A Multicenter, Randomized, Double-Blind, Comparative, Phase 3 Study to Evaluate the Efficacy and Safety of Intravenous Imipenem/Cilastatin/XNW4107 in Comparison With Imipenem/Cilastatin/Relebactam in Adults With Hospital-Acquired Bacterial Pneumonia or Ventilator-Associated Bacterial Pneumonia (EudraCT no. 2022-000081-18) (EUCTR no. 2022-501952-27-00) (IND no. 146614)
Phase: PHASE3
Conditions: Hospital Acquired Bacterial Pneumonia or Ventilator-Associated Bacterial Pneumonia
Sponsor: Evopoint Biosciences Inc.



 
 
 
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SPONSOR APPROVAL 
I have read the following and approve it: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
                      
 
 
 
 
 
 
  
 
 

 
 
 
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INVESTIGATOR AGREEMENT 
I have read the following protocol and agree to conduct the study as described herein. 
 
 
 
 
 
 
 
[Name, Qualification(s)] 
 
Date 
Principal investigator 

 
 
 
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SYNOPSIS 
Title of study: A Multicenter, Randomized, Double-Blind, Comparative, Phase 3 Study to Evaluate 
the Efficacy and Safety of Intravenous Imipenem/Cilastatin-XNW4107 in Comparison with 
Imipenem/Cilastatin/Relebactam in Adults with Hospital -Acquired Bacterial Pneumonia or 
Ventilator -Associated Bacterial Pneumonia 
Indication: Hospital-acquired bacterial pneumonia (HABP), including ventilated HABP (vHABP) and 
ventilator-associated bacterial pneumonia (VABP) caused by Gram-negative bacteria. 
Number of investigators and study centers: 
 
 
 
 
  
Development phase: Phase 3 
Objectives: 
Primary objective 
To evaluate the all-cause mortality rate through Day 14 
 
 
  
 
 
 
 
  
 
 
 group in the Modified Intent-to-Treat (MITT) population. 
Secondary objectives 
The secondary objectives of this study are: 
Efficacy 
• 
To evaluate the all-cause mortality rate through Day 28 
 
 
  
 
 
 
  
 
 
 in the MITT population 
• 
To evaluate the all-cause mortality rate through Day 14 and through Day 28 
 
 
  
 
 
 
  
 
 
 in the Microbiologic MITT 
(micro-MITT), extended micro-MITT, clinically evaluable (CE), microbiologically evaluable 
(ME) and Carbapenem-resistant MITT (CR-MITT) populations 
• 
To evaluate the clinical outcome of 
 
  
  
 , End of 
Treatment (EOT), Test-of-Cure (TOC), and Late Follow-up (LFU) visits in the MITT, micro-
MITT, extended micro-MITT, CE, ME, and CR-MITT populations 
• 
To evaluate the microbiological outcome of 
 
  
 at EOT, TOC, 
and LFU visits in the micro-MITT, extended micro-MITT, ME, and CR-MITT populations 
• 
To evaluate the by-pathogen microbiological outcome of 
 
  
 at 
EOT, TOC, and LFU visits in the micro-MITT, extended micro-MITT, ME, and CR-MITT 
populations 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
Safety 
To evaluate the safety and tolerability of 
 
 
 
 
 
 

 
 
 
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 in subjects with HABP or VABP in the Safety population (SAF). 
Pharmacokinetics 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
Exploratory objective 
Healthcare Utilization 
To determine the healthcare utilization 
  
 
 
  
 
 
 
  
 
 
 in the MITT population. 
Methodology/study design: 
This study is a prospective, multicenter, double-blind, randomized, active-controlled study to evaluate 
the efficacy, safety, and tolerability of IMI-XNW4107 in comparison with IMI/REL in the treatment of 
subjects with HABP/VABP caused by Gram-negative bacteria. 
Approximately 
 subjects with a clinical diagnosis of HABP/VABP who meet all eligibility criteria, 
and assessed by the investigator as requiring 7 to 14 days of IV antibiotic treatment in the hospital will 
be randomized.  
Randomization will be stratified by type of infection (non-ventilated HABP vs. ventilated 
HABP/VABP), Acute Physiology and Chronic Health Evaluation II (APACHE II) score (<15 vs. ≥15), 
and country/region (China vs. Rest of World). 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
Subjects will be randomly assigned to study treatment in a double blind- manner   
 
 via an 
Interactive Web/Voice Response System to receive either imipenem 500 mg/cilastatin 
500 mg-XNW4107 250 mg (N=300) infused IV as a 30-minute infusion (±5 minutes) every 6 hours 
±30 minutes (q6h ±30 minutes) or IMI/REL 1.25 g IV (imipenem 500 mg/cilastatin 500 mg/relebactam 
250 mg) (
) infused IV as a 30-minute infusion (±5 minutes) q6h (±30 minutes) for a 
recommended treatment duration of 7 to 14 days (judged by the investigator). Dose adjustments will be 
required for subjects with abnormal renal function. 
Concomitant treatment with optional linezolid as judged by the investigator can be given to subjects in 
both arms to provide coverage for methicillin-resistant Staphylococcus aureus (MRSA) as per the local 
standard of care. The treatment duration for MRSA will be determined by the investigator. The 
recommended treatment duration for a confirmed MRSA infection is a minimum of 7 days, with a 
minimum of 14 days for MRSA bacteremia. Empiric linezolid treatment will be stopped if the final 
culture results from the baseline lower respiratory tract sample do not demonstrate the presence of 
MRSA. For subjects in whom linezolid cannot be used, IV vancomycin may be used.  
In addition to all-cause mortality (survival) through Day 14 (primary endpoint) and through Day 28, 
assessments of clinical and microbiological outcomes will be performed at Day 4 (clinical outcome 
only), EOT (the last day of study treatment [+1 day]), TOC (Day 21 [±2 days]), and a LFU visit (Day 
28 [±3 days]). 
An independent Data Monitoring Committee (DMC) will be employed to oversee the progress of this 
study and to ensure the ongoing safety of subjects participating in this study. The DMC will regularly 
review the safety data of enrolled subjects. The DMC can only recommend stopping the study early 
based on safety findings. No early stopping for efficacy is planned. Details describing the DMC process 
and procedures, and the timing and frequency of meetings will be outlined in a separate DMC Charter. 

 
 
 
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An independent Data Review Committee (DRC), which will be separated from the DMC, will be 
employed to perform the sample size re-estimation. 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
Number of subjects: 
It is anticipated that approximately 
 
 will be enrolled and randomized into the study in  
 
 
 
  
 
 
 
 
 
  
 
 
 
Diagnosis and main criteria for inclusion and exclusion: 
Subjects must meet the following inclusion criteria to be eligible for the study: 
1. Subjects willing and able to provide written informed consent or where consent is provided by 
legally authorized representatives. 
2. Willing and able to comply with all study assessments and adhere to the protocol schedule. 
3. Male or female subjects ≥18 years on the day of signing informed consent. 
4. Has HABP or VABP as defined below and requires treatment with IV antibiotic therapy. 
NOTE: HABP is defined as the onset of acute bacterial pneumonia symptoms at least 48 hours 
after hospitalization or within 7 days after discharge from an inpatient acute or chronic care 
facility (e.g., long-term care, rehabilitation center, hospital, or skilled nursing home). 
Subjects may experience acute respiratory failure and require mechanical ventilation for HABP 
(vHABP). 
VABP is defined as acute bacterial pneumonia in a subject receiving mechanical ventilation via 
an endotracheal (or nasotracheal) tube or tracheostomy for ≥48 hours. 
5. All subjects must fulfill at least 1 of the following clinical criteria at screening: 
a. New onset or worsening of pulmonary symptoms or signs, such as cough, dyspnea, 
tachypnea (e.g., respiratory rate >25 breaths/minute), expectorated sputum production, 
or requirement for mechanical ventilation 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
c. Need for acute changes in the ventilator support system to enhance oxygenation, as 
determined by worsening oxygenation (ABG or PaO2/FiO2) or needed changes in the 
amount of positive end-expiratory pressure 
d. New onset of or increase in (characteristics or quantity) suctioned respiratory 
secretions, 
 
 
 
 
 
 
 
 
6. All subjects must have at least 1 of the following signs and symptoms/laboratory abnormalities 
at screening: 
a. Documented fever (i.e., 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
b. Hypothermia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c. Leukocytosis with a total peripheral white blood cell (WBC) count ≥10,000 cells/mm3 

 
 
 
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d. Leukopenia with total peripheral WBC count <4500 cells/mm3 
e. Greater than 15% immature neutrophils (bands) noted on peripheral blood smear. 
7. All subjects must have a chest radiograph during screening or have a previous chest radiograph 
within 48 hours prior to randomization showing the presence of new or progressive infiltrate(s) 
suggestive of bacterial pneumonia. A computed tomography scan in the same time window 
showing the same findings could also be acceptable. 
8. All subjects must have a suspected Gram-negative infection involving the lower respiratory 
tract by  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9. Agree to allow any bacterial isolates obtained from protocol-required specimens related to the 
current infection to be provided to the Central Microbiology Reference Laboratory for 
study-related microbiological testing, long-term storage, and other future testing. 
10. Female subjects of childbearing potential, who are willing to use a highly effective method of 
birth control during the study and for at least 30 days following the last dose of study 
medication. 
a. Childbearing potential is defined as any female who has experienced menarche and 
does not meet the criteria for postmenopausal, which is defined as the past 12 months 
with no menses without an alternative medical cause or permanently sterilized (e.g., 
has undergone bilateral tubal occlusion/ligation, hysterectomy, bilateral oophorectomy, 
bilateral salpingectomy) 
b. A highly effective method of birth control is defined as one that results in a low failure 
rate (i.e., <1% per year) when used consistently and correctly, such as implants, 
injectables, combined oral contraceptives, intrauterine devices, sexual abstinence, or a 
vasectomized partner (see also Section 6.2). 
11. Male subjects with female sexual partners of childbearing potential are eligible for inclusion if 
they agree to use medically acceptable birth control for 90 days following the last dose of study 
medication. Sexual abstinence, vasectomy, or a condom used with a spermicide are medically 
acceptable birth control methods for males. Male subjects must agree not to donate sperm for a 
period of 90 days after the last dose of study treatment. 
Subjects who meet any of the following exclusion criteria are not eligible to participate in the study: 
1. If a Gram stain from a respiratory sample is available and shows only Gram-positive cocci. 
2. Subjects who have known or suspected community-acquired bacterial pneumonia, atypical 

 
 
 
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pneumonia, viral pneumonia including Coronavirus disease (COVID-19), or chemical 
pneumonia (including aspiration of gastric contents, inhalation injury). 
3. Subjects who have HABP/VABP caused by an obstructive process, including lung cancer (or 
other malignancy metastatic to the lungs resulting in pulmonary obstruction) or other known 
obstruction. 
4. Have received effective systemic and inhaled Gram-negative antibacterial drug therapy for the 
index infection of HABP/VABP for a continuous duration of more than 24 hours during the 
previous 72 hours prior to randomization. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
5. Has a concurrent condition or infection that, in the investigator's judgment, would preclude 
evaluation of therapeutic response (e.g., active tuberculosis, cystic fibrosis, granulomatous 
disease, a disseminated fungal infection, invasive fungal pulmonary infection, or endocarditis).  
6. Subjects who have central nervous system infection (e.g., meningitis, brain abscess, shunt 
infection). 
7. Documented presence of immunodeficiency or an immunocompromised condition including 
hematologic malignancy, bone marrow transplant, known history of human immunodeficiency 
virus infection with a CD4 count <200/mm3, or requiring frequent or prolonged use of systemic 
corticosteroids (≥20 mg of prednisone/day or equivalent for >4 weeks) or other 
immunosuppressive drugs (e.g., for organ transplantation or autoimmune conditions). 
8. Documented hypersensitivity to any carbapenem antibacterial agent or documented severe 
hypersensitivity to any other type of β-lactam antibacterial agent, or previous severe 
adverse drug reaction to any β-lactam antibiotics, or any of the excipients used in the study 
drug formulations. 
9. History of a seizure disorder (requiring ongoing treatment with anti-convulsive therapy or prior 
treatment with anti-convulsive therapy within the last 3 years). 
10. Renal function at screening as estimated glomerular filtration rate (eGFR) <15 mL/min or ＞
250 mL/min, calculated as individual eGFR derived from Modification of Diet in Renal 
Disease formula. 
11. Subject is receiving hemodialysis or peritoneal dialysis or micro-dialysis or continuous 
venovenous hemofiltration or continuous venovenous hemodialysis.  
12. Subject is anticipated to be treated with any of the following medications during the course of 
study therapy: 
a. Valproic acid or divalproex sodium (or has used valproic acid or divalproex sodium in 
the 2 weeks prior to screening) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
b. Concomitant systemic (IV or oral) Gram-negative antibacterial agents in addition to 
those designated in the study treatment groups 
c. Concomitant systemic (IV or oral) antifungal or antiviral therapy for the index 

 
 
 
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infection of HABP/VABP. 
13. Life expectancy is <3 days. 
14. Subjects in refractory septic shock, defined as persistent hypotension despite adequate fluid 
resuscitation and vasopressive therapy at the time of randomization. 
15. Subjects with 1 or more of the following laboratory abnormalities in baseline specimens: 
aspartate aminotransferase, alanine aminotransferase >3 × the upper limit of normal (ULN), 
total bilirubin level >2 × ULN (except for isolated hyperbilirubinemia due to known Gilbert’s 
disease), neutrophils <500 cells/mm3, platelet count <40,000/mm3. 
16. History of active liver disease or cirrhosis. 
17. Subjects with an APACHE II score of >30. 
18. A female who is pregnant or breastfeeding or has a positive pregnancy test at screening. 
19. Subject is participating in any clinical study of any investigational medication (i.e., non-
licensed medication) during the 30 days prior to randomization. COVID-19 vaccines that are 
given under emergency use authorization are not considered investigational agents. 
20. Any other condition or prior therapy, which, in the opinion of the investigator, would make the 
subject unsuitable for this study. 
Test products, dose, and mode of administration: 
All study drugs will be administered in a double-blind manner. The test and the comparator drugs will 
be provided by the sponsor to the site. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Reference therapy, dose, and mode of administration: 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Blinding: 
All study personnel and subjects will be blinded to the treatment assignment with the exception of the 
specific personnel as described in Section 5.10 and in a separate Maintaining Study Blind and 
Unblinding Plan. 
Duration of subject participation in the study: 
Planned screening duration: up to 24 hours 
Planned treatment duration: 7 to 14 calendar days 
Planned follow-up duration: 14 to 21 calendar days 
Total duration of study participation: up to 32 calendar days. 

 
 
 
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Study populations: 
Intent-to-Treat (ITT) population: All subjects who are randomized. Subjects are analyzed according 
to the randomized treatment, regardless of the treatment actually received.  
Safety population (SAF): All subjects who receive at least 1 dose of study drug during the study. 
Subjects are analyzed according to the treatment received during the study. 
Modified Intent-to-Treat (MITT) population: The MITT population will serve as the primary 
population for efficacy analyses in this study. The MITT population is defined as all subjects from the 
ITT who receive at least 1 dose of study drug. 
Microbiologic Modified Intent-to-Treat (micro-MITT) population: The micro-MITT population is 
defined as all subjects from the MITT who have a Gram-negative pathogen identified at baseline and 
the pathogen is susceptible to the investigational medicinal product and comparator. 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic (PK) population: All subjects from the SAF with at least 1 reportable concentration 
of XNW4107, imipenem, or cilastatin.  
Evaluation: Efficacy  
Primary efficacy endpoint: 
The primary endpoint is the Day 14 all-cause mortality rate in the MITT population. 
Secondary efficacy endpoints: 
The secondary endpoints for this study are the following: 
• 
Day 28 all-cause mortality rate in the MITT population 
• 
Day 14 and Day 28 all-cause mortality rate in the micro-MITT, extended micro-MITT, CE, ME, 
and CR-MITT populations 
• 
The proportion of subjects with clinical success as evaluated by the investigator at Day 4, EOT, 
TOC, and LFU visits in the MITT, micro-MITT, extended micro-MITT, CE, ME, and CR-MITT 
populations 
• 
The proportion of subjects with microbiological success at EOT, TOC, and LFU visits in the 
micro-MITT, extended micro-MITT, CR-MITT, and ME populations 

 
 
 
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Evaluation: Safety 
The safety and tolerability endpoints will be evaluated by the following measures in the SAF: 
• 
Incidence of all adverse events (AEs), treatment-emergent AEs (TEAEs), including serious AEs 

 
 
 
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(SAEs) 
• 
12-lead electrocardiogram (ECG) 
• 
Vital sign measurements including body temperature, blood pressure, heart rate, and respiratory 
rate 
• 
Clinical laboratory tests including serum chemistry, hematology, urinalysis, and coagulation 
Physical examination findings. 
Evaluation: Pharmacokinetics 
Blood samples for quantification of XNW4107, imipenem, and cilastatin concentration levels will be 
collected on Day 4 (+2 days) at pre-dose, 5 to 25 minutes, and 2 to 3 hours after completion of one of 
that day’s 30-minute IV infusions for descriptive summary and plotting of XNW4107, imipenem, and 
cilastatin plasma concentrations. 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
General Considerations for Data Analyses 
Complete details of the statistical analyses, methods, and data conventions will be described in the 
statistical analysis plan. Statistical analysis will be performed using SAS System, version 9.4 or higher 
(SAS Institute, Inc., Cary, NC).  
Efficacy Analysis 
Estimand for the Primary Endpoint 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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• 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
. 
Primary Efficacy Analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
In order to determine whether IMI-XNW4107 is non-inferior to IMI/REL in subjects with 
HABP/VABP, a non-inferiority margin of 10% will be used. 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
  
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 . 
Secondary Efficacy Analysis 
The secondary efficacy endpoint, the all-cause mortality rate through Day 28 will be analyzed for the 
MITT population using the same method described for the primary analysis.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
Exploratory Analysis 
For exploratory analysis, descriptive statistics will be provided for total number of days spent in the 

 
 
 
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hospital/ in the ICU/ on mechanical ventilation from time of randomization for the MITT population. 
Number of days on mechanical ventilation will be analyzed in the subgroup of ventilated subjects. 
Safety and Tolerability Analysis 
Safety and tolerability will be evaluated by presenting summaries of TEAEs, routine clinical laboratory 
evaluations, ECGs, vital signs, and physical examination findings for each treatment group and overall. 
All safety and tolerability analyses will be performed using the SAF. 
All analyses of safety and tolerability endpoints will be descriptive only, and no inferential statistics 
will be provided. 
PK Analysis 
Concentration-time data for XNW4107, imipenem, and cilastatin will be analyzed and summarized by 
analyte using descriptive statistics (number of subjects, arithmetic mean, geometric mean, median, 
standard deviation, minimum, maximum, and coefficient of variation) at each scheduled collection time 
interval. Concentration-time data will be displayed graphically on the linear and semi-logarithmic 
scales. 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 

 
 
 
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TABLE OF CONTENTS 
SPONSOR APPROVAL .................................................................................................................................2 
INVESTIGATOR AGREEMENT ..................................................................................................................3 
SYNOPSIS ......................................................................................................................................................4 
TABLE OF CONTENTS .............................................................................................................................. 16 
LIST OF TABLES AND FIGURES ............................................................................................................. 19 
LIST OF ABBREVIATIONS ........................................................................................................................ 20 
1. 
INTRODUCTION ........................................................................................................................ 23 
1.1. 
Study Rationale ......................................................................................................................... 23 
1.2. 
Background ................................................................................................................................ 23 
1.2.1. 
Disease Information ................................................................................................................... 23 
1.2.2. 
XNW4107 for Injection ............................................................................................................. 24 
1.2.3. 
Non-Clinical Experience ........................................................................................................... 24 
1.2.4. 
Clinical Experience .................................................................................................................... 29 
1.3. 
Benefit-Risk Assessment ........................................................................................................... 33 
2. 
OBJECTIVES AND ENDPOINTS .............................................................................................. 35 
2.1. 
Objectives .................................................................................................................................. 35 
2.1.1. 
Primary Objective ...................................................................................................................... 35 
2.1.2. 
Secondary Objectives ................................................................................................................ 35 
2.1.3. 
Exploratory Objective ................................................................................................................ 36 
2.2. 
Endpoints ................................................................................................................................... 36 
2.2.1. 
Primary Efficacy Endpoint ........................................................................................................ 36 
2.2.2. 
Secondary Efficacy Endpoints ................................................................................................... 36 
2.2.3. 
Secondary Safety Endpoints ...................................................................................................... 36 
2.2.4. 
Pharmacokinetic Endpoint ......................................................................................................... 37 
2.2.5. 
Exploratory Endpoints ............................................................................................................... 37 
3. 
INVESTIGATION PLAN ............................................................................................................ 38 
3.1. 
Overall Study Design and Plan Description .............................................................................. 38 
3.2. 
Discussion of Study Design, Including the Choice of Control Groups ..................................... 40 
3.3. 
End of Study Definition ............................................................................................................. 41 
3.4. 
Selection of Doses in the Study ................................................................................................. 41 
4. 
SELECTION OF STUDY POPULATION .................................................................................. 44 
4.1. 
Inclusion Criteria ....................................................................................................................... 44 
4.2. 
Exclusion Criteria ...................................................................................................................... 45 
4.3. 
Discontinuation Criteria ............................................................................................................ 47 
4.3.1. 
Screen Failures .......................................................................................................................... 47 
4.3.2. 
Subject Discontinuation ............................................................................................................. 47 
4.3.3. 
Lost to Follow-up ...................................................................................................................... 49 
4.4. 
Study Termination ..................................................................................................................... 49 
5. 
STUDY TREATMENTS ............................................................................................................. 50 
5.1. 
Treatments Administered........................................................................................................... 50 
5.2. 
Investigational Medicinal Product (XNW4107 in Combination with Imipenem/Cilastatin) ..... 50 
5.2.1. 
Identity of XNW4107 for Injection ........................................................................................... 50 
5.2.2. 
Imipenem/Cilastatin Pharmaceutical Form ............................................................................... 50 
5.2.3. 
Preparation of Infusion .............................................................................................................. 51 
5.2.4. 
Administration of Infusion ........................................................................................................ 51 
5.3. 
Imipenem/Cilastatin/Relebactam ............................................................................................... 51 
5.3.1. 
Pharmaceutical Form ................................................................................................................. 51 
5.3.2. 
Administration of Infusion ........................................................................................................ 51 
5.4. 
Packaging and Labeling ............................................................................................................. 52 
5.5. 
Storage and Stability .................................................................................................................. 52 
5.6. 
Study Treatment Accountability, Reconciliation, and Return ................................................... 53 
5.7. 
Study Treatment Handling and Disposal ................................................................................... 53 
5.8. 
Method of Treatment Assignment ............................................................................................. 53 
5.9. 
Dose Modifications.................................................................................................................... 54 

 
 
 
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5.9.1. 
Imipenem/Cilastatin-XNW4107 ................................................................................................ 54 
5.9.2. 
Imipenem/Cilastatin/Relebactam ............................................................................................... 55 
5.10. 
Blinding ..................................................................................................................................... 55 
5.11. 
Treatment Compliance .............................................................................................................. 57 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ............................................. 58 
6.1. 
Prior and Concomitant Therapy ................................................................................................. 58 
6.1.1. 
Non-Antibiotic Concomitant Medications ................................................................................. 58 
6.1.2. 
Antibiotics Concomitant Medications ....................................................................................... 59 
6.1.3. 
Procedures and Surgeries ........................................................................................................... 60 
6.2. 
Contraception ............................................................................................................................ 60 
7. 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................ 61 
7.1. 
Screening Procedures ................................................................................................................ 61 
7.2. 
Treatment Period (Day 1 to Day 14) ......................................................................................... 62 
7.2.1. 
Randomization (Day 1) ............................................................................................................. 62 
7.2.2. 
Day 2 to Day 3 ........................................................................................................................... 63 
7.2.3. 
Day 4 ......................................................................................................................................... 64 
7.2.4. 
Day 5 to Day 14 ......................................................................................................................... 65 
7.3. 
End of Treatment, Test-of-Cure, and Late Follow-Up Assessments ......................................... 66 
7.4. 
Unscheduled Assessments ......................................................................................................... 67 
7.5. 
Efficacy Assessments ................................................................................................................ 67 
7.5.1. 
Assessment of HABP/VABP Signs and Symptoms .................................................................. 67 
7.5.2. 
Chest Imaging ............................................................................................................................ 68 
7.5.3. 
APACHE II Score ..................................................................................................................... 68 
7.5.4. 
SOFA Score ............................................................................................................................... 69 
7.5.5. 
GCS Score ................................................................................................................................. 69 
7.5.6. 
Microbiological Assessments .................................................................................................... 69 
7.5.7. 
Investigator Assessment of Clinical Outcome ........................................................................... 70 
7.5.8. 
Assessment of Microbiological Outcome .................................................................................. 71 
7.5.9. 
Assessment of Overall Outcome ............................................................................................... 72 
7.5.10. 
Survival...................................................................................................................................... 73 
7.6. 
Safety and Tolerability Assessments ......................................................................................... 73 
7.6.1. 
Adverse Events .......................................................................................................................... 73 
7.6.2. 
Clinical Laboratory Evaluations ................................................................................................ 82 
7.6.3. 
Vital Signs, Physical Examination, and Other Safety Evaluations ............................................ 83 
7.7. 
Pharmacokinetic Analysis ......................................................................................................... 84 
8. 
SAMPLE SIZE AND DATA ANALYSES ................................................................................. 85 
8.1. 
Determination of Sample Size ................................................................................................... 85 
8.2. 
Analysis Populations ................................................................................................................. 85 
8.3. 
General Considerations for Data Analyses ................................................................................ 86 
8.4. 
Demographic and Baseline Characteristics ............................................................................... 86 
8.5. 
Medical History and Prior/Concomitant Medications ............................................................... 86 
8.6. 
Efficacy Analysis ....................................................................................................................... 86 
8.6.1. 
Primary Efficacy Analysis ......................................................................................................... 86 
8.6.2. 
Secondary Efficacy Analysis ..................................................................................................... 87 
8.6.3. 
Exploratory Efficacy Analysis ................................................................................................... 88 
8.7. 
Safety and Tolerability Analysis ............................................................................................... 89 
8.7.1. 
Adverse Events .......................................................................................................................... 89 
8.7.2. 
Clinical Laboratory Evaluations ................................................................................................ 89 
8.7.3. 
Vital Signs ................................................................................................................................. 89 
8.7.4. 
Physical Examination ................................................................................................................ 90 
8.7.5. 
12-Lead Electrocardiogram ....................................................................................................... 90 
8.8. 
Pharmacokinetic Analysis ......................................................................................................... 90 
8.9. 
Data Monitoring Committee ...................................................................................................... 90 
8.10. 
Data Review Committee ............................................................................................................ 90 
9. 
REFERENCES ............................................................................................................................. 92 
10. 
APPENDIX .................................................................................................................................. 94 

 
 
 
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APPENDIX 1 – CLINICAL LABORATORY EVALUATIONS ................................................................. 94 
APPENDIX 2 - APACHE II SCORE ............................................................................................................ 96 
APPENDIX 3 – SEQUENTIAL ORGAN FAILURE ASSESSMENT SCORE ......................................... 100 
APPENDIX 4 – GLASGOW COMA SCALE ............................................................................................ 101 
APPENDIX 5 – REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ......... 102 
APPENDIX 6 – SCHEDULE OF ASSESSMENTS ................................................................................... 107 
APPENDIX 7- MAIN STUDY MEDICAL REPRESENTATIVE ............................................................. 111 
 
 
 

 
 
 
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LIST OF TABLES AND FIGURES 
Table 1: Summary of XNW4107 Dosing in Phase 1 Clinical Studies ......................................................................... 30 
Table 2: Recommended Dosage of IMI-XNW4107, Given as 30(±5) -Minute Infusion, q6h (±30 minutes) ............. 54 
Table 3: Recommended IMI/REL Dosage Given as 30 (±5) - Minute Infusion, q6h (±30 minutes) to Adult Subjects 
with Normal Renal Function and Renal Impairment ................................................................................................... 55 
Table 4: List of Unblinded Parties to Support the Study Conduct ............................................................................... 56 
Table 5: list of clinical laboratory analytes .................................................................................................................. 95 
Table 6: The APACHE II Severity of Disease Classification System ......................................................................... 97 
Table 7： Sequential Organ Failure Assessment Score ............................................................................................ 100 
Table 8：Glasgow Coma Scale ................................................................................................................................. 101 
Table 9: Schedule of Assessments ............................................................................................................................. 107 
Table 10: Main study medical representative ............................................................................................................ 111 
 
Figure 1: 
Study Design ........................................................................................................................................... 39 
 

 
 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
β-hCG  
beta-human chorionic gonadotropin 
ABG 
arterial blood gas 
AE 
adverse event 
ALT 
alanine transaminase 
AM 
alveolar macrophage 
AmpC 
ampicillin C 
APACHE 
Acute Physiology and Chronic Health Evaluation 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC0-6h 
area under the plasma concentration-time curve from time 0 
to 6 hours post-dose 
AUC0-24h 
area under the plasma concentration-time curve from time 0 
to 24 hours post-dose 
AUC0-inf 
area under the plasma concentration-time curve from time 0 
to infinity 
AUCss 
area under the concentration-time curve at steady state 
BAL 
bronchoalveolar lavage 
BID 
twice daily 
BP 
blood pressure 
BSA 
body surface area 
CE 
Clinically Evaluable 
CFR 
Code of Federal Regulations 
CFU 
colony forming unit 
CI 
confidence interval 
CL 
clearance 
CLR 
renal clearance 
CLSI 
Clinical and Laboratory Standards Institute 
Cmax 
maximum concentration  
Cmax,ss 
maximum concentration at steady state 
CNS 
central nervous system 
COVID-19 
coronavirus disease 
CRAB 
Carbapenem-resistant Acinetobacter baumannii 
CRE 
Carbapenem-resistant Enterobacterales 
CR-MITT 
Carbapenem-resistant MITT 
CRPA 
Carbapenem-resistant Pseudomonas aeruginosa 
CSA 
clinical study agreement 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTX-M 
Cefotaximase-Munich 
CYP 
cytochrome P450 
DMC 
Data Monitoring Committee 
DRC 
Data Review Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtrate rate 
ELF 
epithelial lining fluid 

 
 
 
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Abbreviation 
Definition 
EOS 
end of study 
EOT 
end of treatment 
ESBL 
extended-spectrum beta-lactamase 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
FiO2 
fraction of inspired oxygen 
GCP 
Good Clinical Practice 
GCS 
Glasgow Coma Scale 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HABP 
hospital-acquired bacterial pneumonia 
hERG 
human ether-à-go-go-related gene 
HR 
heart rate 
HSR 
human-simulated regimen 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICU 
intensive care unit 
IEC 
independent ethics committee  
IMI/REL 
imipenem/cilastatin/relebactam 
IMP 
investigational medicinal product 
IRB 
institutional review board 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
IV 
Intravenous(ly) 
IXRS 
Interactive Web/Voice Response System 
KPC 
Klebsiella pneumoniae carbapenemase 
LFU 
Late Follow-up 
MATE 
multi-drug and toxin extrusion 
MDR 
multi-drug resistance 
MDRD 
Modification of Diet in Renal Disease 
ME 
Microbiologically Evaluable 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
minimum inhibitory concentration 
micro-MITT 
Microbiologic Modified Intent-to-Treat 
MITT 
Modified Intent-To-Treat 
NMPA 
National Medical Products Adminstration 
MRSA 
methicillin-resistant Staphylococcus aureus 
NOAEL 
no observable adverse effect level 
OATP 
organic anion transporting polypeptide 
OCT 
organic cation transporter 
OXA 
oxacillinase 
PaO2 
partial pressure of oxygen 
PBS 
protected brush specimen 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PopPK 
population pharmacokinetic(s) 
PT 
preferred term 
PTA 
PK/PD target attainment 

 
 
 
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Abbreviation 
Definition 
q6h 
every 6 hours 
RBC 
red blood cell 
RI 
renal impairment 
RR 
respiratory rate 
SAE 
serious adverse event 
SAF 
Safety population 
SBECD 
sulfobutyl-ether-β-cyclodextrin 
SmPC 
Summary of Product Characteristics 
SOC 
System Organ Class 
SOFA 
Sequential Organ Failure Assessment 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
half-life 
TEAE 
treatment-emergent adverse event 
TOC 
Test-of-Cure 
ULN 
upper limit of normal 
VABP 
ventilator-associated bacterial pneumonia 
Vss 
apparent volume of distribution at steady state 
WBC 
white blood cell 
 

 
 
 
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1. INTRODUCTION 
1.1. 
Study Rationale 
Evopoint Biosciences USA, Inc. (hereafter referred as Evopoint), formerly known as Sinovent 
Pharmaceuticals, Inc. (Sinovent), intends to develop XNW4107, a novel β-lactamase inhibitor, in 
combination with imipenem/cilastatin, a β-lactam antibiotic, for intravenous (IV) administration 
to combat severe Gram-negative bacterial infections. This combination of imipenem/cilastatin and 
XNW4107 (from hereon will be referred to as IMI-XNW4107, or investigational medicinal 
product [IMP]) is being developed for subjects 18 years of age and older for the following 
indications in their clinical development program: complicated urinary tract infection including 
acute pyelonephritis, hospital-acquired bacterial pneumonia/ventilator-associated bacterial 
pneumonia (HABP/VABP) which represent diseases with an alarming increase in the incidence of 
β-lactamase-producing organisms. 
This strategy of combining a β-lactam antibiotic and β-lactamase inhibitor for the treatment of 
infections caused by β-lactamases-producing pathogens has been successful in the treatment of a 
variety of bacterial infections. Gram-negative pathogens, including those producing 
extended-spectrum β-lactamases (ESBLs) and carbapenemases, are important causes of 
nosocomial infections. The combination of IMI-XNW4107 is potentially capable of providing an 
effective therapy covering the pathogens commonly responsible for HABP/VABP. 
This is a Phase 3 study to evaluate the efficacy and safety of IMI-XNW4107 with the intention to 
demonstrate that IMI-XNW4107 is non-inferior to imipenem/cilastatin/relebactam (referred to as 
IMI/REL) in the treatment of adult subjects diagnosed with HABP/VABP. 
1.2. 
Background 
1.2.1. 
Disease Information 
HABP/VABP by definition occurs in hospitalized subjects with a hospital stay of 48 hours or more. 
According to the FDA Guidance for Industry in 2020 (FDA, 2020), clinical signs and symptoms 
of HABP include fever or hypothermia, chills, rigors, cough, purulent sputum production, chest 
pain, or dyspnea, accompanied by the presence of a new or progressive infiltrate on a chest 
radiograph in a subject hospitalized for more than 48 hours or developing within 7 days after 
discharge from a hospital. Clinical signs and symptoms of VABP include fever or hypothermia, 
chills, rigors, purulent respiratory secretions, and increased oxygen requirements accompanied by 
the presence of a new or progressive infiltrate on a chest radiograph in a subject receiving 
mechanical ventilation via an endotracheal (or nasotracheal) tube for a minimum of 48 hours. 
Gram-negative bacilli, including Enterobacteriaceae, Pseudomonas aeruginosa (P. aeruginosa), 
and Acinetobacter baumannii (A. baumannii) are among the most common etiologic pathogens for 
HABP/VABP (Jones RN, 2010; Sader HS, 2014), and treatment with HABP/VABP are 
complicated by the increasing prevalence of ESBL-producing pathogens.  
Multi-drug resistance (MDR) in HABP/VABP infections, particularly carbapenem resistance, has 
been an increasing global concern, since carbapenems are often the last resort of antibacterial drugs 
for serious infections caused by multi-drug resistant Gram-negative organisms. 

 
 
 
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There is a high unmet medical need for new treatment of nosocomial infections such as 
HABP/VABP. Based on the demonstrated pre-clinical in vitro and in vivo antimicrobial profiles 
of XNW4107 to restore the antimicrobial activity of imipenem-resistant pathogens including 
carbapenem-resistant Enterobacterales (CRE), MDR of P. aeruginosa, and A. baumannii, and the 
safety and pharmacokinetic (PK) data from the Phase 1 studies, XNW4107 in combination with 
imipenem/cilastatin carries broad spectrum of Gram-negative activity for the treatment of subjects 
with HABP/VABP being studied in this trial. 
1.2.2. 
XNW4107 for Injection 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XNW4107 is being developed to restore the activity of imipenem in carbapenem-resistant 
Gram-negative bacterial infections. 
Imipenem/cilastatin is a combination of imipenem, a carbapenem antibacterial drug, and cilastatin, 
a renal dehydropeptidase inhibitor that limits the renal metabolism of imipenem. Imipenem was 
approved in the US in 1985 and is approved for several indications, including urinary tract, intra-
abdominal, and lower respiratory tract infections, with well-established records of safety and 
effectiveness for clinical use. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.2.3. 
Non-Clinical Experience 
Data as summarized in the XNW4107 investigator brochure (IB) are provided; for details, refer 
to the XNW4107 IB. 
1.2.3.1. Primary and Secondary Pharmacology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
  
 
 
 
  
 
  
 
 
 
 

 
 
 
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. 
1.2.3.2. Safety Pharmacology 
An in vitro tail current assay in human ether-à-go-go-related gene (hERG)-transfected HEK-293 
cells showed that XNW4107 at 225 µM had a minor inhibitory effect on hERG potassium channel 
currents. The vehicle corrected inhibition of the current at a nominal concentration of 225 µM for 
XNW4107 equaled to 12.0 ±1.4%. The half-maximal inhibitory concentration value was not 
determined and considered to be >225 μM, which is unlikely to be of clinical significance. The 
effects of XNW4107 on the cardiovascular system in conscious telemetered male Beagle dogs 
were also evaluated. A transient decrease in PR interval duration and body temperature were 
observed from 10 minutes to 1 hour and 1 to 4 hours after administration of 200 mg/kg of 
XNW4107 (which is equivalent to 7778 mg in 70 kg humans).  
The respiratory effects of XNW4107 were examined in the conscious male Sprague-Dawley rats 
following the infusion of XNW4107 at 0, 50, 150, or 300 mg/kg dose levels. Based on the results 
evaluated by whole-body plethysmography, ≤300 mg/kg of XNW4107 did not affect any of the 
respiratory parameters (including tidal volume, respiratory rate, and minute volume) when 
compared to baseline values. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 No 
other relevant XNW4107-related effects were noted for any of the parameters evaluated or at any 
dose tested. 
1.2.3.3. Pharmacokinetics and Metabolism 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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 f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 No appreciated accumulation of XNW4107 was observed in any of 
the tested species. Both XNW4107 and imipenem can penetrate into the lungs as demonstrated 
concentration levels at BAL in mice.  
1.2.3.4. Toxicology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 f 

 
 
 
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f 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  

 
 
 
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 f 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 f 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 f 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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. 
1.2.4. 
Clinical Experience 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 :  The data 
provided are as summarized in current investigator’s brochure (IB) (XNW4107 IB); for details, 
refer to the XNW4107 IB. 

 
 
 
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Table 1: 
 
 
 
 
 
  
 
  
 
 
 
 
 
 f 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
   
 
  
 
   
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
  
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
  
 
 
  
 
 
 
  
 
  
 
 
 
  
  
 
  
 
 
  
 
 
 
  
 
1.2.4.1. Summary of Pharmacokinetics and Drug Metabolism 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 

 
 
 
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.  
1.2.4.2. Safety 
The 5 Phase 1 studies conducted in healthy subjects or subjects with RI have demonstrated a good 
safety profile with XNW4107 administered alone or in combination with imipenem/cilastatin as a 
single dose or multiple repeated doses. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 

 
 
 
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1.3. 
Benefit-Risk Assessment 
The study may provide individual and general benefits.  
The population for this study consists of subjects with HABP/VABP with serious infections 
requiring IV antibiotics where limited therapeutics options remain despite the availability of recent 
agents to treat these infections.  
There is a potential benefit to the subjects participating in this study to receive effective 
antibacterial treatment, including infections with resistant Gram-negative pathogens.  
In general, the study has the potential benefit to identify a new antibacterial combination for the 
treatment of HABP/VABP in the face of emerging antibacterial resistance and the need for new 
antibacterial agents.  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
.  
The risks for imipenem/cilastatin are well known and widely available in their respective 
Prescribing Information or Summary of Product Characteristic (SmPC). The most frequently 
occurring adverse reactions (≥0.2%) in adults were phlebitis, nausea, diarrhea, vomiting, rash, pain 
at injection site, fever, hypotension, seizures, erythema at injection site, dizziness, pruritus, vein 
induration, urticaria, and somnolence (Imipenem/Cilastatin [Package Insert], 2022). Serious and 
occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in subjects 
receiving therapy with β-lactams; these reactions are more likely to occur in individuals with a 
history of sensitivity to multiple allergens (Imipenem/Cilastatin [Package Insert], 2022). Seizures 
and other CNS adverse experiences, such as confusional states and myoclonic activity, have been 
reported during treatment with imipenem/cilastatin, especially when recommended dosages were 
exceeded. These experiences have occurred most commonly in subjects with CNS disorders (e.g., 
brain lesions or history of seizures) and/or compromised renal function (Imipenem/Cilastatin 
[Package Insert], 2022). Dosage adjustment is necessary for subjects with RI (Imipenem/Cilastatin 
[Package Insert], 2022). Adult subjects with CLCR ≤20 mL/min, whether or not undergoing 
hemodialysis, had a higher risk of seizure activity than those without impairment of renal function. 
Therefore, close adherence to the dosing guidelines and regular monitoring of CLCR for these 
subjects is recommended. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 

 
 
 
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Imipenem/cilastatin/relebactam is approved for the treatment of Gram-negative infections 
including HAPB/VABP in many countries and has a safety profile consistent with 
imipenem/cilastatin. Detailed information on the safety and risk profile of IMI/REL is provided in 
the Package Insert and SmPC. 
Coronavirus Disease (COVID-19) Pandemic 
The safety monitoring and risk mitigations defined in this study protocol and related study 
documents have taken into consideration the additional potential impacts of the COVID-19 
pandemic if still active during the conduct of this study. 

 
 
 
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2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objective 
To evaluate the all-cause mortality rate through Day 14 
 
 
  
 
 
 
 
 
 
 
 
 the Modified Intent-to-Treat (MITT) 
population. 
2.1.2. 
Secondary Objectives 
The secondary objectives of this study are: 
Efficacy 
• To evaluate the all-cause mortality rate through Day 28 p
 
 
  
 
 
 
  
 
 
 in the MITT population 
• To evaluate the all-cause mortality rate through Day 14 and through Day 28 
 
 
 
 
 
 
 
 
 
 
 
 
in the Microbiologic MITT (micro-MITT) population, extended micro-MITT, clinically 
evaluable (CE), microbiologically evaluable (ME), and Carbapenem-resistant MITT 
(CR-MITT) populations 
• To evaluate the clinical outcome 
 
 
 
 
 at Day 4, End of 
Treatment (EOT), Test-of-Cure (TOC), and Late Follow-up (LFU) visits in the MITT, 
micro-MITT, extended micro-MITT, CE, ME, and CR-MITT populations 
• To evaluate the microbiological outcome 
 
 
 
 
 at EOT, 
TOC, and LFU visits in the micro-MITT, extended micro-MITT, ME, and CR-MITT 
populations 
• To evaluate the by-pathogen microbiological outcome 
 
 
 
 
 at EOT, TOC, and LFU visits in the micro-MITT, extended micro-MITT, ME, and 
CR-MITT populations 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
Safety 
To evaluate the safety and tolerability of I
 
 
 
 
 
 
 
  subjects with HABP or VABP in the Safety population (SAF). 
Pharmacokinetics 

 
 
 
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2.1.3. 
Exploratory Objective 
Healthcare Utilization 
To determine healthcare utilization up to 
 
 
  
 
 group 
compared to the IMI/REL group in the MITT population. 
2.2. 
Endpoints 
2.2.1. 
Primary Efficacy Endpoint 
The primary endpoint is the Day 14 all-cause mortality rate in the MITT population. 
2.2.2. 
Secondary Efficacy Endpoints 
The secondary endpoints for this study are the following: 
• Day 28 all-cause mortality rate in the MITT population 
• Day 14 and Day 28 all-cause mortality rate in the micro-MITT, extended micro-MITT, CE, 
ME, and CR-MITT populations 
• The proportion of subjects with clinical success as evaluated by the investigator at Day 4, 
EOT, TOC, and LFU visits in the MITT, micro-MITT, extended micro-MITT, CE, ME, 
and CR-MITT populations 
• The proportion of subjects with microbiological success at EOT, TOC, and LFU visits in 
the micro-MITT, extended micro-MITT, CR-MITT, and ME populations 
• The proportion of subjects with microbiological success by pathogen at EOT, TOC, and 
LFU visits in the micro-MITT, extended micro-MITT, ME, and CR-MITT populations. 
• The proportion of subjects with overall success at EOT, TOC, and LFU visits in the 
micro-MITT, extended micro-MITT, ME, and CR-MITT populations.  
2.2.3. 
Secondary Safety Endpoints 
The safety and tolerability endpoints will be evaluated by the following measures in the SAF: 
• Incidence of all AEs, TEAEs, including SAEs 
• 12-lead electrocardiogram (ECG) 
• Vital sign measurements including body temperature, blood pressure (BP), heart rate (HR), 
and respiratory rate (RR) 

 
 
 
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• Clinical laboratory tests including serum chemistry, hematology, urinalysis, and 
coagulation 
• Physical examination findings. 
2.2.4. 
Pharmacokinetic Endpoint 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
   
 
 
    
 
 
 f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.2.5. 
Exploratory Endpoints 
Healthcare utilization of subjects assessed at LFU visit as follows: 
• Total number of days spent in hospital post-randomization in the MITT population 
• Total days spent in intensive care unit (ICU) post-randomization in the MITT population 
• Total days spent on mechanical ventilation post-randomization for the subgroup of subjects 
on mechanical ventilation at enrollment (VABP/ventilated HABP) in the MITT population. 

 
 
 
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3. INVESTIGATION PLAN 
3.1. 
Overall Study Design and Plan Description 
This is a prospective, multicenter, double-blind, randomized, active-controlled study to evaluate 
the efficacy, safety, and tolerability of IMI-XNW4107 in comparison with IMI/REL in the 
treatment of adults with HABP/VABP caused by Gram-negative bacteria. 
The study will be conducted at approximately 
 study centers globally. 
Approximately 
 subjects with a clinical diagnosis of HABP/VABP who meet all eligibility 
criteria, and assessed by the investigator as requiring 7 to 14 days of IV antibiotic treatment in the 
hospital will be randomized. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
Subjects will be randomly assigned to study treatment in a double-blind manner in a 
 ratio via 
an Interactive Web/Voice Response System (IXRS) to receive either imipenem 500 mg/cilastatin 
500 mg-XNW4107 250 mg (
) infused IV as a 30-minute infusion (±5 minutes) q6h 
(±30 minutes) or IMI/REL 1.25 g (imipenem 500 mg/cilastatin 500 mg/relebactam 250 mg) 
(
 infused IV as a 30-minute infusion (±5 minutes) q6h (±30 minutes) for a recommended 
treatment duration of 7 to 14 days (judged by the investigator). 
Dose adjustments will be required for subjects with abnormal renal function. 
Concomitant treatment with optional linezolid (600 mg as an IV infusion over 30 to 120 minutes 
every 12 hours) as judged by the investigator can be given to subjects in both arms to provide 
coverage for methicillin-resistant Staphylococcus aureus (MRSA) as per local standard of care. 
The treatment duration of MRSA will be determined by the investigator. The recommended 
treatment duration for a confirmed MRSA infection is a minimum of 7 days, with a minimum of 
14 days for MRSA bacteremia. Empiric linezolid treatment will be stopped if the final culture 
results from the baseline lower respiratory tract sample do not demonstrate the presence of MRSA. 
For subjects in whom linezolid cannot be used, IV vancomycin may be used.  
In addition to all-cause mortality (survival) through Day 14 (primary endpoint) and through 
Day 28, assessments of clinical and microbiological outcomes will be performed at Day 4 (clinical 
outcome only), EOT (the last day of study treatment [+1 day]), TOC (Day 21 [±2 days]), and an 
LFU visit (Day 28 [±3 days]). 
Figure 1 presents an overview of the study design. 

 
 
 
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Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will be employed to oversee the progress of 
this study and to ensure the ongoing safety of subjects participating in this study. The DMC will 
regularly review the safety data of enrolled subjects. The DMC can only recommend stopping the 
study early based on safety findings. No early stopping for efficacy is planned. 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
Data Review Committee 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 f 
 
 
 
 
 
 
 
 
 
 
 
 
 f 
 
 
 
   
 
 
 
3.2. 
Discussion of Study Design, Including the Choice of Control Groups 
Study population: Based on the bacterial etiologic pathogens in HABP and VABP, the spectrum 
of activity of the combination of IMI-XNW4107, and route of administration, the population 
targeted for this trial includes subjects with HABP or VABP. 
Study design: The overall study design and primary endpoint, the all-cause mortality rate through 
Day 14 post-randomization in the MITT population, follows the FDA Guidance for the Industry 
(FDA, 2020), the EMA guideline on the evaluation of medicinal products indicated for the 
treatment of bacterial infections (EMA, 2018), the Chinese technical guidelines for clinical trials 
of antimicrobial drugs for HABP/VABP (CDE, 2020), and similar antibacterial clinical 
development programs for this indication. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
Control group (IMI/REL): Based on the spectrum of β-lactamase inhibition to Ambler class A, C, 
and D, the combination of IMI-XNW4107 is targeting treatment of infections due to 
Gram-negative pathogens, including isolates resistant to carbapenems. IMI/REL has been selected 
as the comparator because of its demonstrated efficacy in subjects with HABP/VABP and due to 

 
 
 
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its microbiological activity against Gram-negative organisms, including carbapenem-resistant 
pathogens; therefore, allowing the enrollment of all HABP/VABP subjects, including infections 
due to carbapenem-resistant pathogens. 
IMI/REL has been approved in many countries due to its demonstrated efficacy and safety. For 
countries in which IMI/REL is not yet approved, the Package Insert and SmPC are provided as 
reference. 
The goal of the Sponsor is to bring additional treatment option to the subjects as quick as possible 
especially for subjects with HABP/VABP that could have A. baumannii with etiologic pathogens 
of up to 25.6% (Yin, 2021), for which the treatment options are limited. 
3.3. 
End of Study Definition 
The end of the study (EOS) is defined as the date of the last visit of the last subject in the study. 
3.4. 
Selection of Doses in the Study 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 

 
 
 
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f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 

 
 
 
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 f 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 

 
 
 
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4. SELECTION OF STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
Subjects ≥18 years of age with a clinical diagnosis of HABP or VABP and requiring treatment 
with IV antibiotic therapy and have a suspected Gram-negative infection involving the lower 
respiratory tract. 
4.1. 
Inclusion Criteria 
Subjects must meet the following inclusion criteria to be eligible for the study: 
1. Subjects willing and able to provide written informed consent or where consent is provided 
by legally authorized representatives. 
2. Willing and able to comply with all study assessments and adhere to the protocol schedule. 
3. Male or female subjects ≥18 years on the day of signing informed consent. 
4. Has HABP or VABP, as defined below and requires treatment with IV antibiotic therapy. 
Note: HABP is defined as the onset of acute bacterial pneumonia symptoms at least 
48 hours after hospitalization or within 7 days after discharge from an inpatient acute or 
chronic care facility (e.g., long-term care, rehabilitation center, hospital, or skilled nursing 
home). Subjects may experience acute respiratory failure and require mechanical 
ventilation for HABP (vHABP). 
VABP is defined as acute bacterial pneumonia in a subject receiving mechanical 
ventilation via an endotracheal (or nasotracheal) tube or tracheostomy for ≥48 hours. 
5. All subjects must fulfill at least 1 of the following clinical criteria at screening: 
a. New onset or worsening of pulmonary symptoms or signs, such as cough, dyspnea, 
tachypnea (e.g., RR >25 breaths/minute), expectorated sputum production, or 
requirement for mechanical ventilation 
b. Hypoxemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 f 
 
 
 
 
  
 
 
 
 
 
 
c. Need for acute changes in the ventilator support system to enhance oxygenation, as 
determined by worsening oxygenation (ABG or PaO2/FiO2) or needed changes in 
the amount of positive end-expiratory pressure 
d. New onset of or increase in (characteristics or quantity) suctioned respiratory 
secretions, 
 
 
 
 
 
 
 
. 
6. All subjects must have at least 1 of the following signs and symptoms/laboratory 
abnormalities at screening: 
a. Documented fever 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
b. Hypothermia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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c. Leukocytosis with a total peripheral white blood cell (WBC) count 
≥10,000 cells/mm3 
d. Leukopenia with total peripheral WBC count <4500 cells/mm3 
e. Greater than 15% immature neutrophils (bands) noted on peripheral blood smear. 
7. All subjects must have a chest radiograph during screening or have a previous chest 
radiograph within 48 hours prior to randomization showing the presence of new or 
progressive infiltrate(s) suggestive of bacterial pneumonia. A computed tomography scan 
in the same time window showing the same findings could also be acceptable. 
 All subjects must have a suspected Gram-negative infection involving the lower respiratory 
tract by  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 f 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 f 
 
 
 
 
 
 
 
 
 
f 
 
 
 
9. Agree to allow any bacterial isolates obtained from protocol-required specimens related to 
the current infection to be provided to the Central Microbiology Reference Laboratory for 
study-related microbiological testing, long-term storage, and other future testing. 
10. Female subjects of childbearing potential, who are willing to use a highly effective method 
of birth control during the study and for at least 30 days following the last dose of study 
medication. 
a. Childbearing potential is defined as any female who has experienced menarche and 
does not meet the criteria for postmenopausal, which is defined as the past 
12 months with no menses without an alternative medical cause or permanently 
sterilized (e.g., has undergone bilateral tubal occlusion/ligation, hysterectomy, 
bilateral oophorectomy, bilateral salpingectomy) 
b. A highly effective method of birth control is defined as one that results in a low 
failure rate (i.e., <1% per year) when used consistently and correctly, such as 
implants, injectables, combined oral contraceptives, intrauterine devices, sexual 
abstinence, or a vasectomized partner (see also Section 6.2). 
11. Male subjects with female sexual partners of childbearing potential are eligible for 
inclusion if they agree to use medically acceptable birth control for 90 days following the 
last dose of study medication. Sexual abstinence, vasectomy, or a condom used with a 
spermicide are medically acceptable birth control methods for males. Male subjects must 
agree not to donate sperm for a period of 90 days after the last dose of study treatment. 
4.2. 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria are not eligible to participate in the study: 

 
 
 
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1. If a Gram stain from a respiratory sample is available and sample shows only Gram-
positive cocci. 
2. Subjects who have known or suspected community-acquired bacterial pneumonia, atypical 
pneumonia, viral pneumonia including COVID-19, or chemical pneumonia (including 
aspiration of gastric contents, inhalation injury). 
3. Subject who has HABP/VABP caused by an obstructive process, including lung cancer (or 
other malignancy metastatic to the lungs resulting in pulmonary obstruction) or other 
known obstruction. 
4. Have received effective systemic and inhaled Gram-negative antibacterial drug therapy for 
the index infection of HABP/VABP for a continuous duration of more than 24 hours during 
the previous 72 hours prior to randomization. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5. Has a concurrent condition or infection that, in the investigator's judgment, would preclude 
evaluation of therapeutic response (e.g., active tuberculosis, cystic fibrosis, granulomatous 
disease, a disseminated fungal infection, invasive fungal pulmonary infection, or 
endocarditis).  
6. Subjects who have central nervous system infection (e.g., meningitis, brain abscess, shunt 
infection). 
7. Documented presence of immunodeficiency or an immunocompromised condition 
including hematologic malignancy, bone marrow transplant, known history of human 
immunodeficiency virus infection  with a CD4 count <200/mm3, or requiring frequent or 
prolonged use of systemic corticosteroids (≥20 mg of prednisone/day or equivalent 
for >4 weeks) or other immunosuppressive drugs (e.g., for organ transplantation or 
autoimmune conditions). 
8. Documented hypersensitivity to any carbapenem antibacterial agent or documented severe 
hypersensitivity to any other type of beta-lactam antibacterial agent, or previous severe 
adverse drug reaction to any β-lactam antibiotics, or any of the excipients used in the study 
drug formulations. 
9. History of a seizure disorder (requiring ongoing treatment with anti-convulsive therapy or 
prior treatment with anti-convulsive therapy within the last 3 years). 
10. Renal function at screening as estimated eGFR <15 mL/min or ＞250 mL/min, calculated 
as individual eGFR derived from Modification of Diet in Renal Disease formula. 
11. Subject is receiving hemodialysis or peritoneal dialysis or micro-dialysis or continuous 
venovenous hemofiltration or continuous venovenous hemodialysis.  
12. Subject is anticipated to be treated with any of the following medications during the course 
of study therapy: 
a. Valproic acid or divalproex sodium (or has used valproic acid or divalproex sodium 
in the 2 weeks prior to screening) 

 
 
 
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b. Concomitant systemic (IV or oral) Gram-negative antibacterial agents in addition 
to those designated in the study treatment groups 
c. Concomitant systemic (IV or oral) antifungal or antiviral therapy for the index 
infection of HABP/VABP. 
13. Life expectancy is <3 days. 
14. Subjects in refractory septic shock, defined as persistent hypotension despite adequate fluid 
resuscitation and vasopressive therapy at the time of randomization. 
15. Subjects with 1 or more of the following laboratory abnormalities in baseline specimens: 
aspartate aminotransferase, alanine aminotransferase >3 × the upper limit of normal (ULN), 
total bilirubin level >2 × ULN (except for isolated hyperbilirubinemia due to known 
Gilbert’s disease), neutrophils <500 cells/mm3, platelet count <40,000/mm3. 
16. History of active liver disease or cirrhosis. 
17. Subjects with an APACHE II score of >30. 
18. A female who is pregnant or breastfeeding or has a positive pregnancy test as screening. 
19. Subject is participating in any clinical study of any investigational medication (i.e., 
non-licensed medication) during the 30 days prior to randomization. COVID-19 vaccines 
that are given under emergency use authorization are not considered investigational agents. 
20. Any other condition or prior therapy, which, in the opinion of the investigator, would make 
the subject unsuitable for this study. 
4.3. 
Discontinuation Criteria 
4.3.1. 
Screen Failures 
Screen failures are defined as subjects from whom consent to participate in the clinical study is 
obtained, but who are not subsequently randomized. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure subjects to meet the Consolidated 
Standards of Reporting Trials publishing requirements and to respond to queries from regulatory 
authorities.  
4.3.2. 
Subject Discontinuation 
The investigator has the right to discontinue a subject from study treatment or withdraw a subject 
from the study. In addition, subjects have the right to voluntarily discontinue study treatment or 
withdraw from the study at any time at his/her request for any reason. 
In instances where a subject discontinues study treatment early, the investigator should strongly 
encourage the subject to continue the study and complete all scheduled visits, including any 
standard of care treatment. The site should continue to obtain vital status at Day 14 and Day 28 
even if the subject withdraws consent. Rescue antibiotics are to be given to the subject as judged 
by the investigator. The discontinuation of study treatment will be registered in the IXRS. 

 
 
 
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Subjects who discontinue study treatment early and complete all scheduled visits will be 
considered study completers. If the subject is unwilling or unable to attend the scheduled site visits 
after hospital discharge, every effort should be made by the investigator (or qualified designee) to 
obtain data for the visits by either telephone, telemedicine, and/or home health visit. 
Reasons for discontinuation of study treatment may include, but are not limited to: 
• Insufficient therapeutic effect of the study drug (i.e., requirement for additional non-study 
antibacterial therapy to treat HABP/VABP based on the investigator’s clinical judgment) 
• AEs requiring discontinuation (e.g., hypersensitivity reactions based on investigator’s 
clinical judgment) 
• Any of the following post-baseline elevations in liver transaminase levels: 
• 
ALT or aspartate aminotransferase (AST) ≥8 × ULN 
• 
ALT or AST ≥3 × ULN, accompanied by total bilirubin >2 × ULN OR 
international normalized ratio >1.5 
• 
ALT or AST ≥3 × ULN, accompanied with signs and symptoms compatible with 
hepatitis. 
• 
 
 
 
 
 
 
 
 
 
 
 
 
• Pregnancy 
• Important protocol deviation (i.e., affecting the subject's safety) as judged by the 
investigator 
• Investigator or sponsor determines it is in the best interest of the subject 
• Subject withdrawal of consent to receive further study treatment. 
Reasons for withdrawal from the study may include, but are not limited to: 
• Subject, or his or her legally authorized representative, withdrawal of consent 
• Subject lost to follow-up 
• Death 
• Study termination by the Sponsor, or investigator decision, or by regulatory authorities. 
In instances where a subject withdraws consent prior to completion of study treatment, the 
investigator should strongly encourage the subject to complete the EOT assessments (see 
Table 9). 

 
 
 
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The primary reason for premature study drug treatment discontinuation and study withdrawal 
should be documented on the medical record and the appropriate electronic case report form 
(eCRF). 
4.3.3. 
Lost to Follow-up 
A subject will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• Every effort should be made for subjects to complete the TOC visit as soon as possible. If 
the TOC visit is missed, but completed before the LFU window, the visit should be assessed 
as the TOC visit. Subjects should be counseled on the importance of maintaining the 
assigned visit schedule as outlined in the Schedule of Assessments (Table 9), and ascertain 
whether or not the subject wishes to and/or should continue in the study 
• In cases in which the subject is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the subject (where possible, 3 telephone calls and, 
if necessary, a certified letter to the subject’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the subject’s medical record 
• Should the subject continue to be unreachable, he/she will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up. 
4.4. 
Study Termination 
The Sponsor reserves the right to close a study site or terminate the study at any time for any reason 
at the sole discretion of the Sponsor. Study sites will be closed upon study completion. A study 
site is considered closed when all required documents and study supplies have been collected and 
a study site closure visit has been performed, except for the sites without any subjects enrolled 
which could be administratively closed by a close-out letter. 
Reasons for study termination may include, but are not limited to: 
• AEs unknown to date (i.e., not previously reported in any similar investigational study drug 
trial with respect to their nature, severity, and/or duration) 
• Increased frequency and/or severity and/or duration of known, anticipated, or previously 
reported AEs (this may also apply to AEs defined at check-in as baseline signs and 
symptoms) 
• Medical or ethical reasons affecting the continued performance of the study 
• Difficulties in the recruitment of subjects 
• Cancellation of drug development. 

 
 
 
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5. STUDY TREATMENTS 
A detailed process for ordering, storage and preparation of final volume for the IV infusion for 
subjects with different renal functions, packaging and labeling of the IMP and comparator for 
administration are specified in the Pharmacy Manual. 
5.1. 
Treatments Administered 
All study drugs will be administered in a double-blinded manner. All study drugs (test and 
comparator) will be provided by the Sponsor to the site. 
Intravenous linezolid or vancomycin will be allowed as local standard of care for the treatment of 
MRSA (see Section 6.1.2). 
5.2. 
Investigational Medicinal Product (XNW4107 in Combination with 
Imipenem/Cilastatin) 
5.2.1. 
Identity of XNW4107 for Injection 
Below is a summary of the physical and chemical properties of the XNW4107. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
Further details are presented in the IB (XNW4107 IB). 
5.2.2. 
Imipenem/Cilastatin Pharmaceutical Form 
Imipenem/cilastatin is a white to light yellow powder for solution for infusion in a glass vial. 
The active substances are imipenem and cilastatin. Each vial contains imipenem monohydrate 
equivalent to 500 mg imipenem and cilastatin sodium equivalent to 500 mg cilastatin. The other 
ingredient is sodium bicarbonate. 
XNW4107 will be supplied in a single dose 50R Type I glass vial sealed with a 20 mm rubber 
stopper and a 20-mm aluminum cap with flip-off seal. It is intended for administration by IV 

 
 
 
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infusion. Each vial containing nominal 250 mg of active ingredient XNW4107 is intended for 
reconstitution with normal saline (0.9% sodium chloride injection). 
5.2.3. 
Preparation of Infusion 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
. 
Imipenem/cilastatin will be reconstituted with saline according to the instructions of the Package 
Insert and the reconstituted suspension will be transferred to the IV infusion bag and mixed with 
XNW4107. 
The mixed solution of XNW4107 and imipenem/cilastatin in one IV infusion bag will be further 
diluted with saline to a final volume of 100 mL. The dose and final infusion volume will be 
adjusted according to the renal function of the subject prior to the IV administration (
 
.  
The investigator or pharmacist at the investigational site will undertake specific training on 
handling and preparing study treatment and will ensure Good Pharmacy Practices are followed 
during the preparation and reconstitution process of IMI-XNW4107 infusion. 
5.2.4. 
Administration of Infusion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
. 
5.3. 
Imipenem/Cilastatin/Relebactam 
5.3.1. 
Pharmaceutical Form 
IMI/REL is provided as single dose clear glass vials containing imipenem monohydrate equivalent 
to 500 mg imipenem, cilastatin sodium equivalent to 500 mg cilastatin, and relebactam 
monohydrate equivalent to 250 mg relebactam as a white to light yellow powder for injection. 
5.3.2. 
Administration of Infusion 
IMI/REL will be administered IV as 1.25 g dose (imipenem 500 mg/ cilastatin 500 mg/relebactam 
250 mg) diluted in normal saline to a final volume of 100 mL and will be infused over 
30 minutes (±5 minutes) q6h (±30 minutes) for subjects with eGFR ≥90 mL/min. Dose and final 

 
 
 
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infusion volume are adjusted according to renal function. See dose adjustments for lower renal 
function in Section 5.9. The detailed infusion volume adjustments are provided in the Pharmacy 
Manual. If the scheduled infusion starting time (±30 minutes) is missed, the subsequent infusion 
must return to the originally scheduled starting time of the IV infusion. 
5.4. 
Packaging and Labeling 
The final IMI-XNW4107 and IMI/REL infusions will be prepared by the investigational site 
pharmacy using standard institutional procedures and according to the Package Insert for 
imipenem/cilastatin and IMI/REL. 
Adequate supplies of all study drugs will be provided to each investigational site. 
The manufacture of drug product XNW4107 for injection will be carried out under GMP. 
Labeling and packaging of IMI-XNW4107 and IMI/REL will meet applicable regulatory 
requirements and country-specific requirements and label text will be approved by the Sponsor. 
All drug shipment requests for IMI-XNW4107 and IMI/REL will be processed and approved by 
the Sponsor or designee. A complete record of batch numbers and expiry dates of all study drugs 
and labels will be maintained in the Sponsor’s study file. 
5.5. 
Storage and Stability 
XNW4107 for injection (250 mg) must be stored in a secure area (e.g., a locked cabinet), protected 
from moisture, and kept at controlled temperature of 5°C (±3°C) until the time of preparation for 
study drug administration.  
Imipenem/cilastatin should be stored as indicated in the Package Insert (see also the label). 
 For lower and normal dose groups, drug concentration of XNW4107 and imipenem and cilastatin 
is 2.5/5/5mg/mL or lower in final infusion solution, it is stable at room temperature of 25°C±2°C 
for 2 hours or at 5°C±3°C for 24 hours, respectively. For higher dose group, drug concentration of 
XNW4107 and imipenem and cilastatin is 3.75/7.5/7.5mg/mL in final infusion solution, it is stable 
at room temperature of 25°C±2°C for 2 hours or at 5°C±3°C for 8 hours, respectively. All stability 
and compatibility data show appropriate support for the planned clinical use. The color of the IV 
solution of XNW4107 and imipenem/cilastatin may turn from colorless (zero point) to slightly 
yellow or yellow (2°C to 8°C for 24 hours) which originates from the imipenem/cilastatin solution, 
however, this will not affect the potency which is described in the FDA-approved drug product 
label of imipenem/cilastatin. 
IMI/REL should be stored as indicated in the Package Insert (see also label). A detailed process 
for handling and administration of IMI/REL will be specified in the Prescribing 
Information/Package Insert and SmPC. 

 
 
 
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5.6. 
Study Treatment Accountability, Reconciliation, and Return 
Upon completion and termination of the study, all unused and/or partially unused study treatment 
shall be returned to the Sponsor or other authorized party if not authorized by the Sponsor to be 
destroyed at the site. 
All study treatments returned to the Sponsor or other authorized party must be accompanied by 
the appropriate documentation and be clearly identified. Study treatment may only be returned 
after drug accountability is completed. Returned supplies should be in their original containers 
(component vials that have clinical labels attached). 
Empty vials may not be destroyed until drug accountability is completed. Empty vials DO NOT 
need to be returned to the Sponsor. It is the investigator’s responsibility to arrange disposal of all 
empty vials according to the institutional regulations. 
The return or destruction of unused study treatment should be arranged by the site monitor. 
5.7. 
Study Treatment Handling and Disposal 
The Sponsor will be responsible for ensuring that the quality of the study treatment is adequate for 
the duration of the study. 
It is the responsibility of the investigator or designee to ensure that the study treatment is only 
dispensed to the subject. The study treatment must be dispensed from official study sites by 
authorized personnel according to local regulations. The investigator or designee must maintain 
accurate records of the study treatment receipt, dispensing information, and disposition. 
If study treatment is to be destroyed at the site, it is the investigator or designee’s responsibility to 
ensure that arrangements have been made for disposal, drug accountability has been completed by 
the site monitor, procedures for proper disposal have been established according to applicable 
regulations, guidelines, and institutional procedures, and appropriate records of the disposal have 
been documented and provided to the Sponsor or designee. 
Further guidance and information for the final disposition of unused study treatment are provided 
in the Pharmacy Manual. 
5.8. 
Method of Treatment Assignment 
In this study, subjects will be randomized on Day 1 by IXRS, a computer-generated random 
sequence system. Randomization will be stratified by type of infection (non-ventilated HABP vs. 
ventilated HABP/VABP), APACHE II score (<15 vs. ≥15) (see Appendix 2), and country/region 
(China vs. Rest of World). The number of subjects randomized with ventilated HABP/VABP will 
be at least 50% of the randomized population. 
Subjects will be randomized in a 
 ratio to receive either combination treatment IMI-XNW4107 
administered IV q6h or IMI/REL administered IV q6h in a double-blinded fashion. 

 
 
 
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All study drugs will be dispensed from numerically coded containers. The code will remain with 
the IXRS until it is required for study unblinding following lock of the database. 
5.9. 
Dose Modifications 
No dose reduction is recommended in subjects with impaired hepatic function. 
No dose adjustment is required for elderly subjects with normal renal function. 
Dose adjustments will be required for subjects with abnormal renal function (see below) and will 
be based on the subject’s calculated eGFR using the Modification of Diet in Renal Disease (MDRD) 
4-variable equation. 
MDRD equation (https://www.hepatitisc.uw.edu/page/clinical-calculators/mdrd)  
eGFR in mL/min per 1.73 m2 = 175 × SerumCr-1.154 × age-0.203 × 1.212 (if subject is Black 
or African American) × 0.742 (if female). 
Individual eGFR will be used to determine the requirement of dose adjustment. The individual 
eGFR (mL/min) is derived by (eGFR by MDRD/1.73 m2) × BSA, where BSA is the individual 
body surface area calculated as: 0.20247 × height (m)0.725 × mass (kg)0.425. The eGFR will be 
referred to the individual eGFR in the unit of mL/min thereafter per the calculation described above 
if no unit of 1.73 m2 is carried on. 
The eGFR will be calculated based on results from the local laboratory. The initial dose should be 
based on the calculated individual eGFR at screening. Since renal function can fluctuate quickly 
in ill subjects, renal function will be monitored daily during the first 3 days after initiation of study 
therapy, then subsequently, based on investigator’s judgment, as clinically indicated. The local 
creatinine and individual eGFR calculated using MDRD will be recorded in the eCRF. 
Refer to the Pharmacy Manual for specific instructions regarding preparation of doses following 
adjustments. 
5.9.1. 
Imipenem/Cilastatin-XNW4107 
Table 2 shows the recommended dose adjustments for IMI-XNW4107. 
Table 2: Recommended Dosage of IMI-XNW4107, Given as 30(±5) -Minute Infusion, q6h 
(±30 minutes)  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 

 
 
 
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. 
 
5.9.2. 
Imipenem/Cilastatin/Relebactam 
IMI/REL dosage should be reduced in subjects with eGFR of <90 mL/min. 
Table 3: Recommended IMI/REL Dosage Given as 30 (±5) - Minute Infusion, q6h (±30 
minutes) to Adult Subjects with Normal Renal Function and Renal Impairment 
Individual eGFR (mL/min)a 
Recommended Dosage of IMI/REL 
(g) 
Dosing Interval 
≥90b 
1.25 g 
(imipenem 500 mg, cilastatin 
500 mg, and relebactam 250 mg) 
q6h 
60 to <90 
1 g 
(imipenem 400 mg, cilastatin 
400 mg, and relebactam 200 mg) 
q6h 
30 to <60 
0.75 g 
(imipenem 300 mg, cilastatin 
300 mg, and relebactam 150 mg) 
q6h 
15 to <30 
0.5 g 
(imipenem 200 mg, cilastatin 
200 mg, and relebactam 100 mg) 
q6h 
<15 
Excluded from the study 
Abbreviations: 
BSA = body 
surface 
area; 
eGFR = estimated 
glomerular 
filtration 
rate; 
IMI/REL = imipenem/cilastatin/relebactam, MDRD = Modification of Diet in Renal Disease; q6h = every 6 hours. 
a: calculated using the MDRD equation and individual BSA by (eGFR by MDRD/1.73 m2) × BSA. Where BSA is the 
individual body surface area calculated as: 0.20247 × height (m)0.725 × mass (kg)0.425 
Source: imipenem/cilastatin/relebactam label 
b: subjects with individual eGFR ＞250 mL/min will also be excluded from the study. 
5.10. Blinding 
This is a double-blinded study. 

 
 
 
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All study personnel and subjects will be blinded to the treatment assignment with the exception of 
specific personnel as described in Table 4, and in a separate Maintaining Study Blind and 
Unblinding Plan. 
Table 4: List of Unblinded Parties to Support the Study Conduct 
Unblinded Parties 
Reason to be Unblinded 
 
Unblinded pharmacist(s) 
and/or other unblinded 
qualified personnel (e.g., 
unblinded nurse[s])  
 
 
Reconstitute the study drug onsite, prepare the infusions for each day of 
dosing, and dispense either imipenem/cilastatin-XNW4107 or 
imipenem/cilastatin/relebactam in a blinded manner. 
Unblinded CRA/Site 
Monitor 
Review the unblinded pharmacist’s documentation and oversee the drug 
dispensing activity periodically throughout the study. The unblinded CRA 
will have specific responsibility limited only to monitoring the work of the 
unblinded pharmacist at each study site.  
Unblinded visit report 
and study file reviewers 
Review of unblinded visit reports and periodic reviews of the unblinded 
sections of the Trial Master File 
Drug supply chain and 
IRT vendor personnel 
Responsible for production of the randomization scheme and have an 
unblinded inventory manager role in the IRT system for purposes of study 
drug inventory management. 
Bioanalytical laboratory 
personnel 
Facilitate PK sample management. 
Independent 
biostatistician and 
programmers 
Facilitate the DMC data reviews and safety surveillance. 
Individuals in 
pharmacovigilance and 
regulatory 
IND safety reporting and/or expedited reporting SUSARs to Health 
Authorities. These individuals are not part of the core study team and not 
directly involved in any study conduct. 
Abbreviations: CRA = clinical research associate; DMC = Data Monitoring Committee; IND = investigational new 
drug; IRT = interactive response technology; PK = pharmacokinetics; SUSAR = suspected unexpected serious adverse 
reaction. 
Covers will be provided for infusion bags and lines to maintain blinding.  
To also preserve blinding, the active drug and IMI/REL will be identical in appearance. 
Unblinding should only occur in the event of a medical emergency. Investigators should note that 
the occurrence of an SAE should not routinely precipitate the immediate unbinding of the label. 
When knowledge of the study drug is essential for the clinical management or welfare of the 
subject, the investigator may unblind a subject’s treatment assignment. In the event of an 
emergency unblinding by the investigator, the Sponsor must be informed as soon as possible. The 
medical monitor is available to discuss the need to unblind any subject and can be contacted if 
needed. 
For SUSAR (suspected, unexpected, serious adverse reactions) cases where the investigator has 
not broken the blind, the Sponsor will break the blind in accordance to Sponsor/clinical research 

 
 
 
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organization (CRO) global standard operating procedure before reporting to health authorities, 
institutional review boards (IRBs)/independent ethics committees (IECs) and investigators if the 
SUSAR was related to the blinded treatment. The information will be maintained in the Global 
Pharmacovigilance database. 
Any reported SAEs that refer to a failure of the expected pharmacological action, are not 
considered SUSAR cases and are therefore exempted from unblinding. 
5.11. Treatment Compliance 
Since all treatments are administered at the clinical site by site personnel, the investigator or 
designee must maintain accurate records of all study treatments, including dates of study drug 
receipt, quantities received and dispensed, and batch/lot numbers. In addition, the study treatment 
must be noted in the subject’s medical records and eCRF, with the date and time of administration 
and dose of each study treatment. 

 
 
 
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6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Prior and Concomitant Therapy 
The investigator must record the use of all prior and concomitant medications (both prescribed and 
over-the-counter, including herbal remedies) or vaccines taken during 14 days prior to the first 
dose of study drug through the LFU visit in the source documents and eCRF along with: 
• Reasons for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency. 
The medical monitor should be contacted if there are any questions regarding concomitant or prior 
therapy. 
Subjects should receive full supportive care during and after the administration of IMI-XNW4107 
injection or IMI/REL or standard of care treatment per local practice and according to the judgment 
of the investigator or treating physician. 
Subjects should be discouraged from starting any new medication, both prescribed and 
over-the-counter, including herbal remedies without consulting the investigator unless the new 
medication is required for emergency. 
6.1.1. 
Non-Antibiotic Concomitant Medications 
Subjects are not permitted to take those medications specified in the exclusion criteria (Section 4.2), 
and the following below: 
For subjects who will receive linezolid as Gram-positive adjunctive therapy, the following are 
prohibited: 
• Prior use of a monoamine oxidase inhibitor within 14 days of the first dose of linezolid 
• Concomitant use of any of the following medications during linezolid therapy: 
• 
Serotonin re-uptake inhibitors 
• 
Tricyclic antidepressants  
• 
Serotonin 5-HTI receptor agonists (triptans) 
• 
Meperidine 
• 
Buspirone 
• 
Monoamine oxidase inhibitors. 

 
 
 
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Investigator should also follow the local Prescribing Information for imipenem/cilastatin and 
IMI/REL when determining whether a medication should or should not be given. 
In case of infusion-related reactions, administration of paracetamol and/or antihistamine drugs is 
acceptable. 
All other concomitant medications necessary for the health and well-being of the subject which 
are permitted will be recorded (using the generic name) on the concomitant medications page of 
the eCRF. 
COVID-19 vaccines that are given under emergency use authorization are not considered 
investigational agents. 
6.1.2. 
Antibiotics Concomitant Medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
. 
No sequential oral antibiotic (step-down) therapy is permitted. 
Use of systemic antibacterial other than study drug therapy is not permitted during the study except 
in the following circumstances: 
• Failure of study drug and need for rescue antibiotic therapy as judged by the investigator 
• For the treatment of an AE (i.e., a new infection develops at a different site). The 
investigator should try to use an antibiotic not active against the baseline Gram-negative 
pathogen 
• Use of antibiotics (not active against Gram-negative pathogens) for surgical prophylaxis 
• Local care for superficial wounds is permitted (i.e., topical antiseptic therapy, topical 
antibiotic ointment, wet-to-dry dressing change). The use of topical antibiotic therapy with 
activity against Gram-negative organisms is discouraged, but will not constitute a failure 
of the primary antibiotic regimen if administered. Topical antifungal treatment or a single 
oral dose of any antifungal treatment of vaginal candidiasis will be allowed 
• Oral vancomycin or other agents not active against Gram-negative pathogens for the 
treatment of Clostridioides difficile diarrhea will be allowed. 
Optional linezolid as judged by the investigator can be given to subjects in both arms to provide 
coverage for MRSA as per local standard of care. The recommended treatment duration for a 
confirmed MRSA infection is a minimum of 7 days, with a minimum of 14 days for MRSA 
bacteremia. Empiric linezolid treatment will be stopped if the final culture results from the baseline 
lower respiratory tract sample do not demonstrate the presence of MRSA. For subjects in whom 
linezolid cannot be used, IV vancomycin may be used. 

 
 
 
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6.1.3. 
Procedures and Surgeries 
All concomitant diagnostic and therapeutic pulmonary procedures after the administration of the 
first dose of study drug through the LFU visit should be recorded in the eCRF. Concomitant 
diagnostic or therapeutic procedures clinically relevant to the pneumonia under study or any SAE 
should be reported in the eCRF. Note: Repeat pulmonary imaging studies that are not significantly 
changed do not need to be reported. 
6.2. 
Contraception 
Where sexually active, female subjects of childbearing potential (defined as women who are not 
surgically or chemically sterilized and who are between menarche and 1 year post-menopause / 
2 years of amenorrhea) must be willing to use highly effective methods of contraception from the 
signing the informed consent form (ICF) through 1 month after receiving the last dose of study 
treatment to minimize the pregnancy risk. 
Highly effective contraception methods are defined as those that result in a low failure rate (<1% 
per year) when used consistently and correctly. Such methods include a sterile sexual partner, 
hormonal contraceptives (oral, injection, transdermal patch, or implant), or intrauterine device to 
prevent pregnancy for at least 3 months prior to study drug administration. Also, refer to inclusion 
#10 for details (Section 4.1). 
Male subjects with female sexual partners of childbearing potential must be willing to use 
medically acceptable birth control for 90 days following the last dose of study medication. Sexual 
abstinence, vasectomy, or a condom used with a spermicide are medically acceptable birth control 
methods for males. Male subjects must agree not to donate sperm for a period of 90 days after the 
last dose of study treatment. 

 
 
 
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7. STUDY ASSESSMENTS AND PROCEDURES 
A summary of procedures or assessments to be performed at each visit is provided in Section 7.1 
through Section 7.3. Details for each of the procedures are provided in Section 7.5 (efficacy), 
Section 7.6 (safety and tolerability), and Section 7.7 (PK). 
7.1. 
Screening Procedures 
All screening evaluations must be completed and reviewed to confirm that potential subjects meet 
all eligibility criteria within 24 hours (except chest imaging) prior to randomization. Chest imaging 
must be completed and eligibility confirmed within 48 hours prior to randomization. Appropriate 
clinical specimen (lower respiratory specimen and blood for culture) must be obtained from all 
subjects within 48 hours prior to randomization. 
The investigator will maintain a screening log to record details of all subjects screened and to 
confirm eligibility or record reasons for screening failure (Section 4.3.1), as applicable. Procedures 
conducted as part of the subject’s routine clinical management (e.g., blood count, chest imaging) 
and obtained within 24 hours prior to randomization (or 48 hours for chest imaging) may be 
utilized for screening eligibility.  
All screening laboratory, baseline (screening or Day 1 before the first dose of study drug) and post-
baseline safety laboratory tests will be performed locally. 
The maximum amount of blood from each subject over the duration of the study including any 
extra assessments that may be required will not exceed volumes as stated by local regulations. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
Subjects cannot be rescreened. However, assessment (e.g., eGFR) can be repeated within the 
24-hour screening window period if the initial assessment failed to meet eligibility. 
The following procedures or assessments will be performed: 
• Informed consent 
• Inclusion/exclusion criteria (eligibility review) 
• Demographics: sex, race, age and ethnicity. Race will be collected only in countries that 
permit 
• Medical history 
• Prior and concomitant medications or vaccines taken within 14 days prior to the planned 
first dose of the study drug 
• Standard physical examination 
 
 
 
 
  

 
 
 
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f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.2. 
Treatment Period (Day 1 to Day 14) 
Subjects may receive treatment for a recommended duration of 7 to 14 calendar days (judged by 
the investigator). 
7.2.1. 
Randomization (Day 1) 
Stratification in IXRS will be done at the time of randomization. If screening and randomization 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
The following procedures or assessments will be performed before the first dose administration: 

 
 
 
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• Prior and concomitant medications 
• Concomitant diagnostic and therapeutic procedures 
• Symptom-oriented physical examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 5.9 
 
  
 
 
 
    
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 7.5.4 
 
 
  
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
• Survival 
• Record AEs. 
7.2.2. 
Day 2 to Day 3 
The following procedures or assessments will be performed: 
• Concomitant medications 
• Concomitant diagnostic and therapeutic procedures 

 
 
 
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• Symptom-oriented physical examination 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 5.9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Record AEs. 
7.2.3. 
Day 4 
The following procedures or assessments will be performed: 
• Concomitant medications 
• Concomitant diagnostic and therapeutic procedures 
• Symptom-oriented physical examination 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 

 
 
 
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 5.9 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
• Survival 
• Record AEs. 
7.2.4. 
Day 5 to Day 14 
The following procedures or assessments will be performed: 
• Concomitant medications 
• Concomitant diagnostic and therapeutic procedures 
• Symptom-oriented physical examination 
 
 
 
 
 
 
 
  
 
 
  

 
 
 
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• Record AEs. 
7.3. 
End of Treatment, Test-of-Cure, and Late Follow-Up Assessments 
The EOT visit will occur on the day of last IV study therapy or the day after. Duplication of 
assessments for a given day and EOT is not necessary. If EOT occurs on Day 14, survival needs 
to be evaluated.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
The following procedures or assessments will be performed: 
• Concomitant medications 
• Concomitant diagnostic and therapeutic procedures 

 
 
 
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• Symptom-oriented physical examination 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
  
 
 
  
 
 
 
 
 
• Record AEs. 
7.4. 
Unscheduled Assessments 
Unscheduled assessments may be conducted at any time according to the investigator’s discretion, 
as clinically appropriate. 
7.5. 
Efficacy Assessments 
7.5.1. 
Assessment of HABP/VABP Signs and Symptoms 
Infection-specific clinical signs and symptoms will be evaluated by the investigator at each 
specified visit in the Schedule of Assessments (Table 9) to determine the clinical response 
assessment. 

 
 
 
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Signs and symptoms specific to HABP/VABP including expectorated sputum production, 
increased tracheal secretions, cough, dyspnea, pleuritic chest pain, wheezing, rales, tachypnea, 
rhonchi, egophony, dullness to percussion, and bronchial breath sounds will be assessed at baseline 
as absent, mild, moderate, severe, or unknown. 
Whenever possible the same person should conduct these assessments for any given subject 
throughout the study. 
7.5.1.1. Oxygenation Status 
The subject’s oxygenation status, including PaO2, FiO2, and O2 saturation, will be assessed at the 
specified visits in the Schedule of Assessments (Table 9). The oxygenation status will be 
determined by arterial blood gases or pulse oximetry. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
. 
7.5.1.2. Status of Ventilator Support 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
7.5.2. 
Chest Imaging 
Chest imaging (Chest x-ray or computed tomography scan) will be performed at screening and is 
required for diagnosis and assessment of eligibility. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
 The investigator’s (or qualified 
designee’s at the site) interpretation of the chest imaging may be used to make the enrollment 
decision if a radiologist’s interpretation is not available. 
Local reading of screening chest imaging by a radiologist is required for all subjects including 
subjects enrolled based on the interpretation of the investigator. The local radiologist’s 
interpretation will be captured.  
Details on the interpretation from both the investigator (if used for enrollment) and the radiologist 
report will be collected including the presence and location of pneumonia findings such as 
infiltrates, opacities, and consolidation for all screening films. In addition, any radiology reports 
will be collected if relevant to an SAE as well as follow-up reports if results are clinically 
significant. 
7.5.3. 
APACHE II Score 
APACHE II score will be collected and used as a method to establish the severity of disease at 
screening. The APACHE II score calculation will be based on details provided in Appendix 2, and 
entered in the eCRF at screening by the investigator or qualified designee. 

 
 
 
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7.5.4. 
SOFA Score 
The SOFA is a scoring system to determine the extent of a subject’s organ function or rate of 
failure. The investigator or qualified designee will record the components required to calculate a 
SOFA score (see Appendix 3). Daily SOFA will be done while the subject is in the ICU based on 
local laboratory tests from samples obtained as standard of care. The most recent available 
laboratory results will be used to calculate the SOFA score. No additional laboratories samples 
will be obtained beyond the local standard of care. The local laboratory tests must include the 
required parameters for SOFA scoring: platelets, total bilirubin, creatinine if not using urine 
output, and oxygen saturation if PaO2 is not available (Oxygen saturation can be converted to 
PaO2 for the SOFA score calculation). Refer to Table 9 for timings of SOFA assessment. 
7.5.5. 
GCS Score 
The GCS is an adopted standard for assessment of impaired consciousness and coma in acutely ill 
trauma and non-trauma subject and assists with predictions of neurological outcomes 
(complications, impaired recovery) and mortality. The investigator or qualified designee will 
record the components required to calculate GCS (see Appendix 4), and use it to complete the 
APACHE II and SOFA scores. Daily GCS will be done while the subject is in the ICU. Refer to 
Table 9 for timings of GCS assessment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
  
 
 
 
  
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
   
 
 
 
 
 
 
 
 

 
 
 
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• 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
. 
7.5.10. 
Survival 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
7.6. 
Safety and Tolerability Assessments 
Safety endpoints will be assessed by review of AE summaries which will include SAEs, unless 
stated otherwise. Adverse events will be categorized by System Organ Class (SOC) and preferred 
term (PT) using the Medical Dictionary for Regulatory Activities (MedDRA) and the severity of 
AEs will be assessed. 
7.6.1. 
Adverse Events 
Adverse events will be monitored throughout the study. Serious AEs will be collected from the 
time informed consent is signed and non-serious AEs from the first dose of study treatment until 
LFU visit.  
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE. 
7.6.1.1. Definitions 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug-related. This includes the following: 
• Any clinically significant worsening of a pre-existing condition 
Note: Emergence of a new pathogen associated with a clinical event during therapy at a site other 
than the initial site of infection will be considered an AE 
• Any recurrence of a pre-existing condition 

 
 
 
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• An AE occurring from an overdose of a Sponsor study drug whether accidental or 
intentional (i.e., a dose higher than that prescribed by a health care professional for clinical 
reasons) 
• An AE occurring from abuse of a Sponsor study drug (i.e., use for non-clinical reasons) 
• An AE that has been associated with the discontinuation of the use of a Sponsor study drug. 
Note: A procedure is not an AE, but the reason for a procedure may be an AE. 
A pre-existing condition is a clinical condition (including a condition being treated) that is 
diagnosed before the subject signs the informed consent and that is documented as part of the 
subject’s medical history. Pre-existing medical conditions/diseases/symptoms that worsen after 
signing the informed consent are SAEs/AEs. However, only SAEs will be collected from the time 
informed consent is signed while non-serious AEs will be collected from the first dose of study 
treatment. 
An AE or SAE will be considered treatment-emergent if they occur any time after the first dose of 
study treatment. 
In case of fatality, the cause of death is considered as the SAE, and the death is considered as its 
outcome, and the end date of the SAE is the date of death. 
Information about all AEs, whether volunteered by the subject, discovered by the investigator or 
designee questioning, or detected through physical examination, laboratory test or other means, 
will be collected and recorded, as appropriate. 
All AEs will be treated appropriately. Such treatment may include discontinuation of study 
treatment, if necessary. 
Events associated to progression of the disease under study (e.g., progression of pneumonia) are 
not reported as AEs.  
Assessment of Severity 
The investigator will be asked to provide an assessment of the severity or intensity of the AE using 
the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 grading as shown 
below:  
• Grade 1: Mild; usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily living 
• Grade 2: Moderate; minimal, local or non-invasive intervention indicated 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated, disabling  
• Grade 4: Life-threatening consequences; urgent intervention indicated 

 
 
 
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• Grade 5: Death related to AE. 
The CTCAE can be found via the website: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_refere
nce_5x7.pdf. 
Relationship to Study Treatment 
The investigator will make a determination of the relationship of the AE to the study drug using a 
five-category system according to the following guidelines: 
• Not Related: when the AE is definitely caused by the subject’s clinical state, or the study 
procedure/conditions 
• Unlikely Related: when the temporal association between the AE and the drug is such that 
the drug is not likely to have any reasonable association with the AE 
• Possibly Related: when the AE follows a reasonable temporal sequence from the time of 
drug administration but could have been produced by the subject’s clinical state or the 
study procedures/conditions 
• Probably Related: when the AE follows a reasonable temporal sequence from the time of 
drug administration but could not have been produced by the subject’s clinical state or the 
study procedures/conditions 
• Definitely Related: when the AE follows a reasonable temporal sequence from the 
administration of the drug, abates upon discontinuation of the drug, follows a known or 
hypothesized cause-effect relationship, and (if appropriate) reappears when the drug is 
reintroduced. 
For the purposes of Investigational New Drug safety reporting, the below will be considered: 
Causality Assessment Options 
(from SAE form / EDC)  
Considered Related?  
Not related 
Considered not related  
Unlikely related 
Possibly related 
 Considered related  
Probably related 
Definitely related 
 
Action Taken with Study Treatment for Adverse Events 
The investigator or designee will record the action taken for the AE in the eCRF. Actions taken 
will include: 
• Dose Not Changed: The medication schedule was not changed 

 
 
 
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• Drug Interrupted: The medication schedule was modified by temporarily terminating the 
prescribed regimen of medication 
• Drug Withdrawn: The medication schedule was modified through termination of the 
prescribed regimen of medication 
• Not Applicable 
• Unknown 
Serious Adverse Events 
An SAE is any AE occurring at any dose that meets one or more of the following criteria: 
• Results in death 
• Is life-threatening (see below) 
• Requires subject hospitalization or prolongation of an existing hospitalization (see below) 
• Results in a persistent or significant disability or incapacity (see below) 
• Results in a congenital anomaly or birth defect 
• Results in an important medical event (see below). 
Additionally, important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not require 
hospitalization, or development of drug dependency or drug abuse. 
A life-threatening AE is any AE that places the subject at immediate risk of death from the event 
as it occurred. A life-threatening event does not include an event that might have caused death had 
it occurred in a more severe form but that did not create an immediate risk of death as it actually 
occurred. For example, drug-induced hepatitis that resolved without evidence of hepatic failure 
would not be considered life-threatening, even though drug-induced hepatitis of a more severe 
nature can be fatal.  
Hospitalization or prolongation of hospitalization is considered an SAE criterion. In the absence 
of an AE, the participating investigator should not report hospitalization or prolongation of 
hospitalization. This is the case in the following situations: 
• Hospitalization or prolongation of hospitalization is needed for a procedure required by the 
protocol. Day or night survey visits for biopsy or surgery required by the protocol are not 
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• Hospitalization or prolongation of hospitalization is part of a routine procedure followed 
by the study center (e.g., stent removal after surgery). This should be recorded in the study 
file. 
• Hospitalization for survey visits or annual physicals fall in the same category. 
In addition, a hospitalization planned before the start of the study for a pre-existing condition that 
has not worsened does not constitute an SAE (e.g., elective hospitalization for a total knee 
replacement due to a pre-existing condition of osteoarthritis of the knee that has not worsened 
during the study). Hospitalization is to be considered only as an overnight admission. 
Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions (i.e., the AE resulted in a significant, persistent, or permanent change, impairment, 
damage, or disruption in the subject’s bodily function/structure, physical activities, or quality of 
life).  
If there is any doubt as to whether a case constitutes an AE or SAE based on the information 
available, the case should be treated as an SAE. 
Medical and scientific judgment should be exercised in deciding whether a case is serious in those 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalization, disability, or incapacity. These include events that may jeopardize the 
subject or may require medical intervention to prevent one or more outcomes listed in the 
definition of serious. Such events should usually be considered as serious. 
Toxicities that fall within the SAE definitions listed above must be reported as an SAE regardless 
of whether they are felt to be treatment-related or not. Toxicities unrelated to treatment that do 
NOT fall within the SAE definitions above must be documented as AEs in the subject’s source 
documents and eCRF. 
Suspected Unexpected Serious Adverse Reactions 
SUSARs are serious events with at least a reasonable possibility to be causally related to the IMP 
and/or comparator drug, that are not listed in the applicable product information (e.g., IB for an 
unapproved Investigational medicinal product). Suspected adverse reaction means any AE for 
which there is a reasonable possibility that the drug caused the AE. For the purposes of 
Investigational New Drug safety reporting, ‘reasonable possibility’ means there is evidence to 
suggest a causal relationship between the drug and the AE. 
For XNW4107, the reference document for definition of expectedness is the Reference Safety 
Information from globally approved version of IB at the time of start date of the event. 
For imipenem/cilastatin the reference document for assessment of expectedness is the current 
United States Prescribing Information (USPI) or/and SmPC for this product. 
For comparator (Imipenem/Cilastatin/Relebactam), the reference document for assessment of 
expectedness is the current United States Prescribing Information (USPI) or/and SmPC for this 
product. 

 
 
 
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7.6.1.2. Reporting Adverse Events 
Reporting of Adverse Events 
At each visit, the investigator or delegate will determine whether or not any AEs have occurred. 
Non-leading questions such as “How are you feeling today?” or “Have you had any health 
concerns since your last visit?” should be used to elicit the subject to report any possible AEs. If 
any AEs have occurred, they will be recorded in the AE section of the eCRF and in the subject’s 
source documents. If known, the diagnosis should be recorded, in preference to listing the 
individual signs and symptoms. 
Reporting of Serious Adverse Events 
All SAEs, occurring after the signing of the ICF until LFU visit and regardless of study drug 
relationship, must be entered into the clinical database and the investigator or delegate must report 
the SAE(s)/pregnancy reports to the Sponsor or designee within 24 hours of obtaining knowledge 
of the event, by reporting the SAE electronically via the eCRF and pregnancy reports via paper 
form, or in case of eCRF unavailability, by emailing a copy of a paper SAE form to 
SAEIntake@labcorp.com and safety@evopointbio.com for cases occurred in ex-China. For cases 
occurred in China, the China investigator will directly complete a China-specific manual 
SAE/pregnancy report, including date and signature and send to safety@evopointbio.com within 
24 hours of awareness.  
The initial SAE form must contain as much information as possible and be updated if more 
information becomes available.  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The trial site should notify the site monitor via phone or email about the submission of the SAE 
report.  
All sites will follow their institutional requirements for submission of SAEs to their IRBs/IECs. 
The Sponsor should be notified if the investigator becomes aware of any SAEs/Pregnancies that 
occur after the end of the SAE reporting period and is believed to be related to prior study treatment. 
The investigator should report these post-study events to the Sponsor via email  
4107Safety@evopointbio-us.com and safety@evopointbio.com. 

 
 
 
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7.6.1.3. Follow-up of Adverse Events/Serious Adverse Events 
Adverse events/SAEs will be followed until resolution or stabilization of the event, completion of 
the subject’s participation, or study termination, or the investigator or designee and Sponsor agree 
that follow-up is no longer necessary, whichever occurs first. 
Assessments should be made at each visit (or more frequently, if necessary) of any changes in 
severity, the relationship to the study drug, the intervention required to treat it, and the outcome. 
Side effects known for XNW4107 or imipenem/cilastatin or IMI/REL are provided in the 
XNW4107 IB or respective Prescribing Information or SmPCs. All AEs will be immediately 
recorded in the subject’s source documents. 
7.6.1.4. Procedures for Recording Adverse Events 
7.6.1.4.1. 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between clinical visits. Such 
events should only be recorded once on the AE eCRF page. The initial severity of the event will 
be recorded at the time the event is first reported. If the severity or seriousness of a persistent AE 
changes a new record should be added on the AE eCRF page to report each severity or seriousness 
change with the corresponding start/end date. If the event becomes serious, it should be reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning that the event became serious; 
see Section 7.6.1.2 for reporting instructions). 
A recurrent AE is one that resolves between subject evaluation timepoints and subsequently recurs. 
Each recurrence of an AE should be recorded separately on the AE eCRF page. 
7.6.1.4.2. 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an AE. A laboratory test result should be reported 
as an AE if clinically significant by meeting any of the following criteria: 
• Is accompanied by clinical symptoms 
• Results in a change in study treatment (e.g., treatment interruption or treatment 
discontinuation) 
• Results in a medical intervention or a change in concomitant therapy. 
It is the investigator’s responsibility to review all laboratory findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated laboratory abnormality should be 
classified as an AE. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin ≥5 × ULN associated with cholecystitis), only the diagnosis (i.e., 
cholecystitis) should be recorded on the AE eCRF page. 

 
 
 
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If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded on the AE eCRF page, along with a descriptor indicating if 
the test result is above or below the normal range (e.g., "elevated potassium," as opposed to 
"abnormal potassium"). If the laboratory abnormality can be characterized by a precise clinical 
term per standard definitions, the clinical term should be recorded as the AE. For example, an 
elevated serum potassium level of 7.0 mEq/L should be recorded as “hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit should 
only be recorded once on the AE eCRF page (see Section 7.6.1.4.1) for details on recording 
persistent AEs). 
7.6.1.4.3. 
Vital Sign Abnormalities 
Not every vital sign abnormality qualifies as an AE. A vital sign result should be reported as an 
AE if clinically significant by meeting any of the following criteria: 
• Accompanied by clinical symptoms 
• Results in a change in study treatment (e.g., treatment interruption or treatment 
discontinuation) 
• Results in a medical intervention or a change in concomitant therapy. 
It is the investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality should be 
classified as an AE and further investigated as clinically indicated. 
7.6.1.4.4. 
Pre-Existing Medical Conditions 
A pre-existing medical condition is one that is present at the screening visit for this study. Such 
conditions should be recorded on the Medical History eCRF page. 
A pre-existing medical condition should be recorded as an AE only if the frequency, severity, or 
character of the condition worsens from the first start dose to the LFU visit. When recording such 
events on the AE eCRF page, it is important to convey the concept that the pre-existing condition 
has changed by including applicable descriptors (e.g., “more frequent headaches”). 
7.6.1.4.5. 
Adverse Events Associated with an Overdose or Error in Treatment 
Administration 
Study drug overdose is the accidental or intentional use of the drug in an amount higher than the 
dose being studied. An overdose or incorrect administration of study drug is not an AE unless it 
results in untoward medical effects.  
Any study drug overdose or incorrect administration of study drug should be noted on the Study 
Drug Administration eCRF page.  
All AEs associated with an overdose or incorrect administration of study drug should be recorded 

 
 
 
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on the AE eCRF page. If the associated AE fulfills serious criteria, the event should be reported to 
the Sponsor immediately (i.e., no more than 24 hours after learning of the event; see Section 7.6.1.2 
for reporting instructions). 
7.6.1.4.6. 
Planned Hospitalizations 
A hospitalization planned prior to the first dose of study medication is considered a therapeutic 
intervention and not the result of a new AE. If the planned hospitalization or procedure is executed 
as planned, it should be recorded in the subject’s medical history. However, if complications arise 
during the planned hospitalization or procedure or the subject experiences an AE during the 
planned hospitalization or procedure, it must be reported as an AE. 
7.6.1.5. Investigator’s Notification of Adverse Events to the Sponsor 
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
investigator’s reporting obligations for SAEs. This information, including all relevant contact 
details, is summarized in the investigational site file. This information will be updated as needed. 
Serious AEs occurring during the study must immediately (within 24 hours of investigator 
awareness) be reported per Section 7.6.1.2. 
Serious AEs occurring after the protocol-defined observation period will be processed by the 
Sponsor according to applicable regulations. 
7.6.1.6. Expedited Reporting of Adverse Events to Regulatory Agencies/Authorities 
7.6.1.6.1. 
Notification to the Independent Ethics Committee/Institutional Review Board 
Notification to the IEC/IRB about all relevant events (e.g., SAEs/SUSARs) will be performed by 
the Sponsor or Sponsor’s designee and/or by the investigator according to all applicable 
rules/regulations. 
7.6.1.6.2. 
Notification to the Authorities 
The processing and reporting of all relevant events (e.g., SAEs) to the authorities will be done by 
the Sponsor or Sponsor’s designee and/or by the investigator according to all applicable 
rules/regulations. 
7.6.1.6.3. 
Sponsor’s Notification to the Investigational Site 
The Sponsor or designee will inform all investigational sites about reported relevant events 
according to applicable regulations. The Sponsor or Sponsor’s designee will send the events to a 
site once the site initiation visit has occurred and will stop sending to the site once the last subject 
has completed their LFU visit. 
7.6.1.7. Post-Study Adverse Events 
The Sponsor should be notified if the investigator becomes aware of any SAEs that occur after the 
end of the AE reporting period and is believed to be related to prior study treatment.  

 
 
 
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The investigator should report these post-study events to the Sponsor or its designee, either by 
faxing or by scanning and emailing the SAE Reporting Form using the fax number or email address 
provided to investigators. 
7.6.1.8. Pregnancy 
Although not considered an AE, it is the responsibility of the investigator or their designee to report 
any pregnancy in a subject or the subject’s sexual partner that occurs during the study. All subjects 
who become pregnant must immediately discontinue the study drug and be withdrawn from the 
study. The subject or subject’s sexual partner will be followed to completion/termination of the 
pregnancy. This information is important for both drug safety and public health concerns. If a 
subject is found to be pregnant after the study treatment was administered, the investigator should 
report this to the CRO and Sponsor within 24 hours and document the pregnancy either by 
electronic media or paper. 
The investigator must make every effort to follow the subject until completion/termination of 
pregnancy. If the events during the pregnancy and/or outcome of pregnancy (i.e., complications 
regarding mother/baby) meet the criteria for classification of an SAE, the investigator must follow 
the procedures for reporting SAEs. 
7.6.2. 
Clinical Laboratory Evaluations 
All Screening laboratory tests will be performed locally to assess study eligibility. The list of 
required local laboratory tests is in Appendix 1.  Baseline and post-baseline safety laboratory 
tests will also be performed locally. The timepoints at which these samples will be collected are 
shown in the Schedule of Assessments (Table 9)  
The total volume to be drawn in the study may vary based on local/regional specific laboratory 
requirements. 
A full list of laboratory parameters is provided in Appendix 1. 
The investigator will record on the laboratory report his/her medical opinion of the clinical 
significance of all laboratory values that are outside the laboratory reference range. The 
investigator will sign and date each laboratory report form. Clinically significant laboratory 
findings made after the start of study medication that meet the definition of an AE must be recorded 
on the eCRF (see Section 7.6.1.1 and Section 7.6.1.4.2). 
The investigator will provide the Sponsor or Sponsor’s designee with a copy of each laboratory’s 
certification and a tabulation of the normal ranges. 

 
 
 
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7.6.2.1. Pregnancy Testing 
Urine or serum pregnancy test only for females who are not postmenopausal or surgically sterile. 
A serum pregnancy test will be performed at screening on females of childbearing potential. If the 
results of the serum β-human chorionic gonadotropin (β-hCG) cannot be obtained prior to dosing 
of IMP, a subject may be enrolled on the basis of a negative urine pregnancy test, though serum 
β-hCG must still be obtained.  
7.6.2.2. Stool Samples 
If a subject experiences significant diarrhea during or after study therapy, the investigator is 
strongly recommended to obtain a stool sample and test locally for Clostridioides difficile. 
7.6.3. 
Vital Signs, Physical Examination, and Other Safety Evaluations 
7.6.3.1. Vital Signs 
Measurement of vital signs will include an assessment of HR, systolic and diastolic BP, body 
temperature, and RR. 
Vital signs should be collected daily while on IV study therapy and at other timepoints/visits as 
specified in the Schedule of Assessments (Table 9). Collection on Day 1 should be performed prior 
to initiation of IV therapy. 
Subject should be resting in a seated or semi-recumbent position for at least 5 minutes prior to 
having vital sign measurements obtained. For subjects who cannot sit up, HR, BP, and RR may be 
taken in a supine or semi-recumbent position. 
Body temperature may be taken per the site’s preferred method (i.e., one of core temperature 
[tympanic, rectal, or esophageal], oral and axillary temperatures). Method of measuring body 
temperature will be recorded in the appropriate eCRF. The same method of measuring a subject’s 
body temperature should be used throughout the study. 
Refer to Section 7.6.1.4.3 for vital sign abnormalities. 
7.6.3.2. Physical Examination 
Standard physical examination will be performed at screening. Unscheduled physical examination 
(standard or symptom directed) may be performed as needed. 
Standard physical examinations include body weight and height, general appearance, 
skin/subcutaneous tissue, head, ears, nose, throat, neck and thyroid, thorax, lungs, cardiovascular, 
lymph nodes, abdomen, musculoskeletal, and neurological examinations. Genitalia, rectal, and 
breast examinations will only be performed if medically indicated. 
Symptom-oriented physical examinations will be performed daily during IV study therapy after 
screening. This is a target physical examination based on the investigator’s judgment of the 
subject’s symptoms. 

 
 
 
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Abnormal findings on physical examination will be documented in the source documentation and 
eCRF. New or worsened clinically significant abnormalities should be recorded as AEs, if 
applicable. 
7.6.3.3. 12-Lead Electrocardiogram 
All subjects will have a standard 12-lead ECG performed locally at screening and at EOT visit. 
Additional ECGs can be performed as clinically indicated. The ECG will be performed after the 
subject has been in a supine or semi-recumbent position for at least 5 minutes. 
The following ECG parameters will be recorded: HR, PR interval, R-R interval, QRS duration, 
QT interval, and diagnostic statements. The QTc data will be calculated using Fridericia's 
correction. 
The investigator will assess whether the ECG is normal or abnormal, if abnormal, was it clinically 
significant or not. The results of this ECG evaluation and its interpretation will be captured. Any 
clinically significant abnormalities should be reported as AEs or medical history on the eCRF.  
7.7. 
Pharmacokinetic Analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
   
 
 
    
 
 
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8. SAMPLE SIZE AND DATA ANALYSES 
8.1. 
Determination of Sample Size 
Assuming an all-cause mortality rate of 10% at Day 14 for both treatment groups, a 
 
randomization ratio, and a one-sided significance level of 0.025, a study of approximately 
450 subjects will have more than 90% power to show non-inferiority with a 10% non-inferiority 
margin. 
A blinded sample size re-estimation will occur after approximately 
 subjects (approximately 
 
 
 
 and have recruited, randomized and had an opportunity to reach Day 
14 to assess the blinded all-cause mortality rate (pooled across treatment groups) at Day 14 to 
ensure the study assumptions are as expected. The sample size may be increased if required. 
8.2. 
Analysis Populations 
There are 9 analysis populations for this study: 
Intent-to-Treat (ITT) population: All subjects who are randomized. Subjects are analyzed 
according to the randomized treatment, regardless of the treatment actually received.  
SAF population: All subjects who receive at least 1 dose of study drug during the study. Subjects 
are analyzed according to the treatment received during the study. 
MITT population: The MITT population will serve as the primary population for efficacy 
analyses in this study. The MITT population is defined as all subjects from the ITT who receive at 
least 1 dose of study drug. 
micro-MITT population: The micro-MITT population is defined as all subjects from the MITT 
who have a Gram-negative pathogen identified at baseline and the pathogen is susceptible to the 
investigational medicinal product and comparator.  
CR-MITT population: All subjects from the MITT who have a baseline Gram-negative pathogen 
identified which is resistant to any carbapenem. 
Extended micro-MITT population: All subjects from the MITT who have a baseline 
Gram-negative pathogen identified which is susceptible to either the investigational medicinal 
product or comparator. 
CE population: All subjects from the MITT who receive at least 72 hours of IV study treatment, 
have an appropriate diagnosis of HABP/VABP, have no important protocol deviations that would 
affect the assessment of clinical outcome, and have no missing nor indeterminate assessment of 
clinical outcome. 
ME population: All subjects from the micro-MITT who receive at least 72 hours of IV study 
treatment, have an appropriate diagnosis of HABP/VABP, have no important protocol deviations 
that would affect the assessment of microbiological outcome, and have no missing nor 
indeterminate assessment of microbiological outcome. 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  

 
 
 
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8.3. 
General Considerations for Data Analyses 
Complete details of the statistical analyses, methods, and data conventions will be described in the 
statistical analysis plan. Statistical analysis will be performed using SAS System, version 9.4 or 
higher (SAS Institute, Inc., Cary, NC). 
In general, continuous data will be presented using descriptive statistics: number of subjects, mean, 
standard deviation, minimum, the first quartile, median, the third quartile, and maximum. 
Geometric means and coefficient of variation will also be provided where applicable. Categorical 
data will be presented as frequencies with percentages per category. All reported confidence 
intervals (CIs) will be two-sided 95% CIs. 
Summary data will be presented by treatment group and overall, and when applicable, by 
assessment time. Individual subject data will be listed by subject number, and, where applicable, 
by assessment time. 
8.4. 
Demographic and Baseline Characteristics 
Demographics and other baseline characteristics will be presented using descriptive statistics for 
continuous and categorical data. 
8.5. 
Medical History and Prior/Concomitant Medications 
Medical history records will be summarized using descriptive statistics by SOC and PT within 
each SOC.  
Prior/concomitant medications will be summarized separately using descriptive statistics for 
categorical data. 
8.6. 
Efficacy Analysis 
8.6.1. 
Estimand for the Primary Endpoint 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 

 
 
 
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8.6.1.2. Primary Efficacy Analysis   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.6.2. 
Secondary Efficacy Analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.6.3. 
Exploratory Efficacy Analysis 
Descriptive statistics will be provided for the total number of days spent in the hospital/ in the 
ICU/ on mechanical ventilation from the time of post-randomization for the MITT population. 
Number of days on mechanical ventilation will be analyzed in the subgroup of ventilated subjects.  

 
 
 
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8.7. 
Safety and Tolerability Analysis 
Safety and tolerability will be evaluated by presenting summaries of treatment-emergent AEs, 
routine clinical laboratory evaluations, vital signs, physical examination findings, and ECGs for 
each treatment group and overall. 
All safety and tolerability analyses will be performed using the SAF. 
All analyses of safety and tolerability endpoints will be descriptive only, and no inferential 
statistics will be provided. 
8.7.1. 
Adverse Events 
Treatment-emergent AEs are defined as any AEs with an onset date on or after the study drug start 
date. 
Summary tables will be provided for all TEAEs by treatment group. The number and percentage 
of subjects with TEAEs, related TEAEs, SAEs, and TEAEs leading to discontinuation of the study 
treatment will be presented by the current MedDRA version, SOC and PT. In addition, the number 
and percentage of subjects with TEAEs will be presented by SOC and PT by maximum severity.  
In the TEAE summaries, subjects will be counted only once for each SOC if one or more TEAEs 
are reported. Similarly, subjects with more than one episode of a TEAE will be counted only once 
within a PT. 
For summaries by maximum severity, subjects with multiple TEAEs within a particular SOC or 
PT will be counted under the category of their most severe TEAE within that SOC or PT. 
Listings will be produced for all AEs (TEAEs and non-treatment-emergent). In addition, listings 
will be provided for those subjects who experience an SAE, including death, or who experience 
an AE associated with early withdrawal from the study or from study drug. 
8.7.2. 
Clinical Laboratory Evaluations 
Clinical laboratory data (including abnormal laboratory values and changes in abnormalities) will 
be summarized using descriptive statistics for continuous or categorical variables by visit. Where 
appropriate, absolute change from baseline will also be presented. 
Selected clinical laboratory data will be presented graphically using scatterplots and/or boxplots. 
Clinical laboratory tests data will be listed. 
8.7.3. 
Vital Signs 
Descriptive statistics of vital signs measurements and their change from baseline at each visit will 
be presented by treatment group.  

 
 
 
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8.7.4. 
Physical Examination 
Physical examination findings will only be listed for each subject. 
8.7.5. 
12-Lead Electrocardiogram 
Descriptive statistics will be provided. The ECG results (including QTc change) will be 
summarized by treatment group and will also be listed. 
8.8. 
Pharmacokinetic Analysis 
Concentration-time data for XNW4107, imipenem, and cilastatin will be analyzed and summarized 
by analyte using descriptive statistics (number of subjects, arithmetic mean, geometric mean, 
median, standard deviation, minimum, maximum, and coefficient of variation) at each scheduled 
collection time interval. Concentration-time data will be displayed graphically on the linear and 
semi-logarithmic scales. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
8.9. 
Data Monitoring Committee 
An independent DMC will be employed to oversee the progress of this study and to ensure the 
ongoing safety of the subjects participating in this study. The DMC will regularly review the safety 
data of enrolled subjects. The DMC can only recommend stopping the study early based on safety 
findings. No early stopping for efficacy is planned. Details describing the DMC process and 
procedures, and the timing and frequency of meetings will be outlined in a separate DMC Charter. 
8.10. Data Review Committee 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
  

 
 
 
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 DRC Charter  

 
 
 
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9. REFERENCES 
Andes D and Craig WA. Animal model pharmacokinetics and pharmacodynamics: a critical 
review. Int J Antimicrob Agents. 2002;19(4):261-268. 
Center for Drug Evaluation of NMPA (CDE). Technical guidelines for clinical trials of 
antimicrobial drugs for hospital-acquired bacterial pneumonia/ventilator-associated bacterial 
pneumonia, 2020. 
Clinical and Laboratory Standards Institute (CLSI) 2021. M100Ed31. Performance standards for 
antimicrobial susceptibility testing: 29th informational supplement. Clinical and Laboratory 
Standards Institute, Wayne, PA. 
Das S, Zhou D, Nichols W, et al. Selecting the dosage of ceftazidime–avibactam in the perfect 
storm of nosocomial pneumonia. Eur J of Clin Pharmacol. 2020, 76:349–361. 
Drusano GL. Prevention of resistance: a goal for dose selection for antimicrobial agents. Clin 
Infect Dis. 2003;36(Suppl 1):S42-S50. 
European Medicines Agency. Guideline on the evaluation of medicinal products indicated for 
treatment of bacterial infections. 844951/2018 Rev. 3 3 Committee for Human Medicinal Products 
(CHMP), December 2018. 
Food and Drug Administration (FDA). Guidance for Industry: Hospital-Acquired Bacterial 
Pneumonia and Ventilator-Associated Bacterial Pneumonia: Developing Drugs for Treatment, 
June 2020. 
Food and Drug Administration (FDA). 2021, Antibacterial Susceptibility Test Interpretive Criteria. 
Available at https://www.fda.gov/drugs/development-resources/antibacterial-susceptibility-test-
interpretive-criteria. Accessed at January 2022. 
Ferreira FL, Bota DP, Bross A, Mélot C, Vincent JL. Serial evaluation of the SOFA score to predict 
outcome in critically ill patients. JAMA. 2001;286(14):1754-1758. 
Jones RN. Microbial etiologies of hospital-acquired bacterial pneumonia and ventilator-associated 
bacterial pneumonia. Clin Infect Dis. 2010;51(Suppl 1):S81-87. 
Koch GG, Carr GJ, Amara IA, et al. Categorical Data Analysis. Chapter 13 in Berry, D.A. (ed.). 
Statistical Methodology in the Pharmaceutical Sciences. New York: Marcel Dekker, Inc., 1989:pp. 
414-241.  
Knaus WA, Draper EA, Wagner DP, et al. APACHE II: A severity of disease classification system. 
Crit Care Med. 1985;13(10):818-829. 
Nicolau DP, Siew L, Armstrong J, et al. Phase 1 study assessing the steady-state concentration of 
ceftazidime and avibactam in plasma and epithelial lining fluid following two dosing regimens. J 
Antimicrob Chemother 2015; 70: 2862–2869. 
Primaxin® (imipenem/cilastatin) for Injection [Package Insert]. Whitehouse Station, NJ: Merk and 

 
 
 
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Co, Inc.; Revised January 2022. 
Primaxin® (imipenem/cilastatin) SmPC/Product Information. London, UK: Merck Sharp & 
Dohme (UK) Limited; Revised January 2021. 
Recarbrio® (imipenem/cilastatin/relebactam) for Injection [Package Insert]. Rahway, NJ: Merck 
and Co, Inc.; Revised May 2022. 
Recarbrio® (imipenem/cilastatin/relebactam) SmPC/Product Information. London, UK: Merck 
Sharp & Dohme (UK) Limited; Revised January 2021. 
Sader HS, Farrell DJ, Flamm RK, Jones RN. Antimicrobial susceptibility of gram-negative 
organisms isolated from patients hospitalised with pneumonia in US and European hospitals: 
results from the SENTRY Antimicrobial Surveillance Program, 2009–2012. Int J Antimicrob 
Agents. 2014;43(4):328-334. 
Torres A, Rank D, Melnick D, et al. Randomized Trial of Ceftazidime-Avibactam vs Meropenem 
for Treatment of Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia (REPROVE): 
Analyses per US FDA–Specified End Points. Open Forum Infectious Diseases, 2019,1-11. 
XNW4107 [Investigator’s Brochure]. 
Yin Y, Zhao C, Li H, et al. Clinical and microbiological characteristics of adults with hospital-
acquired pneumonia: a 10-year prospective observational study in China. Eur J Clin Microbiol 
Infect Dis. 2021;40(4):683-690. 
 
 
 
 
 

 
 
 
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10. APPENDIX 
Appendix 1 – Clinical Laboratory Evaluations 
All screening laboratory tests will be performed locally to assess study eligibility.  
The screening laboratory parameters required for determination of subject eligibility are listed in 
Table 5, of note, there are some parameters as follows must be done（ indispensable ） to 
ensure these are included in local clinical laboratory evaluations. 
Hematology must include: 
• 
CBC with WBC differential  
• 
Platelets 
• 
Hematocrit 
• 
Optional #1: Greater than 15% immature neutrophils (bands) noted on peripheral blood 
smear (not mandatory) 
Serum Chemistry must include: 
• 
ALT, AST and Total Bilirubin 
• 
Creatinine 
• 
Sodium 
• 
Potassium 
• 
Serum bicarbonate if ABG is not performed 
Serum pregnancy test 
Urine pregnancy test is required if not feasible to obtain results of serum pregnancy test prior to 
randomization. 
 
 
 
 

 
 
 
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The following clinical laboratory analytes will be assessed at screening, baseline and post-
baseline locally:  
Table 5: list of clinical laboratory analytes 
Chemistry 
Hematology (CBC): 
Albumin 
Hematocrit 
ALP 
Hemoglobin 
ALT 
MCH 
AST 
MCHC 
BUN/Urea 
MCV 
Calcium 
Platelet count  
Chloride 
RBC count 
Cholesterol 
WBC count 
Creatinine 
WBC differential 
GGT 
(% & ABS): 
Glucose 
Basophils 
LDH 
Eosinophils 
Phosphorus 
Lymphocytes 
Potassium 
Monocytes 
Sodium 
Neutrophils 
Total bilirubin 
 
Total CO2 (measured as 
bicarbonate)* 
For women with childbearing potential 
only (only at screening): 
Total protein 
Serum pregnancy test  
Triglycerides 
Urine pregnancy test 
Uric acid 
 
 
 
Urinalysis (UA): 
Renal Function 
Color and/or appearance  
eGFR 
pH and specific gravity 
 
Bilirubin 
Coagulation 
Glucose 
Prothrombin time 
Ketones  
Partial thromboplastin time 
Leukocytes  
INR 
Nitrite  
 
Occult blood  
 
Protein  
 
Microscopic (including RBCs and 
WBCs) 
 
Abbreviations: ABS = absolute; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = 
aspartate aminotransferase; BUN = blood urea nitrogen; CBC = complete blood count; CO2 = carbon 
dioxide; eGFR = estimated glomerular filtration rate; GGT = gamma glutamyl transferase; INR = 
international normalized ratio; LDH = lactate dehydrogenase; MCH = mean corpuscular hemoglobin; 
MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; RBC = red 
blood cell; WBC = white blood cell.  
*：Total CO2 is mandatory only when bicarbonate or pH of ABG is not performed. 

 
 
 
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Appendix 2 - APACHE II Score 
The Acute Physiology and Chronic Health Evaluation II is a severity of disease classification 
system (Knaus, 1985), one of several intensive care unit (ICU) scoring systems. After admission 
of a subject to an ICU, an integer score from 0 to 71 is computed based on several measurements; 
higher scores imply a more severe disease and a higher risk of death. 
APACHE II was designed to measure the severity of disease for adult subjects admitted to ICUs. 
The lower age is not specified in the original article, but a good limit is to use APACHE II only 
for subjects age 15 or older. 
This scoring system is used in many ways: 
• Some procedures and some medicine is only given to subjects with certain APACHE II 
score 
• APACHE II score can be used to describe the morbidity of a subject when comparing the 
outcome with other subjects 
• Predicted mortalities are averaged for groups of subjects in order to specify the group's 
morbidity. 
Even though newer scoring systems, like Simplified Acute Physiology Score II (SAPS II) have 
replaced APACHE II in many institutions, APACHE II continues to be used extensively because 
so much documentation is based on it. 
The point score is calculated from 12 routine physiological measurements (such as blood pressure, 
body temperature, heart rate, etc.) The calculation method is optimized for paper schemas. The 
resulting point score should always be interpreted in relation to the illness of the subject. 
After the initial APACHE II score has been determined, no new score can be entered for this study 
during the hospital stay. 
The appendix of the document that originally described the APACHE II score describes how to 
calculate a predicted death rate for a subject. In order to make this calculation of predicted 
mortality precise, the principal diagnosis leading to ICU admission was added as a category weight: 
the predicted mortality is computed based on the subject's APACHE II score and their principal 
diagnosis at admission. 
 
For convenience to the sites, a website that can be used to calculate APACHE II score is provided 
below as an example of tools for APACHE II calculation:  
 
https://www.mdcalc.com/calc/1868/apache-ii-score 

 
 
 
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Table 6: The APACHE II Severity of Disease Classification System 
Physiologic Variable 
High Abnormal Range 
Low Abnormal Range 
+4 
+3 
+2 
+1 
0 
+1 
+2 
+3 
+4 
Temperature – Rectal* (°C) 
>41 
39 to 
40.9 
38.5 to 
38.9 
36 to 
38.4 
34 to 
35.9 
32 to 
33.9 
30 to 
31.9 
<29.9 
Mean Arterial Pressure - mmHg 
>160 
130 to 
159 
110 to 
129 
70 to 
109 
50 to 69 
<49 
Heart Rate (ventricular 
response) 
>180 
140 to 
179 
110 to 
139 
70 to 
109 
55 to 69 
40 to 54 
<39 
Respiratory Rate 
(non-ventilated or 
ventilated) 
>50 
35 to 49 
25 to 34 
12 to 24 
10 to 11 
6 to 9 
<5 
Oxygenation: A-aDO2 or 
PaO2 (mmHg) 
a. FIO2 >0.5 record A- aDO2 
>500 
350 to 
499 
200 to 
349 
<200 
61 to 70 
55 to 60 
<55 
b. FIO2 <0.5 record PaO2 
>70 
Arterial pH (preferred) 
or 
>7.7 
7.6 to 
7.69 
7.5 to 
7.59 
7.33 to 
7.49 
7.25 to 
7.32 
7.15 to 
7.24 
<7.15 
Serum HCO3 (venous 
mEq/L) 
(not preferred, but may use if 
no ABGs) 
>52 
41 to 
51.9 
32 to 
40.9 
22 to 
31.9 
18 to 
21.9 
15 to 
17.9 
<15 
Serum Sodium (mEq/L) 
>180 
160 to 
179 
155 to 
159 
150 to 
154 
130 to 
149 
120 to 
129 
111 to 
119 
<110 
Serum Potassium 
(mEq/L) 
>7 
6 to 6.9 
5.5 to 5.9 
3.5 to 5.4 
3 to 3.4 
2.5 to 2.9 
<2.5 
Serum Creatinine 
>3.5 
2 to 3.4 
1.5 to 
0.6 to 
<0.6 
(mg/dL) 
1.9 
1.4 
Double point score for 
acute renal failure 
Hematocrit (%) 
>60 
50 to 
59.9 
46 to 
49.9 
30 to 
45.9 
20 to 
29.9 
<20 

 
 
 
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White Blood Cell Count 
(total/mm3) 
(in 1000s) 
>40 
20 to 
39.9 
15 to 
19.9 
3 to 
14.9 
1 to 2.9 
<1 
Glasgow Coma Score (GCS) 
Score = 15 minus actual GCS 
A. Total Acute Physiology Score (sum of 12 above points) 
B. 
Age points (years) ≤44 = 0; 45 to 54 = 2; 55 to 64 = 3; 65 to 74 = 5; ≥75 = 6 
C. 
Chronic Health Points (see below) 
Total APACHE II Score (add together the points from A+B+C) 
Abbreviations: A-aDO2 = alveolar-arterial pressure difference for oxygen; ABG = arterial blood gas; APACHE II = Acute Physiology and Chronic Health Evaluation II; FiO2 
= fraction of inspired oxygen; GCS = Glasgow Comma Score; PaO2 = partial pressure of oxygen. 
* 
If core temperature measurement is not available (i.e., tympanic, rectal, esophageal), oral and axillary temperatures could be adjusted by adding 0.5°C and 1°C, 
respectively.

 
 
 
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Chronic Health Points: If the subject has a history of severe organ system insufficiency or is 
immunocompromised as defined below, assign points as follows: 5 points for non-operative or 
emergency postoperative subjects and 2 points for elective postoperative subjects. 
Definitions: organ insufficiency or immunocompromised state must have been evident prior 
to this hospital admission and conform to the following criteria: 
• 
Liver – biopsy-proven cirrhosis and documented portal hypertension; episodes of past 
upper gastrointestinal bleeding attributed to portal hypertension; or prior episodes of 
hepatic failure/encephalopathy/coma 
• 
Cardiovascular – New York Heart Association Class IV 
• 
Respiratory – chronic restrictive, obstructive, or vascular disease resulting in severe 
exercise restriction (e.g., unable to climb stairs or perform household duties; or 
documented chronic hypoxia, hypercapnia, secondary polycythemia, severe 
pulmonary hypertension [>40 mmHg], or respirator dependency) 
• 
Renal – receiving chronic dialysis 
• 
Immunocompromised – the subject has received therapy that suppresses 
resistance to infection (e.g., immunosuppression, chemotherapy, radiation, 
long-term or recent high dose steroids, or has a disease that is sufficiently  
advanced to suppress resistance to infection [e.g., leukemia, lymphoma, AIDS]). 

 
 
 
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Appendix 3 – Sequential Organ Failure Assessment Score  
The sequential organ failure assessment (SOFA) score is a simple and objective score that allows 
for calculation of both the number and the severity of organ dysfunction in 6 organ systems 
(respiratory, coagulation, hepatic, cardiovascular, neurological, and renal), and the score can 
measure individual or aggregate organ dysfunction.  
For convenience to the sites, a website that can be used to calculate SOFA score is provided below 
as an example of tools for SOFA scoring:    
 
https://www.mdcalc.com/calc/691/sequential-organ-failure-assessment-sofa-score 
 
Table 7： Sequential Organ Failure Assessment Score 
The Sequential Organ Failure Assessment (SOFA) Scorea 
SOFA Score 
Variables 
0 
1 
2 
3 
4 
Respiration 
PaO2/FiO2, mmHg 
> 400 
≤ 400 
≤ 300 
≤ 200b 
≤ 100b 
Coagulation Platelets 
×103/μL 
> 150 
≤ 150 
≤ 100 
≤ 50 
≤ 20 
Liver 
Bilirubin, mg/dLc 
< 1.2 
1.2 – 1.9 
2.0 – 5.9 
6.0 – 11.9 
≥ 12.0 
Cardiovascular 
Hypotension 
No 
hypotension 
Mean 
arterial 
pressure 
< 70 mmHg 
Dop ≤ 5 or 
dob (any 
dose)d 
Dop > 5, epi 
≤ 0.1, or norepi 
≤ 0.1d 
Dop 
> 15, epi 
> 0.1, or 
norepi 
> 0.1d 
Central Nervous System 
Glasgow Coma Score Scale 
15 
13 - 14 
10 - 12 
6 -9 
< 6 
Renal 
Creatinine, mg/dL or 
Urine Output, mL/de 
< 1.2 
1.2 – 1.9 
2.0 – 3.4 
3.5 – 4.9 
or < 500 
≥ 5.0 
or < 200 
Abbreviations: dob = dobutamine, Dop = dopamine, epi = epinephrine, FiO2 = fraction of inspired oxygen; norepi = 
norepinephrine; PaO2 = partial pressure of oxygen. 
a 
In non-ventilated subjects, a respiration score of 0 may be assigned. 
b 
Values are with respiratory support. 
c 
To convert bilirubin from mg/dL to μmol/L, multiply by 17.1. 
d 
Adrenergic agents administered for at least 1 hour (doses given are in μg/kg/minute).  
e 
To convert creatinine from mg/dL to μmol/L, multiply by 88.4. 
 
Source: Ferreira, 2001 
 

 
 
 
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Appendix 4 – Glasgow Coma Scale 
Table 8：Glasgow Coma Scale 
 
 
 
In ventilated and sedated subjects, the GCS cannot be properly assessed, and a normal score of 15 could be used to complete the 
APACHE II and SOFA scores. If a reliable presedation score is available, it can be used. 
Source: GCS-Assessment-Aid-English.pdf (glasgowcomascale.org) 
Permission: https://www.glasgowcomascale.org/permissions/ 
 
 
 
Criterion 
Rating 
Score 
Eye Opening 
Open before stimulus 
Spontaneous 
4 
After spoken or shouted request 
To sound 
3 
After finger tip stimulus 
To pressure 
2 
No opening at any time, no interfering factor 
None 
1 
Closed by local factor 
Non testable 
NT 
Verbal 
Response 
Correctly gives name, place and date 
Orientated 
5 
Not orientated but communication coherently 
Confused 
4 
Intelligible single words 
Words 
3 
Only moans/groans 
Sounds 
2 
No audible response, no interfering factor 
None 
1 
Factor interfering with communication 
Non testable 
NT 
Best 
Motor 
Response 
Obey 2-part request 
Obey commands 
6 
Brings hand above clavicle to stimulus on 
head neck 
Localizing 
5 
Bends arm at elbow rapidly but features not 
predominantly abnormal 
Normal flexion 
4 
Bends arm at elbow, features clearly 
predominantly abnormal 
Abnormal flexion 
3 
Extends arm at elbow 
Extension 
2 
No movement in arms/legs, no interfering 
factor 
None 
1 
Paralysed or other limiting factor 
Non testable 
NT 

 
 
 
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Appendix 5 – Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines 
• Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines 
• Applicable laws and regulations. 
The protocol, protocol amendments, informed consent form (ICF), investigator’s brochure, and 
other relevant documents (e.g., advertisements) must be submitted to an institutional review board 
(IRB)/independent ethics committee (IEC) by the investigator and reviewed and approved by the 
IRB/IEC before the study is initiated.  
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC 
• Notifying the IRB/IEC of serious adverse events (SAEs) or other significant safety findings 
as required by IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies 
(if applicable), and all other applicable local regulations. 
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
Informed Consent 
Written informed consent to participate in the study will be obtained from all subjects before any 
protocol specific procedures are conducted. In the instance that subjects are unable to provide 
consent by themselves, consent must be obtained from the subject’s legally authorized 
representative (according to local regulations). The ICF generated by the Sponsor or designee will 
be approved (along with the protocol) by the IRB/IEC. 
Information about the study will be given to the subject both verbally and in writing. The written 
subject information sheet will explain the objectives of the study and its potential risk and benefits. 
The subject should have adequate time to read the information sheet and to ask the investigator 

 
 
 
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any questions. The investigator must be satisfied that the subject has understood the information 
provided before written consent is obtained. If there is any doubt as to whether the subject has 
understood the written and verbal information, the subject should not enter the study. 
If a subject agrees to participate, he/she will be asked to sign and date the study ICF which will be 
retained by the investigator. A copy of the signed ICF will be given to the subject. The informed 
consent process must be documented in the subject’s source documents. The original ICF must be 
retained by the investigator and made available for inspection by the study monitor. 
Future Use of Subject Samples 
No human samples will be stored for future biomedical research. Plasma samples for 
pharmacokinetic analysis will be stored for concentration assessments until the end of the study. 
Bacterial isolates (not human samples) will be stored until the completion of all regulatory 
requirements for registration. 
Subject Data Protection 
Subjects will be assigned a unique identifier and will not be identified by name in the electronic 
case report forms (eCRFs), study-related forms, study reports, or any related publications. Subject 
and investigator personal data will be treated in compliance with all applicable laws and 
regulations. In the event the study protocol, study report, or study data are included in a public 
registry, all identifiable information from individual subjects or investigators will be redacted 
according to applicable laws and regulations.  
The subject, or their legally authorized representative, must be informed that their personal 
study-related data will be used by the Sponsor in accordance with local data protection law. The 
level of disclosure must also be explained to the subject. The subject must also be informed that 
his/her medical records may be examined by Sponsor or contract research organization (CRO) 
auditors or other authorized personnel appointed by the Sponsor, by appropriate IRB/IEC members, 
and by inspectors from regulatory authorities. 
Investigator Documentation Responsibilities 
All individual, subject-specific study data will be entered into a 21 CFR Part 11-compliant 
electronic data capture (EDC) system on an eCRF in a timely fashion. All data generated from 
external sources (e.g., central laboratory) and transmitted to the Sponsor or designee electronically 
will be integrated with the subject’s eCRF data. 
An eCRF must be completed for each subject who signs an ICF and undergoes any screening 
procedures, according to the eCRF completion instructions. The Sponsor, or CRO, will review the 
supporting source documentation against the data entered into the eCRFs to verify the accuracy of 
the electronic data. The investigator will ensure that corrections are made to the eCRFs and that 
data queries are resolved in a timely fashion by the study staff.  
The investigator will sign and date the eCRF via the EDC system’s electronic signature procedure. 
These signatures will indicate that the investigator reviewed and approved the data on the eCRF, 
the data queries, and the site notifications. 

 
 
 
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Electronic Data Capture 
The Sponsor will supply the investigational site with access to a web-based EDC computer system. 
Edit checks and data logic checks are at the point of entry and are validated according to company 
standard operating procedures. All data entered into the system are transferred to a secure database. 
Access to the EDC system at the site, for vendors, at the Sponsor, and at the CRO is password 
protected. Study access is granted to site personnel only after they have been trained in the use of 
the EDC system at the investigational site. 
The EDC system contains a system generated audit trail that captures any changes made to a data 
field, including who made the change, and the date and time it was made. This information is 
available at the investigator’s site, at the CRO, and at the Sponsor. 
Data entries made in the EDC screens should be completed within 5 days of the subject’s study 
visit and must be supported by source documents maintained for all subjects enrolled in the study. 
The data collection tool for this study will be the validated electronic system. Subject data 
necessary for analysis and reporting will be entered and transmitted via the electronic system. 
Clinical data management will be performed in accordance with applicable standards and data 
cleaning procedures. For data coding (e.g., adverse events [AEs], medication), internationally 
recognized and accepted dictionaries will be used. 
After database lock has been declared all data will be delivered to the Sponsor. 
Study Monitoring and Data Quality Assurance 
The Sponsor or Sponsor’s designee performs quality control and assurance checks on all clinical 
studies that it conducts. Before enrolling any subjects in this study, the Sponsor or Sponsor’s 
designee and the investigator will review the protocol, the XNW4107 IB, the eCRF and 
instructions for their completion, the procedure for obtaining informed consent, and the procedure 
for reporting AEs and SAEs. The Sponsor’s designee will monitor the conduct of the study at the 
site and will verify eCRF against source documents. Additionally, the Sponsor’s designee will use 
automated validation programs to help identify missing data, selected protocol deviations, out-of-
range data, and other data inconsistencies. Requests for data clarification or correction will be 
electronically provided to the investigator for resolution. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor or Sponsor’s designee. Inspection of site facilities (e.g., 
pharmacy drug storage areas, laboratories, etc.) and review of study-related records will occur to 
evaluate the study conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements. 

 
 
 
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Review of Source Documents 
The investigator agrees that the study monitor (and other qualified personnel as appropriate) will 
be allowed to conduct site visits to the investigational facilities for the purpose of reviewing source 
records pertinent to the study. The investigator will make the study files available during 
monitoring visits. These files will also be available for inspection by representatives of the Sponsor, 
competent authorities, and/or the IEC/IRB. Subjects will not be identified by name on any of the 
study documents utilized by the Sponsor for their analysis, and confidentiality of information in 
medical records will be preserved. Every effort will be made to maintain the confidentiality of the 
subject unless disclosure is required by regulations. 
Protocol Amendments 
Any substantial amendments in the research protocol during the period, for which the IEC/IRB 
approval had already been given, will not be initiated without submission of an amendment for 
IEC/IRB review and approval. 
These requirements for approval will in no way prevent any immediate action from being taken 
by the investigator in the interest of preserving the safety of all subjects included in the trial. 
Protocol Deviations 
A protocol deviation is any departure from the defined procedures and treatment plans as outlined 
in the protocol version submitted and previously approved by the IEC/IRB. Protocol deviations 
have the potential to place participants at risk and can also undermine the scientific integrity of the 
study thus jeopardizing the justification for the research. Protocol deviations are unplanned and 
unintentional events. 
Important protocol deviations, such as significant non-compliance or other serious unforeseen 
deviations deemed to invalidate the data collected in lieu of the purpose of the study will lead to 
exclusion of data from analysis. In case of non-protocol deviations, data will not be excluded from 
the data analysis.  
All decisions regarding the type of deviations (important or non-important) will be made prior to 
commencing the final analysis on the final locked database. A listing of all subjects with protocol 
deviations will be maintained by the Sponsor and a listing of all important protocol deviations will 
be presented in the final study report. 
Investigational sites will report protocol deviations to their IEC/IRB per institutional reporting 
requirements. 
Change in Investigator 
If any investigator retires, relocates, or otherwise withdraws from conducting the study, the 
responsibility for maintaining records may be transferred to the Sponsor or designee, IEC/IRB, or 
another investigator. The Sponsor or designee must be notified of and agree to the change. 
Regulatory agencies will be notified with the appropriate documentation. 

 
 
 
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Clinical Study Report 
A clinical study report will be prepared following the completion of the study. 
Confidentiality/Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of the study, will be regarded as confidential. The investigator (or 
designee) agrees not to disclose such information in any way without prior written permission 
from the Sponsor. 
Records Retention 
Essential documents must be retained for longer than 5 years after completion of the study, 2 years 
after the final marketing authorization in an ICH region or until at least 2 years have elapsed since 
the discontinuation of clinical development of the study drug. If it becomes necessary for the 
Sponsor or the Competent Authority to review any documentation relating to the study, the 
investigator must permit access to such records. 
Study files may be discarded upon written notification by the Sponsor. To avoid error, the 
investigator must contact the Sponsor before destroying any records or reports pertaining to the 
study, to ensure that retention is no longer required. Other source documents, such as subject’s 
medical records, must be retained for the maximum period of time permitted by the hospital or 
institution and until such time when the investigator is informed by the Sponsor that there is no 
further need to do so. 
In addition, in accordance with the investigator agreement, the Sponsor should be contacted if the 
site’s principal investigator plans to leave the investigational site so that appropriate arrangements 
can be made. 
Publications 
If on completion of the study the data warrant publication, the investigator may publish the results 
in recognized (refereed) scientific journals subject to the provisions of the clinical study agreement 
(CSA). Unless otherwise specified in the CSA, the following process shall occur. 
The institution and investigator shall not publish or present data from an individual study center 
until the complete multicenter study has been presented in full or for 2 years after the termination 
of the multicenter study, whichever occurs first. Subsequent publications must refer to the 
multicenter findings. Thereafter, if the investigator expects to participate in the publication of data 
generated from this site, the institution and investigator shall submit reports, abstracts, manuscripts, 
and/or other presentation materials to the Sponsor for review before submission for publication or 
presentation. The Sponsor shall have 60 days to respond with any requested revisions, including 
(without limitation) the deletion of confidential information. The investigator shall act in good 
faith upon requested revisions, except the investigator shall delete any confidential information 
from such proposed publications. The investigator shall delay submission of such publication or 
presentation materials for up to an additional 90 days in order to have a patent application(s) filed. 

 
 
 
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Protocol Version 4.1  
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Protocol Version 4.1  
Evopoint Biosciences USA, Inc. 
Appendix 7- Main study medical representative 
Table 10: Main study medical representative 
ROLE 
NAME 
CONTACT 
Sponsor  
Sponsor’s Medical 
Representative(China) 
Jing Feng, 
Medical Monitor 
E-mail:jing.feng@evopointbio.com 
phone: 0512-89162086 
 
Sponsor’s Medical 
Representative 
(Ex-China) 
Cuiqiong Du, 
Medical Director 
 
E-mail:tracy.du@evopointbio.com 
Phone: 14437660326 
Clinical Research Organization (CRO) 
CRO Medical 
Monitor 
Soto Norberto, 
Medical Director 
E-mail:norberto.soto@labcorp.com 
Phone:1 609 212 7892