A Phase 3, Randomized, Double-blind, Double-dummy, Multicenter, Multinational Study to Assess the Efficacy and Safety of Orally Administered Tebipenem Pivoxil Hydrobromide (TBP-PI-HBr) Compared to Intravenously Administered Imipenem-cilastatin in Patients With Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP)
Phase: PHASE3
Conditions: Urinary Tract Infection, Acute Pyelonephritis
Sponsor: Spero Therapeutics



Spero Therapeutics, Inc. 
26Aug2024 
Protocol No: SPR994-305 
Amendment 3, V4.1 
Protocol Name: PIVOT-PO 
CONFIDENTIAL 
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Clinical Study Protocol 
PROTOCOL NUMBER: 
SPR994-305 
PROTOCOL TITLE: 
A Phase 3, randomized, double-blind, double-dummy, multicenter, multinational study 
to assess the efficacy and safety of orally administered tebipenem pivoxil 
hydrobromide (TBP-PI-HBr) compared to intravenously administered imipenem-
cilastatin in patients with complicated urinary tract infection (cUTI) or acute 
pyelonephritis (AP) 
PROTOCOL NAME: 
PIVOT-PO 
INVESTIGATIONAL 
AGENT DRUG (Active): 
Tebipenem pivoxil hydrobromide (TBP-PI-HBr, previously known as SPR994) 
SPONSOR NAME AND 
ADDRESS: 
Spero Therapeutics, Inc. 
675 Massachusetts Ave. 
Cambridge, MA 02139, USA 
EU CT NUMBER: 
2023-503785-22-00 
ClinicalTrials.gov ID 
NCT06059846 
IND: 
132744 
MEDICAL 
EXPERT/QUALIFIED 
PHYSICIAN NAME, 
TITLE, ADDRESS, AND 
TELEPHONE NUMBER: 
, MD 
Sponsor Medical Monitor 
675 Massachusetts Ave 
Cambridge, MA 02139 
USA 
SPONSOR 
REPRESENTATIVE 
AUTHORIZED TO SIGN 
PROTOCOL: 
, MD 
 
Spero Therapeutics, Inc. 
CLINICAL 
LABORATORIES/ 
BIOANALYTICAL 
FACILITY: 
Clinical Laboratories: 
ICON Laboratory Services Inc. 
South County Business Park 
Leopardstown 
Dublin 18, Ireland 
Tel: +353 1 2912409 
Bioanalytical Laboratories: 
Keystone Bioanalytical, Inc. 
501 Dickerson Road 
North Wales, PA 19454 USA 
Tel: (215) 699-8885 
Charles River Laboratories, Inc. 
334 South St., Shrewsbury, MA 01545 USA 
Tel: (508) 753-5000 
DATE: 
26Aug2024 

Spero Therapeutics, Inc. 
 
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GCP Statement: This study is to be conducted according to the protocol and in compliance with Good Clinical 
Practice (GCP), EU CT Regulation 536/2014, and, where applicable, local country regulations relevant to the use of 
new therapeutic agents in the country/countries of conduct, including the archiving of essential documents. 
Confidentiality Statement: Information contained in this protocol should not be disclosed, other than to those directly 
involved in the execution or ethical review of the study, without written authorization from Spero Therapeutics. It is, 
however, permissible to provide information to a volunteer in order to obtain consent. 

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INVESTIGATORS ACKNOWLEDGEMENT 
I have read the PIVOT-PO protocol, Study SPR994-305, a Phase 3, randomized, double-blind, 
double-dummy, multicenter, multinational study to assess the efficacy and safety of orally 
administered tebipenem pivoxil hydrobromide (TBP-PI-HBr) compared to intravenously (IV) 
administered imipenem-cilastatin in patients with complicated urinary tract infection (cUTI) or 
acute pyelonephritis (AP). 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
Sponsor’s representative. 
I understand that the information in this protocol is confidential and not to be disclosed, other 
than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the Sponsor. It is, however, permissible to provide the 
information contained herein to a patient in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Council for Harmonisation (ICH) E6(R2) Good Clinical Practice 
(GCP) Guidance (FDA 2018a), European Union (EU) Clinical Trials (CT) Regulation 536/2014 
(European Commission 2014), and with the applicable Regulatory Authority (RA) requirements. 
I understand that failure to comply with the requirements of the protocol may lead to my 
termination as an Investigator for this study. 
I understand that the Sponsor may decide to suspend or prematurely terminate the study at any 
time, or for any reason, communication of such a decision may be in writing. Conversely, should 
I decide to withdraw from execution of the study I will communicate my intention immediately 
in writing to the Sponsor. 
 
Principal Investigator (PI) Name:  
Site Name: 
Site Number: 
 
 
 
Signature: 
 
Date: 
 
 

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EMERGENCY CONTACT INFORMATION 
In the event of a Serious Adverse Event (SAE), the Investigator must e-mail or fax the Clinical 
Trial SAE Form within 24 hours to Parexel: 
• E-mail: sperosafety@parexel.com 
• Pharmacovigilance SAE Fax Number:  1-781-434-5957 
• For protocol- or safety-related issues during normal business hours, the 
Investigator must contact the PSI CRO Medical Monitor. 

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PRODUCT QUALITY COMPLAINTS 
Investigators are required to report investigational product (IP) quality complaints to Spero 
Therapeutics, Inc. or its representative within one business day. This includes any instances 
wherein the quality or performance of a Spero Therapeutics, Inc. product (marketed or 
investigational) does not meet expectations (e.g., inadequate, or faulty closure, product 
contamination) or that the product did not meet the specifications defined in the application for 
the product (e.g., wrong product such that the label and contents are different products). 
Please see the pharmacy manual for product quality complaint contact information. 
 
 
 

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TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................3 
INVESTIGATORS ACKNOWLEDGEMENT...............................................................................4 
EMERGENCY CONTACT INFORMATION ................................................................................5 
PRODUCT QUALITY COMPLAINTS..........................................................................................6 
TABLE OF CONTENTS .................................................................................................................7 
LIST OF TABLES .........................................................................................................................12 
LIST OF FIGURES .......................................................................................................................12 
1. 
SYNOPSIS .................................................................................................................13 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................25 
2. 
INTRODUCTION ......................................................................................................29 
2.1. 
Background and Rationale for the Study ....................................................................29 
2.2. 
Tebipenem-Pivoxil-Hydrobromide (TBP-PI-HBr) ....................................................30 
2.2.1. 
Nonclinical Information ..............................................................................................30 
2.2.2. 
Microbiologic Activity ...............................................................................................30 
2.2.3. 
Clinical Information ....................................................................................................31 
2.3. 
Benefit/Risk Assessment ............................................................................................32 
3. 
STUDY OBJECTIVES AND ESTIMANDS/ENDPOINTS ......................................33 
3.1. 
Objectives and Endpoints ...........................................................................................33 
3.1.1. 
Primary Objective and Estimand ................................................................................34 
3.1.2. 
Secondary Objectives and Estimand ..........................................................................36 
4. 
STUDY DESIGN .......................................................................................................38 
4.1. 
Overview of Study Design and Procedures ................................................................38 
4.2. 
Rationale for Study Design .........................................................................................41 
4.3. 
Rationale for TBP-PI-HBr Dose .................................................................................41 
4.4. 
Rationale for Comparator ...........................................................................................41 
4.5. 
Measures to Minimize Bias: Randomization and Blinding ........................................42 
4.5.1. 
Allocation of Patients to Treatment ............................................................................42 
4.5.2. 
Blinding the Treatment Assignment ...........................................................................42 
4.5.3. 
Unblinding the Treatment Assignment .......................................................................43 
5. 
STUDY POPULATION .............................................................................................45 
5.1. 
Inclusion Criteria ........................................................................................................45 

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5.2. 
Exclusion Criteria .......................................................................................................47 
6. 
STUDY TREATMENTS............................................................................................50 
6.1. 
Identity of Investigational Products ............................................................................50 
6.2. 
Dosing and Treatment Regimens ................................................................................51 
6.2.1. 
TBP-PI-HBr Dosing in Patients with CrCl >50 mL/min ...........................................51 
6.2.1.1. 
TBP-PI-HBr Dose Adjustments in Patients with Impaired Renal Function 
(CrCl ≤50 mL/min) .....................................................................................................52 
6.2.2. 
Imipenem-cilastatin Dosing in Patients with CrCl ≥90 mL/min ................................52 
6.2.2.1. 
Imipenem-cilastatin Dose Adjustments in Patients with Impaired Renal 
Function (CrCl <90 mL/min)......................................................................................52 
6.3. 
Timing of Dose Administration ..................................................................................53 
6.3.1. 
Monitoring of CrCl during Investigational Product Therapy .....................................53 
6.4. 
Treatment Compliance ................................................................................................54 
6.4.1. 
Dosing Interruptions, Incomplete Doses, and Missed Doses .....................................54 
6.4.2. 
Treatment Administration ...........................................................................................55 
6.4.3. 
Drug Accountability ...................................................................................................55 
6.5. 
Storage ........................................................................................................................56 
6.6. 
Prior and Concomitant Therapy ..................................................................................57 
6.6.1. 
Prohibited Concomitant Medications .........................................................................57 
6.7. 
Discontinuation of Study Treatment and Patient Discontinuation/Withdrawal .........57 
6.7.1. 
Withdrawal from Study ..............................................................................................57 
6.7.2. 
Premature Discontinuation of Study Treatment .........................................................58 
6.7.3. 
Patients Lost to Follow-up Prior to Last Scheduled Visit ..........................................59 
7. 
STUDY PROCEDURES AND OUTCOME ASSESSMENTS .................................60 
7.1. 
Study Visits .................................................................................................................60 
7.1.1. 
Screening Visit (Day -1 or 1)......................................................................................60 
7.1.2. 
Treatment Visits (Days 1 up to 10) .............................................................................61 
7.1.3. 
End-of-Treatment (EOT) Visit ...................................................................................61 
7.1.4. 
Test-of-Cure (TOC) Visit (Day 17 ±2 Days) .............................................................62 
7.1.5. 
Late Follow-Up (LFU) Visit (Day 28 ±2 Days) .........................................................62 
7.1.6. 
Additional Care of Patients after the Study ................................................................62 
7.2. 
Outcome Assessments ................................................................................................62 

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7.2.1. 
Efficacy Assessment and Outcome Definitions .........................................................62 
7.2.1.1. 
Investigator Assessment of Clinical Outcomes at EOT, TOC and LFU ....................63 
 
63 
 
64 
7.2.2. 
Microbiological Assessment .......................................................................................65 
 
66 
7.2.2.2. 
Blood Cultures ............................................................................................................68 
7.2.3. 
Safety Assessment ......................................................................................................68 
7.2.3.1. 
Medical/Surgical and Prior/Concomitant Medication History ...................................68 
7.2.3.2. 
Physical Examination .................................................................................................68 
7.2.3.3. 
Adverse Event Collection ...........................................................................................69 
7.2.3.4. 
Vital Signs ..................................................................................................................69 
7.2.3.5. 
Clinical Laboratory Evaluations .................................................................................69 
7.2.3.6. 
Pregnancy Testing ......................................................................................................71 
7.2.3.7. 
Electrocardiograms .....................................................................................................71 
7.2.4. 
Pharmacokinetics Assessment ....................................................................................71 
7.2.4.1. 
Blood Sampling for Plasma Pharmacokinetics ...........................................................71 
 
72 
7.2.5. 
Volume of Blood to be Drawn from Each Patient ......................................................72 
7.2.6. 
Other Tests ..................................................................................................................72 
 
72 
7.2.7. 
Samples and Data for Future Research .......................................................................72 
8. 
ASSESSMENT OF ADVERSE EVENTS .................................................................73 
8.1. 
Adverse Event Definitions ..........................................................................................73 
8.2. 
Evaluating Adverse Events and Serious Adverse Events ...........................................74 
8.2.1. 
Assessment of Intensity and Outcome ........................................................................74 
8.2.2. 
Assessment of Causality .............................................................................................75 
8.2.3. 
Adverse Events of Special Interest .............................................................................76 
8.3. 
Time Period, Frequency and Method of Detecting AEs .............................................76 
8.4. 
Adverse Event Management .......................................................................................77 
8.5. 
Recording of AEs and SAEs .......................................................................................77 
8.6. 
SAE Reporting ............................................................................................................77 

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8.6.1. 
Regulatory Reporting Requirements for Reporting of SAEs .....................................77 
8.6.2. 
Completion and Transmission of the SAE Reports ....................................................78 
8.6.3. 
Post-study AEs and SAEs ...........................................................................................78 
8.7. 
Follow-up of AEs and SAEs .......................................................................................79 
8.8. 
Pregnancy ...................................................................................................................79 
8.9. 
Abuse, Misuse, Overdose, and Medication Error .......................................................80 
8.10. 
Serious Adverse Event Procedures .............................................................................81 
8.10.1. 
Reference Safety Information .....................................................................................81 
8.10.2. 
Regulatory Agency, Institutional Review Board, Independent Ethics 
Committee, and Site Reporting ...................................................................................81 
9. 
DATA MANAGEMENT ...........................................................................................82 
9.1. 
Data Collection ...........................................................................................................82 
9.2. 
Clinical Data Management .........................................................................................82 
10. 
STATISTICAL ANALYSES .....................................................................................83 
10.1. 
Planned Interim Analysis, Independent Data Monitoring Committee .......................83 
10.2. 
Sample Size Determination ........................................................................................84 
10.2.1. 
Justification of Sample Size ........................................................................................84 
10.2.2. 
Sample Size Sensitivity ..............................................................................................85 
10.3. 
Analysis Populations ..................................................................................................86 
10.4. 
Patient Disposition ......................................................................................................87 
10.5. 
Demographic and Baseline Characteristics ................................................................87 
10.6. 
Prior and Concomitant Medication .............................................................................88 
10.7. 
Investigational Product Exposure ...............................................................................88 
10.8. 
Efficacy Analyses .......................................................................................................88 
10.8.1. 
General Considerations ...............................................................................................88 
10.8.2. 
Handling of Missing Data ...........................................................................................88 
10.8.3. 
Primary Efficacy Endpoint .........................................................................................88 
10.8.4. 
Secondary Efficacy Analyses .....................................................................................90 
 
90 
10.9. 
Safety Analyses ..........................................................................................................90 
10.10. 
Other Analyses ............................................................................................................91 
10.10.1. 
Pharmacokinetic Analyses ..........................................................................................91 

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11. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES ...............................92 
11.1. 
Sponsor’s Responsibilities ..........................................................................................92 
11.1.1. 
Good Clinical Practice Compliance............................................................................92 
11.1.2. 
Indemnity/Liability and Insurance ..............................................................................92 
11.1.3. 
Public Posting of Study Information ..........................................................................92 
11.1.4. 
Submission of Summary of Clinical Study Report to Regulatory Agencies 
and Independent Ethics Committees ..........................................................................93 
11.1.5. 
Study Suspension, Termination, and Completion ......................................................93 
11.2. 
Investigator Responsibilities .......................................................................................93 
11.2.1. 
Good Clinical Practice Compliance............................................................................93 
11.2.2. 
Protocol Adherence and Investigator Agreement .......................................................94 
11.2.3. 
Documentation and Retention of Records ..................................................................94 
11.2.3.1. 
Microbiological Reports .............................................................................................94 
11.2.3.2. 
Case Report Forms .....................................................................................................94 
11.2.3.3. 
Recording, Access, and Retention of Source Data and Study Documents .................94 
11.2.3.4. 
Audit/Inspection .........................................................................................................95 
11.2.3.5. 
Financial Disclosure ...................................................................................................95 
11.2.4. 
Compliance to all Local, State, and National Infectious Disease Regulations 
and Legislation ............................................................................................................96 
11.3. 
Ethical Considerations ................................................................................................96 
11.3.1. 
Informed Consent .......................................................................................................96 
11.3.2. 
Institutional Review Board or Independent Ethics Committee ..................................96 
11.4. 
Privacy and Confidentiality ........................................................................................97 
11.5. 
Publication Policy .......................................................................................................98 
12. 
REFERENCES ...........................................................................................................99 
APPENDIX 1. SECONDARY ESTIMANDS TABLE............................................................101 
APPENDIX 2. SCHEDULE OF ASSESSMENTS ..................................................................105 
 
 

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LIST OF TABLES 
Table 1: 
Objectives and Endpoints ...........................................................................................33 
Table 2: 
Summary of Investigational and Comparator Products Dosage Form and 
Strength .......................................................................................................................50 
Table 3 
TBP-PI-HBr Dosage Regimen by Estimated Creatinine Clearance Category ...........52 
Table 4: 
Imipenem-cilastatin Dosage Regimen by Estimated Creatinine Clearance 
Category ......................................................................................................................53 
Table 5: 
Estimated Minimal Response Rate Difference for Efficacy and Futility 
Interim Analysis ..........................................................................................................84 
Table 6: 
Power of the Study Under Various Assumptions of the True Therapeutic 
Success Rates for Efficacy and Futility Group Sequential Design .............................85 
Table 7: 
Impact of Evaluability Rate on ITT Population .........................................................86 
 
LIST OF FIGURES 
Figure 1: 
Study Design Flow Chart............................................................................................40 
 

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1.
SYNOPSIS
Study Title: 
A Phase 3, randomized, double-blind, double-dummy, multicenter, 
multinational study to assess the efficacy and safety of orally administered 
tebipenem pivoxil hydrobromide (TBP-PI-HBr) compared to 
intravenously administered imipenem-cilastatin in patients with 
complicated urinary tract infection (cUTI) or acute pyelonephritis (AP) 
Study Number: 
SPR994-305 
Phase of Development: 
3 
Version/Date: 
26Aug2024; Version 4.1 
Investigational Product: 
Tebipenem pivoxil hydrobromide (TBP-PI-HBr; previously known as 
SPR994) 
Comparator Product: 
Imipenem-cilastatin 
Investigational and 
Comparator Product 
Dose, and Mode of 
Administration: 
Treatment Group 1: TBP-PI-HBr 600 mg (2×300 mg film-coated 
immediate-release tablets), administered orally (PO) every 6 hours 
(q6h ±1 hour [h]) plus dummy infusion (0.9% sodium chloride) 
administered intravenously (IV) over 30 minutes (min) q6h (±1 h) 
Treatment Group 2: Imipenem-cilastatin, 500 mg administered IV over 
30 min q6h (±1 h) plus matched dummy tablets administered PO q6h 
(±1 h) 
The total duration of study treatment will be 7-10 days. 
Study Population: 
Male and female patients aged 18 years or older, hospitalized for the 
treatment of cUTI or AP 
Planned Sample Size: 
The study is planned to enroll approximately 2648 patients (1324 per 
treatment group) to achieve a target sample size of approximately 
1588 patients (794 per treatment group) for the primary analysis 
population (Microbiological Intent-to-Treat [micro-ITT] Population). The 
final number of randomized patients may vary based on the evaluability 
rate for the micro-ITT Population. The target sample size assumes a 60% 
evaluability rate for the micro-ITT Population. Response rates of 60% and 
58% are assumed for IV imipenem-cilastatin and oral TBP-PI-HBr, 
respectively. The proposed sample size will yield approximately 1588 
evaluable patients (794 per treatment group) for the primary analysis, 
which will provide 89% power with a 1-sided significance level of 0.025 
for the assessment of non-inferiority (NI) of oral TBP-PI-HBr to IV 
imipenem-cilastatin with a -10% margin. 
An unblinded interim analysis (IA) to assess both efficacy and futility will 
be performed by an unblinded Independent Data Monitoring Committee 
(IDMC) when 60% of the patients in the micro-ITT Population 
(approximately 954 patients) have achieved the TOC visit, potentially 
allowing for early termination of the study based on certain pre-specified 
criteria. 
The study will utilize a group sequential design with one planned IA using 
error spending boundaries. Refer to Section 10.1 for additional details. 

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Number of Clinical 
Centers: 
Approximately 160 clinical centers 
Primary Objective 
To assess the efficacy of oral TBP-PI-HBr as compared with IV 
imipenem-cilastatin with respect to the overall response (combined clinical 
cure plus microbiological eradication) at the Test-of-Cure (TOC) visit in 
hospitalized adult patients (≥18 years of age) with cUTI/AP. 
A description of the primary estimand and estimand rationale is presented 
in Section 3.1. 
Secondary Objectives: 
• 
To assess the efficacy of oral TBP-PI-HBr as compared with IV 
imipenem-cilastatin with respect to overall response rates at the TOC 
visit in patients with cUTI/AP in the Microbiologically Evaluable 
(ME) Population. 
• 
To assess the efficacy of oral TBP-PI-HBr as compared with IV 
imipenem-cilastatin with respect to overall response rates at End-of-
Treatment (EOT) and Late Follow-up (LFU) visits in patients with 
cUTI/AP. 
• 
To assess the efficacy of oral TBP-PI-HBr as compared with IV 
imipenem-cilastatin with respect to clinical response rates at EOT, 
TOC, and LFU visits in patients with cUTI/AP. 
• 
To assess the efficacy of oral TBP-PI-HBr as compared with IV 
imipenem-cilastatin with respect to microbiological response rates at 
EOT, TOC, and LFU visits in patients with cUTI/AP. 
• 
To assess the efficacy of oral TBP-PI-HBr as compared with IV 
imipenem-cilastatin with respect to overall, clinical and 
microbiological response rates at TOC, EOT and LFU visits among 
cUTI/AP patients infected with drug-resistant Enterobacterales 
uropathogens, e.g., extended spectrum β-lactamase (ESBL)-producing, 
fluoroquinolone-nonsusceptible (FQ-NS), and/or trimethoprim-
sulfamethoxazole-resistant (TMP-SMX-R) strains. 
• 
To assess the safety and tolerability of oral TBP-PI-HBr as compared 
to IV imipenem-cilastatin in patients with cUTI/AP. 
• 
To provide tebipenem (TBP) plasma concentration data to characterize 
the pharmacokinetics (PK) of TBP in the target population using PK 
modelling. 
A description of the secondary estimands and estimands rationale is 
presented in Section 3.1.2. 
 
 
 
 

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Permitted/Prohibited 
Adjunctive Antimicrobial 
Therapy: 
Concomitant administration of non-study, potentially effective, systemic 
antimicrobial therapy that would potentially confound the assessment of 
treatment outcomes is not allowed, except in cases of cUTI/AP study 
treatment clinical failure. 
Topical antimicrobials and antimicrobials for the treatment of 
Clostridioides difficile infection are permitted. For treatment of new and 
unexpected infections other than cUTI/AP (i.e., adverse events [AEs]), 
narrow spectrum antimicrobials which are not expected to have potential 
to treat the causative pathogen(s) should be selected whenever possible. 
Study Design/Methods: 
 
This is a Phase 3, randomized double-blind, double-dummy, multicenter, 
multinational prospective study to assess the efficacy and safety of 
TBP- PI- HBr compared to IV imipenem-cilastatin in patients with 
cUTI/AP. 
Eligible patients with a clinical diagnosis of cUTI/AP suitable to start 
empiric IV antimicrobials, who can tolerate oral medication will be 
randomized in a 1:1 ratio to receive either oral TBP-PI-HBr (600 mg PO 
q6h) or IV imipenem-cilastatin (500 mg IV q6h) with matched dummy 
oral or IV administration. 
Randomization will be stratified by age at time of consent (≥18 to 
<65 years vs. ≥65 years), baseline diagnosis (cUTI vs. AP), and presence 
or absence of urinary tract instrumentation at Baseline. 
Patients who meet the disease definition of cUTI (e.g., underlying 
functional or anatomical urinary tract abnormality; per Inclusion 
Criterion 4.a) and have additional clinical evidence of AP (e.g., flank pain 
or costovertebral angle tenderness; per Inclusion Criterion 4.b) should be 
randomized as cUTI. At least 30% of patients will be randomized with a 
diagnosis of AP at study entry. 
Rationale for 
Comparator: 
Imipenem-cilastatin is a parenteral carbapenem antimicrobial approved for 
the treatment of cUTI/AP in many countries and is considered an empiric 
standard-of-care (SOC) treatment option for patients with serious bacterial 
infections, including cUTI/AP. Imipenem has a similar spectrum of in 
vitro and in vivo antimicrobial activity to TBP against common pathogens 

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that cause cUTI/AP, including ESBL-producing Enterobacterales and 
certain Gram-positive uropathogens (e.g., Enterococcus faecalis, 
Staphylococcus aureus, Staphylococcus saprophyticus). 
Study Duration: 
The total duration of study participation will be approximately 28 days 
following the first dose of trial therapy. The total duration of study 
treatment (IV or oral) will be 7-10 calendar days. 
Study procedures will be completed at the following visits: 
• 
Screening Visit, Day -1 to 1: Screening procedures must be 
performed within 24 h prior to randomization on Day 1 to determine 
study eligibility. 
• 
Treatment Visits: Day 1 up to Day 10: Following initial urine and 
blood cultures, eligible patients will be randomized and receive 
IP(TBP-PI-HBr or imipenem-cilastatin) and matched dummy tablets 
or dummy infusions during this treatment period. Study treatment may 
start on the same calendar day as the Screening visit. 
• 
End-of-Treatment (EOT) Visit will be completed on the last day of 
study treatment administration (e.g., Day 7-10), or the following day 
(e.g., allowing a 1-day window to complete EOT procedures). Patients 
requiring more than 10 days of treatment will be discontinued from IP 
or comparator, assessed at EOT as clinical failure, and treated with an 
appropriate open-label antimicrobial at the discretion of the 
Investigator. The patient will remain in the study for the remaining 
visits. 
• 
Test-of-Cure (TOC) Visit, Day 17 (±2 days) post randomization 
• 
Late Follow-Up (LFU) Visit, Day 28 (±2 days) post randomization 
Inclusion Criteria: 
Patients meeting all the following inclusion criteria should be considered 
for randomization in the study: 
1. male and female patients at least 18 years of age; patients enrolled in 
India must be ≤90 years of age 
2. able to provide informed consent (for further details regarding patient 
consenting, refer to Section 11.3.1) 
3. able to ingest oral tablets for the anticipated treatment duration. If 
present at Baseline, nausea and/or vomiting should be mild or well 
controlled with antiemetic therapy 
4. have a diagnosis of cUTI or AP as defined below: 
a.  cUTI definition: 
at least TWO of the following signs and symptoms: 
i. chills, rigors, or fever (oral, tympanic, rectal or core 
temperature >38.0°C [>100.4°F]); fever must be observed 
and documented by a health care provider 
ii. dysuria, urgency to void, or increased urinary frequency 
iii. nausea or vomiting, as reported by the patient 
iv. lower abdominal pain, suprapubic pain, pelvic pain, or flank 
pain/costovertebral angle tenderness 

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AND at least ONE of the following risk factors for cUTI: 
i. implanted urinary tract instrumentation (e.g., nephrostomy 
tube, ureteric stents, or other urinary tract prosthetic 
material), ongoing intermittent bladder catheterization, or 
presence of an indwelling bladder catheter (Note: bladder 
catheters that have been in place for >24 h prior to Screening 
must be removed or replaced prior to collection of the 
Screening urine for urinalysis and culture, unless removal or 
replacement is considered unsafe or contraindicated) 
ii. current known functional or anatomical abnormality of the 
urogenital tract, including anatomic abnormalities of the 
urinary tract, neurogenic bladder, or post-void residual urine 
volume of ≥100 milliliters (mL) within the past 6 months 
iii. complete or partial obstructive uropathy (e.g., nephrolithiasis, 
tumor, fibrosis, urethral stricture) that is expected to be 
medically or surgically treated during study drug therapy 
(prior to EOT visit) 
iv. known intrinsic renal disease with blood urea nitrogen 
(BUN) >20 mg/deciliter (dL), or blood urea >42.8 mg/dL, or 
serum creatinine (Cr) >1.4 mg/dL 
v. urinary retention, including urinary retention in men due to 
previously diagnosed benign prostatic hyperplasia (BPH). 
b. AP definition: 
acute flank pain (onset within 7 days prior to randomization) or 
costovertebral angle tenderness on physical examination AND at 
least ONE of the following signs and symptoms: 
i. chills, rigors, or fever (oral, tympanic, rectal or core 
temperature >38.0°C [>100.4°F]); fever must be observed 
and documented by a health care provider 
ii. peripheral white blood cell count (WBC) >10,000/cubic 
millimeter (mm3) or bandemia (>15% immature 
polymorphonuclear neutrophils [PMNs], regardless of WBC 
count) 
iii. nausea or vomiting, as reported by the patient 
iv. dysuria, urgency to void, or increased urinary frequency. 
Note: Patients who meet the definition for cUTI (refer to 
Inclusion Criterion a) and have flank pain or costovertebral 
tenderness should be randomized as cUTI rather than AP. 
5. have an adequate urine specimen for evaluation and culture obtained 
within 24 h prior to randomization with evidence of pyuria that 
includes at least one of the following: 
a. at least 10 WBCs per high power field (HPF) in urine sediment 
b. at least 10 WBCs per mm3 in unspun urine 
c. positive leukocyte esterase (LE) on urinalysis. 

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Note: Patients may be randomized and administered study drug prior 
to knowledge of urine culture results, but pyuria must be 
documented. 
6. expectation, in the judgment of the Investigator, that the patient will 
survive with effective antimicrobial therapy and appropriate 
supportive care for the anticipated duration of the study 
7. willing to comply with all the study activities and procedures 
throughout the duration of the study 
8. willing to agree to use a highly effective method of birth control; 
male patients must agree to not engage in sexual activity with a 
female partner that could lead to pregnancy (i.e., heterosexual 
vaginal intercourse) or must agree to use an effective barrier method 
of contraception from Screening through the LFU visit and for 
90 days following the last dose; females of childbearing potential 
(FOCP) must have a negative pregnancy test at Screening and agree 
to abstain from sexual activity that could lead to pregnancy (i.e., 
heterosexual vaginal intercourse or in vitro fertilization) from the 
time of Screening through the EOT visit, or agree to use a highly 
effective method of contraception from the time of Screening 
throughout the study (through the LFU visit). Highly effective 
methods of birth control include one or more of the following: 
a. an approved hormonal contraceptive associated with inhibition of 
ovulation including oral, implantable, transdermal, injectable, 
intravaginal contraceptive used consistently for at least 1 month 
prior to study drug dosing 
b. an intrauterine device or intrauterine hormone-releasing system 
c. male sexual partner who has been vasectomized for at least 
3 months prior to Screening and who has obtained a follow-up 
negative sperm count. 
9. female of nonchildbearing potential based on at least 1 of the 
following criteria: 
a. post-menopausal status defined as amenorrhea for at least 
12 months prior to randomization 
b. Follicle Stimulating Hormone (FSH) levels in the laboratory 
defined post-menopausal range; in the absence of amenorrhea 
for at least 12 months prior to randomization, at least two FSH 
measurements demonstrating levels in the post-menopausal 
range are required 
c. patient report of surgical sterilization (i.e., bilateral tubal ligation, 
hysterectomy, bilateral oophorectomy/salpingectomy) at least 
6 weeks prior to randomization. 

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Exclusion Criteria: 
Patients meeting any of the following exclusion criteria will not be 
enrolled in the study: 
1. presence of any known or suspected disease or condition that may 
confound the assessment of efficacy, including but not limited to the 
following: 
a. perinephric or renal corticomedullary abscess 
b. uncomplicated urinary tract infection (uUTI [acute cystitis that 
does not meet the cUTI disease definition; refer to Inclusion 
Criterion 4.a]) 
c. polycystic kidney disease 
d. recent history of trauma to the pelvis or urinary tract 
e. confirmed or suspected acute or chronic bacterial prostatitis, 
orchitis, or epididymitis 
f. chronic vesicoureteral reflux 
g. previous or planned renal transplantation 
h. previous or planned cystectomy or ileal loop surgery 
i. 
known or suspected non-renal source of infection (e.g., infective 
endocarditis, osteomyelitis, meningitis, pneumonia) 
j. 
confirmed or suspected infection that is caused by a pathogen that 
is resistant to either study drug (e.g., carbapenem-resistant 
pathogen), including infection caused by fungi (e.g., candiduria) 
or mycobacteria (e.g., urogenital tuberculosis) or an 
intrinsically-resistant bacterial species not expected to respond to 
oral IP or comparator IV (e.g., Pseudomonas species). 
2. gross hematuria requiring intervention other than administration of 
study drug or removal/placement of urinary tract instrumentation 
3. urine Gram stain (if performed by site) fails to demonstrate a Gram-
negative bacillus (i.e., negative Gram stain or Gram stain 
demonstrating only a Gram-positive organism) 
Note: Urine Gram stain should be performed, if possible, to inform 
eligibility but is not mandatory for Screening. 
4. urinary tract surgery within 7 days prior to randomization or urinary 
tract surgery planned during the study period (except surgery required 
for relieving an obstruction or placing urinary tract instrumentation) 
5. creatinine clearance (CrCl) of ≤30 mL/min, as estimated by the 
Cockcroft-Gault formula: 
eCCr[mL/min] =
(140−Age [yrs])×Body Weight [kg]×[0.85 if Female]
72×Serum Creatinine [mg dL
⁄
]
  
6. anticipated concomitant use of non-study antimicrobial drug therapy 
between randomization and the LFU visit that would potentially effect 
outcome evaluations of cUTI/AP, including but not limited to 
antimicrobials with potential activity against Gram-negative 
pathogens, antimicrobial drug prophylaxis, and antimicrobial bladder 
irrigation 

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7. receipt of a potentially effective antimicrobial within 72 h prior to 
study randomization 
8. severe hepatic impairment at Screening, as evidenced by alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) 
>5×upper limit of normal (ULN) or total bilirubin >3×ULN, or 
clinical signs of cirrhosis or end-stage hepatic disease (e.g., ascites, 
hepatic encephalopathy) 
9. pregnant or lactating women 
10. history of epilepsy or known seizure disorder (excluding a history of 
childhood febrile seizures) 
11. history of proven or suspected Clostridioides difficile associated 
diarrhea 
12. receipt of any investigational device or investigational medication 
during the last 30 days or 5 half-lives, whichever is longer, prior to 
randomization 
13. known history of human immunodeficiency virus (HIV) infection with 
known CD4 count <200/mm3 or acquired immunodeficiency 
syndrome (AIDS)-defining illness within the past year 
14. presence of immunodeficiency or an immunocompromised condition 
including neutropenia (<1,000 neutrophils/mm3 obtained from the 
local laboratory at Screening), hematologic malignancy, bone marrow 
transplant, or receiving immunosuppressive therapy such as cancer 
chemotherapy, medications for the rejection of transplantation, and 
long-term use of systemic corticosteroids (e.g., ≥20 mg/day of 
prednisone or systemic equivalent for at least 2 weeks) 
15. QT interval corrected using Fridericia’s formula (QTcF) >480 msec 
based on screening electrocardiogram (ECG) 
16. history of significant hypersensitivity or allergic reaction to β-lactam 
antimicrobials (e.g., cephalosporins, penicillins, carbapenems), 
product excipients (mannitol, microcrystalline cellulose, 
crospovidone, magnesium stearate, colloidal silicon dioxide, and 
Opadry®) or any contraindication to the use of imipenem-cilastatin 
17. history of known genetic metabolism anomaly associated with 
carnitine deficiency (e.g., carnitine transporter defect, methylmalonic 
aciduria, propionic acidemia) 
18. requirement for concomitant use of valproic acid, divalproex sodium, 
or probenecid between randomization and EOT 
19. unable or unwilling to comply with the protocol 
20. an employee of the Investigator or study center with direct 
involvement in the proposed study or other studies under the direction 
of that Investigator or study center, as well as a family member of the 
employee or the Investigator. 
 
 
 

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E.faecalis, S. aureus, or S. saprophyticus are identified, imipenem 
must have antibacterial activity. 
o No more than 2 microorganisms identified in the baseline urine 
culture, regardless of colony count 
Note: For Enterobacterales, antimicrobial activity for imipenem is 
defined as Susceptible according to CLSI Criteria (MIC 
≤1 µg/mL); CLSI 2023. For E. faecalis, antimicrobial activity will 
be presumed where the ampicillin MIC is ≤8 µg/mL. 
For S. aureus, antimicrobial activity will be presumed where the 
oxacillin MIC is ≤2 µg/mL. For S. saprophyticus, antimicrobial 
activity will be presumed where the oxacillin MIC is ≤0.5 µg/mL. 
• 
Clinically Evaluable (CE) Population: Patients who meet the 
definition for the ITT Population, have no important protocol 
deviations that would affect the assessment of efficacy including, but 
not limited to, a minimum duration of study treatment and treatment 
compliance ≥80% of expected number of doses (additional deviations 
as further defined in the Statistical Analysis Plan [SAP]), and had an 
outcome assessed as clinical cure or clinical failure at EOT, TOC, 
and/or LFU visits, respectively. 
• 
Microbiologically Evaluable (ME) Population: Patients who meet 
the definitions of both the micro-ITT Population and CE Population. 
In addition, to be included in the ME Population, patients must not 
have a microbiological outcome of indeterminate. 
Note: The ME and CE Populations will be defined for each respective 
visit (e.g., ME-EOT, ME-TOC, and ME-LFU). 
• 
PK Population: All patients treated with at least one relevant dose of 
TBP-PI-HBr with at least one quantifiable plasma or 
 sample 
according to the subpopulations outlined below: 
o Intensive Plasma PK Subgroup: approximately 20 TBP-PI-HBr-
treated patients with at least one quantifiable plasma PK sample 
o Sparse Plasma PK Subgroup: all remaining TBP-PI-HBr-treated 
patients with at least one quantifiable plasma PK sample 
o 
 
. 
• 
Gram-positive Population: All patients in the ITT population with a 
baseline urine culture demonstrating ≥105 CFU/mL of E. faecalis, 
S. aureus, and/or S. saprophyticus (or the same pathogen is present 
concurrently in blood cultures and in urine) against which imipenem 
has antibacterial activity AND no more than 2 microorganisms are 
identified in the urine culture regardless of colony count. Additionally, 
if a patient has more than 1 pathogen identified, the second pathogen 

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must be E. faecalis, S. aureus, S. saprophyticus, or an 
Enterobacterales spp. This population will be used for supplemental 
analysis of the treatment effect for these Gram-positive pathogens and 
will be described in the SAP. 
Statistical Analysis: 
The primary analysis will be the comparison of the overall response at the 
TOC visit for patients in the micro-ITT Population. The testing procedure 
at the IA and the final analysis will compare the NI test statistics with the 
stopping boundaries. Test statistics of the response rate difference between 
the two treatment groups for NI (using -10% margin for oral TBP-PI-HBr 
minus IV imipenem-cilastatin) will be calculated using the Miettinen and 
Nurminen method stratified by age category (≥18 to <65 and ≥65 years), 
baseline diagnosis (AP or cUTI), and presence or absence of urinary tract 
instrumentation at Baseline and compared to the stopping boundaries. If 
NI is established, test statistics of the success rate difference between the 
two treatment groups for superiority will be calculated using the same 
method to compare with the stopping boundary for superiority. Details on 
the testing procedure and stopping boundaries are provided in the IDMC 
analysis plan. For details about handling of missing data refer to 
Section 10.8.2. 
Secondary efficacy endpoints for clinical response and microbiological 
response will not include formal hypothesis testing or adjustments for 
multiplicity. 
Safety data will be summarized using descriptive statistics for the Safety 
Population. 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
AIDS 
acquired immunodeficiency syndrome 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
AP 
acute pyelonephritis 
AST 
aspartate aminotransferase (SGOT) 
AUC 
area under the plasma drug concentration-time curve 
AUC0-24 
area under the plasma drug concentration time curve from time 0 to 
24 hours 
β-HCG 
serum beta human chorionic gonadotropin  
Beta-lactamases 
β-lactamases 
BP 
blood pressure 
BPH 
benign prostatic hyperplasia 
BUN 
blood urea nitrogen 
CE 
Clinically Evaluable 
CFU 
colony forming unit 
CLSI 
Clinical and Laboratory Standards Institute 
Cmax 
maximum observed concentration 
Cr 
creatinine 
CrCl 
creatinine clearance 
CRF 
case report form 
CRO 
Contract Research Organization 
CS 
clinically significant  
CT 
clinical trial 
CTCAE 
Common Terminology Criteria for Adverse Events 
cUTI 
complicated urinary tract infection 
eCRF 
electronic case report form 
EC 
Ethics Committee 
ECG 
electrocardiogram 
EMA 
European Medicines Agency 

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Abbreviation 
Definition 
EOT 
End-of-Treatment 
ESBL 
extended spectrum β-lactamase 
EU 
European Union 
f 
free drug 
FDA 
Food and Drug Administration 
FQs 
fluoroquinolones 
FQ-NS 
fluoroquinolone-nonsusceptible 
FOCP 
female of childbearing potential 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
h 
hour 
Hb 
hemoglobin 
HCG 
human chorionic gonadotropin 
HEENT 
head, eyes, ears, nose, and throat 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HPF 
high power field 
IA 
interim analysis 
IB 
Investigational Brochure 
ICE 
intercurrent events 
ICH 
International Council for Harmonization 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IP 
investigational product  
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
IV 
intravenous(ly) 
LC/MS/MS 
liquid chromatography tandem mass spectrometry 
LE 
leukocyte esterase 

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Abbreviation 
Definition 
LFU 
Late Follow-Up 
MDR 
multidrug-resistant 
ME 
Microbiologically Evaluable 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
minimum inhibitory concentration 
micro-ITT 
Microbiological Intent-to-Treat 
min 
minutes 
MRSA 
methicillin-resistant Staphylococcus aureus 
NI 
non-inferiority 
NOAEL 
no observed adverse effect level 
OTC 
over-the-counter 
P 
pulse 
PD 
Pharmacodynamic(s) 
PI 
Principal Investigator 
PK 
pharmacokinetic(s) 
PMN 
polymorphonuclear neutrophils 
PO 
orally 
QTcF 
Fridericia’s formula 
qXh 
every X hours 
QD 
once daily 
RA 
Regulatory Authority 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SmPC 
Summary of Product Characteristics 
SOA 
Schedule of Assessments 
SOC 
Standard-of-Care 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
λz 
terminal disposition rate constant/terminal rate constant 
TBP 
tebipenem 
TBP-PI 
tebipenem pivoxil 

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Abbreviation 
Definition 
TBP-PI-HBr 
tebipenem pivoxil hydrobromide 
TEAE 
treatment-emergent adverse event 
T 
temperature 
TOC 
Test-of-Cure 
TMP-SMX 
trimethoprim-sulfamethoxazole 
ULN 
upper limit of normal 
US 
United States 
USPI 
United States Package Insert 
UTI 
urinary tract infection 
uUTI 
uncomplicated urinary tract infection 
WBC 
white blood cell 
WHO 
World Health Organization 

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2. 
INTRODUCTION 
2.1. 
Background and Rationale for the Study 
Urinary tract infection (UTI) is one of the most common bacterial infections in adults in both the 
community and hospital setting. Complicated UTI (cUTI) is a subset of UTIs in which the 
infection has extended beyond the bladder, frequently associated with functional or anatomic 
urinary tract abnormalities; acute pyelonephritis (AP), infection of the renal parenchyma, can 
occur in patients with or without functional or anatomic abnormalities of the urinary tract. Gram-
negative bacteria of the Enterobacterales order (e.g., Escherichia coli, Klebsiella spp., 
Enterobacter spp., and Proteus spp.) are the predominant pathogens causing cUTI and AP, 
although Gram-positive bacteria e.g., Enterococcus spp., Staphylococcus aureus and coagulase 
negative staphylococci are also implicated. 
Oral antibiotics including cephalosporins, fluoroquinolones (FQs), and trimethoprim-
sulfamethoxazole (TMP-SMX) have been widely used for treating cUTI/AP in the outpatient 
setting. However, the management of cUTI/AP is increasingly complicated by the rising 
prevalence of bacterial resistance to existing oral agents, predominantly due to 
β-lactamase-producing uropathogens (e.g., Enterobacterales pathogens producing extended 
spectrum β-lactamases [ESBLs] or AmpC, β-lactamases) (Critchley 2019). These resistant 
strains are often co-resistant to other standard-of-care (SOC) oral antibiotics, including the FQs 
and TMP-SMX. Among US patients hospitalized with UTI, the incidence of ESBL-producing 
and FQ-resistant Enterobacterales are 20% and 33%, respectively – exceeding guideline 
thresholds for avoiding empiric use of existing oral agents (Talan 2021). The increasing 
prevalence of multi-drug resistant (MDR) Gram-negative pathogens causing serious bacterial 
infections such as cUTI/AP has been associated with increased morbidity, mortality, and greater 
costs of care and represents a serious global threat to public health (Carreno 2020, CDC 2019, 
Lancet 2022, Zilberberg 2021). Despite this increase, resistance to carbapenems remains low 
(<2%) (Critchley 2019, Talan 2021, CDC 2019). 
In the setting of resistance to other classes of antibiotics and lack of alternative oral options, 
patients with cUTI/AP are commonly hospitalized to receive intravenous (IV) antibiotic therapy, 
most commonly with a carbapenem antibiotic (e.g., ertapenem, imipenem and meropenem) 
which have demonstrated efficacy in complicated bacterial infections, including cUTI/AP, and 
remain active against most MDR Gram-negative uropathogens due to their inherent stability 
against most ESBL and Class C beta-lactamases (β-lactamases). 
There is an urgent need for new oral options for the treatment of cUTI/AP, including those 
infections caused by MDR Gram-negative uropathogens. No oral carbapenem options currently 
exist for patients with cUTI/AP who would be otherwise appropriate for oral therapy. Tebipenem 
pivoxil hydrobromide (TBP-PI-HBr) is being developed as an oral carbapenem alternative to IV 
carbapenems with broad-spectrum activity against common uropathogens. A new effective oral 
cUTI/AP treatment option would potentially limit the need for hospitalization and/or venous 
catheterization for patients otherwise appropriate for oral therapy, thereby reducing risk of 
treatment associated complications and nosocomial infections and ultimately decreasing costs of 
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This Phase 3 study is designed to assess the safety, tolerability, and effectiveness of TBP-PI-HBr 
as compared with a SOC IV carbapenem, imipenem-cilastatin in the treatment of patients with 
cUTI/AP. A previous Phase 3 Study of TBP-PI-HBr versus IV ertapenem (ADAPT-PO) 
provided preliminary safety and efficacy data for TBP-PI-HBr in the treatment of patients with 
cUTI/AP (Eckburg 2022; refer to Section 2.2.3). The current study is designed to provide 
confirmatory evidence of the safety and efficacy of TBP-PI-HBr versus an alternate IV 
carbapenem comparator. 
2.2. 
Tebipenem-Pivoxil-Hydrobromide (TBP-PI-HBr) 
TBP-PI-HBr is an oral prodrug of tebipenem (TBP, the active moiety), a broad-spectrum 
carbapenem antimicrobial from the β-lactam class of antibiotics with demonstrated in vitro and 
in vivo activity against both Gram-negative and Gram-positive bacteria. 
Tebipenem pivoxil (TBP-PI) is a related pivaloyloxymethyl prodrug formulation of TBP which 
allows for oral absorption and improved bioavailability of TBP. TBP-PI is currently approved 
and marketed only in Japan as a pediatric oral granule formulation for the treatment of otitis 
media, sinusitis, and pneumonia in children (Orapenem® Fine Granules 10%; Meiji Seika 
Pharma Co., Ltd, “Meiji”). 
TBP-PI-HBr is the HBr salt form of TBP-PI, which has improved drug product properties that 
enable a high dosage strength tablet formulation relative to those of Orapenem. Both 
TBP-PI-HBr and TBP-PI are prodrugs that rapidly convert to the same active moiety, TBP, in 
enterocytes of the gastrointestinal (GI) tract by intestinal esterases (Kato 2010). Accordingly, 
nonclinical data for TBP and/or TBP-PI provide supportive data for TBP-PI-HBr. 
Of note, tebipenem pivoxil hydrobromide, tebipenem pivoxil, and tebipenem have been 
abbreviated as TBP-PI-HBr, TBP-PI, and TBP, respectively, in this document but may appear as 
TBPM-PI-HBr, TBPM-PI, and TBPM, respectively, in earlier protocols, data in the TBP- PI-
HBr Investigator’s Brochure (IB), and/or published data relevant to tebipenem. TBPM has been 
adapted to TBP in recent documents to align with the Clinical and Laboratory Standards Institute 
(CLSI) abbreviation for tebipenem (CLSI 2023). 
2.2.1. 
Nonclinical Information 
Comprehensive nonclinical safety pharmacology, pharmacokinetics (PK) and microbiology 
studies have been conducted with TBP, TBP-PI and TBP-PI-HBr. Please refer to the current 
TBP-PI-HBr IB for detailed summaries of preclinical data. 
2.2.2. 
Microbiologic Activity 
TBP, the pharmacologically active moiety of TBP-PI-HBr, has demonstrated broad-spectrum 
activity against clinically important Gram-positive and Gram-negative pathogens causing 
cUTI/AP, including MDR organisms, e.g., ESBL and AmpC β-lactamase-producing 
Enterobacterales, including strains co-resistant to FQs and/or TMP-SMX. 
TBP activity against common Enterobacterales bacteria is consistent with that of currently 
available IV carbapenems such as imipenem and meropenem. Among 1717 clinical 
Enterobacterales isolates collected from patients with UTIs in the 2019 US surveillance, TBP 

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drug concentration that inhibits the growth of 90% of test organisms (MIC90) value was 
0.06 μg/mL compared with MIC90 values of 1.0 and 0.06 μg/mL for imipenem and meropenem, 
respectively. Specifically, among E. coli, the most frequently encountered uropathogen, the 
MIC90 value for TBP was 0.015 μg/mL. TBP was active against prevalent ESBL-producing and 
Class C β-lactamase-producing Enterobacterales isolates. All phenotypic ESBL-producing, 
meropenem-susceptible, levofloxacin non-susceptible and/or TMP-SMX-R E. coli isolates were 
inhibited by TBP at concentrations ≤0.5 μg/mL. 
The broad-spectrum activity of TBP against β-lactamase-producing organisms was confirmed 
against an extensive collection of isogenic strains of E. coli expressing narrow spectrum 
β-lactamases (TEM, SHV), ESBLs such as CTX-M-15, and Class C β-lactamase-producing 
organisms. The stability of TBP to hydrolysis by these enzymes has also been established in 
biochemical studies. TBP, like the other carbapenems, was not active against organisms 
producing carbapenemases such as K. pneumoniae carbapenemase, OXA-48, NDM, and VIM β-
lactamase. 
TBP-PI-HBr does not have clinically significant (CS) activity against nonfermenting Gram-
negative pathogens including Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and 
Acinetobacter spp.) which are therefore not considered to be target pathogens for TBP-PI-HBr. 
As such, patients with confirmed or suspected cUTI/AP caused by nonfermenting Gram-negative 
bacilli are excluded from the study. 
2.2.3. 
Clinical Information 
The TBP-PI-HBr safety and PK profile has been well-characterized in eight Phase 1 clinical 
pharmacology studies enrolling healthy volunteers and patients with renal impairment as well as 
a recently completed Phase 3 comparative study (ADAPT-PO) in patients with cUTI/AP. Across 
all clinical studies to date, a total of 944 patients have received TBP-PI-HBr, including 896 
patients receiving the planned dose (600 mg) or higher in single or repeat dose administrations. 
Please refer to the current TBP-PI-HBr IB for detailed summaries of clinical PK, safety, and 
efficacy data. 
Following oral administration of TBP-PI-HBr in both fasted and fed states, there is a generally 
linear relationship between dose and TBP exposure with no accumulation of TBP following 
dosing. 
The effect of renal impairment on the PK of TBP is well-characterized in patients with various 
degrees of renal function and in patients with cUTI/AP. Similar to other β-lactam agents, TBP is 
predominantly renally cleared. The relationship between renal clearance and calculated 
creatinine clearance (CrCl) was found to be linear. Dose adjustment is recommended for TBP-
PI-HBr in patients with CrCl <50 mL/minute (min) (refer to Section 6.2.1). Patients with severe 
renal impairment and end-stage renal disease (CrCl≤30 mL/min) are excluded from the study 
due to labeled precautions (for imipenem-cilastatin noting an increased potential for seizure 
activity in patients with CrCl ≤30 mL/min (PRIMAXIN® I.V. United States Package Insert 
[USPI]; PRIMAXIN® I.V. Summary of Product Characteristics [SmPC]). 
No dose adjustments are required in adult patients with cUTI/AP based on age, weight, BMI, 
sex, or race/ethnicity as none of these covariates were associated with substantial differences in 

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TBP exposure in patients with cUTI/AP. Based on in vitro studies and in vivo studies, the 
potential for drug-drug interactions with TBP-PI-HBr is low. TBP-PI-HBr may be administered 
without respect to meals. Two prior Phase 1 studies demonstrated non-clinically meaningful 
differences in the absorption or TBP systemic exposure when oral TBP-PI-HBr was administered 
in a fasting or fed state. 
Clinical data supporting the safety and preliminary efficacy of oral TBP-PI-HBr in patients with 
cUTI/AP are provided by a completed Phase 3, global, randomized, double-blind, double-
dummy, comparative study of oral TBP-PI-HBr versus IV ertapenem in 1372 hospitalized adult 
patients with cUTI/AP (ADAPT-PO) (Eckburg 2022). Patients from Europe, South Africa, and 
the United States (US) were randomly assigned 1:1 to receive oral TBP-PI-HBr (600 mg 
administered every 8 hours [h]) or IV ertapenem (1 g administered every 24 h) for a duration of 
7-10 days (up to 14 days in patients with bacteremia). Across all visits, clinical response rates 
were high in both treatment groups (>97% at End-of-Treatment [EOT], >93% at Test-of-Cure 
[TOC], and >88% at Late Follow-Up [LFU]), with the majority of microbiological failures at 
each visit being asymptomatic patients with recurrent bacteriuria. Secondary and subgroup 
analyses were consistent with the primary analysis. 
Oral TBP-PI-HBr was well-tolerated in patients with cUTI/AP in the completed Phase 3 study 
and had a comparable safety profile to that of IV ertapenem. The overall incidence of adverse 
events (AEs) was approximately 26% in both treatment groups. The most commonly reported 
AEs were consistent with carbapenem class effects and/or expected changes for patients with 
cUTI/AP (Eckburg 2022, Vardakas 2018). Diarrhea, headache, and nausea were the only AEs 
reported in >1% of patients from either treatment group. Most AEs were mild or moderate in 
severity and non-treatment-limiting. 
2.3. 
Benefit/Risk Assessment 
Patients participating in this study will have a diagnosis of cUTI/AP with sufficient severity to 
warrant hospitalization and treatment with IV antimicrobials. Potential benefits to patients 
enrolled in the study include receipt of potentially effective antimicrobial therapy and medical 
management treatment for their infection. Consistent with the established unmet need for new 
oral therapies for the treatment of cUTI/AP, there is an overall potential benefit of the study to 
confirm the efficacy of a new effective carbapenem antimicrobial agent. 
Potential risks include the possibility that TBP-PI-HBr will not be as effective as the comparator 
treatment, however this risk is mitigated by the study design which allows for the close 
monitoring of patients and option for change in therapy by the treating investigator. 
The identified risks of TBP-PI-HBr to date suggest minimal safety or toxicity risks associated 
with TBP-PI-HBr which are considered consistent with that of IV carbapenems and will be well-
monitored based on the study procedures. Detailed risk information is provided in the IB. 
Imipenem-cilastatin is approved for the treatment of patients with cUTI and identified potential 
risks associated with imipenem-cilastatin are outlined in the product labeling (PRIMAXIN® I.V. 
USPI; PRIMAXIN® I.V. SmPC). 

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3. 
STUDY OBJECTIVES AND ESTIMANDS/ENDPOINTS 
3.1. 
Objectives and Endpoints 
The study objectives and endpoints are outlined in Table 1. 
Table 1: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To assess the efficacy of oral TBP-PI-HBr as 
compared with IV imipenem-cilastatin with respect 
to the overall response (combined clinical cure plus 
microbiological eradication) at the TOC visit in 
hospitalized adult patients (≥18 years of age) with 
cUTI/AP 
Overall response (combined per-patient clinical cure 
and favorable microbiological response) at the TOC 
visit in the micro-ITT Population, as defined by: 
a. 
clinical cure: complete resolution or significant 
improvement of signs and symptoms of cUTI or 
AP that were present at Baseline and no new 
symptoms, such that no further antimicrobial 
therapy is warranted, and patient is alive 
b. favorable microbiological response 
(microbiological eradication): reduction of 
Baseline uropathogens to <103 CFU/mL and 
negative repeated blood culture if blood culture 
was positive for uropathogen growth at Baseline 
and patient is alive 
Secondary 
1. To assess the efficacy of oral TBP-PI-HBr as 
compared with IV imipenem-cilastatin with 
respect to overall response rates at the TOC visit 
in patients with cUTI/AP in the ME Population 
1. Overall response at the TOC visit in the ME 
Population 
2. To assess the efficacy of oral TBP-PI-HBr as 
compared with IV imipenem-cilastatin with 
respect to overall response rates at EOT and 
LFU visits in patients with cUTI/AP 
2. Overall response at the EOT and LFU visits in 
the micro-ITT and ME Populations 
3. To assess the efficacy of oral TBP-PI-HBr as 
compared with IV imipenem-cilastatin with 
respect to clinical response rates at EOT, TOC, 
LFU visits in patients with cUTI/AP 
3. Clinical response at the EOT, TOC and LFU 
visits in the micro-ITT, Clinically Evaluable 
(CE) and ME Populations 
4. To assess the efficacy of oral TBP-PI-HBr as 
compared with IV imipenem-cilastatin with 
respect to microbiological response rates at EOT, 
TOC, and LFU visits in patients with cUTI/AP 
4. Microbiological response at the EOT, TOC and 
LFU visits in the micro-ITT and ME Populations 
5. To assess the efficacy of oral TBP-PI-HBr as 
compared with IV imipenem-cilastatin with 
respect to overall, clinical and microbiological 
response rates at TOC, EOT and LFU visits 
among cUTI/AP patients infected with drug-
resistant Enterobacterales uropathogens e.g., 
ESBL-producing, fluoroquinolone-
5. Overall, Clinical and Microbiological response at 
the TOC, EOT and LFU visits in the micro-ITT 
and ME Populations in patients with drug-
resistant Enterobacterales 

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Primary Estimand: 
The primary clinical question of interest is: What is the treatment effect with respect to the 
overall response at the TOC visit following treatment with oral TBP-PI-HBr 600 mg q6h 
compared to IV imipenem-cilastatin 500 mg q6h, each administered over 7-10 days duration, in 
patients with cUTI or AP due to qualifying uropathogens, regardless of treatment discontinuation 
for any reason? 
Receipt of non-study systemic antimicrobial therapy for treatment of the index infection 
(cUTI/AP) will impact the endpoint definition. 
The primary estimand is described by the following attributes: 
• Population: Patients with cUTI or AP included in the Microbiological Intent-to-Treat 
(micro-ITT) Population (refer to Section 10.3) 
• Treatment Condition: TBP-PI-HBr 600 mg PO q6h versus imipenem-cilastatin 
500 mg IV q6h, each administered for 7-10 days duration 
• Variables: Overall response (combined per-patient clinical cure and favorable 
microbiological response) at the TOC visit 
o Clinical cure is defined as complete resolution or significant improvement of 
signs and symptoms of cUTI or AP present at Baseline and no new signs or 
symptoms requiring such that no further antimicrobial therapy is warranted, and 
patient is alive 
o Favorable microbiological response (microbiological eradication) is defined as a 
reduction of Baseline uropathogens to <103 CFU/mL and negative repeated blood 
culture if blood culture was positive for uropathogen growth at Baseline and 
patient is alive 
• Summary Measure: Difference in the overall response rates between the TBP- PI-HBr 
and imipenem-cilastatin treatment groups 
• Intercurrent Events (ICE): 
o Study treatment discontinuation due to any reason will be evaluated using a 
treatment policy strategy, e.g., evaluation of the treatment effect regardless of 
study treatment discontinuation, or noncompliance (missed doses) 
o Use of non-study, potentially effective systemic antimicrobials to treat the 
cUTI/AP infection prior to the TOC visit will be evaluated using a composite 
strategy as captured through the clinical outcome definition, with these events 
defined as overall failures 
If the patient experiences both of these ICE then a composite strategy (assigning 
overall response as a failure) will be used from the point that the relevant systemic 
antimicrobial was taken. 
The rationale for the primary estimand includes: 

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Assessment of the treatment effect regardless of whether the full course of therapy (7-10 days of 
treatment) was received reflects how patients may be treated in clinical practice. Hence, a 
treatment policy strategy is appropriate for treatment withdrawal before completion of 7-10 days 
of treatment. 
Use of non-study potentially effective systemic antimicrobials may confound the interpretation 
of the clinical response to treatment and/or the interpretation of microbiologic outcome based on 
bacterial culture results; thus, receipt of concurrent non-study potentially effective systemic 
antimicrobials for treatment of the index infection (cUTI/AP) will be considered as a clinical 
failure. 
Use of non-study systemic antimicrobial agents for infections other than cUTI/AP should be 
restricted to agents without anticipated activity against the Baseline pathogen whenever possible. 
Therefore, a favorable overall response precludes the use of other potentially effective systemic 
antimicrobials with potential activity against the Baseline pathogen(s) when initiated for the 
treatment of the index infection (cUTI/AP). 
3.1.2. 
Secondary Objectives and Estimand 
Secondary Objectives: 
• To assess the efficacy of oral TBP-PI-HBr as compared with IV imipenem-cilastatin with 
respect to overall response rates at the TOC visit in patients with cUTI/AP in the ME 
population 
• To assess the efficacy of oral TBP-PI-HBr as compared with IV imipenem-cilastatin with 
respect to overall response rates at EOT and LFU visits in patients with cUTI/AP 
• To assess the efficacy of oral TBP-PI-HBr as compared with IV imipenem-cilastatin with 
respect to clinical response rates at EOT, TOC, and LFU visits in patients with cUTI/AP 
• To assess the efficacy of oral TBP-PI-HBr as compared with IV imipenem-cilastatin with 
respect to microbiological response rates at EOT, TOC, and LFU visits in patients with 
cUTI/AP 
• To assess the efficacy of oral TBP-PI-HBr as compared with IV imipenem-cilastatin with 
respect to microbiological response rates at EOT, TOC, and LFU visits among cUTI/AP 
patients infected with drug-resistant Enterobacterales uropathogens, e.g., ESBL-producing, 
fluoroquinolone-nonsusceptible (FQ-NS), and/or trimethoprim-sulfamethoxazole-resistant 
(TMP-SMX-R) strains 
• To assess the safety and tolerability of oral TBP-PI-HBr as compared to IV imipenem-
cilastatin in patients with cUTI/AP 
• To provide tebipenem (TBP) plasma concentration data to characterize the pharmacokinetics 
of TBP in the target population using PK modeling. 
 
 

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Secondary Estimands: 
Efficacy: 
The secondary clinical efficacy questions of interest are: What is the treatment effect (with 
respect to the overall, clinical, and microbiological endpoints) for oral TBP-PI 600 mg q6h 
compared to IV imipenem-cilastatin 500 mg q6h, each administered for 7-10 days in patients 
with cUTI or AP due to qualifying Baseline uropathogen(s)? 
Receipt of non-study systemic antimicrobials impacts the endpoint outcome definitions (see 
above). 
For each of the secondary endpoints the estimand will follow a similar approach to the estimand 
for the primary endpoint and will use the same general strategies for the ICEs. 
The summary measure for the secondary endpoints is based on the difference between treatment 
groups (TBP-PI-HBr vs. imipenem-cilastatin) and these endpoints will be descriptively 
summarized (i.e., no direct inferential comparison between treatment groups will be made). 
Safety: 
The safety endpoint will use a treatment policy strategy of the ICEs of withdrawal from 
treatment as the safety will be assessed at all post-Baseline assessments irrespective of whether 
the participant completed the treatment or received non-study concomitant antimicrobial therapy. 
PK: 
The TBP plasma concentrations will be assessed to inform population PK modeling and will be 
separately reported. Refer to Appendix 1 for the components of estimand for the secondary 
endpoints. 

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4. 
STUDY DESIGN 
4.1. 
Overview of Study Design and Procedures 
This is a Phase 3, randomized double-blind, double-dummy, multicenter, multinational 
prospective study to assess the efficacy and safety of oral TBP-PI-HBr compared to IV 
imipenem-cilastatin for the treatment of patients with cUTI/AP. 
Eligible patients with a clinical diagnosis of cUTI/AP and suitable to start empiric IV 
antimicrobials, and who are able to tolerate oral medication, will be randomized in a 1:1 ratio to 
receive either: 
• TBP-PI-HBr 600 mg (2×300 mg film-coated immediate-release tablets), administered 
orally (PO) every 6 h (q6h ±1 h) plus dummy infusion (0.9% sodium chloride) 
administered intravenously (IV) over 30 min q6h (±1 h) 
• Imipenem-cilastatin, 500 mg administered IV over 30 min q6h (±1 h) plus matched 
dummy tablets administered PO q6h (±1 h) 
A dummy infusion of normal saline and dummy matching placebo tablets will be used to 
maintain the blind. For further treatment group details refer to Section 6.1. 
Randomization will be stratified by age at time of consent (≥18 to <65 years vs. ≥65 years), 
baseline diagnosis (cUTI vs. AP), and presence or absence of urinary tract instrumentation at 
Baseline (refer to Section 4.5.1). For the purposes of stratification, Baseline Instrumentation 
should be considered present if the patient has a urinary tract instrument anytime from the 
beginning of Screening until Randomization. 
Patients who meet the disease definition of cUTI (e.g., underlying functional or anatomical 
urinary tract abnormality; per Inclusion Criterion 4.a) and have additional clinical evidence of 
AP (e.g., flank pain or costovertebral angle tenderness; per Inclusion Criterion 4.b) should be 
randomized as cUTI. At least 30% of patients will be randomized with a diagnosis of AP at study 
entry. 
The study plans to enroll approximately 2648 patients (1324 per treatment group) to achieve a 
target sample size of approximately 1588 evaluable patients (794 per treatment group) for the 
primary analysis population (micro-ITT Population) which would provide 89% power with a 
1-sided significance level of 0.025 for assessment of NI of oral TBP-PI-HBr to IV imipenem-
cilastatin (refer to Section 10.2). The final number of randomized patients will depend on a 
planned interim analysis (IA) to be performed when 60% of the patients in the micro-ITT 
Population (approximately 954 patients) have response data available at the TOC visit, 
potentially allowing for early termination of the study based on certain pre-specified criteria 
(refer to Section 10.1). 
Receipt of potentially effective systemic antimicrobials with activity against the Baseline 
uropathogen within the 72-hour window prior to randomization could impact the assessment of 
efficacy. Patients who received potentially effective systemic antimicrobials within 72 h prior to 
randomization will be excluded.  
Refer to Section 5.1 and Section 5.2 for study inclusion and exclusion criteria, respectively. 

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Refer to Section 7.1 for study visit details, and Section 7.2 for study outcome assessments and 
procedures detail. 
The total duration of study participation will be approximately 28 days following the first dose of 
trial therapy. The total duration of study treatment (IV or oral) will be 7-10 calendar days. All 
patients will be treated for a minimum of 7 days (i.e., will be considered to have completed 
therapy after the last scheduled dose on study Day 7); however, treatment may continue for up to 
10 days at the discretion of the Investigator. Patients will be hospitalized for the duration of their 
treatment. 
Day 1 is the first day of IP or comparator administration. Patients who are prematurely 
discontinued from IP or comparator treatment should undergo all EOT visit procedures and 
should be followed through the LFU visit for Safety assessments, regardless of the reason for 
early treatment discontinuation (refer to Figure 1). 
The end of study is defined as the last patient study visit. 
 
 

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Figure 1: 
Study Design Flow Chart 
 
a The first dose of the study treatment may occur on the same calendar day as the Screening visit. 
b The EOT visit occurs on the day or the calendar day following (+1 day) of the last dose of study treatment. 
EOT, End-of-Treatment; h, hour; IV, intravenously; PO, orally; q6h, every 6 hours; TOC, Test-of-Cure. 

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4.2. 
Rationale for Study Design 
The overall study design and key study-specific elements included in this protocol are in general 
alignment with recommendations outlined for registrational cUTI/AP trials in current regulatory 
guidance (FDA 2018b), Sponsor agreements with the Food and Drug Administration (FDA) 
throughout the TBP-PI-HBr development program and/or applicable clinical practice guidelines. 
4.3. 
Rationale for TBP-PI-HBr Dose 
The TBP-PI-HBr dosing regimen in this study (i.e., 600 mg PO q6h) is supported by 
pharmacodynamic (PD) modeling across both in vivo and in vitro infection models, a population 
PK model developed from data from both healthy adult subjects and patients with cUTI, and 
clinical PK/PD modeling demonstrating high predicted target attainment across the MIC90 for 
relevant Enterobacterales uropathogens. In addition, the dosage regimen of 600 mg q6h matches 
both the plasma free drug (f) predicted PK/PD target attainment for Enterobacterales and the 
urine concentration-time profile of the comparator, imipenem-cilastatin. As further described in 
the IB, PK/PD analyses of data from nonclinical in vitro and in vivo studies conducted by Spero 
Therapeutics, Inc. indicate that the PK/PD driver predictive of TBP efficacy is best described as 
the ratio of f area under the plasma drug concentration-time curve (AUC) to the minimum 
inhibitory concentration (MIC) adjusted for the dosing interval (f AUC:MIC • 1/τ).  
As for other β-lactam agents, TBP is predominantly renally cleared. TBP-PI-HBr dose 
adjustment is required for in patients with CrCl <50 mL/min as outlined in Section 6.2. 
A steady-state arithmetic mean Cmax of 7.99 ug/mL and steady-state arithmetic mean AUC0-24 of 
84.7 μg.h/mL for TBP from a TBP-PI-HBr dosage regimen of 600 mg PO q6h have been 
calculated by simulation of the patient exposure data from SPR994-301 using PK modeling. The 
steady-state exposure toxicology safety margins for the TBP-PI-HBr dosage regimen of 600 mg 
PO q6h for human compared to the no observed adverse effect level (NOAEL) dose in rat and 
monkey, respectively, are 9.11 and 2.75 for Cmax and 4.48 and 1.14 for AUC. 
In both species the GI effects defined the NOAEL, and the small safety margin changes from a 
dosage regimen of 600 mg PO q8h for human compared to the NOAEL dose in rat and monkey 
(8.6 and 2.6 for Cmax and 5.1 and 1.3 for AUC, respectively) are not considered to alter the 
assessment of non-clinical safety particularly as these findings are reversible and monitorable, 
and well characterized by marketed carbapenems. Across the clinical development program, the 
safety profile of a 600 mg PO q8h dosing regimen of TBP-PI-HBr was consistent with that for 
carbapenem and the β-lactam class. The reversibility of adverse GI effects that defined the 
NOAEL, as well as the absence of the drug accumulation due to the short one-hour half-life, 
provide further reassurance that the safety profile of the 600 mg q6h PO dose regimen should be 
largely similar with what was previously seen in 600 mg q8h PO dose regimen. 
4.4. 
Rationale for Comparator 
Imipenem-cilastatin is a parenteral carbapenem antimicrobial approved for the treatment of 
cUTI/AP in many countries and is considered an empiric SOC treatment option for patients with 
serious bacterial infections, including cUTI/AP. Imipenem has a similar spectrum of in vitro and 

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in vivo antimicrobial activity to TBP-PI-HBr against common pathogens that cause cUTI/AP, 
including ESBL-producing Enterobacterales and certain Gram-positive uropathogens (e.g., 
Enterococcus faecalis). 
Likewise, imipenem-cilastatin (500 mg IV q6h) is selected as the active comparator to TBP-PI 
(600 mg PO q6h) by nature of its comparable plasma, tissue, and urine PK and similar dosing 
frequency. 
4.5. 
Measures to Minimize Bias: Randomization and Blinding 
4.5.1. 
Allocation of Patients to Treatment 
Once informed consent has been obtained and eligibility has been determined, site personnel will 
obtain a patient number from a computer-generated randomization scheme using the Interactive 
Response Technology (IRT). An IRT is used for study treatment management tasks. This may 
include, for example, randomization, study treatment supply management, inventory 
management and supply ordering, study treatment expiration tracking, and emergency 
unblinding. Patients will be identified by a unique ten-digit patient identifier (e.g., 305-XXX-
ZZZZ) in which the first three digits indicate the study identifier (e.g., 305), the second three 
digits indicate the site number, and the final four digits indicate the number assigned at 
randomization by IRT. For example, the first patient randomized at site 001 will be identified by 
the number 305-001-0001. The Sponsor will assign site numbers. 
Randomization to treatment groups will occur in a 1:1 ratio. For this study, randomization is 
considered to occur at the time the patient’s study entry criteria is confirmed. Once a 
randomization number has been assigned, that number must not be used again if, for example, a 
patient is withdrawn from the study. If a randomization number is allocated incorrectly, the 
Study Monitor must be notified as soon as the error is discovered. 
To ensure balance among treatment groups, the randomization will be stratified by age at 
informed consent (≥18 to <65 years vs. ≥65 years), baseline diagnosis (AP vs. cUTI), and 
presence or absence of urinary tract instrumentation at Baseline. For the purposes of 
stratification, Baseline Instrumentation should be considered present if the patient has a urinary 
tract instrument anytime from the beginning of Screening until Randomization. 
4.5.2. 
Blinding the Treatment Assignment 
This is a randomized, double-blind, double-dummy study. Access to treatment allocation will be 
limited to unblinded members of the study team only, such as unblinded pharmacists and/or 
unblinded delegates and unblinded study monitors. Identification of study team member roles 
and their blinding status will be detailed in the study Blinding Plan. Investigators and patients 
will remain blinded to each patient’s assigned treatment group through the course of the study 
with the exception of a few select independent PK analysts to support PK model development 
and refinement. All study assessments will be performed by blinded study staff. In order to 
maintain study treatment blinding, patients will receive, in addition to their randomized active 
treatment (TBP-PI-HBr or imipenem-cilastatin), a matching placebo form of the active treatment 
to which they were not assigned. The matching placebos will look identical to the active form. 

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Individual participant-level, de-identified, unblinded, and scrambled (i.e., random reassignment 
of participant identification numbers) drug concentration information will be analyzed prior to 
unblinding the study. In that case, independent clinical PK analysts (who are not involved in 
study conduct) will have access to an unblinded scrambled population PK-specific dataset (e.g., 
drug concentrations, actual dosing information, demographics, and laboratory details, but no AE 
or efficacy data) at 1 or more time points (e.g., prior to the interim or primary analysis) 
throughout the study for population PK model development and refinement. 
The Sponsor and its designees (CRO/vendors) responsible for monitoring safety and 
microbiological (i.e., pathogen identification, susceptibility data, and the number par participants 
eligible for the micro-ITT population) data instream will remain blinded to patient treatment 
assignments throughout the study. Blinded monitoring of pathogens will be conducted, to 
determine whether end-of-study targets are likely to be achieved. Procedures will be described in 
a separate evaluability review plan, and no impact on trial integrity is expected. 
4.5.3. 
Unblinding the Treatment Assignment 
The IRT will be programmed with blind-breaking instructions. Backup Code-break information 
is held by the unblinded pharmacist or designated unblinded person at the site and by the 
Contract Research Organization (CRO) Unblinded Medical Monitor for the study or unblinded 
designee. 
Treatment assignment must not be broken during the study except in emergencies where the 
identification of the IP/comparator is required for further treatment of the patient. In case of an 
emergency, the Investigator has the sole responsibility for determining if unblinding of a 
patient’s treatment assignment is warranted. Patient safety must always be the first consideration 
in making such a determination. 
In the event that the treatment assignment is broken, the date, the signature of the person who 
broke the code, and the reason for breaking the code are recorded in the IRT and the source 
documents. After breaking the blind and the patient is withdrawn from study treatment, he or she 
should receive follow-up for safety purposes. Any code-breaks that occur must be reported to the 
Sponsor or its designee within 24 h. 
Unblinding measures for safety will be detailed in the Medical Monitoring Plan; 
blinding/unblinding details of data will be detailed in the Data Management Plan; and details 
regarding monitoring of unblinding source documents and data will be captured in the Clinical 
Monitoring Plan. 
Data that may potentially unblind the treatment assignment (e.g., IP/comparator concentrations, 
treatment allocation, and IP/comparator preparation/accountability data) will be handled with 
special care during the data cleaning and review process. These data points will be presented as 
blinded information or otherwise will not be made available. If applicable, unblinded data may 
be made available to unblinded quality assurance representatives or unblinded monitors for the 
purposes of conducting independent drug audits. 
The Independent Data Monitoring Committee (IDMC) and CRO/vendors performing statistical 
analyses will be unblinded for the IA (refer to Section 10.1). The IDMC details will be described 

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in a separate charter and analysis plan. Study team members from the Sponsor and CRO who are 
operating the study and conducting the final analysis will remain blinded. 
The Pharmacovigilance CRO may unblind the treatment assignment for any patient with a 
related serious adverse event (SAE). If the SAE requires that an expedited regulatory report be 
sent to one or more regulatory agencies, a copy of the report, identifying the patient’s treatment 
assignment, may be sent to investigators in accordance with local regulation and/or Sponsor 
policy. 

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5. 
STUDY POPULATION 
5.1. 
Inclusion Criteria 
Patients meeting all the following inclusion criteria should be considered for randomization in 
the study: 
1. male and female patients at least 18 years of age; patients enrolled in India must be 
≤90 years of age 
2. able to provide informed consent (for further details regarding patient consenting, refer to 
Section 11.3.1) 
3. able to ingest oral tablets for the anticipated treatment duration. If present at Baseline, 
nausea and/or vomiting should be mild or well controlled with antiemetic therapy. 
4. have a diagnosis of cUTI or AP as defined below: 
a. cUTI definition: 
at least TWO of the following signs and symptoms: 
i. 
chills, rigors, or fever (oral, tympanic, rectal or core temperature >38.0°C 
[>100.4°F]); fever must be observed and documented by a health care 
provider 
ii. 
dysuria, urgency to void, or increased urinary frequency 
iii. 
nausea or vomiting, as reported by the patient 
iv. 
lower abdominal pain, suprapubic pain, pelvic pain, or flank 
pain/costovertebral angle tenderness. 
AND at least ONE of the following risk factors for cUTI: 
i. 
implanted urinary tract instrumentation (e.g., nephrostomy tube, ureteric 
stents, or other urinary tract prosthetic material), ongoing intermittent 
bladder catheterization, or presence of an indwelling bladder catheter (Note: 
bladder catheters that have been in place for >24 h prior to Screening must 
be removed or replaced prior to collection of the Screening urine for 
urinalysis and culture, unless removal or replacement is considered unsafe or 
contraindicated) 
ii. 
current known functional or anatomical abnormality of the urogenital tract, 
including anatomic abnormalities of the urinary tract, neurogenic bladder, or 
post-void residual urine volume of ≥100 milliliters (mL) within the past 
6 months 
iii. 
complete or partial obstructive uropathy (e.g., nephrolithiasis, tumor, 
fibrosis, urethral stricture) that is expected to be medically or surgically 
treated during study drug therapy (prior to EOT visit) 
iv. 
known intrinsic renal disease with blood urea nitrogen (BUN) 
>20 mg/deciliter (dL), or blood urea >42.8 mg/dL, or serum creatinine (Cr) 
>1.4 mg/dL 
v. 
urinary retention, including urinary retention in men due to previously 
diagnosed benign prostatic hyperplasia (BPH) 
 

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b. AP definition: 
acute flank pain (onset within 7 days prior to randomization) or costovertebral angle 
tenderness on physical examination AND at least ONE of the following signs and 
symptoms: 
i. 
chills, rigors, or fever (oral, tympanic, rectal or core temperature >38.0°C 
[>100.4°F]); fever must be observed and documented by a health care 
provider  
ii. 
peripheral white blood cell count (WBC) >10,000/cubic millimeter (mm3) or 
bandemia (>15% immature polymorphonuclear neutrophils [PMNs], 
regardless of WBC count) 
iii. 
nausea or vomiting, as reported by the patient 
iv. 
dysuria, urgency to void, or increased urinary frequency. 
Note: Patients who meet the definition for cUTI (refer to Inclusion Criterion 4.a) and 
have flank pain or costovertebral tenderness should be randomized as cUTI rather 
than AP. 
5. have an adequate urine specimen for evaluation of culture obtained within 24 h prior to 
randomization with evidence of pyuria that includes at least one of the following: 
a. at least 10 WBCs per high power field (HPF) in urine sediment 
b. at least 10 WBCs per mm3 in unspun urine 
c. positive leukocyte esterase (LE) on urinalysis 
Note: Patients may be randomized and administered study drug prior to knowledge of 
urine culture results, but pyuria must be documented. 
6. expectation, in the judgment of the Investigator, that the patient will survive with 
effective antimicrobial therapy and appropriate supportive care for the anticipated 
duration of the study 
7. willing to comply with all the study activities and procedures throughout the duration of 
the study 
8. willing to agree to use a highly effective method of birth control; male patients must 
agree to not engage in sexual activity with a female partner that could lead to pregnancy 
(i.e., heterosexual vaginal intercourse) or must agree to use an effective barrier method of 
contraception from Screening through the LFU visit and for 90 days following the last 
dose; females of childbearing potential (FOCP) must have a negative pregnancy test at 
Screening and agree to abstain from sexual activity that could lead to pregnancy (i.e., 
heterosexual vaginal intercourse or in vitro fertilization) from the time of Screening 
through the EOT visit, or agree to use a highly effective method of contraception from 
the time of Screening throughout the study (through the LFU visit). Highly effective 
methods of birth control include one or more of the following: 
a. an approved hormonal contraceptive associated with inhibition of ovulation including 
oral, implantable, transdermal, injectable, or intravaginal contraceptive used 
consistently for at least 1 month prior to study drug dosing 
b. an intrauterine device or intrauterine hormone-releasing system 

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c. male sexual partner who has been vasectomized for at least 3 months prior to 
Screening and who has obtained a follow-up negative sperm count. 
9. female of nonchildbearing potential based on at least 1 of the following criteria: 
a. post-menopausal status defined as amenorrhea for at least 12 months prior to 
randomization 
b. Follicle Stimulating Hormone (FSH) levels in the laboratory defined post-menopausal 
range; in the absence of amenorrhea for at least 12 months prior to randomization, at 
least two FSH measurements demonstrating levels in the post-menopausal range are 
required 
c. patient report of surgical sterilization (i.e., bilateral tubal ligation, hysterectomy, 
bilateral oophorectomy/salpingectomy) at least 6 weeks prior to randomization. 
5.2. 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria will not be enrolled in the study: 
1. presence of any known or suspected disease or condition that may confound the 
assessment of efficacy, including but not limited to the following: 
a. perinephric or renal corticomedullary abscess 
b. uncomplicated urinary tract infection (uUTI [acute cystitis that does not meet the 
cUTI disease definition; refer to Inclusion Criterion 4.a]) 
c. polycystic kidney disease 
d. recent history of trauma to the pelvis or urinary tract 
e. confirmed or suspected acute or chronic bacterial prostatitis, orchitis, or epididymitis 
f. chronic vesicoureteral reflux 
g. previous or planned renal transplantation 
h. previous or planned cystectomy or ileal loop surgery 
i. known or suspected non-renal source of infection (e.g., infective endocarditis, 
osteomyelitis, meningitis, pneumonia)  
j. confirmed or suspected infection that is caused by a pathogen that is resistant to either 
study drug (e.g., carbapenem-resistant pathogen), including infection caused by fungi 
(e.g., candiduria) or mycobacteria (e.g., urogenital tuberculosis) or an 
intrinsically-resistant bacterial species not expected to respond to oral IP or comparator 
IV (e.g., Pseudomonas species) 
2. gross hematuria requiring intervention other than administration of study drug or 
removal/placement of urinary tract instrumentation 
3. urine Gram stain (if performed by site) fails to demonstrate a Gram-negative bacillus 
(i.e., negative Gram stain or Gram stain demonstrating only a Gram-positive organism) 
Note: Urine Gram stain should be performed, if possible, to inform eligibility but is not 
mandatory for Screening. 
4. urinary tract surgery within 7 days prior to randomization or urinary tract surgery planned 
during the study period (except surgery required for relieving an obstruction or placing 
urinary tract instrumentation) 

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5. creatinine clearance (CrCl) of ≤30 mL/minute (min), as estimated by the Cockcroft-Gault 
formula: 
eCCr[mL/min] = (140 −Age [yrs]) × Body Weight [kg] × [0.85 if Female]
72 × Serum Creatinine [mg dL
⁄
]
 
6. anticipated concomitant use of non-study antimicrobial drug therapy between 
randomization and the LFU visit that would potentially effect outcome evaluations of 
cUTI/AP, including but not limited to antimicrobials with potential activity against 
Gram-negative pathogens, antimicrobial drug prophylaxis, and antimicrobial bladder 
irrigation 
7. receipt of a potentially effective antimicrobial within 72 h prior to study randomization 
8. severe hepatic impairment at Screening, as evidenced by alanine aminotransferase (ALT) 
or aspartate aminotransferase (AST) >5×upper limit of normal (ULN) or total 
bilirubin>3×ULN, or clinical signs of cirrhosis or end-stage hepatic disease (e.g., ascites, 
hepatic encephalopathy) 
9. pregnant or lactating women 
10. history of epilepsy or known seizure disorder (excluding a history of childhood febrile 
seizures) 
11. history of proven or suspected Clostridioides difficile associated diarrhea 
12. receipt of any investigational device or investigational medication during the last 30 days 
or 5 half-lives, whichever is longer, prior to randomization 
13. known history of human immunodeficiency virus (HIV) infection with known CD4 count 
<200/mm3 or acquired immunodeficiency syndrome (AIDS)-defining illness within the 
past year 
14. presence of immunodeficiency or an immunocompromised condition including 
neutropenia (<1,000 neutrophils/mm3 obtained from the local laboratory at Screening), 
hematologic malignancy, bone marrow transplant, or receiving immunosuppressive 
therapy such as cancer chemotherapy, medications for the rejection of transplantation, 
and long-term use of systemic corticosteroids (e.g., ≥20 mg/day of prednisone or 
systemic equivalent for at least 2 weeks) 
15. QT interval corrected using Fridericia’s formula (QTcF) >480 msec based on Screening 
electrocardiogram (ECG) 
16. history of significant hypersensitivity or allergic reaction to β-lactam antimicrobials (e.g., 
cephalosporins, penicillins, carbapenems), product excipients (mannitol, microcrystalline 
cellulose, crospovidone, magnesium stearate, colloidal silicon dioxide, and Opadry®) or 
any contraindication to the use of imipenem-cilastatin 
17. history of known genetic metabolism anomaly associated with carnitine deficiency (e.g., 
carnitine transporter defect, methylmalonic aciduria, propionic acidemia) 

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18. requirement for concomitant use of valproic acid, divalproex sodium, or probenecid 
between randomization and EOT 
19. unable or unwilling to comply with the protocol 
20. an employee of the Investigator or study center with direct involvement in the proposed 
study or other studies under the direction of that Investigator or study center, as well as a 
family member of the employee or the Investigator. 

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6. 
STUDY TREATMENTS 
6.1. 
Identity of Investigational Products 
TBP-PI-HBr is the hydrobromide salt of TBP-PI, a pivoxil prodrug which rapidly converts to 
TBP, the active moiety, in vivo. The pivoxil prodrug formulation enables oral absorption and 
improved bioavailability of TBP (Kato 2010) while the hydrobromide salt formulation improves 
the drug substance and drug product properties, including stability. Additional details are 
provided in Section 2.2 and the current TBP-PI-HBr IB. 
TBP-PI-HBr tablets will be administered PO as one or two 300 mg film-coated immediate-
release tablets (depending on renal function). TBP-PI-HBr tablets will be supplied by a Sponsor-
qualified Contract Manufacturing Company. 
The comparator, imipenem-cilastatin, is a commercially available parenteral carbapenem 
(β-lactam antibacterial) with a similar spectrum of microbiologic activity to that described for 
TBP-PI-HBr. It is the combination of imipenem, the carbapenem antibacterial, and cilastatin, a 
renal dehydropeptidase inhibitor. Imipenem-cilastatin will be provided as a sterile, lyophilized 
powder for reconstitution in vials. Commercially available imipenem-cilastatin will be procured 
from a qualified manufacturer/vendor supplied by the Sponsor. Please refer to the SmPC 
(PRIMAXIN® I.V. SmPC)/ Product Package Insert (PRIMAXIN® I.V. USPI) for detailed 
information regarding imipenem-cilastatin. 
A matching dummy/placebo infusion of normal saline solution (0.9%) and matching dummy TBP-
PI-HBr tablets will be used to maintain the blind. Normal saline and matching dummy TBP-PI-
HBr tablets will be supplied by the Sponsor. Standard operating procedures will be followed for 
the receipt, handling, and accountability of the study formulations. 
A summary of the IP (TBP-PI-HBr or imipenem-cilastatin) dosage form and strength are 
provided in Table 2. Dosage regimens are outlined in Section 6.2. 
Table 2: 
Summary of Investigational and Comparator Products Dosage Form and 
Strength 
Study Treatment  
Dosage Form and Strength 
TBP-PI-HBr (oral IP) 
300 mg green, round, biconvex, film-coated immediate-release tablets 
debossed with “TBP” on one side and “300” on the other side 
Each TBP-PI-HBr tablet contains 348.8 mg TBP PI HBr, which is 
equivalent to a 300 mg dose of TBP-PI containing 231 mg of TBP 
Clinically labeled per health authority regulations 
Matching dummy TBP-PI-HBr 
tablets 
Green, round, biconvex, film-coated tablets pressed from a blend 
consisting of similar inactive ingredients as active TBP-PI-HBr and uses 
mannitol, which replaces the active pharmaceutical ingredient (TBP) 
Imipenem-cilastatin (IV 
comparator) 
Sterile powder for reconstitution in single-dose vials containing 500 mg 
imipenem (anhydrous equivalent) and 500 mg cilastatin (free acid 
equivalent) 
Clinically labeled per health authority regulations 
Sodium chloride injection 
0.9% sodium chloride injection, 100 mL 
IP, investigational product; IV, intravenous; TBP, tebipenem; TBP-PI-HBr, tebipenem pivoxil hydrobromide. 

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6.2. 
Dosing and Treatment Regimens  
Eligible patients with a clinical diagnosis of cUTI/AP of sufficient severity to start empiric IV 
antimicrobials, and who can tolerate oral medication, will be randomized in a 1:1 ratio to receive 
either: 
• TBP-PI-HBr 600 mg (2×300 mg film-coated tablets), administered PO q6h (±1 h) 
plus dummy infusion (0.9% sodium chloride) administered IV over 30 min q6h (±1 h) 
• Imipenem-cilastatin, 500 mg administered IV over 30 min q6h (±1 h) plus matched 
dummy tablets administered PO q6h (±1 h) 
The total duration of study treatment will be 7-10 days. All patients will be treated for a 
minimum of 7 days (i.e., will be considered to have completed therapy after the last scheduled 
dose on study Day 7); however, treatment may continue for up to 10 days at the discretion of the 
Investigator. 
Each patient will receive oral dosing with TBP-PI-HBr or matched dummy/placebo tablets q6h 
(depending on renal function) followed by a 30-minute infusion of imipenem-cilastatin or 
matched dummy infusion every 6h as outlined below. 
Both TBP-PI-HBr and imipenem-cilastatin require dosage adjustment in the setting of renal 
insufficiency as outlined in Section 6.2.1 and Section 6.2.2, respectively. Additional details 
regarding post-Baseline monitoring of CrCl and dosage adjustment are provided in Section 6.3.1. 
Note: Dosage adjustments by CrCl category are different for the oral IP and IV comparator. 
Renal function as estimated by CrCl will be assessed using the Cockcroft-Gault formula 
(Cockcroft 1976) as outlined below using serum Cr levels obtained at the local laboratory at 
Screening (Baseline) and throughout the study: 
Cockroft-Gault Formula: 
eCCr[mL/min] = (140 −Age [yrs]) × Body Weight [kg] × [0.85 if Female]
72 × Serum Creatinine [mg dL
⁄
]
 
Actual weight in kilograms (not ideal weight) is required for the CrCl calculation. If available, 
the weight obtained on the day of the serum Cr measurement should be used for calculating 
CrCl; however, the Baseline weight may be used throughout the study for CrCl estimations if 
repeated weights cannot be obtained. The weight used to calculate CrCl will be recorded in the 
electronic case report form (eCRF). 
Dosing of oral IP tablets may be administered irrespective to the timing of meals. 
6.2.1. 
TBP-PI-HBr Dosing in Patients with CrCl >50 mL/min 
Patients randomized to receive TBP-PI-HBr with estimated Baseline CrCl >50 mL/min will 
receive TBP-PI-HBr 600 mg (two 300 mg tablets) PO q6h (±1 h) plus dummy (0.9% normal 
saline) IV infusion administered in a total volume of 100 mL over 30 min q6h (±1 h). 
Dose adjustment is required for patients with estimated Baseline CrCl ≤50 mL/min as outlined in 
Section 6.2.1.1. However, for patients who have a Screening/Baseline CrCl near the 50 mL/min 

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threshold (i.e., 45-50 mL/min) in whom the CrCl is expected to increase to >50 mL/min over the 
first day of therapy (e.g., after IV fluid hydration in patients who are volume depleted in setting 
of acute infection), the Investigator may choose to administer TBP-PI-HBr 600 mg while 
reassessing the need for a dosage adjustment based on a subsequent CrCl assessment (refer to 
Section 6.2.1.1 for details). 
6.2.1.1. 
TBP-PI-HBr Dose Adjustments in Patients with Impaired Renal Function (CrCl 
≤50 mL/min) 
TBP-PI-HBr dosage adjustment is required for patients with CrCl ≤50 mL/min as outlined in 
Table 3. Data supporting the dosage adjustments in patients with impaired renal function are 
provided in the IB.  
Table 3 
TBP-PI-HBr Dosage Regimen by Estimated Creatinine Clearance Category 
CrCl (mL/min)a 
TBP-PI-HBr Dosage 
TBP-PI-HBr (300 mg) 
Dummy/Placebo 
>50 
600 mg PO q6h 
two tablets PO q6h (±1 h) 
>30 to ≤50 
300 mg PO q6h 
one tablet PO q6h (±1 h) 
Note: For patients with moderate/severe renal insufficiency who have a Screening/Baseline CrCl near the threshold 
of mild renal insufficiency (i.e., 45-50 mL/min for moderate renal insufficiency) in whom the CrCl is expected to 
increase above the threshold (e.g., >50 mL)/min over the first day of therapy (e.g., after IV fluid hydration), the 
Investigator may choose to administer TBP-PI-HBr dosage of 600 mg while reassessing the need for a dosage 
adjustment based on a subsequent CrCl assessment. 
a As estimated by Cockroft-Gault Formula. 
CrCl, creatinine clearance; h, hour; mL, milliliter; min, minute; PO, orally; TBP-PM-HBr, tebipenem pivoxil 
hydrobromide; q6h, every 6 hours. 
6.2.2. 
Imipenem-cilastatin Dosing in Patients with CrCl ≥90 mL/min 
Patients randomized to receive imipenem-cilastatin with estimated Baseline CrCl ≥90 mL/min 
will receive 500 mg IV over 30 min q6h (±1 h) plus matched dummy TBP-PI-HBr tablets 
administered PO q6h (±1 h). 
Dose adjustment is required for patients with estimated Baseline CrCl <90 mL/min as outlined in 
Section 6.2.2.1. However, for patients who have a Screening/Baseline CrCl near the 90 mL/min 
threshold (i.e., 85-90 mL/min) in whom the CrCl is expected to increase to >90 mL/min over the 
first day of therapy (e.g., after IV fluid hydration), the Investigator may choose to administer 
imipenem-cilastatin 500 mg while reassessing the need for a dosage adjustment based on a 
subsequent CrCl assessment (refer to Section 6.2.1.1 for details). 
6.2.2.1. 
Imipenem-cilastatin Dose Adjustments in Patients with Impaired Renal 
Function (CrCl <90 mL/min) 
Imipenem-cilastatin dosage adjustment is required for patients with CrCl <90 mL/min as 
outlined in Table 4, consistent with the product labeling (Primaxin I.V. USPI, Primaxin I.V. 
SmPC). 

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Table 4: 
Imipenem-cilastatin Dosage Regimen by Estimated Creatinine Clearance 
Category 
CrCl (mL/min)a 
Imipenem-cilastatin dosage 
≥90 
500 mg IV q6h 
≥60 to <90 
400 mg IV q6h 
>30 to <60 
300 mg IV q6h 
Source: Primaxin I.V USPI. 
CrCl, creatinine clearance; h, hour(s); IV, intravenous; min, minute; q6h, every 6 hours. 
6.3. 
Timing of Dose Administration 
Early delivery of antimicrobial therapy is critical to efficacy outcomes, thus the first dose of oral 
and IV study therapy should be administered as soon as possible following randomization on 
Day 1. The oral and IV doses may be administered simultaneously or if consecutive, the oral IP 
should directly precede dosing of IV comparator administration. 
Following the first dose of either IP or comparator, a one-time dose adjustment (of the second 
dose only) is allowed, to align with site-specific medication dosing schedules. Exceptions are 
made in the case of a post-Baseline adjustment in dosing due to change in CrCl (refer to 
Section 6.3.1). The dosing interval adjustment must be such that the next dose of oral IP is 
administered a minimum of 4 h after the preceding dose and a maximum of 8 h (±1 h) after the 
preceding dose, and the next dose of IV comparator (if adjusted) must be administered within 4 h 
of its planned dosing schedule. Additional doses may be adjusted within the protocol-defined 
window of ±1 h per dose. 
As study days are defined as calendar days, every effort should be made to complete 
administration of both IP or comparator doses within the same calendar day (e.g., avoid starting a 
dose of IP/comparator before midnight [00:00] and stopping the dose after midnight). 
6.3.1. 
Monitoring of CrCl during Investigational Product Therapy 
Patients with cUTI/AP are at risk for volume depletion, fluctuating renal function, renal 
insufficiency and/or acute kidney injury; therefore, study patients require frequent monitoring of 
their renal function while on antimicrobial therapy to determine the need for IP/comparator 
dosage adjustment based on a change in renal function category at any time during the treatment 
period from Baseline to last dose of IP/comparator. 
Estimated CrCl should be calculated based on local laboratory assessment of serum creatinine 
according to the frequency outlined below: 
• For patients with Baseline CrCl ≥90 mL/min and presumed stable renal function, serum 
Cr and estimated CrCl should be assessed at least every 3 days and the necessary dosage 
adjustments made as outlined in Table 3 or Table 4 for any decrease in CrCl <90 mL/min. 

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• For patients with CrCl <90 mL/min or patients suspected to have fluctuating renal 
function, serum Cr and estimated CrCl should be assessed at least once daily (QD) from the 
time of first dose until the CrCl stabilizes (i.e., no change CrCl category) over 3 consecutive 
daily measurements in order to determine whether a dosage adjustment as outlined in Table 3 
or Table 4 is necessary. 
• For all patients: If the CrCl changes to a value that falls within 5 mL/min of the threshold 
requiring a change in IP/comparator dosing, the Investigator may choose to implement the 
dosage adjustment or continue to monitor the patient and reassess the need for a dosage 
adjustment based on a subsequent CrCl assessment. 
If a post-Baseline dosage adjustment is determined necessary, the Investigator should inform the 
pharmacist immediately so that the appropriate changes to IP/comparator may be implemented 
within approximately 24 hours when the next doses of IP/comparator are prepared. 
Note: Patients with Baseline CrCl ≤30 mL/min are excluded from the study (refer to Exclusion 
Criterion 5). After randomization, if the estimated CrCl decreases to ≤30 mL/min during the 
treatment period, further dosing of IP/comparator should be suspended and a repeat serum Cr 
measurement and recalculated CrCl performed to verify the need for IP/comparator 
discontinuation. If the repeated CrCl is ≤30 mL/min, IP/comparator should be discontinued. 
6.4. 
Treatment Compliance 
6.4.1. 
Dosing Interruptions, Incomplete Doses, and Missed Doses 
All instances of noncompliance with the pre-specified dosage regimens (refer to Section 6.2.1 
[for TBP-PI-HBr] and Section 6.2.2 [for imipenem]) will be documented as protocol deviations, 
including dosing interruptions (dosing paused or temporarily suspended for any reason), 
incomplete doses, missed doses, or doses administered out of window. 
If planned dosing of oral IP or IV comparator is missed for any reason, the planned dose should 
be administered as quickly as possible at the time of discovery if clinically feasible based on the 
patient’s continued ability to tolerate oral IP and/or IV comparator dosing, with the following 
adjustment to the dosing schedule. 
For missed or delayed oral IP doses: 
• If the dose is administered within 4 h of its intended dosing time, the subsequent doses 
should be administered at the pre-planned q6h intervals as originally scheduled. 
• If the dose is administered after 4 h of its intended dosing time, the remaining doses 
should be administered according to a new q6h regimen starting with the timing of the 
restarted oral IP administration. 
If a patient vomits within 30 min of oral IP dose administration, the oral IP dose should be re-
administered as soon as possible following resolution of nausea and/or administration of 
antiemetics and the subsequent dosing schedule adjusted as noted above. If the patient vomits 
after 30 min of oral IP dose administration, subsequent dose administration should proceed 
according to the original dosing schedule. 

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For missed or delayed IV comparator doses: 
1. If the dose is administered within 4 h of its intended dosing time, the remainder of the 
doses should be administered at the pre-planned q6h intervals (i.e., the previous q6h 
dosage interval should remain as scheduled). 
2. If the dose is administered after 4 h of its intended dosing time, the remainder of the 
doses should be administered in a new q6h regimen starting with the timing of the 
restarted IV comparator administration. 
If dosing of IV comparator is interrupted or incomplete, no adjustment to the dosing schedule is 
required. 
Investigators are encouraged to discuss continued comparator administration options after 
interrupted dosing, incomplete, or missed doses with the Medical Monitor on a case-by-case 
basis. 
6.4.2. 
Treatment Administration 
Oral IP and IV comparator will be administered by qualified facility personnel at the site. The 
date and time of administration of oral IP or IV comparator will be recorded in the CRF along 
with the start and stop time of IV comparator. 
The Investigator or his/her designee (as documented by the Investigator in the applicable study 
delegation of authority form) will administer the IP/comparator only to patients included in this 
study following the procedures set out in the study protocol. Each patient will be given only the 
treatment-assignment IP or comparator. All IP/comparator administrations will be documented 
on the CRFs and/or other IP/comparator record. 
6.4.3. 
Drug Accountability 
Investigators will be provided with sufficient amounts of the IP/comparator to carry out this 
protocol for the agreed number of patients. The Investigator or designee will acknowledge 
receipt of the IP/comparator documenting shipment content and condition. Accurate records of 
all IP/comparator dispensed, used, returned, and/or destroyed must be maintained as detailed 
further in this section. 
Drug accountability must be assessed at the container/packaging level for unused IP/comparator 
that is contained within the original tamper-evident sealed container or at the individual count 
level for opened containers/packaging. The pharmacist/nominated person will record details on 
the drug accountability form. 
No IP/comparator stock or returned inventory from a Spero Therapeutics Inc., sponsored study 
may be removed from the site where originally shipped without prior knowledge and consent by 
the Sponsor. The Sponsor or its representatives must be permitted access to review the supplies 
storage and distribution procedures and records if the blind of the study is not compromised. 
At the end of the study, or as instructed by the Sponsor, all unused stock and empty/used 
IP/comparator packaging are to be sent to a nominated contractor on behalf of the Sponsor. Any 
unused IP/comparator stock being returned to the Sponsor’s designated contractors must be 
counted and verified by clinical site personnel and the Sponsor or designee. For unused supplies 

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where the original supplied tamper-evident feature is verified as intact, the tamper-evident 
feature must not be broken and the labeled amount is to be documented in lieu of counting. All 
certificates of delivery/drug receipts should be signed by the site representative to confirm 
contents of shipment. Shipment return forms, when used, must be signed prior to shipment from 
the site. Validated electronic return systems do not require a shipment form. Returned 
IP/comparator stock must be packed in a tamper-evident manner to ensure product integrity. 
Contact the Sponsor for authorization to return any IP/comparator stock prior to shipment. 
Shipment of all returned IP/comparator stock must comply with local, state, and national laws. 
With the written agreement of the Sponsor, at the end of the study all unused stock and 
empty/used IP/comparator packaging may be destroyed at the site or a local facility. In this case, 
destruction records identifying what was destroyed, when and how must be obtained with copies 
provided to the Sponsor. Destruction of IP/comparators stock must be in accordance with local, 
state, and national laws. 
Based on entries in the site-drug accountability forms, it must be possible to reconcile 
IP/comparator stock delivered with those used and returned. All IP/comparator must be 
accounted for and all discrepancies investigated and documented to the Sponsor’s satisfaction. 
Procedures for return or destruction of both the used and unused IP/comparator stock will be 
described in the drug distribution plan. 
6.5. 
Storage 
TBP-PI-HBr 300 mg film-coated tablets are dispensed in a sealed, light-resistant container. Both 
IP and comparator supplies must be stored as labeled in a secure area with access limited to the 
Investigator and authorized staff. IP and comparator supplies will be stored securely under the 
appropriate conditions detailed in the pharmacy manual and according to local standard 
operating procedures. The Investigator has overall responsibility for ensuring that IP/comparator 
supplies are stored in a secure, limited-access location. Limited responsibility may be delegated 
to the pharmacy or members of the study team, but this delegation must be documented. 
Temperature monitoring is required at the storage location to ensure that the IP/comparator 
supplies are maintained within an established temperature range (refer to the Pharmacy Manual). 
The Investigator is responsible for ensuring that the temperature is monitored throughout the 
duration of the study and that records are maintained. 
The temperature should be either monitored continuously by using an in-house system, a 
mechanical recording device, such as a calibrated chart recorder, or by manual means, such that 
both minimum and maximum thermometric values over a specific period can be recorded and 
retrieved as required. Such a device (e.g., certified min/max thermometer) would require manual 
resetting upon each recording. 
The Sponsor must be notified upon discovery of any excursion from the established range. 
Temperature excursions will require site investigation as to cause and remediation. The Sponsor 
will determine the ultimate impact of any product temperature excursions and will provide 
supportive documentation as necessary. Under no circumstances should any product be 
dispensed to patients until the impact is determined and deemed appropriate for use by the 
Sponsor. 

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6.6. 
Prior and Concomitant Therapy 
Review of medical history during screening or while on study will capture prior and/or 
concomitant receipt of any pharmacologic and/or non-pharmacologic treatments (including over-
the-counter [OTC] treatments such as herbal treatments, vitamins, diet aids, and hormone 
supplements) in addition to medications received within 30 days prior to the data of first dose of 
IP or comparator. 
6.6.1. 
Prohibited Concomitant Medications 
Concomitant administration of non-study, potentially effective, systemic antimicrobial therapy 
that would potentially confound the assessment of treatment outcomes is not allowed (between 
randomization and LFU), except in cases of cUTI/AP study treatment clinical failure.  
Topical antimicrobials and antimicrobials for the treatment of Clostridioides difficile infection 
are permitted. For treatment of new and unexpected infections other than cUTI/AP (i.e., adverse 
events [AEs]), narrow spectrum antimicrobials which are not expected to have potential to treat 
the causative pathogen(s) for cUTI/AP should be selected whenever possible.  
Questions regarding the use of concomitant non-study-specific systemic antimicrobial therapy 
should be directed to the Medical Monitor prior to administration. 
Treatment with any of the following concomitant medications is prohibited between 
randomization and the end of therapy due to potential drug-drug interactions with either IP or 
comparator agent: 
• Valproic acid or divalproex sodium 
• Probenecid 
• Ganciclovir or valganciclovir 
As noted in Section 2.2.3, the potential for drug-drug interactions with TBP-PI-HBr is otherwise 
low. As noted in Inclusion Criterion 3, TBP-PI-HBr may be co-administered with antiemetic 
therapy in order to control nausea and/or vomiting if present at Baseline. 
All instances of noncompliance with prohibited concomitant therapies will be documented as 
protocol deviations. 
6.7. 
Discontinuation of Study Treatment and Patient 
Discontinuation/Withdrawal 
6.7.1. 
Withdrawal from Study 
Patients may withdraw from the study or be withdrawn at the request of the Investigator or 
Sponsor at any time. Examples of reasons for study withdrawal include: 
• the patient withdraws consent or requests withdrawal from the study for any reason 
• the patient is lost to follow-up 
• the patient fails to comply with protocol requirements or study-related procedures 

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• the Investigator determines that it is in the best interest of the patient to withdraw 
from the study protocol, for reasons other than an AE 
• the study is terminated or temporarily suspended by the Sponsor or a Regulatory 
Authority (RA) for any reason, including but not limited to IP-related or comparator-
related unexpected life-threatening SAEs detected during safety monitoring (e.g., 
Torsade des Pointes or other ventricular arrhythmias). 
Patients who wish to withdraw completely from this clinical study during the treatment period 
should be encouraged to undergo EOT safety and efficacy assessments at the time of withdrawal. 
Patients who are withdrawn from the study will not be replaced. 
6.7.2. 
Premature Discontinuation of Study Treatment 
Premature discontinuation of study treatment by the Investigator is an important discussion, 
which should include the Medical Monitor, if feasible, before the IP or comparator is 
discontinued. 
Possible reasons for premature discontinuation from IP or comparator due to safety reasons 
include, but are not limited to, the following: occurrence of an AE that, in the opinion of the 
Investigator, warrants the patient’s permanent discontinuation from study treatment 
administration; Hy’s law criteria are met, defined by at least 3-fold elevations of ALT or AST 
above the ULN, elevation of serum total bilirubin to >2 times ULN without elevated serum 
alkaline phosphatase (ALP), and no other disease or condition can be found to explain the liver 
test abnormalities; or known pregnancy or breastfeeding during the study treatment 
administration period; decline in post-Baseline renal function such that the estimated CrCl falls 
to ≤30 mL/min (refer to Section 6.3.1). 
Patients prematurely discontinued from IP or comparator for any reason and for whom further 
antimicrobial therapy is not required for treatment of the primary infection (e.g., the cUTI/AP 
has resolved completely or improved to the point where no further antimicrobial therapy is 
necessary), may be assessed as a clinical cure. Patients prematurely discontinued from study 
treatment who require further antimicrobial therapy for the cUTI/AP should be assessed as a 
clinical failure. 
Possible reasons for discontinuation from study treatment due to insufficient therapeutic effect 
include, but are not limited to, clinical worsening or lack of clinical progress. If the Investigator 
deems the benefit-to-risk ratio of study treatment continuance acceptable, IP or comparator 
administration of at least 48 h is encouraged before discontinuation from study treatment for 
insufficient effect. 
Refer to the EOT visit procedures (refer to Section 7.1.3) regarding the clinical assessment of 
patients who prematurely discontinue IP. Patients who are prematurely discontinued from IP or 
comparator administration for the reasons other than study consent withdrawal should remain in 
the study and continue to undergo study assessments at every subsequent study visit (e.g., TOC, 
LFU), and should not be withdrawn from study. 

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6.7.3. 
Patients Lost to Follow-up Prior to Last Scheduled Visit 
At least 3 documented attempts must be made to contact any patient lost to follow-up at any time 
point prior to the last scheduled contact (office visit or telephone contact). One of these 
documented attempts must include a written communication sent to the patient’s last known 
address via courier or mail (with an acknowledgement of receipt request) asking that they return 
to the site for final safety evaluations. 

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7. 
STUDY PROCEDURES AND OUTCOME ASSESSMENTS 
7.1. 
Study Visits 
Refer to Schedule of Assessments (SOA; Appendix 2) for details regarding the study visits and 
procedures. 
The duration of study participation for each patient is approximately 28 days. 
7.1.1. 
Screening Visit (Day -1 or 1) 
Day -1 to 1: Screening procedures must be performed within 24 h prior to randomization on Day 
1 to determine study eligibility. 
Standard-of-care (SOC) assessments performed at the site within the Screening period (within 
24 h of randomization) may be used to determine patient eligibility even if performed prior to 
signing the informed consent form (ICF). Other routine clinical assessments may be used to 
determine eligibility if performed prior to informed consent but within the 24-hour Screening 
period. 
Note: bladder catheters that have been in place for >24 h prior to Screening must be removed or 
replaced prior to collection of the screening urine for urinalysis and culture, unless removal or 
replacement is considered unsafe or contraindicated 
Specifically, the following assessments may be used in determining study eligibility if performed 
prior to signing the ICF but within the 24-hour Screening window: 
• medical and surgical history (refer to SOA footnote e) including review of urinary 
tract instrumentation status (refer to SOA footnote q) 
• prior and concomitant medications review 
• complete physical exam (consist of skin, head and neck, heart, lung, abdomen 
(including suprapubic area), extremities, back/flank/costovertebral angle tenderness, 
and neuromuscular assessments) 
• vital signs (including blood pressure [BP], pulse [P], respiratory rate [RR], and 
temperature [T]) (refer to SOA footnote g) 
• cUTI/AP symptoms and signs 
• local serum Cr and calculated CrCl for dose adjustments (refer to SOA footnote j) 
• urine Gram stain and culture collection (Gram stain is optional, but should be done 
when possible, to confirm eligibility); refer to SOA footnote l 
• blood culture collection: 2 sets of blood cultures (each set is 1 aerobic and 
1 anaerobic (if possible) blood culture bottle) from 2 separate venipuncture sites to be 
collected at Screening. Blood cultures should be repeated on the day that a previous 
(e.g., Baseline) blood culture is determined to be positive (e.g., reveals growth of a 
pathogen). Blood cultures should be repeated as necessary until negative blood 
cultures are obtained (refer to SOA footnote m). 

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• Local labs for safety and pregnancy testing (refer to SOA footnote i) 
• Single 12-lead ECG (refer to SOA footnote h) 
Study specific Screening assessments, including blood and urine (for safety) collected for 
analysis by the central laboratory (refer to SOA footnote k), must be performed after signing the 
ICF. 
7.1.2. 
Treatment Visits (Days 1 up to 10) 
Treatment Visits, Day 1 up to Day 10: Patients receive IP (TBP-PI-HBr) or comparator 
(imipenem-cilastatin) and dummy infusions or matched dummy tablets during this treatment 
period. The first treatment with the IP or comparator may occur on the same calendar day as the 
Screening visit or on the next calendar day. Day 1 is the first day of study treatment 
administration. The duration of study treatment will be 7-10 calendar days. 
If the Screening visit and Day 1 occur on the same calendar day, the physical exam, vital signs, 
and assessment of cUTI/AP clinical signs and symptoms do not need to be repeated twice in the 
same calendar day (repeated assessments within the same calendar day are optional). However, 
separate Screening and Day 1 ECGs must be performed per the protocol SOA, as Day 1 ECGs 
are timed from the first dose of study treatment (refer to SOA footnote h). 
Specifically, if Screening visit and Day 1 occur on the same calendar day: 
• complete physical exam at Screening is required, while Day 1 focused physical exam 
is optional (refer to SOA footnote a) 
• vital signs at Screening are required, while repeated Day 1 vital signs are optional. If 
repeated vital signs are collected, record the highest daily temperature in the eCRF 
day (refer to SOA footnote a) 
• assessment of cUTI/AP clinical signs and symptoms at Screening is required, while 
Day 1 assessment of clinical signs and symptoms is optional day (refer to SOA 
footnote a) 
• separate Screening and Day 1 ECGs must be performed. For Screening ECGs, 
perform single 12-lead ECGs for assessment of eligibility. Repeat single 12-lead 
ECGs will be performed on Day 1 and at the EOT visit 1 h (±15 min) after oral IP 
dose administration and as clinically indicated (refer to SOA footnote h). 
For a complete summary of treatment assessments during study Days 1-10, please see the SOA 
(refer to Appendix 2). 
7.1.3. 
End-of-Treatment (EOT) Visit 
The EOT visit will be completed on the last day of study treatment administration, or the 
following day, allowing a one-day window to complete the EOT procedures, or when a patient 
prematurely discontinues treatment (refer to Section 6.7). An exception is the EOT ECG which 
must be performed 1 h [±15 min] after the last dose. The EOT visit and procedures should be 
performed regardless of whether the patient completes the full course of treatment (e.g., 7-10 
days) or discontinues study treatment early. Decision on treatment completion and total 

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treatment duration should be made by the Investigator based on his/ her clinical judgment of the 
clinical status of the patient (e.g., resolution or significant improvement of signs and symptoms 
of cUTI/AP that were present at Baseline such that no further antibacterial treatment is 
warranted). Patients requiring more than 10 days of treatment will be discontinued from either IP 
or comparator treatment. Patients receiving less than 7 days of treatment (i.e., discontinuation 
before the last dose on study Day 7) will be considered early withdrawal or treatment 
discontinuation (refer to Section 6.7.1). The patients should remain in the study for the remaining 
visits unless they have withdrawn consent for study participation. 
7.1.4. 
Test-of-Cure (TOC) Visit (Day 17 ±2 Days) 
The TOC Visit is Day 17 (±2 days) for all patients. A complete summary of TOC visit 
assessments is presented in the SOA (refer to Appendix 2). 
7.1.5. 
Late Follow-Up (LFU) Visit (Day 28 ±2 Days) 
The LFU visit is Day 28 (±2 days) for all patients. A complete summary of LFU visit 
assessments is presented in the SOA (refer to Appendix 2). 
7.1.6. 
Additional Care of Patients after the Study 
No after care is planned for patients in this study. 
7.2. 
Outcome Assessments 
7.2.1. 
Efficacy Assessment and Outcome Definitions 
Efficacy will be evaluated through assessment of post-Baseline clinical outcomes (signs and 
symptoms of cUTI/AP), and post-Baseline microbiological outcomes (based on available urine 
and/or blood culture data) at each study visit (refer to SOA, Appendix 2). 
Overall response (combined clinical cure plus favorable microbiological response) at TOC in the 
micro-ITT Population (primary endpoint); and at EOT, TOC, and LFU visits will be assessed in 
the micro-ITT Population and ME Populations (secondary endpoint) where: 
• Clinical cure is defined as a complete resolution or significant improvement of signs 
and symptoms of cUTI or AP that were present at Baseline and no new symptoms, 
such that no further antibacterial therapy is warranted, and patient is alive 
• Favorable microbiological response (microbiological eradication) is defined as a 
reduction of Baseline uropathogens to <103 CFU/mL and negative repeated blood 
culture if blood culture was positive for uropathogen growth at Baseline and patient is 
alive. 
Patients who require non-study antibacterial therapy for treatment of the index infection prior to 
assessment will be assessed as clinical failure at subsequent visits. 

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physical examinations between Day 1 and EOT are symptom-based assessments. If the 
Screening visit and Day 1 occur on the same calendar day, the focused physical exam on Day 1 
is optional. Standard-of-care (SOC) assessments performed at the site within the Screening 
period (within 24 h of randomization) may be used to determine patient eligibility even if 
performed prior to signing the ICF. 
7.2.3.3. 
Adverse Event Collection 
At each study visit, following first study treatment administration, patients will be questioned in 
a general way to ascertain if AEs have occurred since the previous visit (e.g., “Have you had any 
health problems since your last visit?”). Adverse events will be collected from the time of the 
first dose of study treatment. Assessment and management of AEs is further discussed in 
Section 8. 
7.2.3.4. 
Vital Signs 
Vital sign assessments include blood pressure (BP), pulse (P), respiratory rate (RR), and 
temperature (T). In cases where temperature has been measured multiple times in a single day, 
maximum daily temperature (defined as the maximum temperature reported on a single calendar 
day) will be collected at Screening, daily Day 1 through EOT (prior to daily IV infusions for 
imipenem- cilastatin or placebo-IV treated patients), TOC, and LFU. If the Screening visit and 
Day 1 occur on the same calendar day, repeated vital signs on Day 1 are optional. Standard-of-
care (SOC) assessments performed at the site within the Screening period (within 24 h of 
randomization) may be used to determine patient eligibility even if performed prior to signing 
the ICF. Body temperature may be taken per the site’s preferred method but limited to oral, 
tympanic, rectal, or core measurements. The same method of measuring a patient’s body 
temperature should be used throughout the study. Blood pressure should be determined by cuff 
(using the same method, the same arm, and in the same position throughout the study). Any CS 
deviations from Baseline vital signs, which are deemed CS in the opinion of the Investigator, 
will be recorded as an AE. 
7.2.3.5. 
Clinical Laboratory Evaluations  
The name and address of each clinical laboratory used in this study will be maintained in the 
Investigator files at each site. 
All clinical laboratory assays will be performed according to the laboratory’s normal procedures. 
Reference ranges supplied by the laboratory are used to assess the clinical laboratory data for 
clinical significance and out-of-range pathological changes. The Investigator should assess out-
of-range clinical laboratory values for clinical significance, indicating if the value(s) is/are not 
CS. Abnormal clinical laboratory values, that are unexpected or not explained by the patient’s 
clinical condition may be, at the discretion of the Investigator or Sponsor, explained or resolved 
as soon as possible. 
Laboratory Assessments for Eligibility 
Local/regional laboratory results from blood and urine samples collected at Screening are used to 
determine eligibility (results can be from samples obtained up to 24 h prior to randomization). 

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The SOC assessments performed at the site within the Screening period (within 24 h of 
randomization) may be used to determine patient eligibility even if performed prior to signing 
the ICF. Assessments include serum Cr (for CrCl calculation), ALT, AST, total bilirubin, 
absolute neutrophil count, BUN (or blood urea), and urinalysis with microscopy. 
Central Laboratory Assessments for Safety 
The central safety lab will perform the following evaluations on blood and urine samples on 
Screening, Day1 (if the Screening central laboratory samples are collected on Day 1, the Day 1 
safety laboratory samples do not need to be repeated), Day 3, Day 5, Day 7, Day 9 (if still 
receiving IP or comparator), EOT, TOC, and LFU: 
• hematology (hemoglobin [Hb], hematocrit, red blood cell [RBC] indices) 
• thrombocyte count (platelets) 
• reticulocyte count 
• white blood cell (WBC) count with differential (including neutrophils, eosinophils, 
basophils, lymphocytes and monocytes) 
• coagulation (prothrombin time, international normalized ratio, activated partial 
thromboplastin time) 
• blood chemistry:  
− electrolytes (sodium, potassium, chloride, bicarbonate) 
− non-fasting glucose 
− blood urea nitrogen (BUN) 
− creatinine (Cr) (including calculated CrCl using Cockcroft-Gault formula) 
− l-carnitine 
• creatine kinase 
• urate 
• phosphate 
• total calcium 
• cholesterol 
• albumin 
• total protein 
• total bilirubin 
• conjugated bilirubin 
• gamma-glutamyl transferase 
• alanine aminotransferase (ALT) 

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• aspartate aminotransferase (AST) 
• alkaline phosphatase (ALP) 
• lactate dehydrogenase 
• triglycerides 
• complete urinalysis (pH, specific gravity, protein, glucose, ketones, bilirubin, blood, 
nitrites, urobilinogen and leukocytes). 
Note: Microscopic urinalysis will be performed, if indicated, and to include WBC, RBC, 
epithelial cells, and bacteria testing. 
7.2.3.6. 
Pregnancy Testing 
A urine or serum beta human chorionic gonadotropin (β-HCG) pregnancy test (according to local 
SOC) is performed by the local laboratory on all females of childbearing potential (FOCP) at the 
Screening visit and if pregnancy is suspected at any time. 
In addition, a serum beta human chorionic gonadotropin (β-HCG) pregnancy test is performed by 
the central laboratory on all FOCP at the Screening visit and at the patient’s final visit (LFU visit 
or time of early withdrawal from the study) (refer to SOA, Appendix 2). 
7.2.3.7. 
Electrocardiograms 
At Screening, perform a single 12-lead ECG. Repeat single 12-lead ECGs will be performed on 
Day 1 (after the first dose of oral dose administration) and the EOT visit (after the last dose of 
oral dose administration) 1 h (±15 min) after oral dose administration, and as otherwise clinically 
indicated after oral. 
7.2.4. 
Pharmacokinetics Assessment 
7.2.4.1. 
Blood Sampling for Plasma Pharmacokinetics 
Blood samples will be collected for the measurement of plasma TBP. 
Intensive blood sampling for plasma PK assessment will be performed in a subset of patients (at 
selected sites; approximately 40 patients, 20 per treatment group, 7 samples per patient). This is 
optional for the patient and will require a separate consent. 
Blood samples for intensive PK sampling (7 samples per patient) will be collected following any 
oral dose on Day 2 or Day 3 (fifth, sixth, seventh, or eighth dose) at the following time intervals 
after oral dose administration: at 15 min (±2 min), 30 min (±5 min), 1 h (±5 min), 1.5 h (±5 min), 
2 h (±10 min), 4 h (±10 min), and 6 h (±15 min but prior to the next scheduled dose). 
Sparse PK sampling will be performed for all other patients. Blood samples using sparse 
sampling (3 samples/patient) will be collected following any oral dose on Day 2 or Day 3 (fifth, 
sixth, seventh, or eighth dose) at the following time intervals after oral dose administration of IP: 
1 h (±15 min), 4 h (±0.5 h), and 6 h (±1 h but prior to the next scheduled dose). 

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8. 
ASSESSMENT OF ADVERSE EVENTS 
8.1. 
Adverse Event Definitions 
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical 
investigation participant administered a pharmaceutical product, which does not necessarily have 
to have a causal relationship with the treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational/experimental) product, whether or not 
related to this product. This includes any newly occurring event or previous condition that has 
increased in severity or frequency since starting active or randomized treatment. 
A Serious Adverse Event (SAE) is any AE occurring at any dose and regardless of causality 
that: 
• results in death 
• is life-threatening, (Note: The term ‘life-threatening’ in the definition of ‘serious’ 
refers to an event/reaction in which the participant was at risk of death at the time of 
the event/reaction; it does not refer to an event/reaction which hypothetically might 
have caused death, if it were more severe) 
• requires inpatient hospitalization or prolongation of an existing hospitalization. 
Hospitalization admissions and/or surgical operations scheduled to occur during the 
study period, but planned prior to study entry, are not considered AEs if the illness or 
disease existed before the patient was enrolled in the trial, provided that it did not 
deteriorate in an unexpected manner during the study (e.g., surgery performed earlier 
than planned) 
Note: The prolongation of hospitalization criterion is based on best clinical judgment 
of the PI. For the purposes of this study, duration of intended hospitalization at the 
time of study randomization may be reasonably presumed to be approximately 10 
days, as this is the maximum allowed duration of study treatment. Therefore, cases of 
clinical failure leading to prolongation of hospitalization beyond approximately 10 
days should be evaluated for the potential of meeting SAE criteria. The Medical 
Monitor should be contacted if help is needed in determining reportability of a 
potential SAE. 
• results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions 
• is a congenital anomaly/birth defect 
• is a medically important event or reaction. 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but might jeopardize the participant or might 
require medical or surgical intervention to prevent one of the other outcomes listed in the above 
definition. These should also be considered serious. Examples of such events are intensive 

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treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or drug 
abuse. 
In this study, progression or worsening of the index infection (cUTI/AP) is captured as an 
efficacy outcome (clinical failure) rather than as an AE. However, if clinical failure or 
complications of the index cUTI/AP meets any of the above seriousness criteria, the event must 
be reported as a SAE. Examples include: clinical failure leading to death, prolongation of 
hospitalization, or life-threatening complications (e.g., septic shock). 
Clarification should be made between the terms “serious” and “severe” since the terms are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event (as in mild, moderate, or severe myocardial infarction); the event itself, however, may be 
of relatively minor medical significance (such as a severe headache). This is NOT the same as 
“serious,” which is based on patient/event outcome or action criteria described above and is 
usually associated with events that pose a threat to a patient’s life or functioning. A severe AE 
does not necessarily need to be considered serious. For example, persistent nausea of several 
hours’ duration may be considered severe nausea but not an SAE. On the other hand, a stroke 
resulting in only a minor degree of disability may be considered mild but would be defined as an 
SAE based on the above noted criteria. Seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations. 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is an SAE that is reported as 
related to study treatment and is unexpected. The assessment of the expectedness is done by the 
Sponsor as per applicable regulations. Both expectedness and causality assessment drive the 
decision for the sponsor to report the SUSAR to Health Authorities and other entities. An AE is 
considered "unexpected" if it is not listed in the Reference Safety Information (RSI) section of 
the Investigational Brochure. All SAEs, independently of the expectedness, need to be reported 
by the site to the Sponsor as described in Section 8.6. 
Abnormal Lab findings (e.g., clinical chemistry, hematology, coagulation, and urinalysis) or 
other abnormal assessments (e.g., ECG parameters, vital signs) that are judged by the 
Investigator as clinically significant will be recorded as AEs or SAEs if they meet the definitions 
stated above. CS abnormal laboratory findings or other abnormal assessments that are detected 
during the study or are present at Baseline and significantly worsen following the start of the 
study will be reported as AEs or SAEs. The Investigator will exercise his/her medical and 
scientific judgment in deciding whether an abnormal laboratory finding, or other abnormal 
assessment is CS. 
8.2. 
Evaluating Adverse Events and Serious Adverse Events 
8.2.1. 
Assessment of Intensity and Outcome 
The PI will assess intensity for each AE and SAE reported during the study. The assessment will 
be based on the PI’s clinical judgment using the latest version of the National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE) (Version 5.0) as a guideline, 
wherever possible. The intensity of each AE and SAE recorded in the CRF should be assigned to 
one of the following categories: 

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• Mild: An event that is easily tolerated by the patient, causing minimal discomfort and 
not interfering with everyday activities 
• Moderate: An event that is sufficiently discomforting to interfere with normal 
everyday activities 
• Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe 
• Life-Threatening or Disabling: An event that poses an immediate risk of death from 
the reaction as it occurred 
• Death: The event resulted in death  
The following terms and definitions are used in assessing the final outcome of an AE:  
• Recovered/Resolved: The patient has fully recovered, or by medical or surgical 
treatment, the condition has returned to the level observed at the first trial-related 
activity after the patient signed the informed consent 
• Recovering/Resolving: This term is only applicable if the patient has completed the 
trial or has died from another AE. The condition is improving and the patient is 
expected to recover from the event 
• Recovered/Resolved with sequelae: The patient has recovered from the condition, 
but with lasting effect due to a disease, injury, treatment or procedure; If a sequela 
meets an SAE criterion, the AE must be reported as an SAE 
• Not Recovered/Not Resolved: The condition of the patient has not improved and the 
symptoms are unchanged, or the outcome is not known at the time of reporting 
• Fatal: This term is only applicable if the patient died from a condition related to the 
reported AE. Outcomes of other reported AEs in a patient before he/she died should 
be assessed as “recovered/resolved”, “recovering/resolving”, “recovered/resolved 
with sequelae” or “not recovered/not resolved”. An AE with fatal outcome must be 
reported as an SAE 
• Unknown: This term is only applicable if the patient is lost to follow-up. 
8.2.2. 
Assessment of Causality 
The Investigator is obligated to assess the relationship between the study treatment and each 
occurrence of each AE/SAE. The Investigator will use clinical judgment to determine the 
relationship. Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment, will be 
considered and investigated. The Investigator will also consult the IB and/or Product Information 
for marketed products, in their assessment. For each AE/SAE, the Investigator must document in 
the medical notes that they have reviewed the AE/SAE and provided an assessment of causality. 
 

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There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report. However, it is very important that the Investigator 
always make an assessment of causality for every event before the initial transmission of the 
SAE data. The Investigator may change their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment and 
rationale for the change. The causality assessment is one of the criteria used when determining 
regulatory reporting requirements. The Sponsor will also provide a separate causality assessment 
of the event, in addition to the Investigator's causality. The combination of the Sponsor and 
Investigator causalities will drive the reportability of the AE report to Health Authorities and 
other entities according to the applicable regulations. 
The causal relationship between the study treatment and the AE will be assessed according to the 
following 4-point scale: 
• Unrelated: clearly and incontrovertibly due only to extraneous causes, and does not meet 
criteria listed under unlikely, possible, or probable 
 
• Unlikely: does not follow a reasonable temporal sequence from administration; may have 
been produced by the patient’s clinical state or by environmental factors or other 
therapies administered  
 
• Possible: follows a reasonable temporal sequence from administration; may have been 
produced by the patient’s clinical state or by environmental factors or other therapies 
administered 
 
• Probable: clear temporal association with improvement on cessation of study drug or 
reduction in dose; reappears upon re-challenge or follows a known pattern of response to 
the study drug. 
8.2.3. 
Adverse Events of Special Interest 
Previous studies of TBP-PI-HBr did not identify any specific adverse events of special interest 
(AESI). However, medically important safety topics based on the known class effect for other 
carbapenem antibiotics and/or the β-lactam class (e.g., hypersensitivity, C. difficile infection, 
hematologic disorders representing low blood counts, etc.), or based on safety topics that are 
known to result in severe complications for any drug (e.g., liver disorders and/or drug-induced 
liver injury) will be reviewed. 
Further details regarding the search strategy and analysis of potential AESIs will be outlined in 
the SAP. 
8.3. 
Time Period, Frequency and Method of Detecting AEs 
All AEs, including SAEs, will be collected from the time of first study treatment dosing until the 
LFU visit. As a consistent method of soliciting AEs, the participant shall be asked a non-leading 
question such as: "How do you feel?” 

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Any pre-existing conditions or signs and/or symptoms present in a participant prior to the start of 
the study (e.g., before informed consent) should be recorded as Medical/Surgical History. In 
addition, any change in health status, which is reported after informed consent, is obtained but 
prior to receipt of study treatment will be documented as Medical/Surgical History. 
Any medical occurrence reported or observed after the first dose of study treatment will be 
recorded as an AE. AEs will be evaluated by the PI (or designee) and recorded. 
Any AEs already documented at a previous assessment and designated as ongoing, should be 
reviewed at subsequent assessments as necessary. If these have been resolved, this should be 
documented. 
8.4. 
Adverse Event Management 
The PI (or designee) will provide appropriate medical care for the clinical management of any 
AEs related to study participation, whether identified during or after the course of study 
participation. Evaluation and treatment of any AE (or CS laboratory abnormality) is at the 
discretion of the Investigator based on their clinical judgment. The applied measures should be 
recorded in the patient source documents and entered into the CRF as applicable. Referral or 
collaborative care will be organized if considered necessary by the Investigator. As noted in 
Section 8.7, the Sponsor may request additional supplemental investigations as needed to 
elucidate the nature and/or causality of an SAE. 
SAEs will be reported to competent authorities by the Sponsor (or delegate) in accordance with 
national requirements. 
8.5. 
Recording of AEs and SAEs 
When an AE/SAE occurs, it is the responsibility of the PI (or designee) to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) relative to the 
event. The PI (or designee) will then record all relevant information regarding an AE/SAE in the 
CRF. It is not acceptable for the PI (or designee) to send photocopies of the patient’s medical 
records to the Sponsor in lieu of completion of the appropriate AE/SAE CRF pages. However, 
there may be instances when the Sponsor requests copies of medical records for certain cases. In 
this instance, all patient identifiers will be blinded on the copies of the medical records prior to 
submission to the Sponsor. 
The PI (or designee) will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis should be documented as the 
AE/SAE and not the individual signs/symptoms. 
8.6. 
SAE Reporting 
8.6.1. 
Regulatory Reporting Requirements for Reporting of SAEs  
The PI (or designee) will promptly (within 24 h) report all SAEs to the Sponsor (or delegate). 
Prompt notification of SAEs by the PI (or designee) to the appropriate Sponsor (or delegate) 
contact for SAE receipt is essential so that the Sponsor may comply with its regulatory 
obligations. SAEs will be reported to competent authorities in accordance with national 

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requirements (refer to emergency contact information page at beginning of protocol). For Death 
and Life-Threatening SUSARs, the timelines for the Sponsor to report to the Health Authorities 
are 7 calendar days from receipt of the initial information from the PI and a follow-up within 
8 calendar days. For all other SUSARs, the timeline for the Sponsor to report to Regulatory 
Authorities is 15 calendar days from the receipt of the information from the PI. 
The PI (or designee) is responsible for notifying the local Institutional Review Board (IRB), 
local Independent Ethics Committee (IEC), or the relevant local RA of all SAEs that occur at his 
or her site as required. 
8.6.2. 
Completion and Transmission of the SAE Reports 
Once the PI (or designee) becomes aware that an SAE has occurred in a study patient, he/she will 
report the information to the Sponsor (or delegate) within 24 h. The SAE form (and CRF) will 
always be completed as thoroughly as possible with all available details of the event, signed by 
the PI (or designee), and forwarded to the Sponsor (or delegate) and Medical Monitor within the 
24 h of the SAE identification. If the PI does not have all information regarding an SAE, he/she 
will not wait to receive additional information before notifying the Sponsor (or delegate) and 
Medical Monitor of the event and completing the form. The form will be updated as soon as 
possible when additional information becomes available. 
The PI will always provide an assessment of causality at the time of the initial report. If no 
causality is provided, the Sponsor will handle the AE as related for regulatory reporting purposes 
until clarification is obtained from the PI.  
Facsimile transmission or e-mail of scanned copy of the SAE form is the preferred method to 
transmit this information to the Sponsor (or delegate) and Medical Monitor for SAE receipt. In 
rare circumstances and in the absence of facsimile, computer and scanner equipment, notification 
by telephone is acceptable, with a copy of the SAE form sent by overnight mail. Initial 
notification via the telephone does not replace the need for the PI (or designee) to complete and 
sign the SAE form within the outlined time frames. 
Any event that in the opinion of the PI (or designee) may be of immediate or potential concern 
for the participant’s health or well-being will be reported to the Sponsor Medical Monitor (or 
delegate). 
AEs will be classified as SUSARs if the SAE is assessed as related and meets the definition of 
“unexpected” in Section 8.1. SUSARs should be reported to the Ethics Committees (ECs) and to 
the RAs in accordance with applicable regulatory requirements for expedited reporting. It is the 
Investigator’s responsibility to report SUSARs to the ECs. Sponsor or designee is responsible for 
notifying the relevant RAs (including the authorities in the EEA via EudraVigilance and the 
IRBs/IECs) and the investigative sites within the specified timeframes of all SUSARs, as 
applicable per local requirements. 
8.6.3. 
Post-study AEs and SAEs 
A post-study AE/SAE is defined as any event that occurs outside of the nominal AE/SAE study 
detection period. 

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Investigators are not obligated to actively seek AE/SAE in former study patients. However, if the 
PI (or designee) learns of any SAE, including a death, at any time after a participant has 
completed the study and he/she considers the event reasonably related to the study treatment, the 
Investigator would promptly notify the Sponsor. 
8.7. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the PI (or designee) is required to proactively follow each 
patient and provide further information to the Sponsor on the patient’s condition. SAE 
follow--up should be sent to the Sponsor (or delegate) and Medical Monitor within 24 h using 
the same timelines and process as described in Section 8.6.2. 
All AEs and SAEs documented at a previous visit/contact and are designated as ongoing and will 
be reviewed at subsequent visits/contacts. All AEs must be followed until the patient has 
recovered/resolved and all queries have been resolved, or until deemed medically stable by the 
PI (or designee). For cases of chronic conditions or if the patient dies from another event, follow-
up until the outcome category is “recovered/resolved” is not required, as these cases can be 
closed with an outcome of “recovering/resolving” or “not recovered/not resolved”. 
All patients with SAEs will be followed until they have recovered/resolved, recovered/resolved 
with sequelae or the event was fatal or until all queries have been resolved, or until the 
participant is lost to follow-up. Once resolved, the appropriate SAE CRF page(s) will be 
updated. The Investigator will ensure that follow-up includes any supplemental investigations as 
may be indicated to elucidate the nature and/or causality of the SAE. This may include additional 
laboratory tests or investigations, histopathological examinations, or consultation with other 
health care professionals. 
The Sponsor may request that the PI perform or arrange for the conduct of supplemental 
measurements and/or evaluations to elucidate as fully as possible the nature and/or causality of 
the SAE. If a participant dies during participation in the study or during a recognized follow-up 
period, the Sponsor will be provided with a copy of any post-mortem findings, including 
histopathology. 
New or updated information will be recorded on the originally completed SAE form and the 
CRF, with all changes signed and dated by the PI. The updated SAE form should be sent to the 
Sponsor using the same timelines and process as described in Section 8.6.2. 
8.8. 
Pregnancy 
Any report of pregnancy for any female study patient or male study patient’s partner must be 
reported within 1 business day to the Sponsor using the designated pregnancy form. The female 
study participant must be withdrawn from the study. 
A urine or serum β-HCG pregnancy test (according to local SOC) is performed by the local 
laboratory on all FOCP at the Screening visit and if pregnancy is suspected at any time. 
In addition, a serum β-HCG pregnancy test is performed by the central laboratory on all FOCP at 
the Screening visit and at the patient’s final visit (LFU visit or time of early withdrawal from the 
study) (refer to SOA, Appendix 2). 

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Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the Investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30-calendar days post-partum. 
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported to the Sponsor (or designee) and the Medical Monitor.  
Note: An elective abortion is not considered an SAE. 
In addition to the above, if the Investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE. The test date of the first positive serum/urine β-HCG test or 
ultrasound result will determine the pregnancy onset date. 
8.9. 
Abuse, Misuse, Overdose, and Medication Error 
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the Sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE. Note: The 
one business day reporting requirement for SAEs also applies to reports of abuse, misuse, 
overdose, or medication errors. 
The categories below are not mutually exclusive; the event can meet more than 1 category. 
• Abuse: Persistent or sporadic intentional intake of study treatment when used for a 
non-medical purpose (e.g., to alter one’s state of consciousness or get high) in a 
manner that may be detrimental to the individual and/or society 
• Medication Error: An error made in prescribing, dispensing, administration, and/or 
use of study treatment (For studies, medication errors are reportable to the Sponsor) 
• Misuse: Intentional use of the study treatment other than as directed or indicated at 
any dose (Note: this includes a situation where the study treatment is not used as 
directed at the dose prescribed by the protocol) 
• Overdose: Intentional or unintentional intake of a dose of the study treatment 
exceeding a pre-specified total daily dose of the product as per protocol. 
Cases of patients missing doses of product are not considered reportable as medication errors. 
Minor dosing errors (i.e., within 20% of correct dose), such as failure to change dosing with 
small changes in estimated Creatinine Clearance, should not be reported as medication errors and 
should be captured as protocol deviations. 
Medication errors should be collected/reported for all products under investigation. 
The administration and/or use of the unassigned treatment is always reportable as a medication 
error. The administration and/or use of an expired product should be considered as a reportable 
medication error. 
Infusion errors related to rate of administration, reconstitution and/or dilution of study treatment, 
including use of appropriate diluent and the timeframe in which the study treatment is to be used 
after reconstitution and/or dilution, are reportable as medication errors. 

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Intentional overdosing of the study treatment is unlikely. In the event of overdose in general, 
treatment should be supportive and symptomatic according to the patient's clinical presentation.  
8.10. 
Serious Adverse Event Procedures 
8.10.1. 
Reference Safety Information 
The reference safety information for this study is the IB, which the Sponsor is providing 
separately to all Investigators. 
The reference safety information for the comparator in this study is the imipenem-cilastatin 
SmPC (PRIMAXIN I.V. SmPC)/USPI (PRIMAXIN I.V. USPI), which the Sponsor is providing 
separately to all investigators. 
8.10.2. 
Regulatory Agency, Institutional Review Board, Independent Ethics Committee, 
and Site Reporting 
The Investigator is responsible for notifying the local IRB or local IEC of all SAEs that occur at 
his or her site as required. The Sponsor or delegate is responsible for reporting to the relevant 
local RA as required. 

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9. 
DATA MANAGEMENT 
9.1. 
Data Collection 
The Investigators’ authorized site personnel must enter the information required by the protocol 
on the CRF. Study Monitors (blinded and unblinded) will visit each site in accordance with the 
monitoring plan and review the CRF data against the source data for completeness and accuracy. 
Qualified site personnel will address discrepancies between source data and data entered on the 
CRF. When a data discrepancy warrants correction, authorized site personnel will make the 
correction. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the Investigator’s Meeting. 
9.2. 
Clinical Data Management 
Data are to be entered into a clinical database as specified in the Data Management Plan. Quality 
control and data validation procedures are applied to ensure the validity and accuracy of the 
clinical database. 
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner. 

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10. 
STATISTICAL ANALYSES 
This section outlines the general study design, study endpoints, and statistical analysis strategy 
for the study. If, after the study has begun, changes are made to the primary endpoint of the 
study, the protocol will be amended. If the statistical methods related to those primary 
hypotheses are amended, this will either be documented via a protocol amendment or explicitly 
stated in the Statistical Analysis Plan (SAP). 
All continuous variables will be summarized using number of observations, mean, standard 
deviation, median, minimum, and maximum values. Categorical variables will be summarized 
using the number of observations and percentages for each category. Percentages will be based 
on non-missing data unless otherwise specified. 
Details of the handling of missing data for the primary efficacy endpoint are given in 
Section 10.8.2 all other details of handling missing data will be provided in the SAP. 
Except where indicated in the SAP, Baseline is defined as the most recent value prior to the start 
of treatment with the study treatment. 
All statistical analyses will be performed using SAS® version 9.4 or higher (SAS Institute, Cary, 
NC 27513, USA). The SAP will be finalized prior to unblinding to preserve the integrity of the 
statistical analysis and study conclusions. 
10.1. 
Planned Interim Analysis, Independent Data Monitoring Committee 
One IA is planned to assess both efficacy and futility by the IDMC. The IDMC will meet when 
approximately 60% of patients in the micro-ITT Population have achieved the TOC Visit to 
evaluate the primary endpoint, identify potential treatment benefit, review safety data, and make 
recommendations for continuing or stopping the study, as per the IDMC charter. The IDMC can 
also be convened on an ad hoc basis if the blinded study team identifies a potential safety signal 
and escalates this to the IDMC to review unblinded data for further evaluation. The IDMC 
members will include at least five independent experts, including an infectious disease clinician, 
a chairperson with experience chairing IDMC meetings, a clinical microbiologist, and a 
statistician with infectious disease experience. Details regarding the IDMC process will be 
described in the IDMC charter. 
An independent unblinded statistical team will conduct and provide all unblinded analyses to the 
IDMC before the meeting is held. Details on the content and structure of the data output will be 
described in a separate IDMC analysis plan. Study team members from the Sponsor and CRO 
that are operating the study and conducting the final analysis will remain blinded. The IDMC and 
independent team will maintain unblinded data in a secure area to ensure the integrity of the data 
until the study is completed. Details on protecting blind and data integrity will be described in a 
blinding plan. 
An IA with stopping rules for both efficacy and futility will be performed. The nominal 
significance levels for the interim and final analyses will be determined using Rho family error 
spending boundaries (Jennison 2000). The stopping boundary for assessing efficacy at interim 
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futility bounds of this study are nonbinding and are considered guidance rather than strict 
bounds. 
During IA, if efficacy success (i.e., non-inferiority [NI]) is reached, one-sided p-value for 
response rate difference between the two treatment groups will be calculated using the same 
method to compare against the p-value boundary for superiority. 
During the IA, the accrual of the study will continue. If efficacy success (i.e., NI) is reached at 
the IA and the study is stopped early, the IA will be the primary analysis and data collected 
between the IA data cut and the time when the study is stopped will be considered overrun. 
Overrun data will be pooled with the IA data to repeat the primary efficacy analysis as sensitivity 
analysis. If efficacy success is not reached as assessed by the IDMC at the IA and there are no 
reasons to stop the study early based on safety concern(s) or futility, the study may continue to 
the maximum target sample size for the micro-ITT population of approximately 1588 patients. 
Details for the IA are described in the IDMC charter. 
The Sponsor will review the blinded safety data of this study at regular intervals. Details 
regarding the safety review process will be available in relevant safety review documents. The 
safety review group will inform the IDMC if any safety signals are identified. 
10.2. 
Sample Size Determination 
10.2.1. 
Justification of Sample Size 
Patients will be randomized to TBP-PI-HBr and imipenem-cilastatin in a 1:1 ratio. Assuming a 
60% overall response rate for imipenem-cilastatin and 58% overall response rate for TBP-PI-
HBr, a sample size of approximately 1588 patients in the micro-ITT Population is required, for a 
design with one IA allowing for stopping the study based on efficacy or futility, to provide 89% 
power to demonstrate NI in the overall response rate of TBP-PI-HBr and imipenem-cilastatin 
with a 0.025 one-sided alpha level and a -10.0% NI margin. The minimal response rate 
difference that is estimated to meet the statistical criterion for NI is provided in Table 5. 
Table 5: 
Estimated Minimal Response Rate Difference for Efficacy and Futility 
Interim Analysis 
Design 
Information 
Fraction 
micro-ITT 
Sample Size 
Estimated Minimal Response Rate 
Difference for Non-inferiority 
Analysis for Efficacy and Futility 
60% 
954 
-2.5% 
100% 
1588 
-5.0% 
micro-ITT, microbiological Intent-to-Treat. 
The study is planned to enroll approximately 2648 patients (1324 per treatment group) to ensure 
a sufficient number of patients in the primary analysis population (micro-ITT Population) 
assuming a 60% evaluability rate. The final number of randomized patients may vary based on 
the evaluability rate for the micro-ITT Population. Response rates of 60% and 58% are assumed 
for IV imipenem-cilastatin and oral TBP-PI-HBr, respectively. 

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If the study proceeds after an efficacy and futility IA, the maximum target sample size (assuming 
there is a decision to continue the study at the IA) for the primary analysis population (micro-ITT 
Population) will be around 1588 patients (794 patients per treatment group). 
10.2.2. 
Sample Size Sensitivity 
Sensitivity of the sample size has been explored considering various overall response rates. 
Table 6 and Table 7 display the minimum power under various assumptions of “true” therapeutic 
success rates of TBP-PI-HBr and imipenem-cilastatin under different IA designs, when the IA is 
conducted at approximately 60% information fraction of the design allowing for efficacy and 
futility stop at the IA. For all of these cases, the 1-sided type I error is 0.025, the NI margin 
is -10.0% is used. 
Table 6: 
Power of the Study Under Various Assumptions of the True Therapeutic 
Success Rates for Efficacy and Futility Group Sequential Design 
Therapeutic 
Success Rate of 
Imipenem-
cilastatin  
Therapeutic 
Success Rate of 
TBP-PI-HBr   
Total Number of 
Patients in the 
Primary Analysis  
Number of Patients in the 
Primary Analysis in the 
Interim Analysisa  
Power  
60%  
60%  
1588  
954  
97.8%  
60%  
59%  
1588  
954  
94.6%  
60%  
58%  
1588  
954  
88.6%  
59%  
60%  
1588  
954  
99.2%  
59%  
59%  
1588  
954  
97.7%  
59%  
58%  
1588  
954  
94.5%  
58%  
60%  
1588  
954  
99.7%  
58%  
59%  
1588  
954  
99.2%  
58%  
58%  
1588  
954  
97.7%  
a Number of Patients are rounded up to even numbers. 
 
 

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Table 7: 
Impact of Evaluability Rate on ITT Population 
Therapeutic Success 
Rate of Imipenem-
cilastatin  
Therapeutic 
Success Rate of 
TBP-PI-HBr   
Evaluability Rate  
Total Number of 
Patients in the 
ITT  
Total Number of Patients in 
the micro-ITT  
60%  
58%  
70%  
2270  
1588  
60%  
58%  
60%  
2648  
1588  
60%  
58%  
50%  
3176  
1588  
60%  
58%  
45%  
3530  
1588  
ITT, Intent-to-Treat; micro-ITT, microbiological Intent-to-Treat; TBP-PI-HBr, tebipenem pivoxil hydrobromide. 
10.3. 
Analysis Populations 
Analysis populations are defined below. Please refer to the SAP for additional details. 
Intent-to-Treat (ITT) Population: All patients who were randomized, regardless of whether 
they received any IP or comparator. Patients will be summarized by the treatment to which they 
were randomized. 
Safety Population: Randomized patients who received any amount of IP or comparator. Patients 
will be summarized by the treatment which they received. 
Microbiological Intent-to-Treat (micro-ITT) Population: All randomized patients who have 
all of the following: 
• a baseline urine culture demonstrating ≥105 CFU/mL of an Enterobacterales 
uropathogen (or the same Enterobacterales pathogen is present concurrently in blood 
cultures and in urine) against which imipenem has antibacterial activity 
• no additional pathogens other than an additional Enterobacterales species, E. faecalis, 
S. aureus, or S. saprophyticus are identified in the baseline urine culture at 
≥105 CFU/mL (or the same pathogen is present concurrently in blood cultures and in 
urine). In addition, where E. faecalis, S. aureus, or S. saprophyticus are identified, 
imipenem must have antibacterial activity 
• no more than 2 microorganisms identified in the baseline urine culture, regardless of 
colony count. 
Note: For Enterobacterales, antimicrobial activity for imipenem is defined as Susceptible 
according to CLSI Criteria (MIC ≤1 µg/mL); CLSI 2023. For E. faecalis, antimicrobial 
activity will be presumed where the ampicillin MIC is ≤8 µg/mL. 
For S. aureus, antimicrobial activity will be presumed where the oxacillin MIC is 
≤2 µg/mL. For S. saprophyticus, antimicrobial activity will be presumed where the 
oxacillin MIC is ≤0.5 µg/mL. 
Clinically Evaluable (CE) Population: Patients who meet the definition for the ITT Population, 
have no important protocol deviations that would affect the assessment of efficacy including, but 

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10.6. 
Prior and Concomitant Medication 
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary (WHODRUG/2006QA or newer version). 
Any patient record of prior treatment must be documented on the appropriate Case Report Form 
(CRF) page. Concomitant therapy taken between the dates of the first dose of study treatment 
and the last study visit, inclusive, are to be listed on the appropriate CRF page. 
10.7. 
Investigational Product Exposure  
The number of patients receiving TBP-PI-HBr and imipenem-cilastatin, the planned and total 
doses received, and along with the duration of exposure and compliance, will be summarized by 
treatment groups in the study for all patients in the Safety Population. 
10.8. 
Efficacy Analyses 
10.8.1. 
General Considerations 
Treatment effect to be estimated for primary and secondary estimands are overall response, 
clinical response, and microbiological response at the designated visits in patients included in 
micro-ITT. Intercurrent events (ICE) include receiving other systemic antibacterials and 
treatment discontinuation; a combination of composite strategy and treatment policy strategy will 
be implemented to account for the 2 ICEs, respectively. The ICE event strategies determine that: 
• treatment effects will be estimated regardless of study treatment discontinuation) 
when the analysis population is the ITT Population or its derivatives; and 
• the definition of a successful response or a positive outcome (clinical resolution and 
microbiological eradication) precludes the use of other systemic antibacterials prior to 
the assessment. 
Any supplemental analyses will be detailed in the SAP.  
10.8.2. 
Handling of Missing Data 
Missing data will be treated as failures for efficacy endpoints as defined in Section 7.2.1. 
Detailed handling of missing data for other safety endpoints will be presented in the SAP.  
10.8.3. 
Primary Efficacy Endpoint 
The primary treatment effect to be estimated (estimand) is overall response (combined clinical 
cure plus microbiological eradication, defined below) at the TOC visit in the micro-ITT 
Population. The primary treatment effect will be estimated regardless of treatment 
discontinuation, as per the treatment policy strategy. The ICE of use of non-study potentially 
effective systemic antibacterial therapy for the treatment of the index infection (cUTI/AP) is 
captured through the definitions of microbiological and clinical response and will be counted as 
failures (composite strategy). If a participant experiences both ICEs of study treatment 
discontinuation and use of potentially effective systemic antibacterials, then a composite strategy 

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(assigning overall response as a failure) will be used from the point that the relevant systemic 
antibacterial was taken. Further details on the primary estimand are provided in Section 3.1.1. 
The study is designed to determine whether TBP-PI-HBr, administered PO is non-inferior 
compared to intravenously administered imipenem-cilastatin with respect to the primary efficacy 
endpoint of overall response (defined in Section 3.1) at the TOC Visit in the micro-ITT 
Population. 
For the overall response, patients will be categorized as a responder (clinical cure plus 
microbiological eradication), non-responder (clinical cure only, microbiological eradication only, 
or neither), or indeterminate response (indeterminate clinical response or indeterminate 
microbiological response, or both) at TOC. Patients with missing data at TOC, or who are lost to 
follow-up, will be defined as indeterminate for the primary analysis and will be included in the 
denominator for the calculation of overall response rate. Thus, patients with an indeterminate 
outcome will be considered failures for the primary analysis. The number and percentage of 
patients in each treatment group in each response category at TOC will be reported. 
The null and alternative hypothesis are the following: 
H0: P1−P2≤-Δ  
H1: P1–P2>-Δ 
  Where: 
P1=overall responder (success) rate in the TBP-PI-HBr group, 
P2=overall responder (success) rate in the imipenem-cilastatin group, 
Δ=10% the NI margin 
The population-level effect will be estimated by the difference in percentage response and its 
95% CI. 
The number and percentage of participants with overall success will be summarized, along with 
the 95% CI, at the TOC visit by treatment group. 
At the IA, if the Z statistic (for the primary analysis population [micro-ITT Population]) is higher 
than the Z statistic boundary for NI, the study will be stopped for efficacy and NI will be 
declared. 
At the final analysis (if the study continues at the IA), if the Z statistic (for the primary analysis 
population [micro-ITT Population]) is higher than the Z statistic boundary for NI the study will 
be declared successful and NI will be declared. Refer to Section 7.2.1 for further details on study 
success definition and Section 10.1 for IA recommendation framework. 
If NI is declared between TBP-PI-HBr and imipenem-cilastatin, superiority will be tested in the 
primary analysis population (micro-ITT Population) with the following null and alternative 
hypotheses: 
H0: P1−P2≤0 
H1: P1–P2>0 

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clinical laboratory (hematology, clinical chemistry, and urinalysis) changes, ECGs, and vital sign 
changes. 
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 23.0 
or higher. AEs will be recorded from the first dose of study treatment through LFU. TEAEs are 
defined as events that are newly occurring or worsening from the time of the first dose of study 
treatment through LFU. 
The number of events, incidence, and percentage of TEAEs will be summarized by treatment 
group and overall, and by system organ class and preferred term. TEAEs will also be 
summarized by severity, relationship to study treatment leading to withdrawal, SAEs, and deaths. 
These AEs will also be listed. For all analyses of TEAEs, if the same AE (based on preferred 
term) is reported for the same patient more than once, the AE is counted only once for that 
preferred term and at the highest severity and strongest relationship to study treatment. 
Clinical laboratory tests, vital signs, and ECG findings will be summarized by treatment group 
and overall using descriptive statistics for the actual value at each time point. 
Change from Baseline will be calculated for vital signs and selected clinical laboratory tests 
WBC count, Hgb, liver function tests [AST, ALT, ALP], BUN, serum Cr, and estimated CrCl 
[based on Cockcroft-Gault formula]) at each time point by treatment group. Shift tables of the 
worst on-study laboratory toxicity based on CTCAE v 5.0 grading relative to Baseline will be 
presented by treatment group for these selected clinical laboratory tests. Plots of laboratory 
values versus time for key laboratory parameters may also be provided. 
Abnormal physical examination results will be recorded as part of the medical history (if at 
Screening) or will be captured as AEs (when appropriate on-study); therefore, physical exam 
data will not be summarized in a table. All safety data will also be listed. 
10.10. 
Other Analyses 
10.10.1. 
Pharmacokinetic Analyses 
TBP plasma concentration-time data from TBP-PI-HBr treated (Treatment Group 1) patients will 
be used to characterize the PK of TBP in the target population using PK modeling, to be 
separately reported. Concentration values will be listed by patient and actual time after dose. 
 
 
 
 

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11. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
This study is to be conducted in accordance with the protocol and current applicable RA 
guidelines, International Council for Harmonisation (ICH) E6(R2) Good Clinical Practice (GCP) 
Guidance (FDA 2018a), European Union (EU) Clinical Trials (CT) Regulation 536/2014 
(European Commission 2014) and its updates, and local ethical and legal requirements. 
11.1. 
Sponsor’s Responsibilities 
11.1.1. 
Good Clinical Practice Compliance 
The study start date is the date on which the clinical study will be open for recruitment of 
participants (i.e., when the first site is open). The study Sponsor and any third party to whom 
aspects of the study management or monitoring have been delegated will undertake their 
assigned roles for this study in compliance with all applicable industry regulations and ICH 
E6(R2) GCP Guidance (FDA 2018a) and EU CT Regulation 536/2014 (European Commission 
2014). 
Representatives of the study Sponsor and/or the company organizing/managing the research on 
behalf of the Sponsor to inspect study data, patients’ medical records, and CRFs in accordance 
with current GCP and the respective local and (inter)national government regulations and 
guidelines conduct visits to sites. Records and data may additionally be reviewed by auditors or 
by regulatory authorities. 
The Sponsor ensures that local RA requirements are met before the start of the study. The 
Sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any RA approvals required prior to release of study treatment for 
shipment to the site. 
The sponsor will notify the authorities as applicable (in line with country/region requirements) 
about a serious breach of the regulations or of the version of the protocol applicable at the time 
of the breach. A ‘serious breach’ means a breach likely to affect to a significant degree the safety 
and rights of a participant or the reliability and robustness of the data generated in the CT. 
11.1.2. 
Indemnity/Liability and Insurance 
The Sponsor ensures that suitable clinical study insurance coverage is in place prior to the start 
of the study. An insurance certificate is supplied to the CRO/Investigator as necessary. 
11.1.3. 
Public Posting of Study Information 
The Sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating Investigators’ names 
and contact information. 

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11.1.4. 
Submission of Summary of Clinical Study Report to Regulatory Agencies and 
Independent Ethics Committees 
The Sponsor will provide a Clinical Study Report (or its summary) within one year of the end of 
the study completion date to the agencies, and IECs, as applicable, in line with country 
requirements. 
For the EU countries: irrespective of the outcome of the CT, the Sponsor will submit a summary 
of the intermediate results of the clinical study to the relevant EU clinical study database (the CT 
Information System database at https://euclinicaltrials.eu/home) in a timely manner. As 
appropriate, the final study results posting this will be accompanied by a summary written in a 
manner that is understandable to laypersons. 
11.1.5. 
Study Suspension, Termination, and Completion 
The Sponsor may suspend or terminate the study or part of the study at any time for any reason. 
If the study is suspended or terminated, the Sponsor will ensure that applicable regulatory 
agencies and IRBs/IECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study, which has been posted to a designated public website, will be updated 
accordingly. 
Reasons for terminating the study may include but are not limited to: 
• if efficacy success (NI) is reached at the IA 
• the discovery of an unexpected, significant, or unacceptable risk to the patients 
enrolled in the study 
• failure to enroll patients at an acceptable rate 
• a decision on the part of the Sponsor to suspend or discontinue development of the IP 
• regulatory agency decision. 
Notification of the end of study will be done in accordance with EU CT Regulation 536/2014. 
End of study is the time at which all required data has been collected to answer the research 
question(s) in the protocol. 
11.2. 
Investigator Responsibilities 
11.2.1. 
Good Clinical Practice Compliance 
The Investigator must undertake to perform the study in accordance with ICH GCP Guideline 
E6(R2) (1996), EU CT Regulation 536/2014, and applicable regulatory requirements and 
guidelines. 
It is the Investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
Investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable patients within the agreed recruitment period. 

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The Investigator will maintain a list of appropriately qualified persons to whom the Investigator 
has delegated significant study-related tasks. Curriculum vitae for Investigators and 
sub-Investigators will be provided to the study Sponsor (or designee) before starting the study. 
If a potential research patient has a primary care physician, the Investigator should, with the 
patient’s consent, inform them of the patient’s participation in the study. 
11.2.2. 
Protocol Adherence and Investigator Agreement 
The Investigator and any co-Investigators must adhere to the protocol as detailed in this 
document. The Investigator is responsible for enrolling only those patients who have met 
protocol eligibility criteria. Investigators are required to sign an Investigator Agreement to 
confirm acceptance and willingness to comply with the study protocol. 
If the Investigator suspends or terminates the study at their site, the Investigator will promptly 
inform the Sponsor and the IRB/IEC and provide them with a detailed written explanation. The 
Investigator will also return all drug product, containers, and other study materials to the 
Sponsor. Upon study completion, the Investigator will provide the Sponsor, IRB/IEC, and 
regulatory agency with final reports and summaries as required by national or regional 
regulations. 
Communication with local IRBs/IECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the Sponsor, CRO, Investigator, or for multi-site 
studies, the Coordinating PI according to national provisions and will be documented in the 
Investigator Agreement. 
11.2.3. 
Documentation and Retention of Records 
11.2.3.1. Microbiological Reports 
Microbiological reports will be retained according to applicable laws and regulations. 
11.2.3.2. Case Report Forms 
Electronic Case Report Forms (eCRFs) and CRFs will be handled in accordance with 
instructions from the Sponsor. 
The Investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded to CRFs/eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. The Investigator or designee as 
stated in the site delegation log must complete eCRFs. 
11.2.3.3. Recording, Access, and Retention of Source Data and Study Documents 
Original source data to be reviewed during this study will include, but is not limited to patient’s 
medical file, original clinical laboratory reports, and histology and pathology reports. All key 
data must be recorded in the patient’s medical records. Data reported on the CRF or entered in 
the eCRF that are transcribed from source documents must be consistent with the source 
documents or the discrepancies must be explained. The Investigator may need to request 
previous medical records or transfer records, depending on the study. Also, current medical 

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records must be available. Definition of what constitutes source data can be found in the 
Monitoring Plan. 
Investigators and institutions involved in the CT must permit clinical-trial monitoring and permit 
authorized representatives of the Sponsor, the respective national, local, or foreign regulatory 
authorities, the IRB/IEC, and auditors to inspect facilities and to have direct access to original 
source records relevant to this study, regardless of media. 
The Study Monitor (and auditors, IRB/IEC or regulatory inspectors) may check the CRF entries 
against the source documents. The consent form includes a statement by which the patient agrees 
to the monitor/auditor from the Sponsor or its representatives, national or local regulatory 
authorities, or the IRB/IEC having access to source data (e.g., patient’s medical file, appointment 
books, original laboratory reports, X-rays). 
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (e.g., the US FDA, 
European Medicines Agency [EMA], or an auditor). 
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the Sponsor. 
11.2.3.4. Audit/Inspection 
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local RAs), the EMA, other RAs, the Sponsor or its representatives, and the 
IRB/IEC for each site. 
11.2.3.5. Financial Disclosure 
Upon submission of a marketing application to the FDA for any drug, the Sponsor must provide 
the FDA with a list of clinical Investigators who conducted a sponsored clinical study and certify 
or disclose financial arrangements. 
The Investigator is required to disclose any financial arrangement during the study and for 
one year after, whereby the value of the compensation for conducting the study could be 
influenced by the outcome of the study. The following information is collected: any significant 
payments from the Sponsor or subsidiaries such as a grant to fund ongoing research; 
compensation in the form of equipment; retainer for ongoing consultation or honoraria; any 
proprietary interest in IP; any significant equity interest in the Sponsor or subsidiaries as defined 
in 21 CFR 54 2(b) (1998). 
In consideration of participation in the study, the Sponsor pays the Investigator or nominated 
payee the sums set out in the payment schedule attached to the Investigator Agreement. 

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11.2.4. 
Compliance to all Local, State, and National Infectious Disease Regulations and 
Legislation 
When using substances for infectious diseases, the Investigator must at all times comply with all 
local, state, and national laws pertaining to registration and reporting with the appropriate 
regulatory body and control and handling of such substances. 
11.3. 
Ethical Considerations 
11.3.1. 
Informed Consent 
It is the responsibility of the Investigator to obtain written informed consent from all study 
patients prior to any study-specific procedures including Screening assessments. All consent 
documentation must be in accordance with applicable regulations and GCP. Each patient or the 
patient’s legally-authorized representative is requested to sign the patient Informed Consent 
Form or a translation, after the patient has received and read (or been read) the written patient 
information and received an explanation of what the study involves. This includes, but is not 
limited to the objectives, potential benefits and risk, inconveniences, and the patient’s rights and 
responsibilities. A copy of the informed consent documentation (e.g., a complete set of patient 
information sheets and fully executed signature pages) must be given to the patient or the 
legally-authorized representative of the patient. If applicable, a consent form provided in a 
certified translation of the local language. Signed consent forms must remain in each patient’s 
study file and must be available for verification at any time. 
If patients will be included who are incapable of giving informed consent, a justification for 
including them should be provided. 
The PI will provide the Sponsor with a copy of the consent form, which was reviewed by the 
IRB/IEC and which received their favorable opinion/approval. A copy of the IRB/IEC’s written 
favorable opinion/approval of these documents must be provided to the Sponsor, prior to the start 
of the study unless it is agreed to and documented (abiding by regulatory guidelines and national 
provisions) prior to study start that another party (e.g., Sponsor or Coordinating PI) is 
responsible for this action. Additionally, if the IRB/IEC requires modification of the sample 
patient Information and Consent document provided by the Sponsor, the documentation 
supporting this requirement must be provided to the Sponsor. 
11.3.2. 
Institutional Review Board or Independent Ethics Committee 
For sites in the EU, study sponsor or its delegate will perform submissions to the Member States 
for the study review as defined by the EU CT Regulation 536/2014. 
For sites outside the EU, it is the responsibility of the Investigator to submit this protocol, the 
informed consent document (approved by the Sponsor or their designee), relevant supporting 
information and all types of patient recruitment information to the IRB/IEC for review, and all 
must be approved prior to site initiation. 
Responsibility for coordinating with IRBs/IECs is defined in the Investigator Agreement. 

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Prior to implementing changes in the study, the Sponsor and the IRB/IEC must approve any 
revisions of any revised informed consent documents and amendments to the protocol unless 
there is a patient safety issue. 
Drug product supplies will not be released until the Sponsor/CRO has received written IRB/IEC 
approval of and copies of revised documents. 
For sites outside the EU, the Investigator is responsible for keeping the IRB/IEC apprised of the 
progress of the study and changes made to the protocol, at least once a year. Sites within the EU 
can receive an update by the Sponsor, the Investigator or, for multi-site studies the Coordinating 
PI, according to national provisions. The Investigator must also keep the local IRB/IEC informed 
of any serious and significant AEs. 
11.4. 
Privacy and Confidentiality 
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act of 1996 
(HIPAA). A site that is not a Covered Entity as defined by HIPAA must provide documentation 
of this fact to the CRO/Sponsor. 
The General Data Protection Regulation requires that data is not kept as identifiable personal 
data for longer than is necessary in relation to the purposes for which it is processed. Personal 
data processed solely for research purposes may be stored for longer periods as long as 
appropriate safeguards are in place. All data and remaining samples may be used by the Sponsor 
for 15 years. Use of individual patient data and/or remaining samples may result in patents or 
have other monetary value. These patents or other products resulting from patient 
samples/microorganisms/data will be owned by the Sponsor. There will be no financial benefit 
from future research on patient data and microorganism samples. 
The confidentiality of records that may be able to identify patients will be protected in 
accordance with applicable laws, regulations, and guidelines. 
Measures must be described that will be implemented to ensure confidentiality of records 
containing personal data of patients. In particular, that personnel of the site, sponsor, CRO and 
any vendors involved in data processing by the Sponsor, are bound by obligations of 
confidentiality and the patients will be assigned a unique identifier. Any patient records or 
datasets that are transferred to the Sponsor will contain this unique identifier only; patient names 
or any information which can re-identify the patient will not be transferred. 
The patient must be informed that his/her personal study-related data will be used by the Sponsor 
in accordance with local data protection law. Such information shall be provided as part of the 
ICF or a stand-alone form added to the ICF. The patient must be informed that his/her medical 
records containing identifying personal data will be reviewed by the Sponsor monitors and may 
be examined by Clinical Quality Assurance auditors or other authorized personnel appointed by 
the Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
The contract between Sponsor and study sites specifies the responsibilities of the parties 
regarding data protection, including handling of data security breaches and respective 
communication and cooperation of the parties. The process to handle data security breaches, in 

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order to mitigate the possible adverse effects of such breaches to the privacy of study patients, 
must be described. 
Organizational and technical arrangements that will be implemented to avoid unauthorized 
access, disclosure, dissemination, alteration, or loss of personal data processed must be described 
in study documents. In particular, the information technology systems used to collect, process, 
and store study-related data are secured through the implementation such as technical and 
organizational security measures. 
11.5. 
Publication Policy 
All manuscripts, abstracts, or other modes of presentation arising from the results of the study 
must be reviewed and approved in writing by the Sponsor, in advance of submission. The review 
is aimed at protecting the Sponsor’s proprietary information existing either at the date of the 
commencement of the study or generated during the study. 

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12. 
REFERENCES 
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2019: a systematic analysis. Lancet. 2022 Feb 12;399(10325):629-655. 
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nationwide, cohort study to assess incidence, outcomes, and costs associated with complicated  
urinary tract infection. Open Forum Infect Dis. 2019;6(11):446. 
Clinical and Laboratory Standards Institute (CLSI) (2023). Performance Standards for 
Antimicrobial Susceptibility Testing. 33rd ed. M100-Ed33. Clinical and Laboratory Standards 
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Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16(1):31–41. 
Critchley I, Cotroneo N, Pucci M, Mendes R. The burden of antimicrobial resistance among 
urinary tract isolates of Escherichia coli in the United States in 2017. PLoS One. 2019;14(12). 
Eckburg P, Muir L, Critchley I, Walpole S, Kwak H, Phelan AM, Moore G, et al. Oral 
Tebipenem Pivoxil Hydrobromide in Complicated Urinary Tract Infection. N Engl J Med. 
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European Commission (2014). Clinical trials - Regulation EU No 536/2014. Available from 
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5362014_en. Accessed February 17, 2023. 
FDA Drug Safety Communication: FDA advises restricting fluoroquinolone antibiotic use for 
certain uncomplicated infections; warns about disabling side effects that can occur together. 
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2023. 
Food and Drug Administration Center for Drugs Evaluation and Research (2018a). Guidance for 
Industry: E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1). Available from: 
https://www.fda.gov/media/93884/download. Accessed February 17, 2023. 
Food and Drug Administration Center for Drugs Evaluation and Research (2018b). Guidance for 
Industry: Complicated Urinary Tract Infections: Developing Drugs for Treatment. Available 
from: https://www.fda.gov/files/drugs/published/Complicated-Urinary-Tract-Infections---
Developing-Drugs-for-Treatment.pdf. Accessed February 17, 2023. 
Health Insurance Portability and Accountability Act of 1996 (HIPAA). Available from: 
https://www.cdc.gov/phlp/publications/topic/hipaa.html. Accessed February 17, 2023. 
Jennison C, Turnbull BW. “Group Sequential Methods with Applications to Clinical Trials,” 
Chapman & Hall/CRC, Boca Raton, 2000. 
Kato K, Shirasaka Y, Kuraoka, E Kikuchi A, Iguchi M, Suzuki H,† Shibasaki S, Kurosawa T 
and Tamai I (2010) Intestinal Absorption Mechanism of Tebipenem Pivoxil, a Novel Oral 
Carbapenem: Involvement of Human OATP Family in Apical Membrane Transport. Molecular 
Pharmaceutics. 2010;7(5):1747–1756. 

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Merck & CO., Inc. PRIMAXIN I.V. (Imipenem and Cilastatin for Injection) [package insert]. 
U.S. Food and Drug Administration website. Available from: 
https://www.merck.com/product/usa/pi_circulars/p/primaxin/primaxin_iv_pi.pdf. Revised 
5/2022. Accessed February 17, 2023. 
Merck & CO., Inc. PRIMAXIN I.V. (Imipenem and Cilastatin for Injection) [Summary of 
Product Characteristics]. Electronic Medicines Compendium website. Available from: 
https://www.medicines.org.uk/emc/product/1515. Accessed February 17, 2023. 
Miettinen O, Nurminen M. Comparative Analysis of Two Rates. Statistics in Medicine. 
1985;(4)2:213-226.Muratani T, Doi K, Kobayashi T, Nakamura T, Matsumoto T. Antimicrobial 
activity of tebipenem against various clinical isolates from various specimen, mainly urinary 
tract. Jpn J Antibiot. 2009 Apr;62(2):116-26. 
Patient CDC 2019. Antibiotic Resistance Threats in the Unites States. Available from: 
https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf. Accessed 
February 17, 2023. 
Talan DA, Takhar SS, Krishnadasan A, Mower WR, Pallin DJ, Garg M, et al. Emergence of 
extended‑spectrum β‑lactamase urinary tract infections among hospitalized emergency 
department patients in the United States. Ann Emerg Med. 2021;77(1):32-43. 
Vardakas KZ, Kalimeris GD, Triarides NA, Falagas ME. An update on adverse drug reactions 
related to β-lactam antibiotics. Expert Opin Drug Saf. 2018;17(5):499-508. 
Zilberberg MD, Nathanson BH, Sulham K, Shorr AF. Multiple antimicrobial resistance and 
outcomes among hospitalized patients with complicated urinary tract infections in the US, 
2013‑2018: a retrospective cohort study. BMC Infect Dis. 2021;21(1):159. 

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APPENDIX 1. SECONDARY ESTIMANDS TABLE 
Secondary 
Endpoint 
Population(s) Treatment Condition 
Variable 
Summary Measure 
Intercurrent 
Eventa 
Overall response 
at TOC among 
cUTI/AP patients 
infected with 
Enterobacterales 
uropathogens at 
Baseline  
micro-ITT 
 
TBP-PI-HBr 600 mg 
every 6 hours daily 
compared with 
imipenem-cilastatin 500 
mg every 6 hours daily 
for 7-10 days 
Overall 
response 
Difference in the overall 
response rate in the 
TBP- PI-HBr and 
imipenem-cilastatin 
treatment groups in the 
designated subset 
Study treatment 
discontinuation 
(due to any 
reason) – 
treatment 
policy 
Use of 
systemic 
antibacterials– 
composite 
strategy 
Overall response 
(combined clinical 
cure plus 
microbiological 
eradication) at 
TOC  
ME 
 
TBP-PI-HBr 600 mg 
every 6 hours daily 
compared with 
imipenem-cilastatin 500 
mg every 6 hours daily 
for 7-10 days 
Overall 
response 
 
Difference in the overall 
response rate in the 
TBP- PI-HBr and 
imipenem-cilastatin 
treatment groups 
Study treatment 
discontinuation 
(due to any 
reason) – 
treatment 
policy 
Use of 
systemic 
antibacterials – 
composite 
strategy 
Overall response 
(combined clinical 
cure plus 
microbiological 
eradication) as 
defined at the 
EOT, TOC and 
LFU  
micro-ITT  
TBP-PI-HBr 600 mg 
every 6 hours daily 
compared with 
imipenem-cilastatin 500 
mg every 6 hours daily 
for 7-10 days 
Overall 
response 
 
Difference in the overall 
response rate in the 
TBP- PI-HBr and 
imipenem-cilastatin 
treatment groups 
Study treatment 
discontinuation 
(due to any 
reason) – 
treatment 
policy 
Use of 
systemic 
antibacterials – 
composite 
strategy 
Overall response 
(combined clinical 
cure plus 
microbiological 
eradication) as 
defined at the 
EOT, TOC and 
LFU 
ME 
TBP-PI-HBr 600 mg 
every 6 hours daily 
compared with 
imipenem-cilastatin 500 
mg every 6 hours daily 
for 7-10 days 
Overall 
response 
 
Difference in the overall 
response rate in the 
TBP- PI-HBr and 
imipenem-cilastatin 
treatment groups 
Study treatment 
discontinuation 
(due to any 
reason) – 
treatment 
policy 
Use of 
systemic 
antibacterials – 
composite 
strategy 

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Protocol No: SPR994-305 
 
Amendment 3, V4.1 
Protocol Name: PIVOT-PO 
 
CONFIDENTIAL 
Page 102 of 107 
Secondary 
Endpoint 
Population(s) Treatment Condition 
Variable 
Summary Measure 
Intercurrent 
Eventa 
Clinical response 
at EOT, TOC, and 
LFU 
micro-ITT 
TBP-PI-HBr 600 mg 
every 6 hours daily 
compared with 
imipenem-cilastatin 500 
mg every 6 hours daily 
for 7-10 days 
Clinical 
response 
Difference in the clinical 
response rate in the 
TBP- PI-HBr and 
imipenem-cilastatin 
treatment groups 
Study treatment 
discontinuation 
(due to any 
reason) – 
treatment 
policy 
Use of 
systemic 
antibacterials – 
composite 
strategy 
Clinical response 
at EOT, TOC, and 
LFU 
CE 
TBP-PI-HBr 600 mg 
every 6 hours daily 
compared with 
imipenem-cilastatin 500 
mg every 6 hours daily 
for 7-10 days 
Clinical 
response 
Difference in the clinical 
response rate in the 
TBP- PI-HBr and 
imipenem-cilastatin 
treatment groups 
Study treatment 
discontinuation 
(due to any 
reason) – 
treatment 
policy 
Use of 
systemic 
antibacterials – 
composite 
strategy 
Per-patient and 
by-pathogen 
microbiological 
response rates at 
EOT, TOC, and 
LFU 
micro-ITT 
TBP-PI-HBr 600 mg 
every 6 hours daily 
compared with 
imipenem-cilastatin 500 
mg every 6 hours daily 
for 7-10 days 
Per-patient 
microbiologic 
outcome and 
by-pathogen 
microbiologic 
outcome 
Difference in the 
microbiological success rate 
in the TBP-PI-HBr and 
imipenem-cilastatin 
treatment groups 
Study treatment 
discontinuation 
(due to any 
reason) – 
treatment 
policy 
Use of 
systemic 
antibacterials –
composite 
strategy 
Per-patient and 
by-pathogen 
microbiological 
response rates at 
EOT, TOC, and 
LFU 
micro-ITT 
TBP-PI-HBr 600 mg 
every 6 hours daily 
compared with 
imipenem-cilastatin 500 
mg every 6 hours daily 
for 7-10 days 
Per-patient 
microbiologic 
outcome and 
by-pathogen 
microbiologic 
outcome 
Difference in the 
microbiological success rate 
in the TBP-PI-HBr and 
imipenem-cilastatin 
treatment groups 
Study treatment 
discontinuation 
(due to any 
reason) – 
treatment 
policy 
Use of 
systemic 
antibacterials –
composite 
strategy 

Spero Therapeutics, Inc. 
 
26Aug2024 
Protocol No: SPR994-305 
 
Amendment 3, V4.1 
Protocol Name: PIVOT-PO 
 
CONFIDENTIAL 
Page 103 of 107 
Secondary 
Endpoint 
Population(s) Treatment Condition 
Variable 
Summary Measure 
Intercurrent 
Eventa 
Per-patient and 
by-pathogen 
microbiological 
response rates at 
EOT, TOC, and 
LFU  
ME 
TBP-PI-HBr 600 mg 
every 6 hours daily 
compared with 
imipenem-cilastatin 500 
mg every 6 hours daily 
for 7-10 days 
Per-patient 
microbiologic 
outcome and 
by-pathogen 
microbiologic 
outcome 
Difference in the 
microbiological success rate 
in the TBP-PI-HBr and 
imipenem-cilastatin 
treatment groups 
Study treatment 
discontinuation 
(due to any 
reason) – 
treatment 
policy 
Use of 
systemic 
antibacterials –
composite 
strategy 
Overall, clinical 
and 
microbiological 
response rates at 
EOT, TOC and 
LFU among 
patients infected 
with drug-resistant 
Enterobacterales 
uropathogens e.g., 
extended spectrum 
β-lactamase 
(ESBL)-
producing, 
fluoroquinolone-
nonsusceptible 
(FQ-NS), and/or 
trimethoprim-
sulfamethoxazole-
resistant 
(TMP/SMX-R) 
strains 
micro-ITT 
TBP-PI-HBr 600 mg 
every 6 hours daily 
compared with 
imipenem-cilastatin 500 
mg every 6 hours daily 
for 7-10 days 
Overall, 
clinical and 
microbiologic 
response 
Difference in the overall, 
clinical and microbiological 
response rates in the TBP-
PI-HBr and imipenem-
cilastatin treatment groups 
in the designated subset 
Study treatment 
discontinuation 
(due to any 
reason) – 
treatment 
policy 
Use of 
systemic 
antibacterials – 
composite 
strategy 
Safety 
Safety 
Population 
TBP-PI-HBr 600 mg 
every 6 hours daily 
compared with 
imipenem-cilastatin 500 
mg every 6 hours daily 
for 7-10 days 
TEAEs, 
SAEs, as well 
as change 
from Baseline 
results for 
clinical 
laboratory 
tests, ECGs, 
and vital 
sign 
measurements
Summary statistics 
(appropriate for each type of 
endpoint) in the TBP- PI-
HBr and imipenem-
cilastatin treatment groups 
separately 
Study treatment 
discontinuation 
(due to any 
reason) – 
treatment 
policy 
 
Use of 
systemic 
antibacterials – 
treatment 
policy 

Spero Therapeutics, Inc. 
 
26Aug2024 
Protocol No: SPR994-305 
 
Amendment 3, V4.1 
Protocol Name: PIVOT-PO 
 
CONFIDENTIAL 
Page 104 of 107 
Secondary 
Endpoint 
Population(s) Treatment Condition 
Variable 
Summary Measure 
Intercurrent 
Eventa 
TBP concentration 
data 
PK 
Population 
TBP-PI-HBr 600 mg 
every 6 hours daily for 
7-10 days 
TBP plasma 
concentration 
Summary statistics 
Study treatment 
discontinuation 
(due to any 
reason) – while 
on treatment 
strategy 
a For each of the secondary endpoints the estimand will follow a similar approach to the estimand for the primary 
endpoint and will use the same general strategies for the ICEs, with necessary adaptations for the ME and CE 
Population definitions. 
CE, clinically evaluable; cUTI, complicated urinary tract infection; ECG, electrocardiogram; EOT, End-of-Treatment; 
ICE, intercurrent event; LFU, Late Follow-up; MIC, minimum inhibitory concentration; ME microbiologically evaluable; 
micro-ITT, Microbiological Intent-to-Treat; PK, Pharmacokinetic; SAE, serious adverse event; TBP, tebipenem; TBP-
PI-HBr, tebipenem pivoxil hydrobromide; TEAE, treatment-emergent adverse event; TOC, Test-of-Cure. 
.

Spero Therapeutics, Inc. 
 
26Aug2024 
Protocol No: SPR994-305 
 
Amendment 3, V4.1 
Protocol Name: PIVOT-PO 
 
CONFIDENTIAL 
Page 105 of 107 
APPENDIX 2. SCHEDULE OF ASSESSMENTS 
Study Period 
Screening/ 
Baseline 
Treatment 
Follow-Up 
Visit or Study Day 
-1 or 1 
Days 1 through 10 
17 ±2 
Days 
28 ±2 
Days 
Study Day 
Screening a 
1 (Post-
Rand.) 
2 – 10 
EOT b 
TOC c 
LFU d 
Informed Consent 
X 
 
 
 
 
 
Medical & Surgical History e 
X 
 
 
 
 
 
Height and Weight  
X 
 
 
 
 
 
Physical Examination f 
C 
F 
F 
C 
C 
C 
Vital Signs (T, P, RR, BP) g 
X 
X 
X 
X 
X 
X 
Collection of cUTI/ AP Signs and 
Symptoms 
X 
X 
X 
X 
X 
X 
12-Lead ECG h 
X 
X 
 
X 
 
 
Local Labs for Eligibility (Safety and 
Pregnancy Testing) i 
X 
 
 
 
 
 
Local Serum Creatinine to Assess Renal 
Function for Dose Adjustments j 
X 
X 
X 
 
 
 
Central Labs (Blood/Urine for Safety) k 
X 
X 
X 
X 
X 
X 
Blood Cultures m 
X 
<--------------------------------X--------------------------> 
Study Treatment Administration n 
 
X 
X 
 
 
 
Blood Sample for Plasma PK o 
 
 
X 
 
 
 
Investigator Assessment of Clinical 
Outcome 
 
 
 
X 
X 
X 
Prior and Concomitant Therapy 
X 
X 
X 
X 
X 
X 
Adverse Events r 
 
X 
X 
X 
X 
X 
a. Screening procedures must be completed within 24 h prior to randomization on Day 1. Screening laboratory 
assessments for eligibility will be performed at the local/regional laboratory. Standard-of-care assessments performed 
at the site within the Screening period (within 24 h of randomization) may be used to determine patient eligibility even 
if performed prior to signing the ICF; however, study-specific assessments such as ECGs, blood cultures (if using a 
study-specific regional laboratory), and Screening safety labs collected for analysis by the central laboratory, must be 
performed after signing the ICF (refer to Section 7.1.1 for details). If Screening visit and Day 1 occur on the same 
calendar day: complete physical exam at Screening is required, while Day 1 focused physical exam is optional; vital 
signs at Screening are required, while repeated Day 1 vital signs are optional (if repeated vital signs are collected, 
record the highest daily temperature in the eCRF); assessment of cUTI/AP clinical signs and symptoms at Screening is 
required, while Day 1 assessment of clinical signs and symptoms is optional; and separate Screening and Day 1 ECGs 
must be performed (i.e., Day 1 single ECG must be performed 1 h [±15 min] after the first oral dose administration) 
(refer to Section 7.1.2 for details). 
b. Study treatment administration is 7-10 calendar days for all patients. The EOT visit occurs on the calendar day or the 
day following (+1 day) the last dose of study treatment. All EOT procedures may be performed the day following last 
dose of study treatment with the exception of the EOT ECGs, which must be performed 1 hour (±15 min) after the last 
dose rather than the following day. Lab assessments that are required on the day of last dose and EOT do not need to 

Spero Therapeutics, Inc. 
 
26Aug2024 
Protocol No: SPR994-305 
 
Amendment 3, V4.1 
Protocol Name: PIVOT-PO 
 
CONFIDENTIAL 
Page 107 of 107 
o. Blood samples using sparse sampling (3 samples/patient) will be collected following any oral dose on Day 2 or Day 3 
(fifth, sixth, seventh, or eighth dose) at the following time intervals after oral administration of IP: 1 h (±15 min), 4 h 
(±0.5 h), and 6 h (±1 h but prior to the next scheduled dose). Blood samples for intensive PK sampling (7 samples per 
patient) will be collected following oral dosing on Day 2 or Day 3 (fifth, sixth, seventh, or eighth dose) at the time 
intervals after oral administration of IP: at 15 min (±2 min), 30 min (±5 min), 1 h (±5 min), 1.5 h (±5 min), 2 h (±10 
min), 4 h (±10 min), and 6 h (±15 min but prior to the next scheduled dose). The exact dose time and the exact PK 
sample time should be collected for all patients when collecting PK samples. Intensive PK assessment is optional, 
patients will need to sign a separate consent. 
r. AEs will be collected from the time of the first dose of study treatment. 
 
ALT, alanine transaminase; AP, acute pyelonephritis; AST, aspartate aminotransferase; β-HCG, beta human chorionic 
gonadotropin; BP, blood pressure; C, complete; CFU, colony forming unit; CrCl, creatinine clearance; cUTI, complicated 
urinary tract infection; ECG, electrocardiogram; eCRF, electronic case report form; EOT, End-of-Treatment; F, focused; 
FOCP, females of childbearing potential; GS, Gram stain; h, hour(s); ICF, informed consent form; IP, investigational 
product; IV, intravenous(ly); LE, leukocyte esterase; LFU, Late Follow-up; min, minute(s); P, pulse; PK, 
pharmacokinetic; q6h; every 6 hours; PO, orally; Rand, randomization; RR, respiratory rate; T, temperature; TBP, 
tebipenem; TOC, Test-of-Cure; UC, urine culture; WBC, white blood cells.