34]. 
2.2.1.4 
In Vitro Drug Interaction Studies 
• CYP450 Studies: ZID up to a 500 μM (equivalent to 195.7 μg/mL) did not induce CYP1A2 
or CYP3A4 enzyme activity and mRNA levels. Hence ZID is unlikely to cause CYP 
mediated drug-drug interactions (DDI) [34]. 
ZID is not an inhibitor of all key human CYP450 isoforms (CYP1A2, CYP2C8, and 
CYP2C9 CYP3A4) up to 2,000 μM (782.5 μg/mL) and it did not inhibit CYP2C19, and 
CYP2D6 up to tested concentration of 300 μM (117.4 μg/mL) [34]. 
• Transporter Studies: ZID is unlikely to cause clinical DDIs involving the human 
transporters due to non-inhibitory potential towards P-gp, BCRP, OATP1B1, OATP1B3, 
OAT1, OAT3, and OCT2 human transporters. Additionally, ZID does not have inhibitory 
activity towards human transporters like MRP4, OCT1 and BSEP [34]. 
ZID substrate potential for renal transporters (OAT1, OAT2, OCT2, MRP4) was studied 
in vitro both in the presence and absence of ERT. ZID did not show substrate potential for 
OAT1, OAT2, OCT2, or MRP4 [34]. 
2.2.1.5 
Genetic Toxicity 
Zidebactam was evaluated through a battery of in-vitro (bacterial reverse mutation assay and 
chromosomal aberration in human lymphocytes) and in-vivo (mouse micronucleus test) 
genotoxicity tests. In mouse micronucleus test, the exposure in terms of AUC at NOAEL dose 
(1302 mg/kg) was 1194.5 to 1441.2 mg·h/L. This exposure is about 3.5 to 4 times of clinical 
exposure obtained at the intended clinical dose of Zidebactam 2 g daily in WCK 6777. 
Zidebactam did not show clastogenic potential in both in-vitro and in-vivo genotoxicity studies. 


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Further studies are needed to assess the risk of mutagenicity.  Thus, considering the available 
data and shorter therapeutic duration envisaged of up to 14 days, the risk of carcinogenicity is 
low. [34]. 
2.2.1.6 
Preclinical In Vivo Safety Profile 
In preclinical safety assessment, ZID was found to be safe for vital organ systems based on their 
extensive evaluation in safety pharmacology studies for cardiovascular, gastrointestinal, 
respiratory and central nervous systems. The IV No Observed Adverse Effect Level (NOAEL) 
doses, based on a 28-day repeat dose toxicity study in rat and dog are 800 and 750 mg/kg/day, 
respectively and the corresponding exposure in terms of 24-hour (h) area under the plasma drug 
concentration -time curves (AUCs) are 1950 and 1962 mg·h/L, respectively. On the basis of ZID 
NOAEL dose exposures in dog (750 mg/kg/day) and rat (800 mg/kg/day) and anticipated ZID 
clinical exposure of 360 mg·h/L at 2 g/day, a safety window of approximately 5.4 times is 
envisaged [34]. 
 
In a 13-week repeat-dose intravenous toxicity study of ZID in Beagle dogs, the NOAEL and 
Low Observed Adverse Effect Level (LOAEL) were 250 and 500 mg/kg, respectively. Based on 
the body surface area, these doses in Beagle dog correspond to per day administration of 9.7 g 
and 19.4 g of ZID for a 70 kg human, respectively [34]. 
2.2.2 
Ertapenem 
2.2.2.1 
Physicochemical Properties 
ERT is generally available as ertapenem sodium (CAS No. 153773-82-1), and chemically 
identified as [4R-[3(3S*,5S*),4α,5β,6β(R*)]]-3-[[5-[[(3-carboxyphenyl)amino] carbonyl]-3-
pyrrolidinyl]thio]-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0] hept-2-ene-2-
carboxylic acid monosodium salt. It has a molecular formula C22H24N3O7SNa and a molecular 
weight of 497.50 daltons. ERT sodium is a white to off-white hygroscopic, weakly crystalline 
powder. It is soluble in water and 0.9% sodium chloride solution, practically insoluble in ethanol, 
and insoluble in isopropyl acetate and tetrahydrofuran [28]. 
2.2.2.2 
Mechanism of Action 
ERT rapidly binds to PBPs of Enterobacterales with greater affinity towards PBP3 and PBP2. 
Such a rapid rate of PBP binding of ERT is an enabling feature as it would be able to induce 
elongation even in the presence of inactivating enzymes. In a Pseudomonas PBP binding study, 
ERT showed high-affinity binding to all the essential PBPs, such as PBP2, PBP3 and PBP1a/b in 
P. aeruginosa [34]. 


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2.2.2.3 
Antibacterial Activity 
ERT is a broad-spectrum, carbapenem antibiotic with coverage spectrum encompassing Gram-
negative (including ESBL-expressing strains), Gram-positive and anaerobic pathogens. ERT has 
potent in vitro activity against β-lactamase-expressing Enterobacterales including those that 
produce class A ESBLs and class C enzymes. ERT is not effective against Enterobacterales 
expressing ERT-hydrolyzing β-lactamases, such as KPC, MBL and Class D- OXA-
carbapenemases. ERT also has limited activity against Pseudomonas aeruginosa owing to its 
vulnerability to pseudomonal efflux and poor uptake [34]. 
2.2.2.4 
In Vitro Drug Interaction Studies 
• CYP450 Studies: In vitro studies in human liver microsomes indicate that ERT does not 
inhibit metabolism mediated by any of the following cytochrome p450 (CYP) isoforms: 
1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 [34]. 
 
• Transporter Studies: In vitro studies have established that ERT does not inhibit  
P-glycoprotein mediated efflux nor it is a substrate of the same efflux pump [21].  
 
ERT in presence and absence of ZID was assessed for its renal transporter substrate 
potential against OAT1, OAT3, OCT2 and MRP4 transporters at higher concentration. 
The results of transporter substrate study indicate that ertapenem is a substrate of OAT3 
transporter; it is likely to be a substrate of OAT1 and MRP4 and non-substrate of OCT2 
transporter. The substrate activity of ERT remained unaffected in presence of ZID 
(1000 µM) [34]. 
2.2.2.5 
Genetic Toxicity 
 No long-term studies in animals have been performed to evaluate the carcinogenic potential of 
ertapenem. Ertapenem was not genotoxic in in vitro or in vivo assays, including: an alkaline 
elution/rat hepatocyte assay, a chromosomal aberration assay in Chinese hamster ovary cells, a 
TK6 human lymphoblastoid cell mutagenesis assay and a mouse micronucleus cells, a TK6 
human lymphoblastoid cell mutagenesis assay and a mouse micronucleus assay [28, 34]. 
2.2.2.6 
Preclinical and Clinical Safety Profile 
The safety of ERT is well established through a range of preclinical studies in rodents and non-
rodents and clinical studies. ERT was approved for marketing in 2001 [28]. Safety and 
tolerability of ERT even at doses higher than the currently approved 1 g/day has been well 
established in clinical studies conducted by Merck. In Phase 1, the maximum dose of ERT 
studied was 3 g/day with no serious adverse events (AEs). In Phase 2 trials, higher ERT dose of 


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1.5 g and 2 g were also evaluated; for which the pattern and frequency of AEs were similar to 
those who received 1 g of ERT [29, 34]. 
2.2.2.7 
Clinical Indication 
In the U.S., ERT is indicated as a once-a-day parenteral carbapenem antibiotic in adults and 
pediatric patients (3 months of age and older) for the treatment of the following moderate to 
severe infections caused by susceptible bacteria: complicated urinary tract infections (cUTI) 
including pyelonephritis, community-acquired pneumonia (CAP), complicated intra-abdominal 
infection (cIAI) and complicated skin and skin-structure infections including diabetic foot 
infections without osteomyelitis, acute pelvic infections including postpartum endomyometritis, 
septic abortion and post-surgical gynecologic infections. ERT is also indicated in adults for the 
prophylaxis of surgical site infection following elective colorectal surgery [28, 34]. 
2.2.3 
WCK 6777 (Combination of ERT and ZID)  
WCK 6777 is a combination of equal amounts of ERT, a carbapenem antibiotic, and ZID, a  
non-β-lactam entity which acts as a β-lactam enhancer. It is being developed as once-a day 
parenteral therapy for the treatment of Gram-negative infections. The indications described for 
ERT would be targeted for WCK 6777 in clinical settings. 
2.2.3.1 
Mechanism of Action 
In Gram-negatives, WCK 6777 operates on the basis of β-lactam enhancer mechanism of action. 
ZID binds to Gram-negative PBP2 and ERT being a potent PBP3 and PBP2 binding agent 
(additional binding to PBP1a/b in Enterobacterales), the combination exerts bactericidal action 
against MDR pathogens through complementary binding of multiple PBPs. This mechanism of 
action obviates the need of β-lactamase inhibition leading to the activity against pathogens 
expressing ZID non-inhibitable β-lactamases, such as MBLs. ERT-ZID combination is further 
benefitted by ZID’s ability to inhibit several class A (including KPC) and class C β-lactamases 
[34]. 
2.2.3.2 
Antibacterial activity – In Vitro 
The MIC50/90 of ERT-ZID against KPC-, OXA-48/181- and MBL-expressing Enterobacterales 
were 0.25/2, 1/2, and 0.5/4 µg/mL, respectively. For these set of organisms, the MIC90 of 
standalone ERT or ZID was >128 µg/mL.  ERT-ZID combination was also active against 
P. aeruginosa with MIC50 of 4 µg/mL and MIC90 of 8 µg/mL. Time-kill studies demonstrated 
synergistic bactericidal action to the extent of 1 to 2 log10 kill upon 4-hour (h) exposure of  
ERT-ZID against wild type, ERT-resistant Enterobacterales and efflux hyper-expressing and 
OprD-down regulated P. aeruginosa. 


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Time-kill studies have shown that ERT’s affinity to bind PBP3 in combination with PBP2 
binding when combined with ZID, elicits potent synergistic bactericidality as a result of the 
inhibition of multiple essential PBPs. Thus, ZID enhances the pharmacodynamic action of ERT 
leading to activity against ERT-resistant MDR strains. With this augmented pharmacodynamic 
effect, the duration of the pharmacodynamic relevant exposures of ERT is significantly lowered, 
enhancing the therapeutic coverage of pathogens including those that express ERT-impacting 
resistance mechanisms. WCK 6777 also evokes a bactericidal response against P. aeruginosa as 
a result of PBP3 and PBP2 binding by ERT and ZID, respectively. Such PBP-mediated 
bactericidal action overcomes ERT-impacting resistance mechanisms such as efflux and ERT-
hydrolysing β-lactamases that likely hamper the in vitro activity of ERT against P. aeruginosa. 
The inclusion of P. aeruginosa within the therapeutic scope of WCK 6777 would broaden its 
therapeutic utility as a step-down de-escalation therapy for several TID and QID combination 
products used for treatment of P. aeruginosa causing nosocomial infections [34]. 
2.2.3.3 
Antibacterial activity – In Vivo 
In vivo efficacy of ERT-ZID was assessed in a translational standard neutropenic mouse lung 
infection. ERT, ZID and ERT-ZID were tested at human-simulated regimens (HSR) in uranyl 
nitrate-treated, neutropenic mice which produced free plasma exposures of respective drugs 
mimicking the human free plasma exposures from once-daily administered 2 g of ERT and 2 g 
ZID. Against 24 carbapenem-resistant Enterobacterales which comprised of KPC or OXA-48-
like or NDM-expressing strains, ERT or ZID HSR was ineffective while ERT-ZID HSR showed 
a consistent 1 to 2.5 log10 kill. A similar study was undertaken independently at Centre for Anti-
infective Research and Development, Hartford Hospitals, wherein ERT/ZID HSR evoked 
>1 log10 CFU reduction (exceeding translational endpoint of 1 log10 kill) in 18/21 of KPC or 
OXA-48-like or NDM Enterobacterales and stasis to 0.5 log10 kill was observed in the remaining 
isolates [27, 34]. 
2.2.3.4 
Safety Pharmacology – In Vitro 
• hERG inhibition assay - At the highest tested concentration (1461 μM), there was a 
10% inhibition of hERG current. The IC50 for ZID could be greater than 1461 μM 
(571.5 μg/mL). This concentration of ZID is 3.8-fold higher than the intended clinical 
Cmax of ZID at dose of 2 g [34]. 
 
• Receptor binding and enzyme assays - ZID did not cause ≥ 50% inhibition of any of 
the enzymes or receptors at concentration of 500 µM (1.3-fold of clinical Cmax of ZID 
2 g), demonstrating lack of secondary pharmacodynamic targets [34]. 


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2.2.3.5 
Preclinical Safety – In Vivo 
ERT-ZID up to the highest dose studied (1,200 + 1,000 mg/kg) in rats did not affect any of the 
respiratory functions or neurobehavioral parameters in a head-out plethysmography and a 
functional observational battery test, respectively. The maximum concentration (Cmax) of ERT 
and ZID at these doses was about 3.9 and 5.3 times higher than the intended therapeutic Cmax 
levels, respectively. Further, in a 28-day repeat dose toxicity study in rats, ERT-ZID (800 + 800 
and 1600 + 1600 mg/kg/day) did not show any clinical signs of systemic toxicity. The no-
observed-adverse-effect-level (NOAEL) of ERT-ZID for this study was adjudged as 
1600+1600 mg/kg/day. The corresponding plasma AUC of ERT and ZID, 3700 and 
4540 mg·h/L, were about 3.6 and 12.6 times higher the expected therapeutic exposures, 
respectively, indicating a broad safety margin. US FDA has granted a waiver for the 28-days 
study in non-rodent species in light of adequate data on preclinical and clinical safety available 
for both ERT and ZID. [34]. 
2.3 
Clinical Experience 
2.3.1 
Human Studies with Zidebactam 
ZID has been studied in Phase 1 human trial as WCK 5107 and is also being developed in 
combination with cefepime (FEP) as WCK 5222 (q8h) and is slated to enter Phase 3 clinical 
studies. 
 
ZID has been administered to 91 healthy adult human volunteers in two Phase 1 double-blind, 
placebo-controlled single ascending dose (SAD) and multiple-ascending dose (MAD) studies 
conducted in the U.S. in healthy volunteers (W-5107-101; NCT02532140, and W-5107-102; 
NCT02674347). Doses ranged from 0.25 g to 3 g daily in the SAD study and 3 g (1 g q8 h) to 
6 g (2 g q8 h) in the MAD study. In addition, 1 g (approximately 200 μCi) of [14C]-ZID has 
been administered to 8 healthy adult male volunteers in a Metabolism and Excretion study [30, 
31, 34]. 
2.3.1.1 
Safety and Tolerability 
In the SAD study (W-5107-101), there were no deaths, serious adverse events (SAEs) or 
discontinuations due to AEs. No subjects on placebo reported any TEAEs. The majority of 
TEAEs were mild. One subject in the 1 g ZID cohort reported urticaria, and 1 subject in the 2 g 
cohort reported headache. In the cross-over cohorts, 5 subjects reported TEAEs that were 
considered treatment related, one with oral hypoesthesia (1 g dose ZID), 1 vulvovaginal mycotic 
infection (2 g FEP), 1 headache (1 g ZID+2 g FEP), 1 headache (2 g ZID+2 g FEP) and 1 
vaginal discharge (2 g ZID+2 g FEP) [34]. 


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In the MAD study (W-5107-102), there were no deaths, serious adverse events (SAEs) or 
discontinuations due to AEs. All TEAEs were mild in severity. Three subjects (37.5%) in 
Cohort 1 reported TEAEs, 2 due to the procedure (infusion site extravasation and 1 infusion site 
erythema), and 1 each myalgia, headache and vulvovaginal discomfort. In Cohort 2, there were 
3 TEAEs of headache, and 2 of vessel puncture site hematoma. In the Placebo Cohort, 2 subjects 
reported headache, 2 infusion site erythema and 2 vessel puncture site pain. In the metabolism 
and excretion study (Q-5107-103), all AEs were mild in severity and were assessed as related to 
ZID. Overall, 3 subjects (37.5%) reported 5 TEAEs (3 AEs of diarrhea, 2 AEs of infrequent 
bowel movements) [34]. 
 
No deaths, serious adverse events (SAEs) or discontinuations due to AEs were reported during 
the study. No subjects on placebo reported any AEs [34]. 
 
Clinical safety of ZID is also supported through WCK 5222 (FEP-ZID) Phase 1 studies, in which 
233 healthy volunteers were dosed with Zidebactam or cefepime/ZID, with ZID doses ranging 
from 3 g (1 g q8h) to 6 g (2 g q8h) daily for 7 to 10 days and FEP 6 g (2 g q8 h) daily. 
(ClinicalTrials.gov Identifiers: NCT02532140, NCT02707107, NCT03554304, NCT03630094, 
NCT02942810). These studies included a thorough QT study, which did not report QT 
prolongation or any cardiovascular AEs. No safety concerns were observed in any study. Both 
cefepime and ZID, at high doses, were well tolerated with a safety profile consistent with the  
β-lactam class [30-34]. 
2.3.1.2 
Pharmacokinetics 
ZID pharmacokinetics (PK), safety and tolerability have been investigated in Phase 1 clinical 
studies (W-5107-101 and W-5107-102). Intravenous ZID was assessed through single ascending 
dose (SAD) and multiple ascending dose (MAD) regimens in healthy adult (>18 years) human 
subjects. These randomized, double-blinded, placebo-controlled studies involved single 
escalating IV doses (0.25 to 3 g) and multiple IV doses (1 and 2 g, q8h for 7 days), administered 
as a 1 h infusion. In single ascending dose studies, ZID showed a linear PK; Geometric mean 
AUC(0- inf) ranged from 44.3 to 458 mg·h/L and Cmax ranged from 16.5 to 174 µg/mL. ZID 
elimination half-life (1.8 to 2.4 h) was appeared to be independent of dose. The observed median 
Tmax coincided with the respective cohort infusion duration within the 0.25 g to 3 g dose range. 
Renal clearance (4.85 L/h to 6.77 L/h) approximated the plasma clearance and appeared to be 
independent of the administered dose. In repeat dose study, exposure parameters were similar for 
each dosing interval within each dosing day. The plasma exposures of ZID were linear and 
comparable on Day 1 and Day 7. The majority (>80%) of the administered dose of ZID in the 
SAD study was excreted as unchanged drug within the first 0 to 6 h of the collection interval, 


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with the complete dose recovered within 24 h post-dose. In the MAD study, the majority of the 
administered q8h doses of ZID were excreted as unchanged drug within each dosing interval 
(0 to 8 h, 8 to 16 h, and 16 to 24 h collection intervals), with near complete dose recovery within 
24 h post AM dosing on Day 1 (92% to 95%), and within 48 h post AM dosing on Day 7 (95% 
to 99%) [34]. 
 
In addition, 1 g (approximately 200 μCi) of [14C]-ZID has been administered to 8 healthy adult 
male volunteers in a Metabolism and Excretion study conducted in U.S. In this study maximum 
plasma ZID concentrations were observed at the end of infusion for all subjects, after which 
plasma concentrations of ZID appeared to decline in a generally monophasic manner, with 
arithmetic mean t1/2 of approximately 2 hours. The primary route of elimination of total 
radioactivity was in urine, with 94.6% of the dose recovered. Excretion of total radioactivity in 
feces was negligible (0.235%). An arithmetic mean of 102% of the administered dose was 
excreted as unchanged ZID in urine, with the majority being recovered within the first 12 hours 
after start of infusion [34]. 
2.3.2 
Human Studies with Ertapenem 
2.3.2.1 
Safety and Tolerability 
ERT is an antibiotic approved by the FDA for human use by prescription in 2001. Extensive 
safety data (mostly post-marketing) is available for standalone ERT, which should be taken into 
account for an ongoing safety assessment of the ERT-ZID combination in clinical studies, both 
of assessment of causality of adverse events, as well as expectedness of any Serious Adverse 
Events (SAE). Clinical trials enrolled 1,954 patients treated with ERT. Most adverse experiences 
reported in these clinical trials were described as mild to moderate in severity. ERT was 
discontinued due to adverse experiences in 4.7% of patients. The most common drug-related 
adverse experiences in patients treated with ERT were diarrhea (5.5%), infused vein 
complication (3.7%), nausea (3.1%), headache (2.2%), and vaginitis in females (2.1%). Merck-
conducted clinical studies involving higher ertapenem doses of 1.5 g, 2 g or 3 g daily were 
administered to approximately 150 subjects [28, 29]. In these studies, ERT 2 g was well-
tolerated with minimal adverse events (AEs) of diarrhea, nausea, vomiting, somnolence and 
headache of mild to moderate severity, and asymptomatic increases in hepatic transaminases and 
platelet counts that were reversible and not clinically significant. The infusion duration of the 3 g 
IV dose initially was 1 h, but this was changed to 2 h due to the apparent association of nausea 
with the more rapid infusion rate. In Phase 2 studies, the pattern and frequency of AEs in patients 
who received 1.5 g or 2 g of ERT were similar to that of 1 g ERT [28, 29, 34]. A complete list of 
TEAEs reported in clinical trials with ERT as well as post-marketing studies is available in the 
Prescribing Information for Ertapenem Sodium for Injection, and in the IB [28, 34, 37]. 


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2.3.2.2 
Pharmacokinetics 
The single- and multiple-dose pharmacokinetics of ERT at doses up to 3 g were examined in 
healthy young men and women volunteers. Plasma and urine samples collected were analyzed 
using reversed-phase high-performance liquid chromatography with UV detection. ERT is highly 
bound to plasma protein. The protein binding changes from ∼95% bound at concentrations of 
<50 μg/ml to ∼92% bound at concentrations of 150 μg/ml (concentration at the end of a 30-min 
infusion following the 1-g dose). The nonlinear protein binding of ERT resulted in a slightly less 
than dose proportional increase in the area under the curve from 0 h to infinity (AUC0-∞) of 
total ERT. The single-dose AUC0-∞ of unbound ERT was nearly dose proportional over the 
dose range of 0.5 to 2 g. The mean concentration of ERT in plasma ranged from ∼145 to 
175 μg/mL at the end of a 30-min infusion, from ∼30 to 34 μg/mL at 6 h, and from ∼9 to 
11 μg/mL at 12 h. The mean plasma t1/2 ranged from 3.8 to 4.4 h. About 45% of the plasma 
clearance (CLp) was via renal clearance. The remainder of the CLp was primarily via the 
formation of the β-lactam ring-opened metabolite that was excreted in urine. There were no 
clinically significant differences between the pharmacokinetics of ERT in men and women. ERT 
does not accumulate after multiple once-daily dosing [35]. 
2.3.3 
Human Studies with WCK 6777 
WCK 6777 has not been studied in humans. This is the first in human study to investigate the 
safety and PK of ERT and ZID in combination. 
2.4 
Rationale  
2.4.1 
Study Rationale 
The aim of the clinical development program for WCK 6777 is to allow a full assessment of 
safety and efficacy as well as ensuring that the product is rapidly made available to fulfill an 
unmet medical need in the treatment of infections due to multi-drug resistant (MDR) bacteria. 
  
A Phase 1 study is required given that human safety and PK data are not available for ERT and 
ZID administered in combination. The following observations support conduct of this study: (a) 
Non-clinical mechanism of action (MOA) and PK/PD studies establish ERT/ZID 2 g/2 g QD as a 
potential treatment of patients with CRE infections; (b) Multiple Phase 1 studies conducted for 
ZID alone or in combination with FEP demonstrated safety and tolerability of ZID at multiple 
daily doses up to 6 g (2 g q8h) administered over 7 to 10 days; (c) Higher IV ERT doses of 2 g 
and 3 g QD have been studied in previous phase 1 and 2 studies (n = 101) [28,29]; (d) The 
preclinical toxicity studies of WCK 6777 in rats and dogs employing doses that generated 


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exposures higher than the clinical exposures reported for ERT 2 g and ZID 2 g suggest that the 
combination would be safe and tolerable. 
2.4.2 
Rationale for Dose Selection 
In vivo PK/PD studies involving neutropenic mouse lung infection models have demonstrated 
that the ERT-ZID combination exerts significant bactericidal action against KPC, OXA-48-like 
and MBL-expressing Enterobacterales at mouse exposures that correspond to 2 g q24h unbound 
clinical exposures of ERT and 2 g q24h unbound exposures of ZID obtained when dosed 
individually [34]. 
 
The IV No Observed Adverse Effect Level (NOAEL) doses, based on a 28-day repeat dose 
toxicity study for ZID in rat and dog, are 800 and 750 mg/kg/day, respectively, and the 
corresponding exposure in terms of 24-hour (h) area under the plasma drug concentration-time 
curves (AUCs) are 1950 and 1962 µg·h/mL, respectively. On the basis of ZID NOAEL dose 
exposures in dog (750 mg/kg/day) and rat (800 mg/kg/day) and anticipated ZID clinical exposure 
of 360 µg·h/mL at 2 g/day, a safety window of approximately 5.4 times is estimated [34]. 
 
Extrapolation of the dog IV NOAEL dose of 750 mg/kg to a human dose (based on body surface 
area) would lead to a human equivalent dose for ZID of 416 mg/kg, corresponding to 29 g for a 
70 kg human. Likewise, considering the NOAEL dose (800 mg/kg) in rat, the human equivalent 
dose for ZID would be 64 mg/kg, corresponding to 9 g for a 70 kg human [34]. 
2.5 
Identified and Potential Risks and Benefits Associated with the Study 
2.5.1 
Risks with ZID 
ZID alone has been administered to 91 healthy adult human volunteers in two Phase 1 studies 
[SAD and MAD] conducted in the U.S. In addition, 1 g (approximately 200 μCi) of [14C]-ZID 
has been administered to 8 healthy adult male volunteers in a Metabolism and Excretion study 
conducted in U.S. 
 
Overall, there were no SAEs or AEs that led to discontinuation of participants. The most 
common AE reported was headache, and it was mild in the majority of subjects, with one subject 
reporting moderate headache. Infusion site erythema and infusion site pain have also been 
reported as side effects, both considered related to the placement of an IV catheter than a 
reaction associated with the study drug. 


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2.5.2 
Risks with ERT 
Extensive safety data (mostly post-marketing) is available for standalone ERT. The latter should 
be taken into account for an ongoing safety assessment of the ERT-ZID combination in clinical 
studies, both for the assessment of causality of adverse events, as well as expectedness of any 
SAEs. 
 
Most adverse experiences reported in clinical studies with ERT, including those involving higher 
ertapenem doses of 1.5 g, 2 g or 3 g daily, were described as mild to moderate in severity. ERT 
was discontinued due to adverse experiences in 4.7% of patients. The most common drug-related 
adverse experiences in patients treated with ERT were diarrhea (5.5%), infused vein 
complication (3.7%), nausea (3.1%), headache (2.2%), and vaginitis in females (2.1%). The 
infusion duration of the 3 g IV dose initially was 1 h, but this was changed to 2 h due to the 
apparent association of nausea with the more rapid infusion rate. In Phase 2 studies, the pattern 
and frequency of AEs in patients who received 1.5 g or 2 g of ERT were similar to that of 1 g 
ERT [28, 29]. The safety profile of ERT is expected to be similar to that described during its 
clinical use when administered alone; however, as for all drug studies, there may be unexpected 
AEs with ERT that have not been observed to date. 
2.5.3 
Risks with WCK 6777 
The ERT-ZID combination has not been tested in humans. Preclinical data suggest that there are 
no significant system organ effects and the doses to be used in the study are below NOAEL for 
both drugs in rats and dogs. The safety profile of WCK 6777 is expected to be similar to that 
described for each drug alone [34]; however, as for all drug studies, there may be unexpected 
AEs with WCK 6777 that have not been observed with ERT or ZID alone to date. 
2.5.4 
Venipuncture and IV Catheter Risks 
Venipuncture: Venipuncture causes transient discomfort and may cause fainting. Bruising at the 
site of venipuncture may occur but can be prevented or lessened by applying pressure for several 
minutes. Infection at the site is possible but highly unlikely as aseptic technique will be used. 
 
IV catheter placement: An indwelling catheter may be placed in an arm vein (preferably 
antecubital) for frequent blood drawing for PK measurements on Days 1 to Day 8 and another 
one in a vein on the opposite arm for IV infusion of the study drugs. The catheter may cause 
phlebitis with signs of redness and warmth at or near the IV insertion site, and thrombophlebitis 
with a hard area palpable near the IV insertion site. These risks are minimal as the IV catheters, 
when used, are only used briefly after dosing. Careful inspection of the catheter site, including 
visualization of blood return, withdrawal of the catheter if needed, and change every 72 to 96 h 


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will minimize this risk. There is a risk of infection; however, this is a small risk as aseptic 
technique will be used. 
2.5.5 
Additional Risks 
ECG: Possible side effects from ECG patches include a rash or minor irritation of the skin. 
 
Blood draws: The amount of blood drawn is about 24 mL at Screening Visit, 15 mL on Day -1, 
371 mL during the inpatient period (Days 1 to 8), 15 mL at Day 11 (last visit), and 425 mL 
during the entire trial. Additionally, small amounts of blood loss may occur if an IV catheter is 
used or additional blood samples are collected (for repeat laboratory testing, TEAE evaluation, 
etc.). Overall, the amount of blood that may be drawn during the trial is within the amount that 
are considered safe to be drawn during short or extended periods, respectively, and not excessive 
for the safety and PK assessment requirements of Phase 1 trials. However, there is a small risk 
that some subjects may develop mild symptoms of hypovolemia or anemia during the trial. 
These are reversible with specific treatments (e.g., fluid replacement, good nutrition, vitamins or 
iron supplementation). 
2.6 
Known Potential Benefits 
The trial has no direct benefit for healthy participants. Knowledge gained in the trial could be of 
future benefit to public health and to individuals with infections, who might benefit if the study 
drug combination is licensed. The medical benefit would be to patients in the future from a 
potential new addition to the drugs available for the treatment of serious, antibiotic-resistant 
nosocomial and community acquired infections with increase efficacy and lower toxicity than 
available drug regiments. An additional benefit to future patients would be the ability to 
administer effective therapy for these infections in an out-patient setting, thus decreasing the 
need for hospitalization and associated costs. 
 
Subjects will be promptly notified of any clinical test results that would have an impact on their 
health. Screening evaluations may detect previously unknown abnormalities that could be 
clinically significant. This could benefit a subject, as it may lead to earlier diagnostic evaluation 
and treatment of an underlying disorder. 
2.7 
Risk/Benefit Ratio 
This ratio cannot be calculated by available data. Since high dose safety has been established for 
ERT and ZID individually, the risk for an SAE occurring in a subject treated with single or daily 
doses of each study drug separately in doses 1 to 3 g is considered to be very low. On the other 
hand, the risk of WCK 6777 (combined ERT and ZID) is not known. Preclinical studies have 
shown no potential DDIs through effects on enzymes and transporters.  Selection of the 


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combined human doses by appropriate methods for estimating human exposures from animal 
studies, suggest that the maximum exposure in humans will be at levels several-fold lower than 
NOAELs in rats and dogs. Data collected in the preclinical and clinical development of ZID and 
ERT/ZID to date, support further clinical development. Subject selection is based on carefully 
considered eligibility criteria. Subjects will be treated in an inpatient unit and closely monitored 
during the trial, so that appropriate emergency care can be provided immediately if an acute 
event occurs. As an additional measure of risk mitigation, each WCK 6777 cohort involves 
sentinel dosing in two subjects and remaining subjects will be dosed if no halting rules have been 
met after 24 hours of dosing to sentinel subjects. 
  
There is no medical benefit to healthy study volunteers from participation in this clinical trial.  


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3 
OBJECTIVES AND OUTCOME MEASURES 
3.1 
Study Objectives 
Primary 
• Assess the safety and tolerability of three dose-escalating regimens of WCK 6777 (ERT 
and ZID combination) and two dose-escalating regimens of standalone ERT or ZID 
following single daily doses for 7 days in healthy adult subjects 
Secondary  
• Characterize the PK profiles in plasma (total and free) and in urine of three dose-
escalating regimens of WCK 6777 (ERT and ZID combination) and the two dose-
escalating regimens of standalone ERT or ZID following single daily doses for 7 days in 
healthy adult subjects 
3.2 
Study Outcome Measures 
Primary 
• Type, incidence, severity, and relatedness to study drug of all treatment-emergent adverse 
events AEs and serious adverse events (SAEs) in each treatment cohort from the first 
dose through the follow-up period 
Secondary  
• PK parameter estimates and calculated exposure measures in plasma (total and free) and 
urine for ERT and ZID, when given alone and in combination following a single initial 
dose on Day 1 and after single daily dose administration for 7 days 


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4 
STUDY DESIGN 
This is a Phase 1, single center study to investigate the safety, tolerability, and pharmacokinetics 
(PK) of three dose-escalating regimens of WCK 6777 (ERT+ZID), and two dose-escalating 
regimens of ERT alone and ZID (WCK 5107) alone in 52 healthy adult male and female subjects 
aged 18 to 45 years old. 
Seven treatment cohorts will be evaluated in this study (Table 1). WCK 6777 (ERT+ZID) will be 
evaluated in three cohorts - Cohorts 1, 4 and 7 - of 8 subjects each (6 study drug combination and 
2 placebos); ERT will be evaluated in two cohorts - Cohorts 2 and 5 - of 8 subject each (6 ERT 
and 2 placebo); and ZID will be evaluated in two cohorts - Cohorts 3 and 6 - of 6 subjects each 
(all 6 ZID). The study will be placebo-controlled and double-blinded in all cohorts except 
Cohorts 3 and 6. No placebo subjects are included in standalone ZID cohorts, since adequate 
safety data for higher doses of ZID are available [34]. 
In each cohort, ERT and ZID will be administered either alone or in combination by a single 
intravenous infusion (IV) of 100 mL daily for 7 consecutive days in Cohort 1 and 250 mL in 
Cohorts 2 to 7. The dose will be progressively escalated from 2 g to 3 g/daily for each study drug 
individually, and from 2 g to 4 g to 6 g for WCK 6777 [ERT+ZID]) and, depending on the 
cohort, the duration of infusion time will increase from 30 min to 1 h to 2 h over the course of 
the study. Thus, in Cohort 1, 2 g WCK 6777 (ERT 1 g combined with ZID 1 g), the infusion 
solution (100 mL) will be administered in 30 (±5) minutes; in Cohort 2 (ERT 2 g/daily), 
Cohort 3 (ZID 2 g/daily) and Cohort 4 (4 g WCK 6777; ERT 2 g combined with ZID 2 g), the 
infusion solution (250 mL) will be administered in 60 (±10) minutes; and in Cohort 5 (ERT 
3 g/daily) , Cohort 6 (ZID 3 g daily) and Cohort 7 (6 g WCK 6777; ERT 3 g combined with ZID 
3 g), the infusion solution (250 mL) will be administered in 120 (±10) minutes. 
 Table 1 Study Treatment Cohort 
Cohort No. 
Study Drug-Dose 
Infusion time - frequency 
Subjects 
Cohort 1 
WCK 6777 2 g 
(ERT 1 g + ZID 1 g)  
or placebo 
30 (±5) minutes - once daily-for 
7 days, 100 mL per dose 
8 (6 drug combination, 2 placebo) 
Cohort 2 
ERT 2 g 
or placebo 
60 (±10) minutes - once daily-for 
7 days, 250 mL per dose 
8 (6 drug, 2 placebo) 
Cohort 3 
ZID 2 g 
60 (±10) minutes - once daily-for 
7 days, 250 mL per dose 
6 (all drug) 
Cohort 4 
WCK 6777 4 g 
(ERT 2 g + ZID 2 g) 
 or placebo 
60 (±10) minutes - once daily-for 
7 days, 250 mL per dose 
8 (6 drug combination, 2 placebo) 
Cohort 5 
ERT 3 g  
or placebo 
120 (±10) minutes - once daily-for 
7 days, 250 mL per dose 
8 (6 drug, 2 placebo) 


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 Table 1 Study Treatment Cohort 
Cohort No. 
Study Drug-Dose 
Infusion time - frequency 
Subjects 
Cohort 6 
ZID 3 g 
120 (±10) minutes - once daily-for 
7 days, 250 mL per dose 
6 (all drug) 
Cohort 7 
WCK 6777 6 g 
(ERT 3 g + ZID 3 g) 
or placebo 
120 (±10) minutes - once daily-for 
7 days, 250 mL per dose 
8 (6 drug combination, 2 placebo) 
 
The treatment regimen for the first combination cohort (Cohort 1), WCK 6777 2 g (ERT 1 g with 
ZID 1 g daily; 30-minute infusion), was selected because there are no human safety and PK data 
available with these agents in combination. The second combination cohort (Cohort 4) will 
evaluate the safety and PK of the anticipated therapeutic combination regimen of WCK 6777 4 g 
(ERT 2 g with ZID 2 g daily; 1-h infusion). The third combination-treatment cohort (Cohort 7) 
will evaluate the safety and PK of higher daily doses of WCK 6777 6 g (ERT 3 g + ZID 3 g 
daily; 2-h infusion). The primary purpose of the ERT 3 g with ZID 3 g combination treatment 
cohort is to ensure maximal flexibility in the clinical development program in the event there is a 
need to evaluate more intensive combination daily dosing regimens and different infusion 
strategies in future clinical trials. Moreover, 3 + 3 g/daily combination regimen will provide 
critical information on dose proportionality, PK linearity, and plasma protein binding linearity. 
As it is well-established that healthy subjects do not fully reflect the real-world inter-subject 
variability observed in patients [36], the higher daily dosing regimen will also provide data on 
the safety, tolerability, and PK of upper range exposures likely to be encountered in clinical 
practice with ERT 2 g + ZID 2 g. To mitigate the risk of higher osmolality-linked infusion 
reactions, the volume of each infusion in the 2-g and 3-g dose standalone and combined groups 
(Cohorts 2-7) will be increased to 250 mL. The duration of infusions in the 2-g and 3-g cohorts 
were chosen to mitigate infusion duration-related AEs (nausea, vomiting) with ERT doses >2 g 
[29]. In four of the seven cohorts (Cohorts 2, 3, 5 and 6), single 2 g and 3 g ERT or ZID 
infusions will be administered. ERT 1 g daily and ZID 1 g daily will not be evaluated as single 
drug treatment cohorts as there are sufficient safety, tolerability, and PK data with these 
standalone regimens [28, 29, 34]. 
In all cohorts, 6 subjects will receive study drug product. Two additional subjects will receive 
placebo in the 2 g/daily and 3 g/daily ERT single treatment cohorts and in ERT-ZID combination 
cohorts to maximize interpretation of the safety and tolerability of the observed results. The 
single drug treatment cohorts are being conducted to collect the baseline safety and 
pharmacokinetic data. Specifically, the single-treatment arms of ERT and ZID are necessary to 
assess for the presence of any PK interactions between the two constituents and to deduce the 
role of each, in the event of any safety or tolerability signals in the combination cohorts. In 
conjunction with the escalating dose combination regimens, the single treatment drug cohorts 


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will also provide information on dose-PK proportionality, which is necessary for building robust 
individual population PK models for ERT and ZID, which, when supplemented with PK/PD 
studies, will help justify the dose regimen for advanced clinical trials. 
Study enrollment will proceed from Cohort 1 to the last Cohort 7 starting with the lowest dose 
and escalating to the next higher dose. Enrollment of single drug Cohorts 2 and 3, and 5 and 6 
will be conducted in parallel and completed before enrollment of combination Cohorts 4 and 7, 
respectively. Placebo subjects will be enrolled in WCK 6777 cohorts (Cohorts 1, 4 and 7) and in 
the ERT alone cohorts (Cohorts 2 and 5), but not in the ZID cohorts (Cohorts 3 and 6). Sentinel 
subjects will be enrolled in the WCK 6777 cohorts but not in the ERT and ZID standalone 
cohorts. For each WCK 6777 cohort (Cohorts 1, 4 and 7), two sentinel subjects will receive 
study drug product on the first day of treatment, one active drug combination and the other 
placebo (normal saline) (active drug/placebo ratio, 1:1) and followed for approximately 24 hours. 
If no halting rules are met after 24 hours of dosing, dosing of sentinel subjects will continue for 
the remainder of the study, and the additional 6 subjects in the cohort will be dosed (5 will 
receive the study drug combination and 1 will receive placebo (active/placebo ratio, 5:1). 
Alternate subjects may be admitted in all cohorts at check-in and, if they are not used on the 
following dosing day, they may be used on another dosing day in the same cohort or in a future 
cohort if they continue to meet eligibility criteria. 
Blood (plasma) and urine samples will be collected for measuring drug concentrations of ERT 
and ZID and for PK analysis in all cohorts before dosing, for 24 h after starting the first IV 
infusion on Day 1, and for 24 h after starting the last IV infusion on Day 7. In addition, blood 
(plasma) will be collected before dosing and 12 hours after dosing on Days 2 to 6 for the 
measurement of concentrations of ERT and ZID. Total and free drug concentration will be 
measured in plasma and total drug concentration in the urine for ERT and ZID by validated LC-
MS/MS assays. The plasma and urine PK profiles for each study drug in the single dose ZID and 
ERT cohorts and the WCK 6777 cohorts will be analyzed by non-compartmental methods 
(NCA). 
Safety data will be monitored from the time of infusion on Day 1 to the last visit, Day 11 
(+3 days), and changes will be compared to the pre-dosing baseline (Day -1). Evaluations will 
consist of: assessments of TEAEs (Day 1 to Day 11), symptom-directed (focused) physical 
examination (PE) as needed (Days 1 to 7) and complete PE (Days 8 and 11); vital signs (Day 1 
to 8, Day 11);  Clinical laboratory safety tests (Days 2, 4, 6, 8 and 11); and 12-lead ECGs (Days 8 
and 11). AEs will be assessed by study clinicians for severity or seriousness and relatedness and 
will include outcome and duration. 
Dose escalation from combination Cohort 1 (1 g ERT + 1 g ZID) to higher single dose Cohorts 2 
(2 g ERT) and 3 (2 g ZID), and from combination Cohort 4 (2 g ERT + 2 g ZID) to higher single 
dose Cohorts 5 (3 g ERT) and 6 (3 g ZID) will be based on the SMC review of unblinded 
cumulative interim safety data collected through study Day 11 (+3 days) in each combination 


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treatment cohort. (See Section 9.5.3). The recommendation to continue to the next planned 
combination cohorts (i.e., Cohort 4 and Cohort 7 [3 g ERT + 3 g ZID]), will be made by the 
study team (DMID MO and MM and the site PI) after review of blinded safety data in Cohorts 2 
and 3 and Cohorts 5 and 6, respectively. The SDCC will provide a report of number of subjects 
meeting dose escalation halting criteria. The decision to continue dose escalation to the next 
single or combination dose cohorts will be made by DMID after review of the SMC or the study 
team recommendation. If the decision is to continue dose escalation, the next in line cohort(s) 
will enroll.  
If halting criteria are met, an ad hoc meeting of the Safety Monitoring Committee (SMC) will 
convene to review blinded data (or unblinded in a closed meeting) and make recommendation 
about dose escalation (See Section 9.5.1). The SMC will also convene in ad hoc meetings per 
DMID request to review a potential safety concern identified by either the Site PI or the DMID 
MM.  
Finally, in scheduled meetings, the SMC will review unblinded aggregate data in the first 
4 cohorts, before dosing will continue in the remaining cohorts (Cohorts 5, 6 and 7), and 
cumulative safety data at the end of the trial after database lock (See Section 9.6.1). 
4.1 
Sub-studies 
No sub-studies are planned. 


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5 
STUDY ENROLLMENT AND WITHDRAWAL 
Only subjects who meet all inclusion criteria and no exclusion criteria will be eligible for 
enrollment into the trial. 
5.1 
Subject Inclusion Criteria 
All must be answered YES for the subject to be eligible for study participation: 
1. Provide a signed and dated written informed consent and agrees to comply with the study 
procedures and length of confinement to the research site. 
2. Be able to understand and willing to comply with study procedures, restrictions, and 
requirements, as determined by the Site Principal Investigator (PI) or authorized 
clinician(s) (listed on FDA Form 1572).  
3. Adults 18 to 45 years of age inclusive, including non-pregnant, non-lactating females. 
4. Have suitable veins for cannulation or repeated venipuncture. 
5. Be in good general health at the time of enrollment. 
• Note 1: Determined by medical history (MH), medication use, physical examination 
(PE), vital signs (VS), clinical laboratory tests including estimated creatinine 
clearance (CLCR) ≥80 mL/min by the Cockcroft-Gault method, and 12-lead ECG 
within reference ranges at Screening and Day-1 (See Sections 8.1 and 8.2 and 
Appendix B, Table 2, Table 3, and Table 4). 
• Note 2: Exceptions to BP, HR and laboratory test values being with normal ranges 
are: 
o Subjects with baseline HR ≥ 45 to 50 bpm may be accepted if otherwise healthy 
adults with known history of asymptomatic bradycardia.  
o Subjects with baseline SBP up to 140 mmHg and DBP up to 90 mmHg may be 
accepted if otherwise healthy.  
o A laboratory value that is Grade 1 will be allowed if not considered to be 
clinically significant by the investigator, with the exception of ALT, AST, AP, 
total and direct bilirubin, BUN, serum creatinine, CLCR, and urine protein.  
6. Sexually active females must be of non-childbearing potential or must use a highly 
effective method of birth control from screening to 30 days following the last dose of 
study product. 
• 
Note 1: A female is considered of childbearing potential unless post-menopausal 
(defined as history of ≥1 year of spontaneous amenorrhea and a FSH level >40 IU/L), 
or permanently surgically sterilized. 
• 
Note 2: Highly effective contraceptive methods include: (a) surgical sterilization 
methods, such as tubal ligation, bilateral oophorectomy, salpingectomy, 
hysterectomy, or successful tubal obliteration (e.g., Essure®) with documented 


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radiological confirmation test at least 90 days after the procedure, or (b) long-acting 
reversible contraception, such as progestin-releasing subdermal implants, copper 
intrauterine devices (IUDs), levonorgestrel-releasing IUDs. 
• 
Note 3: A subject who is not sexually active and abstains from sexual intercourse can 
be enrolled and abstinence documented. 
7. Sexually active males must be vasectomized or agree to use barrier contraception and not 
donate sperm from first dose of study product until 30 days following the last dose. 
• 
Note 1: Barrier contraception includes use of condom with spermicide. 
• 
Note 2: A subject who is not sexually active and abstains from sexual intercourse can 
be enrolled and abstinence documented. 
8. Subjects must be willing to avoid excessive physical exercise within 48 h prior to dosing 
until discharge from the clinical trial unit (CTU) on Day 8, and 24 h before the last visit 
(Day 11 + 3 days). 
9. No history of acute febrile or infectious illness for at least 7 days prior to the 
administration of study drug(s). 
5.2 
Subject Exclusion Criteria 
All must be answered NO for the subject to be eligible for study participation: 
1. Known history of a clinically significant food or drug allergy/hypersensitivity including 
known allergy/hypersensitivity to ERT, any β-lactam drugs or other related drugs. 
2. Current seasonal allergies with ongoing symptoms for more than a week prior to dosing 
requiring glucocorticoids and/or frequent use of antihistamines for treatment. 
3. Any history of a chronic condition including renal failure that may increase risk to 
subject or interfere with endpoint assessment, or any unstable chronic disease. 
• Note 1: Unstable chronic disease is defined by need for frequent medical 
interventions that lead to a change in medications and/or required hospitalization, 
surgery or an invasive procedure or emergency department/urgent care visit, as 
determined by the Site PI. 
• Note 2: Any chronic disease, that has been diagnosed within 90 days of screening is 
excluded. 
4. History of any psychiatric condition that has required hospitalization in the last 
12 months or subject is considered psychologically unstable by the investigator. 
5. History of any clinically significant (CS) disease or disorder, medical/surgical procedure, 
or trauma within 4 weeks prior to initiation of administration of study product(s). 
6. History of Clostridium difficile induced diarrhea within 1 year before screening 
7. Known history of past or current epilepsy or seizure disorders, excluding febrile seizures 
of childhood. 
8. Prior exposure to ZID. 


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9. Use of any prohibited prescription or non-prescription medication within 14 days prior to 
the first dose of study drug(s) as described in Section 6.6. 
10. Use of any investigational drug product within 30 days or 5 half-lives (whichever is 
longer) before investigational product administration in this study. 
11. Planned participation in a clinical research study that requires treatment with a study 
drug, blood draws or other invasive assessments during the study period (screening until 
final visit). 
12. Blood or plasma donation of 500 mL within 3 months or more than 100 mL within 
30 days before signing informed consent or planned donation prior to completion of this 
trial. 
13. Positive serum pregnancy test for women at screening and urine pregnancy test at check-
in. 
14. Positive urine alcohol test or urine drug screen test at screening or check-in (Day -1). 
15. Positive test for HIV antibodies, hepatitis B-virus surface antigen (HBsAg), or  
anti-hepatitis C-virus antibodies (anti-HCV) at screening. 
16. History of ≥10 pack-years smoking in the 5-year period before screening, or positive 
urine cotinine screen at check-in. 
• Note 1: Nicotine products include cigarettes, e-cigarettes, pipe, cigar, chewing 
tobacco, nicotine patch. 
•  Note 2: Positive urine cotinine at screening is allowed if negative at check-in  
(Day -1). 
17. History of binge drinking or heavy drinking of alcohol at any time in the 6 months before 
study product administration. 
• Note 1: Binge drinking is defined as 5 or more drinks during single occasion if male, 
or 4 or more if female. 
• Note 2: Heavy drinking of alcohol is defined as consumption of more than 15 units of 
alcohol per week if male, or more than 8 units if female. 
5.3 
Treatment Assignment Procedures 
5.3.1 
Enrollment and Randomization Procedures 
Fifty-two healthy subjects who consent to participate in the trial and meet the eligibility criteria 
will be enrolled following admittance to the CTU and confirmation of eligibility. Subjects will 
be registered using Advantage eClinical®, a web-based application developed by The Emmes 
Company, LLC, the DMID Statistical and Data Coordinating Center (SDCC) for the trial. 
Reasons for screen failure will be entered in Advantage eClinical®. Instructions for using the 
enrollment module are included in the Advantage eClinical® User’s Guide. 
For the drug combination cohorts (Cohorts 1, 4 and 7) and standalone ERT cohorts (Cohorts 2 
and 5), the trial will be double-blinded, placebo controlled, with eight subjects randomized to 
receive either active drug(s) or placebo (normal saline) in an overall 3:1 ratio (6 subjects study 
drug and 2 subjects placebo). For each drug combination dosing cohort, two sentinel subjects 


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will be randomized in a 1:1 fashion to active drug and placebo and will be followed for 24 h. If 
there are no safety events, the remaining 6 subjects in each cohort will be randomized in a 5:1 
ratio to active drug and placebo. Sentinel subjects will not be used for the randomized, 
standalone ERT cohorts and for the ZID cohorts. 
Randomized treatment assignments for these cohorts will be generated centrally at SDCC 
through the Advantage eClinical® application by the unblinded study biostatistician, and a list 
will be transferred to the unblinded study personnel (i.e., research pharmacists and a verifier) at 
the research site prior to start of the study for the purpose of an emergency back-up, which will 
be kept up in a secure place. The research pharmacists will perform dose preparation; the 
unblinded verifier is a member of the pharmacy team who will not participate in dose 
preparation. 
In the standalone ZID cohorts (Cohorts 3 and 6), 6 subjects will be enrolled, and all will receive 
active drug. All subjects will be registered into the Advantage eClinical®. 
5.3.2 
Masking Procedures 
All investigative site personnel, study volunteers, DMID, Wockhardt and DVC personnel will 
remain blinded through database lock, with the exception of an unblinded pharmacist/verifier at 
the research site, an unblinded SDCC biostatistician, and a DMID/CMS manager responsible for 
PK sample storage. 
 
The randomization scheme will be provided to the unblinded research pharmacist at the site, who 
will perform dose preparation, and a pharmacy verifier who will not participate in dose 
preparation. These pharmacy personnel at the site will not be involved in study-related 
assessments or have subject contact for data collection following study drug administration. 
 
The study staff participating in the administration of study product and assessment of the 
subjects will not be aware of the administered contents of the IV infusion in the randomized arms 
of the study. Study drugs will be diluted in normal saline, and they will look identical to placebo 
in the IV infusion bag so the study staff and the subject will not be able to determine whether 
placebo or active drug are being administered. The label on the IV infusion bag will not have 
information that can identify the contents. 
 
Only plasma and urine PK samples collected from subjects who received active drug(s) will be 
sent to the bioanalytical laboratory, KCAS, for testing. To select these samples, an SDCC 
Unblinded Biostatistics Team will determine which volunteers received active drug and will 
provide the list of samples from those volunteers to DMID-CMS. DMID-CMS repository 
employees will identify those samples and ship to KCAS. KCAS personnel are blinded. 
Individual samples are barcoded, and the barcode includes information that can match the 


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sample to the volunteer identification number, aliquot number, treatment cohort and collection 
timepoint. Data from KCAS will be received by the SDCC Unblinded Biostatistics Team and 
entered into the database after the safety analysis was completed by the SDCC Blinded 
Biostatistics team. 
The SMC will receive blinded data in aggregate and presented by cohort. The SMC may review 
unblinded data prepared by an unblinded biostatistician in the closed session only. 
5.3.3 
Reasons for Withdrawal and Discontinuation of Study Drug Administration 
A subject may withdraw from the trial at any time for any reason, without any consequences. 
A subject will be discontinued from the trial if any of the following occur before dosing: 
• Request by the subject to terminate participation. 
• Failure to receive the study drug due to difficulty initiating or maintaining an intravenous 
infusion line. 
A subject may be removed from the trial after dosing for the following reasons; however, 
whenever possible, the subject will be followed for safety per protocol to Day 11 (+ 3 days): 
• Failure to adhere to protocol requirements. 
• Loss to follow-up. 
• Request of primary care provider. 
• Request of the Institutional Review Board (IRB)/Ethics Committee (EC), FDA or DMID. 
• The occurrence of a Serious AE (SAE) or treatment-emergent AE warranting withdrawal. 
• Any other condition that the study site PI judges to unduly increase the risk to the subject. 
5.3.4 
Handling of Withdrawals and Discontinuation of Study Drug Administration 
• Subjects who are withdrawn before dosing or subjects who do not have at least 1 PK 
blood draw should be replaced with a subject assigned to the same cohort and treatment 
as the subject they replaced. 
• Additionally, subjects will be replaced in each dosing cohort to ensure there are at least 
seven subjects with complete PK profiles in each 8 subject dosing cohort or 5 subjects in 
each 6 subject dosing cohort. A Subject will be considered to have a complete PK profile 
if ≥70% of plasma PK samples are collected. (See the SAP for details). 
• Subjects who withdraw after receiving all study doses and completed scheduled 
assessments to Day 8 will not be replaced unless more than 50% of subjects in a cohort 
are withdrawn from the trial. 


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• Replacement of additional withdrawals is at the discretion of the Investigator in 
consultation with the Sponsor. Replacement subjects should be allocated to the same 
treatment as the subject they replaced. 
Generally, subjects who received any amount of the study drug but withdraw from the trial will 
be encouraged to continue follow-up (with subjects’ consent) for safety assessments until Final 
Visit (Day 11+3) and for completion of scheduled plasma PK sample collection following the 
last dose of study drug they received. Subjects withdrawing will be asked to complete safety 
assessments according to the ET schedule (See Section 7.6).  
5.3.5 
Lost to Follow-up 
If subjects fail to appear for a follow-up assessment, extensive effort (i.e., three documented 
contact attempts via phone calls, e-mail, etc., made on separate occasions and followed by a 
certified letter) will be made to locate or recall them, or at least to determine their health status. 
These efforts will be documented in the subjects’ records. 
5.3.6 
Termination of Study 
Although DMID has every intention of completing the trial, it reserves the right to terminate the 
trial at any time for clinical or administrative reasons. In addition, the trial may be terminated or 
suspended at the request of the FDA, SMC or IRB/EC. 
 


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6 
STUDY INTERVENTION/INVESTIGATIONAL 
PRODUCTS 
6.1 
Description of Study Products 
6.1.1 
Zidebactam for Injection, 1 g/vial  
Zidebactam dihydrate (CAS No. 1996664-59-5) is a proprietary New Chemical Entity (NCE) of 
Wockhardt Bio AG. It is an entity from the diazabicyclooctane (DBO) class and exhibits a novel 
mode of action as a β-lactamase inhibitor and β-lactam enhancer. It is chemically identified as 
(2S, 5R)-7-Oxo-6-sulphooxy-2-[N'-((R)-piperidin-3-carbonyl)-hydrazinocarbonyl]-1, 6-diaza-
bicyclo [3.2.1] octane dihydrate. The structure and absolute stereochemistry of ZID have been 
confirmed though various instrumental methods of analysis. ZID is slightly hygroscopic and is 
freely soluble in water and insoluble in dichloromethane. ZID (WCK 5107) drug substance is 
manufactured at Wockhardt Limited, Ankleshwar, Gujarat, India and/or Aragen Life Sciences 
Private Ltd (formerly GVK Biosciences Pvt. Ltd and Inogent Laboratories Private Ltd.), 
Hyderabad, Telangana, India. ZID for Injection 1g/vial drug product is manufactured at 
Wockhardt Limited, Shendra, Aurangabad, India [34]. 
6.1.2 
Ertapenem Sodium for Injection, 1 g/vial (ERT) 
ERT is a sterile, synthetic, parenteral, 1-β methyl-carbapenem that is structurally related to beta-
lactam antibiotics. It is generally available as ertapenem sodium (CAS No. 153773-82-1), and 
chemically identified as [4R-[3(3S*,5S*),4α,5β,6β(R*)]]-3-[[5-[[(3-carboxyphenyl)amino] 
carbonyl]-3-pyrrolidinyl]thio]-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0] hept-2-
ene-2-carboxylic acid monosodium salt. ERT sodium is a white to off-white hygroscopic, weakly 
crystalline powder. It is soluble in water and 0.9% sodium chloride solution, practically insoluble 
in ethanol, and insoluble in isopropyl acetate and tetrahydrofuran [34]. For this study, a U.S. 
FDA- approved generic ERT for injection will be procured from Dr. Reddy’s Laboratories, Inc., 
in the U.S. by Wockhardt (37). 
6.1.3 
WCK 6777 (ERT-ZID) 
It is a combination of ERT and ZID (WCK 5107). For this clinical trial, single use, sterile, 
lyophilized ZID for Injection, 1 g/ vial and ERT Sodium for Injection, 1 g ertapenem/vial will be 
used and supplied separately by Wockhardt. Solutions for injection containing ZID and ERT will 
be reconstituted in the Pharmacy of the clinical research site in the desired drug doses. 


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6.1.4 
Placebo 
0.9% Sodium Chloride Injection, USP will be used as the placebo for this study. 
Sterile Water for Injection, USP is sterile, nonpyrogenic, distilled water for intravenous 
administration after addition of a suitable solute. No antimicrobial or other substance has been 
added. The pH is 5.5 (5.0 to 7.0). The osmolarity is 0 mOsmol/L. It will be used for 
reconstituting ERT and ZID separately or combined (for WCK 6777) prior to dilution with 
sterile 0.9% Sodium Chloride Injection, USP. 
0.9% Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution. Each 100 mL 
contains 900 mg sodium chloride in water for injection. It contains sodium (Na+) 154 mEq/L and 
chloride (Cl–) 154 mEq/L. The osmolarity is 308 mOsmol/L (calc.). The solution may contain 
hydrochloric acid and/or sodium hydroxide for pH adjustment (pH 5.6, range 4.5 to 7.0). This 
solution contains no bacteriostatic, antimicrobial agent or added buffer. It will be used as the 
secondary diluent for ERT and ZID and as the placebo in this study. 
6.1.5 
Acquisition 
ZID for Injection, 1 g/vial will be provided by Wockhardt. ERT Sodium for Injection, 1 g 
ertapenem/vial will be procured by Wockhardt from a US supplier [37]. Upon request by DMID, 
study products will be shipped for clinical labeling to the DMID Clinical Materials Services 
(DMID-CMS) at the address provided in the protocol-specific MOP. 
The study drugs will be shipped from DMID-CMS to the CTU upon request and approval by 
DMID. Details will be provided in the protocol-specific MOP. 
Sterile Water for Injection, USP and 0.9% Sodium Chloride Injection, USP will be purchased by 
the clinical research site from commercial sources. Details will be described in the protocol-
specific MOP. 
Ancillary supplies required for IV administration (including syringes or infusion bag, tubing and 
IV catheter and line-filter) will be supplied by the clinical research site as described in the 
protocol-specific MOP. 
6.1.6 
Formulation, Packaging, and Labeling 
For this Phase 1 clinical study, individual vials of Zidebactam for Injection 1 g / vial and 
Ertapenem Sodium for Injection, 1 g ertapenem/ vial will be used. 
• Zidebactam for Injection, 1 g/vial will be used in this study. The drug product is 
manufactured by Wockhardt Limited, Shendra, Aurangabad, India according to cGMP 
requirements as a sterile, lyophilized powder. Zidebactam for Injection is packed in 
20 mL USP Type I clear tubular glass vial, stoppered with 20 mm rubber stopper and 


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sealed with aluminum flip-off seal. Product information, packaging and labeling will be 
described in the MOP. 
• Ertapenem Sodium for Injection, 1 g ertapenem/vial is supplied in single dose glass vials 
as a sterile, lyophilized powder. Each vial contains 1.046 grams of ERT sodium, 
equivalent to 1 gram of ERT. The sodium content is approximately 137 mg 
(approximately 6.0 mEq). Each vial of ERT sodium contains the following inactive 
ingredients: 175 mg sodium bicarbonate and sodium hydroxide to adjust pH to 7.5 [37]. 
Commercial source, product information packaging and labeling will be described in the 
MOP. 
• WCK 6777 for Injection (combination of ZID [WCK 5107] and ERT) will be formulated 
for IV infusion at the clinical research pharmacy of the CTU using separate vials of ZID 
for Injection, 1 g/vial and ERT Sodium for Injection, 1 g ertapenem/vial to the desired 
doses. (See Section 6.2)  
• Sterile Water for Injection, USP - Commercial source, product information and 
packaging will be described in the MOP. 
•  0.9% Sodium Chloride Injection, USP - Commercial source, product information and 
packaging of the diluent will be described in the MOP. 
Each product vial and diluent will be labeled in compliance with applicable regulatory 
requirements as described in the MOP and will include FDA-required cautionary statement, 
“Caution – New drug - Limited by United States Federal Law to Investigational Use.”   
6.1.7 
Product Storage and Stability 
6.1.7.1 
Stability in Storage Prior to Reconstitution 
It is recommended that the vials for both drug products should be stored refrigerated at 2°C to 
8°C (35.6°F to 46.4°F) within the packaging until time of preparation for dosing.  
• ZID for Injection, 1 g/vial -  Based on available stability data, the proposed shelf life for 
ZID for Injection, 1 g/vial is 48 months at 2°C to 8°C (35.6°F to 46.4°F). Further stability 
study is on-going up to 60 months at long-term conditions. GMP/ Clinical batch of ZID 
for Injection 1 g/vial (#QV10001 Mfg. date: Dec. 2019), which is intended to be used in 
this WCK 6777 phase 1 study, was found to be stable up to 24 months at accelerated 
conditions (25°C± 2°C / 60% ± 5% RH) and 36 months at long-term conditions (5°C± 
3°C). Extended stability testing is ongoing and proposed “Use by Date” will be based on 
satisfactory stability data and ICH Q1E recommendation. Details will be provided in the 
study-specific MOP. 


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• ERT Sodium for Injection, 1 g ertapenem/vial lyophilized powder should not be stored 
above 25°C (77°F) before reconstitution per product information [37]. For this study, it is 
recommended that lyophilized ERT be stored refrigerated at 2°C to 8°C (35.6°F to 
46.4°F) within the packaging until time of preparation for dosing. The expiration date of 
ERT for Injection 1 g/vial shall be referred from the labelling of the commercial product 
being procured from the US market.  
• Sterile Water for Injection, USP will be stored per manufacturing instructions. Product 
storage and stability will be described in the MOP. 
• The diluent, 0.9% Sodium Chloride Injection, USP, will be stored per manufacturing 
instructions. Product storage and stability will be described in the MOP. 
6.1.7.2 
Stability of ERT or ZID after Reconstitution in Sterile Water for Injection 
The reconstitution of ERT or ZID vial should start within 1 h after removal from refrigeration. 
The reconstituted ERT vials should be immediately diluted in 0.9% Sodium Chloride for the 
preparation of either the ERT standalone infusion solution or the WCK 6777 (ERT+ZID) 
infusion solution.  
Likewise, the reconstituted ZID vials should be immediately diluted in 0.9% Sodium Chloride 
for the preparation of either the ZID standalone infusion solution or the WCK 6777 (ERT+ZID) 
infusion solution.  
6.1.7.3 
Stability of ERT or ZID after Dilution in 0.9% Sodium Chloride 
• ERT or ZID or ERT-ZID infusion solutions in 100 mL (for Cohort 1 - ERT-ZID  1 + 1 g) 
or 250 mL (for remaining Cohorts 2 to 7) were found to be stable for up to 6 hours at 
room temperature (25 ± 2°C) and up to 24 hours at refrigeration (5 ± 3°C). 
In spite of the above-mentioned stability of ERT or ZID or WCK 6777 in 0.9% normal saline, 
to negate the risk of sterility loss uniformly for all the cohorts, the infusion (stored at room 
temperature or refrigerated) should begin within 2 h of preparation. 
6.1.7.4 
Photostability 
• ZID for Injection, 1 g/vial is photostable   
• ERT Sodium for Injection, 1 g ertapenem/vial is photostable 
The clinical supplies storage area at the CTU will be monitored by its staff for temperature 
consistency with the acceptable storage temperature range specified in this protocol or in the 
MOP. Documentation of temperature monitoring will be maintained. 


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6.2 
Dosage, Preparation, and Administration of Study Intervention/ 
Investigational Products 
The site Research Pharmacist (RP) will prepare the study product on the same day as 
administration as instructed in above sections. The study drug will be inspected for damage, 
contamination, discoloration, or particulate matter before use. Any study drug that fails 
inspection will be quarantined at appropriate temperature and labeled ‘Do Not Use’ until further 
notice. The Site Principal Investigator (PI) or responsible person will immediately contact the 
DMID Clinical Project Manager (CPM) and study clinical team for further instructions before 
administering any additional study drug infusions. Based on the information collected, DMID, 
with consultation from Wockhardt, will determine whether the affected study drug can be used. 
If it cannot be used, the CTU will receive specific instructions on how to return it to DMID CMS 
or destroy it on site. 
The site Research Pharmacist will prepare the infusion using aseptic technique under a sterile 
environment (e.g., Biologic Safety Cabinet or laminar flow hood) as described in the protocol-
specific MOP.  
The appropriate number of vials will be removed from storage to prepare the infusion. Each vial 
of ERT Sodium, 1 g ertapenem/vial and/or ZID for Injection, 1 g/vial, depending on the 
treatment cohort, will be reconstituted separately using 5 mL sterile Water for Injection as the 
primary diluent for each ZID 1-g vial and 10 mL sterile Water for Injection as the primary 
diluent for each ERT Sodium, 1-g vial. A 0.9% Sodium Chloride Injection solution will serve as 
the secondary diluent to make up the total volume for IV infusion to 100 mL for Cohort 1 or 
250 mL for Cohorts 2-7. 
The IV administration set must contain a 0.20 µm in-line filter. 
Refer to protocol-specific MOP for detailed information on study product dose and volume 
calculations, documentation of time of placement and removal from refrigeration as well as 
preparation and administration of the study product and handling of infusion interruptions. 
6.3 
Modification of the Study Intervention/ Investigational Products 
6.3.1 
Overdose 
An overdose is defined as a dose greater than the high-dose level evaluated in the trial. 
Intentional overdosing of ERT or ZID is unlikely. 
All overdoses will be reported as a deviation; if the overdose is associated with a TEAE, then the 
TEAE will also be reported. In the event of an overdose, the Investigator will use clinical 
judgment in treating the overdose and contact the DMID Medical Monitor (MM). There is no 
specific information available on the treatment of overdosage with ERT or ZID. 


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Intravenous administration of ERT at a dose of 2 g over 30 min or 3 g over 1h to 2h in healthy 
adult volunteers resulted in an increased incidence of nausea [29]. In clinical trials in adults, 
inadvertent administration of three 1 g doses of ERT in a 24-hour period resulted in diarrhea and 
transient dizziness in one patient [29]. In the event of an overdose, ERT should be discontinued, 
and general supportive treatment given until renal elimination takes place. In case of severe 
overdosage, especially in patients with compromised renal function, hemodialysis will aid in the 
removal of ERT from the body [28]. 
There is no information on overdose with ZID. 
The investigator will refer to the relevant document(s) for detailed information regarding 
warnings, precautions, contraindications, TEAEs, and other significant data pertaining to the 
study drug. Such documentation may include but not be limited to the IB. 
6.4 
Accountability Procedures for the Study Intervention/ 
Investigational Products   
The Site PI is responsible for the distribution and disposition of the study drugs and has ultimate 
responsibility for accountability. The Site PI may delegate this responsibility to the Site RP. If 
delegated, the Site RP will be responsible for maintaining complete records and documentation 
of the study drug’s receipt, accountability, dispensation, temperature monitoring, storage 
conditions, and final disposition. Time of study drug administration to the subject must be 
recorded on the appropriate eCRF. 
All study drugs, whether administered or not, will be documented on the appropriate study drug 
accountability record or dispensing log. Used and unused study drug vials will be retained until 
monitored. Upon completion of the trial and after the final monitoring visit, any remaining 
unused study drugs will either be returned or destroyed appropriately at the CTU as per DMID 
requirements and instructions that will be communicated to the CTU by the DMID CPM. 
Unused study drug vials will be released for disposition per DMID requirements. DMID does not 
require used containers of study product to be maintained at the research pharmacy, except when 
the local institution’s SOP/policy mandates retaining used IV vials. If local SOPs allow 
destruction of used study product containers, the used vials can be destroyed per the site’s SOPs; 
a second staff member must observe the destruction and sign verification (two signatures) that 
the used vials were discarded. 
Any unused solution left in the IV infusion syringe or bag or the IV administration tubing after 
administration to the subject should be discarded as biohazardous waste. If a container of study 
product is unusable due to breakage, or any other reason, this explanation should also be noted 
on the Study Product Accountability Record (e.g., broken – dropped on floor). Details will be 
provided in the MOP. 


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6.5 
Assessment of Subject Compliance with the Study Intervention/ 
Investigational Products 
Since each dose of study drug(s) will be administered by site personnel, subject compliance is 
not anticipated to be an issue. Complete information regarding any partial or interrupted dosing 
will be documented. Subjects unable to receive the full volume of study drug(s) infusion will be 
withdrawn from data analysis and followed up for safety as described in Section 5.3.3.  
6.6 
Prior and  Concomitant Medications/Treatments 
Medications include the following: prescription drugs, birth control hormonal preparations, non-
prescription medication, herbs, vitamins, nutritional supplements, and illicit and recreational 
substances. 
Medications taken before or after dosing will be reported as Prior Medications or Concomitant 
Medications (ConMeds), respectively. 
Prior prescription medications will be recorded at Screening Visit. All prior medications are 
not allowed during the study period with the exception of oral contraceptives, which are 
permitted throughout the study if already used. 
The following medications are prohibited for the indicated periods prior to dosing: 
• 
Receipt of probenecid or furosemide within 14 days prior to study enrollment. 
• 
Receipt of any antibiotics within 14 days prior to study enrollment. 
• 
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). 
• 
Receipt of the following medications that interact with human OAT3 within 14 days prior 
to study enrollment. 
Note: 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. 
• 
Receipt of herbal and dietary supplements (including St. John’s Wort) within 14 days 
prior to study enrollment. 
• 
Receipt of valproic acid within 14 days prior to study enrollment. 


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Non-prescription medications, herbs, vitamins, and nutritional supplements will not be 
taken within 14 days before dosing and during the trial. Exceptions: vitamins and OTC 
medications, taken for <48 h for the treatment of common symptoms (e.g., headache, 
indigestion, muscle pain), including solitary doses of up to 1,000 mg acetaminophen 
(paracetamol), may be allowed if approved by the Site PI or authorized clinician(s). 
Blood/blood products (RBCs, WBCs, platelets, and plasma) donation of 500 mL within 
3 months or more than 100 mL within 30 days before signing informed consent to this trial is not 
allowed, and it is prohibited during the course of this trial. 
Following dosing, each new ConMed and changes to existing medications will be recorded. 
Subjects will be required not to utilize non-study medications during the trial except those 
deemed necessary by the Site PI or authorized clinician(s).  
Any drug (e.g., non-prescription medications, herbal supplements, vitamins, or prescription 
medications) or vaccines or blood/blood products used by the subject during the trial will be 
recorded in the subject’s source documents and on the appropriate electronic case report form 
(eCRF), and the PI or authorized clinician(s) will note whether the use was medically indicated 
and immediately necessary. Any use of medications not authorized by the Site PI or authorized 
clinician(s) will be recorded as a deviation. 
6.7 
 Subject Restrictions and Precautions 
From signing informed consent until end-of-study, the subjects have to follow the instructions of 
the study site. They have to adhere to the following restrictions during participation in the study. 
6.7.1 
Smoking 
Smoking is prohibited during the in-patient period of the study (Day -1 to discharge on Day 8). 
Subjects will be counseled to avoid smoking during the out-patient follow-up period until the last 
visit (Day 11 + 3 days). 
6.7.2 
Physical Activity 
Subjects will be counseled to refrain from excessive physical exercise starting 2 days before 
dosing until discharge from the CTU on Day 8, and 24 hours before the last visit (Day 11 
+ 3 days).  
6.7.3 
Food and Fluid intake 
Subjects will be provided food and non-caffeinated and non-alcoholic beverages by the CTU 
during the dosing period of the trial. Subjects will fast at least 4 hours prior to blood draw on 
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+ 3 days (last visit)). Subjects will fast for at least 4 h before dosing on Day 1 and 1 h after end 
of infusion. Water can be taken ad lib during those periods of fasting. Food may be eaten 1 h 
after the end of infusion.   
6.7.4 
Alcohol, Marijuana and Illicit Drugs 
Alcohol will not be served during the in-patient period from Day -1 check-in to Day 8. 
Marijuana and illicit drugs are prohibited during the course of the trial. 


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7 
STUDY SCHEDULE 
The Schedule of Study Procedures and Evaluations is included as Appendix A. Clinical and 
Laboratory Procedures are described in Section 8. 
7.1 
Recruitment 
The subject population will be recruited by the CTU utilizing the CTU subject database and IRB-
approved advertisements and social media. IRB-approved, prescreening questionnaires will be 
used to determine if subjects meet study requirements before scheduling screening visits. 
7.2 
Screening Visit (Day -28 to Day -2) 
This will be an out-patient visit to complete the following within 28 days before study drug 
dosing: 
Note: A second screening visit may be scheduled to complete screening tests to accommodate 
subjects’ personal schedule. 
• Obtain informed consent. 
• Assign a study ID number to subjects who consent to participate. 
• Record demographics including age, gender, race, and ethnicity. 
• Obtain contact information. 
• Obtain height (ht) and body weight (wt) and calculate Body Mass Index (BMI; wt [kg] / 
ht [m2]).  
• Take VS. 
• Obtain Medical History (MH). 
• Review history of Prior Medications. 
• Perform complete Physical Examination (PE). 
• Obtain fasting (at least 4 hours) blood and urine samples for screening clinical laboratory 
tests that include a calculation of creatinine clearance (CLCR) by the Cockcroft-Gault 
equation. 
• Obtain blood samples for viral serology (HIV antibody, HBsAg, HCV antibody). 
• Obtain serum for β-HCG pregnancy test from all women. 
• Obtain serum for FSH level only from post-menopausal women. 
• Obtain urine sample for illicit drugs and drugs of abuse (urine drug screen), cotinine and 
alcohol. 
• Obtain a triplicate 12-lead ECG with 10-sec rhythm strip. 
• Counsel on use of contraception (males and females), avoidance of pregnancy (women of 
childbearing potential), avoidance of excessive physical exercise, avoidance of prohibited 
medication, illicit drugs, alcohol, and nicotine products. 


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• Confirm eligibility. 
Subjects who meet the eligibility criteria will be contacted by CTU personnel and asked to return 
on Day -1 to complete check-in assessments and be admitted to the CTU if they continue to meet 
eligibility criteria. Subjects will be reminded to avoid excessive physical exercise, prohibited 
medication, illicit drugs, alcohol and nicotine products, and too fast for at least 4 h before the 
Day -1 visit,  
Subjects who fail screening due to a medical condition or abnormal laboratory tests including 
pregnancy test and positive tests for HIV, HBV and HCV will be informed of the findings and 
counseled to seek medical care for further evaluation and treatment. If subjects test positive for 
HIV antibody, HBsAg, and/or HCV antibody, they will be informed that test results may be 
reported to the local health authorities according to state or local law. 
Subjects who fail screening assessments will not be rescreened unless they had an inter-current, 
short-term medical illness per site PI or authorized study clinician (listed on FDA Form 1572) 
discretion. Subjects who meet eligibility criteria but could not be enrolled within permissible 
window may be rescreened. 
7.3 
Baseline / Check-in (Day -1) 
Subjects meeting all inclusion and no exclusion criteria at Screening Visit will check into the 
CTU on Day -1 and the following procedures will be performed: 
• Review inclusion/exclusion criteria to confirm the subject remains eligible for 
enrollment. 
• Update MH. 
• Update Prior Medications. 
• Obtain VS. 
o Note: Obtain VS before blood draws  
• Obtain body weight. 
• Perform complete PE. 
• Obtain blood and urine samples for clinical laboratory tests that include a calculation of 
CLCR by the Cockcroft-Gault equation. 
• For all women, a urine β-HCG pregnancy test will be done, and negative results 
confirmed before dosing. 
• Obtain urine sample for illicit drugs and drugs of abuse (urine drug screen), cotinine, and 
alcohol. 
• Obtain baseline 12-lead standard ECG with 10-sec rhythm strip. 
• Admit eligible subjects in the CTU. 


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• Assign to study treatment cohort and randomize to active drug or placebo, except for 
Cohorts 3 and 6. 
• Counsel to avoid excessive physical exercise, encourage good hydration. 
7.4 
Inpatient Treatment Period (Days 1 to 8) 
The following assessments will be performed daily before and after dosing on study Days 1 to 7, 
and before discharge from the CTU on Day 8. 
7.4.1 
DAY 1 
2+ hours Before Dosing: 
• Withhold solid food at least 4 h before dosing. 
• Allow access to water and non-carbonated beverages. 
• Review inclusion/exclusion criteria to confirm the subject remains eligible for dosing. 
• Update MH. 
• Review any new medications and update list of prior medications as needed. 
• Perform symptom-directed (focused) PE as needed for evaluation of new symptoms. 
 
About 1 – 2 hours Before Dosing: 
• Insert IV line for study drug infusion into a forearm vein 
• Insert IV catheter for blood collection into a vein in the other arm 
 
About 30 – 60 min Before Dosing: 
• Obtain VS within 30 min before dosing (baseline). 
• Obtain pre-dose blood (plasma) PK sample for total and free study drug within 30 min 
before starting administration of study drug. 
• Obtain pre-dose urine PK sample for study drug concentration within 30- 60 min before 
starting drug administration.  
o Void bladder as close to study drug administration as possible. 
Dosing:  
• Administer study drug as a single IV infusion with an infusion pump in a forearm vein. 
The volume and duration of infusion will vary according to study cohort as follows:  
o For Cohort 1: 100 mL, 30 (±5) minutes; 
o For Cohort 2, Cohort 3 and Cohort 4: 250 mL, 60 (±10) minutes; and 
o For Cohort 5, Cohort 6 and Cohort 7: 250 mL, 120 (±10) minutes. 
After Dosing Initiation: 
• Initiate AE assessments until the end of the study. 
• Perform symptom-directed (focused) PE as needed (for TEAE assessments). 


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• Initiate recording of Concomitant Medications (ConMeds). 
• Withhold solid food until at least 1 h after end of infusion.  
• Provide access to water and non-carbonated beverage. 
• Check infusion site for infusion site reactions during the infusion, at the end-of-infusion 
(+10 min), 1 h (±10 min) after the end of infusion, and as needed for evaluation of local 
symptoms at the infusion site. Replace as needed. (Details will be provided in the MOP.) 
• Check IV blood draw lines and replace as needed. 
• Obtain VS at the end of dosing (+10 min), and 1 h (±5 min) after the end of dosing. 
o Note 1: More frequent monitoring will be at the PI’s or authorized study clinician’s 
discretion based on subject’s clinical status. 
o Note 2: Obtain VS before blood draws.  
• Obtain blood (plasma) PK samples for total and free study drug as follows: 
o From Cohort 1 (infusion duration 0.5 h): within 30 min before dosing, and at 0.25 h 
(±5 min), 0.5 h (±5 min) [immediately at end of infusion], 1 h (±5 min), 2 h (±5 min), 
3 h (±10 min), 4 h (±10 min), 8 h (±15 min), 12 h (±15 min), and 18 h (±15 min) after 
the start of the infusion. 
o From Cohorts 2, 3, and 4 (infusion duration 1 h): within 30 min before dosing, and at 
0.5 h (±5 min), 1 h (±5 min) [immediately at end of infusion], 2 h (±5 min), 3 h 
(±10 min), 4 h (±10 min), 8 h (±15 min), 12 h (±15 min), and 18 h (±15 min) after the 
start of the infusion. 
o  From Cohorts 5, 6 and 7 (infusion duration 2 h): within 30 min before dosing and at 
1 h (±5 min), 2 h (±5 min) [immediately at end of infusion], 3 h (±10 min), 4 h 
(±10 min), 8 h (±15 min), 12 h (±15 min), and 18 h (±15 min) after the start of the 
infusion. 
• Obtain post-dose urine PK samples at the following intervals after the start of the 
infusion: 0 to 4 h (±10 min), 4 to 8 h (±15 min), 8 to 12 h (±15 min), and 12 to 24 h 
(±30 min). 
• Counsel to avoid excessive physical exercise, encourage good hydration. 
7.4.2 
DAY 2  
As for DAY 1 with the exception that frequent plasma and urine PK samples are not collected 
after dosing. 
 
Before Dosing: 
• Check the infusion site for any reactions. 
• Assess the IV lines used for infusion and blood PK draws and replace as needed. 
• Obtain VS within 30 min before dosing. 


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• Obtain blood for safety laboratory testing (Hematology [HEM], Coagulation [COAG], 
and Clinical chemistry [CHEM] that includes a calculation of CLCR by the Cockcroft-
Gault equation 30-60 min before dosing. 
• Collect blood (plasma) PK sample at 24 h (±30 min) after initiation of dosing on Day 1. 
o Note: If collected within 30 min prior to dosing, this sample could also be the “pre-
dose” sample for Day 2. 
• Complete collection of the 12 h to 24 h (±30 min) urine PK sample after dosing on Day 1 
before dosing on Day 2. 
Dosing: 
• Administer study drug at approximately the same time (within 24 h +1h) as on Day 1. 
• The duration of infusion will vary according to study cohort as described on Day 1. 
After Dosing Initiation: 
• Check infusion site for infusion site reactions as on Day 1. 
• Assess the IV lines used for infusion and blood PK draws and replace as needed. 
• Obtain VS at the end of dosing (+10 min), and 1 h (±5 min) after the end of dosing. 
o Note 1: More frequent monitoring will be at the PI’s or authorized study clinician’s 
(listed on FDA Form 1572) discretion based on subject’s clinical status. 
o Note 2: Obtain VS before blood draws  
• Perform AE assessments. 
• Perform symptom-directed (focused) PE as needed for TEAE assessments. 
• Document ConMeds. 
• Provide solid food at least 1 h after the end infusion. 
• Collect blood (plasma) for PK 12 h (± 15 min) after the start of infusion. 
• Counsel to avoid excessive physical exercise, encourage good hydration. 
7.4.3 
DAY 3  
As for DAY 1 with the exception that frequent plasma and urine PK samples are not collected 
after dosing. 
Before Dosing: 
• Check the infusion site for any reactions. 
• Assess the IV lines used for infusion and blood PK draws and replace as needed. 
• Obtain VS within 30 min before dosing. 
o 
Note: Obtain VS before blood draws.  
• Collect pre-dose blood (plasma) PK sample within 30 min before starting administration 
of study drug. 
 
 


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Dosing: 
• Administer study drug at approximately the same time (within 24 h +1h) as on Day 1. 
• The duration of infusion will vary according to study cohort as described on Day 1. 
After Dosing Initiation: 
• Check infusion site(s) for infusion site reactions as on Day 1. 
• Obtain VS at the end of dosing (+10 min), and 1 h (±5 min) after the end of dosing. 
o Note 1: More frequent monitoring will be at the PI’s or authorized study clinician’s 
discretion based on subject’s clinical status. 
o Note 2: Obtain VS before blood draws.  
• Perform AE assessments. 
• Perform symptom-directed (focused) PE as needed for TEAE evaluation of TEAEs. 
• Document ConMeds. 
• Provide solid food at least 1 h after the end infusion. 
• Collect blood (plasma) for PK 12 h (± 15 min) after the start of infusion. 
• Counsel to avoid excessive physical exercise, encourage good hydration. 
7.4.4 DAY 4 
As for DAY 1 with the exception that frequent plasma and urine PK samples are not collected 
after dosing. 
 
Before Dosing: 
• Check the infusion site for any reactions. 
• Assess the IV lines used for infusion and blood PK draws. Replace IV catheters as 
needed. 
• Obtain VS within 30 min before dosing  
o Note: Obtain VS before blood draws  
• Obtain blood for safety laboratory testing (Hematology [HEM], Coagulation [COAG], 
and Clinical chemistry [CHEM] that includes a calculation of CLCR by the Cockcroft-
Gault equation 30-60 min before dosing. 
• Obtain urine for urinalysis. 
• Collect pre-dose blood (plasma) PK sample within 30 min before starting administration 
of study drug. 
Dosing: 
• Administer study drug at approximately the same time (within 24 h +1h) as on Day 1. 
• The duration of infusion will vary according to study cohort as described on Day 1. 
After Dosing Initiation: 
• Check infusion site for infusion site reactions as on Day 1. 


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• Remove IV infusion catheter if it has been in use for 3 to 4 days 
• Obtain VS at the end of dosing (+10 min), and 1 h (±5 min) after the end of dosing. 
o Note 1: More frequent monitoring will be at the PI’s or authorized study clinician’s 
(listed on FDA Form 1572) discretion based on subject’s clinical status. 
o Note 2: Obtain VS before blood draws.  
• Perform AE assessments. 
• Perform symptom-directed (focused) PE as needed for TEAE assessments. 
• Document ConMeds. 
• Provide solid food at least 1 h after the end infusion. 
• Collect blood (plasma) for PK 12 h (± 15 min) after the start of infusion. 
• Counsel to avoid excessive physical exercise, encourage good hydration. 
7.4.5 
DAY 5 
As for DAY 1 with the exception that frequent plasma and urine PK samples are not collected 
after dosing. 
 
Before Dosing: 
• Check the infusion site for any reactions. 
• Assess the IV lines used for infusion and blood PK draws. Replace IV catheters as 
needed. 
• Obtain VS within 30 min before dosing. 
o Note: Obtain VS before blood draws  
• Collect pre-dose blood (plasma) PK sample within 30 min before starting administration 
of study drug. 
Dosing: 
• Administer study drug at approximately the same time (within 24 h +1h) as on Day 1. 
• The duration of infusion will vary according to study cohort as described on Day 1. 
After Dosing Initiation: 
• Check infusion site(s) infusion site reactions as on Day 1. 
• Obtain VS at the end of dosing (+10 min), and 1 h (±5 min) after the end of dosing. 
o Note 1: More frequent monitoring will be at the PI’s or authorized study clinician’s 
(listed on FDA Form 1572) discretion based on subject’s clinical status. 
o Note 2: Obtain VS before blood draws.  
• Perform AE assessments. 
• Perform symptom-directed (focused) PE as needed for TEAE assessments. 
• Document ConMeds. 
• Provide solid food at least 1 h after the end infusion. 


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• Collect blood (plasma) for PK 12 h (± 15 min) after the start of infusion. 
• Counsel to avoid excessive physical exercise, encourage good hydration. 
7.4.6 
DAY 6 
As for DAY 1 with the exception that frequent plasma and urine PK samples are not collected 
after dosing. 
 
Before Dosing: 
• Check the infusion site for any reactions. 
• Assess the IV lines used for infusion and blood PK draws. Replace IV catheters as 
needed. 
• Obtain VS within 30 min before dosing. 
o Note: Obtain VS before blood draws.  
• Obtain blood for safety laboratory testing (Hematology [HEM], Coagulation [COAG], 
and Clinical chemistry [CHEM] that includes a calculation of CLCR by the Cockcroft-
Gault equation 30-60 min before dosing. 
• Collect pre-dose blood plasma PK sample within 30 min before starting administration of 
study drug. 
 
Dosing: 
• Administer study drug at approximately the same time (within 24 h +1h) as on Day 1. 
• The duration of infusion will vary according to study cohort as described on Day 1. 
 
After Dosing Initiation:  
• Check infusion site for infusion site reactions as on Day 1. 
• Obtain VS at the end of dosing (+10 min), and 1 h (±5 min) after the end of dosing.  
o Note 1: More frequent monitoring will be at the PI’s or authorized study clinician’s 
(listed on FDA Form 1572) discretion based on subject’s clinical status. 
o Note 2: Obtain VS before blood draws  
• Perform AE assessments. 
• Perform symptom-directed (focused) PE as needed for evaluation of TEAEs. 
• Document ConMeds. 
• Provide solid food at least 1 h after the end infusion. 
• Collect blood (plasma) for PK 12 h (± 15 min) after the start of infusion. 
• Counsel to avoid excessive physical exercise, encourage good hydration. 
7.4.7 
DAY 7 
All procedures and assessments are as on DAY 1. 


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Before Dosing: 
• Check the infusion site for any reactions. 
• Assess the IV lines used for infusion and blood PK draws and replace as needed.  
• Obtain VS within 30 min before dosing. 
• Note: Obtain VS before blood draws Collect pre-dose blood (plasma) PK sample within 
30 min before starting administration of study drug. 
• Obtain pre-dose urine PK sample within 30-60 min before starting administration of 
study drug.  
o Void bladder as close to study drug administration as possible. 
 
Dosing:  
• Administer study drug at approximately the same time (within 24 h +1h) as on Day 1. 
• The volume and duration of infusion will vary according to study cohort as described on 
Day 1. 
 
After Dosing Initiation: 
• Obtain VS at the end of dosing (+10 min), and 1 h (±5 min) after the end of dosing. 
o Note 1: More frequent monitoring will be at the PI’s or authorized study clinician’s 
(listed on FDA Form 1572) discretion based on subject’s clinical status. 
o Note 2: Obtain VS before blood draws. 
• Obtain blood (plasma) PK samples for total and free study drug as follows: 
o From Cohort 1 (infusion duration 0.5 h):  within 30 min before dosing, and at 0.25 h 
(±5 min), 0.5 h (±5 min) [immediately at end of infusion], 1 h (±5 min), 2 h (±5 min), 
3 h (±10 min), 4 h (±10 min), 8 h (±15 min), 12 h (±15 min), 18 h (±15 min) and 24 h 
(± 30 min) after the start of the infusion. 
o  From Cohorts 2, 3, and 4 (infusion duration 1 h): within 30 min before dosing, and at 
0.5 h (±5 min), 1 h (±5 min) [immediately at end of infusion], 2 h (±5 min), 3 h 
(±10 min), 4 h (±10 min), 8 h (±15 min), 12 h (±15 min), 18 h (±15 min) and 24 h 
(± 30 min) after the start of the infusion. 
o o From Cohorts 5, 6 and 7 (infusion duration 2 h): within 30 min before dosing and at 
1 h (±5 min), 2 h (±5 min) [immediately at end of infusion], 3 h (±10 min), 4 h 
(±10 min), 8 h (±15 min), 12 h (±15 min), 18 h (±15 min) and 24 h (± 30 min) after 
the start of the infusion.  
o Obtain post-dose urine PK samples for study drug concentration and at the following 
intervals after the start of the infusion: 0 to 4h (±10 min), 4h to 8h (±15 min), 8h to 
12h (±15 min), and 12h to 24h (±30 min). 
• Check infusion site for infusion site reactions during the infusion, at the end-of-infusion 
(+10 min), 1 h (±10 min) after the end of infusion, and as needed for evaluation of local 
symptoms at the infusion site.  


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• Remove IV infusion line. 
• Perform AE assessments. 
• Perform symptom-directed (focused) PE as needed for TEAE assessments. 
• Document ConMeds 
• Provide solid food at least 1 h after the end infusion. 
• Counsel to avoid excessive physical exercise, encourage good hydration. 
7.4.8 
DAY 8 
• Check the infusion and blood PK draw sites for any reactions. 
• Obtain 12-lead standard ECG with 10-sec rhythm. 
• Obtain VS. 
•  Obtain blood for safety laboratory testing (Clinical chemistry [CHEM], Hematology 
[HEM] and Coagulation [COAG]) that include a calculation of CLCR by the Cockcroft-
Gault equation) at 24 h (± 1 h) after last dose. 
• Obtain urine for urinalysis. 
• Collect blood (plasma) PK samples for total and free study drug at 24 h (±15 min) after 
initiation of study drug infusion on Day 7. 
• Remove catheter for blood draws. 
• Complete collection of the 12h to 24 h (±30 min) urine PK sample after dosing on Day 7. 
• Perform complete PE. 
• Obtain body weight. 
• Perform AE assessments.  
• Document ConMeds. 
• Counsel on use of contraception (males and females), avoidance of pregnancy (women of 
childbearing potential), avoidance of excessive physical exercise 24 h before last visit 
(Day 11 +3 days), avoidance of prohibited medications, illicit drugs, alcohol, and nicotine 
products. 
• Instruct on the next scheduled visit. 
• Discharge subject from the CTU after review of clinical laboratory tests, ECGs and other 
assessments by PI or authorized study clinician. 
o Note: If the time of discharge is late in the evening, due to the time schedule for 
starting procedures on Day 7 or personal reasons (such as distance from residence), 
the subject may stay in the CTU overnight and be discharged the following morning. 
7.5 
Outpatient Follow-up Period / Last Visit (Day 11 + 3 days)  
• Obtain 12-lead standard ECG with 10-sec rhythm. 
• Obtain VS. 
•  Obtain blood for safety laboratory testing (Hematology [HEM], Coagulation [COAG], 
and Clinical chemistry [CHEM] that includes a calculation of CLCR. 
• Obtain urine for urinalysis. 


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• Perform complete PE. 
• Check the venous infusion and blood draw sites for any reactions. 
• Perform AE assessments.  
• Document ConMeds. 
• Counsel on use of contraception (males and females), avoidance of pregnancy (women of 
childbearing potential and males), and sperm donation (males) for 30 days after last dose. 
• Discharge subject from the study. 
7.6 
Early Termination (if needed) 
• Obtain 12-lead standard ECG with 10-sec rhythm. 
• Obtain VS. 
• Obtain blood for safety laboratory testing (Clinical chemistry [CHEM], Hematology 
[HEM] and Coagulation [COAG]) that include a calculation of CLCR. 
• Collect blood (plasma) PK sample. 
• Remove any IV line present. 
• Obtain urine for urinalysis. 
• Perform complete PE. 
• Check the infusion and blood draw site(s) for any reactions.  
• Perform AE assessments.  
• Document ConMeds. 
• Counsel on use of contraception (males and females), avoidance of pregnancy (women of 
childbearing potential and males), and sperm donation (males) for 30 days after last dose. 
• Discharge subject from the study. 
7.7 
Unscheduled Visit (if needed) 
A subject may return to the clinic for an unscheduled visit at any time after discharge on Day 8. 
The following activities may be performed as needed: 
• Obtain 12-lead standard ECG with 10-sec rhythm. 
• Obtain VS. 
•  Obtain blood for safety laboratory testing (Clinical chemistry [CHEM], Hematology 
[HEM] and Coagulation [COAG]) that include a calculation of CLCR. 
• Collect blood (plasma) PK sample. 
• Obtain urine for urinalysis. 
• Check on the infusion and blood draw site(s) for any reactions. 
• Perform AE assessments. 
• Perform symptom-directed (focused) AE as needed for TEAE assessments. 
• Document ConMeds. 


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8 
CLINICAL PROCEDURES / EVALUATIONS 
8.1 
Clinical Procedures and Evaluations 
8.1.1 
Informed Consent 
The informed consent form (ICF) will be approved by the reviewing IRB/EC and executed 
before performing any study-related activities. 
Informed consent will be obtained for all subjects participating in the trial before performing any 
screening assessments. Subjects may withdraw consent at any time. Participation in the trial may 
be terminated at any time without the subject’s consent as determined by the Investigator. 
8.1.2 
Demographics 
Demographic information (date of birth, gender, ethnicity and race) will be recorded on the 
subject’s source documents and eCRF at Screening Visit. Name, address, phone number, and 
emergency contact information will be documented in the source documents only. 
8.1.3 
Inclusion/Exclusion Criteria 
Eligibility screening of healthy subjects will be completed within 28 days before study drug 
dosing and will be documented on the subject’s source documents and eCRF. Confirmation of 
eligibility will be performed before dosing on Day 1. 
Screening failures and the reason for failure to meet the study eligibility requirements will be 
documented in the source documents and entered into the study database. 
8.1.4 
Medical History 
For subjects enrolled in the trial, the medical history (MH) will be obtained by direct interview 
of the subject and recorded on the subject’s source document and eCRF. The MH will capture 
the subject’s current disease processes, past disease processes, history of hospitalization, history 
of surgery, allergies, and prior medications (see Section 6.6). Subjects will be queried regarding 
a history of significant medical disorders of the head, eyes, ears, nose, throat (HEENT), mouth, 
skin, the cardiovascular, respiratory, gastrointestinal, renal, urological, nervous, hematological, 
lymphatic, endocrine, musculoskeletal and genital/reproductive systems. A history of allergies 
including allergies to medications, medication history, and history of substance and alcohol 
abuse will be obtained. The MH will be obtained at Screening Visit and updated on Day -1 
(Check-in) and before dosing on Day 1. After start of study drug dosing, any worsening of pre-
dosing MH or new symptoms will be evaluated and reported as TEAEs. 


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8.1.5 
Physical Examination 
A complete PE – except genital, breast, and rectal exams – will be performed at the Screening 
Visit, check-in visit (Day -1), Day 8, and Final Visit (Day 11 + 3 days), or ET, and will assess 
general appearance, HEENT, heart, lungs, abdomen, skin, musculoskeletal system, lymph nodes, 
and a standard neurological exam. 
A symptom-directed (focused) PE may be performed before dosing on Day 1, at any time after 
dosing on Days 1 to 7, and at Unscheduled visit for evaluation of TEAEs. 
Height and weight will be measured, and BMI calculated at the Screening Visit, and weight on 
Day -1 and Day 8. A subject may be enrolled if BMI is ≥ 18 to 32 kg/m2 or weight is ≥ 100 lbs. 
Refer to the protocol-specific MOP for further details. The findings of each examination will be 
recorded on the subject’s source documents and eCRF. Any new findings on examination or 
worsening of existing conditions after dosing are to be reported as TEAEs. 
8.1.6 
Vital Signs 
VS should be taken while resting (measured after supine for at least 5 min) and include systolic 
blood pressure (SBP) and diastolic BP (DBP), heart rate (HR), respiratory rate (RR) and oral 
temperature (T). VSs will be measured before any blood draws.  BP and pulse measurement will 
be assessed at rest defined above with a completely automated device.  Normal references ranges 
are shown in Appendix B, Table 2. Please reference the study specific MOP for additional detail 
for VS measurements. 
8.1.6.1 
Screening to Predose on Day 1 
Abnormal VSs that are either due to technical or procedural error or the result of an acute, short-
term condition as assessed by the PI (e.g., stress, anxiety, white coat syndrome) may be repeated 
up to twice more at rest and within at least 5 minutes of each other.  
• If the second measurement is abnormal, it will be reported at the highest grade/value of 
severity of the two measurements and will be used for assessment of eligibility (per 
Inclusion Criterion #5, Note 2).   
• If the second measurement is normal, a third measurement will be taken within at least 5 
minutes.   
• If the third measurement is normal, the subject is eligible. If the third measurement is 
abnormal, the value with the highest grade of severity between the first and the third 
measurements will be reported and will be used for assessment of eligibility (per 
Inclusion Criterion #5, Note 2). 
 
 


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8.1.6.2 
Post Dosing on Day 1 through Day 11 (+ 3days) or ET 
Any time after the start of the dose infusion, any abnormalities that occur either due to technical 
or procedural error or the result of an acute, short-term condition as assessed by the PI (e.g., 
stress, anxiety, white coat syndrome) may be repeated twice more at rest and within at least 5 
minutes of each other. 
• If the second VS is abnormal, then the highest severity grade between the first and second 
measurements will be used for assessment of TEAE per Appendix B, Table 2.  
• If the second VS is normal, then a third repeat is to be taken at least after 5 minutes of 
rest.   
• If the third value is abnormal, the highest grade of severity between the first and third 
measurements will be used for assessment of TEAE per Appendix B, Table 2.  
8.1.7 
12-lead Standard Electrocardiogram (ECG) 
Triplicate 12-lead standard ECG and 10-sec rhythm strip will be obtained at the Screening Visit, 
2 minutes apart. Single ECGs will be recorded on Day -1, Day 8 and Day 11 (+3 days), or ET. 
ECGs will be performed after the subject rests quietly in a supine position for at least 10 min. 
The ECGs will be reviewed by the PI or authorized study clinician (listed on FDA Form 1572). 
ECGs will be analyzed for PR, QRS, and QT intervals, and for morphological abnormalities. The 
QT interval will be corrected by the Fridericia (QTcF) formula and recorded. To be eligible for 
participation, the QTcF interval must be within protocol reference range criteria at Screening and 
Day -1 and there must be no clinically significant ECG abnormalities. ECG PR and QTcF 
intervals after dosing will be reported as TEAEs if they meet toxicity grading criteria (See 
Appendix B, Table 4). If a question regarding ECG interpretation arises, the study investigators 
will have the ECG reviewed by a cardiologist. 
8.2 
Laboratory Evaluations 
Venipuncture schedule and blood volumes are shown in Appendix A and Appendix C, 
respectively.  
8.2.1 
Clinical Laboratory Evaluations (Hematology, Coagulation, Chemistry and 
Urinalysis) 
Blood and urine samples for clinical laboratory tests will be collected at the Screening Visit and 
on Day -1 to determine eligibility. For subjects eligible to enroll, measurements on Day-1 will be 
considered “baseline”. Blood (serum) for clinical laboratory tests (HEM, COAG, and CHEM), 
will also be collected on Days 2, 4 and 6 before dosing, and on Day 8 (24 h ± 1 h after last dose), 
and on Day 11 (+3 days), or ET. Urine for UA will also be collected on Day 4 before dosing, and 


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on Days 8, 11 (+3), or ET. Subjects must be fasting at least for 4 h before any blood draw for 
clinical laboratory assessments. These tests will include: 
• HEM: Hgb, Hct, RBC, platelet count, and WBC count with absolute differential count. 
• COAG: INR with prothrombin time, alpha partial thromboplastin time. 
• CHEM: electrolytes (sodium, potassium, chloride, total carbon dioxide [CO2]), creatinine 
with estimation of CLCR by the Cockcroft-Gault method, blood urea nitrogen (BUN), 
calcium, glucose (fasting), total bilirubin, direct bilirubin, alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP), lactic 
dehydrogenase (LDH), total protein, and albumin. 
• UA: Routine dipstick testing of clean-catch urine for occult blood, protein, glucose, 
ketones, nitrate, bilirubin, leucocyte esterase, specific gravity, and pH. 
o If urine dipstick is abnormal for blood, protein, glucose and leukocyte esterase, urine 
microscopy will be performed (for WBC, RBC, bacteria and other cell counts), and the 
results will supersede those of the dipstick UA. 
Clinical laboratory tests at the Screening Visit and Day -1 should be in the normal reference 
range with exceptions. (See Section 5.2, Inclusion Criteria #5 and Appendix B, Table 3). 
Calculated CLCR should be ≥80 mL/min (estimated by the Cockcroft-Gault method). 
Screening laboratory values that are outside the range of eligibility but are thought to be due to 
an acute condition or due to collection or laboratory error may be repeated once, preferably 
within 24 h or as soon as subject is available. 
Laboratory values will be transferred to Advantage eClinical®. 
Abnormal safety laboratory values after dosing will be graded per Appendix B, Table 3. If the 
subject was enrolled at check-in (Day -1) with baseline values within the Grade 1 range in some 
laboratory tests, as allowed by the protocol (per Section 5.3.1, Inclusion Criteria #5 and 
Appendix B, Table 3), abnormal values in the same tests after starting study dosing will only be 
considered TEAEs if they deteriorate to a higher grade. 
8.2.2 
Viral Serology Testing 
Serological testing for HIV antibody, HBsAg, and HCV antibody will be performed only at 
Screening Visit. These tests must be negative for study eligibility. 
8.2.3 
Pregnancy Testing 
In all women, a serum β-HCG pregnancy test will be done at the Screening Visit and a urine 
pregnancy test will be done upon check in on Day -1 and results must be negative for dosing 
with study drug(s). 


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8.2.4 
Serum FSH Testing 
A serum FSH level for confirmation of post-menopausal status in female subjects will be 
measured at the initial Screening Visit only. 
8.2.5 
Urine Toxicology Screening 
A urine toxicology screen will be performed at Screening Visit and on Day -1 to detect the 
presence of amphetamines, cocaine (and metabolite), barbiturates, benzodiazepines, opiates, 
cannabinoids (THC), tricyclic antidepressants (TCAs), and phencyclidine. Results must be 
negative for study eligibility. Urine creatinine will be measured as part of the profile to assess 
quality of collected sample. 
8.2.6 
Urine Alcohol and Cotinine Testing  
Detection of urine alcohol and cotinine, for recent alcohol and tobacco products consumption, 
respectively, will be performed at the Screening Visit, and on Day -1. Results must be negative 
for study eligibility. 
8.3 
Blood and Urine Sampling and Bioanalytical Assays for 
Pharmacokinetics (PK) 
The LC-MS/MS bioanalytical assay methods for total and free ERT and ZID quantitation in 
plasma and total ERT and ZID quantitation in urine will be transferred and validated at the 
bioanalytical lab, KCAS, before subject enrollment starts for determination of plasma and urine 
concentrations of ERT and ZID. 
8.3.1 
Blood Sampling for Plasma Total and Free ERT and ZID Assay 
Blood (plasma) samples for assay of total and free ERT and ZID concentration measurement 
(plasma PK samples) will be collected at the following timepoints: 
• On Day 1 and Day 7, samples will be collected at the following timepoints: 
o From Cohort 1 (infusion duration 0.5 h):  within 30 min before dosing, and at 0.25 h 
(±5 min), 0.5 h (±5 min) [immediately at end of infusion], 1 h (±5 min), 2 h (±5 min), 
3 h (±10 min), 4 h (±10 min), 8 h (±15 min), 12 h (±15 min), 18 h (±15 min) and 24 h 
(± 30 min) after the start of the infusion. 
o  From Cohorts 2, 3, and 4 (infusion duration 1 h): within 30 min before dosing, and at 
0.5 h (±5 min), 1 h (±5 min) [immediately at end of infusion], 2 h (±5 min), 3 h 
(±10 min), 4 h (±10 min), 8 h (±15 min), 12 h (±15 min), 18 h (±15 min) and 24 h 
(± 30 min) after the start of the infusion. 


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o From Cohorts 5, 6 and 7 (infusion duration 2 h): within 30 min before dosing and at 
1 h (±5 min), 2 h (±5 min) [immediately at end of infusion], 3 h (±10 min), 4 h 
(±10 min), 8 h (±15 min), 12 h (±15 min), 18 h (±15 min) and 24 h (± 30 min) after 
the start of the infusion. 
• On Days 2, 3, 4, 5, and 6 within 30 min before dosing and at 12 h (±15 min) after the 
start of the infusion. 
o Note 1: On these days, the pre-dosing PK sample will be collected 24 h (± 30 min) 
after the start of infusion on the previous day. 
o Note 2:  On Day 2, the pre-dosing PK sample can be the same as the 24 h (± 30 min) 
sample after the start of infusion on Day 1. 
Blood samples will be obtained promptly after each corresponding VS assessment before dosing 
on Days 1 to 7. 
Sample collections will be scheduled for the nominal time point and actual collection times 
recorded in source documents. 
Details for collecting blood (plasma) samples for PK analysis and for protein binding estimation 
will be described in the MOP. 
8.3.2 
Collection of Urine for Total ERT and ZID Assay 
Timed urine samples for assay of total ERT and ZID concentration measurement (urine PK 
samples) will be collected at the following periods: 
• On Day 1, before the start of infusion, and at the following intervals after the start of the 
infusion: 0 to 4h (± 10 min), 4 to 8h (± 15 min), 8 to 12h (± 15 min), and 12 to 24h  
(± 30 min). 
• On Day 7, before the start of infusion, and at the following intervals after the start of the 
infusion: 0 to 4h (± 10 min), 4 to 8h (± 15 min), 8 to 12h (± 15 min), and 12 to 24h  
(± 30 min). 
8.3.3 
Specimen Preparation, Handling and Shipping 
8.3.3.1 
Instructions for Specimens Preparation, Handling, and Storage 
Plasma and urine samples collected from subjects treated with ZID, ERT or WCK (6777 
ERT+ZID) need to be processed at 2°C to 8°C (35.6°F to 46.4°F) to avoid degradation. In 
addition, a stabilizing buffer (0.1 M MES) will be added to plasma and urine samples for total 
drug concentration measurements of ERT and ZID, but not to samples for free plasma 
concentration measurements. Details regarding the specimen preparation, handling, and storage 
of bioanalytical samples for the measurement of plasma total and free study drug concentration 
and urine total study drug concentration will be described in the protocol-specific MOP. 


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8.3.3.2 
Specimen Shipment 
Specimen shipment will occur at intervals during the trial following all applicable International 
Air Transport Association (IATA) requirements and according to the specifics for storage 
temperature and documentation as detailed in the central clinical laboratory manual and protocol-
specific MOP, as appropriate. 
All specimens for clinical screening and safety laboratory evaluations will be transported from 
the CTU to the local clinical laboratory. 
Plasma (total and free) and urine (total) PK samples will be collected from all subjects and 
aliquots will be prepared according to protocol-specific MOP. In order to perform bioanalytical 
assays within the stability period of PK samples, primary aliquots of plasma and urine PK 
samples designated by the SDCC (Emmes) picklist will be shipped to the bioanalytical lab, 
KCAS, Inc., directly from the CTU within 3-4 business days after Day 8 collection in each 
cohort and back-up samples will be shipped after Day 11 to the DMID CMS for storage. Details 
will be provided in the study-specific MOP. Methods for maintaining the blind at the 
bioanalytical lab will be described in the Statistical Analysis Plan (SAP). 
Primary aliquots of plasma and urine samples will be provided by the CTU to the bioanalytical 
lab, KCAS Inc., at:  
Test Materials Management (TMM) 
KCAS Bioanalytical and Biomarker Services  
10830 South Clay Blair Boulevard 
Olathe, KS, 66061 
Office: 913-248-3006 
Fax: 913-248-3106  
Email: TMM@kcasbio.com  
Back-up aliquots of plasma and urine PK samples for storage will be shipped from the CTU to 
DMID-CMS at: 
Fisher BioServices 
c/o DMID Clinical Materials Services (CMS) 
20439 Seneca Meadows Parkway 
Germantown, MD 20876 
Phone: 240-477-1350  
Fax: 240-477-1360 
Email: DMID.CMS@thermofisher.com  
Further information will be provided in the study-specific MOP.  


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8.4 
Disposition of Plasma and Urine Samples 
Blood (plasma or serum) and urine samples collected for clinical laboratory testing and PK 
assays will not be used for purposes other than those described. No genetic testing will be done 
on collected blood samples.  
Clinical laboratory samples (Table 5) will be destroyed after tests are completed and results are 
reviewed according to standard practices of the Site Clinical Lab. 
Plasma and urine PK samples used for measurement of the concentration of study drugs at 
KCAS, the bioanalytical lab, will be disposed of per sponsor (DMID) guidance.  


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9 
ASSESSMENT OF SAFETY 
Regulatory requirements including FDA regulations and ICH Guidelines for GCP set forth safety 
monitoring and reporting responsibilities of sponsors and investigators to ensure the safety and 
protection of human subjects participating in clinical trials. 
Responsibilities: 
Investigators participating in this clinical trial are responsible for and will: 
• Evaluate subject safety including assessment of treatment-emergent adverse events 
(TEAEs) for seriousness, severity, and causality (relatedness to study drug). 
• Notify DMID of treatment-emergent serious AEs (SAEs) within 24 h of site awareness. 
• Provide detailed written reports, including necessary documentation requested by DMID or 
IRB/EC, promptly following immediate initial reports of SAEs. 
• Inform the IRB/EC of SAEs and TEAEs as required by applicable regulatory requirements. 
9.1 
 Specification of Safety Parameters 
Safety will be assessed by the timing, frequency, causality, and severity of: 
1. Systemic and infusion site TEAEs and SAEs occurring from time of first dose with study 
drug(s) through Final Visit (Day 11 + 3 days), or ET. 
2. Clinical laboratory TEAEs occurring from time of first dose with study drug(s) through 
Final Visit (Day 11 + 3 days), or ET. 
3. 12-lead standard ECGs performed on Day 8 and on the Final Visit (Day 11 + 3 days), or 
ET. 
4. Physical examinations (PE) and VS measurements performed from time of first dose with 
study drug(s) through Final Visit (Day 11 + 3 days), or ET. 
9.2 
Methods and Timing for Assessing, Recording and Analyzing Safety 
Parameters 
9.2.1 
Adverse Events 
Definitions 
ICH E6 defines an AE as any untoward medical occurrence in a subject or clinical investigation 
subject who was administered a pharmaceutical product, regardless of its causal relationship to the 
product. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with use of the product, and are 
described as treatment-emergent AEs (TEAEs). The occurrence of a TEAE may come to the 


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attention of study personnel during study visits and interviews, or by a subject presenting for 
medical care. 
Expected safety information for ERT and ZID are described in detail in the product information for 
Ertapenem Sodium for Injection [28, 37] and the IB [34]. The severity and frequency of events 
listed in these sources and in the ERT product information will be taken into account for both the 
assessment of causality of AEs, as well as expectedness of any SAEs. 
Any systemic medical condition, and the last VS and ECG measurement and clinical safety lab test 
value that are recorded prior to dosing on Day 1 will be considered a baseline finding for the 
purpose of data analysis. Baseline comprises PE, lab and ECG assessments performed on Day -1 
and VS and focused PE performed on Day 1 prior to initiation of IV infusion of study drug. 
However, if the condition increases in severity or frequency after study drug administration at any 
time during the trial, it will be recorded as a TEAE. 
Any medical condition that is reported after screening but before study drug administration will be 
evaluated and reported as MH update. 
All TEAEs will be graded for severity according to Appendix B, Table 3 and Table 4 and for 
relationship to the study drug. 
9.2.2 
Severity of Events 
Intensity of TEAEs will be graded as follows, unless otherwise specified in Appendix B: 
Mild (Grade 1): Require minimal or no treatment; do not interfere with the subject’s daily 
activities. 
Moderate (Grade 2): Result in a low level of inconvenience or concern with therapeutic 
measures; may cause some interference with functioning. 
Severe (Grade 3): Interrupt a subject’s usual daily activity and may require systemic drug therapy 
or other treatment; are usually incapacitating. 
9.2.3 
Relationship to Study Products 
TEAEs and treatment-emergent SAEs will be assessed by the investigator to determine 
relationship to the study drug, using the following two terms. In a clinical trial, the study drug must 
always be suspect. 
• Related: There is a reasonable possibility that the study drug caused the treatment-
emergent AE/SAE. 
• Not Related: There is not a reasonable possibility that the study drug caused the treatment-
emergent AE/SAE. 
The investigator will provide an assessment of association or relationship of each treatment-
emergent AE/SAE to the study drug based on: 


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• Temporal relationship of the TEAE/SAE to study drug dosing. 
• Whether an alternative etiology has been identified. 
• Biological plausibility. 
• Existing therapy and/or ConMeds. 
9.2.4 
Reporting Adverse Events 
All AEs will be captured on the appropriate subject’s source document and eCRF. Information 
collected for TEAEs includes event description, time of onset, investigator assessment of severity 
and relationship to the study drug, date of resolution of the event, seriousness, and outcome. 
All AEs will be documented from the time of starting study drug administration through the time 
of Final Visit (Day 11 + 3 days), or ET. All AEs including abnormal safety laboratory test results 
will be followed to resolution or until considered stable in the clinical judgment of the study 
investigator. Evaluation of AEs may require unscheduled visits and clinical and laboratory 
investigations, according to the clinical judgment of the Site PI or authorized study clinicians 
(listed on FDA Form 1572). 
9.2.5 
Serious Adverse Events 
A SAE is any treatment-emergent AE that meets at least one of the following criteria: 
• Death. 
• Life-threatening AE*. 
• Inpatient hospitalization or prolongation of existing hospitalization. 
• Persistent or significant disability or incapacity, or substantial disruption of the ability to 
conduct normal life function. 
• Congenital anomaly/birth defect. 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the 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. 
*A treatment-emergent SAE is considered “life-threatening” if, in the view of either the 
investigator or DMID, its occurrence places the subject at immediate risk of death. It does 
not include a TEAE that, had it occurred in a more severe form, might have caused death. 
SAEs will be: 
• Assessed for severity and relationship to study product and alternate etiology by an 
authorized study physician (listed on FDA Form 1572). 


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• Recorded on the appropriate SAE eCRF. 
• Followed through resolution. 
• Reviewed and evaluated by the SMC (periodic review unless related), DMID, and the IRB. 
9.2.6 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings 
A licensed study clinician (listed on FDA Form 1572) will determine seriousness, severity, and 
causality of abnormal laboratory values; provide a medical evaluation of TEAEs; and classify 
TEAEs as clinically significant (CS) or not clinically significant (NCS) based upon medical 
judgment. 
Abnormal laboratory values or clinical findings for all enrolled subjects after dosing will be 
assessed using the toxicity scales in Appendix B, Table 3. Abnormal values assessed as Grade 1 in 
severity and noted at screening or baseline but allowed for enrollment per Section 5.1, Inclusion 
Criteria #5 will only be considered TEAEs if they increase in severity to Grade 2 or higher. For 
abnormalities noted from the time of study drug dosing, any Grade 1 or higher laboratory 
abnormality listed on the toxicity in Appendix B, Table 3will be entered in the database as a 
TEAE. Gross blood in urine that is confirmed due to menses is not a TEAE (but is for all other 
reasons). Abnormal laboratory values, performed as part of HEM, COAG, CHEM, or UA but not 
listed in this toxicity table will be evaluated by the study clinicians, recorded in the source 
document and, if clinically significant, considered TEAEs and graded according to the criteria in 
Section 9.2.1. 
Protocol-specific laboratory normal range values in effect at the time of protocol submission for 
evaluation of TEAEs are included in Appendix B, Table 3.  
9.3 
Reporting Procedures 
9.3.1 
Serious Adverse Events 
SAEs will be followed until resolution even if this extends beyond the study-reporting period. 
Resolution of an SAE is defined as the return to pretreatment status or stabilization of the 
condition with the expectation that it will remain chronic. 
All SAEs will be: 
• Recorded on the appropriate SAE report form and sent to DMID Pharmacovigilance Group 
(PVG). 
• Entered into the appropriate subject source document and eCRF in Advantage eClinical®. 
• Reported to the IRB. 
• Reviewed and followed to resolution or stability by an authorized study physician (listed on 
FDA Form 1572). 


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• Collected on each subject until Day 11 + 3 days (Final Visit), or ET Visit. 
Any AE that meets a protocol-defined serious criterion will be submitted immediately 
(within 24 h of site awareness) on an SAE report form to DMID PVG at the following 
address: 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Drive, 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 report form, selected SAE data fields will also be entered into Advantage 
eClinical®. Please see the protocol-specific MOP for details regarding this procedure. 
Other supporting documentation of the SAE may be requested by DMID PVG and will be 
provided as soon as possible. 
The DMID Medical Monitor (MM) and DMID CPM will be notified of the SAE by the DMID 
PVG. The DMID MM will review and assess the SAE for regulatory reporting and potential 
impact on subject safety and protocol conduct. 
At any time after completion of the trial, if the Site PI or authorized study clinician (listed on FDA 
Form 1572) becomes aware of an SAE that is suspected to be related to study drug, the Site PI or 
authorized study clinician will report the event to the DMID PVG. 
9.3.2 
SUSAR Regulatory Reporting for Studies Conducted under DMID Sponsored 
IND 
Following notification from the investigator, DMID, the Investigational New Drug (IND) sponsor, 
is responsible for making the determination of which SAEs are Suspected unexpected serious 
adverse reactions or SUSARs. A SUSAR, as defined in 21 CFR 312.32, is any SAE where a causal 
relationship with the study product is at least reasonably possible but that adverse event is not 
listed in the IB, Package Insert, and/or Summary of Product Characteristics. 
 
All SUSARs will be reported to the FDA as IND Safety Reports per 21 CFR 312.32 as soon as 
possible but not exceeding 7 calendar days for unexpected fatal or life-threatening events, and not 
exceeding 15 calendar days for other qualifying events. IND Safety Reports will also be provided 
to the IRB. 
 
The DMID Medical Monitor and Clinical Project Manager will be notified of the SAE and 
potential SUSAR by the DMID Pharmacovigilance Group. The DMID Medical Monitor will 


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review and assess SUSARs for regulatory reporting and potential impact on study subjects’ safety 
and protocol conduct. 
DMID will submit an IND safety report to the FDA and will notify all participating site Principal 
Investigators of potential serious risks from clinical studies or any other source, as soon as 
possible. 
All SAEs designated as “not related” to study product(s), will be reported to the FDA and to the 
national regulatory authorities at least annually in a summary format (e.g., IND Annual Report). 
9.3.3 
Other Adverse Events (if applicable) 
9.3.3.1 
Reporting of Overdose 
An overdose is defined as a dose greater than the high-dose level evaluated in the trial as described 
in Section 6.3.1. All overdoses will be reported; if the overdose is associated with a TEAE, then 
the TEAE will also be reported. In the event of an overdose of study drug, the investigator will use 
clinical judgment in treating the overdose and contact the DMID MM. There is no specific antidote 
in case of ERT or ZID or WCK 6777 (ERT plus ZID) overdose. The same measures as 
recommended for other antibiotics belonging to the class of carbapenem antibiotics (treatment 
cessation, supportive treatment, adequate hydration, and hemodialysis in case of severe 
overdosage) should be considered until further clinical data are available for the study drug(s). The 
investigator will refer to the relevant document(s) for detailed information regarding warnings, 
precautions, contraindications, TEAEs, and other significant data pertaining to each study drug. 
Such documentation may include but not be limited to Prescription Information for Ertapenem 
Sodium for Injection (ERT) (28, 37), and the 2022 WCK 6777 Investigator Brochure (34). 
9.3.3.2 
Reporting of Pregnancy 
Pregnancies that occur in female subjects during the trial will be reported via Advantage eClinical® 
on a pregnancy report form. With the subject’s permission, all protocol-required venous blood 
samples will be obtained, and the subject will continue to be followed for safety until 
Day 11 + 3 days (Final Visit). Efforts will be made to follow all pregnancies reported during the 
trial to pregnancy outcome, as described in the protocol-specific MOP (e.g., delivery, spontaneous 
abortion, or therapeutic abortion), pending the subject’s permission. 
A female subject who participates in the trial and becomes pregnant will be asked to inform study 
personnel of a pregnancy occurring within 30 days after Final Visit. For all reported pregnancies, 
subjects will be asked to provide pregnancy outcome upon delivery or pregnancy termination to 
the CTU. 
Serious adverse outcomes of pregnancy affecting the mother and/or fetus or neonate (e.g., 
spontaneous abortion, congenital anomaly(ies) in fetus or child, late fetal death, or reports of 
adverse drug reactions in a newborn/neonate that is fatal, life-threatening, resulting in persistent or 


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significant disability/incapacity or resulting in or prolonging hospitalization) will be documented 
in a SAE form and reported to the CROMS PVG within 24 hours of clinical site awareness of the 
events. 
9.4 
Type and Duration of Follow-up of Subjects after Adverse Events 
Treatment-emergent SAEs and AEs will be followed until resolution or until considered stable in 
the clinical judgment of the investigator. Resolution of an AE is defined as the return to 
pretreatment status or stabilization of the condition in the clinical judgment of the study 
investigator, with the expectation that it will remain chronic. 
Follow-up procedures, evaluations, and outcomes will be recorded in the subject's source 
document and eCRF. 
9.5 
Halting Rules 
9.5.1 
Study Halting Criteria 
• One subject experiences an SAE regardless of the relationship to study product, with the 
exception of accidental injury. from the time of first dose through the last visit (Day 11 +3).  
• Two or more subjects, in the same cohort, experience Grade 3 (severe) AEs (Systemic or 
Laboratory) through the last visit (Day 11+3) regardless of the relationship to study product 
that are coded in the same High Level Term (HLT) per MedDRA classification. 
• In combination treatment cohorts (Cohorts 1, 4 and 7), three or more subjects (cumulative) 
experience Grade 3 (severe) AEs (Systemic or Laboratory) regardless of the relationship to 
study product with the exception of accidental injury that are coded in the same High Level 
Group Term (HLGT) per MedDRA classification. 
o Note: For Grade 3 TEAEs in the situations above, VS abnormalities will be 
considered part of a systemic disorder or an organ-specific condition, as described in 
Appendix B: Adverse Events Toxicity Grading Criteria, in order to be included among 
the Study Halting Criteria. 
If the predefined criteria for the halting rules are met, the SMC will review the study data and 
provide guidance on how to proceed. 
A halted study will resume upon recommendation by the Sponsor (DMID). 
9.5.2 
Individual Subject Halting Criteria 
A subject will be discontinued from further dosing if any of the following criteria are met: 
• A subject experiences a SAE, regardless of the relationship to the study product. 
• A subject develops anaphylaxis within 24 hours after receiving the study product(s). 


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• A subject experiences a suspected drug-related hypersensitivity AE Grade 2 or higher 
during the infusion. In that case, the infusion must be stopped, and that subject will not 
continue with dosing. 
• A subject experiences a Grade 3 AE event (laboratory or systemic) if not resolved within 
24 hours of dosing. 
• If in the opinion of the site PI or authorized study clinician (listed on FDA Form 1572), 
further dosing would not be in the best interest of the subject. 
9.5.3 
Dose Escalation Halting Criteria 
Administration of drug product(s) in the next higher dose cohort should not occur unless all 
participants in the previous dose cohort(s) have received the study products and safety data from 
those participants are reviewed in accordance with the protocol (See Section 4 and Section 9.6.1). 
For dose escalation from the combination Cohort 1 (1 g ERT + 1 g ZID) to higher single dose 
Cohorts 2 (2 g ERT) and 3 (2 g ZID), and from the combination Cohort 4 (2 g ERT + 2 g ZID) to 
higher single dose Cohorts 5 (3 g ERT) and 6 (3 g ZID), the study will proceed to the next planned 
dose level upon recommendation by the SMC following review of cumulative interim safety data 
after completion of Cohort 1 or Cohort 4, respectively. The recommendation to continue to the 
next planned combination treatment cohorts (i.e., Cohort 4 and Cohort 7 [3 g ERT +3 g ZID]) will 
be made by the study team (DMID MO and MM and the site PI) after review of blinded safety data 
in Cohorts 2 and 3 and Cohorts 5 and 6, respectively. For dose escalation to single or combination 
cohorts, the SDCC confirms and notifies the SMC and/or study team (DMID MM, DMID MO and 
study PI) as needed that none of the following criteria were met: 
• Three or more subjects in the same cohort experience an AE, grade 2 or higher (Systemic 
or Laboratory), regardless of the relationship to study the study product with the exception 
of accidental injury in the same system organ Preferred Term (PT) per MedDRA 
classification. 
• Two or more subjects in the same cohort experience at least one Grade 3 AE and at least 
one Grade 2 AE, regardless of the relationship to study product with the exception of 
accidental injury, in the same HLT per MedDRA classification. 
If any of the above criteria is met, escalation to the next planned dose cohort will not proceed until 
all available study data have been reviewed by the SMC. If, following review by the SMC, this is 
deemed acceptable to restart the study, the study will resume with DMID (sponsor) agreement. 


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9.6 
Safety Oversight 
9.6.1 
Safety Monitoring Committee (SMC) 
Safety oversight will be conducted by a SMC, which is an independent group of experts that 
monitors subject safety and advises DMID. SMC members will be separate and independent of 
study personnel participating in the trial and will not have scientific, financial, or other conflicts of 
interest related to the trial. The SMC will consist of a minimum of three members with appropriate 
expertise to contribute to the interpretation of the data from the trial. 
The SMC will meet as follows: 
• Organizational meeting (before study initiation). 
• Ad hoc meeting. 
o When study halting criteria are met following review by the study team (DMID MO 
and MM and the site PI). 
o At the request of DMID to review a potential safety concern identified by either the Site 
PI or DMID MM. 
• Scheduled meeting. 
o The SMC will review cumulative interim safety data after completion of all subjects in 
Cohort 1. 
o The SMC will review cumulative, interim safety data when available after completion 
of all subjects in Cohorts 1 to 4. 
o The SMC will review final safety data in all cohorts when available after database lock. 
Procedures for SMC reviews/meetings will be defined in the SMC charter. The SMC will review 
safety data and provide recommendations to DMID, NIAID on resumption or stopping of a 
temporary halted trial. 


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10 
CLINICAL MONITORING 
10.1 
Site Monitoring Plan 
Site monitoring will be conducted to ensure that human subject protections, study and laboratory 
procedures, study intervention administration, and data collection processes are of high quality and 
meet DMID, GCP/ICH, and regulatory guidelines, when appropriate. Site visits may be conducted 
by an authorized representative of DMID or other regulatory agencies to inspect study data, 
subjects’ medical records, and eCRFs in accordance with ICH guidelines, GCP, and the respective 
local and national government regulations and guidelines. 
The investigator will permit authorized representatives of DMID and the respective local and 
national health authorities to inspect facilities and records relevant to the trial, if needed. 
A separate monitoring plan developed by DMID will describe protocol-specific items to be 
monitored. 
Site visits will be made at standard intervals defined by DMID and may be made more frequently 
as directed by DMID. Monitoring visits will include, but not be limited to, review of regulatory 
files, accountability records, subjects’ source documents, eCRFs, ICFs, clinical and laboratory 
reports, and protocol and GCP compliance. Site monitors will have access to the CTU, study 
personnel, and all study documentation according to the DMID-approved site monitoring plan. 
Study monitors will meet with the Site PI to discuss any problems and actions to be taken and 
document visit findings and discussions. 
 


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11 
STATISTICAL CONSIDERATIONS 
11.1 
Study Hypotheses 
The objectives of the study are to obtain safety data and plasma and urine PK data for 3 escalating 
doses of WCK 6777 (combination of ERT with ZID) and 2 escalating doses of ERT alone and ZID 
alone. There are no formal hypotheses being tested in this Phase 1 trial. 
11.2 
Sample Size Considerations 
The sample size of 52 subjects assigned into 7 treatment cohorts with 8 subjects per cohort (6 
subjects randomized to receive active drug(s) and 2 placebo), with the exception of Cohorts 3 and 
6, where 6 subjects will receive active ZID only, was chosen to obtain reasonable evidence of 
safety without exposing undue numbers of healthy subjects to ERT combined with ZID, ERT 
alone, and ZID alone at this phase of clinical evaluation. Previous experience in Phase 1 studies 
has shown that the sample size being proposed is sufficient to fulfill the primary and secondary 
objectives of the study. Power calculations have not been performed. 
It is expected there will be 7 evaluable subjects in each cohort with 8 subjects each (ERT 
standalone Cohorts 2 and 5 and WCK 6777 cohorts 1, 4 and 7), and 5 subjects in each ZID 
standalone cohort (Cohorts 3 and 6). 
11.3 
 Safety Review 
An SMC will be appointed to oversee the safe conduct of the trial. A scheduled SMC meeting will 
be held to review safety data from Cohorts 1 to 4 and decide on continuation of the study to 
Cohorts 5 to 7. If the study is continued, a final SMC meeting will be held to review cumulative 
data and to make recommendations about the safety profile and safety monitoring of the clinical 
trial. The decision to continue the study after Cohort 1, Cohorts 2 and 3, and Cohorts 5 and 6 will 
be made by DMID based on review of safety data and summary provided by the site PI. If criteria 
for halting the trial (as listed in Section 9.5.1) are met, an ad hoc SMC meeting will be held to 
review all available safety data and to make recommendations about the dosing of all further 
subjects in the trial. Blinded data will be presented at the open SMC meeting. An unblinded 
statistician may present unblinded data in a closed session of an SMC meeting. 
11.4 
Final Analysis Plan 
The ICH Guidance E9 (Statistical Principles for Clinical Trials) will be followed for all statistical 
content. Summaries of frequencies and percentages will be presented for categorical data, and 
summary statistics such as median, mean, standard deviation (SD), minimum and maximum values 
will be presented for continuous data by Dose Cohort. Details of the statistical methods and 
models used for plasma and urine PK analyses, including dose proportionality, and safety data 
analyses and presentations will be described in the Statistical Analysis Plan (SAP) and 


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accompanying Tables, Listings and Figures (TLF) templates. The SAP will be prepared and 
finalized by the SDCC before analysis of the safety and PK data. A final analysis containing safety 
data and PK data from all study cohorts will be performed by the SDCC after final data lock and 
included in the clinical study report (CSR). Any change from originally planned statistical analyses 
will be reported in the CSR. 
11.4.1 
Analysis Populations 
The safety population will include all subjects who received any amount of study drug(s). 
The PK analysis population will consist of all subjects who received at least a single dose of study 
drug and have at least one quantifiable post-dosing plasma drug concentration measured. The PK 
Analysis Subset is defined as the subset of the PK Analysis Population that received the intended 
doses of study drug(s) and have adequate data that permit estimation of PK parameters. For the PK 
analysis and estimates of exposure parameters, 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. Subjects will be analyzed 
by dose as treated. 
If any subjects are found to be noncompliant with respect to dosing or have incomplete data, a 
decision to include them in the analysis will be made by criteria that would be described in the 
Statistical Analysis Plan. 
11.4.2 
Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics will be summarized. The number of subjects 
who enroll in the trial, and the number and percentage of subjects who complete each assessment, 
will be presented. The percentage of subjects who withdraw from the trial or discontinue the study 
drug, and reasons for withdrawal or discontinuation, will be summarized. 
11.4.3 
Safety Analysis 
11.4.3.1 
Adverse and Serious Adverse Events 
Treatment-emergent AEs (TEAEs) and Serious AEs (SAEs) will be coded using the latest version 
of the Medical Dictionary for Regulatory Activities® (MedDRA). All AEs occurring after study 
drug dosing will be summarized using frequency counts and percentages. The following 
summaries will be presented for TEAEs and SAEs: 
• Overall (i.e., regardless of severity or relationship to treatment). 
• By severity grade (mild, moderate, or severe). 
• By relationship to study drug. 


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• By MedDRA level hierarchy (system organ class [SOC], higher level group term [HLGT] 
and preferred term [PT]). 
Unless otherwise specified, at each level of subject summarization in reporting the incidence of 
TEAEs, a subject will be counted once if the subject reported one or more TEAEs. If more than 
one occurrence of a TEAE is reported, the TEAE of the worst severity or the worst-case 
relationship assessment will be summarized. 
11.4.3.2 
Additional Safety Analyses 
Descriptive summary statistics (mean, SD, median, minimum, and maximum) for all clinical 
laboratory data, 12-lead standard ECG parameters, and VS at admission and each applicable post-
dosing visit, including changes from baseline values, will be calculated and presented by treatment 
cohort. Baseline values will be the last values recorded before administration of study drug. For 
change-from-baseline summaries, subjects with an undefined change from baseline, due to missing 
data, will be excluded. Clinical significance of abnormalities, as assessed by the study PI or 
authorized study clinicians, will be indicated. The number and percentage of subjects who meet 
toxicity criteria for clinical laboratory, VS and 12-lead ECG investigations will be listed and 
tabulated by treatment cohort. 
11.4.3.3 
Tolerability Assessment 
Tolerability to study product will be summarized by dose cohort and include number and incidence 
of subjects who: 1) discontinued study drug due to an AE, 2) chose to withdraw from the study due 
to an AE at any time from start of dosing until end of study, or 3) were withdrawn from the study 
by the investigator due to an adverse event at any time from start of dosing until end of study. 
11.4.4 
PK Analysis 
Plasma (total and free) and urine concentrations of ERT and ZID on Day 1 and Day 7 will be 
summarized using descriptive statistics (n, mean, SD, CV%, median, minimum, and maximum) for 
each treatment cohort, study day and nominal timepoint. Plasma (total and free) study drug 
concentrations observed before dosing on Days 2, 3, 4, 5, 6 and 7 and 24 h after dosing on Day 7 
(trough concentrations) and 12 h (± 15 min) after start of infusion on Days 1 to 7 will be 
summarized similarly for each treatment cohort and study day. 
Plasma (total and free) and urine PK parameters will be estimated separately for ERT and ZID by 
noncompartmental analysis (NCA) methods using Phoenix® WinNonlin® version 8.0 or higher and 
presented by treatment cohort.  PK parameters and linearity index and dose-normalized exposure 
parameters (AUC(0-tau)/Dose and Cmax/Dose) after the first dose and multiple doses will be analyzed 
and presented. 
Graphical presentations of plasma concentration vs. time profiles will be provided for ERT and 
ZID and will include individual subject and mean concentration profiles. Semi-log concentration 


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profiles will be provided for individual subjects. Graphical presentation of mean and individual 
trough study drug concentrations and study drug concentrations collected 12 h after dosing through 
Day 7 will be displayed. 
% Protein binding for ERT and ZID will be calculated and presented by treatment cohort at all 
collected timepoints the results will be tabulated and presented graphically. 
11.4.5 
Plasma PK parameters: 
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. 
The following single-dose plasma PK parameters will be computed (if estimable) from the plasma 
total and free concentration-time data over the 24-hour following Dose 1 for each study drug: 
• Cmax:  observed maximum concentration 
• Tmax: Time of maximum concentration (h) 
• Cmin:  observed minimum concentration at the end of the dosing interval 
• AUC(0-t):  area under the plasma concentration -time curve to the last time with a 
concentration greater than or equal to the validated limit of quantitation of the assay 
• AUC(0-∞):  area under the plasma concentration-time curve to infinity 
• AUC(0-24):  area under the plasma concentration - time curve extrapolated to 24 h after 
dosing 
• AUC(0-last): Area under the plasma concentration - time curve from time zero to the last 
concentration above the lower limit of quantitation   
• AUC(0-tau):  area under the plasma concentration - time curve to the end of the dosing 
interval 
• t1/2:  Terminal half-life 
• CLT:  Total clearance 
• Ke: terminal phase elimination rate constant 
• Vd:  Volume of distribution 
• Dose-normalized exposure parameters (AUC(0-tau)/Dose and Cmax/Dose) 
The following multiple-dose plasma PK parameters will be computed (if estimable) from the drug 
total and free concentration-time data over the 24-hour dosing interval following Dose 7 for each 
study drug. 
• Cmax,ss: observed maximum concentration at steady state 
• Cmin,ss: observed minimum concentration at the end of the dosing interval at steady state 
• Cavg: calculated average concentration during the dosing interval 
• Tmax,ss: Time of maximum concentration (Cmax) at steady state 


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• Tmin: Time to minimum concentration (Cmin) 
• AUC(0-24),ss:  area under the plasma concentration - time curve extrapolated to 24 h after 
dosing 
• AUC(0-tau),ss: Area under the plasma concentration - time curve to the end of the dosing 
interval at steady state  
• t1/2: Terminal half-life (Day 7 only) 
• CLT: Total clearance 
• Vd,ss: Volume of distribution at steady state 
• Linearity Index: AUC(0-tau),ss (Day 7) / AUC(0-∞) (Day 1) 
• RAUC : Accumulation ratio for AUC estimated as AUC(0-tau) (Day 7) / AUC(0-24) (Day 1) 
• RCmax: Accumulation ratio for Cmax estimated as Cmax (Day 7) / Cmax (Day 1). 
• Dose-normalized exposure parameters (AUC(0-tau)/Dose and Cmax/Dose) 
11.4.6 
Urine PK parameters: 
The results of urine PK parameters for each individual study drug in each cohort will be listed by 
subject at each dose, and summarized with descriptive statistics (n, mean, SD, coefficient of 
variation, median, minimum, maximum, geometric mean and geometric SD) at each collection 
period. When evaluable, estimated urine PK parameters will include: 
• Ae,urine:  Amount of unchanged drug excreted in urine during each collection interval 
following Dose 1 and Dose 7 (i.e., at 0-4, 4-8, 8-12, 12-24 h after initiation of infusion) 
• Ae,urine(0-24):  Cumulative amount of unchanged drug excreted in urine from zero (predose) 
to 24 h following Dose 1 
• Ae,urine(0-24),ss: Cumulative amount of unchanged drug excreted in urine from zero 
(predose) to 24 h after Dose 7  
• fe,urine: Fraction (%) of dose excreted unchanged in urine during each collection interval 
following Dose 1 and Dose 7 (i.e., at 0-4, 4-8, 8-12, 12-24 h after initiation of infusion) 
• fe,urine(0-24): Fraction (%) of dose excreted unchanged in urine from zero (predose) to 24 h 
after Dose 1 
• fe,urine(0-24),ss: Fraction (%) of dose excreted unchanged in urine from zero (predose) to 
24 h following Dose 7 
• CLr(0-24): Renal clearance (L/h) following Dose 1 
• CLr,ss: Renal clearance following Dose 7 
11.4.7 
Missing Values and Outliers 
All attempts will be made to collect all data per protocol. No imputation will be performed for 
missing values. Rules for identifying outliers will be described in the SAP. Outliers will not be 


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excluded from the primary analyses. Outliers identified during the PK analysis will be discussed in 
the analysis report. 
11.4.8 
Multiple Comparisons / Multiplicity 
This is a small Phase 1 Study with multiple endpoints. Because analyses of endpoints are 
descriptive rather than hypothesis tests, no adjustments for multiplicity testing are planned. 
11.4.9 
Interim Reports 
Interim cumulative safety data will be presented to the SMC after completion of Cohort 1 and 
Cohort 4.  
Blinded safety and tolerability data will be periodically reviewed by DMID and the site PI or 
authorized study clinician (listed on FDA Form 1572) to assess whether rules for halting 
progression to the next study cohort have been met. An ad hoc SMC meeting will review safety 
data if halting criteria have been met. The SMC will receive data in aggregate. The SMC may 
request to receive data by study product vs. placebo in a closed session. The SMC may also request 
that the blind be broken for individual subjects, as needed, to assess safety issues. 


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12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
The CTU will maintain appropriate medical and/or research records for the trial, in compliance 
with ICH E6 GCP, Section 4.9, and regulatory and institutional requirements for the protection of 
confidentiality of subjects. As part of participating in a DMID-sponsored, DMID-affiliated, or 
manufacturer-sponsored trial, the CTU will permit authorized representatives of DMID, to include 
The Emmes Company, LLC (the SDCC), DynPort Vaccine Company, LLC (DVC), and regulatory 
agencies to review (and, when required by applicable law, to copy) clinical records for the 
purposes of quality assurance reviews, audits, and evaluation of the study safety and progress. 
Forms for use as source documents will be derived from eCRFs and will be provided by the SDCC 
and CTU. Additional source data are all information, original records of clinical findings, 
observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of 
the trial. Examples of these original documents and data records include, but are not limited to, 
hospital records, clinical and office charts, laboratory notes, memoranda, 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, ECG print-outs, and subject files and records kept at the pharmacy, 
laboratories, and medico-technical departments involved in the trial. 
 
 
 


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13 
QUALITY CONTROL AND QUALITY ASSURANCE 
Following a written DMID-accepted site quality management plan, the CTU is responsible for 
conducting routine quality assurance and quality control activities to internally monitor study 
progress and protocol compliance. The Site PI will provide direct access to the CTU, source 
data/documents, and reports for monitoring and auditing by DMID, 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 quality control procedures beginning with the data entry system and 
generate data quality control checks that will be run on the database. Any missing data or data 
anomalies will be communicated to the CTU for clarification and resolution. 


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14 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1 
Ethical Standard 
The Site PI will ensure that the trial is conducted in full conformity with principles of the Belmont 
Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research of the 
National Commission for the Protection of Human Subjects of Biomedical and Behavioral 
Research (April 18, 1979) and codified in 45 CFR 46, 21 CFR 50 and 56, and ICH E6; 62 Federal 
Regulations 25692 (1997), if applicable. The Site PI’s institution will hold a current Federal Wide 
Assurance (FWA) issued by the Office of Human Research Protection for federally funded 
research. 
14.2 
Institutional Review Board 
The CTU will provide for the review and approval of this protocol and associated ICFs by an 
appropriate IRB/EC listed on the FWA. Any amendments to the protocol or consent materials will 
also be approved before they are used, unless change is for the safety of the subject. Only those 
IRB members who are independent of the investigators and DMID will provide an opinion on 
study-related matters. Verification of IRB approval of the protocol and the written ICF will be 
transmitted by the investigator or designee before shipment of the study drug. No deviations from 
or changes to the protocol will be initiated without prior approval of an appropriate amendment 
unless change is for the safety of the subject. 
14.3 
Informed Consent Process 
The written consent document will embody the elements of informed consent as described in the 
Declaration of Helsinki and will adhere to the ICH Harmonized Tripartite Guideline for GCP. 
Informed consent will be obtained before any protocol-specified procedures or interventions are 
carried out, and in accordance with 21 CFR 50.25 and 45 CFR 46. Information will be presented 
both orally and in written form. 
An investigator or designee will describe the protocol to potential subjects face-to-face. The ICF 
may be read to the subjects, but, in any event, the investigator shall give the subjects ample 
opportunity to inquire about details of the trial and ask any questions before signing the ICF. 
Study staff will inform subjects that the trial involves research, and explain the purpose of the trial, 
those aspects of the trial that are experimental, 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, the procedures of the research study, 
including all invasive procedures, and the probability for assignment to treatment cohorts. 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. They will also be 


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informed of alternative procedures that may be available, and the important potential benefits and 
risks of these available alternative procedures. 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. Subjects will be informed that 
participation is voluntary and that they are free to withdraw from the trial for any reason at any 
time without penalty or loss of benefits to which the subject is otherwise entitled. 
Neither the investigator, nor the trial staff, will coerce or unduly influence a subject to participate 
or continue to participate in the trial. 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), auditor(s), IRB, DMID, 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 subject’s confidentiality, to the extent 
permitted by 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. 
ICFs will be in a language fully comprehensible to the prospective subjects. Informed consent shall 
be documented using a written consent form approved by the IRB and signed and dated by the 
subject and the person who conducted the informed consent discussion. The signature confirms 
that the consent is based on information that has been provided and all questions have been 
answered to the prospective subject’s satisfaction. Each subject’s signed ICF will be kept on file 
by the investigator for possible inspection by regulatory authorities and/or DMID and regulatory 
compliance persons. The subject will receive a copy of the signed and dated written ICF and any 
other written information provided to the subjects and will receive copies of any signed and dated 
ICF updates and any amendments to the written information provided to subjects. 
14.4 
Exclusion of Women, Minorities and Children (Special Populations) 
Children aged < 18 years will be excluded from participation because insufficient data are 
available in adults to judge potential risk in children, and as a Phase 1 trial, there is no known 
benefit.   
Neither women nor minorities will be routinely excluded from participation in the trial. Subjects 
will be recruited without regard to gender or race. It is expected that race and gender distributions 
in the trial will approximate the proportion to their numbers within the community. 


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Women of childbearing potential will be included but will be repeatedly counseled to use effective 
measures (Section 5.1) to avoid becoming pregnant from the time of screening to 30 days 
following the last dose of study product, because the effects of the study drugs on the unborn fetus 
are not known. 
14.5 
Subject Confidentiality  
Subject confidentiality is held strictly in trust by the participating investigators, their staff, and 
DMID and its agents. This confidentiality is extended to cover testing of biological samples, and 
also clinical information related to participating subjects. 
The study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the trial or data will be released to any unauthorized third 
party without prior written approval from DMID. This information and data will not be used by the 
Site PI or other study personnel for any purpose other than conducting the trial. These restrictions 
do not apply to: (1) information which becomes publicly available through no fault of the Site PI 
or other study personnel; (2) information which is necessary to disclose in confidence to an IRB 
solely for the evaluation of the trial; (3) information which is necessary to disclose in order to 
provide appropriate medical care to a subject; or (4) study results which may be published as 
described in Section 16. 
The study monitors or other authorized representatives of DMID may inspect all documents and 
records required to be maintained by the Site Investigator, including, but not limited to, medical 
records (office, clinic or hospital) and pharmacy records for the subjects in the trial. The CTU will 
permit access to such records. 
14.6 
Certificate of Confidentiality 
To protect privacy, we have received a Certificate of Confidentiality. With this Certificate, the 
researchers cannot be forced to release information that may identify the research subject, even by 
a court subpoena, in any federal, state, or local civil, criminal, administrative, legislative, or other 
proceedings. The researchers will use the Certificate to resist any demands for information that 
would identify the subject, except as explained below. 
The Certificate cannot be used to resist a demand for information from personnel of the 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 Federal 
Food and Drug Administration (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 
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The Certificate of Confidentiality does not prevent the researchers from reporting without the 
subject’s consent, information that would identify the subject as a participant in the research 
project regarding matters that must be legally reported, including child and elder abuse, sexual 
abuse, or wanting to harm themselves or others. 
The release of individual private information or specimens for other research will only occur if 
consent was obtained from the individual to whom the information, document, or biospecimen 
pertains, or for the purposes of other research that is in compliance with applicable Federal 
regulations governing the protection of human subjects in research. 
14.7 
Study Discontinuation 
DMID has the right to terminate the trial or the CTU’s participation at any time. Reasons for 
terminating the trial may include, but are not limited to: 
• Incidence or severity of TEAEs indicates a potential health hazard. 
• Data recording is inaccurate or incomplete. 
• Investigator does not adhere to the protocol or applicable regulatory guidelines in 
conducting the trial. 
If the trial is discontinued, subjects who have signed the ICF and received the study drug will 
continue to be followed for safety for the duration of the trial. No further study treatments will be 
administered to other subjects. 
. 


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15 
DATA HANDLING AND RECORD KEEPING 
The Site PI is responsible to ensure the accuracy, completeness, legibility, and timeliness of 
reported data. All data collection forms will be completed legibly to ensure accurate interpretation 
of data. Black or blue 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. 
Data collection forms will be provided by the SDCC and the CTU will use them to develop the 
CTU’s source documents to record and maintain data for each subject enrolled in the trial. Data 
reported in the eCRF derived from source documents will be consistent with the source documents 
or the discrepancies will be explained. 
DMID and/or its designee will provide guidance to investigators and other study personnel on 
making corrections to the data collection forms, source documents and eCRFs. 
15.1 
Data Management Responsibilities 
All source documents and laboratory reports will be reviewed by the clinical team and data entry 
staff, who will ensure that they are accurate and complete. TEAEs will be graded, assessed for 
severity and causality, and clinical significance as needed, and reviewed by the Site PI or designee. 
Data collection is the responsibility of the clinical trial staff at the CTU under the supervision of 
the Site PI. During the trial, the investigator will maintain complete and accurate documentation 
for the trial. 
The Emmes Company, LLC will serve as the SDCC for the trial, and will be responsible for data 
management, quality review, analysis, and reporting of the study data. 
15.2 
Data Capture Methods 
Clinical data (including, but not limited to treatment-emergent AE/SAEs, ConMeds, MH, PE, 
clinical laboratory data, and ECG data [ECG intervals and interpretations]) will be collected on 
data collection forms by study personnel then entered into eCRFs via a 21 CFR 11-compliant 
Internet Data Entry System provided by the SDCC. The data system includes password protection 
and internal quality checks (e.g., automatic range checks) to identify data that appear inconsistent, 
incomplete, or inaccurate. Clinical data will be entered directly from the source documents by 
CTU study personnel. 
15.3 
Types of Data 
Data for the trial will include clinical and laboratory safety assessments, 12-lead standard ECG 
interval measurements and interpretations, plasma and urine study drug concentrations at each 
specified timepoint and PK parameters for each dose of individual study drugs (ERT and ZID) and 
of WCK 6777 (combination ERT and ZID). 


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15.4 
Timing/Reports 
A final CSR will be prepared after all safety, 12-lead standard ECG, and plasma and urine PK data 
are available. 
15.5 
Study Records Retention 
Study files and ICFs will be maintained for at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the study drug. These documents will be retained for a longer period, 
however, if required by local regulations. No records will be destroyed without the written consent 
of DMID, if applicable. It is DMID’s responsibility to inform the investigator when these 
documents no longer need to be retained. 
15.6 
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 
investigator, or the CTU staff. Corrective actions for protocol deviations are to be developed by the 
CTU 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 and Quality Control, Section 5.1.1 
5.20 Noncompliance, Sections 5.20.1, and 5.20.2. 
It is the responsibility of the Site PI/study staff to use continuous vigilance to identify and report 
deviations within 5 working days of identification of the protocol deviation, or within 5 working 
days of the scheduled protocol-required activity. All deviations will be promptly reported to DMID 
via SDCC’s Advantage eClinical®. 
All protocol deviations, as defined above, will be addressed in subject data collection forms. A 
completed copy of the DMID Protocol Deviation Form will be maintained in the regulatory file, as 
well as in the subject's source document. Protocol deviations will be sent to the local IRB/EC per 
their guidelines. The Site PI/study staff is responsible for knowing and adhering to their IRB 
requirements. 


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16 
PUBLICATION POLICY 
Following completion of the study, the lead Principal Investigator 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/NIAID/NIH, which will 
register the trial and post results. 
 
Refer to: 
• Public Law 110-85, Section 801, Clinical Trial Databases 
• 42CFR11 
• NIH NOT-OD-16-149 
 
 


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17 
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antibiotics-are-urgently-needed. 
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9. ZEMDRI™ (plazomicin) injection, for intravenous use. Prescribing information Available 
from:  https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210303orig1s0 00lbl.pdf 
10. Kelly AM, Mathema, B, Larson EL. Carbapenem-resistant Enterobacteriaceae in the 
community: a scoping review. International Journal of Antimicrobial Agents, 2017. 
50(2):127-134. doi:10.1016/j.ijantimicag.2017.03.012 
11. Norris AH, Shrestha NK, Allison GM, et al. 2018 Infectious Diseases Society of America 
Clinical Practice Guideline for the Management of Outpatient Parenteral Antimicrobial 
Therapy. Clin Infect Dis. 2019;68(1):e1-e35. Doi: 10.1093/cid/ciy745 
12. Nazarko L. Avoiding admission and facilitating early discharge through OPAT. Br J Nurs.  
2014;23(14):S30-6. doi: 10.12968/bjon.2014.23.sup14.s30 
13. Dryden M, Saeed K, Townsend R, et al. Antibiotic stewardship and early discharge from 
hospital: impact of a structured approach to antimicrobial management. J Antimicrob 
Chemother. 2012;67(9):2289-2296. doi:10.1093/jac/dks193 
14. Livermore DM, Sefton AM, Scott GM. Properties and potential of ertapenem. J Antimicrob 
Chemother. 2003;52(3):331-344. doi:10.1093/jac/dkg375 
15. Livermore DM, Meunier D, Hopkins KL, et al. Activity of ceftazidime/avibactam against 
problem Enterobacteriaceae and Pseudomonas aeruginosa in the UK, 2015-16. J Antimicrob 
Chemother. 2018;73(3):648-657. doi:10.1093/jac/dkx438 
16. Papp-Wallace KM, Nguyen NQ, Jacobs MR, et al. Strategic Approaches to Overcome 
Resistance against Gram-Negative Pathogens Using β-Lactamase Inhibitors and β-Lactam 
Enhancers: Activity of Three Novel Diazabicyclooctanes WCK 5153, Zidebactam (WCK 
5107), and WCK 4234. J Med Chem. 2018;61(9):4067-4086. 
doi:10.1021/acs.jmedchem.8b00091 
 


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17. Moya B, Barcelo IM, Bhagwat S, et al. Potent β-Lactam Enhancer Activity of Zidebactam 
and WCK 5153 against Acinetobacter baumannii, Including Carbapenemase-Producing 
Clinical Isolates. Antimicrob Agents Chemother. 2017;61(11):e01238-17. 
doi:10.1128/AAC.01238-17. 
18. Moya B, Barcelo IM, Bhagwat S, et al. WCK 5107 (Zidebactam) and WCK 5153 Are Novel 
Inhibitors of PBP2 Showing Potent "β-Lactam Enhancer" Activity against Pseudomonas 
aeruginosa, Including Multidrug-Resistant Metallo-β-Lactamase-Producing High-Risk 
Clones. Antimicrob Agents Chemother. 2017;61(6):e02529-16. doi:10.1128/AAC.02529-16 
19. Moya B, Barcelo IM, Cabot G, et al. In Vitro and In Vivo Activities of β-Lactams in 
Combination with the Novel β-Lactam Enhancers Zidebactam and WCK 5153 against 
Multidrug-Resistant Metallo-β-Lactamase-Producing Klebsiella pneumoniae. Antimicrob 
Agents Chemother. 2019;63(5):e00128-19. doi:10.1128/AAC.00128-19 
20. Moya B, Bhagwat S, Cabot G, Bou G, Patel M, Oliver A. Effective inhibition of PBPs by 
cefepime and zidebactam in the presence of VIM-1 drives potent bactericidal activity 
against MBL-expressing Pseudomonas aeruginosa. J Antimicrob Chemother. 
2020;75(6):1474-1478. doi:10.1093/jac/dkaa036 
21. Bhagwat SS, Periasamy H, Takalkar SS, Palwe SR, Khande HN, Patel MV. The Novel β-
Lactam Enhancer Zidebactam Augments the In Vivo Pharmacodynamic Activity of 
Cefepime in a Neutropenic Mouse Lung Acinetobacter baumannii Infection Model. 
Antimicrob Agents Chemother. 2019;63(4):e02146-18. doi:10.1128/AAC.02146-18 
22. Lepak AJ, Zhao M, Andes DR. WCK 5222 (Cefepime/Zidebactam) Pharmacodynamic 
Target Analysis against Metallo-β-lactamase producing Enterobacteriaceae in the 
Neutropenic Mouse Pneumonia Model [published online ahead of print, 2019 Oct 7]. 
Antimicrob Agents Chemother. 2019;63(12):e01648-19. doi:10.1128/AAC.01648-19 
23. Avery LM, Abdelraouf K, Nicolau DP. Assessment of the In Vivo Efficacy of WCK 5222 
(Cefepime-Zidebactam) against Carbapenem-Resistant Acinetobacter baumannii in the 
Neutropenic Murine Lung Infection Model. Antimicrob Agents Chemother. 
2018;62(11):e00948-18. doi:10.1128/AAC.00948-18 
24. Monogue ML, Tabor-Rennie J, Abdelraouf K, Nicolau DP. In Vivo Efficacy of WCK 5222 
(Cefepime-Zidebactam) against Multidrug-Resistant Pseudomonas aeruginosa in the 
Neutropenic Murine Thigh Infection Model. Antimicrob Agents Chemother. 
2019;63(7):e00233-19. doi:10.1128/AAC.00233-19 
25. Kidd JM, Abdelraouf K, Nicolau DP. Efficacy of human-simulated bronchopulmonary 
exposures of cefepime, zidebactam and the combination (WCK 5222) against MDR 
Pseudomonas aeruginosa in a neutropenic murine pneumonia model. J Antimicrob 
Chemother. 2020;75(1):149-155. doi:10.1093/jac/dkz414 
26. Almarzoky Abuhussain SS, Avery LM, Abdelraouf K, Nicolau DP. In Vivo Efficacy of 
Humanized WCK 5222 (Cefepime-Zidebactam) Exposures against Carbapenem-Resistant 
Acinetobacter baumannii in the Neutropenic Thigh Model. Antimicrob Agents Chemother. 
2018;63(1):e01931-18. doi:10.1128/AAC.01931-18 
27. Gethers M, Chen I, Abdelraouf K, Nicolau DP. In vivo efficacy of WCK 6777 
(ertapenem/zidebactam) against carbapenemase-producing Klebsiella pneumoniae in the 
neutropenic murine pneumonia model [published online ahead of print, 2022 Apr 12]. J 
Antimicrob Chemother. 2022;dkac110. doi:10.1093/jac/dkac110 
28. INVANZ® (ertapenem sodium injection. Prescribing information, Merck Sharpe and Dohme 
LLC. Available from:  


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https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021337s038lbl. pdf   
29. Teppler H, Gesser RM, Friedland IR, et al. Safety and tolerability of ertapenem. J 
Antimicrob Chemother. 2004;53 Suppl 2:ii75-ii81. doi:10.1093/jac/dkh209 
30. Bhatia A, Chugh R, Friedland D. Zidebactam Phase 1 Single Ascending Dose and Crossover 
Study in Healthy Subjects. Poster 2236,  ID Week, 26th – 30th October, New Orleans, LA, 
USA., 2016. 
31. Chugh R, Lakdavala F, Friedland D, Bhatia A. Safety and pharmacokinetics of multiple 
ascending doses of WCK 5107 (Zidebactam) and WCK 5222 (Cefepime and zidebactam). 
Poster 1301, 27th European Congress of Clinical Microbiology and Infectious Diseases 
(ECCMID), April 22nd - 25th, Vienna, 2017. 
32. Rodvold KA, Gotfried MH, Chugh R, et al. Plasma and Intrapulmonary Concentrations of 
Cefepime and Zidebactam following Intravenous Administration of WCK 5222 to Healthy 
Adult Subjects. Antimicrob Agents Chemother. 2018;62(8):e00682-18. 
doi:10.1128/AAC.00682-18 
33. Preston RA, Mamikonyan G, DeGraff S, et al. Single-Center Evaluation of the 
Pharmacokinetics of WCK 5222 (Cefepime-Zidebactam Combination) in Subjects with 
Renal Impairment. Antimicrob Agents Chemother. 2018;63(1):e01484-18. 
doi:10.1128/AAC.01484-18. 
34. Investigator’s Brochure, WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)], Edition: 7.0, 11 
November 2022, Wockhardt 
35. Majumdar AK, Musson DG, Birk KL, et al. Pharmacokinetics of ertapenem in healthy 
young volunteers. Antimicrob Agents Chemother. 2002;46(11):3506-3511. 
doi:10.1128/AAC.46.11.3506-3511.2002 
36. Ambrose PG, Bhavnani SM, Ellis-Grosse EJ, Drusano GL. Pharmacokinetic-
pharmacodynamic considerations in the design of hospital-acquired or ventilator-associated 
bacterial pneumonia studies: look before you leap! Clin Infect Dis. 2010;51 Suppl 1:S103-
S110. doi:10.1086/653057 
37. Ertapenem Sodium (ertapenem injection). Prescribing information, Dr. Reddy's 
Laboratories, Inc. Available from: 
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=32d9f095-ca39-7e22-6264-
b54f2daaee57 
 


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18 
APPENDICES


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APPENDIX A: SCHEDULE OF STUDY PROCEDURES AND EVALUATIONS 
Evaluation (↓) 
Screening 1 
Check-in/ 
Enrollment 
In-patient Treatment 
Out-
patient 
follow-
up 
Unscheduled / 
Early 
Termination 
Visit (V) -> 
1 
2 
 
 
 
 
 
 
 
 
3 
Study Day (D) -> 
-28 to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
11 (+3) 
Informed consent 
X 
Confirmation of eligibility criteria 
X 
X 2 
X 2 
Medical History 
X 
 
 
Demographics 
X 
 
 
Height, Weight and BMI 3  
X 
Weight 
 
X 2 
 
X 
MH update 
X 2 
X 2 
 
 
 
 
 
 
 
 
 
Prior and Concomitant medications 4 
X 
X 
X 4 
X 4 X 4 
X 4 X 4 
X 4 
X 4 X 4 
X 4 
X 4 
Physical examination (PE) 
X 
X 
X 
X 
X 
Symptom directed (focused) PE 5  
X 
X 
X 
X 
X 
X 
X 
Vital signs 6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 7 
X 
X 
X 
X 
X 
Clinical Laboratory testing (HEM, CHEM, and 
COAG) 8 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 9 
X 
X 
 
X 
 
X 
X 
X 
Viral serology 10 
X 
Serum HCG pregnancy test (all females) and FSH 
(post-menopausal females only) 11 
X 
 
Urine pregnancy test (all females) 11 
 
X 
Urine drug screen 12 
X 
X 
Urine alcohol test 
X 
X 
Urine cotinine test 
X 
X 
Admission of eligible subjects /Assignment to 
treatment cohort / Randomization 13 
X 
 
 
 
 
 
 
 
 
 
 
Study drug administration 14 
X 
X
X 
X
X 
X
X 
 
 
 
Assessment of adverse events 15 
X 
X
X 
X
X 
X
X 
X 
X 
X 
Assessment of infusion and blood drawing sites 16 
X
X
X
X
X
X
X
X
X 
X
Plasma PK 17 
X 17 
X 17 X 17 
X 17 
X 17 
X 17 
X 17 
X 17 
 
X 18 
Urine PK 19 
X 19 
 
X 19 
Discharge from in-patient site 
 
 
   X 
Final visit / Discharge from study 
 
 
     X 
Counseling 
X 
X 
X
X 
X 
X 
X 
X 
X
X 
X 
X 
 
1. Screening evaluations must be completed within 28 days prior to administration of study drug(s). 
2. Confirmation of eligibility for admission and enrollment and randomization on Day -1, and for dosing on Day 1 after completion of all baseline procedures before study intervention  
• Baselines are: Complete PE, weight, Clinical labs and ECG on Day-1; VS (within 30 min before dosing on Day 1), MH and Prior Medications updates, and Focused PE (as needed for new 
symptoms) predose on Day 1 
3. BMI ≥18-32 kg/m2 and Weight ≥ 100 lbs (At Screening). Weight also measured on Day 8.   
4. Concomitant medications include any new medications taken only after initiation of first dose on Day 1. 
5. Symptoms directed (focused) PE for evaluation of new symptoms prior to dosing on Day 1, and for evaluation of TEAEs after dosing on Day 1 to the end of the study, or ET  
6. Vital Signs: collected after 5 minutes of resting in supine position and include SBP, DBP, HR and T (oral measurement). Recorded at Screening, Day -1, Days 1 to 7 (within 30 min prior to 
dosing, at the end of infusion (+10 min) and 1 hour (±5 min) after the end of infusion), Day 8, and Day 11 (+3), or ET.  
7. 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). 
8. Clinical Laboratory testing for Hematology (HEM: Hemoglobin, hematocrit, RBC, WBC with WBC differential count, and platelet count), Clinical Chemistry (CHEM: sodium, potassium, chloride, 
bicarbonate, BUN, creatinine, estimated CLCR (by the Cockcroft-Gault method), calcium, glucose, albumin, total protein, total bilirubin, direct bilirubin, ALT, AST, ALP and LDH) and Coagulation 
(COAG: PT and AP). – Lab values on Day -1 are considered baseline. 
9. Urinalysis: Dipstick urinalysis, including protein, glucose, ketones, bilirubin, occult blood, nitrite, leukocyte esterase, specific gravity, and pH. If dipstick UA is abnormal for blood, protein, glucose 
and leukocyte esterase, a microscopic UA will be done (for WBC, RBC, bacteria, and other cell counts), and results will supersede those of the dipstick UA. Lab values on Day -1 are considered 
baseline. 
10. Viral serology: HIV antibody, HBsAg, HCV antibody 
11. Serum pregnancy at Screening and Urine pregnancy test on Day-1 from all females; FSH at Screening only from post-menopausal females. 
12. Urine drug screen panel for: amphetamines, barbiturates, benzodiazepines, cocaine metabolites, cannabinoids (THC), opiates, phencyclidine, and tri-cyclic antidepressants – At Screening and Day -1  
13. Assignment to dosing cohort and randomization: Must occur after all inclusion and exclusion criteria have been confirmed on Day -1 and subject was admitted to the in-patient site.  
14. Study drug or placebo administered IV according to cohort and randomization assignment. Withhold solid food at least 4 h before starting the infusion and 1 h after completion of infusion. Oral 
liquids are allowed.   
15. Monitoring for treatment-emergent AEs and SAEs will begin upon initiation of the first dose of study product(s) and continue until the last visit, or ET. 
16. Assess and replace IV catheters no more frequently than every 72 to 96 h or as clinically indicated. 
 
  


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17. Plasma PK collection times:   
DAY 1 and DAY 7:  
o 
  For the 30 min infusion (Cohort 1): Predose (within 30 min; t=0) and at 0.25 h (±5 min), 0.5 h (±5 min) (immediately at end of infusion), 1 h (±5 min), 2 h (±5 min), 3 (±10 min),                  
4 h (±10 min), 8 h (±15 min), 12 h (±15 min), 18 (±15 min) and 24 h (±30 min) after start of infusion 
o 
For the 60 min infusion (Cohorts 2, 3 and 4): Predose (within 30 min; t=0) and at 0.5 h (±5 min), 1 h (±5 min) (immediately at end of infusion), 2 h (±5 min), 3 h (±10 min), 4 h (±10 min),  
8 h (±15 min), 12 h (±15 min), 18 h (±15 min) and 24 h (±30 min) after start of infusion 
o 
For the 120 min infusion (Cohorts 5, 6 and 7): Predose (within 30 min; t=0) and at 1 h (±5 min), 2 h (±5 min) (immediately end of infusion), 3 h (±10 min), 4 h (±10 min), 8 h (±15 min),   
12 h (±15 min), 18 (±15 min) and 24 (±30 min) after start of infusion 
DAY 2 to DAY 6:  
o 
Predose (within 30 min) and 12 (±5 min) h after start of infusion. 
18. Unscheduled visit – plasma PK collection is optional 
19. Urine PK collection times 
DAY 1 and DAY 7:  
o 
Before the start of infusion (within 60 min), and at the following intervals after the start of the infusion: 0 to 4 h (±10 min), 4 to 8 h (±15 min), 8 to 12 h (±15 min), and 12 to 24 h (±30 min),   


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APPENDIX B: ADVERSE EVENTS TOXICITY GRADING CRITERIA 
ABBREVIATIONS: Abbreviations utilized in the Tables: 
ADL = Activities of Daily Living 
 
CTU = Clinical Trial Unit 
ULN = Upper Limit of Normal 
IV    = Intravenous 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables, use the scale below to 
estimate grade of severity: 
GRADE 1 
Mild 
Events require minimal or no treatment; do not interfere with the 
subject’s daily activities.  
GRADE 2 
Moderate 
Events result in a low level of inconvenience or concern with 
therapeutic measures; may cause some interference with 
functioning.  
GRADE 3 
Severe 
Events interrupt a subject’s usual daily activity and may require 
systemic drug therapy or other treatment; are usually 
incapacitating.  
SERIOUS OR LIFE-THREATENING AEs 
Clinical events considered to be serious or life-threatening include, but are not limited to 
seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular coagulation, diffuse 
petechiae, paralysis, acute psychosis, and severe depression. 
COMMENTS REGARDING THE USE OF THESE TABLES 
• Standardized and commonly used toxicity tables (Division of AIDS, National Cancer 
Institute [NCI] Common Toxicity Criteria [CTC], and World Health Organization 
[WHO]) have been adapted for use by the Division of Microbiology and Infectious 
Diseases (DMID) and modified to better meet the needs of subjects in DMID trials. 
• For parameters not included in the following Toxicity Tables, the CTU will refer to the 
“Guide for Estimating Severity Grade” located above. 
• Criteria are generally grouped by body system. 
Some protocols may have additional protocol specific grading criteria, which will supersede 
the use of these tables for specified criteria. 
 


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Note 1:   No recent hot or cold beverages or smoking. A protocol should select either 0C or 0F for inclusion. 
Note 2:  Assume awake and in supine position for 5 min at rest. Abnormal HR and BP on first measurement due to a 
technical (procedural) error may be repeated twice more with the subject resting between measurements for 
at least 5 min (See Section 8.1.6 Vital Signs). 
Note 3:   Exceptions to screening BP and HR reference range are: 
(a) Subjects with baseline HR ≥ 45 to 50 bpm may be accepted if otherwise healthy adults with known history 
of asymptomatic bradycardia. 
(b) Subjects with baseline SBP up to 140 mmHg and DBP up to 90 mmHg may be accepted if otherwise 
healthy.  
Note 4:   Isolated/individual abnormalities of VS would not be considered toward halting criteria. Abnormalities of 
VS will be described as “increased X” or “decreased X” (X = HR, BP, RR, temperature) if asymptomatic, 
transient and not associated with a systemic or organ-specific disorder and coded by MedDRA within the 
System Organ Class (SOC) “Investigations.” These abnormalities will be graded per criteria in this table, 
but not considered in determining whether study stopping criteria have been met. On the other hand, 
abnormalities of VS that are either secondary to systemic or organ-specific clinical syndrome or primary 
disorders will be coded in the appropriate SOC (e.g., “cardiac disorders”, “respiratory disorders”, 
“immunological disorders”, etc.). These abnormalities will be considered in determining whether stopping 
criteria have been met. 
 
 
 
 
 
 
Table 2 Toxicity Grading Tables – CLINICAL AEs 
Clinical AEs 
Reference range 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
VITAL SIGNS 1 
Fever - °C 
Fever - °F 
36.1 - 37.2 1 
97.0 - 99.0 1 
37.3 - 38.4 
 99.1 - 101.1 
38.5 - 38.9 
101.2 - 102.0 
>38.9 
>102.0 
Tachycardia - bpm 
50 - 100 2,3,4,5 
101 - 115 
116 - 130 
>130 or ventricular 
dysrhythmias 
Bradycardia – bpm 
45 - 49 
40 - 44 
<40 
Hypertension (systolic) 
- mmHg 
130/89 2,3,4,5 
131 - 150 
151 - 160 
>160 
Hypertension (diastolic) 
- mmHg 
90 - 95 
96 - 100 
>100 
Hypotension (systolic) - 
mmHg 
85 - 88 
80 - 84 
 <80 
Tachypnea – breaths 
per min 
10 - 20 2,3,4,5 
21 - 25 
26 - 30 
>30 


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Table 2 Toxicity Grading Tables – CLINICAL AEs 
Clinical AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
CARDIOVASCULAR DISORDERS 
Arrhythmia (except 
Sinus tachycardia) 
 
Asymptomatic or transient 
signs; no medical intervention 
required. 
Recurrent and/or persistent signs; 
symptomatic medical intervention 
required. 
Hemorrhage 
Estimated blood loss 
<100 mL. 
Estimated blood loss >100 mL; 
no transfusion required. 
Blood transfusion required. 
RESPIRATORY DISORDERS 
Cough  
Transient cough; no treatment 
required. 
Persistent cough; treatment 
required. 
Interferes with daily activities. 
Bronchospasm, Acute 
Transient bronchospasm; no 
treatment required; FEV1 71-
80% of predicted peak flow. 
Requires treatment; 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 usual and social 
activities OR requires treatment. 
EAR AND LABYRINTH DISORDERS  
Tinnitus 
Mild symptoms: intervention 
not indicated. 
Moderate symptoms; limiting 
instrumental ADL. 
Severe symptoms; limiting self-
care ADL. 
Vertigo  
Mild symptoms. 
Moderate symptoms; limiting 
instrumental ADL. 
Severe symptoms; limiting self-
care ADL. 
GASTROINTESTINAL DISORDERS 
Nausea  
No interference with normal 
activity. 
Some interference with normal 
activity. 
Prevents daily activities. 
Vomiting  
No interference with activity 
OR 1-2 episodes in a 24-h 
period. 
Some interference with activity 
OR >2 episodes in a 24-h 
period. 
Prevents daily activity OR 
requires medical intervention. 
Diarrhea  
2-3 loose OR watery stools in 
a 24-h period. 
4-5 loose OR watery stools in a 
24-h period. 
6 or more loose or watery stools 
in a 24-h period OR requires IV 
hydration OR requires medical 
intervention. 
Oral Discomfort / 
Dysphagia 
Mild discomfort; no difficulty 
swallowing. 
Some limits on eating 
/drinking. 
Eating/talking very limited; 
unable to swallow solid foods. 
NEUROLOGICAL DISORDERS 
Dizziness 
Mild unsteadiness or 
sensation of movement 
Moderate unsteadiness or 
sensation of movement; 
limiting instrumental activities 
of daily life (ADL) 
Severe unsteadiness or 
sensation of movement; 
limiting self-care ADL; medical 
intervention required 
Headache  
Mild pain; No interference 
with activity. 
Moderate pain; repeated use of 
non-narcotic pain reliever for 
more than 24 h OR some 
interference with activity. 
Significant pain; any use of 
narcotic pain reliever OR prevents 
daily activity OR requires 
triptans. 


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Table 2 Toxicity Grading Tables – CLINICAL AEs 
Clinical AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Hypersomnia 
Mild increased need for sleep 
Moderate increased need for 
sleep 
Severe increased need for sleep 
including excessive daytime 
sleepiness 
Seizure 
Brief partial seizure and no 
loss of consciousness 
Brief generalized seizure 
New onset seizures (partial or 
generalized); multiple seizures 
despite medical intervention 
Somnolence 
Mild but more than usual 
drowsiness or sleepiness 
Moderate sedation; limiting 
instrumental ADL 
Obtundation or stupor 
Syncope 
- 
- 
Fainting; orthostatic collapse 
Tremor 
Mild symptoms 
Moderate symptoms; limiting 
instrumental ADL 
Severe symptoms; limiting self-
care 
Other 
Asymptomatic or mild 
symptoms; clinical or 
diagnostic observations only; 
intervention not indicated 
Moderate; minimal, local or 
noninvasive intervention 
indicated, limiting age-
appropriate instrumental ADL 
Severe or medically significant 
but not immediately life 
threatening; hospitalization or 
prolongation of existing 
hospitalization indicated;  
limiting self-care 
PSYCHIATRIC DISORDERS 
Altered Mental Status: Includes agitation, confusion, disorientation, decreased mental acuity, changed mental status, 
somnolence, stupor 
Agitation 
Mild mood alteration 
Moderate mood alteration 
Severe agitation; hospitalization 
not indicated 
Confusion 
Mild disorientation 
Moderate disorientation; 
limiting instrumental ADL 
Severe disorientation; limiting 
self-care 
Insomnia 
Mild difficulty falling asleep, 
staying asleep or waking up 
early 
Moderate difficulty falling 
asleep, staying asleep or 
waking up early 
Severe difficulty in falling asleep, 
staying asleep or waking up early; 
medical intervention required 
Psychiatric disorders - 
Other, specify 
Asymptomatic or mild 
symptoms; clinical or 
diagnostic observations only; 
intervention not indicated 
Moderate; minimal, local or 
noninvasive intervention 
indicated; limiting age-
appropriate instrumental ADL 
Severe or medically significant 
but not immediately life-
threatening; limiting self-care; 
psychiatric intervention required 
LOCAL IV CATHETER REACTION 
IV site reaction 
Not applicable. 
Erythema with associated 
symptoms (e.g., edema, pain, 
induration, phlebitis). 
Ulceration or necrosis; severe 
tissue damage; operative 
intervention indicated. 


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Table 2 Toxicity Grading Tables – CLINICAL AEs 
Clinical AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
SYSTEMIC REACTIONS 
Anaphylaxis ** 
-- 
-- 
Symptomatic bronchospasm, with 
or without urticaria; parenteral 
intervention indicated; allergy-
related edema or angioedema; 
hypotension. 
**Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of histamine and histamine-
like substances from mast cells, causing a hypersensitivity immune response. Clinically, it presents with breathing difficulty, 
dizziness, hypotension, cyanosis, and loss of consciousness, and may lead to death. 
Allergic Reaction  
Pruritus without rash. 
Localized urticaria OR requires 
oral therapy. 
Generalized urticaria OR 
angioedema OR anaphylaxis OR 
requires epinephrine 
Hypersensitivity 
(including drug fever) 
Transient flushing or rash; 
temperature 38.0 – 38.4°C 
(100.4 – 101.1°F). 
Rash; flushing; urticaria; 
dyspnea; temperature 38.5 – 
38.9°C (101.2 – 102.0°F). 
Symptomatic bronchospasm 
with or without urticaria; 
parenteral medication indicated; 
allergy-related edema or 
angioedema; hypotension; 
temperature >38.9°C (>102.0°F).  
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. 
SKIN 
Mucocutaneous 
Erythema, pruritus. 
Diffuse, maculo-papular rash, 
dry desquamation. 
Vesiculation OR moist 
desquamation OR ulceration. 
Pruritus 
No or minimal interference 
with usual social and 
functional activities.  
Greater than minimal 
interference with usual social 
and functional activities.  
Inability to perform usual social 
and functional daily activities. 
ALL OTHER CONDITIONS 
Illness or clinical AE 
(as defined according 
to applicable 
regulations) 
Require minimal or no 
treatment; does not interfere 
with the subject’s daily 
activities. 
Result in a low level of 
inconvenience or concern with 
therapeutic measures; may 
cause some interference with 
functioning. 
Interrupt a subject’s usual daily 
activity and may require systemic 
drug therapy or other treatment; 
are usually incapacitating. 
 
 
 


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Table 3 Toxicity Grading Tables – LABORATORY AEs 
Laboratory AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Blood, serum, or plasma * 
HEMATOLOGY 
Hemoglobin decrease,  
Female, 18Y – g/dL 
9.5 – 11.4 
7.9 – 9.4 
<7.9 
Hemoglobin decrease,  
Female, >18Y – g/dL 
9.7 – 11.6 
8.1 – 9.6 
<8.1 
Hemoglobin decrease,  
Male, 18Y – g/dL 
10.0 – 11.9 
8.0 – 9.9 
<8.0 
Hemoglobin decrease,  
Male, >18Y – g/dL 
11.2 – 13.1 
9.2 – 11.1 
<9.2 
WBC increase  
18Y – x103/ µL 
13.1 – 15.0 
15.1 – 20.0 
>20.0 
WBC increase  
>18Y – x103/ µL 
10.9 – 15.0 
15.1 – 20.0 
>20.0 
WBC decrease 
18Y – x103/ µL 
3.0 – 4.4 
1.5 – 2.9 
<1.5 
WBC decrease 
>18Y – x103/ µL  
2.3 – 3.7 
1.1 – 2.2 
<1.1 
Neutrophils decrease  
18Y – cells/ µL 
1,200 – 1,799 
750 – 1,199 
<750  
Neutrophils decrease  
>18Y – cells/ µL 
1,000 – 1,499 
750 – 999 
<750  
Lymphocytes decrease  
18Y– cells/ µL 
850 – 1,199 
400 – 849 
<400 
Lymphocytes decrease  
>18Y – cells/ µL 
500 - 849 
300 - 499 
<300 
Monocytes increase –  
18Y – cells/ µL 
901 – 2,000 
2,001 – 3,000 
>3,000 
Monocytes increase  
>18Y – cells/ µL 
951 – 2,000 
2,001 – 3,000 
>3,000 
Eosinophils increase  
>6Y– cells/ µL 
501 – 750 
751 – 1,000 
>1,000 
Basophils increase  
>6Y– cells/ µL 
201 – 500 
501 – 800 
>800 
Platelets decrease – x103/ µL 
90 – <140 
55 – <90 
<55 
COAGULATION 
PT INR 
>1.1 – 1.8 
>1.8 – 2.1 
>2.1 
Prothrombin Time - sec 
>11.5 – 15.0 
>15.0 – 18.6 
>18.6 
Activated Partial Thromboplastin Time 
(APTT) - sec 
>32 – 54 
>54 – 75 
>75 
CHEMISTRY 
Sodium decrease – mmol/L 
130 - 134 
124 –129 
<124 
Sodium increase – mmol/L 
147 - 150 
 151 – 156 
>156 
Potassium increase, 
19Y - mmol;/L 
5.2 – 6.0 
6.1 – 6.5 
>6.5 
Potassium increase,  
5.4 – 6.0 
6.1 – 6.5 
>6.5 


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Table 3 Toxicity Grading Tables – LABORATORY AEs 
Laboratory AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
>19Y - mmol/L 
Potassium decrease,  
19Y – mmol/L 
3.2 – 3.7 
2.6 – 3.1 
<2.6 
Potassium decrease,   
>19Y - mmol/L 
3.0 – 3.4  
2.5 – 2.9 
<2.5 
Carbon dioxide increase – mmol/L 
33 – 36 
37 – 40 
>40 
Carbon dioxide decrease – mmol/L 
17 – 19 
14 – 16 
<14 
Calcium increase,  
Male,  4 -19Y – mg/dL   
10.5 – 11.2 
11.3 – 12.3 
>12.3 
Calcium increase,  
Male, 20 - 49Y – mg/dL 
10.4 – 11.4 
11.5 – 12.5 
>12.5 
Calcium increase,  
Female, 4 -19Y – mg/dL 
10.5 – 11.4 
11.5 – 12.5 
>12.5 
Calcium increase,  
Female 20 - 49Y – mg/dL 
10.3 – 11.4 
11.5 – 12.5 
>12.5 
Calcium decrease,  
Male, 4 -19Y – mg/dL 
8.1 – 8.8 
7.3 – 8.0 
<7.3 
Calcium decrease,  
Male, 20 - 49Y – mg/dL 
8.1 – 8.5 
7.3 – 8.0 
<7.3 
Calcium decrease,  
Female, 4 -19Y – mg/dL 
8.1 – 8.8 
7.3 – 8.0 
<7.3 
Calcium decrease, 
Female, 20-49Y – mg/dL 
8.1 – 8.5 
7.3 – 8.0 
<7.3 
Blood urea nitrogen (BUN) increase,  
19Y - mg/dL 
21 – 58 
59 – 120 
>120 
Blood urea nitrogen (BUN) increase, 
>19Y- mg/dL  
26 – 58 
59 – 120 
>120 
Glucose decrease, fasting – mg/dL 
47 – 64 
40 – 46 
<40 
Glucose increase, fasting – mg/dL 
100 – 160 
161 – 250 
>250 
Glucose increase, non-fasting – mg/dL 
140 – 200 
201 – 250 
>250 
Creatinine increase,  
Male, 18 - 29Y – mg/dL 
1.25 – 1.62 
1.63 – 2.24 
>2.24 
Creatinine increase,  
Male, 30 – 39 Y – mg/dL 
1.27 – 1.64 
1.65 – 2.27 
>2.27 
Creatinine increase,  
Male, 40 - 49Y – mg/dL 
1.30 – 1.68 
1.69 – 2.32 
>2.32 
Creatinine increase,  
Female, 18 - 29Y – mg/dL 
0.97 – 1.25  
1.26 – 1.73 
>1.73 
Creatinine increase,  
Female, 30 - 39Y – mg/dL 
0.98 – 1.26 
1.27 – 1.75 
>1.75 
Creatinine increase,  
Female, 40 - 49Y – mg/dL 
1.00 – 1.29 
1.30 – 1.78 
>1.78 
Direct bilirubin 
0.3 – 0.6 
0.7 – 1.2 
>1.2 
Total bilirubin (serum) increase 
(with other LFTs in the normal range), 
19Y – mg/dL 
1.2 – 1.7 
1.8 – 2.5 
>2.5 
Total bilirubin (serum) increase  
1.3 – 1.8 
1.9 – 2.6 
>2.6 


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Table 3 Toxicity Grading Tables – LABORATORY AEs 
Laboratory AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
(with other LFTs in the normal range), 
>19Y – mg/dL 
Total bilirubin (serum) increase 
(accompanied by a >3 x ULN increase 
in ALT or AST), 19Y – mg/dL 
1.2 – 2.0 
2.1 – 2.8 
>2.8 
Total bilirubin (serum) increase  
(accompanied by a >3 x ULN increase 
in ALT or AST), >19Y – mg/dL 
1.3 – 2.1 
2.2 – 3.0 
>3.0 
Total protein decrease, 
19Y – g/dL 
5.3 – 6.2 
4.5 – 5.2 
<4.5 
Total protein decrease, 
>19Y – g/dL 
5.1 – 6.0 
4.3 – 5.0 
<4.3 
Albumin, decrease - g/dL 
3.0 – 3.5 
2.0– 2.9 
<2.0 
AST increase,  
19Y – U/L 
33 – 64 
65 – 96 
>96 
AST increase,  
20-49Y – U/L 
41 – 80 
81 – 120 
>120 
ALT increase,   
Male, 19Y – U/L 
47 – 92 
93 – 138 
>138 
ALT increase,   
Male, >19Y – U/L 
47 – 92 
93 – 138 
>138 
ALT increase,   
Female, 19Y – U/L 
33 – 64 
65 – 96 
>96 
ALT increase,   
Female, >19Y – U/L 
30 – 58 
59 – 87 
>87 
Alkaline phosphatase (AP) increase, 
Male, 19Y – U/L 
170 – 338 
339 – 507 
>507 
Alkaline phosphatase (AP) increase,  
Male, ≤49Y – U/L 
131 – 260 
261 – 345 
>345 
Alkaline phosphatase (AP) increase,   
Female, 19Y – U/L 
129 – 256 
257 – 384 
>384 
Alkaline phosphatase (AP) increase,   
Female, ≤49Y – U/L 
126 – 250 
251 – 375 
>375 
Urine  
URINALYSIS by Dipstick 
Protein 
1+ 
2+ 
>2+ 
Blood (occult) 
1+ 
2+ 
>2+ 
Glucose 
1+ 
2+ 
>2+ 
Leukocyte esterase 
1+ 
2+ 
>2+ 
URINE MICROSCOPY 
Red blood cells (RBC) per HPF 
3 – 10 
11 – 40 
>40 and/or gross blood 
WBC (microscopic) – WBC per HPF 
6 – 10 
11 – 40 
>40 and/or symptomatic 
urogenital infection 
Bacteria (microscopic) 
few 
moderate 
many 


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Note 1:  With the exception of AST, ALT, AP, total and direct  bilirubin, BUN, creatinine, CLCR (by the Cockcroft-Gault method), 
and urine protein, which should be within reference range, lab values of other analytes in the grade 1 range are 
acceptable for enrollment if (a) they are not considered to be clinically significant by the investigator and (b) there is no 
cluster of abnormal labs that combined are suggestive of an underlying disorder. 
Note 2: Other Exceptions to screening laboratory tests’ normal reference ranges are: 
a. Racially based low total WBC or neutrophil counts up to toxicity Grade 1 are allowed, but toxicity Grades 2 or 3 are 
exclusionary. 
b. Labs performed as part of a panel but not listed above are to be recorded in the database. If abnormal, they are not 
exclusionary and are not to be graded per Toxicity table, however, the investigator would make a clinical decision about 
their clinical significance and, if clinically significant, they will be graded according to the criteria in Section 9.2.1. 
(Examples include mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular 
hemoglobin concentration (MCHC), red cell distribution width (RDW), mean platelet volume (MPV), and nucleated red 
blood cell count (NRBC CT), which are included in a CBC with differential.)  
Note 3:  If a subject was accepted into the trial with a laboratory value of an analyte that overlaps with values used for grading 
Grade 1 laboratory abnormalities, a TEAE will be reported if the on-study value of the same analyte increases in 
severity to Grade 2 or higher compared to the baseline. 
Note 4: If the dipstick UA is abnormal for blood, protein, glucose and leukocyte esterase, a microscopic UA will be performed, 
and the results will supersede the results of the dipstick UA. 
Note 5: Menstruating females with a positive dipstick UA or microscopic UA may be retested following cessation of menses. 
Gross blood in urine that is confirmed due to menses is not a TEAE (but is for all other reasons. 
Note 6: Isolated laboratory values that are outside the range of eligibility but are thought to be due to an acute condition or due 
to collection or laboratory error may be repeated once. 
Note 7: For the microscopic UA, Lab-reported ranges 3 -10 for RBC and 6-10 for WBC would be Grade 1; 10-20 and 20-40 for 
both RBC and WBC would be Grade 2; and > 40 for both RBC and WBC would be Grade 3. 
 
 
 


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Table 4 Toxicity Grading Tables – ECG 
ECG interval 
abnormality  
Reference 
range 
Grade 1 
Grade 2 
Grade 3 
QTcF interval 
prolonged (msec): 
• 
Male 
• 
Female 
 
 
• 
≤450 msec 
• 
≤470 msec 
Asymptomatic,  
QTcF  
• 
451 - 479 msec 
• 
471 - 479 msec 
Asymptomatic,  
QTcF 480-500 msec  
OR  
increase in interval 30-59 
msec above baseline 
Asymptomatic,  
QTcF >500 msec  
OR 
increase in interval 
≥60 msec above baseline 
PR interval 
prolonged (msec) 
≤ 210 msec 
211-250 msec 
>250 msec 
Type II 2nd degree AV 
block  
OR  
ventricular pause >3.0 sec 
 
Note 1: Events will be coded as treatment-emergent SAEs if there are life-threatening associated symptoms or signs (arrhythmia, 
CHF, hypotension, syncope, TdP, etc.). 
Note 2: If a male subject was accepted into the trial with a QTcF value that overlaps with values used for grading Grade 1 QTcF 
prolongation, a TEAE will be reported if the QTcF value is higher than the baseline value. 


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APPENDIX C: BLOOD VOLUME WITHDRAWN DURING THE TRIAL 
Table 5: Laboratory Samples and Estimated Total Blood Volume (mL) 
Study Periods 
Out-
patient 
In-
patient  
In-patient Dosing Period (Days 1 – 7) 
 
Out-
patient 
 
Study Visit 
Screen 
Check-
in 
Dosing 
Dis-
charge 
Follow-
up 
ET 
Study Day a 
-28 to -2 
-1 
1 
2  
3  
4  
5  
6 
7 
8 
11 (+3 
days) 
HEMATOLOGY 1 
4 
4 
 
4 
 
4 
 
4 
 
4 
4 
4 
COAGULATION 1 
2.7 
2.7 
 
2.7 
 
2.7 
 
2.7 
 
2.7 
2.7 
2.7 
CHEMISTRY 1  
8.5 
8.5 
 
8.5 
 
8.5 
 
8.5 
 
8.5 
8.5 
8.5 
Serum β-HCG and FSH 1 
0 
 
 
 
 
 
 
 
 
 
 
 
Viral Serology (HIV, HBsAg, HCV) 3 
8.5 
 
 
 
 
 
 
 
 
 
 
 
PK 4 
 
 
100 
20 
20 
20 
20 
20 
100 
10 
 
10 
Total volume/visit 
23.7 
15.2 
100 
35.2 
20 
35.2 
20 
35.2 
100 
25.2 
15.2 
31.2 
Cumulative total volume 
23.7 
38.9 
138.9 
174.1 
194.1 
229.3 
249.3 
284.5 
384.5 
409.7 
424.9 
 
a Study Days shown correspond to days in each study period. For a view of the cumulative numbering of study days, please refer to Section 7. 
 
1 Clinical Safety blood tests (HEM, CHEM, COAG) are drawn at Screening Visit, on Day -1, pre-dose on Days 2, 4, and 6, on Days 8 and 11 (+ 3 days), or ET. The test includes 
serum β-HCG and FSH. 
2 Serum pregnancy test (β-HCG) in all women at Screening. FSH at Screening only in post-menopausal women. 
3 Viral serology tests are drawn at Screening. 
4 PK plasma samples are drawn on: 
Day 1 and Day 7: Before and at 7- 9 other timepoints after the start of infusion, depending on duration of infusion (See Appendix A and Section 8.3.1); Day 2 to Day 8: (daily, 
24 h after starting the infusion on the previous day, Day 1 to Day 7); Day 2 to Day 6 (daily, 12 h after the dose), or ET if occurs within 24 h of dosing.