Prospective, Phase 3, Randomized, Multi-center, Double-blind Study of Efiicacy, Tolerability & Safety of Sulopenem & Sulopenem-etzadroxil/Probenecid vs Ertapenem Followed by Cipro-metronidazole for Treatment of cIAI in Adults
Phase: PHASE3
Conditions: Intra Abdominal Infections
Sponsor: Iterum Therapeutics, International Limited

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Clinical Trial Protocol: IT001-303 
May 2018 
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Clinical Trial Protocol: IT001-303 
Study Title: 
A prospective Phase 3, double-blind, multicenter, randomized 
study of the efficacy and safety of sulopenem followed by 
sulopenem etzadroxil with probenecid versus ertapenem followed 
by ciprofloxacin and metronidazole or amoxicillin-clavulanate for 
treatment of complicated intra-abdominal infections in adults. 
Study Number: 
IT001-303 
Study Phase: 
Phase 3 
Product Name: 
Sulopenem (CP-70429), Sulopenem etzadroxil (PF-
03709270)/Probenecid 
IND Number: 
129,849; 129,834 
EudraCT Number 
2017-003773-34 
Indication: 
Complicated intra-abdominal infection 
Investigators: 
Multicenter 
Sponsor: 
Iterum Therapeutics International Limited 
Block 2 Floor 3, Harcourt Centre,  
Harcourt Street, Dublin 2, Ireland 
Sponsor Contact: 
Sailaja Puttagunta 
Sponsor’s US Agent: Iterum Therapeutics US Limited 
20 Research Parkway, Suite A 
Old Saybrook, CT 06475 
Medical Monitor: 
Bernard Brownstein 
Office phone number: +1 (267) 464 2572 ext:2172 
Cell phone number: +1 (267) 858 0655 
Email address: Bernard.Brownstein@psi-cro.com 
Pharmacovigilance 
PSI Pharmacovigilance 
Pharmacovigilance 
Contact 
Email: SafetyDesk@psi-cro.com 
Fax numbers: 1-800-361-9714; +7 (812) 320 3850 
Date 
Original Draft Protocol 
August 23, 2017 
Revised Draft Protoco 
October 04, 2017 
Final Protocol 
May 29, 2018 
Confidentiality Statement 
This document is strictly confidential.  It was developed by Iterum Therapeutics US Limited and 
should not be disclosed to a third party, with the exception of regulatory agencies and study 
audit personnel.  Reproduction, modification or adaptation, in part or in total, is strictly 
forbidden without prior written approval by Iterum Therapeutics US Limited 

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Throughout this document, symbols indicating proprietary names (®, ™) are not displayed.  The appearance of 
product names without these symbols does not imply that these names are not protected. 

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SYNOPSIS 
Sponsor: 
Iterum Therapeutics International Limited 
Name of Finished Product: 
Sulopenem; Sulopenem etzadroxil/probenecid 
Name of Active Ingredient: 
Sulopenem (CP-70429); Sulopenem etzadroxil (PF-03709270)/probenecid 
Study Title: 
A prospective Phase 3, double-blind, multicenter, randomized study of the efficacy and safety 
of sulopenem followed by sulopenem etzadroxil with probenecid versus ertapenem followed 
by ciprofloxacin and metronidazole or amoxicillin-clavulanate for treatment of complicated 
intra-abdominal infections in adults. 
Study Number: 
IT001-303 
Study Phase: Phase 3 
Primary Objective(s):  
To compare the efficacy of sulopenem followed by sulopenem etzadroxil with probenecid 
versus ertapenem followed by ciprofloxacin and metronidazole or amoxicillin-clavulanate for 
treatment of complicated intra-abdominal infection in adults, on Day 28 (test of cure [TOC]) 
post randomization. 
Secondary Objective(s):  
To compare the efficacy outcomes at other relevant time points as well as the safety profile of 
treatment with sulopenem followed by sulopenem etzadroxil plus probenecid versus 
ertapenem followed by ciprofloxacin and metronidazole or amoxicillin-clavulanate for 
treatment of complicated intra-abdominal infection in adults.  
To assess the population PK profile of sulopenem when administered either intravenously or 
as the prodrug, sulopenem etzadroxil, co-administered with probenecid. 
Study Design:  
Sulopenem is an investigational penem antibiotic being developed for treatment of 
uncomplicated urinary tract infections (uUTI), complicated urinary tract infections (cUTI) 
and complicated intra-abdominal infections (cIAI). Sulopenem etzadroxil is an oral pro-drug 
of sulopenem. Upon oral absorption, sulopenem etzadroxil is expected to be rapidly 
hydrolyzed to yield sulopenem, the active moiety, as well as the non-active moieties, 
formaldehyde and 2-ethylbutyric acid (2-EBA).   
Sulopenem possesses potent activity against species of the Enterobacteriaceae that encode 
ESBLs or AmpC-type β-lactamases that confer resistance to third generation cephalosporins. 
Sulopenem etzadroxil is expected to be the first oral penem on the market in the United States 

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or Europe and will offer the option of treatment in the outpatient setting as well as IV to oral 
switch therapy for early discharge of patients hospitalized with serious complicated 
infections.  Probenecid, co-administered with the oral prodrug, will reduce renal clearance 
and increase systemic exposure of the active moiety, sulopenem.   
This Phase 3, multicenter, double-blind, randomized, controlled study compares IV 
sulopenem followed by sulopenem etzadroxil with probenecid and ertapenem IV followed by 
oral ciprofloxacin and metronidazole or amoxicillin-clavulanate for treatment of cIAI. The 
site pharmacist will be unblinded in order to prepare the intravenous study medications and 
select the appropriate oral follow on therapy for patients randomized to the ertapenem 
regimen. Approximately 670 adults with cIAI will be randomized in a 1:1 fashion to receive 
either IV sulopenem 1000 mg once daily for at least 5 days followed by sulopenem etzadroxil 
500 mg co-administered with oral probenecid 500 mg twice daily to complete 7-10 days of 
treatment or ertapenem IV 1000 mg once daily for at least 5 days followed by ciprofloxacin 
and metronidazole or amoxicillin-clavulanate to complete 7-10 days of therapy. Duration of 
therapy in both treatment groups may be extended up to a total duration of 14 days if both (a) 
approved by the medical monitor, and (b) the patient has either multiple abscesses or non-
appendix-related diffuse peritonitis AND has one of the following: fever or hypothermia 
(temperature ≥38°C or <35°C), leukocytosis defined as WBC ≥12,000/mm3, or ileus. 
The primary outcome measure (clinical response) for the efficacy evaluation will be assessed 
programmatically on Day 28 (TOC) as either:  
Clinical cure, defined as:  
• Patient is alive 
• Resolution in baseline signs and symptoms of the index infection 
o No new symptoms 
• No new antibiotics or interventions for treatment failure are required 
Clinical failure, defined as: 
• death due to cIAI  
• Surgical site wound infection requiring non-study systemic antibiotic therapy 
• Unplanned surgical procedures or percutaneous drainage procedures for complication 
or recurrence of cIAI based on documented worsening symptoms or signs of cIAI 
• Initiation of non-trial antibacterial drug therapy for treatment of cIAI based on 
documented worsening symptoms or signs of cIAI 
If data are unavailable to determine if the patient is a cure or a failure, the patient outcome 
will be considered an indeterminate response. 
For the primary efficacy evaluation, the proportions of patients achieving cure, failure or 
indeterminate will be determined in the microbiologic-modified intent to treat population (m-
MITT). The m-MITT population will be comprised of all randomized patients who received 
at least one dose of study drug and had a baseline pathogen causing cIAI isolated from a 
culture specimen taken at baseline, prior to initiation of study drug therapy. 

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Study Population:  
A total of 670 patients are planned; the sample size will be adjusted at the blinded interim 
analysis if the baseline assumptions for clinical cure rate are not met.  
Patients will be randomized using an Interactive Web Randomization System (IWRS) system 
into the study, provided they have satisfied all patient selection criteria. The randomization 
schedule will be stratified by the type of infection. The proportion of patients who have cIAI 
caused by appendicitis with perforation or peri-appendiceal abscess will not exceed 
approximately 50 percent. 
Inclusion Criteria: 
1. Patient or the patient’s legally acceptable representative able to provide a signed written 
informed consent prior to any study-specific procedures.  
2. Adult patients ≥18 years of age.  
3. EITHER: 
a. Intra-operative/post-operative enrollment with visual confirmation (presence of pus 
within the abdominal cavity) of an intra-abdominal infection associated with 
peritonitis including at least 1 of the following diagnosed during the surgical 
intervention: 
i. 
Cholecystitis with gangrenous rupture or perforation or progression of the 
infection beyond the gallbladder wall 
ii. 
Diverticular disease with perforation or abscess 
iii. 
Appendiceal perforation or peri-appendiceal abscess 
iv. 
Traumatic perforation of the intestines, only if operated on >12 hours after 
perforation occurs 
v. 
Secondary peritonitis (but not spontaneous bacterial peritonitis associated 
with cirrhosis and chronic ascites) 
vi. 
Intra-abdominal abscess (including of liver or spleen provided that there was 
extension beyond the organ with evidence of intraperitoneal involvement). 
OR: 
b. Pre-operative enrollment where one of the following surgical procedures are 
planned within 24 hours of the first dose of study drug: 
i. 
Open laparotomy, percutaneous drainage of an intra-abdominal abscess, or 
laparoscopic surgery. 
4. Evidence of systemic inflammatory indicators, with at least one of the following: 
a. Fever (defined as body temperature >38°C) or hypothermia with a core body 
temperature <35°C 
b. Elevated white blood cell count (>12,000 cells/mm3), or leukopenia (defined as 
white blood cell count <4,000 cells/mm3) 
c. Drop in blood pressure (systolic BP must be <90 mm Hg without pressor support) 
d. Increased heart rate (>90 bpm) and respiratory rate (>20 breaths/min) 
e. Hypoxia (oxygen saturation ≤90 percent on room air) 
5. Physical findings consistent with intra-abdominal infection, such as: 

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a. Abdominal pain and/or tenderness, with or without rebound 
b. Localized or diffuse abdominal wall rigidity 
c. Abdominal mass 
d. Nausea and/or vomiting 
e. Altered mental status 
6. Specimen/s from the surgical intervention were sent (or planned to be sent in case of pre-
operative enrollment) for culture.  
Microbiologic specimens collected during routine operative care prior to subject providing 
informed consent may be used for study purposes. 
Exclusion Criteria 
1. Patient diagnosed with traumatic bowel perforation undergoing surgery within 12 hours; 
perforation of gastroduodenal ulcers undergoing surgery within 24 hours. Other intra-
abdominal processes in which the primary etiology was not likely to be infectious. 
2. Patient has abdominal wall abscess or bowel obstruction without perforation or ischemic 
bowel without perforation. 
3. Patient has simple cholecystitis or gangrenous cholecystitis without rupture, or simple 
appendicitis, or acute suppurative cholangitis, or infected necrotizing pancreatitis or 
pancreatic abscess. 
4. Patient whose surgery included staged abdominal repair, or “open abdomen” technique, 
or marsupialization. 
5. Patient known at study entry to have a complicated intra-abdominal infection caused by 
pathogens non-susceptible to the study antimicrobial agents. 
6. Patient needed effective concomitant systemic antibacterials (oral, IV, or intramuscular) 
or antifungals in addition to those designated in the 2 study groups, except vancomycin, 
linezolid, or daptomycin if started for known or suspected methicillin-resistant 
Staphylococcus aureus (MRSA) or Enterococcus spp..  
7. Patient has perinephric infections or an indwelling peritoneal dialysis catheter. 
8. Patient has suspected intra-abdominal infections due to fungus, parasites (e.g., amoebic 
liver abscess), virus, or tuberculosis. 
9. Patient has a known history of serious allergy, hypersensitivity or any serious reaction to 
carbapenem antibiotics, other β-lactam antibiotics, quinolones, metronidazole, or 
probenecid. 
10. Patient is known to have any of the following laboratory values as defined below: 
a. Hematocrit <25% or hemoglobin <8 g/dL 
b. Absolute neutrophil count <1000/mm3 
c. Platelet count <75,000/mm3 
d. Bilirubin >3 x the upper limit of normal (ULN), unless isolated hyperbilirubinemia 
was directly related to the acute infection or known Gilbert’s disease 
e. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 x ULN 
values at Screening. Patients with elevations of AST and/or ALT up to 5 x ULN 

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will be eligible if these elevations are acute and directly related to the infectious 
process being treated. This must be documented. 
f. Alkaline phosphatase (ALP) >3 x ULN. Patients with values >3.0 x ULN and <5.0 
x ULN are eligible if this value is acute and directly related to the infectious 
process being treated. This must be documented. 
11. Patient has a body mass index >45 kg/m2. 
12. Patient has APACHE II score >30 (serum bicarbonate may be used in place of arterial 
blood gases; see Appendix 5) 
13. Patient considered unlikely to survive the 4 week study period or has a rapidly 
progressive or terminal illness, including septic shock that was associated with a high 
risk of mortality. 
14. Patient unlikely to respond to 10–14 days of treatment with antibiotics. 
15. Patient received systemic antibacterial agents within the 72-hour period prior to study 
entry, unless either of the following pertained: 
a. Patient has a new infection (not considered a treatment failure) and both of the 
following were met: 
i. Patient received no more than 24 hours of total prior antibiotic therapy 
ii. Patient received ≤1 dose of a treatment regimen post-operatively and 
antibiotics were not received more than 6 hours post-procedure. 
b. Patient considered to have failed the previous treatment regimen i.e., pre-operative 
treatment of any duration with non-study systemic antimicrobial therapy for 
peritonitis or abscess permitted provided that all of the following are met: 
i. The treatment regimen had been administered for at least 72 hours and was 
judged to have been inadequate 
ii. The patient had an operative intervention that was just completed or was 
intended no more than 24 hours after study entry 
iii. Findings of infection were documented at surgery 
iv. Specimens for bacterial cultures and susceptibility testing were taken at 
operative intervention 
v. No further non-study antibacterials were administered after randomization. 
16. Patient has a concurrent infection that may interfere with the evaluation of response to 
the study antibiotic. 
17. Patient receiving hemodialysis, hemofiltration or peritoneal dialysis. 
18. Patient has a history of acute hepatitis in the recent past (3 months prior to study entry), 
chronic hepatitis, cirrhosis, acute hepatic failure, or acute decompensation of chronic 
hepatic failure. 
19. Patient has past or current history of epilepsy or seizure disorders excluding febrile 
seizures of childhood. 
20. Patient immunocompromised as evidenced by any of the following: 
a. Human immunodeficiency virus infection, with either a recent (in the past 6 
months) acquired immune deficiency syndrome-defining condition or a CD4 + T 
lymphocyte count <200/mm3  

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b. Systemic or hematological malignancy requiring chemotherapeutic or 
radiation/immunologic interventions within 6 weeks prior to randomization or 
anticipated to begin prior to completion of study 
c. Immunosuppressive therapy, including maintenance corticosteroid therapy (>40 
mg/day equivalent prednisolone for 5 days or more). 
21. Patient participating in any other clinical study that involved the administration of an 
investigational medication at the time of presentation, during the course of the study, or 
who had received treatment with an investigational medication in the 30 days prior to 
study enrollment, or had previously been enrolled in this study or had been treated with 
sulopenem. 
22. Patient is in a situation or has a condition that, in the investigator’s opinion, may interfere 
with optimal participation in the study. 
23. Patient unlikely to comply with protocol e.g., uncooperative attitude, inability to return 
for follow-up visits, and unlikely to complete the study. 
24. Patient has known inflammatory bowel disease (ulcerative colitis or Crohn’s disease) or 
Clostridium difficile-associated diarrhea 
25. Patients with a history of blood dyscrasias 
26. Patients with a history of uric acid kidney stones 
27. Patients with acute gouty attack 
28. Patients on chronic methotrexate therapy 
29. Females of child-bearing potential who are unable to take adequate contraceptive 
precautions (refer to Section 4.4.1), have a positive pregnancy test result within 24 hours 
of study entry, are otherwise known to be pregnant, or are currently breastfeeding an 
infant. 
30.  Male subjects who do not agree to use an effective barrier method of contraception 
during the study and for 14 days post treatment (refer to Section 4.4.2). 
Test Product, Dose, and Mode of Administration:  
Investigational study medications include sulopenem 1000 mg IV over 3 hours, sulopenem 
etzadroxil  500 mg PO twice daily co-administered with probenecid 500 mg PO twice daily, 
ertapenem 1000 mg once daily IV over 30 minutes, ciprofloxacin 500 mg PO twice daily 
along with metronidazole 500 mg PO four times daily. If patients on the ertapenem arm are 
found to have causative pathogens that are non-susceptible to ciprofloxacin, but susceptible to 
amoxicillin-clavulanate, they may receive amoxicillin-clavulanate 875 mg PO twice daily 
instead. 
Other Systemic Antibiotics: 
Vancomycin IV, linezolid IV or PO, or daptomycin IV can be given for known or suspected 
methicillin-resistant Staphylococcus aureus (MRSA) or Enterococcus spp. 

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Formulation and Packaging: 
Sulopenem treatment group: Sulopenem 1000 mg IV will be supplied as a single-use vial 
with lyophilized powder for injection.  The IV solution will be prepared for dosing by an 
unblinded pharmacist.  The oral medications will be packaged in a suitable packaging 
container and provided to the sites.  
Comparator treatment group:  Ertapenem 1000 mg IV will be supplied as a single-use vial. 
The IV solution will be prepared for dosing by an unblinded pharmacist.  The oral 
medications will be packaged in a suitable packaging container and provided to the sites. 

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Preparation and Dispensing 
Sulopenem or ertapenem IV: Each dose of IV study medication will be prepared by an 
unblinded pharmacist or other qualified personnel at the site according to the dosing 
instruction provided by the sponsor.  The pharmacy manual will be provided under separate 
cover for preparation of doses using the sulopenem vials and comparator.  
Sulopenem etzadroxil/probenecid or comparator oral solid dose (OSD): All OSD study drugs 
will be provided to the study site by Iterum Therapeutics. Preparation and administration of 
study medication will be done and documented in accordance with the treatment schedule as 
outlined in the study protocol. Written study medication preparation and administration 
instructions will be provided to each study site in a study pharmacy manual.   
This pharmacy manual will contain detailed instructions for the preparation and 
administration of study medication. 
Administration 
Sulopenem arm:  
Patients with normal renal function: Patients randomized to the sulopenem treatment group 
will receive 1000 mg sulopenem IV infused over 3 hours, once daily for 5 days, and a saline 
IV infusion over 30 minutes to simulate the comparator. 
After at least 5 days of intravenous therapy, those patients with a baseline pathogen 
susceptible to ciprofloxacin and who meet criteria for oral step-down will take one sulopenem 
etzadroxil/probenecid tablet twice daily, one over-encapsulated placebo ciprofloxacin tablet 
twice daily and one over encapsulated placebo metronidazole capsule four times daily to 
complete 7-10 total days of treatment (may be extended to 14 days for certain patients if 
approved by the medical monitor and meets criteria).  
For patients found to have a baseline organism non-susceptible to ciprofloxacin, but 
susceptible to amoxicillin-clavulanate after at least 5 days of IV therapy those patients who 
meet criteria for oral step-down will take one sulopenem etzadroxil/probenecid tablet twice 
daily, one over-encapsulated placebo amoxicillin-clavulanate capsule twice daily, and one 
over encapsulated placebo metronidazole capsule four times daily to complete 7-10 total days 
of treatment (may be extended to 14 days for certain patients if approved by the medical 
monitor and meets criteria). Patients with baseline pathogens non-susceptible to both 
ciprofloxacin and amoxicillin-clavulanate will need to continue on IV saline infusions over 
30 minutes to match IV ertapenem for the entire duration of therapy, and take one sulopenem 
etzadroxil/probenecid tablet twice daily, in order to keep blinding intact.  
Patients with severe renal impairment (CrCl <30mL/min): Patients with severe renal 
impairment randomized to the sulopenem treatment group will receive 250 mg sulopenem IV 
infused over 3 hours once daily for 5 days and a saline IV infusion over 30 minutes to 
simulate the comparator. 
After at least 5 days of intravenous therapy those patients with a baseline pathogen 
susceptible to ciprofloxacin and who meet criteria for oral step-down will take one sulopenem 
etzadroxil/probenecid tablet twice daily, one over-encapsulated placebo ciprofloxacin capsule 
approximately every 18 hours and one over encapsulated placebo metronidazole capsule four 

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times daily to complete 7-10 total days of treatment. Patients with a baseline pathogen non-
susceptible to ciprofloxacin will need to continue on IV saline infusions over 30 minutes once 
daily to match the comparator infusion and will take one sulopenem etzadroxil/probenecid 
tablet twice daily to complete 7-10 total days of treatment (may be extended to 14 days for 
certain patients if approved by the medical monitor and meets criteria).  
Comparator arm:  
Patients with normal renal function: Patients randomized to the comparator treatment group 
will receive 1000 mg of ertapenem IV infused over 30 minutes, once daily for 5 days, and a 
saline IV infusion over 3 hours to simulate the comparator.  
After at least 5 days of intravenous therapy those patients with a baseline pathogen 
susceptible to ciprofloxacin who meet criteria for oral step-down will take one placebo 
sulopenem etzadroxil/probenecid tablet twice daily, one over-encapsulated ciprofloxacin 
capsule twice daily, and one over-encapsulated metronidazole capsule four times daily to 
complete 7-10 total days of treatment (duration may be extended to 14 days for certain 
patients if approved by the medical monitor and meets criteria).  
For patients found to have a baseline organism non-susceptible to ciprofloxacin, but 
susceptible to amoxicillin-clavulanate, after at least 5 days of IV therapy, those patients who 
meet criteria for oral step-down will take one placebo sulopenem etzadroxil/probenecid tablet 
twice daily, one over-encapsulated amoxicillin-clavulanate capsule twice daily and one over-
encapsulated placebo metronidazole capsule four times daily to complete 7-10 total days of 
treatment (duration may be extended to 14 days for certain patients if approved by the 
medical monitor and meets criteria). Patients with baseline pathogens non-susceptible to both 
ciprofloxacin and amoxicillin-clavulanate will need to continue on IV ertapenem infusions 
over 30 minutes for the entire duration of therapy, and take one placebo sulopenem 
etzadroxil/probenecid tablet twice daily, in order to keep blinding intact. The total duration of 
treatment may be extended to 14 days for certain patients if approved by the medical monitor 
and meet criteria. 
Patients with severe renal impairment (CrCl <30mL/min): Patients with severe renal 
impairment randomized to the comparator treatment group will receive 500 mg ertapenem IV 
infused over 30 minutes once daily for 5 days and a saline IV infusion over 3 hours to 
simulate the comparator. 
After at least 5 days of intravenous therapy those patients with a baseline pathogen 
susceptible to ciprofloxacin and who meet criteria for oral step-down will take one placebo 
sulopenem etzadroxil/probenecid tablet twice daily, one over-encapsulated ciprofloxacin 
capsule approximately every 18 hours and one over encapsulated placebo metronidazole 
capsule four times daily to complete 7-10 total days of treatment. Patients with a baseline 
pathogen non-susceptible to ciprofloxacin will need to continue on IV ertapenem infusions 
over 30 minutes once daily and will take one placebo sulopenem etzadroxil/probenecid tablet 
twice daily to complete 7-10 total days of treatment. The total duration of treatment may be 
extended to 14 days for certain patients if approved by the medical monitor and meet criteria. 
 

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Study drug administration will be documented in accordance with the Pharmacy Manual. 
Both Treatment Groups:  
In both treatment groups, patients found to have pathogens isolated from blood cultures that 
are resistant to carbapenems including ertapenem should be discontinued from study drug 
therapy, but should remain in the study and treated appropriately. Patients found to have 
pathogens isolated from intra-abdominal cultures that are resistant to carbapenems including 
ertapenem, may be allowed to continue on study drug therapy based on clinical response and 
investigator judgement. 
Dosing with food: Food significantly increases bioavailability of sulopenem and consequently 
results in decreased rates of diarrhea. Therefore, dosing of oral sulopenem 
etzadroxil/probenecid with food whenever possible is recommended.  Since adequate target 
attainment appears to be achieved in the fasted state, an inability to administer the dose with 
food should not preclude dosing. The overall absorption of ciprofloxacin is not substantially 
affected by food. 
Efficacy Assessments: 
The assessment of clinical response includes a review of the following signs and symptoms of 
cIAI:  fever, leukocytosis, systolic blood pressure, heart rate, respiratory rate, oxygen 
saturation, abdominal pain or tenderness, abdominal mass, altered mental status, and nausea 
or vomiting.  
Microbiologic response assessments will be made based on cultures performed on collected 
surgical specimens. 
Other Assessments 
Plasma sampling for population PK evaluations will be collected in a subset of patients at 
selected study sites. 
Safety Assessments 
Safety will be assessed by means of vital signs, collection of adverse events and clinical 
laboratory tests. A targeted physical examination will be performed at the Screening visit, 
Day 5, Day 10 (+/- 1 day) or Day 11-14 (+/- 1 day), and Day 28 (+/- 1 day) visits or at 
premature discontinuation; a targeted physical examination may also be performed as needed 
according to symptoms. Vital signs will be collected at the Screening Visit, and at Day 5, Day 
10 (+/- 1 day) or Day 11-14 (+/- 1 day), and Day 28 (+/- 1 days) or premature 
discontinuation. Adverse events will be collected at every visit, beginning from the signing of 
Informed Consent. Clinical laboratory tests will be obtained at the Screening Visit, and at 
Day 5, Day 10 (+/- 1 day), or Day 11-14 (+/- 1 day), and Day 28 (+/- 1 day) visit, and in 
follow-up of any clinically significant laboratory finding or at premature discontinuation. 
Statistical Methods:  
Sample Size Considerations:  
The study is designed to determine whether sulopenem IV followed by sulopenem etzadroxil 
co-administered with probenecid is non-inferior (NI) to ertapenem followed by oral 
ciprofloxacin and metronidazole or amoxicillin-clavulanate on Day 28 for the outcome 
measure of clinical response, defined as resolution of the signs and symptoms of cIAI present 

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at trial entry with no new symptoms such that no new antibiotics or interventions are 
required. 
The proposed sample size for the ITT population is 670 patients.  This ITT sample size 
estimate is based on the assumption that 80%, or 536 patients, of this ITT population will be 
m-MITT evaluable.  The sample size of the m-MITT population is 268 patients per arm based 
on a Z-test with unpooled variance. This 536 m-MITT sample size assumes a non-inferiority 
margin of 10%, a power of 90%, a one-sided alpha level of 0.025 and an 85% clinical cure 
rate in both treatment groups. The final ITT sample size may be increased based on the 
observed clinical cure rate at the blinded interim analysis, as well as the evaluability rate, to 
maintain a power of 90%. 
General Statistical Considerations:   
Descriptive statistics, including the numbers and percentages for categorical variables, and 
the numbers, means, standard deviations, medians, minimums, and maximums for continuous 
variables will be provided. All comparisons will be for sulopenem/sulopenem etzadroxil plus 
probenecid versus ertapenem/ ciprofloxacin plus metronidazole or amoxicillin-clavulanate. 
Exploratory analyses may also be performed.  Listings of individual patient’s data will be 
produced. 
A comprehensive Statistical Analysis Plan (SAP) will be finalized prior to the interim 
analysis. 
Efficacy Analyses:   
The study is designed to determine whether sulopenem/sulopenem etzadroxil co-administered 
with probenecid is NI to ertapenem/ciprofloxacin plus metronidazole or amoxicillin-
clavulanate for the outcome measure of clinical response on Day 28.  
The number and percentage of patients assessed as a clinical cure, failure and indeterminate 
will be determined in each treatment group in the m-MITT population. The observed 
difference in the percentage of patients with a clinical cure at Day 28 (+/- 1 day) 
(sulopenem/sulopenem etzadroxil plus probenecid group minus the ertapenem/ciprofloxacin 
plus metronidazole or amoxicillin-clavulanate group) will be determined and a 95% 
confidence interval (CI) for the observed difference will be computed using a Z-statistic. The 
NI hypothesis test is a one-sided hypothesis test performed at the 2.5% level of significance. 
If the lower limit of the 95% CI for the difference in clinical cure rates in the m-MITT 
population is greater than -10% the NI of sulopenem to the comparator group will be 
concluded. 
Safety analyses will be conducted in the Safety population (all patients who received any 
amount of study drug).  Safety will be assessed through summaries of AEs, laboratory 
evaluations, and vital signs. All safety analyses will be based on the Safety population and 
will be summarized by treatment group.  
Date of Original Approved Protocol:  May 29, 2018 
Date of Most Recent Protocol Amendment (if applicable):  NA 
Prepared in:  Microsoft Word 2016 

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TABLE OF CONTENTS 
SYNOPSIS ................................................................................................................................ 3 
LIST OF IN-TEXT TABLES ................................................................................................. 18 
LIST OF APPENDICES ......................................................................................................... 18 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................... 19 
1 
INTRODUCTION ........................................................................................................... 22 
1.1 
Indication ............................................................................................................... 22 
1.2 
Background and Rationale .................................................................................... 22 
1.2.1 
Safety data ................................................................................................... 24 
1.2.1.1 
Sulopenem etzadroxil (oral prodrug) ................................................ 24 
1.2.1.2 
Sulopenem (CP-70,429) (Intravenous) ............................................. 26 
1.2.2 
Rationale for Study...................................................................................... 27 
1.2.3 
Dose Rationale ............................................................................................ 28 
2 
STUDY OBJECTIVES ................................................................................................... 29 
2.1 
Objectives .............................................................................................................. 29 
3 
STUDY DESIGN ............................................................................................................ 30 
3.1 
Investigational Study Medications ........................................................................ 30 
3.2 
Adjunctive Systemic Antibiotics ........................................................................... 31 
4 
STUDY POPULATION SELECTION ........................................................................... 31 
4.1 
Inclusion Criteria ................................................................................................... 31 
4.2 
Exclusion Criteria .................................................................................................. 32 
4.3 
Randomization Criteria ......................................................................................... 34 
4.4 
Life Style Guidelines ............................................................................................. 35 
4.4.1 
Women of Child-Bearing Potential ............................................................. 35 
4.4.2 
Males ........................................................................................................... 35 
5 
STUDY TREATMENTS ................................................................................................ 35 
5.1 
Allocation to Treatment ........................................................................................ 35 
5.1.1 
Criteria for Switch from IV to Oral Therapy .............................................. 36 
5.2 
Drug Supplies ........................................................................................................ 36 
5.2.1 
Formulation and Packaging ......................................................................... 36 
5.2.2 
Preparation and Dispensing ......................................................................... 36 
5.2.3 
Administration ............................................................................................. 37 
5.2.4 
Compliance.................................................................................................. 39 
5.3 
Drug Storage and Drug Accountability ................................................................. 39 
5.4 
Concomitant Medication(s), Adjunctive Therapy and Non-drug Therapy ........... 39 
5.4.1 
Concomitant Medications ........................................................................... 39 
5.4.2 
Concomitant Antibacterial Medications...................................................... 40 
5.4.3 
Non-drug Adjunctive Therapy .................................................................... 40 

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6 
STUDY PROCEDURES ................................................................................................ 40 
6.1 
Screening (Day -1) - Within 24 Hours Prior to First Dose ................................... 40 
6.2 
Treatment Period ................................................................................................... 41 
6.2.1 
Day 1 ........................................................................................................... 41 
6.2.2 
Day 5 ........................................................................................................... 41 
6.2.3 
Day 10 (End of Treatment) ......................................................................... 41 
6.2.4 
Day 11-14 (End of Treatment) – only to be conducted for patients who 
receive longer than 10 days of treatment, instead of Day 10 visit .............. 42 
6.3 
Follow-Up Period .................................................................................................. 42 
6.3.1 
Day 21 (+/- 1 day) – Phone Call ................................................................. 42 
6.3.2   Day 28 (+/- 1 day) – (Test of Cure) ................................................................. 42 
6.4 
Premature Discontinuation from Study ................................................................. 43 
6.5 
Patient Withdrawal from Treatment or Study ....................................................... 43 
7 
ASSESSMENTS ............................................................................................................. 43 
7.1 
Safety ..................................................................................................................... 43 
7.1.1 
Physical Examination .................................................................................. 43 
7.1.2 
Vital Signs (Blood Pressure, Respiration Rate, Temperature and 
Pulse Rate)................................................................................................... 44 
7.1.3 
Clinical Laboratory Assays ......................................................................... 44 
7.1.4 
Clinically Significant Laboratory Tests ...................................................... 44 
7.2 
Efficacy ................................................................................................................. 45 
7.2.1 
Clinical Response ........................................................................................ 45 
7.2.2 
Investigator Assessment of Clinical Response............................................ 45 
7.2.3 
Other Efficacy Outcomes ............................................................................ 46 
8 
ADVERSE EVENT REPORTING ................................................................................. 47 
8.1 
Adverse Events ...................................................................................................... 47 
8.2 
Reporting Period ................................................................................................... 47 
8.3 
Definition of an AE ............................................................................................... 47 
8.4 
Abnormal Test Findings ........................................................................................ 48 
8.5 
SAEs ...................................................................................................................... 48 
8.6 
Hospitalization ...................................................................................................... 49 
8.7 
Severity Assessment .............................................................................................. 50 
8.8 
Causality Assessment ............................................................................................ 50 
8.9 
Exposure during Pregnancy .................................................................................. 51 
8.10 
Discontinuation from Study Drug Due to AEs (See also Patient Withdrawal, 
Section 6.4)............................................................................................................ 52 
8.11 
Eliciting AE Information ....................................................................................... 52 
8.12 
Reporting Requirements ........................................................................................ 52 
8.12.1 
SAE Reporting Requirements ..................................................................... 52 

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8.12.2 
Non-SAE Reporting Requirements ............................................................. 53 
8.12.3 
Sponsor Reporting Requirements to Regulatory Authorities ...................... 53 
9 
DATA ANALYSIS/STATISTICAL METHODS .......................................................... 53 
9.1 
Sample Size Determination ................................................................................... 53 
9.2 
Definition of Analysis Populations ....................................................................... 54 
9.3 
General Statistical Considerations ........................................................................ 54 
9.4 
Patient Characteristics ........................................................................................... 55 
9.5 
Efficacy Analysis .................................................................................................. 55 
9.5.1 
Analysis of Primary Outcome Measure ...................................................... 55 
9.5.1.1 
Additional Analyses of the Primary Efficacy Outcome .................... 55 
9.5.2 
Analysis of Secondary Efficacy Outcome Measure .................................... 55 
9.5.3 
Analysis of Additional Efficacy Outcome Measures .................................. 56 
9.6 
Safety Analyses ..................................................................................................... 56 
9.7 
Interim Analysis .................................................................................................... 57 
9.8 
Handling of Missing Data ..................................................................................... 57 
10 QUALITY CONTROL AND QUALITY ASSURANCE .............................................. 57 
11 DATA HANDLING AND RECORD KEEPING ........................................................... 58 
11.1 
Case Report Forms / Electronic Data Record ....................................................... 58 
11.2 
Record Retention ................................................................................................... 58 
12 ETHICS ........................................................................................................................... 58 
12.1 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............ 58 
12.2 
Ethical Conduct of the Study ................................................................................ 59 
12.3 
Patient Information and Consent ........................................................................... 59 
12.4 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP ... 59 
13 DEFINITION OF END OF STUDY .............................................................................. 60 
13.1 End of Study in a Member State................................................................................ 60 
13.2 
End of Study in all Participating Countries ........................................................... 60 
14 SPONSOR STUDY TERMINATION CRITERIA ........................................................ 60 
15 PUBLICATION OF STUDY RESULTS ....................................................................... 60 
15.1 
Communication of Results by Iterum ................................................................... 60 
15.2 
Publications by Investigators ................................................................................ 60 
16 REFERENCE LIST......................................................................................................... 62 
APPENDIX 1 
 SCHEDULE OF ACTIVITIES .................................................................. 63 
APPENDIX 2 
 MICROBIOLOGY ..................................................................................... 64 
APPENDIX 3 
 METHOD FOR DETERMINATION OF CREATININE        
CLEARANCE ................................................................................................................. 66 
APPENDIX 4 
 POPULATION PK SUBSTUDY ............................................................... 67 
APPENDIX 5 
 APACHE II SCORE .................................................................................. 72 

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APPENDIX 6 
 CRITERIA FOR SAFETY VALUES OF POTENTIAL        
CLINICAL CONCERN .................................................................................................. 73 
APPENDIX 7 
 INVESTIGATOR’S SIGNATURE ........................................................... 74 
 

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LIST OF IN-TEXT TABLES 
Table 1 Sulopenem In-Vitro Susceptibility (2013-2015) ........................................................ 23 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Activities ..................................................................................... 63 
Appendix 2 
Microbiology ................................................................................................... 64 
Appendix 3 
Method for determination of creatinine clearance .......................................... 66 
Appendix 4 
Population PK Substudy .................................................................................. 67 
Appendix 5 
APACHE II Score ........................................................................................... 72 
Appendix 6 
Criteria for Safety Values of Potential Clinical Concern ................................ 73 
Appendix 7 
Investigator’s Signature................................................................................... 74 
 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALP 
Alkaline phosphatase 
AST 
Aspartate Aminotransferase 
AUC0-24 
Area under the curve from zero to 24 hours 
βhCG 
Beta Human Chorionic Gonadotropin 
BID 
Bis-in-die 
BUN 
Blood Urea Nitrogen 
Cmax 
Maximum concentration 
CA 
Community-acquired 
CBC 
Complete Blood Count 
CE 
Clinically Evaluable 
CI 
Confidence Interval 
CFU 
Colony forming units 
CLSI 
Clinical and Laboratory Standards Institute 
Cmax 
Maximum concentration 
CrCl 
Creatinine Clearance 
CRE 
Carbapenem resistant Enterobacteriaceae 
CRF 
Case Report Form 
CTA 
Clinical Trial Application 
cUTI 
Complicated urinary tract infections 
DMC 
Data monitoring committee 
EARS-NET 
European Antimicrobial Resistance Surveillance Network 
ECG 
Electrocardiogram 
E.coli 
Escherichia coli 
EIU 
Exposure in Utero 
EOT 
End of Treatment Visit 
ESBL 
Extended Spectrum Beta-lactamase 

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FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating Hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl Transpeptidase 
GMP 
Good Manufacturing Practice 
hERG 
Human Ether-a-go-go-Related Gene 
HIV 
Human Immunodeficiency Virus  
hs-CRP 
High-sensitivity C-reactive Protein 
ICH 
International Conference on Harmonisation 
ICF 
Informed Consent Form 
IRB/IEC 
Institutional Review Board /Independent Ethics Committee  
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device 
IV 
Intravenous 
IWRS 
Interactive Web Randomization System  
LDH 
Lactate Dehydrogenase 
LTFU 
Lost to Follow-Up 
ME 
Microbiologically Evaluable 
MEDRA 
Medical Dictionary of Regulatory Activities 
MIC 
Minimal Inhibitory Concentration 
MITT 
Modified ITT 
m-MITT 
Microbiologic-MITT (micro-MITT) 
MRSA 
Methicillin-resistant Staphylococcus aureus 
NI 
Non-inferior 
NOAEL 
No Observed Adverse Effect Level  
OSD 
Oral solid dose 
PBP 
Penicillin-Binding Proteins 
PCS 
Potentially clinically significant 
PK 
Pharmacokinetic 

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PK/PD 
Pharmacokinetic / Pharmacodynamic 
PO 
Per-oral 
PV 
Pharmacovigilance 
RBC 
Red blood cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System organ class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TA 
Target attainment 
TEAE 
Treatment Emergent Adverse Event 
TOC 
Test of Cure 
Tmax 
Time to maximum concentration 
uUTI 
Uncomplicated urinary tract infection 
WBC 
White Blood Cell 
2-EBA 
2-Ethylbutryic Acid 
 

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1 
INTRODUCTION 
1.1 Indication 
Sulopenem is being studied for the treatment of the following indications: 
- 
Complicated and uncomplicated urinary tract infections 
- 
Complicated intra-abdominal infections 
1.2 Background and Rationale 
β-lactam antimicrobials are widely recognized for their efficacy and low toxicity and form the 
cornerstone of therapy for the treatment of infections caused by gram-positive and gram-
negative bacteria.  However, extensive use of β-lactams during the past 50 years has resulted in 
the development of microbial resistance to these agents among clinically important bacteria.  
This resistance commonly takes the form of β-lactamase production, expression of porins in the 
bacterial outer membrane or alterations in penicillin-binding proteins (PBPs).  Such mechanisms 
have reduced the clinical utility of frequently prescribed β-lactams such as amoxicillin, 
amoxicillin plus clavulanate (a β-lactamase inhibitor), and cephalosporins.  The issue of 
resistance continues to drive the search for new compounds with increased stability and efficacy 
against resistant pathogens. 
The prevalence of infections caused by extended-spectrum β-lactamases (ESBL) producing 
Enterobacteriaceae has been increasing worldwide and includes both hospital acquired and 
community onset infections. An analysis of data reported from 2011 to 2014 to the National 
Healthcare Safety Network performed by the Centers for Disease Control in March 2016 
revealed that the proportion of E.coli resistant to extended-spectrum cephalosporins causing 
hospital-acquired infection was 13.4% nationally, with rates as high as 24% reported in some 
Northeastern, Southern and Western states.  The same analysis also demonstrated that over a 
third of E.coli isolates in 2014 were resistant to quinolones. Oral antibiotic treatment options are 
extremely limited for patients with these infections, resulting in lengthy hospital stays to 
facilitate administration of intravenous antibiotics. Data reported by the European Antimicrobial 
Resistance Surveillance Network (EARS-NET) in Europe demonstrate that the prevalence of 
quinolone resistant E.coli and E.coli resistant to third-generation cephalosporins is > 25% and 
E.coli resistant to third generation cephalosporins, aminoglycosides and quinolones has 
increased to >10% in some southern and eastern European countries. Consequently, options for 
oral antibiotic step-down therapy for patients with resistant gram-negative infections are limited. 
Sulopenem (CP-70,429) is a broad-spectrum penem β-lactam antibiotic which is being 
developed for the treatment of infections caused by multi-drug resistant bacteria. Sulopenem 
possesses potent activity against species of the Enterobacteriaceae that encode ESBLs or 
AmpC-type β-lactamases that confer resistance to third generation cephalosporins. The targeted 
gram-negative spectrum of sulopenem is balanced by its potent in vitro activity against 
anaerobic pathogens, which is similar to that of imipenem.  
An in-vitro susceptibility study of sulopenem was conducted in April 2016 utilizing 
contemporary clinical bacterial isolates from patients in the United States and Europe. Minimal 
inhibitory concentrations (MICs) of sulopenem and 18 comparators were determined against  

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1,122 recent (2013-2015) clinical isolates following Clinical and Laboratory Standards Institute 
(CLSI) guidelines.  The study collection included 872 aerobes (811 gram-negative, 61 gram-
positive) and 250 anaerobes.  Isolates were chosen randomly from the IHMA (International 
Health Management Associates, Inc., Schaumburg, IL) repository, which is a global collection 
of single patient clinical isolates.   For this study the selection of isolates focused on infection 
source (IAI and UTI) and region (US and Europe) for the inclusive years. Aerobes were tested 
by broth microdilution and anaerobes were tested by agar dilution. Results from this study 
presented below demonstrate that sulopenem retains potent in vitro activity against common 
pathogens implicated in urinary tract infections and intra-abdominal infections, including those 
that are caused by organisms that produce ESBLs. Carbapenem resistant Enterobacteriaceae 
(CRE) were excluded from the analysis shown below, but the MIC90 of Enterobacteriaceae 
remains at 0.25 µg/mL even if CRE are included, given that their overall prevalence is low (data 
on file). 
Table 1 Sulopenem In-Vitro Susceptibility (2013-2015) 
Organism Class 
N 
MIC50 
MIC90 
Enterobacteriaceae 
636 
0.03 
0.25 
E. coli                       ESBL negative 
169 
0.015 
0.03 
                                 ESBL positive 
20 
0.03 
0.06 
Klebsiella spp.         ESBL negative 
108 
0.03 
0.06 
                                 EBSL positive 
16 
0.03 
0.25 
P. mirabilis 
14 
0.12 
0.25 
E. aerogenes 
57 
0.06 
0.25 
C. koseri 
60 
0.03 
0.03 
S. marcescens 
55 
0.12 
0.5 
Gram-Negative Anaerobes 
121 
0.12 
0.25 
Staphylococcus saprophyticus 
31 
0.25 
0.25 
As in the case of most β-lactams, sulopenem is not active against methicillin-resistant 
staphylococci or MDR enterococci. Sulopenem also does not have activity against 
Pseudomonas aeruginosa, therefore its broad use for treating such cephalosporin-resistant 
hospital isolates should not select for resistant P. aeruginosa as can occur with imipenem and 
meropenem. 
Sulopenem is available as an intravenous formulation (CP-70,429 is active moiety). Intravenous 
sulopenem was previously evaluated in Phase 1 and Phase 2 clinical studies in Japan in 
approximately 1474 subjects, at doses up to 1 g BID administered intravenously over 3-14 days 
in the early 1990’s. Safety data collected from these trials regarding both adverse events as well 
as laboratory examinations provides support for the safety and tolerability of sulopenem in 
patients and its further development.   
Sulopenem and its oral pro-drug, sulopenem etzadroxil, have been studied in single and multiple 
dose Phase 1 studies, and the oral prodrug has been studied with and without co-administration 
of probenecid. One small Phase 2 study in patients with community acquired pneumonia was 

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conducted, in which 35 adult patients were randomized to one of three treatment groups to 
receive either: a single loading dose of intravenous (IV) sulopenem with switch to oral 
sulopenem etzadroxil, 4 dose minimum of IV sulopenem with switch to oral sulopenem 
etzadroxil, or ceftriaxone (IV) for a minimum of 2 doses, with step down to amoxicillin/ 
clavulanate. The cure rates in the clinically evaluable subjects in this study at TOC were 90%, 
88% and 63% in the single IV dose sulopenem, multiple IV dose sulopenem and ceftriaxone 
groups (IV), respectively. While these efficacy results were not statistically significant due to 
the small numbers enrolled, they provide encouraging support for further clinical testing in this 
indication.  Phase 2 studies in patients with urinary tract infection or intra-abdominal infection 
have not been conducted in the United States. 
Sulopenem etzadroxil has minimal in vitro antibacterial activity.  Upon oral absorption, 
sulopenem etzadroxil yields the active moiety sulopenem in addition to the non-active moieties 
formaldehyde and 2-ethylbutyric acid (2-EBA).  
The currently proposed study will compare the safety, tolerability and efficacy of sulopenem 
followed by sulopenem etzadroxil co-administered with oral probenecid with ertapenem 
followed by oral ciprofloxacin and metronidazole or amoxicillin-clavulanate for the treatment of 
complicated intra-abdominal infection. 
1.2.1 
Safety data 
1.2.1.1 
Sulopenem etzadroxil (oral prodrug) 
Pre-clinical data 
The non-clinical program to assess toxicity of sulopenem etzadroxil consisted of acute oral and 
repeat-dose toxicity studies, safety pharmacology studies, genetic toxicity assessments, and 
reproductive development toxicity studies in multiple species of animals.  Following oral 
administration of sulopenem etzadroxil in rats and monkeys, circulating concentrations of 
sulopenem etzadroxil were variable and minimal or below limits of quantitation, whereas 
significant levels of sulopenem and 2-EBA were present in whole blood. Effects observed in 
rats and monkeys from the repeat dose toxicology studies were generally consistent with those 
expected from the active moiety sulopenem. The NOAEL in the rat is 100 mg/kg with a Cmax 
of 1.90 µg/mL and AUC of 7.24 µg•h/mL for sulopenem, and the NOAEL in the monkey is 50 
mg/kg with a Cmax of 4.63 µg/mL and an AUC of 11.1 µg•h/mL for sulopenem, respectively. 
Sulopenem etzadroxil was negative in mutagenicity and in vivo clastogenicity tests but 
positive for clastogenic activity in human lymphocytes. Sulopenem etzadroxil had no effects 
on male and female rat fertility and early embryonic development and was not teratogenic to 
rats or rabbits. Developmental toxicity was observed in both rats and rabbits with the NOAEL 
being 100 mg/kg and 5 mg/kg, respectively, at doses where maternal toxicity was also 
observed.

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Previous human experience 
The sulopenem etzadroxil clinical studies have investigated the pharmacokinetics, safety and 
tolerability of single oral doses ranging from 400 mg to 8000 mg. The pharmacokinetics, 
safety and tolerability of multiple oral doses of sulopenem etzadroxil at a dose of 2000 mg 
BID for 10 days and 1200 mg plus 1000 mg probenecid BID for 10 days, 500 mg, 1000 mg 
and 1500 mg BID for 7 days have also been investigated. 
Single doses of sulopenem etzadroxil of 400 mg, 600 mg, 1000 mg, and 2000 mg produced 
an approximately linear increase in sulopenem mean exposure. The apparent terminal half 
life of sulopenem was generally dose independent and ranged from 0.76 hours to 1.10 hours. 
Mean time to observed maximum concentration (Tmax) was on average 1 hour for all doses. 
Neither sulopenem etzadroxil nor formic acid has been detected in either plasma or whole 
blood following dosing with sulopenem etzadroxil. In addition, the levels of 2 EBA were 
much lower (~1/20) than sulopenem concentrations. During the administration of multiple 
doses of sulopenem etzadroxil for 10 days due to the short half-life of sulopenem there is no 
accumulation on Day 10 of dosing.  Sulopenem etzadroxil doses of 2000 mg produced a 
mean sulopenem Cmax of 4.7 µg/mL and a mean AUClast of 13.1 h•µg/mL. Sulopenem 
systemic exposure parameters (Cmax and AUClast) following sulopenem etzadroxil single 
doses ranging from 400 to 2000 mg, increased in a dose-related manner. 
There is a significant effect of food (high fat meal) on the PK of sulopenem, given as 
sulopenem etzadroxil orally. The mean AUCinf  and Cmax increased 69% and 13.5% 
respectively, with a longer mean time above MIC of 1 µg/mL (1.91 hours).  Mean t1/2 was 
similar between the fed and fasted states (0.98-1.14 hr). 
The concentrations of radioactivity in plasma and whole blood, the excretion of radioactivity 
and the metabolic pathways of [14C] sulopenem etzadroxil have been determined in healthy 
male volunteers (N = 4) following single oral solution (2000 mg) administration. The majority 
of the radioactivity was excreted in the urine and feces (40.8 and 44.3% respectively). Total 
mean recovery of radioactivity ranged from 80.2 to 95%. 
Overall sulopenem etzadroxil was well tolerated in the Phase 1 program. The most common 
adverse events occurring in the program were diarrhea and abnormal urine odor.

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1.2.1.2 
Sulopenem (CP-70,429) (Intravenous) 
Preclinical intravenous data 
In non-clinical evaluations of intravenous administration of sulopenem, the NOAEL in the 
2-week toxicity study in rats was 200 mg/kg with extrapolated AUC(0-tlast) of 50 µg•h/mL.  
NOAEL was based on increases in kidney and liver weights, erythema, and salivation at 
800 mg/kg.  
The NOAELs in the 4-week toxicity studies in rats and monkeys were both 60 mg/kg.  In rats, 
the NOAEL was based on a slight decrease in RBC parameters and increases in liver, kidney, 
and cecum weights at ≥60 mg/kg.  In monkeys, the NOAEL was based on a decrease in RBC 
parameters and increased bilirubin at 200 mg/kg.  
The NOAELs in the 3-month studies were 120 mg/kg in the rat; AUC(0-tlast) of 29.2 ug•hr/mL 
(AUC(0-tlast) represents 0-2 h), and 60 mg/kg in the monkey; AUC(0-tlast) of 49.2 ug•hr/mL; 
(AUC(0-tlast) represents 0-8 h).  The NOAEL in rats was based on adverse effects on body weight 
and food consumption, and slight decreases in RBC parameters at 600 mg/kg.  The NOAEL in 
monkeys was based on a positive Direct Coombs test result, decreases in RBC parameters, 
increased bilirubin, moribundity in 2 animals, bone marrow hyperplasia, and soft stools at 
200 mg/kg.  
No change in heart rate or QTc was observed in a single-dose cardiovascular safety 
pharmacology study in anesthetized dogs up to 300 mg/kg, yielding an average blood level of 
258 µg/mL (total). Similarly, no change in heart rate or QTc was observed in the cardiovascular 
study in telemetry-implanted monkeys at 1000 mg/kg, yielding a blood concentration of 
2270 µg/mL (total).    
In a safety pharmacology study evaluating the effect on the hERG potassium channel, 
sulopenem inhibited the hERG current by approximately 50% at the maximum concentration of 
300 µM (105 µg/mL; free).  There were no changes in action potential duration in the in vitro 
Purkinje fiber assay at concentrations up to 300 µM (105 µg/mL; free).   
Previous human experience (intravenous) 
The pharmacokinetics and safety of sulopenem have been evaluated in Phase 1 single and 
multiple dose studies. Doses of 400 mg, 800 mg, 1600 mg, 2400 mg and 2800 mg of sulopenem 
were evaluated in a single dose ascending study, and doses of 800 mg infused over 3 hours, 1200 
mg infused over 1 hour, 1200 mg infused over 2.5 hours, 1600 mg infused over 1.5 hours for 14 
days and 2000 mg infused over 1.5 hours for 7 days were evaluated in a multiple dose study in 
healthy volunteers (8 subjects in each dose group). There were no deaths or serious adverse 
events (SAEs) in either study. One subject who received 1200 mg IV BID was discontinued on 
Day 4 from study drug therapy due to an adverse event (AE) of mildly increased troponin (0.107 
ng/mL [normal limit <0.04 ng/mL]); the AE was reported to be resolved on Day 8. The most 
frequently reported AEs were gastrointestinal events (nausea, vomiting). Severe AEs included 
nausea and vomiting, and were reported only in the highest dose groups (>2000 mg), indicating 
that MTD had been reached. All AEs in the lower dose groups (<2000 mg) were considered mild 
to moderate in severity. No clinical laboratory abnormalities occurred that were considered to be 
clinically significant by the investigator. There were no vital signs or ECG changes (including 
QTc interval changes) of clinical concern.  

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Pharmacokinetic analysis revealed a dose proportional increase in Cmax and AUClast. The mean t 
½ remained constant over the dose range. Following a 1 hour intravenous infusion, all doses 
higher than 400 mg produced mean concentrations above 1.0 μg/mL for > 3.3 hours, allowing 
for a twice daily dosing and potentially a single daily dose with a longer infusion duration.  
In healthy adults, intravenous sulopenem doses up to 1000 mg BID were studied in 3 small 
Phase 1 studies (two in Japan and one in the US) in the early 1990’s; sulopenem was well 
tolerated.  The mean Cmax and AUCinf were 61.5 µg/mL and 51.9 µg•h/mL, respectively for a 
single 1000 mg dose infused over 30 minutes in the Japanese study.  The mean Cmax and AUCinf 
were 69.8 µg/mL and 54.1 µg•h/mL, respectively, for a single 1000 mg dose infused over 
10 minutes in the US study.  
The IV formulation of sulopenem was also investigated in four Phase 2 clinical efficacy studies 
in Japan in the early 1990s.  Fourteen hundred and seventy six patients with hospital and 
community acquired infections were administered primarily 250 or 500 mg BID dosing 
regimens of IV sulopenem for 3 to 14 days.   
Complete information on sulopenem etzadroxil and sulopenem are available in the Investigator’s 
Brochure. 
1.2.2 
Rationale for Study  
ß-lactam antimicrobials are widely recognized for their efficacy and low toxicity and form the 
cornerstone of therapy for the treatment of infections caused by gram-positive and gram-
negative bacteria. However, extensive use of ß-lactams during the past 50 years has resulted in 
the development of microbial resistance to these agents among clinically important bacteria. This 
resistance commonly takes the form of ß-lactamase production, development of porins or 
alterations in penicillin-binding proteins (PBPs). Such mechanisms have reduced the clinical 
utility of frequently prescribed ß-lactams such as amoxicillin, amoxicillin plus clavulanate (a ß-
lactamase inhibitor), and cephalosporins. The issue of resistance continues to drive the search for 
new compounds with increased stability and activity against resistant pathogens. Nowhere is the 
importance of resistance more evident than among agents of the ß-lactam family.  
For Escherichia coli, ampicillin resistance has risen to ≥50% in high-risk populations, and 
resistance to third generation cephalosporins is now increasingly common in certain areas. Only 
through the recognition of factors associated with increasing resistance and the mechanisms 
responsible can strategies be designed for minimizing ß-lactam resistance. As antibiotic 
resistance leads to increased costs of treatment, increased morbidity as well as increased 
mortality, there is an unmet urgent medical need for antimicrobial agents that can be utilized in 
serious hospital and community infections, especially agents that can be delivered orally. 
The penems are considered to exhibit advantages to the ß-lactam class as they possess good 
antibacterial activity against gram-negative pathogens commonly responsible for a wide range of 
community and hospital infections, and are stable to many ß-lactamases. 
Sulopenem has in vitro activity against many common hospital pathogens, including extended 
spectrum ß-lactamase (ESBL) producing gram-negative pathogens (except Pseudomonas spp., 
Acinetobacter spp., Stenotrophomonas spp.), and anaerobes such as Bacteroides fragilis.  
 

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Rationale for probenecid 
Probenecid has been shown in a dog model to increase the systemic exposure of a penem 
CP-65,207 (sulopenem [CP-70,429] is the S-isomer of CP-65,207) by about 2-fold, suggesting a 
role of active renal tubular secretion in drug elimination. Findings from a previous clinical 
pharmacokinetic study indicate that renal clearance accounts for a significant proportion 
(approximately 50%) of total clearance of sulopenem in healthy volunteers suggesting that 
probenecid could increase exposure and thus time over MIC for sulopenem.  Probenecid is 
known to increase plasma levels of weak organic acids such as penicillins, cephalosporins, and 
other beta-lactam antibiotics, including penems, by competitively inhibiting their renal tubular 
secretion.  Probenecid has been used safely with other beta-lactam antibiotics, to either reduce 
dose or dosing frequency of beta-lactams when used to treat infectious diseases in human beings.  
Please refer to probenecid product label for more pharmacology information on probenecid. 
The pharmacokinetics, safety and tolerability of sulopenem etzadroxil in combination with 
probenecid 1000 mg was evaluated in 6 subjects in Study A8811006. Escalating oral doses of 
sulopenem etzadroxil administered with 1000 mg probenecid produced approximately 
proportional increases in systemic exposure of sulopenem over the dose range of 800 mg to 1200 
mg. The combination of sulopenem etzadrozil 500 mg and probenecid 500 mg was evaluated in 
study IT001-101. Results from this study were consistent with those observed in previous 
studies. 
Thus probenecid has the potential to be used as a PK booster with sulopenem etzadroxil, 
optimizing the time over MIC for any given sulopenem dose while minimizing the 
gastrointestinal exposure of the parent compound and subsequent gastrointestinal adverse events 
such as diarrhea.  
Rationale for dosing with food 
In a multiple dose (A8811003) study, at higher doses of sulopenem etzadroxil, there is a higher 
rate of gastrointestinal symptoms especially diarrhea in a fasted state.  It has therefore been 
postulated that if the fraction of sulopenem etzadroxil absorbed and bioavailability of sulopenem 
(the active moiety) can be increased, the gastrointestinal toleration and pharmacokinetics of the 
compound can be improved. 
In Study A8811008 there was an increase in relative bioavailability of sulopenem when 
sulopenem etzadroxil was administered in the fed state (~82% increase in mean AUC).  In Study 
IT001-101, sulopenem etzadroxil was evaluated in a fasted and fed state at a dose of 500 mg 
BID. Results from this study indicate that food significantly increases bioavailability of 
sulopenem and consequently results in decreased rates of diarrhea. Therefore, dosing of oral 
sulopenem etzadroxil with food whenever possible is recommended.  Since adequate target 
attainment appears to be achieved in the fasted state, an inability to administer the dose with 
food should not preclude dosing. 
1.2.3 
Dose Rationale  
Sulopenem and Sulopenem etzadroxil  
Doses of sulopenem and sulopenem etzadroxil were chosen by PK/PD modeling using a 
combination of (1) modeling (Naïve Pool analysis) of the sulopenem effect on net change in 
colony forming units (CFU) over 24 hours of clinically relevant organisms in an 

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immunocompetent mouse thigh infection model, (2) defining targets of percent time above the 
MIC (T>MIC) for sulopenem from this mouse model, and (3) population PK modeling using 
nonlinear mixed effects models, generated from clinical data in multiple IV sulopenem and oral 
sulopenem etzadroxil Phase 1 studies in healthy volunteers.  
Monte Carlo simulations were performed using the human population PK parameters for 
sulopenem etzadroxil and mean pharmacodynamic parameters from a murine thigh infection 
model to determine % target achievement (TA) for the selected doses. A %TA of ≥90% was 
deemed desirable for selecting particular doses. The 1000 mg IV dose delivered over 3 hours and 
the 500 mg dose of sulopenem etzadroxil co-administered with 500 mg of probenecid 
administered twice daily meets the criteria of %T>MIC for achieving 1-log kill in >90% of 
bacteria with MIC’s expected in this indication.  
Probenecid 
The maximum total daily dose of probenecid will be 1000 mg (500 mg BID) which is within the 
recommended dosage of 2000 mg daily in divided doses.  
Ertapenem 
The recommended dose of IV ertapenem in this study is 1000 mg administered over 30 minutes 
and is consistent with the ertapenem USPI and SmPC for treatment of complicated intra-
abdominal infections.  
Amoxicillin-clavulanate 
The recommended dose of oral amoxicillin-clavulanate in this study is 875 mg bid, consistent 
with the amoxicillin-clavulanate US FDA Package Insert and SmPC for severe infections. 
Ciprofloxacin 
The recommended dose of oral ciprofloxacin in this study is 500 mg bid following an initial 
course of ertapenem IV to complete 10 days of therapy, consistent with the ciprofloxacin USPI 
and SmPC for treatment of cIAI. 
Metronidazole 
The recommended dose of oral metronidazole in this study is 500 mg qid, consistent with the 
metronidazole USPI and SmPC for treatment of IAI. 
For the full prescribing information for probenecid and all comparator study drugs, please refer 
to respective local country product labels (USPI or SmPC). 
2 
STUDY OBJECTIVES 
2.1 
Objectives 
The primary objective of this study is to compare the efficacy of sulopenem followed by 
sulopenem etzadroxil with probenecid versus ertapenem followed by ciprofloxacin and 
metronidazole or amoxicillin-clavulanate for treatment of complicated intra-abdominal infection 
in adults, on Day 28 (TOC) post-randomization. 
The secondary objectives of this study are: 

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To compare the efficacy outcomes at other relevant time points as well as the safety profile of 
treatment with sulopenem followed by sulopenem etzadroxil plus probenecid versus ertapenem 
followed by ciprofloxacin and metronidazole or amoxicillin-clavulanate for treatment of 
complicated intra-abdominal infection in adults.  
To assess the population PK profile of sulopenem when administered either intravenously or as 
the prodrug of sulopenem etzadroxil co-administered with probenecid. 
3 
STUDY DESIGN 
Sulopenem is an investigational penem antibiotic being developed for treatment of uUTI , 
complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI). 
Sulopenem etzadroxil is an oral pro-drug of sulopenem. Upon oral absorption, sulopenem 
etzadroxil is expected to be rapidly hydrolyzed to yield sulopenem, the active moiety, as well as 
the non-active moieties, formaldehyde and 2-ethylbutyric acid (2-EBA).   
Sulopenem possesses potent activity against species of the Enterobacteriaceae that encode 
ESBLs or AmpC-type β-lactamases that confer resistance to third generation cephalosporins. 
Sulopenem etzadroxil is expected to be the first oral penem on the market in the United States or 
Europe and will offer the option of treatment in the outpatient setting as well as IV to oral switch 
therapy for early discharge of patients hospitalized with serious complicated infections.  
Probenecid, co-administered with the oral prodrug, will reduce renal clearance and increase 
systemic exposure of the active moiety, sulopenem.   
This Phase 3, multicenter, double-blind, randomized, controlled study compares IV sulopenem 
followed by sulopenem etzadroxil with probenecid and ertapenem IV followed by an oral 
regimen of ciprofloxacin and metronidazole or amoxicillin-clavulanate for treatment of cIAI. 
The site pharmacist will be unblinded in order to prepare the intravenous study medications and 
select the appropriate oral follow on therapy for patients randomized to the ertapenem regimen. 
Approximately 670 adults with cIAI will be randomized in a 1:1 fashion to receive either IV 
sulopenem for at least 5 days followed by sulopenem etzadroxil 500mg co-administered with 
oral probenecid 500 mg twice daily to complete 7-10 days of treatment or ertapenem IV for at 
least 5 days followed by ciprofloxacin and metronidazole or amoxicillin-clavulanate, based on 
quinolone susceptibility of baseline pathogen to complete 7-10 days of therapy. Duration of 
therapy in both treatment groups may be extended up to a total duration of 14 days if both (a) 
approved by the medical monitor, and (b) the patient has either multiple abscesses or non-
appendix-related diffuse peritonitis AND has one of the following: fever or hypothermia 
(temperature ≥38°C or <35°C), leukocytosis defined as WBC ≥12,000/mm3, or ileus. 
The primary outcome measure for efficacy evaluation on Day 28 will be the resolution of the 
symptoms of cIAI present at trial entry.  
See Appendix 1, Schedule of Activities Table. 
3.1 
Investigational Study Medications 
Investigational study medications include sulopenem 1000 mg IV over 3 hours, sulopenem 
etzadroxil (PF-03709270) 500 mg PO twice daily co-administered with probenecid 500 mg PO 
twice daily, ertapenem 1000 mg once daily IV over 30 minutes,  and ciprofloxacin 500 mg PO 
twice daily along with metronidazole 500 mg PO four times daily. If patients on the ertapenem 

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arm are found to have causative pathogens that are non-susceptible to ciprofloxacin, they will 
receive amoxicillin-clavulanate 875 mg PO twice daily. 
3.2 
Adjunctive Systemic Antibiotics 
Other Systemic Antibiotics: 
Vancomycin IV, linezolid IV or PO, or daptomycin IV can be given for known or suspected 
methicillin-resistant Staphylococcus aureus (MRSA) or Enterococcus spp. 
4 
STUDY POPULATION SELECTION 
Male or female patients who present with cIAI and who meet all of the inclusion and none of the 
exclusion criteria will be eligible for participation in this study. 
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into consideration 
when deciding whether a particular patient is suitable for enrollment under this protocol 
4.1 
Inclusion Criteria 
1. Patient or the patient’s legally acceptable representative able to provide a signed written 
informed consent prior to any study-specific procedures.  
2. Adult patients ≥18 years of age  
3. EITHER: 
a. Intra-operative/post-operative enrollment with visual confirmation (presence of 
pus within the abdominal cavity) of an intra-abdominal infection associated 
with peritonitis including at least 1 of the following diagnosed during the 
surgical intervention: 
i. 
Cholecystitis with gangrenous rupture or perforation or progression of the 
infection beyond the gallbladder wall 
ii. 
Diverticular disease with perforation or abscess 
iii. 
Appendiceal perforation or peri-appendiceal abscess 
iv. 
Traumatic perforation of the intestines, only if operated on >12 hours after 
perforation occurs 
v. 
Secondary peritonitis (but not spontaneous bacterial peritonitis associated 
with cirrhosis and chronic ascites) 
vi. 
Intra-abdominal abscess (including of liver or spleen provided that there 
was extension beyond the organ with evidence of intraperitoneal 
involvement). 
OR: 
b. Pre-operative enrollment where one of the following surgical procedures are 
planned within 24 hours of the first dose of study drug: 

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i. Open laparotomy, percutaneous drainage of an intra-abdominal abscess, or 
laparoscopic surgery. 
4. 
Evidence of systemic inflammatory indicators, with at least one of the following: 
a. Fever (defined as body temperature >38°C) or hypothermia with a core body 
temperature <35°C 
b. Elevated white blood cell count (>12,000 cells/mm3) or leukopenia (defined as 
white blood cell count <4,000 cells/mm3) 
c. Drop in blood pressure (systolic BP must be <90 mmHg without pressor support) 
d. Increased heart rate (>90 bpm) and respiratory rate (>20 breaths/min) 
5. Hypoxia (oxygen saturation ≤90 percent on room air) 
Physical findings or symptoms consistent with intra-abdominal infection, with at least one 
of the following: 
a. Abdominal pain and/or tenderness, with or without rebound 
b. Localized or diffuse abdominal wall rigidity 
c. Abdominal mass 
d. Nausea and/or vomiting 
e. Altered Mental Status 
6. 
Specimen/s from the surgical intervention were sent or planned to be sent for culture. 
Microbiologic specimens collected during routine operative care prior to subject providing 
informed consent may be used for study purposes. 
4.2 
Exclusion Criteria 
1. Patient diagnosed with traumatic bowel perforation undergoing surgery within 12 hours; 
perforation of gastroduodenal ulcers undergoing surgery within 24 hours. Other intra-
abdominal processes in which the primary etiology was not likely to be infectious. 
2. Patient has abdominal wall abscess or bowel obstruction without perforation or ischemic 
bowel without perforation. 
3. Patient has simple cholecystitis or gangrenous cholecystitis without rupture, or simple 
appendicitis, or acute suppurative cholangitis; or infected necrotizing pancreatitis or 
pancreatic abscess. 
4. Patient whose surgery included staged abdominal repair, or “open abdomen” technique, or 
marsupialization. 
5. Patient known at study entry to have a complicated intra-abdominal infection caused by 
pathogens non-susceptible to the study antimicrobial agents. 
6. Patient needed effective concomitant systemic antibacterials (oral, IV, or intramuscular) or 
antifungals in addition to those designated in the 2 study groups, except vancomycin, 
linezolid, or daptomycin if started for known or suspected methicillin-resistant 
Staphylococcus aureus (MRSA) or Enterococcus spp.   
7. Patient has perinephric infections or an indwelling peritoneal dialysis catheter. 

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8. Patient has suspected intra-abdominal infections due to fungus, parasites (e.g., amoebic liver 
abscess), virus, or tuberculosis. 
9. Patient has a known history of serious allergy, hypersensitivity or any serious reaction to 
carbapenem antibiotics, other β-lactam antibiotics, quinolones, metronidazole, or 
probenecid. 
10. Patient known to have any of the following laboratory values as defined below: 
a. Hematocrit <25% or hemoglobin <8 g/dL 
b. Absolute neutrophil count <1000/mm3 
c. Platelet count <75,000/mm3 
d. Bilirubin >3 x the upper limit of normal (ULN), unless isolated hyperbilirubinemia 
was directly related to the acute infection or known Gilbert’s disease 
e. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 x ULN 
values at Screening. Patients with elevations of AST and/or ALT up to 5 x ULN will 
be eligible if these elevations are acute and directly related to the infectious process 
being treated. This must be documented 
f. Alkaline phosphatase (ALP) >3 x ULN. Patients with values >3.0 x ULN and <5.0 x 
ULN are eligible if this value is acute and directly related to the infectious process 
being treated. This must be documented. 
11. Patient has a body mass index >45 kg/m2. 
12. Patient has APACHE II score >30 (serum bicarbonate may be used in place of arterial blood 
gases; see Appendix 5). 
13. Patient considered unlikely to survive the 4-week study period or has a rapidly progressive 
or terminal illness, including septic shock that was associated with a high risk of mortality. 
14. Patient unlikely to respond to 10–14 days of treatment with antibiotics. 
15. Patient received systemic antibacterial agents within the 72-hour period prior to study entry, 
unless either of the following pertained: 
a. Patient has a new infection (not considered a treatment failure) and both of the 
following were met: 
i. Patient received no more than 24 hours of total prior antibiotic therapy 
ii. Patient received ≤1 dose of a treatment regimen post-operatively and antibiotics 
were not received more than 6 hours post-procedure. 
b. Patient considered to have failed the previous treatment regimen i.e., pre-operative 
treatment of any duration with non-study systemic antimicrobial therapy for peritonitis 
or abscess permitted provided that all of the following are met: 
i. The treatment regimen had been administered for at least 72 hours and was 
judged to have been inadequate 
ii. The patient had an operative intervention that was just completed or was intended 
no more than 24 hours after study entry 
iii. Findings of infection were documented at surgery 
iv. Specimens for bacterial cultures and susceptibility testing were taken at operative 
intervention 
v. No further non-study antibacterials were administered after randomization. 

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16. Patient has a concurrent infection that may interfere with the evaluation of response to the 
study antibiotic. 
17. Patient receiving hemodialysis, hemofiltration, or peritoneal dialysis. 
18. Patient has a history of acute hepatitis in the recent past (3 months prior to study entry), 
chronic hepatitis, cirrhosis, acute hepatic failure, or acute decompensation of chronic hepatic 
failure. 
19. Patient has past or current history of epilepsy or seizure disorders excluding febrile seizures 
of childhood. 
20. Patient immunocompromised as evidenced by any of the following: 
a. Human immunodeficiency virus infection, with either a recent (in the past 6 months) 
acquired immune deficiency syndrome-defining condition or a CD4 + T lymphocyte 
count <200/mm3  
b. Systemic or hematological malignancy requiring chemotherapeutic or 
radiologic/immunologic interventions within 6 weeks prior to randomization, or 
anticipated to begin prior to completion of study 
c. Immunosuppressive therapy, including maintenance corticosteroid therapy (>40 
mg/day equivalent prednisolone for 5 days or more). 
21. Patient participating in any other clinical study that involved the administration of an 
investigational medication at the time of presentation, during the course of the study, or who 
had received treatment with an investigational medication in the 30 days prior to study 
enrollment, or had previously been enrolled in this study or had been treated with 
sulopenem. 
22. Patient is in a situation or has a condition that, in the investigator’s opinion, may interfere 
with optimal participation in the study. 
23. Patient unlikely to comply with protocol e.g., uncooperative attitude, inability to return for 
follow-up visits, and unlikely to complete the study. 
24. Patient has known inflammatory bowel disease (ulcerative colitis or Crohn’s disease) or 
Clostridium difficile-associated diarrhea. 
25. Patients with a history of blood dyscrasias 
26. Patients with a history of uric acid kidney stones 
27. Patients with acute gouty attack 
28. Patients on chronic methotrexate therapy 
29. Females of child-bearing potential who are unable to take adequate contraceptive 
precautions (refer to Section 4.4.1), have a positive pregnancy test result within 24 hours of 
study entry, are otherwise known to be pregnant, or are currently breastfeeding an infant. 
30. Male subjects who do not agree to use an effective barrier method of contraception during 
 
the study and for 14 days post treatment (refer to Section 4.4.2). 
4.3 
Randomization Criteria 
Patients will be randomized in a 1:1 ratio to sulopenem followed by sulopenem etzadroxil with 
probenecid versus ertapenem followed by ciprofloxacin plus metronidazole or amoxicillin-

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clavulanate using an IWRS system provided they have satisfied all patient selection criteria.  
Randomization will be stratified by the type of infection (cIAI caused by appendicitis with 
perforation or peri-appendiceal abscess versus all other cIAI diagnoses). The proportion of 
patients who have cIAI caused by appendicitis with perforation or peri-appendiceal abscess will 
not exceed approximately 50%. 
4.4 
Life Style Guidelines 
For the duration of the study, all female patients of child-bearing potential, and all male patients 
must agree to be strictly abstinent from sexual intercourse with any individual of the opposite 
sex, or to follow the following instructions for contraception. 
4.4.1 
Women of Child-Bearing Potential 
If the patient is a woman of childbearing potential, she and any male partner are required to 
simultaneously use 2 effective contraceptive methods, from the following list of 5: 
1. A barrier (condoms, diaphragm or cervical cap) with spermicide; 
2. A second, different barrier method (condoms, diaphragm or cervical cap); 
3. Oral or similar contraceptive, which includes, but is not limited to: injectable, implanted, or 
patch hormone therapy, and intrauterine device (IUD); 
4. Documented surgical sterilization at least 4 weeks prior to baseline; 
5. Partner vasectomy at least 6 months prior to baseline. 
She and any male partner must agree to continue all of these contraceptive methods until the last 
Study Visit. Within these limits, the specific forms of contraception employed are left to the 
discretion of the patient, and/or the principal investigator, and/or the patient’s physician. 
4.4.2 
Males 
It is required that all male subjects use one of the following methods of contraception from the 
first dose of study medication and until 28 days after last dosing: 
1. Abstinence 
2. Use of condom for males that have not been vasectomized for at least 6 months. 
3. Male subjects who have not had a vasectomy must use a condom.  In addition, such a male 
subject should be instructed that, unless his female partner has had a tubal ligation, 
hysterectomy, or bilateral oophorectomy or is post-menopausal, his female partner should 
use another form of contraception from the time of the first dose of study medication until 28 
days after dosing.  Such other forms of contraception include an IUD, spermicidal 
foam/gel/film/cream/suppository, diaphragm with spermicide, oral contraceptive, injectable 
progesterone, or subdermal implant. 
5 
STUDY TREATMENTS 
5.1 
Allocation to Treatment 
This is a randomized double blind study in which approximately 670 patients will be randomized 
to receive either sulopenem followed by sulopenem etzadroxil plus probenecid or ertapenem 

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followed by ciprofloxacin plus metronidazole or oral amoxicillin-clavulanate in the treatment of 
cIAI. Randomization will be based on an IWRS-generated schedule in a 1:1 allocation ratio. 
A patient will be eligible for randomization once it has been determined that he/she meets all 
inclusion criteria and has none of the exclusion criteria. On the day the patient is to receive the 
first dose of study drug, a designated member of the clinical pharmacy staff will contact the 
IWRS to obtain the study treatment assignment and dispense therapy accordingly. The IWRS 
will associate that patient with the next available treatment in the appropriate stratum on the 
randomization schedule.  The IWRS will then give the investigative site information which 
corresponds to study medication that has been previously shipped to the site and is in the site’s 
inventory ready to be dispensed. A patient is considered randomized when the pharmacist or 
designee receives the treatment assignment associated with the patient entered into the IWRS. 
5.1.1 
Criteria for Switch from IV to Oral Therapy 
After 5 days of IV treatment (at least 5 administrations of IV therapy) patients are eligible to 
switch to oral treatment if they have met the following criteria: 
1. Patient can tolerate oral medications 
2. Fever and white blood cell count are improving; these signs of infection do not 
have to return to normal 
3. Clinical signs or symptoms such as ileus, abdominal pain or tenderness, 
abdominal wall rigidity or guarding, nausea or vomiting, if present at baseline, are 
improving. 
5.2 
Drug Supplies 
5.2.1 
Formulation and Packaging 
Sulopenem treatment group: Sulopenem 1000 mg IV will be supplied as a single-use vial with 
lyophilized powder for injection.  The IV solution will be prepared for dosing by an unblinded 
pharmacist.  The oral medications will be packaged in a suitable packaging container and 
provided to the sites. 
Comparator treatment group:  Ertapenem 1000 mg IV will be supplied as a single-use vial. The 
IV solution will be prepared for dosing by an unblinded pharmacist.  The oral medications will 
be packaged in a suitable packaging container and provided to the sites. 
 
All supplies packed and labeled will be formally released in accordance with both Good 
Manufacturing Practice (GMP) and Good Clinical Practice (GCP) guidelines. 
5.2.2 
Preparation and Dispensing 
Sulopenem or ertapenem IV: Each dose of IV study medication will be prepared by an unblinded 
pharmacist or other qualified personnel at the site according to the dosing instruction provided 
by the sponsor.  Dosage Administration Instructions (DAI) will be provided under separate cover 
for preparation of doses using the sulopenem vials and comparator.  
Sulopenem etzadroxil/probenecid or comparator oral solid dose (OSD): All OSD study drugs 
will be provided to the study site by Iterum Therapeutics. Preparation and administration of 

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study medication will be done and documented in accordance with the treatment schedule as 
outlined in the study protocol.     
5.2.3 Administration 
Sulopenem arm:  
Patients with normal renal function: Patients randomized to the sulopenem treatment group will 
receive 1000 mg sulopenem IV infused over 3 hours, once daily for 5 days, and a saline IV 
infusion over 30 minutes to simulate the comparator. 
After at least 5 days of intravenous therapy, those patients with a baseline pathogen susceptible 
to ciprofloxacin and who meet criteria for oral step-down will take one sulopenem 
etzadroxil/probenecid tablet twice daily, one over-encapsulated placebo ciprofloxacin tablet 
twice daily and one over encapsulated placebo metronidazole capsule four times daily to 
complete 7-10 total days of treatment (may be extended to 14 days for certain patients if 
approved by the medical monitor and meets criteria).  
For patients found to have a baseline organism non-susceptible to ciprofloxacin but susceptible 
to amoxicillin-clavulanate, after at least 5 days of IV therapy those patients who meet criteria for 
oral step-down will take one sulopenem etzadroxil/probenecid tablet twice daily, one over-
encapsulated placebo amoxicillin-clavulanate capsule twice daily, and one over encapsulated 
placebo metronidazole capsule four times daily to complete 7-10 total days of treatment (may be 
extended to 14 days for certain patients if approved by the medical monitor and meets criteria). 
Patients with baseline pathogens non-susceptible to both ciprofloxacin and amoxicillin-
clavulanate will need to continue on IV saline infusions over 30 minutes to match IV ertapenem 
for the entire duration of therapy, and take one sulopenem etzadroxil/probenecid tablet twice 
daily, in order to keep blinding intact. 
Patients with severe renal impairment (CrCl <30mL/min): Patients with severe renal impairment 
randomized to the sulopenem treatment group will receive 250 mg sulopenem IV infused over 3 
hours once daily for 5 days and a saline IV infusion over 30 minutes to simulate the comparator. 
After at least 5 days of intravenous therapy those patients with a baseline pathogen susceptible to 
ciprofloxacin and who meet criteria for oral step-down will take one sulopenem 
etzadroxil/probenecid tablet twice daily, one over-encapsulated placebo ciprofloxacin capsule 
approximately every 18 hours and one over encapsulated placebo metronidazole capsule four 
times daily to complete 7-10 total days of treatment (may be extended to 14 days for certain 
patients if approved by the medical monitor and meets criteria). Patients with a baseline 
pathogen non-susceptible to ciprofloxacin will need to continue on IV saline infusions over 30 
minutes once daily to match the comparator infusion and will take one sulopenem 
etzadroxil/probenecid tablet twice daily to complete 7-10 total days of treatment (may be 
extended to 14 days for certain patients if approved by the medical monitor and meets criteria).  
Comparator arm:  
Patients with normal renal function: Patients randomized to the comparator treatment group will 
receive 1000 mg of ertapenem IV infused over 30 minutes, once daily for 5 days, and a saline IV 
infusion over 3 hours to simulate the comparator.  
After at least 5 days of intravenous therapy those patients with a baseline pathogen susceptible to 
ciprofloxacin who meet criteria for oral step-down will take one placebo sulopenem 

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etzadroxil/probenecid tablet twice daily, one over-encapsulated ciprofloxacin capsule twice 
daily, and one over-encapsulated metronidazole capsule four times daily to complete 7-10 total 
days of treatment (may be extended to 14 days for certain patients if approved by the medical 
monitor and meets criteria).  
For patients found to have a baseline organism non-susceptible to ciprofloxacin but susceptible 
to amoxicillin-clavulanate, after at least 5 days of IV therapy, those patients who meet criteria 
for oral step-down will take one placebo sulopenem etzadroxil/probenecid tablet twice daily, one 
over-encapsulated amoxicillin-clavulanate capsule twice daily, and one over encapsulated 
placebo metronidazole capsule four times daily to complete 7-10 total days of treatment (may be 
extended to 14 days for certain patients if approved by the medical monitor and meets criteria). 
Patients with baseline pathogens non-susceptible to both ciprofloxacin and amoxicillin-
clavulanate will need to continue on IV ertapenem infusions over 30 minutes for the entire 
duration of therapy, and take one placebo sulopenem etzadroxil/probenecid tablet twice daily, in 
order to keep blinding intact. The total duration of treatment may be extended to 14 days for 
certain patients if approved by the medical monitor and meet criteria. 
Patients with severe renal impairment (CrCl <30mL/min): Patients with severe renal impairment 
randomized to the comparator treatment group will receive 500 mg ertapenem IV infused over 
30 minutes once daily for 5 days and a saline IV infusion over 3 hours to simulate the 
comparator. 
After at least 5 days of intravenous therapy those patients with a baseline pathogen susceptible to 
ciprofloxacin and who meet criteria for oral step-down will take one placebo sulopenem 
etzadroxil/probenecid tablet twice daily, one over-encapsulated ciprofloxacin capsule 
approximately every 18 hours and one over encapsulated placebo metronidazole capsule four 
times daily to complete 7-10 total days of treatment (may be extended to 14 days for certain 
patients if approved by the medical monitor and meets criteria). Patients with a baseline 
pathogen non-susceptible to ciprofloxacin will need to continue on IV ertapenem infusions over 
30 minutes once daily and will take one placebo sulopenem etzadroxil/probenecid tablet twice 
daily to complete 7-10 total days of treatment. The total duration of treatment may be extended 
to 14 days for certain patients if approved by the medical monitor and meet criteria. 
Study drug administration will be documented in accordance with the Pharmacy Manual. 
The site pharmacist will be unblinded in order to prepare the intravenous study medications and 
select the appropriate oral follow on therapy for patients randomized to the ertapenem regimen. 
Both Treatment Groups:  
In both treatment groups, patients found to have pathogens isolated from blood cultures that are 
resistant to carbapenems including ertapenem should be discontinued from study drug therapy, 
but should remain in the study and treated appropriately. Patients found to have pathogens 
isolated from intra-abdominal cultures that are resistant to carbapenems including ertapenem, 
may be allowed to continue on study drug therapy based on clinical response and investigator 
judgement. 
Dosing with food: Food significantly increases bioavailability of sulopenem and consequently 
results in decreased rates of diarrhea. Therefore, dosing of oral sulopenem etzadroxil/probenecid 
with food whenever possible is recommended.  Since adequate target attainment appears to be 

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achieved in the fasted state, an inability to administer the dose with food should not preclude 
dosing. The overall absorption of ciprofloxacin is not substantially affected by food. 
5.2.4 Compliance 
All patients should be informed that compliance with taking all medication as instructed is 
imperative. Intravenous treatment will be administered under the supervision of investigative site 
personnel at a hospital or, for centers approved by the Sponsor to do so, in an outpatient infusion 
center, and infusion date, start and stop time will be documented on the CRF. 
Patients discharged on oral medication will be asked to bring all study medication bottles (used 
and unused) to the next scheduled study visit for drug accountability. Patients will be asked to 
record oral dosing on a dosing record and bring it to the site at each visit. The total amount of 
oral dosing completed (determined by tablet count from returned bottles/blister packs) will be 
recorded on the CRF.  A urine sample will be collected and frozen for all patients at the EOT 
visit if a need to confirm compliance with study drug therapy arises for any patient. 
5.3 
Drug Storage and Drug Accountability  
The investigator, or an approved representative, e.g., pharmacist/designee, will ensure that all 
investigational products are stored in a secured area, under recommended storage conditions, and 
in accordance with applicable regulatory requirements. To ensure adequate records, all study 
drugs will be accounted for by using site standard accountability form or forms provided by 
Iterum Therapeutics. In either case, the forms must identify the investigational product, 
including batch or code numbers, and account for its disposition on a patient-by-patient basis, 
including specific dates and quantities. 
At the end of the study, Iterum Therapeutics will provide instructions as to disposition of any 
unused investigational product.  If Iterum Therapeutics authorizes destruction at the study site, 
the investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by Iterum 
Therapeutics.  Destruction must be adequately documented. 
5.4 
Concomitant Medication(s), Adjunctive Therapy and Non-drug 
Therapy 
5.4.1 
Concomitant Medications 
Any medication taken by the patient, other than study drug, is considered a concomitant 
medication.  All concomitant medications from Screening (Day -1) through the Day 28 (TOC) 
must be recorded in the patient's source record and on the CRFs. 
At each visit, the investigator/site designee will obtain information on any therapeutic 
interventions (e.g., drug and non-drug therapy, surgery, etc.) provided.  The use of any other 
investigational drug is prohibited and patients may not participate in any other studies involving 
marketed products concomitantly while in this study.  
The use of other (non-antibacterial) medications should be limited to those essential for the care 
of the patient.  All medications required by the patient to manage underlying illnesses, other than 

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infection under study, and any drugs that may be required for emergency treatments must be 
recorded on the CRF.   
5.4.2 
Concomitant Antibacterial Medications 
Concomitant systemic antibacterials are prohibited during the study, up to the EOT visit, with 
the following exceptions: 
• 
Vancomycin IV, linezolid IV or PO, or daptomycin IV can be given for known or suspected 
methicillin-resistant Staphylococcus aureus (MRSA) or Enterococcus spp. The Sponsor will not 
provide any of these medications. 
5.4.3 
Non-drug Adjunctive Therapy 
The potential need for surgical intervention in patients with cIAI during the study must be 
prospectively defined at Baseline. Patients expected to require more than 2 surgical 
interventions for the cIAI under study are not to be enrolled. 
The following adjunctive therapies are permitted for the treatment of cIAI: 
• Percutaneous drainage procedures, open laparotomy or laparoscopic surgery  
• Topical solutions including antiseptic agents such as povidine-iodine; 
• Local bedside wound care as per hospital protocol. 
6 
STUDY PROCEDURES 
6.1 
Screening (Day -1) - Within 24 Hours Prior to First Dose 
The investigator (or an appropriate delegate at the investigator site) will obtain written informed 
consent from each patient prior to the initiation of any study related activities. Sites participating 
in the population PK substudy should obtain written consent from willing patients. PK sampling 
procedures are detailed in Appendix 4. 
The following procedures will be performed prior to randomization and study drug 
administration: 
• Demographics and medical history. 
• Targeted physical examination (including general appearance, examination of heart, lungs, 
abdomen, and extremities) 
• Vital signs (temperature, blood pressure, pulse rate, respiratory rate) and height and weight 
• Assess cIAI specific signs and symptoms 
• Blood for laboratory testing (including hematology and chemistry studies as well as urine or 
serum (βhCG) pregnancy test (women of child-bearing potential, including peri- 
menopausal women until FSH value is known); serum follicle stimulating hormone [FSH] 
for postmenopausal females <50 years of age or those ≥50 years of age who have been 
post-menopausal for <2 years.  
• Banked serum and urine for retrospective safety and efficacy assessments 
• Collect urine for urinalysis  

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• Infection site specimen collection (including Gram-stain, culture and susceptibility 
[Appendix 2]) and blood cultures 
• Adverse events occurring after signing of ICF 
• Review previous (defined as within the prior 30 days) and concomitant drug and non-drug 
treatments 
To prepare for trial participation, patients will be instructed on the use of Life Style Guidelines 
and Concomitant Medications. 
6.2 
Treatment Period  
For the study period described below, where multiple procedures are scheduled at the same time 
point(s) relative to dosing, the following chronology of events should be adhered to, where 
possible. 
• Blood pressure/pulse rate: obtain as close as possible to scheduled time, but prior to blood 
specimen collection. 
• Pharmacokinetic blood specimens: obtain at scheduled time. 
6.2.1 Day 1 
The following activities will be completed: 
• Review concomitant drug and non-drug treatments 
• Administer the study medication as described in the Study Treatment Section 
(Administration Section) 
• Collect blood samples for PK analyses for patients in the PK substudy (Appendix 4) 
• Assess symptoms by spontaneous reporting of adverse events and by asking the subjects to 
respond to a non-leading question such as “How do you feel? 
6.2.2  Day 5 
• Targeted physical examination, if required, based on patient’s symptoms 
• Vital signs (temperature, blood pressure, pulse rate, respiratory rate) 
• Assess cIAI specific signs and symptoms 
• Blood for laboratory testing (including hematology and chemistry studies) 
• Collect blood samples for PK analyses for patients in the PK substudy (Appendix 4) 
• Review concomitant drug and non-drug treatments 
• Assess symptoms by spontaneous reporting of adverse events and by asking the subjects to 
respond to a non-leading question such as “How do you feel? 
6.2.3 Day 10 (End of Treatment) 
• Targeted physical examination, if required, based on patient’s symptoms 
• Vital signs (temperature, blood pressure, pulse rate, respiratory rate) 
• Assess cIAI specific signs and symptoms 

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• Blood for laboratory testing (including hematology and chemistry studies) 
• Review concomitant drug and non-drug treatments 
• Check and document compliance with study medication if stepped down to oral therapy 
• Banked urine specimen to document compliance if needed 
• Assess symptoms by spontaneous reporting of adverse events and by asking the subjects to 
respond to a non-leading question such as “How do you feel? 
• Investigator Assessment of Clinical Response (Section 7.2.2) 
6.2.4 Day 11-14 (End of Treatment) – only to be conducted for patients who receive 
longer than 10 days of treatment, instead of Day 10 visit 
• Targeted physical examination, if required, based on patient’s symptoms 
• Vital signs (temperature, blood pressure, pulse rate, respiratory rate) 
• Assess cIAI specific signs and symptoms 
• Blood for laboratory testing (including hematology and chemistry studies) 
• Review concomitant drug and non-drug treatments 
• Check and document compliance with study medication if stepped down to oral therapy 
• Banked urine specimen to document compliance if needed 
• Assess symptoms by spontaneous reporting of adverse events and by asking the subjects to 
respond to a non-leading question such as “How do you feel? 
• Investigator Assessment of Clinical Response (Section 7.2.2) 
6.3 
Follow-Up Period  
6.3.1 Day 21 (+/- 1 day) – Phone Call 
• Assess cIAI specific signs and symptoms 
• Review concomitant drug and non-drug treatments 
• Assess symptoms by spontaneous reporting of adverse events and by asking the subjects to 
respond to a non-leading question such as “How do you feel? 
• Investigator Assessment of Clinical Response (Section 7.2.2) 
6.3.2   Day 28 (+/- 1 day) – (Test of Cure) 
• Targeted physical examination, if required, based on patient’s symptoms 
• Vital signs (temperature, blood pressure, pulse rate, respiratory rate) 
• Assess cIAI specific signs and symptoms 
• Blood for laboratory testing if needed to follow up on abnormal test results from the Day 10 
visit (including hematology and chemistry studies) 
• Urine pregnancy test 
• Review concomitant drug and non-drug treatments 

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• Assess symptoms by spontaneous reporting of adverse events and by asking the subjects to 
respond to a non-leading question such as “How do you feel? 
• Investigator Assessment of Clinical Response (Section 7.2.2) 
6.4 
Premature Discontinuation from Study 
• Targeted physical examination, if required, based on patient’s symptoms 
• Vital signs (temperature, blood pressure, pulse rate, respiratory rate) 
• Assess cIAI specific signs and symptoms 
• Blood for laboratory testing (including hematology and chemistry studies) 
• Review concomitant drug and non-drug treatments 
• Check and document compliance with study medication, if applicable 
• Assess symptoms by spontaneous reporting of adverse events and by asking the subjects to 
respond to a non-leading question such as “How do you feel? 
• Investigator Assessment of Clinical Response (Section 7.2.2) 
6.5 
Patient Withdrawal from Treatment or Study 
Patients may withdraw from the study or study drug at any time at their own request, or they 
may be withdrawn at any time at the discretion of the investigator or sponsor for safety, 
behavioral, or administrative reasons.  If a patient does not return for a scheduled visit, every 
effort should be made to contact the patient.  In any circumstance, every effort should be made to 
document patient outcome, if possible.  If the patient withdraws or is withdrawn from study drug 
treatment, the investigator should inquire about the reason for withdrawal, request the patient to 
return for all protocol-specified assessments, if possible, and follow-up with the patient 
regarding any unresolved AEs through Day 28. 
For patients who discontinue from the study early, a Premature Discontinuation visit should be 
performed within 3 calendar days after decision to discontinue (Section 6.4) and no further visits 
are required. 
If the patient discontinues from the study, and also withdraws consent for disclosure of future 
information, no further study-specific evaluations should be performed, and no additional data 
should be collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent. 
7 
ASSESSMENTS 
7.1 
Safety 
7.1.1 
Physical Examination 
A targeted physical examination will be performed at Baseline (including general appearance, 
examination of heart, lungs, abdomen, and extremities). A targeted physical exam may be 
conducted at any visit to address patient’s symptoms if needed. 

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7.1.2 
Vital Signs (Blood Pressure, Respiration Rate, Temperature and Pulse Rate) 
Vital signs are performed at Baseline, Day 5, Day 10 (or Day 11-14) and Day 28 (+/- 1 days). 
Blood pressure will be measured and recorded to the nearest mm Hg.  All blood pressure 
measurements should be taken at rest.  The same size blood pressure cuff will be used to 
measure blood pressure each time.  When the timing of these measurements coincides with a 
blood collection, blood pressure and pulse rate are to be obtained first.  Temperature will be 
measured as an oral, rectal, tympanic (ear) or core temperature.  
7.1.3 
Clinical Laboratory Assays 
The following laboratory parameters will be measured: 
• Hematology: Complete blood count (CBC), including white blood cell (WBC) and 
differential counts; at Baseline, Day 5, Day 10 (or Day 11-14), and premature 
discontinuation. If abnormal at the Day 10 or Day 11-14 visit, need to repeat on Day 28. 
• Serum Clinical Chemistry: AST, ALT, GGT, alkaline phosphatase, albumin, total and 
direct bilirubin, BUN or urea, creatinine, Na+, K+, Cl-, total CO2 (Bicarbonate), glucose, 
C-reactive protein (CRP) and LDH at Baseline, Day 5, Day 10 (or Day 11-14) and 
premature discontinuation. If abnormal at the Day 10 or Day 11-14 visit, need to repeat on 
Day 28. 
• Urinalysis at Baseline. 
• Pregnancy Test (women of child-bearing potential): Urine or serum βhCG only at 
Baseline/Day 1; urine βhCG at Day 28 or premature discontinuation; Pregnancy test at 
Baseline should also be performed on peri-menopausal women until FSH value is available. 
• Serum FSH (to confirm postmenopausal status [amenorrheic for at least 1 year] for women 
<50 years of age or those ≥50 years of age who have been post-menopausal for <2 years): 
FSH at Baseline only, as needed. 
• Blood cultures: Blood cultures (aerobic and anaerobic) should be drawn at Baseline (prior 
to study drug treatment) from 2 different anatomical sites and not through an existing 
intravascular line. If positive, blood cultures should be repeated immediately (no later than 
24 hours after notification) and repeated until negative. If baseline cultures are negative, 
follow up cultures should be obtained only if clinically indicated (eg, worsening of signs 
and symptoms, relapse, or new infection). Specific instructions for sample collection, 
processing, and shipment can be found in the laboratory manual(s) for this study. 
• In addition, serum and urine samples will be banked at baseline for retrospective safety and 
efficacy analyses if needed. Urine specimens may be collected at EOT and banked if a need 
to document compliance with study drug therapy is identified.  
7.1.4 
Clinically Significant Laboratory Tests 
Clinical laboratory tests may be repeated during the study if deemed necessary as part of routine 
practice based on investigator judgment.  All clinically significant abnormal laboratory test 
results occurring during the study will be repeated at appropriate intervals until they return either 
to baseline or to a level deemed acceptable by the investigator and the Iterum appointed medical 
monitor.  

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7.2 
Efficacy 
7.2.1 
Clinical Response 
A patient’s outcome will be programmatically defined as a clinical cure if the following criteria 
are met: 
• Patient is alive 
• Resolution of baseline signs and symptoms of the index infection 
o No new symptoms 
• No new antibiotics or interventions for treatment failure are required 
Clinical failure is defined as: 
• Death due to cIAI  
• Surgical site wound infection requiring non-study systemic antibiotic therapy 
• Unplanned surgical procedures or percutaneous drainage procedures for complication or 
recurrence of cIAI based on documented worsening symptoms or signs of cIAI  
• Initiation of non-trial antibacterial drug therapy for treatment of cIAI based on 
documented worsening symptoms or signs of cIAI 
If data are unavailable to determine if the patient is a cure or a failure the patient outcome will be 
considered indeterminate. Deaths not due to cIAI will also be considered indeterminate. Patients 
with an indeterminate response are included in the denominator for determination of the clinical 
cure rate in the m-MITT population.  
7.2.2 
Investigator Assessment of Clinical Response 
Investigators will use the definitions below to document clinical response at the EOT, TOC and 
premature discontinuation visits: 
Clinical response 
Definition 
Clinical cure 
Pre-therapy signs and symptoms of the index infection had resolved such that 
no additional antibiotics or interventions were required 
Clinical failure 
Patients who met any one of the criteria below were considered as failure: 
Death related to cIAI prior to EOT or TOC for the EOT or TOC assessments, 
respectively 
No apparent response to treatment defined as:persistence or progression of 
most or all pre-therapy signs and symptoms or use of additional antibiotics or 
additional interventions for the current infection 
Patient previously met criteria for failure based on receipt of rescue antibiotics 
or death, as above 

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Clinical response 
Definition 
Indeterminate 
Study data were not available for evaluation of efficacy for any reason, 
including: 
Patient lost to follow-up or assessment not undertaken such that a 
determination of clinical response could not be made at either the EOT or 
TOC visit 
Death prior to EOT or TOC for the EOT and TOC assessments, respectively, 
where cIAI was clearly noncontributory 
 
7.2.3 
Other Efficacy Outcomes  
Microbiologic response will be determined at EOT and TOC in the ME and m-MITT 
populations. For each pathogen, microbiologic response will be defined as follows: 
• Eradication: An acceptable specimen at a post-baseline visit indicates absence of the 
baseline pathogen 
• Presumed eradication: There was no acceptable post-baseline specimen for culture 
and the patient was assessed as a clinical curebased on the programmatic 
determination of clinical response. 
• Persistence: An acceptable post-baseline specimen indicates presence of the baseline 
pathogen 
• Presumed persistence: There was no acceptable post-baseline specimen for culture 
and the patient was assessed as a clinical failure based on the programmatic 
determination of clinical response. 
• Persistence with increasing MIC: An acceptable post-baseline culture taken after at 
least 2 full days of treatment indicates presence of the baseline pathogen and 
displayed ≥4-fold higher MIC to study drug therapy after treatment with study 
therapy. For patients with bacteremia at Baseline, follow-up blood cultures after 72 
hours of treatment show growth of baseline pathogen and displayed ≥4-fold higher 
MIC to study drug therapy. 
• Indeterminate: Study data were not available for evaluation of efficacy, for any 
reason including: 
o Patient was lost to follow up or an assessment was not undertaken such 
that no culture was obtained (or culture results could not be interpreted for 
any reason) at either the Day 5, EOT or the TOC visit 
o Death prior to Day 5, EOT or TOC respectively, where the underlying 
infection was clearly non-contributory 
o Circumstances that precluded classification as an eradication, persistence, 
or persistence with increasing MIC 
A microbiologic success is defined as eradication or presumed eradication whereas a failure is 
defined as persistence or presumed persistence. 
The per-patient microbiological response is based on the outcomes for each baseline pathogen. 
For a subject to be a microbiological success, the outcome for each baseline pathogen must be a 

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success (eradication or presumed eradication). If the outcome is failure for any pathogen (as 
defined by persistence or presumed persistence) then the patient will be regarded as a per-patient 
microbiologic failure. 
8 
ADVERSE EVENT REPORTING 
8.1 
Adverse Events 
All observed or volunteered AEs regardless of treatment group or suspected causal relationship 
to the investigational product(s) will be reported as described in the following sections.  
For all AEs, the investigator must pursue and obtain adequate information both to determine the 
outcome of the AE and to assess whether it meets the criteria for classification as a serious AE 
(SAE) requiring immediate notification to Iterum Therapeutics designated pharmacovigilance 
provider.  For all AEs, sufficient information should be obtained by the investigator to determine 
the causality of the AE.  The investigator is required to assess causality.  All AEs will be 
followed-up by the investigator until the event or its sequel resolve or stabilize at a level 
acceptable to the investigator, and Iterum concurs with that assessment. 
8.2 
Reporting Period 
Adverse events will be collected from the time that the patient provides informed consent 
through the Day 28 (TOC) visit.  
For SAEs, the reporting period to Iterum Therapeutics begins from the time that the patient 
provides informed consent, which is obtained prior to the patient’s participation in the study, i.e., 
prior to undergoing any study-related procedure and/or receiving investigational product, 
through the Final Visit.  Any SAE occurring any time after the reporting period must be 
promptly reported if a causal relationship to investigational product is suspected.  
All AEs should be recorded on the CRF if they occur from the time the patient provides 
informed consent through the Day 28 (TOC) visit. 
8.3 
Definition of an AE 
An AE is any untoward medical occurrence in a clinical investigation patient administered a 
product or medical device, unless the event is captured in the study endpoint, as defined below; 
the event need not necessarily have a causal relationship with the treatment or usage.   
An event would be considered as adequately captured in the study endpoint if it is accurately and 
fully represented by a protocol-defined reason for clinical failure (other than mortality) or 
relapse.  Such an event should not be reported as an adverse event unless it is a serious adverse 
event as defined in this protocol.   
Events represented by the study endpoints include all of the following: 
• Symptoms of cIAI have not resolved from Baseline to such an extent that new antibiotics 
are not needed for the infection under study 
• Development of new cIAI symptoms not present at Baseline 

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Except for circumstances as defined above, examples of AEs include but are not limited to:   
• Abnormal test findings (see Section 8.4); 
• Clinically significant symptoms and signs; 
• Changes in physical examination findings; 
• Hypersensitivity; 
• Progression/worsening of underlying disease.  
Additionally, they may include the signs or symptoms resulting from: 
• Drug overdose; 
• Drug withdrawal; 
• Drug abuse; 
• Drug misuse;  
• Drug interactions; 
• Drug dependency; 
• Extravasation of study drug; 
• Exposure during Pregnancy. 
8.4 
Abnormal Test Findings 
An abnormal objective test finding (e.g., an abnormal liver function test result) should be 
reported as an AE only if the following conditions apply:  
• Test result is associated with accompanying symptoms and/or signs, constituting a clinical 
syndrome (e.g., abnormal liver function test results, jaundice, and hepatic tenderness 
suggesting a diagnosis of hepatitis), and/or 
• Test result requires medical/surgical intervention, and/or 
• Test result leads to a change in study dosing or withdrawal from the study, significant 
additional concomitant drug treatment, or other therapy. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not define 
the abnormal objective test finding as an AE.  Any abnormal test result that is determined to be 
an error does not require reporting as an AE.  Additional diagnostic testing and /or 
medical/surgical interventions that occur as a result of an adverse event due to an abnormal lab 
test finding should be noted in the CRF.  
8.5 
SAEs 
An SAE or serious adverse drug reaction is any untoward medical occurrence at any dose that: 
• Results in death; 
• Is life-threatening (immediate risk of death); 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability/incapacity; 

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• Results in congenital anomaly/birth defect; 
• Is assessed as being a medically important event based on medical and scientific judgment.  
Such medically important events may not be immediately life-threatening or result in death 
or hospitalization, but may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the above outcomes.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development 
of drug dependency or drug abuse. 
8.6 
Hospitalization 
Adverse events associated with hospitalization or prolongations of hospitalization are considered 
serious.  Admission also includes transfer within the hospital to an acute/intensive care unit (e.g., 
from the psychiatric wing to a medical floor, medical floor to a coronary care unit, neurological 
floor to a tuberculosis unit). 
Hospitalization does not include the following: 
• Rehabilitation facilities; 
• Hospice facilities; 
• Respite care (e.g., caregiver relief); 
• Skilled nursing facilities; 
• Nursing homes; 
• Routine emergency room evaluation; 
• Same day surgeries (as outpatient/same day/ambulatory procedures). 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical AE is 
not in itself an SAE.  Examples include:  
• Admission for treatment of a preexisting condition not associated with the development of a 
new AE or with a worsening of the preexisting condition (e.g., for work-up of persistent pre-
treatment laboratory abnormality); 
• Social admission (e.g., patient has no place to sleep); 
• Administrative admission (e.g., for yearly physical exam); 
• Protocol-specified admission during a study (e.g., for a procedure required by the study 
protocol); 
• Optional admission not associated with a precipitating clinical AE (e.g., for elective cosmetic 
surgery).  Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient; 
• Admission exclusively for the administration of blood products. 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not be 
reported as an AE.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis that 

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begins during the AE reporting period should be reported as the AE and the resulting 
appendectomy should be recorded as treatment of the AE. 
8.7 
Severity Assessment 
The investigator will use the adjectives MILD, MODERATE, or SEVERE to describe the 
maximum intensity of the AE.  For purposes of consistency, these intensity grades are defined as 
follows: 
• MILD:  Does not interfere with the patient's usual function. 
• MODERATE:  Interferes to some extent with the patient's usual function. 
• SEVERE:  Interferes significantly with the patient's usual function.  
Note the distinction between the severity and the seriousness of an adverse event.  A severe 
event is not necessarily a serious event.  For example, a headache may be severe (interferes 
significantly with subject's usual function) but would not be classified as serious unless it met 
one of the criteria for serious adverse events, listed above. 
8.8 
Causality Assessment 
The investigator’s assessment of causality must be provided for all AEs (serious and non-
serious); the investigator must record the causal relationship in the CRF, as appropriate, and 
report such an assessment in accordance with the serious adverse reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there exists a 
reasonable possibility that the investigational product caused or contributed to an AE.  If the 
investigator does not know whether or not investigational product caused the event, then the 
event will be handled as “related to investigational product” for reporting purposes, as defined 
by the Sponsor (see Section 8.12 on Reporting Requirements).  If the investigator's causality 
assessment is "unknown but not related to investigational product", this should be clearly 
documented on study records.  Specifically, the investigator will choose whether the AE is 
unrelated, unlikely related, possibly related or probably related to the investigational product. 
In addition, if the investigator determines an SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting requirements, 
if applicable. 
The Investigator will assess causality of the event in relation to study drugs based on the 
following defined criteria:  
• UNRELATED: No relationship between the event and medicinal product 
• UNLIKELY, Event or laboratory test abnormality, with a time to drug intake that makes a 
relationship improbable (but not impossible); Disease or other drugs provide plausible 
explanations 
• POSSIBLY, Event or laboratory test abnormality, with reasonable time relationship to drug 
intake; Could also be explained by disease or other drugs; Information on drug withdrawal 
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• PROBABLY, Event or laboratory test abnormality, with reasonable time relationship to drug 
intake; Unlikely to be attributed to disease or other drugs; Response to withdrawal clinically 
reasonable; Rechallenge not required 
8.9 
Exposure during Pregnancy 
For investigational products and for marketed products, an exposure during pregnancy (also 
referred to as exposure in-utero [EIU]) occurs if: 
1. A female becomes, or is found to be, pregnant either while receiving or having been directly 
exposed to (e.g., environmental exposure) the investigational product, or the female 
becomes, or is found to be, pregnant after discontinuing and/or being directly exposed to the 
investigational product (maternal exposure); 
2. A male has been exposed, either due to treatment or environmental exposure, to the 
investigational product prior to or around the time of his partner’s conception and/or is 
exposed during his partner’s pregnancy (paternal exposure). 
If any study patient or study patient’s partner becomes or is found to be pregnant during the 
study patient’s treatment with the investigational product, no further study drugs should be given 
and the investigator must submit this information to Iterum Therapeutics on a Pregnancy Form.  
In addition, the investigator must submit information regarding environmental exposure to 
sulopenem in a pregnant woman (e.g., a nurse reports that she is pregnant and has been exposed 
to sulopenem by spillage) using the Pregnancy Form.  This reporting must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the pregnancy.  The 
information submitted should include the anticipated date of delivery (see below for information 
related to induced termination of pregnancy). 
Follow-up is conducted to obtain pregnancy outcome information on all Pregnancy reports with 
an unknown outcome.  The investigator will follow the pregnancy until completion or until 
pregnancy termination (i.e., induced abortion) and then notify Iterum of the outcome.  The 
investigator will provide this information as a follow up to the initial Pregnancy Form.  The 
reason(s) for an induced abortion should be specified.  A Pregnancy report is not created when 
an ectopic pregnancy report is received since this pregnancy is not usually viable.  Rather, an 
SAE case is created with the event of ectopic pregnancy. 
If the outcome of the pregnancy meets the criteria for immediate classification as an SAE 
(i.e., spontaneous abortion, stillbirth, neonatal death, or congenital anomaly [including that in an 
aborted fetus, stillbirth or neonatal death]), the investigator should follow the procedures for 
reporting SAEs. 
In the case of a live birth, the “normality” of the newborn can be assessed at the time of birth 
(i.e., no minimum follow-up period of a presumably normal infant is required before a 
Pregnancy Form can be completed).  The “normality” of an aborted fetus can be assessed by 
gross visual inspection, unless pre-abortion test findings are suggestive of a congenital anomaly. 
Additional information about pregnancy outcomes that are classified as SAEs follows:  
• “Spontaneous abortion” includes miscarriage and missed abortion. 

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• All neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 1 month that the investigator assesses 
as possibly related to the exposure during pregnancy to the investigational medication should 
be reported. 
Additional information regarding the exposure during pregnancy may be requested by the 
investigator.  Further follow-up of birth outcomes will be handled on a case-by-case basis 
(e.g., follow-up on preterm infants to identify developmental delays).  In the case of paternal 
exposure, the investigator must obtain permission from the patient’s partner in order to conduct 
any follow-up or collect any information. 
8.10 Discontinuation from Study Drug Due to AEs (See also Patient 
Withdrawal, Section 6.4) 
Discontinuation from study drug due to an AE should be distinguished from discontinuation due 
to insufficient response, according to the definition of AE noted earlier, and recorded on the 
appropriate AE CRF page.   
When a patient discontinues study drug due to an SAE, the SAE must be reported in accordance 
with the reporting requirements defined below. 
8.11 Eliciting AE Information 
The investigator is to report all directly observed AEs and all AEs spontaneously reported by the 
study patient through the Final Visit.  In addition, each study patient will be questioned about the 
occurrence of any AEs. 
8.12 Reporting Requirements 
Each AE is to be assessed to determine if it meets the criteria for an SAE.  If an SAE occurs that 
is considered by the investigator or the Sponsor to be at least possibly related to study drug, 
expedited reporting will follow local and international regulations, as appropriate. 
8.12.1 
SAE Reporting Requirements 
If an SAE or exposure during pregnancy occurs, Iterum Therapeutics (Iterum’s PV Service 
provider) is to be notified within 24 hours of awareness of the event by the investigator on an 
SAE form or Pregnancy form.  If the SAE is fatal or life-threatening, notification to Iterum must 
be made immediately, irrespective of the extent of available event information.  This timeframe 
also applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of Pregnancy cases.   
In the rare instance that the investigator does not become aware of the occurrence of an SAE 
immediately (e.g., if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time of 
his/her first awareness of the AE. 
For all SAEs and pregnancies, the investigator is obligated to pursue and provide information to 
Iterum in accordance with the timeframes for reporting specified above.  In addition, an 
investigator may be requested by Iterum Therapeutics to obtain specific additional follow-up 

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information in an expedited fashion.  This information may be more detailed than that captured 
on the SAE form.  In general, this information may include hospital discharge summary, 
laboratory test and X-ray results.  Information on other possible causes of the event, such as 
concomitant medications and illnesses must be provided.  In the case of a patient death, a 
summary of available autopsy findings must be submitted as soon as possible to Iterum 
Therapeutics.  The information should be reported on an SAE/Pregnancy form and sent to the 
PSI Pharmacovigilance unit. 
8.12.2 
Non-SAE Reporting Requirements 
All AEs will be reported on the AE page(s) of the CRF.  Please note that while all AEs are 
reported on the AE page of the CRF, there is an additional form used for collection of SAE 
information, as described in Section 8.12.1, which is not the same as the AE CRF.  When the 
same data are collected, the two forms must be completed in a consistent manner.  For example, 
the same AE term should be used on both forms.  Adverse events should be reported using 
concise medical terminology on the CRFs as well as on the form for collection of SAE 
information.  The information on the AE CRF and the SAE form must be the same and will be 
reconciled at defined periods throughout the study to ensure that they do. 
8.12.3 
Sponsor Reporting Requirements to Regulatory Authorities 
Adverse event reporting, including reporting of suspected serious unexpected adverse reactions, 
will be carried out in accordance with applicable local regulations.  Death and life-threatening 
Suspected, Unexpected Serious Adverse Reactions (SUSARs) are subject to expedited reporting 
within a 7 calendar day (life-threatening and fatal) or 15 calendar day (all other SUSARs) 
timeframe. 
9 
DATA ANALYSIS/STATISTICAL METHODS 
9.1 
Sample Size Determination 
The study is designed to determine whether sulopenem IV followed by sulopenem etzadroxil co-
administered with probenecid is non-inferior (NI) to ertapenem followed by oral ciprofloxacin 
and metronidazole or amoxicillin-clavulanate on Day 28 for the outcome measure of clinical 
response, defined as resolution of the signs and symptoms of cIAI present at trial entry with no 
new symptoms such that no new antibiotics or interventions are required. 
The expected clinical cure rate is estimated from numerous large randomized controlled trials in 
a similar cIAI patient population. In those studies, the estimated cure rate for the proposed 
primary efficacy outcome measure of clinical cure on Day 28 in the m-MITT population was 
85%. 
The proposed sample size for the ITT population is 670 patients.  This ITT sample size estimate 
is based on the assumption that 80%, or 536 patients, of this ITT population will be m-MITT 
evaluable.  The sample size of the m-MITT population is 268 patients per arm based on a Z-test 
with unpooled variance. This 536 m-MITT sample size assumes a non-inferiority margin of 
10%, a power of 90%, a one-sided alpha level of 0.025 and an 85% treatment response rate in 
both treatment groups.  
The aggregate blinded clinical cure rate will be assessed when approximately 60% of the 
subjects have been randomized and have efficacy outcome data at TOC available. If the 

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aggregate response rate at that point is <85%, the final ITT sample size may be increased 
based on the observed clinical cure rate at that blinded interim analysis, as well as the 
evaluability rate, to maintain a power of 90%.  See Section 9.7. 
9.2 
Definition of Analysis Populations 
1. Intent-to-Treat (ITT): all randomized patients regardless of whether or not the subjects 
received study drug 
2. Modified ITT (MITT): randomized patients who received at least a single-dose of study 
medication 
3. Safety: randomized patients who received any amount of a single-dose of study 
medication 
4. Micro-MITT (m-MITT): All MITT patients who have at least one gram-negative 
pathogen identified at study entry (regardless of isolate susceptibilities). Patients with a 
bacterial species typically not expected to respond to either study drug (e.g. 
Acinetobacter spp., Stenotrophomonas spp., Pseudomonas spp.) will be excluded.  
5. Clinically evaluable: Clinically evaluable (CE) at the EOT and TOC visits 
population:  
a) Received a minimum number of days of study drug (to be defined in the 
Statistical Analysis Plan [SAP]) 
b) Had no important protocol deviations that would affect the assessment of efficacy 
(to be defined in the SAP) 
c) Had an outcome assessment of clinical cure or failure (and not indeterminate) at 
the EOT or TOC visits (ie, within the protocol allowed visit window), respectively.   
d) Had not received prior antibiotic within 48 hours of the initiation of study therapy 
for this infection unless the patient had received only 1 dose of a short-acting 
antibiotic regimen within 24 hours 
e) Did not receive any non-study antibiotic therapy with potential activity against 
any of the baseline pathogens collected at screening between the time of the baseline 
culture and the EOT or TOC culture, respectively.  This excludes the protocol defined 
study therapy and patients who were considered clinical failures and required 
additional antibiotic therapy.  Patients with a coinfection with a gram-positive 
pathogen resistant to study drugs are allowed to receive agents with narrow spectrum 
gram-positive coverage (ie, such as linezolid, daptomycin or vancomycin)  
6. Microbiologically evaluable (ME): all patients included in both the m-MITT and CE 
populations at the EOT visit (ME-EOT) and at the TOC visit (ME-TOC).  
9.3 
General Statistical Considerations 
Descriptive statistics, including the numbers and percentages for categorical variables, and the 
numbers, means, standard deviations, medians, minimums, and maximums for continuous 
variables will be provided. All comparisons will be for the sulopenem treatment group and the 
comparator treatment group. Exploratory analyses may also be performed. Listings of individual 

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patient’s data will be produced. A comprehensive SAP will be finalized prior to the interim 
analysis. 
9.4 
Patient Characteristics 
Enrollment, protocol deviations, discontinuations from the study drug and withdrawal from the 
study will be summarized by treatment group.  Demographics (age, race, sex), medical and 
surgical history, baseline assessment of the symptoms of cIAI, baseline pathogen, and study drug 
administration will also be summarized.  Differences between treatment groups will be analyzed 
using the chi-square or Fisher’s exact test for dichotomous variables and the Wilcoxon Rank 
Sum test for ordinal variables and continuous variables.   
9.5 
Efficacy Analysis 
For all efficacy analyses, patient data will be analyzed in the treatment group to which the 
patient was randomized.  For the primary analysis, patients who were randomized to the wrong 
type of infection will be analyzed in the stratum to which they were randomized.  
9.5.1 
Analysis of Primary Outcome Measure 
The primary efficacy outcome is clinical response at the Day 28 (TOC) visit in the m-MITT 
population. The number and percentage of patients in each treatment group defined as a clinical 
cure, failure and indeterminate will tabulated. The observed difference in percentage of patients 
with a clinical cure at the Day 28 (TOC) visit (+/- 1 day) (sulopenem group minus the 
comparator group) will be determined and a 95% confidence interval (CI) for the observed 
difference will be computed using a Z-statistic. The NI hypothesis test is a one-sided hypothesis 
test performed at the 2.5% level of significance. If the lower limit of the 95% CI for the 
difference in response rates in the m-MITT population is greater than -10% the NI of sulopenem 
to the comparator group will be concluded. 
9.5.1.1 
Additional Analyses of the Primary Efficacy Outcome 
The primary efficacy outcome will also be assessed within each geographic region and by type 
of infection by treatment group. For each geographic region, a two-sided 95% CI for the 
observed difference in the clinical cure rates in the m-MITT population will be calculated. For 
each type of infection, a two-sided 95% CI for the observed difference in the clinical cure rates 
in the m-MITT population will be calculated. 
Sensitivity analyses of the primary outcome will also be conducted. An adjusted analysis (95% 
CI will be adjusted for the stratification factor of type of infection using the stratified method of 
Miettinen and Nurminen) will be provided for the difference in the clinical cure rate between the 
two treatment groups. Cochran-Mantel-Haenszel weights will be used for the stratum weights in 
the calculation of the CI. 
9.5.2 
Analysis of Secondary Efficacy Outcome Measure 
The number and percentage of patients with a clinical cure, failure and indeterminate response at 
the EOT (+/- 1 day) visit will be determined in each treatment group in the m-MITT population. 
The observed difference in percentage of patients with a clinical cure (sulopenem minus the 

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comparator group) will be determined and a 95% CI for the observed difference will be 
computed using the method of Miettinen and Nurminen. 
 
9.5.3 
Analysis of Additional Efficacy Outcome Measures 
Additional efficacy outcome measures will be presented for the following time points and 
analysis populations: 
1. Clinical response at Day 28 (TOC)  in the MITT, CE-TOC and ME-TOC populations. 
2. Clinical response at EOT (+/- 1 day) in the MITT, CE-EOT and ME-EOT populations. 
3. Clinical response by pathogen for key pathogens at TOC in the ME and m-MITT 
populations  
4. Per-subject microbiologic response at EOT and TOC in the ME and m-MITT populations. 
Per-pathogen microbiologic response at EOT and TOC in the ME and m-MITT populations 
5.   Investigators assessment of response (clinical cure, failure and indeterminate) at the EOT 
and TOC visits will be presented by treatment group for the m-MITT and CE populations. 
6.   Efficacy analyses in the subgroups of patients who did and did not receive prior effective 
antibiotic therapy will be presented. 
7. Other analyses of the impact on clinical efficacy of baseline demographic variables such as 
age, APACHE score, etc. may be performed. 
For selected additional efficacy outcome measures, two-sided 95% unstratified CIs will be 
constructed for the observed difference between the treatment groups for descriptive purposes; 
no conclusion of NI will be made. 
9.6 
Safety Analyses 
Safety will be assessed through summaries of AEs, clinical laboratory tests and vital signs.  All 
safety analyses will be based on the Safety population.  Patients who receive the wrong regimen 
of study drug for their entire course of treatment will be analyzed in the group based on the 
regimen received. 
Summary tables of treatment-emergent AEs (TEAEs) will be provided.  A TEAE is any AE that 
newly appeared, increased in frequency, or worsened in severity following initiation of study 
drug.  The incidence of TEAEs will be tabulated by system organ class and preferred term for 
each treatment group, and by severity and relationship to treatment.  Tables of TEAEs leading to 
study drug discontinuation, withdrawal from the study or an SAE will be provided.  AEs 
occurring prior to the first dose of study drug (AEs are recorded from the time of informed 
consent) will be provided in a listing. 
Descriptive statistics summarizing central laboratory data (hematology and chemistry) will be 
presented for all study visits.  The change from baseline to each post-baseline visit and to the 
overall worst post-baseline value will also be summarized by treatment group.  Laboratory 
values will be classified as of potential clinical concern and the number and percentage of 
patients with a lab value of potential clinical concern will be summarized by visit and treatment 
group.  Descriptive statistics of the vital signs will be presented by treatment group and study 
visit, as well as the change from baseline at each study visit.   

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9.7 
Interim Analysis  
In order to ensure that the point estimate of clinical cure used in the estimation of sample size is 
valid for this study, an interim analysis for sample size re-estimation will be performed when 
response data at the TOC visit are available for approximately 60% of the patients (402 
patients).  The FDA Guidance “Non-inferiority Clinical Trials” [FDA Guidance 2010] notes 
that such a sample size re-estimation if based on the blinded overall response rates is not only 
acceptable but is advisable.  The interim analysis will involve a sample size re-estimation to 
either confirm the initial sample size estimate is adequate or increase the sample size (number 
of randomized patients) to ensure the study has adequate power for determining whether 
sulopenem/sulopenem etzadroxil plus probenecid is NI to the comparator regimen for the 
primary outcome measure. In addition, the sample size may be increased based on a lower than 
expected evaluability rate.  The sample size re-estimation will be based on the blinded overall 
(not by treatment group) outcome rate and will be conducted by an independent, blinded 
statistician. A Data Monitoring Committee (DMC) will be provided the results of the interim 
analysis by the independent, blinded statistician and make a recommendation regarding 
changes to the sample size.  A detailed DMC charter will be developed which outlines the 
analyses to be completed, statistical rules, the potential changes to the sample size, and the 
recommendations that can be made to the Sponsor. 
9.8 
Handling of Missing Data 
Details of the handling of missing data will be provided in the SAP.  For the primary and 
secondary efficacy analyses, if any data field needed to determine clinical response is missing 
at the TOC visit, the patient will be considered an indeterminate response. By definition, 
patients with an indeterminate response are included in the denominator in the m-MITT 
population and thus, are analyzed in the same manner as clinical failures. Additional sensitivity 
analyses for handling missing data will be detailed in the SAP. Imputation may be performed to 
understand the impact of any imbalance in indeterminate outcomes between treatment 
regimens. By definition, patients with missing data are excluded from the CE populations. 
10 QUALITY CONTROL AND QUALITY ASSURANCE 
During study conduct, Iterum or its agent will conduct periodic monitoring visits to ensure that 
the protocol and GCPs are being followed.  The monitors may review source documents to 
confirm that the data recorded on CRFs are accurate.  The investigator and institution will allow 
Iterum monitors or its agents and appropriate regulatory authorities direct access to source 
documents to perform this verification. 
The study site may be subject to review by the institutional review board (IRB)/independent 
ethics committee (IEC), and/or to quality assurance audits performed by Iterum, or companies 
working with or on behalf of Iterum, and/or to inspection by appropriate regulatory authorities. 
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 

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11 DATA HANDLING AND RECORD KEEPING 
11.1 Case Report Forms / Electronic Data Record 
As used in this protocol, the term CRF should be understood to refer to either a paper form or an 
electronic data record or both, depending on the data collection method used in this study. 
A CRF is required and should be completed for each included patient.  The completed original 
CRFs are the sole property of Iterum and should not be made available in any form to third 
parties, except for authorized representatives of Iterum or appropriate regulatory authorities, 
without written permission from Iterum. 
The investigator has ultimate responsibility for the accuracy, authenticity, and timely collection 
and reporting of all clinical, safety, laboratory data entered on the CRFs and any other data 
collection forms.  The CRFs must be signed by the investigator or by an authorized staff member 
to attest that the data contained on the CRFs are true.  Any corrections to entries made in the 
CRFs and source documents must be dated, initialed and explained (if necessary) and should not 
obscure the original entry.  
In most cases, the source documents are the hospital's or the physician's patient chart.  In these 
cases, data collected on the CRFs must match the data in those charts.  
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these cases, 
a document should be available at the investigator’s site as well as at Iterum and clearly identify 
those data that will be recorded in the CRF, and for which the CRF will stand as the source 
document. 
11.2 Record Retention 
To enable evaluations and/or audits from regulatory authorities or Iterum, the investigator agrees 
to keep records, including the identity of all participating patients (sufficient information to link 
records, e.g., CRFs and hospital records), all original signed informed consent forms, copies of 
all CRFs, SAE forms, source documents, and detailed records of treatment disposition, and 
adequate documentation of relevant correspondence (e.g., letters, meeting minutes, telephone 
call reports).  The records should be retained by the investigator according to ICH, local 
regulations, or as specified in the Clinical Study Agreement, whichever is longer. 
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (e.g., retirement, relocation), Iterum should be prospectively notified.  The study 
records must be transferred to a designee acceptable to Iterum, such as another investigator, 
another institution, or to Iterum.  The investigator must obtain Iterum's written permission before 
disposing of any records, even if retention requirements have been met. 
12 ETHICS 
12.1 Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent forms, and other relevant documents, e.g., recruitment 
advertisements, if applicable, from the IRB/IEC.  All correspondence with the IRB/IEC should 

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be retained in the Investigator File.  Copies of IRB/IEC approvals should be forwarded to 
Iterum. 
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In that 
event, the investigator must notify the IRB/IEC and Iterum in writing immediately after the 
implementation. 
12.2 Ethical Conduct of the Study 
The study will be conducted in accordance with the Declaration of Helsinki on Ethical Principles 
for Medical Research Involving Human Patients, adopted by the General Assembly of the World 
Medical Association (2013).  
In addition, the study will be conducted in accordance with the protocol, the International 
Conference on Harmonisation (ICH) guideline on Good Clinical Practice (GCP), and applicable 
local regulatory requirements and laws. 
12.3 Patient Information and Consent 
All parties will ensure protection of patient personal data and will not include patient names on 
any sponsor forms, reports, publications, or in any other disclosures, except where required by 
laws.  In case of data transfer, Iterum will maintain high standards of confidentiality and 
protection of patient personal data. 
The informed consent form must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements. 
The informed consent form used in this study, and any changes made during the course of the 
study, must be prospectively approved by both the IRB/IEC and Iterum before use. 
The investigator must ensure that each study patient, or his/her legally acceptable representative, 
is fully informed about the nature and objectives of the study and possible risks associated with 
participation.  The investigator, or a person designated by the investigator, will obtain written 
informed consent from each patient or the patient's legally acceptable representative before any 
study-specific activity is performed.  The investigator will retain the original of each patient's 
signed consent form. 
12.4 Reporting of Safety Issues and Serious Breaches of the Protocol or 
ICH GCP 
In the event of any prohibition or restriction imposed (i.e., clinical hold) by an applicable 
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the investigational 
product, Iterum should be informed immediately.   
In addition, the investigator will inform Iterum immediately of any urgent safety measures taken 
by the investigator to protect the study patients against any immediate hazard, and of any serious 
breaches of this protocol or of ICH GCP that the investigator becomes aware of. 

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13 DEFINITION OF END OF STUDY 
13.1 End of Study in a Member State 
End of Trial in a Member State of the European Union is defined as the time at which it is 
deemed that sufficient patients have been recruited and have completed the study as stated in 
the regulatory application (i.e., Clinical Trial Application [CTA]) and ethics application in the 
Member State. Poor recruitment (recruiting less than the anticipated number in the CTA) by a 
Member State is not a reason for premature termination but is considered a normal conclusion 
to the study in that Member State. 
13.2 End of Study in all Participating Countries 
End of Study in all participating countries is defined as the last patient’s Final Visit. 
14 SPONSOR STUDY TERMINATION CRITERIA 
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, drug safety problems, or at the discretion of Iterum.  In 
addition, Iterum retains the right to discontinue development of sulopenem at any time. 
If a study is prematurely terminated, Iterum will promptly notify the investigator and the 
investigator must also inform the IRB/IEC.  After notification, the investigator must contact all 
participating patients and the hospital pharmacy (if applicable) within 90 days.  Investigator 
must also inform the IRB/IEC.  As directed by Iterum, all study materials must be collected and 
all CRFs completed to the greatest extent possible. 
15 PUBLICATION OF STUDY RESULTS 
Publication of study results is discussed in the Clinical Study Agreement. 
15.1 Communication of Results by Iterum 
Iterum fulfills its commitment to publicly disclose the results of studies through registration and 
posting of the results of this study on clinicaltrials.gov and EudraCT.   
15.2 Publications by Investigators 
Iterum has no objection to publication by the Investigator of any information collected or 
generated by the Investigator, whether or not the results are favorable to the Investigational 
Drug.  However, to ensure against inadvertent disclosure of Confidential Information or 
unprotected Inventions, the Investigator will provide Iterum an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed. 
The Investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to Iterum at 
least 30 days before they are submitted for publication or otherwise disclosed.  If any patent 

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action is required to protect intellectual property rights, the Investigator agrees to delay the 
disclosure for a period not to exceed an additional 60 days. 
The Investigator will, on request, remove any previously undisclosed Confidential Information 
(other than the study results themselves) before disclosure. 
If the study is part of a multi-center study, the Investigator agrees that the first publication is to 
be a joint publication covering all centers.  However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the study at all 
participating sites, the Investigator is free to publish separately, subject to the other requirements 
of this section. 
For all publications relating to the study, the Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical Considerations 
in the Conduct and Reporting of Research” of the Uniform Requirements for Manuscripts 
Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, established by 
the International Committee of Medical Journal Editors. 
Publication of study results is also provided for in the Clinical Study Agreement between Iterum 
and the Institution.  In this section entitled Publications by Investigators, the defined terms shall 
have the meanings given to them in the Clinical Study Agreement. 
 

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16 REFERENCE LIST 
John E. Mazuski, Leanne B. Gasink, Jon Armstrong, Helen Broadhurst, Greg G. Stone, Douglas 
Rank, Lily Llorens, Paul Newell, and Jan Pachl. Efficacy and Safety of Ceftazidime-Avibactam 
Plus Metronidazole Versus Meropenem in the Treatment of Complicated Intra-abdominal 
Infection: Results From a Randomized, Controlled, Double-Blind, Phase 3 Program. Clin Inf Dis 
2106; 62: 1380-1389. 
Complicated Intra-Abdominal Infections: Developing Drugs for Treatment. Guidance for 
Industry. U.S. Department of Health and Human Services. Food and Drug Administration Center 
for Drug Evaluation and Research (CDER). February 2015 
Committee for Medicinal Products for Human Use (CHMP). Guideline on the evaluation of 
medicinal products indicated for treatment of bacterial infections. 15 December 2011. 
CPMP/EWP/558/95 rev 2. 
 
 

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APPENDIX 1  
SCHEDULE OF ACTIVITIES 
 
SCREENING 
TREATMENT 
PERIOD 
END OF 
TREATMENT 
FOLLOW-UP PERIOD 
Protocol Activity 
Screening/ 
Baseline 
(D-1 to D1) 
Day 1 
Day 5 
Day 10 
(+/- 1 day) 
 
Day 11-14 
(+/- 1 day)7 
 
Day 21 
Phone Call 8 
(+/- 1 day) 
Day 28 
(TOC) 
(+/- 1 day) 
Premature 
Discontinuation 
Informed consent 
X 
 
 
 
 
 
 
 
Medical history and 
demographics 
X 
 
 
 
 
 
 
 
Targeted physical 
examination1 
X 
 
X 
X 
X 
 
X 
X 
Vital signs 
X 
 
X 
X 
X 
 
X 
X 
cIAI signs and symptoms 
X 
 
X 
X 
X 
X 
X 
X 
Hematology 
X 
 
X 
X 
X 
 
X2 
X 
Serum chemistry 
X 
 
X 
X 
X 
 
X2 
X 
Pregnancy testing 
X 
 
 
 
 
 
X 
 
FSH 
X 
 
 
 
 
 
 
 
Banked serum sample 
X 
 
 
 
 
 
 
 
Banked urine sample 
X 
 
 
X3 
X3 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
Intra-operative Gram 
stain and culture4  
X 
 
 
 
 
 
 
 
Peripheral blood 
cultures5 
X 
 
 
 
 
 
 
 
Plasma PK sampling for 
CP-70,4296 
 
X 
X 
 
 
 
 
 
Previous drug and non-
drug treatments 
X 
 
 
 
 
 
 
 
Concomitant drug and 
non-drug treatments 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment  
 
    X (each day for a duration of 5-14 days) 
 
 
 
Compliance with oral 
therapy check 
 
 
 
X 
X 
 
 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
Investigator determined 
clinical response 
evaluation 
 
 
 
X 
X 
X 
X 
X 
Schedule of Activities Footnotes: 
1 Post-baseline, to be done if needed, based on symptoms 
2     As needed to follow up on abnormal labs from Day 10 or Day 11-14 visits 
3   Urine samples may be collected at EOT and banked if a need to document compliance with study drug therapy is identified 
4    Follow up cultures to be obtained if needed based upon clinical signs and symptoms 
5   Blood cultures (aerobic and anaerobic) should be drawn at Baseline (prior to study drug treatment) from 2 different anatomical sites and not 
through an existing intravascular line. If positive, blood cultures should be repeated immediately (no later than 24 hours after notification) 
until negative 
6  In subset of patients enrolled in the PK substudy, collect plasma for PK analysis 2 hours and 4 hours post-dose on Day 1; collect plasma for 
PK analysis 2 hours, 4 hours and 6 hours post-dose after first oral dose. 
7 This visit applicable only to those patients who receive more than 10 days of study drug therapy, and should be conducted instead of the Day 
10 visit 
8 Targeted physical examination can be performed if necessary based on symptoms 

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APPENDIX 2  
MICROBIOLOGY 
Culture and Susceptibility testing  
 
At baseline, intra-abdominal specimens should be sent for culture of aerobes and anaerobes. 
Samples collected from abdominal drains are not allowed. Samples should be inoculated into 
aerobic and anaerobic culture bottles, incubated at 35°C–37°C, and transferred to the 
microbiology laboratory. All gram-negative pathogens will be tested locally for antimicrobial 
susceptibility, as appropriate. Specific instructions for sample collection, processing, and 
shipment can be found in the laboratory manual(s) for this study. 
 
The local laboratory should retain all isolates until the end of the study, if possible, or until 
confirmation of a viable organism is received from the central laboratory. Back-up cultures will 
be requested when the central laboratory does not receive a viable culture, or recovers an 
organism different from the one recorded by the local laboratory.  
 
Gram-staining of material from the site of infection  
One slide for Gram-stain is to be prepared from each specimen obtained from the site of the 
intra-abdominal infection. The slide is to be stained and read by the local laboratory and then 
sent to the central laboratory for re-reading and confirmation.  
Organisms considered as pathogens 
The following organisms will always be considered a pathogen when isolated from an acceptable 
culture specimen: 
• Monomicrobial or polymicrobial infections caused by: 
• Enterobacteriaceae 
• Staphylococcus aureus 
• Streptococci 
• Enterococci  
• Anaerobes 
• Pseudomonas spp. 
• Even if the organism was isolated from an acceptable culture specimen, the following are 
never a pathogen: 
• S. saprophyticus 
• Corynebacterium spp. 
• S. epidermidis 
• Bacillus spp. 
• Diphtheroids 
• Micrococcus spp. 
• Lactobacillus spp. 
All isolates not defined above will be assessed on a case-by-case basis via manual review by the 
Sponsor. If needed, patient clinical (e.g., type of infection, type of specimen, patient underlying 
conditions, etc.) and microbiological information (e.g., Gram stain) will be used to assist in 

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determining if the isolate is a pathogen. All organisms isolated from a blood culture will be 
reviewed by the Sponsor to determine if the organism is a pathogen. 
Based on the results of in vitro testing, animal studies, PK/PD modeling, surveillance programs 
and clinical trial data, a provisional breakpoint for susceptibility of sulopenem to 
Enterobacteriaceae, Streptococci and methicillin-susceptible Staphylococcus aureus is ≤ 0.5 
µg/mL. Disc diffusion interpretive criteria are available for sulopenem. A detailed description of 
the relevant microbiology data is available in the investigator brochure. 
 
 

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APPENDIX 3  
METHOD FOR DETERMINATION OF CREATININE  
 
 
 
 
 
 
CLEARANCE 
Creatinine clearance should be determined by the method of Cockroft-Gault based on serum 
creatinine concentrations obtained at Baseline, using ideal body weight instead of actual weight. 
For females: 
GFR = [(140-age) * (Ideal body wt in kg) * 0.85] / (72 * Cr) 
For males: 
GFR = [(140-age) * (Ideal body wt in kg)] / (72 * Cr) 
Ideal body weight is calculated as: 
For females:  
If height (H) > 152.5 cm 
Ideal body weight = 45.4 + [(H-152.4) * 0.89] 
If H < 152.5 cm 
Ideal body weight = 45.4 – [(152.4 – H)* 0.89] 
For males: 
If H > 152.5 cm 
Ideal body weight = 50 + [(H-152.4) * 0.89]  
If H < 152.5 cm 
Ideal body weight = 50 – [(152.4 – H)* 0.89] 
In order to determine the need to adjust the dose and/or dosing interval of IV study therapy to be 
administered, the patient’s estimated CrCl should be calculated using the most recent serum 
creatinine value obtained at the local laboratory. 
Dose adjustments for each of the study drugs based on estimated CrCl are outlined below.  
Study Drug 
CrCl ≥30 mL/min 
CrCl <30 mL/min 
Sulopenem IV 
1000 mg QD 
250 mg QD 
Ertapenem IV 
1000 mg QD 
500 mg QD 
Ciprofloxacin 
500 mg BID 
500 mg every 18 hours 
 
No dose adjustment is required for metronidazole in patients with renal impairment, however, a 
50% dose reduction is required for patients with severe hepatic impairment (Child-Pugh C). 
 

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APPENDIX 4  
POPULATION PK SUBSTUDY 
1 INTRODUCTION 
This study will be conducted within the context of an ongoing Phase 3 sulopenem clinical trial 
in order to generate confirmatory data for the population PK profile of both the IV and oral 
pro-drug regimens of sulopenem. 
1.1 Overall Study Design and Plan 
This protocol appendix describes the plan for collection, processing and analysis of 
population PK samples collected within Study IT001-303. 
At selected IT001-303 study sites, randomized patients will also be asked to provide plasma 
samples for population PK, according to the schedule noted below. Samples will be collected 
from subjects in both treatment arms. The study will remain blinded, regardless of whether or 
not any individual patient chooses to participate in the population PK sampling. 
See Study Events Table below. 
1.2 Rationale for Study Design and Control Group 
Population PK sample requires sampling from an adequate number of patients and must 
necessarily be done in the setting of a therapeutic clinical trial. The number of subjects and 
samples, and the sampling schedule has been determined using accepted population PK 
principles. A subset of the treatment population is needed for the study to meet its objectives, 
thus this study will be conducted at a subset of sites selected for their ability and willingness to 
collect and process the additional plasma samples. 
2 STUDY PROCEDURES 
2.1 Study Population 
Patients at selected investigational sites who meet the inclusion criteria and none of the 
exclusion criteria for study IT001-303 will be eligible for participation in this study. 
This study can fulfill its objectives only if appropriate patients are enrolled. All relevant 
medical and non-medical conditions should be taken into consideration when deciding 
whether a particular patient is suitable for enrollment under this protocol. 
2.2 Inclusion Criteria 
Each patient must meet the following criteria to be enrolled in this study. 
• Patient is randomized into study IT001-303 
• Patient has given informed consent to participate in the population PK sampling. 
2.3 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from the study. 

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• Patients who are not participating in clinical study IT001-303 
• Patients in study IT001-303 who have not received study treatment. 
2.4 
Pharmacokinetic Assessments 
A blood sample will be collected at the following time points: 
• Two hours (+/- 30 minutes) after end of Day 1 infusion 
• Four hours (+/- 2 hours) after end of Day 1 infusion 
• Two hours (+/- 1 hour) after end of administration of first dose of oral study drug after IV 
to oral switch 
• Four hours (+/- 2 hours) after end of administration of first dose of oral study drug after IV 
to oral switch 
• Six hours (+/- 2 hours) after end of administration of first dose of oral study drug after IV 
to oral switch 
4 mL of blood will be collected at each time point in Gray top Sodium Fluoride (2.5 
mg/mL)/Potassium Oxalate (2 mg/mL) tubes (BD part#368587). The labels for all biological 
sample collection and storage containers will contain, at a minimum, the subject’s number, 
study number, collection date and collection time. Additional details are provided in the Study 
Laboratory Manual. 
3. PLANNED STATISTICAL METHODS 
3.1 General Considerations 
The statistical methods for analysis of clinical data are described in detail in the protocol for 
the primary study. Relevant clinical data, including baseline and demographic data and data 
on clinical outcomes will be excerpted from the primary database for use in the PK/PD 
analyses. 
3.2 Sample Size Considerations 
For this class of drugs, the pharmacokinetic-pharmacodynamic (PK-PD) index which best 
describes efficacy is the time of free concentration of sulopenem above MIC (T>MIC). 
Therefore, the sparse pharmacokinetic (PK) sampling strategy chosen for this study are the 
times which are most informative of the T>MIC, as determined using optimal sampling 
theory. The optimal times at which the five samples should be drawn, in hours after the 
beginning of the first infusion are as follows (the acceptable sampling window is provided in 
parentheses): 2 (1.5-2.5) and 4 (2-6); and after the first dose of oral medication, are as follows: 
2 (1-3), 4 (2-6), and 6 (4-8). 

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The number of subjects (with pharmacokinetic sampling) needed to provide adequate 
precision for a PK-PD model is described above. The intention is to gather quality PK-PD 
data in several studies and to pool the concentration and effect data to achieve reasonable 
precision. Therefore, as many subjects as possible should be studied during this trial. It has 
been determined that up to 125 sulopenem treated subjects will have pharmacokinetic 
samples drawn in this study. 
4 
PLASMA SAMPLE HANDLING AND ANALYSIS 
Detailed instructions for the collection, processing, storage and shipment of samples will 
be provided in the study Laboratory Manual. 
4.1 
Sample Collection and Processing 
• Blood samples for PK analysis of sulopenem levels will be collected via direct 
venipuncture using 4 mL Gray top Sodium Fluoride (2.5 mg/mL)/Potassium 
Oxalate (2 mg/mL) tubes (BD part#368587). 
• Immediately after the sample is drawn, the tube must be mixed gently by 
inversion 8 to 10 times and placed on ice. 
• The samples will be centrifuged at 2500 g for 10 minutes at 4ºC within 60 
minutes of collection to achieve a clear plasma layer over the red cells.  
• The plasma will be immediately separated into two 0.5 ml aliquots, transferred 
into 1.8 mL NUNC Cryovials and stored at approximately -70ºC or -20ºC 
within 60 minutes of collection. Samples may only be stored at -20ºC for a 
maximum of 5 days. Samples stored at -20ºC must be shipped on dry ice for -
70ºC storage prior to the 7 day expiry. 
• The time of the sampling as well as the time when the dose was administered 
prior to the sampling will be noted in the CRF. 
4.2 
Transport of Samples 
The clinical staff will inventory the samples which are to be shipped to the central lab for 
accessioning and storage. The central lab will ship samples to the bioanalytic lab for 
measurement of sulopenem plasma concentrations. Each shipment will contain a complete 
set of samples. 
For sample shipment, the samples will be packed in ample dry ice within a Styrofoam 
container to ensure the samples will remain frozen for at least 72 hours and shipped 
via express delivery to the central lab. Written notification of sample shipment will be 
communicated to the bioanalytical facility and Sponsor. The samples will be tracked 
to assure arrival in a safe and timely manner. 
The shipment will be accompanied by logs showing the name of the study drug product, 
the protocol number, and the subjects and samples included in the shipment. 
Documentation noting the conditions of the samples upon arrival at the central lab and the 
bioanalytical laboratory will be forwarded to the Sponsor/and or Representative. 

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4.3 
Bioanalytical Sample Analyses 
The sulopenem plasma concentrations will be measured using a validated bioanalytical 
method and according to the Bioanalytical Laboratory’s Standard Operating Procedures and 
FDA Guidances. 
4.4 
Bioanalytical Methodology 
A full validation of a sensitive assay for the appropriate analytes in each biological matrix, 
including precision, accuracy, reproducibility, limit of quantitation, recovery, and 
selectivity will be completed and approved prior to sample analysis. The bioanalytical 
summary report will include the stability of the frozen samples, and a summary of the 
standard curves and quality control samples. 
4.5 
Patient Withdrawal 
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, 
behavioral, or administrative reasons 
4.6 
Handling Dropout and Withdrawn Subjects 
Samples from subjects will be analyzed by the bioanalytical laboratory and concentration 
data will be included in the pharmacokinetic and statistical analyses if the subject 
completes the study. 
Samples from subjects who choose to discontinue their participation in the study without 
submitting a written request to withdraw consent or are dropped by the Investigator(s) or 
the Sponsor may be analyzed and included in the pharmacokinetic and statistical analyses, 
if pharmacokinetic parameters can be estimated using the remaining data points, or if 
requested by the Sponsor.  Unanalyzed samples from subjects who submit a written request 
to withdraw consent authorization from the study will not be analyzed. 
4.7 
Final Integrated Report 
A final report will be issued by the Sponsor after it has been reviewed and released by a 
quality assurance specialist, and this report will be appended to the clinical study report for 
the primary study. Where applicable, it will contain a narrative description of the clinical, 
bioanalytical, pharmacokinetic, and statistical procedures used during the conduct of the 
study.  Appropriate tables and graphs will be created to summarize the data. 
The regulatory agency for submission will include the U.S. Food and Drug 
Administration and other Health Agencies, as deemed appropriate for the purpose of 
study conduct or product registration. 
5 
PHARMACOKINETIC AND STATISTICAL DATA ANALYSES 
Pharmacokinetic and statistical analyses will be performed for sulopenem plasma data. 

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Data from subjects with missing concentration values (missed blood draws, lost 
samples, samples unable to be quantitated) may be used if pharmacokinetic parameters 
can be estimated using the remaining data points. 
5.1 
Pharmacokinetic Data Analyses 
PK-PD analyses will include all patients who are clinically and/or microbiologically 
evaluable and for whom sulopenem concentration-time data are available. An estimate of 
sulopenem PK parameters will be derived for every patient who undergoes PK sampling. 
This will be accomplished by fitting the population PK model developed for sulopenem 
using the data from patients from multiple Phase 1 studies to the sulopenem concentration-
time data. The PK PD index (T>MIC) will be calculated. The PK-PD index data as well as 
patient demographics and outcome information may also be pooled with other Phase 3 
studies of sulopenem for the conduct of the population PK and PK-PD analysis. The results 
of the PK-PD analysis will be reported separate from the clinical study report. 
6 
SCHEDULE OF EVENTS 
 
Evaluation 
Baseline 
Day 1 
Day 6-14: IV to Oral Switch 
 
Within 24 
hours 
prior to 
first dose 
Dose Day 1a Sample 1 
2 hr ± 
0.5 hr b 
Sample 2 
4 hrs 
±2 hrs 
First dose of 
oral 
medication 
Sample 3 
2 hrs ± 
1 hr 
Sample 4 
4 hrs ± 
2 hrs 
Sample 5 
6 hrs ± 
2 hrs 
Informed Consent 
X 
 
 
 
 
 
 
 
Study drug dose 
 
X 
 
 
X 
 
 
 
PK sample 
collection 
 
 
X 
X 
 
X 
X 
X 
a 
Study "Day" is calendar day beginning with Day 1, the calendar day the first infusion of study medication is started. 
b      All times from end of study drug infusion. 

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APPENDIX 5  
APACHE II SCORE 
 

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APPENDIX 6  
CRITERIA FOR SAFETY VALUES OF POTENTIAL  
 
 
 
 
 
 
CLINICAL CONCERN 
Hematology 
 
Hemoglobin 
<0.8 times the lower limit of the reference range 
Leukocytes 
<1.5 or >20 x 103/mm3 
Platelets 
<75 or >700 x 103/mm3 
Chemistry 
 
Total bilirubin 
>2 times the upper limit of the reference range 
Direct bilirubin 
>2 times the upper limit of the reference range 
AST 
>3 times upper limit of the reference range 
ALT 
>3 times upper limit of the reference range 
GGT 
>3 times upper limit of the reference range 
Alk Phosphatase 
>3 times upper limit of the reference range 
Creatinine 
>1.5 times upper limit of the reference range 
BUN/Urea 
>1.3 times upper limit of the reference range 
Sodium 
<0.95 or >1.05 times the limits of the reference range 
Potassium 
<0.9 or >1.1 times the limits of the reference range 
Calcium 
<0.9 or >1.1 times the limits of the reference range 
Albumin 
<0.8 times the lower limit of the reference range 
Total protein 
<0.8 times the lower limit of the reference range 
Creatine Kinase 
>3.0 times upper limit of the reference range 
Urinalysis 
 
Urine WBC 
≥10/HPF 
Urine RBC 
≥50/HPF 
Vital Signs 
 
Pulse Rate 
<40 or >130 bpm, when baseline resting heart rate is 60-120 bpm 
Blood Pressure 
Systolic ≥30 mm Hg change from baseline in same posture 
 
Systolic <80 mm Hg 
 
Diastolic ≥20 mm Hg change from baseline in same posture 
 
Diastolic <50 mm Hg 
 
 
 

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APPENDIX 7  
INVESTIGATOR’S SIGNATURE 
Study Title: 
A prospective Phase 3, double-blind, multicenter, randomized 
study of the efficacy and safety of sulopenem followed by 
sulopenem etzadroxil with probenecid versus ertapenem followed 
by ciprofloxacin and metronidazole or amoxicillin-clavulanate for 
treatment of complicated intra-abdominal infections in adults. 
Study Number: 
IT001-303 
Final Date: 
May 29, 2018 
 
 
I have read the protocol described above.  I agree to comply with all applicable regulations 
and to conduct the study as described in the protocol.  I understand the study protocol and 
will conduct the study according to the procedures therein and according to the principles of 
good clinical practice. 
 
 
Name: 
 
 
 
 
 
 
 
 
 
 
 
Signature: 
 
Date: