Clinical trial NCT03788967
Conditions: Complicated Urinary Tract Infection Acute Pyelonephritis
Keywords: Complicated Urinary Tract Infection Acute Pyelonephritis
Sponsor: Spero Therapeutics
Start date: 2019-06-03; Completion date: 2020-05-27
Enrollment: 1372 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The key purpose of this study is to evaluate the efficacy, safety and pharmacokinetics (PK) of tebipenem pivoxil hydrobromide (TBPM-PI-HBr) compared to intravenous (IV) ertapenem, in participants with complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP).

Detailed description:

Arms: arm 1: TBPM-PI-HBr 600 mg (300 mg×2 ) film-coated tablets, administered orally three times per day (every 8 hours \[q8h\] ± 0.5 h) plus a single dummy IV infusion over 30 minutes (min) once daily (every 24 hours \[q24h\] ± 0.5 h) up to Day 15; participants with moderate renal insufficiency (creatinine clearance \[CrCl\] \>30 to ≤50 mL/min) required TBPM-PI-HBr dosage adjustment to 300 mg (one tablet) q8h ± 0.5 h. arm 2: Ertapenem for IV injection, administered as a 1-gram IV infusion over 30 min once daily (q24h ± 0.5 h) plus dummy placebo tablets administered orally q8h (±0.5 h) up to Day 14; no dose adjustment of ertapenem was required for participants with renal insufficiency.
Interventions: intervention 1: TBPM-PI-HBr intervention 2: Ertapenem intervention 3: Dummy Infusion intervention 4: Dummy tablets
Intervention descriptions: intervention 1: TBPM-PI-HBr tablets administered orally. intervention 2: Antibiotic Therapy for cUTI. intervention 3: Dummy intravenous infusion. intervention 4: Dummy tablets orally.

Protocol documents:
Prot_000.pdf: 
Official Title: 
A Phase 3, Randomized, Double-blind, Double-dummy, Multicenter, 
Prospective Study to Assess the Efficacy, Safety and Pharmacokinetics 
of Orally Administered Tebipenem Pivoxil Hydrobromide (SPR994) 
Compared to Intravenous Ertapenem in Patients with Complicated Urinary 
Tract Infection (cUTI) or Acute Pyelonephritis (AP) 
NCT Number: 
NCT03788967 
Document Date: 
Protocol Version 4.0: 26 May 2020 


 
PROTOCOL 
TITLE: 
A Phase 3, Randomized, Double-blind, Double-dummy, Multicenter, 
Prospective Study to Assess the Efficacy, Safety and Pharmacokinetics 
of Orally Administered Tebipenem Pivoxil Hydrobromide (SPR994) 
Compared to Intravenous Ertapenem in Patients with Complicated 
Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP)  
PROTOCOL 
NAME: 
ADAPT-PO 
PROTOCOL 
NUMBER: 
SPR994-301 
DRUG: 
Tebipenem Pivoxil Hydrobromide 300 mg film-coated tablet (also known 
as SPR994) and Ertapenem (comparator) 
IND: 
132744 
EUDRACT NO.: 
2018-003671-35 
SPONSOR: 
Spero Therapeutics, Inc. 
675 Massachusetts Avenue 
14th Floor 
Cambridge, MA 02139 
https://sperotherapeutics.com/ 
PROTOCOL 
VERSION AND 
DATE: 
Version 4.0, 26 MAY 2020  
 
GCP Statement: This study will be conducted in compliance with Good Clinical Practice 
(GCP) guidelines 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: This report is the property of Spero Therapeutics, Inc. and may 
not in full or in part be passed on, reproduced, published or otherwise used without the 
express written permission of Spero Therapeutics, Inc. 




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Protocol No: SPR994-301 
 
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Protocol Name: ADAPT-PO                                                                         
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INVESTIGATORS ACKNOWLEDGEMENT 
I have read the ADAPT-PO protocol, numbered SPR994-301, A Phase 3, Randomized, 
Double-blind, Double-dummy, Multicenter, Prospective Study to Assess the Efficacy, Safety 
and Pharmacokinetics of Orally Administered Tebipenem Pivoxil Hydrobromide (SPR994) 
Compared to Intravenous Ertapenem 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 subject 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 Conference on Harmonisation guidelines on Good Clinical 
Practice and with the applicable regulatory 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 Name:  
Site Name:  
Site Number: 
 
 
 
Signature: 
 
   Date:  
 
 
 
 
 
 
 
 
 
       DD-MMM-YYYY 




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Protocol Name: ADAPT-PO                                                                         
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PRODUCT QUALITY COMPLAINTS 
Investigators are required to report investigational product quality complaints to Spero 
Therapeutics, Inc. 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 use the information below as applicable to report the Product Quality Complaint: 
Origin of Product Quality Complaint 
E-mail Address 
North and South America 
 
European Union (EU) and Rest of World 
 
  
 


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Protocol Name: ADAPT-PO                                                                         
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STUDY SYNOPSIS 
Protocol number: 
SPR994-301                           
Investigational Product (IP): Tebipenem pivoxil 
hydrobromide 300 mg film-coated tablet (also known as 
SPR994) and Ertapenem (Comparator) 
Protocol Title: A Phase 3, Randomized, Double-blind, Double-dummy, Multicenter, 
Prospective Study to Assess the Efficacy, Safety and Pharmacokinetics of Orally 
Administered Tebipenem Pivoxil Hydrobromide (SPR994) Compared to Intravenous 
Ertapenem in Patients with Complicated Urinary Tract Infection (cUTI) or Acute 
Pyelonephritis (AP)  
Indication: cUTI including AP  
Number of Subjects (total and for each treatment arm): 
A total of approximately 1,200 subjects, up to a maximum of 1,450 (contingent on a 
sufficient number of evaluable subjects): 
 
• Tebipenem Pivoxil Hydrobromide (TBPM-PI-HBr) = approximately 600 subjects 
• Ertapenem = approximately 600 subjects 
 
Site(s): Approximately 95 sites in Central and Eastern Europe, South Africa and the United 
States 
Study Period (planned): ~Q1 (FPI) 2019 – Q3 (LPO) 2020 
 
Objectives:  
 Primary:   
• 
To assess the overall response (combined clinical cure plus microbiological 
eradication) of oral TBPM-PI-HBr compared to intravenous (IV) ertapenem in 
subjects ≥18 years of age with cUTI/AP 
• 
To assess the safety of oral TBPM-PI-HBr compared to IV ertapenem in subjects 
≥18 years of age with cUTI/AP 
Secondary:  
• 
To compare clinical cure rates between treatment groups 
• 
To compare microbiological eradication rates between treatment groups 
• 
To assess the population pharmacokinetics (PK) of TBPM-PI-HBr in subjects with 
cUTI/AP; the dosage of TBPM-PI-HBr will be confirmed based off a blinded 
analysis of PK data from the first approximately 35 enrolled TBPM-PI-HBr subjects 
Exploratory:  
• 
To determine whether treatment with TBPM-PI-HBr or ertapenem is associated 
with enteric colonization with antibiotic-resistant Enterobacteriaceae 


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Protocol Name: ADAPT-PO                                                                         
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• 
To compare microbiological eradication rates and clinical improvement at Day 5 
between treatment groups 
• 
To assess clinical, microbiological, and overall responses in subjects with cUTI/AP 
caused by ESBL-producing Enterobacteriaceae 
Rationale: 
The key purpose of this study is to evaluate the efficacy, safety and PK of TBPM-PI-HBr 
compared to IV ertapenem, in subjects with cUTI/AP.  
Rationale for Comparator:  
Ertapenem was chosen as the comparator for this study because it is approved for the 
treatment of cUTI/AP in many countries, and is considered an empiric standard-of-care 
treatment option. Ertapenem has bactericidal activity against primary pathogens that cause 
cUTI/AP, including extended spectrum β-lactamase (ESBL)-producing 
Enterobacteriaceae. Ertapenem is associated with high urinary concentrations, has a 
similar in vitro spectrum of activity, and is in the same antibiotic class (carbapenem) as 
TBPM-PI-HBr. 
Investigational Product, Dose, and Mode of Administration: 
• TBPM-PI-HBr 300 mg film-coated tablets, administered orally 600 mg (2 tablets) three 
times per day (q8h ±0.5 h) plus a single dummy IV infusion over 30 minutes (min) once 
daily (q24h ± 0.5h); subjects with moderate renal insufficiency (creatinine clearance 
[CrCl] >30 to ≤50 mL/min) require TBPM-PI-HBr dosage adjustment to 300 mg (1 
tablet) q8h ± 0.5 h 
• Ertapenem for IV injection, administered as a 1-gram IV infusion over 30 min once 
daily (q24h ± 0.5h) plus dummy placebo tablets administered orally q8h (±0.5 h) 
• Dummy: Normal saline (0.9% sodium chloride) for IV infusion or placebo tablets 
Methodology: 
This is a Phase 3, randomized, double-blind, double-dummy, multicenter, multinational, 
prospective study to assess the efficacy, safety and PK of TBPM-PI-HBr administered 
orally compared to subjects receiving ertapenem administered IV for cUTI/AP.  
This study will enroll approximately 1,200 subjects. All subjects will present with a clinical 
diagnosis of cUTI/AP sufficient to start empiric antibiotics and be able to tolerate oral 
medication. A dummy infusion of normal saline and dummy placebo tablets will be used to 
maintain the blind. 
Subjects will be randomized (enrolled) to one of two treatment arms at a 1:1 ratio receiving 
(i) TBPM-PI-HBr or (ii) ertapenem. Randomization will be stratified by: 
• Baseline diagnosis (AP vs. cUTI) 
• Age at informed consent (≥18 to <65 years vs. ≥65 years) 
Subjects who meet the disease definition of cUTI (e.g., underlying functional or anatomical 
urinary tract abnormality) and have additional clinical evidence of AP (e.g., flank pain or 


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Protocol Name: ADAPT-PO                                                                         
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costovertebral angle tenderness) should be randomized as cUTI. At least 30% of subjects 
will be randomized with a diagnosis of AP at study entry.  
A blinded assessment of evaluability rates and response rates will be performed when 70% 
of the subjects have response data at Test-of-Cure (TOC) available and will be performed 
by the blinded Sponsor Data Review Committee. If assumptions are very different from 
those expected, the sample size may be increased to a maximum of 1,450 subjects. 
Inclusion and Exclusion Criteria: 
Inclusion Criteria: 
1. Male and female subjects at least 18 years of age 
2. Able to provide informed consent 
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, in order to tolerate oral study drug. 
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; fever must be observed and documented by 
a health care provider (oral, tympanic, rectal or core temperature 
>38.0°C [>100.4°F]) 
ii. Dysuria, urgency to void, or increased urinary frequency 
iii. Nausea or vomiting, as reported by the subject 
iv. Lower abdominal, suprapubic, or pelvic pain  
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 hours 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 milliliter (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 End-of-
Treatment [EOT]) 
iv. 
Known intrinsic renal disease with blood urea nitrogen (BUN) 
>20 mg/deciliter (dL), or blood urea >42.8 mg/dL, or serum 
creatinine >1.4 mg/dL 


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Protocol Name: ADAPT-PO                                                                         
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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; fever must be observed and documented by 
a health care provider (oral, tympanic, rectal or core temperature 
>38.0°C [>100.4°F]) 
ii. Peripheral white blood cell count (WBC) >10,000/mm3 or 
bandemia (> 15% immature polymorphonuclear neutrophils 
[PMNs], regardless of WBC count) 
iii. Nausea or vomiting, as reported by the subject 
iv. Dysuria, urgency to void, or increased urinary frequency 
Note: Subjects who meet the definition for cUTI (Inclusion Criterion 4a) and 
also 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 
hours 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 cubic millimeter (mm3) in unspun urine 
c. Positive leukocyte esterase (LE) on urinalysis 
Note: Subjects may be randomized and administered IP prior to knowledge of 
urine culture results. 
6. Expectation, in the judgment of the Investigator, that the subject will survive with 
effective antibiotic 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. Subjects must agree to use a highly-effective method of birth control; male 
subjects must agree to use an effective barrier method of contraception from 
Screening through Late Follow-Up (LFU) and for 90 days following the last dose 
if sexually active with a female of childbearing potential (FOCP); female subjects 
must not be pregnant or nursing, and must commit to either sexual abstinence or 
use at least 2 medically accepted, effective methods of birth control (e.g., condom, 
spermicidal gel, oral contraceptive, indwelling intrauterine device, hormonal 
implant/patch, injections, approved cervical ring) from Screening through LFU and 
for 90 days following the last dose.  
Exclusion Criteria: 
1. Presence of any known or suspected disease or condition that, in the opinion of the 
Investigator, may confound the assessment of efficacy, including but not limited to 
the following: 


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Protocol Name: ADAPT-PO                                                                         
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a. Perinephric or renal corticomedullary abscess 
b. Uncomplicated urinary tract infection (uUTI [acute cystitis that does not 
meet the cUTI disease definition, see Inclusion Criterion 4a]) 
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 IP (e.g., carbapenem-resistant pathogen), including 
infection caused by fungi (e.g., candiduria) or mycobacteria (e.g., urogenital 
tuberculosis) 
2. Gross hematuria requiring intervention other than administration of IP or 
removal/placement of urinary tract instrumentation 
3. Urinary tract surgery within 7 days prior to randomization or urinary tract surgery 
planned during the study period (except surgery required relieving an obstruction or 
placing urinary tract instrumentation) 
4. 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
⁄
]
 
5. Anticipated concomitant use of non-study antibacterial drug therapy between 
randomization and the LFU Visit that would potentially effect outcome evaluations 
of cUTI/ AP, including but not limited to antibacterials with potential activity 
versus uropathogens, antibacterial drug prophylaxis, and antibacterial bladder 
irrigation  
6. Anticipated concomitant use of gastric acid-reducing medications between 
randomization and EOT, including proton pump inhibitors, histamine-2 receptor 
antagonists and antacids 
7. Receipt of more than a single dose of a short-acting potentially effective antibiotic 
started within 72 h prior to randomization (see Appendix 2 for allowed single dose, 
short-acting antibiotics) 
Exception: Subjects who received more than a single dose of short-acting potentially 
effective antibiotic within 72 h prior to randomization may be eligible for 
enrollment if they meet all of the following criteria: (a) In the opinion of the 
Investigator they have failed the prior antibiotic therapy (e.g., have worsening signs 
and symptoms of cUTI/AP); (b) have a documented uropathogen (growth in urine 


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Protocol Name: ADAPT-PO                                                                         
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culture ≥105 Colony forming unit (CFU)/mL) that is resistant to the prior antibiotic 
therapy; (c) have a documented uropathogen that is carbapenem-susceptible; and (d) 
receives approval from the Medical Monitor to enroll the subject 
8. Severe hepatic impairment at Screening, as evidenced by alanine aminotransferase 
(ALT) or aspartate aminotransferase (AST) >5x upper limit of normal (ULN) or 
total bilirubin >3x ULN, or clinical signs of cirrhosis or end-stage hepatic disease 
(e.g., ascites, hepatic encephalopathy) 
9. Any signs of severe sepsis, including shock or profound hypotension defined as 
systolic blood pressure <90 mmHg or a decrease of >40 mmHg from baseline that is 
not responsive to fluid challenge 
10. Pregnant or breastfeeding women 
11. History of epilepsy or known seizure disorder (excluding a history of childhood 
febrile seizures) 
12. Receipt of any 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 and acquired 
immunodeficiency syndrome (AIDS)-defining illness, or known history of HIV 
infection and known CD4 count <200/mm3 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. A mean QT interval corrected using Fridericia’s formula (QTcF) >480 msec based 
on triplicate electrocardiograms (ECGs) at Screening 
16. History of significant hypersensitivity or allergic reaction to β-lactam antibiotics 
(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 ertapenem 
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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Protocol Name: ADAPT-PO                                                                         
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Duration of Subject Involvement in the Study:  
The duration of study participation for each subject is approximately 30 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 14: Subjects receive study drug (TBPM-PI-HBr 
or ertapenem) and dummy tablets or dummy infusions during this treatment period. 
The first dose of the study drug may occur on the same calendar day as the 
Screening Visit. The duration of study drug therapy will be 7-10 calendar days; 
however, if the subject has a positive Screening or Day 1 blood culture for 
uropathogen growth, the duration of study drug therapy may be extended to up to a 
maximum of 14 calendar days at the discretion of the Investigator.  
• End-of-Treatment (EOT) Visit will be completed on the last day of study drug 
administration (Day 7-10, or up to Day 14 for bacteremic subjects), or the following 
day (e.g., allowing a 1 day window to complete EOT procedures with the exception 
of EOT ECGs which must be performed 1 hour (±15 min) after the last dose, rather 
than the following day). Subjects requiring more than 10 days of treatment (or more 
than 14 days of treatment for bacteremic subjects) will be discontinued from IP, 
assessed at EOT as clinical failure, and treated with an appropriate open-label 
antibiotic at the discretion of the Investigator. The subject will remain in the study 
for the remaining visits. 
• Test-of-Cure (TOC) Visit, Day 19 (± 2 days) for all subjects. 
• Late Follow-Up (LFU) Visit, Day 25 (± 2 days) for all subjects. 
Statistical Considerations:  
Analysis Populations: 
• Intent-to-Treat (ITT) Population: All subjects who were randomized, regardless 
of whether they received any study drug. Subjects will be summarized by the 
treatment to which they were randomized. 
• Safety Analysis Population: Randomized subjects who received any amount of 
study drug. Subjects will be summarized by the treatment which they received. 
• Microbiological Intent-to-Treat (micro-ITT) Population: All randomized 
subjects with a confirmed diagnosis of cUTI or AP (Inclusion Criterion 4) and a 
positive Screening urine culture defined as growth of one or two uropathogens at 
≥105 CFU/mL. Subjects with Screening urine culture growth of more than 2 species 
of microorganisms will be excluded from the micro-ITT population, regardless of 
colony count. Any subject with cUTI or AP caused by a pathogen that is typically 
not expected to respond to either carbapenem study drug (e.g., Acinetobacter spp., 
Stenotrophomonas spp., Pseudomonas aeruginosa, methicillin-resistant 
Staphylococcus aureus [MRSA]) will also be excluded from this population.  
• Clinically Evaluable (CE) Population: Subjects who meet the definition for the 
ITT population, have no important protocol deviations that would affect the 
assessment of efficacy (to be defined in the Statistical Analysis Plan [SAP]), and 


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Protocol Name: ADAPT-PO                                                                         
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had an outcome assessed as clinical cure or clinical failure at EOT, TOC, and/or 
LFU.  
• Microbiologically Evaluable (ME) Population: Subjects who meet the definitions 
of both the micro-ITT population and CE population.  
• PK Population: All subjects treated with at least one dose of TBPM-PI-HBr with at 
least one analyzable plasma or urine PK sample. 
• Statistical Analysis: The primary analysis will be the comparison of the overall 
response (clinical cure plus microbiological eradication) at the TOC Visit in the 
micro-ITT population. The 95% confidence interval (CI) will be calculated using 
the method of Mietennen and Nurminen. If the lower limit of the 95% CI for the 
difference in overall response is greater than or equal to -12.5%, non-inferiority will 
be declared. Other secondary analyses related to clinical response and 
microbiological response will present the 95% CI using the same method as for the 
primary endpoint.  
In the setting of the ongoing COVID-19 pandemic, the statistical analyses and assessment 
of non-inferiority for the primary endpoint were revised in consultation with the US FDA, 
in order to preserve data integrity and to ensure the safety of patients and study team by 
limiting further enrollment into the study. The justification for this NI margin is provided in 
the June 2018 (Revision 1) FDA Guidance “Complicated Urinary Tract Infections: 
Developing Drugs for Treatment”. This guidance demonstrates that the benefit of active 
antibacterial therapy over no treatment (M1) is estimated to be 30%. Therefore, an NI 
margin of -12.5% is deemed appropriate given the proposed margin is well below the M1 
of 30% and retains greater than 50% of the clinical benefit (M1), whilst comparing TBPM-
PI-HBr to an IV carbapenem comparator. 
Presentation of safety data will be produced for the Safety Analysis population.  
Assuming a response rate of 70% for both treatment groups, a pre-specified NI margin of 
10%, a 1:1 randomization ratio, and a one-sided significance level of 0.025, a trial 
including 884 evaluable subjects would have approximately 90% power to show NI within 
a 10% margin. This trial aims to recruit 884 subjects for inclusion in the micro-ITT 
population. Assuming 75% of randomized subjects are included in the micro-ITT 
population, approximately 1,180 subjects will be recruited to ensure 884 subjects in the 
micro-ITT population. This size study would also have 90% power for an analysis of the 
ME population, assuming a 75% response rate and 67% of randomized subjects are 
included in the ME population. A blinded assessment of overall evaluability rates (the 
proportion of randomized subjects in the micro-ITT and ME populations) and response 
rates (pooled across treatment groups) will be performed during the study, and if 
assumptions are very different to those expected, the sample size may be increased 
according to pre-specified criteria. 
 
Changes Due to the COVID-19 Pandemic: 
At the time of the interim analysis (March 2020) the Data Review Committee (DRC) 
performed the planned blinded sample size reassessment after response data at TOC was 
available for 70% of patients. Based on the preliminary review of blinded data, the DRC 
recommended continuing recruitment up to the protocol-allowed maximum of 1,450 


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Protocol Name: ADAPT-PO                                                                         
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patients in order to ensure inclusion of 884 eligible patients in the primary analysis 
population. 
Based on the DRC recommendation, enrollment in the study continued, however the rate of 
enrollment dramatically decreased in the setting of the global COVID-19 pandemic and 
related impact at multiple sites in countries where the study is being conducted. The 
Sponsor performed a continuous risk assessment in order to determine which sites could 
continue enrollment with minimal impact to patient/staff safety and post-treatment data 
collection. This ongoing risk assessment identified potential for significant impact to study 
conduct and data integrity based on difficulties in conducting post-treatment follow-up 
visits necessary for assessment of the primary endpoint, along with data monitoring of case 
records. Ultimately these challenges suggested that a progressively increasing proportion of 
indeterminate outcomes for the primary endpoint is likely with continued enrollment, which 
could bias the study towards non-inferiority.  Therefore, the Sponsor, considered it in the 
best interest of the study, and study participants, to conclude enrollment and revise the 
planned analyses based on the available dataset. 
Thus, the original NI margin of -10% was modified to -12.5% in consultation with FDA. 
Based on this modification, it is expected that at least 670 patients will be included in the 
micro-ITT population, which ensures that the study will have >90% power to show non-
inferiority when using a -12.5% NI margin assuming a true response rate of at least 60% 
across both treatment groups. 
 
Endpoints and Assessments: 
Primary Endpoints:  
1. Overall response (combined clinical cure plus microbiological eradication) at TOC 
in the micro­ITT population 
• 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  
• Microbiological eradication: Reduction of baseline urine pathogen(s) to <103 
CFU/mL and negative repeated blood culture if blood culture was positive 
for uropathogen growth at baseline 
2. Assessment of treatment emergent adverse events (TEAEs), clinical laboratory 
(hematology, clinical chemistry, and urinalysis) changes, ECGs, and vital sign 
changes in the Safety Analysis population 
Secondary Endpoints: 
 
 
1. Overall response (combined clinical cure plus microbiological eradication as 
defined above) at the TOC Visit in the ME population 
2. Clinical cure at EOT, TOC, and LFU Visits in the micro-ITT, CE, and ME 
populations 
3. By-subject and by-pathogen microbiological eradication at EOT, TOC, and LFU in 
the micro-ITT and ME populations 
4. Overall response in subgroups, including: 
• Stratified infection category 
• Stratified age category 


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• Country/Region 
5. Time (days) to resolution or improvement of signs and symptoms of cUTI and AP 
present at baseline in the micro-ITT populations 
6. Time (days) to defervescence in micro-ITT subjects with a documented fever at 
Screening or Day 1 
7. Rate of clinical relapse at the LFU Visit in the micro-ITT population 
8. Rates of superinfection and new infection in the micro-ITT population 
9. Determine PK parameters (e.g., Vd, Cmax, AUC, T>MIC) in TBPM-PI-HBr 
recipients in the PK population 
Exploratory Endpoints: 
 
 
1. Enteric colonization with antibiotic-resistant Enterobacteriaceae at the TOC Visit in 
the micro-ITT population 
2. By-subject and by-pathogen microbiological eradication and by-subject and by-
pathogen clinical improvement at Day 5 in the micro-ITT, CE, and ME populations 
3. Clinical, microbiological, and overall responses at TOC among subjects with 
cUTI/AP caused by ESBL-producing Enterobacteriaceae 
Safety:  
 
Assessments of safety will include the following: 
• Clinical observations 
• Vital sign measurement  
• Laboratory tests 
• Physical examination 
• ECG 
• Reported adverse events 
 
Some key safety endpoints will include: 
• Frequency of adverse events by severity, seriousness, system organ class, preferred 
term, and treatment group 
• Change from baseline in selected laboratory assays, including WBC count, 
hemoglobin (Hb), liver function tests (AST, ALT, ALP), BUN, serum creatinine 
(Cr), and estimated Cr clearance (based on Cockcroft-Gault formula) by treatment 
group and L-carnitine 
• Grade shift in selected laboratory assays from baseline 
• Change from baseline in vital signs 
Pharmacokinetics: 
The PK population includes all subjects treated with at least one dose of TBPM-PI-HBr 
with at least one analyzable plasma or urine PK sample. The PK population includes two 
sets of TBPM-PI-HBr-treated subjects, the Sentinel PK Analysis Group and the Sparse PK 
Analysis Group: 
Sentinel PK Analysis Group (first approximately 35 TBPM-PI-HBr-treated subjects 
among the first approximately 70 subjects enrolled):  


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• Plasma PK Assessments: Blood samples will be collected following an oral dose 
(first, second, or third) on Day 2 at the following time intervals after oral 
administration  of study drug: 0.25 h (±5 min); 0.5 h (±5 min); 1 h (±15 min); 2 h 
(±15 min); 8 h (±15 min but prior to the next scheduled dose). These samples will 
be used to estimate PK parameters, such as AUC, Cmax, Tmax, CL, t1/2, Cmin, and VSS. 
• Urine PK Assessments: Twenty-four (24) h urine collection will be collected 
roughly in three (3) 8-h aliquots starting on Day 1. TBPM concentrations will be 
measured and total 8h, 16h, and 24h urine elimination will be estimated. 
Sparse PK Analysis Group (All subjects enrolled after the first approximately 70 
subjects):  
• Plasma PK Assessments: Blood samples, using sparse sampling (3 samples/subject), 
will be collected following an oral dose (first, second, or third) on Day 2 of 
treatment at the following time intervals after oral administration of study drug: 1 h 
(± 15 min); 4h (±1h); and 8 h (+30 min but prior to the next scheduled dose).  
 
• Urine PK Assessments will not be performed for this set of subjects. 
Masked individual and composite PK data from the first approximately 35 TBPM-PI-HBr-
treated subjects enrolled (among the first approximately 70 total subjects enrolled) will be 
reviewed by a blinded, independent PK Data Review Committee to verify the TBPM-PI-
HBr dose. This review will be blinded and will only be a review of PK data; this is not a 
formal review of safety or efficacy. PK samples obtained from the TBPM-PI-HBr group 
will be analyzed using a validated assay by a central bioanalytical laboratory. Study 
enrollment will continue uninterrupted during this blinded, interim PK data assessment, and 
the remaining subjects will undergo sparse PK sampling. If TBPM-PI-HBr dose alteration 
needs to be considered, enrollment may be paused for sample size adjustment and protocol 
amendment. If a change in dose is required, the planned total enrollment may be adjusted as 
needed to ensure sufficient data are available from 884 evaluable subjects receiving the 
amended dose (Section 9.13).  
Data Safety Monitoring Board (DSMB): 
A DSMB will be involved in the management of this study to review safety. The DSMB 
will review safety data upon enrollment of 25% and 50% of subjects. Full details regarding 
the DSMB (e.g., committee composition, the criteria for scheduling an ad hoc meeting, 
what will be presented/decided) will be specified in the DSMB charter. The DSMB charter 
will be approved and finalized by the DSMB members prior to the first meeting. 
 
 


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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE ............................................................................... 2 
INVESTIGATORS ACKNOWLEDGEMENT ............................................................ 3 
EMERGENCY CONTACT INFORMATION ............................................................. 4 
PRODUCT QUALITY COMPLAINTS ....................................................................... 5 
STUDY SYNOPSIS ...................................................................................................... 6 
TABLE OF CONTENTS ............................................................................................ 17 
LIST OF TABLES ....................................................................................................... 22 
LIST OF FIGURES ..................................................................................................... 22 
ABBREVIATIONS ..................................................................................................... 23 
1. 
BACKGROUND INFORMATION ......................................................... 27 
1.1. 
Condition Background and Current Treatment ........................................ 27 
1.2. 
Product Background ................................................................................. 27 
1.2.1. 
Preclinical Information ............................................................................. 27 
1.2.2. 
Clinical Information ................................................................................. 28 
2. 
STUDY OBJECTIVES AND PURPOSE ................................................ 29 
2.1. 
Rationale for the Study ............................................................................. 29 
2.1.1. 
Primary Objectives ................................................................................... 30 
2.1.2. 
Secondary Objectives ............................................................................... 30 
2.1.3. 
Exploratory Objectives ............................................................................. 30 
3. 
STUDY DESIGN ..................................................................................... 32 
3.1. 
Study Design ............................................................................................ 32 
3.2. 
Number and Type of Subjects .................................................................. 35 
3.2.1. 
Investigational Product ............................................................................. 35 
3.3. 
Sites and Regions ..................................................................................... 35 
4. 
STUDY POPULATION ........................................................................... 36 
4.1. 
Inclusion Criteria ...................................................................................... 36 
4.2. 
Exclusion Criteria ..................................................................................... 37 
4.3. 
Reproductive Potential ............................................................................. 39 
4.4. 
Withdrawal from Study ............................................................................ 40 
4.5. 
Premature Discontinuation of Investigational Product ............................. 41 


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4.6. 
Subjects Lost to Follow-up Prior to Last Scheduled Visit ....................... 41 
5. 
PRIOR AND CONCOMITANT TREATMENT ..................................... 43 
5.1. 
Concomitant Treatment ............................................................................ 43 
6. 
INVESTIGATIONAL PRODUCT .......................................................... 44 
6.1. 
Identity of Investigational Product ........................................................... 44 
6.2. 
Administration of Investigational Product(s) ........................................... 44 
6.2.1. 
Interactive Web Response System for Investigational Product 
Management ............................................................................................. 44 
6.2.2. 
Dosing in Subjects with CrCl >50 mL/min .............................................. 44 
6.2.3. 
Timing of Dose Administration................................................................ 45 
6.2.4. 
TBPM-PI-HBr Dose Adjustments in Subjects with Moderate Renal 
Insufficiency (CrCl >30 to ≤50 mL/min) ................................................. 45 
6.2.5. 
Monitoring of CrCl during Study Drug Therapy ..................................... 46 
6.2.6. 
Dosing Interruptions, Incomplete Doses, and Missed Doses ................... 47 
6.2.7. 
Blinding the Treatment Assignment ......................................................... 48 
6.2.8. 
Allocation of Subjects to Treatment ......................................................... 48 
6.2.9. 
Unblinding the Treatment Assignment .................................................... 49 
6.3. 
Labeling, Packaging, Storage, and Handling ........................................... 49 
6.3.1. 
Labeling .................................................................................................... 49 
6.3.2. 
Packaging ................................................................................................. 49 
6.3.3. 
Storage ...................................................................................................... 50 
6.3.4. 
Handling ................................................................................................... 50 
6.4. 
Investigational Product Quality Complaints ............................................ 51 
6.5. 
Drug Accountability ................................................................................. 51 
6.6. 
Subject Compliance .................................................................................. 52 
7. 
STUDY PROCEDURES .......................................................................... 53 
7.1. 
Study Schedule ......................................................................................... 53 
7.1.1. 
Screening Visit ......................................................................................... 53 
7.1.2. 
Treatment Visits ....................................................................................... 53 
7.1.3. 
End-of-Treatment Visit ............................................................................ 54 
7.1.4. 
Test-of-Cure Visit ..................................................................................... 54 
7.1.5. 
Late Follow-Up Visit ................................................................................ 54 


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7.1.6. 
Additional Care of Subjects after the Study ............................................. 54 
7.2. 
Study Evaluations and Procedures ........................................................... 55 
7.2.1. 
Efficacy ..................................................................................................... 55 
7.2.1.1. 
Investigator Assessment of Clinical Outcomes ........................................ 55 
7.2.1.2. 
Microbiologic Outcomes .......................................................................... 56 
7.2.2. 
Microbiological Assessment .................................................................... 57 
7.2.2.1. 
Urine Cultures .......................................................................................... 57 
7.2.2.2. 
Blood Cultures .......................................................................................... 59 
7.2.2.3. 
Rectal Swab Samples ............................................................................... 59 
7.2.2.4. 
Central Microbiology Laboratory Procedures .......................................... 59 
7.2.3. 
Safety ........................................................................................................ 60 
7.2.3.1. 
Medical/Surgical and Medication History ................................................ 60 
7.2.3.2. 
Physical Examination ............................................................................... 60 
7.2.3.3. 
Adverse Event Collection ......................................................................... 60 
7.2.3.4. 
Vital Signs ................................................................................................ 60 
7.2.3.5. 
Clinical Laboratory Evaluations ............................................................... 61 
7.2.3.6. 
Pregnancy Test ......................................................................................... 62 
7.2.3.7. 
Electrocardiograms ................................................................................... 62 
7.2.4. 
Pharmacokinetics ...................................................................................... 63 
7.2.4.1. 
Blood Sample for Plasma Pharmacokinetics ............................................ 63 
7.2.4.2. 
Urine Collection for Pharmacokinetics .................................................... 63 
7.2.5. 
Volume of Blood to be Drawn from Each Subject ................................... 64 
7.2.6. 
Other Tests................................................................................................ 64 
7.2.6.1. 
Urinary Tract Instrumentation Status ....................................................... 64 
7.2.6.2. 
Site of Care ............................................................................................... 64 
8. 
ASSESSMENT AND MANAGEMENT OF ADVERSE EVENTS ....... 65 
8.1. 
Adverse Event Definitions ....................................................................... 65 
8.2. 
Evaluating AEs and SAEs ........................................................................ 67 
8.2.1. 
Assessment of Intensity ............................................................................ 67 
8.2.2. 
Assessment of Causality ........................................................................... 68 
8.3. 
Time Period, Frequency and Method of Detecting AEs .......................... 68 


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8.4. 
Adverse Event Management ..................................................................... 69 
8.5. 
Recording of AEs and SAEs .................................................................... 69 
8.6. 
SAE Reporting.......................................................................................... 69 
8.6.1. 
Regulatory Reporting Requirements for Reporting of SAEs ................... 69 
8.6.2. 
Completion and Transmission of the SAE Reports .................................. 69 
8.6.3. 
Post-study AEs and SAEs ........................................................................ 70 
8.7. 
Follow-up of AEs and SAEs .................................................................... 70 
8.8. 
Clinical Laboratory Evaluations ............................................................... 71 
8.9. 
Pregnancy ................................................................................................. 71 
8.10. 
Abuse, Misuse, Overdose, and Medication Error ..................................... 72 
8.11. 
Serious Adverse Event Procedures ........................................................... 73 
8.11.1. 
Reference Safety Information ................................................................... 73 
8.11.2. 
Regulatory Agency, Institutional Review Board, Independent Ethics 
Committee, and Site Reporting ................................................................ 73 
9. 
DATA MANAGEMENT AND STATISTICAL METHODS ................. 74 
9.1. 
Data Collection ......................................................................................... 74 
9.2. 
Clinical Data Management ....................................................................... 74 
9.3. 
Statistical Analysis Process ...................................................................... 74 
9.4. 
Planned Interim Analysis, Adaptive Design, Sponsor Data Review 
Committee, and Data Safety Monitoring Board ....................................... 75 
9.5. 
Selection of Subjects to be Included in the Analyses ............................... 75 
9.6. 
Subject Disposition ................................................................................... 76 
9.7. 
Demographic and Baseline Characteristics .............................................. 76 
9.8. 
Investigational Product Exposure ............................................................. 76 
9.9. 
Prior and Concomitant Medication .......................................................... 76 
9.9.1. 
Prohibited Concomitant Medications ....................................................... 77 
9.9.2. 
Permitted Concomitant Medications ........................................................ 77 
9.10. 
Efficacy Analyses ..................................................................................... 78 
9.10.1. 
Primary Efficacy Variables ...................................................................... 78 
9.10.2. 
Secondary Efficacy Variables .................................................................. 79 
9.10.3. 
Exploratory Efficacy Variables ................................................................ 80 
9.11. 
Safety Analyses ........................................................................................ 80 


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9.12. 
Other Analyses ......................................................................................... 81 
9.12.1. 
Pharmacokinetic Analyses ........................................................................ 81 
9.13. 
Sample Size Calculation and Power Considerations ................................ 82 
9.13.1. 
Changes Due to the COVID-19 Pandemic ............................................... 82 
10. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES ............. 84 
10.1. 
Sponsor’s Responsibilities........................................................................ 84 
10.1.1. 
Good Clinical Practice Compliance ......................................................... 84 
10.1.2. 
Indemnity/Liability and Insurance ........................................................... 84 
10.1.3. 
Public Posting of Study Information ........................................................ 84 
10.1.4. 
Submission of Summary of Clinical Study Report to Competent 
Authorities of Member States Concerned and Independent Ethics 
Committees ............................................................................................... 84 
10.1.5. 
Study Suspension, Termination, and Completion .................................... 84 
10.2. 
Investigator Responsibilities .................................................................... 85 
10.2.1. 
Good Clinical Practice Compliance ......................................................... 85 
10.2.2. 
Protocol Adherence and Investigator Agreement ..................................... 85 
10.2.3. 
Documentation and Retention of Records ................................................ 86 
10.2.3.1. 
Case Report Forms ................................................................................... 86 
10.2.3.2. 
Recording, Access, and Retention of Source Data and Study Documents
 .................................................................................................................. 86 
10.2.3.3. 
Audit/Inspection ....................................................................................... 86 
10.2.3.4. 
Financial Disclosure ................................................................................. 87 
10.2.4. 
Compliance to all Local, State, and National Infectious Disease 
Regulations and Legislation ..................................................................... 87 
10.3. 
Ethical Considerations .............................................................................. 87 
10.3.1. 
Informed Consent ..................................................................................... 87 
10.3.2. 
Institutional Review Board or Independent Ethics Committee ................ 88 
10.4. 
Privacy and Confidentiality ...................................................................... 88 
11. 
REFERENCES ......................................................................................... 90 
APPENDIX 1. SCHEDULE OF ASSESSMENTS .................................................. 92 
APPENDIX 2. LIST OF SHORT-ACTING ANTIBIOTICS ................................... 95 
 
 
 


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LIST OF TABLES 
Table 1: 
TBPM-PI-HBr Dosage Regimen by Estimated Renal Function Category.
 .................................................................................................................. 46 
 
LIST OF FIGURES 
Figure 1: 
Study Design Flow Chart ......................................................................... 34 
 


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ABBREVIATIONS 
AE 
Adverse Event 
AIDS 
Acquired immunodeficiency syndrome 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase (SGPT) 
AP 
Acute pyelonephritis 
API 
Active Pharmaceutical Ingredient 
AST 
Aspartate aminotransferase (SGOT) 
AUC 
Area under the curve 
AUC0-∞ 
Area under the concentration-time curve estimated from time zero to infinity as 
the sum of the 2 areas: AUC0-t and AUCextrap, where AUCextrap is calculated as Ct 
/ λz 
AUC0-t 
Area under the concentration versus time curve from time zero to the sampling 
time at the last quantifiable concentration (Ct) at the time of the last quantifiable 
concentration (tlast) calculated by the linear trapezoidal rule 
AUCextrap 
Area under the plasma concentration-time curve extrapolated from time t to 
infinity as a percentage of total AUC 
BPH 
Benign prostatic hyperplasia 
BUN 
Blood Urea Nitrogen 
Cmax 
Maximum observed concentration 
Cmin 
Minimum observed concentration 
CDC 
Centers for Disease Control and Prevention 
CE 
Clinically Evaluable 
CFU 
Colony forming unit 
CI 
Confidence interval 
CL 
The systemic clearance calculated as: Dose/AUC0-oo 
Cr 
Creatinine 
CrCl 
Creatinine clearance 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CS 
Clinically significant  
CTCAE  
Common Terminology Criteria for Adverse Events 
cUTI 
Complicated urinary tract infection 


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AE 
Adverse Event 
dL 
Deciliter 
DRC 
DSMB 
Data Review Committee 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
EOT 
End-of-Treatment 
ESBL 
Extended Spectrum Beta-Lactamase 
EU 
European Union 
FDA 
Food and Drug Administration 
FOCP 
Females of childbearing potential 
FPI 
First Patient In 
g 
gram 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
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 
IB 
Investigator’s Brochure 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IP 
Investigational product (tebipenem pivoxil hydrobromide 300 mg film-coated 
tablets and comparator) 
IR 
Immediate release 
IRB 
Institutional Review Board 


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AE 
Adverse Event 
ITT 
Intent-to-Treat 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
LC/MS/MS 
Liquid chromatography tandem mass spectrometry 
LE 
Leukocyte esterase 
LFU 
Late Follow-Up 
LPO 
Last Patient Out 
MDR 
Multidrug-resistant 
ME 
Microbiologically evaluable 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MHRA 
Medicines and Healthcare Products Regulatory Agency (UK) 
MIC 
Minimum inhibitory concentration 
micro-ITT 
Microbiological Intent-to-Treat 
min 
minutes 
mL 
milliliter 
mm3 
Cubic millimeter 
NCS 
Not clinically significant 
NI 
Non-inferiority 
OTC 
Over-the-Counter 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PMN 
Polymorphonuclear neutrophils 
PO 
Orally 
QTcF 
Fridericia’s formula 
qXh 
Every X hours 
QD 
Once daily 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected unexpected serious adverse reaction 


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AE 
Adverse Event 
λz 
Terminal disposition rate constant/terminal rate constant 
T>MIC 
The time above the minimum inhibitory concentration 
t½ 
The apparent terminal half-life, calculated from Ln 2 / λz 
Tmax 
Time at which Cmax was apparent 
TBPM 
Tebipenem 
TBPM-PI 
Tebipenem pivoxil  
TBPM-PI-HBr 
Tebipenem pivoxil hydrobromide 
TEAE 
Treatment Emergent Adverse Event 
TOC 
Test-of-Cure 
ULN 
Upper Limit of Normal 
US 
United States 
UTI 
Urinary tract infection 
uUTI 
Uncomplicated urinary tract infection 
Vd 
The apparent volume of distribution, calculated as the amount of drug in the 
body divided by the concentration of drug in the blood/plasma 
VSS 
The apparent volume of distribution at steady state 
WBC 
White blood cell 
WHO 
World Health Organization  
 
 


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1. 
BACKGROUND INFORMATION  
1.1. 
Condition Background and Current Treatment  
Tebipenem pivoxil hydrobromide (TBPM-PI-HBr), also known as SPR994, is under 
investigation by Spero Therapeutics, Inc. (Spero) to treat serious life-threatening infections 
with unmet need. The current indication under investigation is for the treatment of 
complicated urinary tract infection (cUTI) including AP.  
1.2. 
Product Background 
Tebipenem (TBPM) is a broad-spectrum antibiotic from the carbapenem subgroup of β-
lactam antibiotics. Tebipenem pivoxil (TBPM-PI), a pivaloyloxymethyl prodrug of TBPM, is 
administered orally due to the better absorption and improved bioavailability of this prodrug 
form. TBPM-PI is currently marketed only in Japan (Meiji Seika Pharma Co., Ltd, “Meiji”) as 
a pediatric granule formulation (Orapenem® Fine Granules 10%) for pediatric use in the 
treatment of otitis media, sinusitis, and pneumonia. 
TBPM-PI-HBr, Spero’s proprietary hydrobromide salt form of TBPM-PI, is being developed 
to improve drug substance and drug product properties including stability. 
Based on the outcome of the SPR994-101 study, an immediate release formulation (600 mg, 
q8h [±0.5 h]) has been selected for the ADAPT-PO (SPR994-301) study. 
1.2.1. 
Preclinical Information 
Please refer to the current Investigator’s Brochure (IB) for detailed information regarding 
preclinical safety data. 
The pharmacokinetic (PK) profile of TBPM-PI-HBr (IR formulation) has been demonstrated 
to be similar to that of TBPM-PI both with in vitro dissolution and in vivo dog and monkey 
PK studies. In addition, TBPM-PI-HBr and TBPM-PI both metabolize to TBPM and the 
Sponsor views the toxicity profile of TBPM-PI as representative and supportive of TBPM-PI-
HBr. Further, the toxicology studies in rats and cynomolgus monkeys indicate that the target 
organ of toxicity is the GI tract as demonstrated by the diarrhea, vomiting, and gastric 
irritancy of TBPM-PI, which is consistent with the clinical safety profile observed in studies 
conducted by Meiji.  
In single dose toxicity studies, the acute toxicity of TBPM-PI in rats and monkeys was 
assessed. In repeated-dose toxicity studies, rats and monkeys were administered TBPM-PI for 
28 days, observed for clinical signs, body weight, food consumption, and organ weights, and 
underwent ophthalmology, urinalysis, hematology, clinical chemistry, necropsy with 
macroscopic assessment of tissues, and histopathology. Genotoxicity studies of TBPM-PI and 
TBPM included bacterial reverse mutation, chromosome aberration, and gene mutation 
studies. Additionally, TBPM-PI in vivo genetic toxicology studies including bone marrow 
micronucleus, liver unscheduled DNA synthesis, and gastrointestinal single cell gel studies 
were conducted. Reproductive and developmental toxicity studies conducted in mice, rats, 
and monkeys included embryo-fetal development. No toxicity studies of metabolites were 


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conducted because there are no human-specific metabolites of TBPM-PI identified, as such; 
all metabolites that may be formed in humans have been fully assessed in the current 
nonclinical studies. 
1.2.2. 
Clinical Information 
Please refer to the current IB for detailed information regarding clinical safety data. 
TBPM-PI is a carbapenem antibiotic and has demonstrated a similar safety profile to other 
carbapenems. In studies conducted by Meiji, the most common adverse events (AEs) were 
gastrointestinal (GI) AEs, in children and adults. Diarrhea was also documented as a common 
AE, and sometimes severe in children younger than 3 years, but was less frequent in adults 
with no severe or serious GI AEs reported. Skin disorders such as rash occurred infrequently 
in children and adults with few discontinuations, and none were serious. Transient increases 
in hepatic enzymes occurred in less than 10% of adults and resolved or were resolving upon 
discontinuation; no hepatic SAEs or severe events were reported. Though decreases in serum 
carnitine were observed, no associated AEs were reported; these observations in humans are 
consistent with the 28-day toxicity study where decreases in serum total carnitine levels were 
observed at all dose levels without any relevant toxicological change SAEs in both children 
and adults appear to have been incidental to administration. Additional safety considerations 
with the use of TBPM-PI include avoidance of use with valproic acid, caution in individuals 
with a history of carbapenem-, penicillin-, and cephalosporin-antibiotics sensitivity and 
adjustment of dose in individuals with advanced renal impairment.  


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2. 
STUDY OBJECTIVES AND PURPOSE 
2.1. 
Rationale for the Study 
There is a great need for alternative oral therapies for the treatment of cUTI and AP caused by 
multidrug-resistant (MDR) Gram-negative pathogens, including ESBL-producing 
Enterobacteriaceae and pathogens resistant to commonly used agents such as 
fluoroquinolones, aminoglycosides, and trimethoprim/sulfamethoxazole. The Centers for 
Disease Control and Prevention (CDC) estimates that an estimated 140,000 healthcare-
associated Enterobacteriaceae infections occur annually in the US with 26,000 drug-resistant 
infections and 1,700 deaths caused by ESBL-producing Enterobacteriaceae. Of these 
healthcare- associated infections, the CDC estimates that 17,000 are attributable to ESBL-
producing Klebsiella spp. and 9,000 are attributable to ESBL-producing Escherichia coli (E. 
coli) (CDC 2013). Urinary tract infections in the US due to fluoroquinolone-resistant 
pathogens are now >10% and as high as 50% is some hospital centers (Talan 2016).  
E. coli is the most common cause of UTI and AP, whether complicated or uncomplicated. 
Until recently, fluoroquinolones were the preferred agents for treating cUTI and AP; however, 
fluoroquinolone resistance is rapidly spreading. This is in part due to the global spread of a 
uropathogenic E. coli clone, ST131, which harbors a number of ESBLs, particularly CTX-M-
15, which has become one of the predominant CTX-M type β-lactamases in the world. ESBLs 
render these uropathogenic strains resistant to all β-lactams except carbapenems. In addition, 
E. coli ST131 strains also carry resistance to trimethoprim/sulfamethoxazole and 
aminoglycosides. Unfortunately, a subclone H30 ST131 that also brings fluoroquinolone 
resistance has emerged and become prevalent in the US. This subclone appears to have 
several advantages that will continue to drive its clinical dominance, including a broad host 
range and adaptive mutations that confer greater fitness in the pathologic niche. The rise of 
fluoroquinolone resistance in the US has been dramatic in the last decade (Johnson 2013), and 
cUTI caused by this MDR strain currently requires IV therapy with a carbapenem. 
TBPM-PI-HBr administered orally may provide a favorable alternative therapy for subjects 
experiencing cUTI caused by ESBL-producing MDR pathogens. Considering the rising 
prevalence of fluoroquinolone-resistant, ESBL-producing E. coli, this is an important unmet 
need. Alternative oral options such as TBPM-PI-HBr may be expected to decrease the need 
for hospitalization and the use of venous catheterization, thus reducing costs and associated 
complications.  
Tebipenem exhibits antibacterial activity against most Gram-negative pathogens frequently 
implicated in UTI, including E. coli and Klebsiella pneumoniae (Mendes et al., 2018, 
Muratani et al., 2009). E. coli is the most common pathogen causing both community-
associated and healthcare-associated UTI (Doi et al., 2013). In recent years, many of these 
organisms have been shown to harbor MDR mechanisms that include extended spectrum β-
lactamases (ESBLs) and/or AmpC β-lactamases that limit the effectiveness of many of the 
currently available oral step down agents such as the fluoroquinolones and trimethoprim-
sulfamethoxazole. In common with other carbapenems such as ertapenem, tebipenem 
maintains antibacterial activity against both the ESBL and/or AmpC β-lactamase-producing 


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organisms collected from subjects with UTI in the US and Europe during 2016 (Mendes et al, 
2018). Like other carbapenems, tebipenem does not have antibacterial activity against 
carbapenemase-producing Enterobacteriaceae (KPC and metallo-β-lactamase producing 
organisms). The potent in vitro activity of tebipenem also translates to in vivo efficacy in a 
murine ascending E. coli urine tract infection model, where significant reduction in bacterial 
burden was observed in the kidney, bladder and urine (Heang et al, 2018). Tebipenem 
displays efficacy in multiple animal models of infection caused by a broad range of pathogens 
(Yao 2016, Fujimoto 2013, and Meiji J-NDA). Collectively these data provide support for the 
clinical development of tebipenem and an oral option for treating cUTI/AP. 
Ertapenem was chosen as the comparator for this study because it is approved for the 
treatment of cUTI/AP in many countries, and is considered an empiric standard-of-care 
treatment option. Ertapenem has bactericidal activity against primary pathogens that cause 
cUTI/AP, including extended spectrum β-lactamase (ESBL)-producing Enterobacteriaceae. 
Ertapenem is associated with high urinary concentrations, has a similar in vitro spectrum of 
activity, and is in the same antibiotic class (carbapenem) as TBPM-PI-HBr. 
2.1.1. 
Primary Objectives 
The primary objectives are:  
• To assess the overall response (combined clinical cure plus microbiological 
eradication) of oral TBPM-PI-HBr compared to IV ertapenem in subjects ≥18 
years of age with cUTI/AP 
• To assess the safety of oral TBPM-PI-HBr compared to IV ertapenem in subjects 
≥18 years of age with cUTI/ AP 
2.1.2. 
Secondary Objectives 
The secondary objectives are: 
• To compare clinical cure rates between treatment groups 
• To compare microbiological eradication rates between treatment groups 
• To assess the population PK of TBPM-PI-HBr in subjects with cUTI/AP; the 
dosage of TBPM-PI-HBr will be confirmed based off a blinded analysis of PK 
data from the first approximately 35 enrolled TBPM-PI-HBr subjects 
2.1.3. 
Exploratory Objectives 
The exploratory objectives are: 
• To determine whether treatment with TBPM-PI-HBr or ertapenem is associated 
with enteric colonization with antibiotic-resistant Enterobacteriaceae 
• To compare microbiological eradication rates and clinical improvement at Day 5 
between treatment groups 


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• To assess clinical, microbiological, and overall responses in subjects with 
cUTI/AP caused by ESBL-producing Enterobacteriaceae 


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3. 
STUDY DESIGN 
3.1. 
Study Design 
This is a Phase 3, randomized, double-blind, double-dummy, multicenter, multinational, 
prospective study to assess the efficacy, safety and PK of TBPM-PI-HBr administered orally 
compared with ertapenem administered IV for cUTI/AP.  
This study will enroll approximately 1,200 subjects, up to a maximum of 1,450 subjects 
(contingent upon a sufficient number of evaluable subjects; Section 9.13). For this study, 
enrollment occurs at the time of randomization, and it is expected that more subjects will be 
screened than enrolled into the study. All subjects with a clinical diagnosis of cUTI/AP 
sufficient to start empiric antibiotics, and who are able to tolerate oral medication will be 
randomly assigned to one of the following groups: 
• TBPM-PI-HBr: 600 mg (2 tablets) PO q8h (±0.5 h) plus dummy IV infusion q24h 
(±0.5 h) (n=600); subjects with moderate renal insufficiency (CrCl >30 to ≤50 
mL/min) require TBPM-PI-HBr dosage adjustment to 300 mg (1 tablet) q8h ± 0.5 
• Ertapenem: 1 gram IV q24h (±0.5 h) plus dummy oral tablets q8h (±0.5 h) (n=600) 
A dummy infusion of normal saline and dummy placebo tablets will be used to maintain the 
blind.  
Day 1 is the first day of study drug administration. The duration of study drug therapy will be 
7-10 calendar days; however, if the subject has a positive Screening or Day 1 blood culture 
for uropathogen growth, the duration of study drug therapy may be extended to up to a 
maximum of 14 calendar days at the discretion of the Investigator. Subjects who are 
prematurely discontinued from study drug dosing should undergo all End-of-Treatment 
(EOT) Visit procedures and should be followed through the Late Follow-Up (LFU) Visit for 
safety assessments, regardless of the reason for early study drug discontinuation.  
Randomization will be stratified by baseline infection type (AP and cUTI) and age (≥18 to 
<65 years, ≥65 years). Subjects who meet the disease definition of cUTI (e.g., underlying 
functional or anatomical urinary tract abnormality) and have additional clinical evidence of 
AP (e.g., flank pain or costovertebral angle tenderness) should be randomized as cUTI. At 
least 30% of subjects will be randomized with a diagnosis of AP at study entry.  
Receipt of any potentially effective systemic antibiotic with activity against Gram-negative 
uropathogens within the 72 h window prior to randomization is an exclusion criterion. 
However, subjects who received a single dose of a short-acting systemic antibiotic up to 72 h 
prior to randomization (see Appendix 2 for list of allowed short-acting antibiotics) may be 
randomized up to a maximum of 25% of the study enrollment. In this study, a short-acting 
antibiotic is defined as having a dosage frequency of more than once daily (e.g., q12 h or 
more frequently).  
All organisms isolated from blood or urine cultures will be identified to the genus and species 
level. Uropathogens isolated from blood or urine cultures will be cultured and quantified at 
the local/regional laboratory, and antimicrobial susceptibility testing may be performed per 


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local standards of care (including carbapenem susceptibilities); however, specific 
susceptibility testing for TBPM-PI-HBr will not be available to the local/regional laboratories 
and will only be performed at the central laboratory. All baseline or post-baseline urine 
culture isolates that grow ≥103 Colony forming unit (CFU)/milliliter (mL), and all blood 
culture isolates, will be sent to the central laboratory for identification and susceptibility 
testing, and stored for possible further characterization of the organisms. Additional details 
are provided in a laboratory manual.  
Although local susceptibility testing is not a requirement, when local susceptibility testing 
indicates non-susceptibility to study drug (e.g., intermediate susceptibility or resistance to a 
carbapenem antibiotic) but the subject is stable or clinically improving, the subject should 
remain on blinded study drug at the Investigator’s discretion. Similarly, if baseline blood 
cultures become positive after randomization but the subject is stable or clinically improving, 
the subject should remain on blinded study drug at the Investigator’s discretion. In such cases, 
prior to premature discontinuation from study drug, the Investigator should discuss the cases 
with the Medical Monitor. Subjects will be hospitalized for the duration of their treatment. 
Exceptions may be made for US sites that have qualified, Sponsor-approved outpatient 
infusion centers for receipt of daily-blinded IV study drug (ertapenem or placebo), provided 
study staff is able to manage all required study activities in the subject setting.  
After the first approximately 70 subjects have been enrolled, masked individual and 
composite PK data will be reviewed by a blinded, independent PK Data Review Committee to 
verify the TBPM-PI-HBr dose. This review will occur after approximately 70 subjects in 
order for the PK assessment to include approximately 35 subjects receiving TBPM-PI-HBr. 
PK samples obtained from the TBPM-PI-HBr group will be analyzed using a validated assay 
by a central bioanalytical laboratory. Study enrollment will continue uninterrupted during this 
blinded, interim PK data assessment, and the remaining subjects (approximately 1,130 
subjects) will undergo sparse PK sampling. If TBPM-PI-HBr dose alteration needs to be 
adjusted, enrollment may be paused for sample size adjustment and protocol amendment. If a 
change in dose is required, the planned total enrolment may be adjusted as needed to ensure 
sufficient data are available from 884 evaluable subjects receiving the amended dose 
(Section 9.13).  
 




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3.2. 
Number and Type of Subjects 
Approximately 1,200 subjects aged ≥18 years with cUTI/AP will be enrolled in the study, up 
to a maximum of 1,450 (contingent on a sufficient number of evaluable subjects; Section 
9.13). For this study, enrollment occurs at the time of randomization. It is expected that more 
subjects will be screened than enrolled into the study. 
3.2.1. 
Investigational Product 
• TBPM-PI-HBr 300 mg film-coated tablet:  
− For subjects with normal renal function or mild renal insufficiency (CrCl >50 
mL/min): 600 mg (2 tablets) PO q8h (±0.5 h) plus dummy IV infusion q24h 
(±0.5 h)  
− For subjects with moderate renal insufficiency (CrCl >30 to ≤50 mL/min): 300 
mg (1 tablet) PO q8h (±0.5 h) plus dummy IV infusion q24h (±0.5 h) 
• Ertapenem: 1gram IV q24h (±0.5 h) for all subjects (CrCl >30 mL/min) 
− Plus 2 dummy oral tablets q8h (±0.5 h) for subjects with normal renal function 
or mild renal insufficiency (CrCl >50 mL/min) 
− Plus 1 dummy oral tablet q8h (±0.5 h) for subjects with moderate renal 
insufficiency (CrCl >30 to ≤50 mL/min) 
• A dummy infusion of normal saline (0.9%) and dummy placebo tablets will be 
used to maintain the blind 
3.3. 
Sites and Regions 
Approximately 95 sites in Central and Eastern Europe, South Africa, and the United States are 
planned for this study. 


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4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
1. Male and female subjects at least 18 years of age 
2. Able to provide informed consent 
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, in 
order to tolerate oral study drug. 
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; fever must be observed and documented by a 
health care provider (oral, tympanic, rectal or core temperature 
>38.0°C [>100.4°F]) 
ii. Dysuria, urgency to void, or increased urinary frequency 
iii. Nausea or vomiting, as reported by the subject 
iv. Lower abdominal, suprapubic, or pelvic pain  
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 hours 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 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) 
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. 
 


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AND at least ONE of the following signs and symptoms: 
v. Chills, rigors, or fever; fever must be observed and documented by a 
health care provider (oral, tympanic, rectal or core temperature 
>38.0°C [>100.4°F]) 
vi. Peripheral white blood cell count (WBC) >10,000/mm3 or bandemia 
(≥15% immature polymorphonuclear neutrophils [PMNs], regardless 
of WBC count) 
vii. Nausea or vomiting, as reported by the subject 
viii. Dysuria, urgency to void, or increased urinary frequency 
Note: Subjects who meet the definition for cUTI (Inclusion Criterion 4a) and also 
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 cubic millimeter (mm3) in unspun urine 
c. Positive LE on urinalysis 
Note: Subjects may be randomized and administered IP prior to knowledge of urine 
culture results. 
6. Expectation, in the judgment of the Investigator, that the subject will survive with 
effective antibiotic 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. Subjects must agree to use a highly-effective method of birth control; male subjects 
must agree to use an effective barrier method of contraception from Screening through 
LFU and for 90 days following the last dose if sexually active with a female of 
childbearing potential (FOCP); female subjects must not be pregnant or nursing, and 
must commit to either sexual abstinence or use at least two medically accepted, 
effective methods of birth control (e.g., condom, spermicidal gel, oral contraceptive, 
indwelling intrauterine device, hormonal implant/patch, injections, approved cervical 
ring) from Screening through LFU and for 90 days following the last dose.  
4.2. 
Exclusion Criteria 
1. Presence of any known or suspected disease or condition that, in the opinion of the 
Investigator, may confound the assessment of efficacy, including but not limited to the 
following: 
a. Perinephric or renal corticomedullary abscess 
b. uUTI (acute cystitis that does not meet the cUTI disease definition, see Inclusion 
Criterion 4a) 
c. Polycystic kidney disease 


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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 IP (e.g., carbapenem-resistant pathogen), including infection caused by 
fungi (e.g., candiduria) or mycobacteria (e.g., urogenital tuberculosis) 
2. Gross hematuria requiring intervention other than administration of IP or 
removal/placement of urinary tract instrumentation 
3. Urinary tract surgery within 7 days prior to randomization or urinary tract surgery 
planned during the study period (except surgery required relieving an obstruction or 
placing urinary tract instrumentation) 
4. 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
⁄
]
 
5. Anticipated concomitant use of non-study antibacterial drug therapy between 
randomization and the LFU Visit that would potentially effect outcome evaluations of 
cUTI/ AP, including but not limited to antibacterials with potential activity versus 
uropathogens, antibacterial drug prophylaxis, and antibacterial bladder irrigation 
6. Anticipated concomitant use of gastric acid-reducing medications between 
randomization and EOT, including proton pump inhibitors, histamine-2 receptor 
antagonists, and antacids 
7. Receipt of more than a single dose of a short-acting potentially effective antibiotic 
started within 72 h prior to randomization (see Appendix 2 for allowed single dose, 
short-acting antibiotics) 
Exception: Subjects who received more than a single dose of short-acting potentially 
effective antibiotic within 72 h prior to randomization may be eligible for enrollment 
if they meet all of the following criteria:  
a. In the opinion of the Investigator they have failed the prior antibiotic therapy (e.g., 
have worsening signs and symptoms of cUTI/AP) 
b. Have a documented uropathogen (growth in urine culture ≥105 CFU/mL or in 
blood) that is resistant to the prior antibiotic therapy 
c. Have a documented uropathogen that is carbapenem-susceptible  
d. Receives approval from the Medical Monitor to enroll the subject 


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8. Severe hepatic impairment at Screening, as evidenced by alanine aminotransferase 
(ALT) or aspartate aminotransferase (AST) >5x upper limit of normal (ULN) or total 
bilirubin >3x ULN, or clinical signs of cirrhosis or end-stage hepatic disease (e.g., 
ascites, hepatic encephalopathy) 
9. Any signs of severe sepsis, including shock or profound hypotension defined as 
systolic blood pressure <90 mmHg or a decrease of >40 mmHg from baseline that is 
not responsive to fluid challenge 
10. Pregnant or breastfeeding women 
11. History of epilepsy or known seizure disorder (excluding a history of childhood febrile 
seizures) 
12. Receipt of any 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 and acquired 
immunodeficiency syndrome (AIDS)-defining illness, or known history of HIV 
infection and known CD4 count <200/mm3 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. A mean QT interval corrected using Fridericia’s formula (QTcF) >480 msec based on 
triplicate ECGs at Screening 
16. History of significant hypersensitivity or allergic reaction to β-lactam antibiotics (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 ertapenem 
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 
4.3. 
Reproductive Potential 
Female subjects should be either: 


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• Post-menopausal (12 consecutive months of spontaneous amenorrhea and age ³51 
years), or 
• Surgically sterile and at least 6 weeks post-sterilization, or 
• Subjects with a negative pregnancy test at the Screening Visit prior to 
randomization and who are using or agree to use acceptable methods of 
contraception. 
Condoms should be used with the following acceptable contraceptives: 
• Intrauterine devices  
• Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring) 
Other acceptable contraception methods are: 
• Double barrier methods (e.g., condoms and diaphragms with spermicidal gel or 
foam) 
• Sexual abstinence 
Sexually active FOCP must agree to use an acceptable form of contraception. FOCP must be 
advised to use acceptable contraceptives throughout the study period and for 90 days 
following the last dose of IP. If hormonal contraceptives are used, they should be 
administered according to the package insert. FOCP who are not currently sexually active 
must agree to use acceptable contraception, as defined above, if they become sexually active 
during the period of the study, and for 90 days following the last dose of IP. Male subjects 
must agree to use an effective barrier method of contraception during the study and for 90 
days following the last dose if sexually active with a FOCP. 
4.4. 
Withdrawal from Study 
Subjects 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 subject withdraws consent or requests withdrawal from the study for any 
reason 
• The subject is lost to follow-up 
• The subject fails to comply with protocol requirements or study-related procedures 
• The Investigator determines that it is in the best interest of the subject 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 for any reason, including but not limited to study drug-related 
unexpected life-threatening SAEs detected during safety monitoring (e.g., Torsade 
des Pointes or other ventricular arrhythmias) 


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Subjects 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.  
Subjects who withdraw from the study should be assessed as indeterminate at EOT, TOC, 
and/or LFU, as appropriate at the time of withdrawal.  
Subjects who are withdrawn from the study will not be replaced.  
4.5. 
Premature Discontinuation of Investigational Product 
Premature discontinuation of investigational product by the Investigator is an important 
discussion, which should include the Medical Monitor, if feasible, before IP is discontinued. 
Possible reasons for premature discontinuation from IP 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 subject’s permanent discontinuation from IP 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, and no other 
disease or condition can be found to explain the liver test abnormalities; or known pregnancy 
or breastfeeding during the study drug administration period; decline in post-baseline renal 
function such that the estimated CrCl falls to ≤30 mL/min (Section 6.2.5).  
Subjects prematurely discontinued from IP for safety reasons and for whom further 
antibacterial 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 antibacterial therapy is 
necessary), may be assessed as a clinical cure at the EOT and TOC Visits. Subjects 
prematurely discontinued from IP for safety reasons and who require further antibacterial 
therapy for the cUTI/AP should be assessed as a clinical and microbiological failure at EOT 
and TOC. 
Possible reasons for discontinuation from IP 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 IP continuance acceptable, study drug administration of at least 48 h is 
encouraged before discontinuation from IP therapy for insufficient effect. 
Refer to Section 9.10.1 on handling of data for patients who discontinue IP.  
Subjects who are prematurely discontinued from IP administration should remain in 
the study and continue to undergo study assessments at every subsequent study visit 
(e.g., TOC, LFU), and not be withdrawn from study. 
4.6. 
Subjects Lost to Follow-up Prior to Last Scheduled Visit 
At least 3 documented attempts must be made to contact any subject 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 subject’s last known 
address via courier or mail (with an acknowledgement of receipt request) asking that they 


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return any unused IP, if applicable, and return to the site for final safety evaluations. The 
return of unused IPs will be handled at individual sites. 


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5. 
PRIOR AND CONCOMITANT TREATMENT 
For purposes of evaluating inclusion criteria, all prior treatment includes all treatment 
(including over-the-counter [OTC] treatments such as herbal treatments, vitamins, diet aids, 
and hormone supplements; and non-pharmacological treatment such as psychotherapy as 
appropriate) received within 30 days prior to the date of first dose of IP.  
Subjects who had antibacterial drug therapy started within 72 h prior to enrollment may only 
be randomized if they meet the exception in Exclusion Criterion 7, as follows: 
Subjects who received more than a single dose of short-acting potentially effective antibiotic 
started within 72 h prior to randomization may be eligible for enrollment if they meet all of 
the following criteria:  
a. In the opinion of the Investigator they have failed the prior antibiotic therapy (e.g., 
have worsening signs and symptoms of cUTI/AP) 
b. Have a documented uropathogen (growth in urine culture ≥105 CFU/mL or in 
blood) that is resistant to the prior antibiotic therapy 
c. Have a documented uropathogen that is carbapenem-susceptible  
d. Receives approval from the Medical Monitor to enroll the subject 
Any subject record of prior treatment must be documented on the appropriate Case Report 
Form (CRF) page. 
5.1. 
Concomitant Treatment  
Concomitant treatment taken between the dates of the first dose of IP and the last study visit, 
inclusive, are to be listed on the appropriate CRF page.  
Concomitant administration of additional or adjunctive non-study-specific, potentially 
effective, systemic antibiotic therapy for reasons other than clinical failure of IP (in treating 
the index cUTI/ AP) is not allowed. Questions regarding the use of concomitant non-study-
specific systemic antibiotic therapy should be directed to the Medical Monitor prior to 
administration.  


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6. 
INVESTIGATIONAL PRODUCT 
6.1. 
Identity of Investigational Product 
The IP is TBPM-PI-HBr, the hydrobromide salt of pivoxil prodrug of TBPM, which will be 
administered orally as one or two 300 mg film-coated, immediate release tablets, depending 
on renal function. The pivoxil prodrug enables high oral absorption and improved 
bioavailability of tebipenem (Kato 2010) while the hydrobromide salt form improves the drug 
substance and drug product properties, including stability. TBPM is active against Gram-
negative and Gram-positive pathogens that cause serious and life-threatening infections, 
including ESBL producers as well as strains resistant to levofloxacin and 
trimethoprim/sulfamethoxazole.  
The comparator is ertapenem, a commercially available carbapenem (β-lactam antibiotic) with 
a similar spectrum of microbiologic activity to that described for TBPM-PI-HBr. Ertapenem 
will be provided as a sterile, lyophilized powder packaged in vials. Each vial contains 1.046 g 
ertapenem sodium equivalent to 1 g of ertapenem for IV infusion following reconstitution and 
dilution. Please refer to the Summary of Product Characteristics (SmPC)/ Product Package 
Insert for detailed information regarding ertapenem. 
TBPM-PI-HBr tablets will be supplied by a designated manufacturer/vendor of Spero 
Therapeutics, Inc., and commercially available ertapenem will be procured from a qualified 
manufacturer/vendor. Standard operating procedures will be followed for the receipt, 
handling, and accountability of the study formulations. 
A Normal saline solution (0.9%) and water for injection for dummy/placebo and ertapenem 
infusions will be supplied. Placebo tablets (300 mg) are pressed from a single placebo blend 
consisting of the same inactive ingredients as active TBPM-PI-HBr and Mannitol 200SD 
Microcrystalline cellulose, which replaces the API. 
Spero Therapeutics, Inc. or designee will provide study sites with a sufficient quantity of IP 
supplies. 
6.2. 
Administration of Investigational Product(s) 
6.2.1. 
Interactive Web Response System for Investigational Product Management 
An Interactive Web Response System (IWRS) is used for IP management tasks. This may 
include, for example, randomization, IP supply management, inventory management and 
supply ordering, IP expiration tracking, and emergency unblinding. 
6.2.2. 
Dosing in Subjects with CrCl >50 mL/min 
Eligible subjects with a clinical diagnosis of cUTI/AP sufficient to start empiric antibiotics, 
have normal renal function or mild renal insufficiency (CrCl >50 mL/min), and who are able 
to tolerate oral medication will be randomly assigned at a 1:1 ratio to one of the following 
groups: 


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• TBPM-PI-HBr: 600 mg (2 tablets) PO q8h (±0.5 h) plus dummy placebo (0.9% 
normal saline) IV infusion administered in a total volume of 60 ml over 30 
minutes q24h (±0.5 h)  
Note: Dose adjustment is required for subjects with estimated baseline CrCl ≤50 
mL/min as outlined in Section 6.2.4. However, for subjects who have a 
baseline/screening CrCl near the 50 mL/min 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), the Investigator may choose to administer TBPM-
PI-HBr 600 mg, as a single initial dose while reassessing the need for a dosage 
adjustment based on a subsequent CrCl assessment (see Section 6.2.4 for details). 
• Ertapenem: 1 gram administered by IV infusion in a total volume of 60 mL over 
30 min q24h (±0.5 h) plus 2 dummy placebo tablets administered orally q8h 
(±0.5 h) 
Dosing of oral study drug tablets may be administered irrespective to the timing of meals. The 
administration of TBPM-PI-HBr with or without food was previously evaluated in a study in 
healthy volunteers which demonstrated negligible differences in the absorption or systemic 
exposure of oral TBPM-PI-HBr administered in a fasting or fed state (Study 994-101, 
described in the Investigator’s Brochure).  
A dummy infusion of normal saline (0.9%) and dummy placebo tablets will be used to 
maintain the blind.  
6.2.3. 
Timing of Dose Administration 
Early delivery of antibiotic 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. Following the first dose of 
IP, a one-time dose adjustment (of the second dose only) of either oral or IV study drug 
administration is allowed, to align with site-specific medication dosing schedules. The dosing 
interval adjustment must be such that the next dose of oral study drug is administered a 
minimum of 4 hours after the preceding dose and a maximum of 8 (±0.5 h) hours after the 
preceding dose, and the next dose of IV study drug (if adjusted) must be administered within 
4 hours of its planned dosing schedule. Additional doses may be adjusted within the protocol-
defined window of ±30 minutes per dose.  
As study days are defined as calendar days, every effort should be made to complete 
administration of each dose of study drug within the same calendar day (e.g., avoid starting a 
dose of study drug before midnight [00:00] and stopping the dose after midnight). 
6.2.4. 
TBPM-PI-HBr Dose Adjustments in Subjects with Moderate Renal 
Insufficiency (CrCl >30 to ≤50 mL/min) 
Model-based simulations using Phase 1 PK data from normal healthy volunteers and subjects 
with renal impairment indicate that reduction in TBPM-PI-HBr dosage is required for subjects 
with moderate renal insufficiency (CrCl >30 to ≤50 mL/min); therefore, subjects with 


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Protocol Name: ADAPT-PO                                                                         
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moderate renal insufficiency randomized to receive TBPM-PI-HBr will receive an adjusted 
dose of 300 mg PO q8h (Table 1). The dose rationale for TBPM-PI-HBr in moderate renal 
insufficiency is provided in the Investigator’s Brochure.  
No dose adjustment is required for ertapenem in subjects with moderate renal insufficiency. 
Renal function as estimated by CrCl will be assessed using the Cockcroft-Gault formula 
(Exclusion Criterion 4) using serum creatinine levels obtained at the local laboratory at 
screening (baseline) and throughout the study. Subjects in either treatment group with 
moderate renal insufficiency identified at baseline/enrollment or while on study therapy will 
receive TBPM-PI-HBr (or dummy placebo) dosed as a single tablet according to their 
randomization assignment. 
Table 1: 
TBPM-PI-HBr Dosage Regimen by Estimated Renal Function Category. 
Renal function 
category 
CrCl (mL/min) 
TBPM-PI-HBr 
Dosage 
TBPM-PI-HBr (300 mg)/Placebo 
Administration 
Normal or mild 
insufficiency 
>50 
600 mg PO q8h 
Two tablets PO q8h (±0.5 h) 
Moderate 
insufficiency 
>30 to ≤50 
300 mg PO q8h 
One tablet PO q8h (±0.5 h) 
Severe 
insufficiency 
≤30 
Excluded 
Not applicable 
Note: For subjects with moderate renal insufficiency who have a baseline/screening CrCl near 
the threshold of mild renal insufficiency (i.e., 45-50 mL/min) in whom the CrCl is expected to 
increase >50 mL/min over the first day of therapy (e.g., after IV fluid hydration), the 
Investigator may choose to administer TBPM-PI-HBr dosage of 600 mg as a single initial 
dose (followed by 300 mg PO q8h starting with the second dose), while reassessing the need 
for a dosage adjustment based on a subsequent CrCl assessment. 
6.2.5. 
Monitoring of CrCl during Study Drug Therapy 
Subjects with cUTI/AP are at risk for renal insufficiency and/or acute kidney injury; 
therefore, study subjects require frequent monitoring of their renal function while on 
antibiotic therapy in order to determine the need for a TBPM-PI-HBr dosage adjustment 
based on a change in renal function category at any time during the treatment period from 
baseline to last dose of study drug. 
• For subjects with CrCl >50 ml/min and presumed stable renal function, serum 
creatinine (measured by the local lab) and CrCl should be assessed at least every 3 
days and the necessary dosage adjustments made as outlined in Table 1 for any 
decrease in CrCl ≤50mL/min. 
• For subjects with CrCl >30 to ≤50 mL/min or subjects suspected to have 
fluctuating renal function, serum creatinine (measured by the local lab) and CrCl 
should be assessed at least once daily from the time of first dose until the CrCl 
stabilizes (i.e., no change renal function category) over 3 consecutive daily 


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measurements in order to determine whether a dosage adjustment as outlined in 
Table 1 is necessary. 
• For all subjects: If the CrCl changes to a value that falls within 5 mL/min of the 
threshold requiring a change in study drug dosing, the Investigator may choose to 
implement the dosage adjustment or continue to monitor the subject over the next 
24 hours and reassess the need for a dosage adjustment based on a subsequent 
CrCl assessment.  
• Note: Subjects with baseline CrCl ≤30 mL/min are excluded from the study 
(Exclusion Criterion 4). After randomization, if the estimated CrCl decreases to 
≤30 mL/min during the treatment period, further dosing of study drug should be 
suspended and a repeat serum creatinine measurement and recalculated CrCl 
performed to verify the need for study drug discontinuation. If the repeated CrCl is 
≤30mL/min, study drug should be discontinued.  
If a post-baseline dosage adjustment is determined necessary, the Investigator should inform 
the pharmacist immediately so that the appropriate changes to study drug may be 
implemented with the next possible dose of oral study drug (TBPR-PI-HBr/placebo). 
Estimated CrCl should be calculated every time a local laboratory assessment of serum 
creatinine is performed. Local laboratory assessments of serum creatinine are required 
in these subjects due to the time delay in obtaining results from the central laboratory. 
Actual weight in kilograms (not ideal weight) is required for the CrCl calculation. If available, 
the weight obtained on the day of the serum creatinine 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 eCRF. 
6.2.6. 
Dosing Interruptions, Incomplete Doses, and Missed Doses 
All instances of noncompliance with the pre-specified dosage regimen (oral study drug dosed 
q8h [±0.5 h] and IV study drug dosed q24h [±0.5 h]) 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 dosing is interrupted or incomplete, no adjustment to the dosing schedule is required. 
If dosing is missed for any reason, the next planned dose should be administered as quickly as 
possible at the time of discovery.  
For missed oral study drug doses, if the next planned dose is administered within 4 hours of 
its intended dosing time, the remainder of the doses should be administered at the pre-planned 
q8h intervals (i.e., the previous q8h dosage interval should remain as scheduled). If the next 
planned dose is administered after 4 hours of its intended dosing time, the remainder of the 
doses should be administered in a new q8h regimen starting with the timing of the restarted 
oral study drug administration. 


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Protocol Name: ADAPT-PO                                                                         
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For missed IV study drug doses, if the next planned dose is administered within 12 hours of 
its intended dosing time, the remainder of the doses should be administered at the pre-planned 
q24h intervals (i.e., the previous q24h dosage interval should remain as scheduled). If the next 
planned dose is administered after 12 hours of its intended dosing time, the remainder of the 
doses should be administered in a new q24h regimen starting with the timing of the restarted 
IV study drug administration. 
Investigators are encouraged to discuss continued study drug administration options after 
interrupted dosing, incomplete, or missed doses with the Medical Monitor on a case-by-case 
basis. 
6.2.7. 
Blinding the Treatment Assignment 
This is a randomized, double-blind, double-dummy study; therefore, access to treatment 
allocation will be limited to unblinded members of the study team only. 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. 
6.2.8. 
Allocation of Subjects to Treatment 
Once informed consent has been obtained and eligibility has been determined, site personnel 
will obtain a subject number from a computer-generated randomization scheme using an 
interactive response technology (IRT). Subjects will be identified by a unique ten-digit subject 
identifier (e.g., 301-XXX-ZZZZ) in which the first three digits indicate the study identifier 
(e.g., 301), the second three digits indicate the site number, and the final four digits indicate 
the number assigned at randomization. For example, the first subject randomized at site 001 
will be identified by the number 301-001-0001. Spero Therapeutics, Inc. will assign site 
numbers. 
Randomization to treatment arms will occur in a 1:1 ratio. For this study, enrollment is 
considered to occur at the time a subject is randomized. Once a randomization number has 
been assigned, that number must not be used again if, for example, a subject 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 arms, the randomization will be stratified by type of 
infection and age of the subject at informed consent as follows: 
Baseline Diagnosis 
• AP 
• cUTI  
Age Group  
• ≥18 to <65 years  
• ≥65 years 


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6.2.9. 
Unblinding the Treatment Assignment  
Data that may potentially unblind the treatment assignment (e.g., IP serum concentrations, 
treatment allocation, and IP preparation/accountability data) will be handled with special care 
during the data cleaning and review process. These data points will be handled in such a way 
that, prior to unblinding, any data that may unblind study team personnel will be presented as 
blinded information or otherwise will not be made available. In the case of the blinded PK 
analysis of the first approximately 35 TBPM-PI-HBr subjects (among the first approximately 
70 subjects enrolled), a masked data transfer will be sent to a blinded, independent PK Data 
Review Committee. 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 treatment assignment must not be broken during the study except in emergencies where 
the identification of the IP is required for further treatment of the subject.   
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 IWRS and the source 
documents. After breaking the blind and the subject is withdrawn from the study, he or she 
should receive follow-up for safety purposes. Any code-breaks that occur must be reported to 
Spero Therapeutics, Inc. or its designee. Code-break information is held by the pharmacist or 
designated person at the site and by the CRO Medical Monitor for the study or designee. 
6.3. 
Labeling, Packaging, Storage, and Handling 
6.3.1. 
Labeling 
Labels containing study information and packing identification will be handled via Spero 
Therapeutics, Inc. 
Space is allocated on the label so that the site representative can record a unique subject 
identifier. Additional labels (e.g., those used when dispensing marketed product) may be 
applied, in certain cases, to the IP in order to satisfy local or institutional requirements, but 
must not: 
• Contradict the clinical study label 
• Identify the study subject by name 
• Obscure the clinical study label 
Additional labels may not be added without the Sponsor’s prior full agreement in advance. 
6.3.2. 
Packaging 
IP is packaged via Spero Therapeutics-approved vendors. Any changes to Sponsor-supplied 
packaging prior to dosing may not occur without full agreement in advance by the Sponsor. 


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6.3.3. 
Storage 
TBPM-PI-HBr 300 mg film-coated tablets are packaged in 75cc white round high-density 
polyethylene bottles; 30 tablets/bottle and are stable after storage under accelerated conditions 
at 40°C/75% relative humidity for 3 months (supported by data generated on SPR994-101 
GMP batch). Tablets are dispensed in a sealed, light-resistant container. The IPs must be 
stored as labeled in a secure area with access limited to the Investigator and authorized staff. 
IP supplies will be stored securely under the appropriate conditions according to local 
standard operating procedures. The Investigator has overall responsibility for ensuring that IP 
is stored in a secure, limited-access location. Limited responsibility may be delegated to the 
pharmacy or member of the study team, but this delegation must be documented.  
Temperature monitoring is required at the storage location to ensure that the IP is maintained 
within an established temperature range. 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 excursions on the IP and will provide 
supportive documentation as necessary. Under no circumstances should any product be 
dispensed to subjects until the impact is determined and deemed appropriate for use by the 
Sponsor. 
6.3.4. 
Handling 
The Sponsor will provide a sufficient quantity of IP supplies to each study site. Study sites 
must ensure that a responsible person correctly receives deliveries of IPs from the Sponsor, 
that all receipts of drug shipments are recorded on the appropriate drug accountability forms, 
and that the products are stored in a secure area under recommended storage conditions. It is 
also the responsibility of the Investigator to ensure that the integrity of packaged IPs not be 
jeopardized prior to dispensing. Only participants enrolled in the study may receive the IPs, in 
accordance with all applicable regulatory requirements. Only authorized and trained site staff 
may supply or administer the IPs. 
An authorized and trained staff member at each study site will dispense the IPs according to 
pre-defined drug dispensing requirements. A second member of staff will verify the 
dispensing and administration. The staff member, not associated with any study assessments, 
will be responsible for dispensing study treatment in accordance with the randomization 
schedule. Individual doses will be dispensed by the pharmacy staff member on site the day of 
dosing and recorded in the drug accountability records. A study pharmacy manual will be 
prepared to define the procedures for dispensing. 


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Protocol Name: ADAPT-PO                                                                         
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6.4. 
Investigational Product Quality Complaints 
Investigators are required to report IP quality complaints to Spero Therapeutics, Inc. within 
1 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). 
6.5. 
Drug Accountability 
Investigators will be provided with sufficient amounts of the IP to carry out this protocol for 
the agreed number of subjects. The Investigator or designee will acknowledge receipt of the 
IP documenting shipment content and condition. Accurate records of all IP dispensed, used, 
returned, and/or destroyed must be maintained as detailed further in this section. 
The Investigator has overall responsibility for administering IP. Where permissible, tasks may 
be delegated to a qualified designee (e.g., a pharmacist) who is adequately trained in the 
protocol and who works under the direct supervision of the Investigator. This delegation must 
be documented in the applicable study delegation of authority form. 
The Investigator or his/her designee (as documented by the Investigator in the applicable 
study delegation of authority form) will administer the IP only to subjects included in this 
study following the procedures set out in the study protocol. Each subject will be given only 
the IP carrying his/her treatment assignment. All administrations will be documented on the 
CRFs and/or other IP record. 
No IP 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 
packaging are to be sent to a nominated contractor on behalf of the Sponsor. IPs 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 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 IPs must be packed in a tamper-
evident manner to ensure product integrity. Contact the Sponsor for authorization to return 
any IP prior to shipment. Shipment of all returned IP 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 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 


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copies provided to the Sponsor. Destruction of IPs 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 IPs 
delivered with those used and returned. All IPs 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 IPs will be described in the drug distribution plan.  
6.6. 
Subject Compliance 
Trained clinical facility personnel will facilitate and observe the administration of the IPs. The 
clinical facility personnel will record the exact dose and time of infusion. 
Drug accountability must be assessed at the container/packaging level for unused IP 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. 


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Protocol Name: ADAPT-PO                                                                         
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7. 
STUDY PROCEDURES 
7.1. 
Study Schedule 
See Appendix 1  Schedule of Assessments. 
The duration of study participation for each subject is approximately 30 days.  
7.1.1. 
Screening Visit 
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 assessments performed at the site within the Screening period (within 24 
hours of randomization) may be used to determine subject eligibility even if performed prior 
to signing the informed consent form (ICF). For example, the Schedule of Assessments Table 
(Appendix 1) notes that “urine cultures collected per standard-of-care up to 24 h prior to 
randomization may be used for eligibility” (footnote j). Other routine clinical assessments 
may be used to determine eligibility if performed prior to informed consent but within the 24-
hour Screening period.  
Specifically, the following SOC assessments may be used in determining study eligibility if 
performed prior to signing the ICF but within the 24-hour Screening window: 
• Physical exam and vital signs 
• cUTI/AP symptoms and signs 
• Local serum creatinine and calculated CrCl 
• Urine culture collection 
• Blood culture collection (if analysis is to be performed by the local laboratory 
rather than a regional laboratory) 
Study SPR994-301-specific assessments, such as triplicate electrocardiograms, 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. 
7.1.2. 
Treatment Visits 
Treatment Visits, Day 1 up to Day 14: Subjects receive study drug (TBPM-PI-HBr or 
ertapenem) and dummy infusions or dummy tablets during this treatment period. The first 
treatment with the study drug may occur on the same calendar day as the Screening Visit. Day 
1 is the first day of study drug administration. The duration of study drug therapy will be 7-10 
calendar days; however, if the subject has a positive Screening or Day 1 blood culture for 
uropathogen growth, the duration of study drug therapy may be extended to up to a maximum 
of 14 calendar days at the discretion of the Investigator. 
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 


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Protocol Name: ADAPT-PO                                                                         
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optional).  However, separate Screening and Day 1 ECGs must be performed per the protocol 
Schedule of Assessments, as Day 1 ECGs are timed from the first dose of study drug. 
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 
• 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 
• Separate Screening and Day 1 ECGs must be performed. For Screening ECGs, 
perform 12-lead ECGs in triplicate at 1-5 minute intervals (calculate mean QTcF 
value for eligibility). For Day 1 ECGs, perform 12-lead ECGs in triplicate at 1-5 
minute intervals 1h (±15 min) after the first oral dose administration. 
7.1.3. 
End-of-Treatment Visit  
The EOT Visit will be completed on the last day of study drug administration (Day 7-10, or 
up to Day 14 for bacteremic subjects), or the following day (e.g., allowing a one-day window 
to complete procedures with the exception of EOT ECGs which must be performed one hour 
(±15 min) after the last dose rather than the following day). Decision on treatment completion 
should be made by the Investigator based on his/ her clinical judgment (e.g., complete 
resolution or significant improvement of signs and symptoms of cUTI/AP that were present at 
baseline with no need for further antibiotic treatment). Subjects requiring more than 10 days 
of treatment (or more than 14 days of treatment for bacteremic subjects) will be discontinued 
from the study drug. These subjects will be assessed at EOT as clinical and microbiological 
failures, and treated with an appropriate open-label antibiotic at the discretion of the 
Investigator. The subjects will remain in the study for the remaining visits. 
7.1.4. 
Test-of-Cure Visit  
The TOC Visit is Day 19 (± 2) for all subjects. 
7.1.5. 
Late Follow-Up Visit 
The LFU Visit is Day 25 (± 2) for all subjects. 
7.1.6. 
Additional Care of Subjects after the Study 
No after care is planned for this study. 


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Protocol Name: ADAPT-PO                                                                         
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7.2. 
Study Evaluations and Procedures 
7.2.1. 
Efficacy 
Efficacy will be evaluated through assessment of clinical outcomes, microbiological culture, 
and susceptibility testing of bacterial isolates. Measures of clinical efficacy will be assessed at 
baseline and at multiple time points during the study.  
Overall response (combined clinical cure plus microbiological eradication) at TOC will be 
assessed in the micro-ITT population, 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 antimicrobial therapy is warranted and subject is 
alive 
• Microbiological eradication is defined as a reduction of baseline urine pathogen(s) 
to <103 CFU/mL and negative repeated blood culture if blood culture was positive 
for uropathogen growth at baseline and subject is alive 
Subjects prematurely discontinued from IP for safety reasons and who require further 
antibacterial therapy for the cUTI/AP should be assessed as a clinical and microbiological 
failure at EOT and TOC. 
7.2.1.1. 
Investigator Assessment of Clinical Outcomes 
Based on the assessment of signs and symptoms, the Investigator will choose one of the 
following clinical outcomes at the EOT and TOC Visits: 
• Clinical cure: Subject is alive with 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 
• Clinical failure: Symptoms of cUTI or AP present at study entry have not 
completely resolved or new symptoms have developed and require the initiation of 
a non-study antibacterial drug therapy, or death 
• Clinical indeterminate: Insufficient data are available to determine if the subject is 
a cure or failure 
Subjects deemed clinical failures at EOT or TOC should be considered for further diagnostic 
workup, including urinary tract imaging (e.g., ultrasound), to assess for undiagnosed 
anatomical, obstructive, or neurogenic abnormalities, according to the best clinical judgment 
of the Investigator. 
Based on the assessment of signs and symptoms, the Investigator will choose one of the 
following clinical outcomes at the LFU Visit: 
• Sustained clinical cure: Met criteria for clinical cure at TOC, and remained free of 
signs and symptoms of cUTI or AP at LFU Visit 


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• Clinical relapse: Met criteria for clinical cure at TOC, but new signs and 
symptoms of cUTI or AP are present at the LFU Visit and the subject requires 
antibiotic therapy for the cUTI 
• Clinical indeterminate: Insufficient data are available to determine if the subject is 
a sustained clinical cure or clinical relapse 
Note: If a subject is assessed as a clinical failure at EOT, the subject is automatically 
considered a failure at the TOC and LFU Visits, and an assessment of clinical 
response by the Investigator will be listed as “failure at EOT.” 
7.2.1.2. 
Microbiologic Outcomes 
Per-subject microbiological response at the EOT and TOC visits is determined 
programmatically based on the results of blood and urine cultures as one of the following 
outcomes: 
• Microbiologic eradication: Subject is alive and all baseline uropathogen(s) are 
reduced to <103 CFU/mL on urine culture and negative on repeat blood culture (if 
positive at baseline) 
• Microbiologic persistence: Isolation from urine culture of ≥103 CFU/mL or from 
blood of any of the baseline uropathogen(s) identified at study entry; subjects with 
a microbiologic persistence outcome at EOT will be considered a persistence at 
TOC 
• Microbiologic indeterminate: No follow-up urine culture is available, or the 
follow-up urine culture cannot be interpreted for any reason, or the follow-up urine 
culture is considered contaminated 
Per-subject microbiological response at the LFU visit is determined based on outcomes at the 
TOC visit and subsequent blood and urine cultures as one of the following outcomes: 
• Sustained microbiologic eradication: Microbiologic eradication at the TOC and no 
subsequent urine culture after TOC demonstrating recurrence of the original 
baseline uropathogen at ≥105 CFU/mL 
• Microbiologic recurrence: Isolation from urine culture at ≥103 CFU/mL or blood 
culture of any of the baseline uropathogen(s) at any time after documented 
eradication at the TOC Visit up to and including the LFU visit 
• Microbiologic indeterminate: No follow-up urine culture is available, or the 
follow-up urine culture cannot be interpreted for any reason, or the follow-up urine 
culture is considered contaminated 
Additional microbiologic outcomes include the following: 
• Colonization: Isolation of a new pathogen(s) at ≥105 CFU/mL (other than the 
original baseline pathogen[s]) from a urine culture in a subject who is assessed as a 
clinical cure or sustained clinical cure (e.g., requires no additional or alternative 
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• Superinfection: Isolation of a new pathogen(s) at ≥105 CFU/mL (other than the 
original baseline pathogen[s]) from a urine culture that is accompanied by clinical 
signs and symptoms of infection requiring alternative antimicrobial therapy (e.g., 
the subject is assessed by the Investigator as a clinical failure) during the period up 
to and including EOT 
• New infection: Isolation of a new pathogen(s) at ≥105 CFU/mL (other than the 
original baseline pathogen[s]) from a urine culture that is accompanied by clinical 
signs and symptoms of infection requiring alternative antimicrobial therapy (e.g., 
the subject is assessed by the Investigator as a clinical failure) in the time period 
after EOT 
7.2.2. 
Microbiological Assessment 
Microbiological assessment will be performed with urine cultures, blood cultures, and rectal 
swabs. All microbiological assessments will be initiated at the local or regional laboratory, 
including specimen collection, analysis of isolates, and shipment of isolates. Additional 
details with regard to handling and processing of microbiological specimens at the local or 
regional laboratory vs. Central Microbiology Laboratory are provided in a laboratory manual. 
Local or regional microbiology laboratory sample processing, including isolate identification 
and quantification, will be used to help guide clinical care and support Investigator 
assessments. Local or regional laboratory susceptibility testing, if available, will be performed 
per local standards. The Central Microbiology Laboratory will be used for evaluating 
isolate(s), identification, and antimicrobial susceptibility testing; Central Microbiology 
Laboratory data will be used for microbiologic outcome determinations. 
7.2.2.1. 
Urine Cultures 
Urine specimens for culture will be obtained at the Screening, Day 5, EOT, TOC, and LFU 
Visits and, in addition, as clinically indicated throughout the study. At LFU, urine culture 
must be obtained only in subjects with a positive urine culture (growth of urine culture 
bacterial pathogen(s) ≥105 CFU/mL) on or after the TOC Visit. In addition, at any time the 
subject is deemed a clinical failure, a urine specimen should be obtained for culture prior to 
the start of any rescue antimicrobial therapy. 
All urine culture specimens must be obtained through one of the following methods that 
minimizes the risk of bacterial contamination: 
• Clean-catch mid-stream 
• Newly-inserted Foley catheter (bag specimens are not permitted) 
• Bladder needle aspiration 
• Ureter aspiration 
Urine specimens should be processed for culture by the local lab within 2 h of collection. If 
the local laboratory cannot process the sample within 2 h of collection, the sample may be 
stored at 4°C (during transport and holding period) for up to 24 h. If refrigeration is not 


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possible and specimens are delayed in transport and/or processing, the urine specimen should 
be collected in transport tubes with preservatives, as directed in a laboratory manual. 
All Screening urine cultures will require the use of a 1 µL loop to obtain a <105 CFU/mL 
threshold; 1 µL loops will be provided by the Central Microbiology Laboratory. All Screening 
urine culture pathogens that grow at ≥103 CFU/mL will be sent to the central laboratory. To 
be considered an eligible uropathogen for micro-ITT analysis, the baseline urine culture must 
grow 1 or 2 bacterial isolates, each at ≥105 CFU/mL. If ≥3 bacterial isolates are identified, the 
culture will be considered contaminated, regardless of colony count, unless one of the 
organisms present in urine at ≥105 CFU/mL comprises ≥80% of the total growth 
(predominant), or ≥1 of the organisms is cultured from a Screening or Day 1 blood culture. 
All post-baseline cultures will require the use of a 1 µL loop and a 10 µL loop to obtain a 
<103 CFU/mL threshold; 1 µL loops and 10 µL loops will be provided by the Central 
Microbiology Laboratory. For post-baseline urine cultures, all isolates that grow ≥103 
CFU/mL will be sent to the central laboratory. Culture results are to report pathogen 
identification to the species level.  
Susceptibility testing for TBPM-PI-HBr will not be available to the local laboratory; however, 
TBPM-PI-HBr susceptibility will be assessed at the Central Microbiology Laboratory by MIC 
and disk method. These centrally-determined susceptibility results will not be available to the 
Investigator during real-time management of the subjects; therefore, decisions related to 
subject care (e.g., study drug discontinuation) will be based on the evolution of the clinical 
signs and symptoms of the index cUTI or AP, rather than specific TBPM-PI-HBr 
susceptibility data. Susceptibility testing for carbapenems (e.g., ertapenem) can be performed 
locally using routine standard materials and methods by the laboratory. Results of this testing 
can be used by Investigators along with clinical findings to help guide therapy. When local 
susceptibility testing suggests non-susceptibility to study drug (e.g., intermediate 
susceptibility or resistance to ertapenem) but the subject is stable or clinically improving, the 
subject should remain on the study drug at the Investigator’s discretion. Such cases should be 
discussed with the Medical Monitor prior to study drug discontinuation. 
With the exception of the “contaminants” listed below, all isolates from urine cultures that 
grow ≥103 CFU/mL are to be sent to the Central Microbiology Laboratory. The Central 
Microbiology Laboratory will reculture the shipped isolates, confirm genus and species 
identification, and determine pathogen susceptibility by standardized broth microdilution and 
disk diffusion methods for TBPM-PI-HBr and ertapenem. In the event that local laboratory 
genus and species identification are not consistent with central laboratory results, a back-up 
isolate should be sent to the Central Microbiology Laboratory. 
For the purposes of this study, the following organisms are considered “contaminants” and 
should not to be sent to the Central Microbiology Laboratory: 
• Non-group D streptococci (e.g., any streptococcal species with the exception of 
Lancefield Group D streptococci; examples of Group D streptococci include 
Streptococcus bovis, S. equinus, S. gallolyticus, S. pateuriaus, S. infantarius, S. 
lutetiensis) 


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• Coagulase-negative staphylococci with the exception of Staphylococcus 
saprophyticus (e.g., S. epidermidis, S. haemolyticus, S. hominis) 
• Corynebacterium spp. with the exception of Corynebactrium urealyticum 
• Lactobacillus spp. 
• Propionibacterium spp. 
• Yeast (e.g., Candida spp.) 
Refer to the study-specific laboratory manual for further detail, including specific procedures 
pertaining to the collection, processing, storage, and shipment of microbiological samples.  
7.2.2.2. 
Blood Cultures 
At Screening, two sets of blood cultures (i.e. one aerobic blood culture bottle and one 
anaerobic blood culture bottle from two separate venipuncture sites for a total of four bottles) 
must be collected.  
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 uropathogen). Blood cultures should be 
repeated as necessary until negative blood cultures are obtained.  
Culture results are to include identification of pathogens to the level of genus and species. As 
described in the laboratory manual, susceptibility testing for TBPM-PI-HBr will not be 
available to the local laboratory; TBPM-PI-HBr susceptibility will be assessed at the central 
laboratory. Therefore, decisions related to subject care (e.g., study drug discontinuation) will 
be based on the evolution of the clinical signs and symptoms of the index cUTI or AP. All 
isolates cultured from blood samples (whether Screening or post- baseline), with the 
exception of “contaminants” listed in Section 7.2.2.1, are to be sent to the central laboratory 
for identification verification and susceptibility testing. Either an automated system or a 
manual system can be used for blood cultures according to the preference of the local/regional 
microbiological laboratory performing the testing. Refer to the laboratory manual for details.  
7.2.2.3. 
Rectal Swab Samples 
Rectal swab samples for antibiotic-resistant Enterobacteriaceae culture will be obtained prior 
to randomization and at TOC. Additional detail is available in the laboratory manual. 
7.2.2.4. 
Central Microbiology Laboratory Procedures 
With the exception of “contaminants” defined above, all isolates from urine cultures that grow 
≥103 CFU/mL and all bacterial isolates from blood cultures collected at each defined visit will 
be shipped to the designated Central Microbiology Laboratory from each study site. The 
Central Microbiology Laboratory will confirm the identity of all bacterial isolates to the genus 
and species level and perform susceptibility testing against all bacterial isolates for TBPM-PI-
HBr and ertapenem using standardized susceptibility testing methods.  


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Any questions regarding microbiological procedures, interpretation of results, or storage of 
isolates should be discussed with the Sponsor or designee. Additional detail is available in the 
laboratory manual. 
7.2.3. 
Safety 
7.2.3.1. 
Medical/Surgical and Medication History 
The medical/surgical history of the subject will be obtained at the Screening Visit. Specific 
information will be recorded on the CRF relating to any prior or existing medical 
conditions/surgical procedures involving the following: infectious diseases (including viral 
infections, like Hepatitis and HIV), allergies, metabolic/endocrine/nutritional, hematopoietic, 
musculoskeletal, dermatologic, Head, Ears, Eyes, Nose, and Throat (HEENT), breasts, 
respiratory, cardiovascular, gastrointestinal/hepatic, genitourinary/renal, neurologic, and 
psychiatric/psychosocial.  
Data related to the current infection under study must not be recorded in the medical history 
page of the CRF but in the signs and symptoms pages of the CRF. 
History of prior medications will be recorded in the CRF at the Screening Visit. 
7.2.3.2. 
Physical Examination  
Abnormalities identified at the Screening Visit (Day -1 or 1) will be documented in the 
subject’s source documents and on the medical history CRF. Height and weight will be taken 
during this physical exam. Complete physical examinations at Screening, EOT, TOC, and 
LFU consist of skin, head and neck, heart, lung, abdomen, extremities, 
back/flank/costovertebral angle tenderness, and neuromuscular assessments. Limited physical 
examinations between Day 1 and EOT are focused, 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. 
7.2.3.3. 
Adverse Event Collection 
At each study visit, subjects 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?”). AEs will be collected from the time of the first dose of IP. 
7.2.3.4. 
Vital Signs 
Vital sign assessments include blood pressure, pulse, respiratory rate, and temperature. 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), TOC, and LFU. 
If the Screening Visit and Day 1 occur on the same calendar day, repeated vital signs on Day 
1 are optional. 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 subject’s body 
temperature should be used throughout the study. Blood pressure should be determined by 


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cuff (using the same method, the same arm, and in the same position throughout the study). 
Any clinically significant deviations from baseline vital signs, which are deemed clinically 
significant 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 clinically significant (NCS) or clinically significant (CS). 
Abnormal clinical laboratory values, that are unexpected or not explained by the subject’s 
clinical condition may be, at the discretion of the Investigator or Sponsor, explained or 
resolved as soon as possible. 
Laboratory Assessments for Eligibility 
Results from the local blood and urine samples are used to determine eligibility (results can be 
from samples obtained up to 24 h prior to randomization). Assessments include serum 
creatinine (for CrCl calculation), ALT, AST, total bilirubin, absolute neutrophil count, blood 
urea nitrogen (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, Day 3, Day 5, Day 7, Day 9 (if still receiving IP), Day 11 (if still receiving 
IP), Day 13 (if still receiving IP), EOT, TOC, and LFU.  
• Hematology (hemoglobin [Hb], hematocrit, red blood cell [RBC] indices) 
• Thrombocyte count (platelets) 
• Reticulocyte count 
• White blood cell count with differential (including neutrophils, eosinophils, 
basophils, lymphocytes and monocytes) 
• Coagulation (prothrombin time, international normalized ratio, thrombin time, 
activated partial thromboplastin time) 
• Serum Chemistry:  
− Electrolytes (sodium, potassium, chloride, bicarbonate) 
− Non-fasting glucose 
− Blood urea nitrogen (BUN) 
− Creatinine (including calculated creatinine clearance (CrCl) using Cockcroft-
Gault formula) 


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− L-carnitine 
• Creatine kinase 
• Urate 
• Phosphate 
• Total calcium 
• Cholesterol 
• Albumin 
• Globulins 
• Protein 
• Total bilirubin 
• Conjugated bilirubin 
• Gamma-glutamyl transferase 
• Alanine aminotransferase (ALT) 
• 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 include WBC, RBC, 
epithelial cells and bacteria testing. 
7.2.3.6. 
Pregnancy Test 
A urine or serum beta human chorionic gonadotropin (β-HCG) pregnancy test (according to 
local standard-of-care) 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 subject’s final visit (LFU Visit or time of early 
withdrawal from the study) (Appendix 1).  
7.2.3.7. 
Electrocardiograms 
At Screening, perform 12-lead ECGs in triplicate at 1-5 minute intervals. On Day 1, perform 
12-lead ECGs in triplicate at 1-5 minute intervals 1h (±15 min) after the first oral dose 
administration. At EOT, perform 12-lead ECGs in triplicate at 1-5 minute intervals 1h (±15 
min) after the final oral dose administration. At TOC, perform a single 12-lead ECG. 


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7.2.4. 
Pharmacokinetics 
7.2.4.1. 
Blood Sample for Plasma Pharmacokinetics 
Blood samples will be collected for assessment of PK parameters for TBPM-PI-HBr. Refer to 
the laboratory manual for detailed instructions on sample processing, storage, and shipping. 
Blood samples include: 
Sentinel PK Analysis Group: First approximately 35 TBPM-PI-HBr-treated subjects among 
the first approximately 70 subjects enrolled. 
• Plasma PK Assessments: Blood samples will be collected following an oral dose 
(first, second, or third) on Day 2 at the following time intervals after oral 
administration of  study drug: 0.25 h (± 5 min); 0.5 h (± 5 min); 1 h (±15); 2 h 
(±15); and 8 h (±15 min but prior to the next scheduled dose). These samples will 
be used to estimate PK parameters, such as AUC, Cmax, Tmax, CL, t1/2, Cmin, and VSS 
Sparse PK Analysis Group: For all subjects enrolled after the first approximately 70 subjects 
enrolled.  
• Plasma PK Assessments: Blood samples, using sparse sampling (3 
samples/subject), will be collected following an oral dose (first, second, or third) 
on Day 2 of treatment at the following time intervals after oral administration of 
study drug: 1 h (±15 min), 4 h (±1 h); and 8 h (±30 min but prior to the next 
scheduled dose).  
Whole blood samples will be assayed by validated liquid chromatography tandem mass 
spectrometry (LC/MS/MS) methods, which are specific for the determination of TBPM. 
Blood samples will be collected from all subjects. Only samples from subjects who receive a 
dose of TBPM-PI-HBr will be analyzed. Selected comparator samples may be analyzed at the 
request of the Sponsor. The criteria for repeat analysis, as defined in the respective in-house 
procedure, will be followed. 
When collecting PK blood samples for both the Sentinel and Sparse PK Analysis Group, the 
exact dose time and the exact PK sample time should be collected. 
The validation study conducted by the appointed bioanalytical laboratory to establish validity 
including accuracy, precision, reproducibility, specificity, recovery and frozen stability of the 
analytical method will be appended to the final report. 
7.2.4.2. 
Urine Collection for Pharmacokinetics 
For the first approximately 70 subjects, a 24 h urine collection will be collected in roughly 
three (3) 8-h aliquots after the first dose of the study drug on Day 1. These collections should 
occur as close as possible to the 8 hour time limit.  Deviations will only be documented for 
those collections that occur outside of a 7-9 hour window. 


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7.2.5. 
Volume of Blood to be Drawn from Each Subject 
During this study it is expected that blood will be taken from all subjects, regardless of sex. 
Exact blood volumes to be drawn can be found in the study lab manual. 
7.2.6. 
Other Tests 
7.2.6.1. 
Urinary Tract Instrumentation Status 
Record all start times and end times of all urinary tract instrumentation, including but not 
limited to bladder catheters, stents, nephrostomy tubes, and other urological prosthetic 
material. 
7.2.6.2. 
Site of Care 
Record the site of care (e.g., acute care hospital ward, long-term care facility [US only]), 
outpatient infusion center (US only). 


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8. 
ASSESSMENT AND MANAGEMENT OF ADVERSE EVENTS 
8.1. 
Adverse Event Definitions  
An Adverse Event (AE) is any untoward medical occurrence in a subject 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 subject 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 Principal Investigator. For the purposes of this study, duration of 
intended hospitalization at the time of study randomization may be reasonably 
presumed to be approximately 14 days, as this is the maximum allowed duration of 
study drug. Therefore, cases of clinical failure leading to prolongation of 
hospitalization beyond approximately 14 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 


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the above definition. These should also be considered serious. Examples of such events are 
intensive 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 adverse event (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 serious adverse event (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 subject/event outcome or action criteria described above and 
is usually associated with events that pose a threat to a subject’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): An AE or suspected adverse 
reaction is considered "unexpected" if: 
• It is not listed in the Investigators Brochure  
• It is not listed at the specificity or severity that has been observed 
• The IB is not required or available or not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application 
For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater 
severity) if the IB referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater 
specificity) if the IB listed only cerebral vascular accidents. "Unexpected," as used in this 
definition, also refers to AEs or suspected adverse reactions that are mentioned in the IB as 
occurring with a class of drugs or as anticipated from the pharmacological properties of the 
drug, but are not specifically mentioned as occurring with the particular drug under 
investigation. 
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 CS 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 


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judgment in deciding whether an abnormal laboratory finding or other abnormal assessment is 
CS. 
8.2. 
Evaluating AEs and SAEs 
8.2.1. 
Assessment of Intensity 
The Principal Investigator (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: 
• Mild: An event that is easily tolerated by the subject, 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 subject 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 subject signed the informed consent 
• Recovering/Resolving: This term is only applicable if the subject has completed 
the trial or has died from another AE. The condition is improving and the subject 
is expected to recover from the event 
• Recovered/Resolved with sequelae: The subject 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 subject 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 subject died from a condition related to 
the reported AE. Outcomes of other reported AEs in a subject 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 


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• Unknown: This term is only applicable if the subject is lost to follow-up 
8.2.2. 
Assessment of Causality 
The PI (or designee) will make an assessment as to the relationship between IP and the 
occurrence of each AE/SAE. The PI (or designee) will use clinical judgment to determine 
whether or not the AE/SAE is causally related to the IP. Alternative causes, such as natural 
history of the underlying diseases, concomitant therapy, other risk factors, and the temporal 
relationship of the event to the IP will be considered and investigated. The PI (or designee) 
will also consult the IB in the determination of his/her assessment.  
The causal relationship of the study drug to an AE will be rated 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 subject’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 subject’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 
There may be situations when an SAE has occurred and the PI (or designee) has minimal 
information to include in the initial report to the Sponsor. However, it is very important that 
the PI (or designee) always make an assessment of causality for every event, prior to 
transmission of the SAE form to the Sponsor. The PI (or designee) may change his/her 
opinion of causality in light of follow-up information, amending the SAE form and the CRF 
accordingly. The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. The PI (or designee) will provide an assessment of causality as per 
instructions on the SAE form. 
8.3. 
Time Period, Frequency and Method of Detecting AEs 
As a consistent method of soliciting AEs, the participant shall be asked a non-leading question 
such as: "How do you feel?” 
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 IP will be documented as Medical/Surgical History.  
Any medical occurrence reported or observed after the first dose of IP will be recorded as an 
AE. AEs will be evaluated by the PI (or designee) and recorded. 


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Any AEs already documented at a previous assessment and designated as ongoing, should be 
reviewed at subsequent assessments as necessary. If these have 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 subject 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 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 subject’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 subject 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 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 requirements. 
The PI (or designee) is responsible for notifying the local IRB, local IEC, or the relevant local 
regulatory authority 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 subject, he/she 
will report the information to the Sponsor (or delegate) and Medical Monitor within 24 hours. 
The SAE form (and CRF) will always be completed as thoroughly as possible with all 


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available details of the event, signed by the PI (or designee), and forwarded to the Sponsor (or 
delegate) and Medical Monitor within the designated time frames. 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. 
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 
Representative or emergency contact.  
AEs will be classified as SUSARs if the AE or suspected adverse reaction meets the definition 
of “unexpected” in Section 8.1. SUSARs should be reported to the Ethics Committees and to 
the Regulatory Authority in accordance with applicable regulatory requirements for expedited 
reporting. It is the Investigator’s responsibility to report SUSARs to the Ethics Committee and 
Regulatory Authority. 
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.  
Investigators are not obligated to actively seek AE/SAE in former study participants. 
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 
IP, 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 
subject and provide further information to the Sponsor on the subject’s condition.  
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 subject 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 subject 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 subjects 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 


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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. 
8.8. 
Clinical Laboratory Evaluations 
A change in the value of a clinical laboratory assessment can represent an AE if the change is 
clinically relevant or if, during treatment with the IP, a shift of a parameter is observed from a 
normal value to an abnormal value, or a further worsening of an already abnormal value. 
When evaluating such changes, the extent of deviation from the reference range, the duration 
until return to the reference range, either while continuing treatment or after the EOT with the 
IP, and the range of variation of the respective parameter within its reference range, must be 
taken into consideration. 
If, at the end of the treatment phase, there are abnormal clinical laboratory values, which were 
not present at baseline, further clinical or laboratory investigations should be performed until 
the values return to within the reference range or until a plausible explanation (e.g., 
concomitant disease) is found for the abnormal clinical laboratory values. 
The Investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory parameter is CS, and therefore represents an 
AE. 
8.9. 
Pregnancy 
Any report of pregnancy for any female study subject or male study subject’s partner must be 
reported within 1 business day to the CRO. The female study participant must be withdrawn 
from the study. 
A urine or serum beta human chorionic gonadotropin (β-HCG) pregnancy test (according to 
local standard-of-care) 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 subject’s final visit (LFU Visit or time of early 
withdrawal from the study) (Appendix 1). 


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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.  
Pregnancy outcomes should be collected for female partners of any males who took the IP if 
possible. Consent to report information regarding these pregnancy outcomes should be 
obtained from the mother. 
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 HCG test 
or ultrasound result will determine the pregnancy onset date. 
8.10. 
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 1 business day reporting requirement for SAEs does not apply to reports of abuse, 
misuse, overdose, or medication errors unless these result in an SAE.  
The categories below are not mutually exclusive; the event can meet more than 1 category. 
• Abuse: Persistent or sporadic intentional intake of IP 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 an IP (For studies, medication errors are reportable to the Sponsor) 
• Misuse: Intentional use of IP other than as directed or indicated at any dose (Note: 
this includes a situation where the IP is not used as directed at the dose prescribed 
by the protocol) 
• Overdose: Intentional or unintentional intake of a dose of an IP exceeding a pre-
specified total daily dose of the product 
Cases of subjects missing doses of product are not considered reportable as medication errors.  
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. 


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Infusion errors related to rate of administration, reconstitution and/or dilution of IP, including 
use of appropriate diluent and the timeframe in which IP is to be used after reconstitution 
and/or dilution, are reportable as medication errors. 
Intentional overdosing of IP is unlikely. In the event of overdose in general, treatment should 
be supportive and symptomatic according the subject's clinical presentation.  
8.11. 
Serious Adverse Event Procedures 
8.11.1. 
Reference Safety Information 
The reference for safety information for this study is the IB, which the Sponsor has provided 
separately to all Investigators.  
The reference for safety information for the comparator in this study is the ertapenem 
SmPC/Product Package Insert, which the Sponsor has provided separately to all Investigators. 
8.11.2. 
Regulatory Agency, Institutional Review Board, Independent Ethics 
Committee, and Site Reporting 
The Investigator is responsible for notifying the local IRB, local IEC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required. 


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9. 
DATA MANAGEMENT AND STATISTICAL METHODS 
9.1. 
Data Collection 
The Investigators’ authorized site personnel must enter the information required by the 
protocol on the CRF. A Study Monitor 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. 
9.3. 
Statistical Analysis Process 
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 or to the data to be collected from a subject, 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 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 9.10.1; 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 study drug. 
All statistical analyses will be performed using SASÒ version 9.4 or higher (SAS Institute, 
Cary, NC 27513). The SAP will be finalized prior to unblinding to preserve the integrity of 
the statistical analysis and study conclusions.  


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9.4. 
Planned Interim Analysis, Adaptive Design, Sponsor Data Review 
Committee, and Data Safety Monitoring Board 
Masked individual and composite PK data from the first approximately 35 TBPM-PI-HBr 
subjects enrolled (among the first approximately 70 total subjects enrolled) will be reviewed 
by a blinded, independent PK Data Review Committee to verify the TBPM-PI-HBr dose. This 
review will be blinded and will only be a review of PK data; this is not a formal review of 
either safety or efficacy. PK samples obtained from the TBPM-PI-HBr group will be analyzed 
using a validated assay by a central bioanalytical laboratory. Study enrollment will continue 
uninterrupted during this blinded interim PK data assessment, and the remaining subjects will 
undergo sparse PK sampling. If TBPM-PI-HBr dose alteration needs to be considered, 
enrollment may be paused for sample size adjustment and protocol amendment. If a change in 
dose is required, the planned total enrolment may be adjusted as needed to ensure sufficient 
data are available from 884 evaluable subjects receiving the amended dose (Section 9.13). 
A blinded sample size reassessment will take place after 70% of the subjects have response 
data at TOC available and will be performed by the blinded Sponsor Data Review Committee 
(DRC). The blinded sample size re-estimation will either confirm the initial sample size 
estimate is adequate or increase the sample size (number of randomized subjects) to ensure 
the study has adequate power for the primary outcome measure, up to a maximum of 1,450 
subjects. In addition, the sample size may be increased based on a lower than expected 
evaluability rate (the proportion of randomized subjects included in the microbiological ITT 
population). No sample size adjustment downwards will be performed. 
The sample size re-estimation will be based on a blinded review of the overall response rate 
and evaluability rate according to pre-specified criteria documented in a sample size 
reassessment document (DRC Charter).  
No alpha adjustment will be made as this will be a blinded reassessment and no treatment 
group comparison will be performed for any endpoint.  
A DSMB will be involved in the management of this study to review safety. The DSMB will 
review safety data upon enrollment of 25% and 50% of subjects. Full details regarding the 
DSMB (e.g., committee composition, the criteria for scheduling an ad hoc meeting, what will 
be presented/decided) will be specified in the DSMB charter. The DSMB charter will be 
approved and finalized by the DSMB members prior to the first DSMB meeting. 
9.5. 
Selection of Subjects to be Included in the Analyses 
Intent-to-Treat (ITT) Population: All subjects who were randomized, regardless of whether 
they received any study drug. Subjects will be summarized by treatment to which they were 
randomized. 
Safety Analysis Population: Randomized subjects who received any amount of study drug. 
Subjects will be summarized by treatment to which they received. 
Microbiological Intent-to-Treat (micro-ITT) Population: All randomized subjects with a 
confirmed diagnosis of cUTI or AP (Inclusion Criterion 4) and a positive Screening urine 
culture defined as growth of one or two uropathogens at ≥105 CFU/mL. Subjects with 


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Screening urine culture growth of more than 2 species of microorganisms will be excluded 
from the micro-ITT Population, regardless of colony count. Any subject with cUTI or AP 
caused by a pathogen that is typically not expected to respond to either carbapenem study 
drug (e.g., Acinetobacter spp., Stenotrophomonas spp., Pseudomonas aeruginosa, methicillin-
resistant Staphylococcus aureus [MRSA]) will also be excluded from this population.  
Clinically Evaluable (CE) Population: Subjects who meet the definition for the ITT 
population, have no important protocol deviations that would affect the assessment of efficacy 
(to be defined in the SAP), and had an outcome assessed as clinical cure or clinical failure at 
EOT, TOC, and/or LFU.  
Microbiologically Evaluable (ME) Population: Subjects who meet the definitions of both 
the micro-ITT Population and CE Population.  
Pharmacokinetic (PK) Population: All subjects treated with at least one dose of TBPM-PI-
HBr with at least one analyzable plasma or urine PK sample. 
9.6. 
Subject Disposition 
Subjects in each analysis population, as well as subjects who complete the study, and subjects 
who prematurely discontinue from the study will be summarized by treatment group using 
descriptive statistics. In addition, for subjects who prematurely discontinue from the study, the 
reasons for discontinuation will be summarized by treatment group. All subjects enrolled in 
the study will be accounted for in the summation. 
9.7. 
Demographic and Baseline Characteristics 
Demographic and baseline disease characteristic data will be summarized for each treatment 
with frequency distributions and/or descriptive statistics. Descriptive summaries of 
demographic and baseline characteristics will be presented by treatment group and overall for 
the ITT and Safety Analysis population. Demographic and baseline disease characteristic data 
will also be listed. 
9.8. 
Investigational Product Exposure  
The number of subjects receiving TBPM-PI-HBr and ertapenem, the planned and total doses 
received, and along with the duration of exposure, will be summarized by treatment groups in 
the study for all subjects in the Safety Analysis population. 
9.9. 
Prior and Concomitant Medication 
Prior and concomitant medications will be coded using the World Health Organization 
(WHO) Drug Dictionary (WHODRUG/2006QA or newer version). 
Prior treatment includes all treatment (including OTC treatments such as herbal treatments, 
vitamins, diet aids, hormone supplements; and non-pharmacological treatment such as 
psychotherapy, as appropriate) received within 30 days (or pharmacokinetic equivalent of 
5 half-lives, whichever is longer) of and discontinued prior to the date of first dose of IP. 


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Prior and concomitant medications will be listed and summarized by preferred drug name and 
treatment group for the ITT and Safety Analysis population. See Inclusion/Exclusion criteria. 
9.9.1. 
Prohibited Concomitant Medications 
Treatment with any of the following concomitant medications or procedures is prohibited: 
• Any additional or adjunctive, non-study-specific, antibacterial drug therapy 
(between randomization and LFU) that would potentially effect outcome 
evaluations of cUTI/AP, except in cases of clinical failure of study drug therapy 
for the index cUTI/AP, including but not limited to systemic antibacterials with 
potential activity vs. uropathogens (e.g., Enterobacteriaceae), antibacterial drug 
prophylaxis, and antibacterial bladder irrigation  
• Gastric acid-reducing medications (between randomization and EOT), including 
but not limited to proton pump inhibitors (e.g., omeprazole, esomeprazole, 
lansoprazole), histamine-2 receptor antagonists (e.g., nizatidine, famotidine, 
cimetidine, ranitidine), and antacids (e.g., Alka-Seltzer, Milk of Magnesia, 
Amphojel, Gelusil, Maalox, Mylanta, Rolaids, Pepto-Bismol) 
• Valproic acid or divalproex sodium (between randomization and EOT) 
• Probenecid (between randomization and EOT) 
9.9.2. 
Permitted Concomitant Medications 
With the exception of prohibited concomitant medications discussed above (Section 9.9.1), 
other concomitant medications are permitted. For example, the following concomitant 
medications are permitted: 
• Antibiotics for the treatment of C. difficile (e.g., metronidazole, oral vancomycin, 
fidaxomicin) 
• Antiemetics, including but not limited to: 5-HT3 receptor antagonists (e.g., 
ondansetron, mirtazapine, dolasetron), dopamine antagonists (e.g., olanzapine, 
droperidol, domperidone), NK1 receptor antagonists (e.g., aprepitant, rolapitant), 
antihistamines (e.g., diphenhydramine, dimenhydrinate, promethazine), and 
anticholinergics (e.g., hyoscine) 
− Note that concomitant gastric acid-reducing medications are prohibited 
(Section 9.9.1) and should not be used to alleviate nausea or vomiting 
• Topical antibiotics other than those used for bladder irrigation 
• Antibiotics for the treatment of infections other than cUTI/AP that do not have a 
gram-negative spectrum of activity. For example, agents with Gram-positive only 
coverage (e.g., vancomycin, daptomycin, or linezolid) for suspected or identified 
carbapenem-resistant Gram-positive pathogens may be considered. 
Administration of non-study antibacterials for reasons other than clinical 


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failure of study drug for the index cUTI/AP requires approval by the Medical 
Monitor. 
9.10. 
Efficacy Analyses 
9.10.1. 
Primary Efficacy Variables 
Overall response (combined clinical cure plus microbiological eradication) at TOC in the 
micro-ITT population, 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 antimicrobial therapy is warranted and subject is 
alive 
• Microbiological Eradication is defined as a reduction of baseline urine pathogen(s) 
to <103 CFU/mL and negative repeated blood culture if blood culture was positive 
for uropathogen growth at baseline and subject is alive 
Subjects prematurely discontinued from IP for safety reasons and who require further 
antibacterial therapy for the cUTI/AP should be assessed as a clinical and microbiological 
failure at EOT and TOC. Subjects who are prematurely discontinued from IP administration 
due to insufficient therapeutic effect should be assessed as clinical and microbiological failure 
at EOT and automatically assigned an outcome of clinical and microbiological failure at TOC. 
For the overall response, subjects 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 response to either clinical cure, 
microbiological eradication, or both) at TOC. Subjects 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, subjects with 
an indeterminate outcome will be considered failures for the primary analysis. The number 
and percentage of subjects 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 TBPM-PI-HBr group,  
P2 = overall responder (success) rate in the ertapenem group,  
Δ = the non-inferiority margin 
The non-inferiority hypothesis test is a 1-sided hypothesis test performed at the 2.5% level of 
significance. The 95% CI will be calculated using the method of Mietennen and Nurminen. If 


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the lower limit of the 95% CI for the difference in overall response is greater than -12.5%, 
non-inferiority will be declared. 
The primary efficacy data will also be listed for the micro-ITT population. In addition, a 
sensitivity analysis of the primary endpoint will be performed for the CE population to assess 
general consistency with the primary analysis. 
As outlined in Section 9.13.1, in the setting of the ongoing COVID-19 pandemic, the 
statistical analyses and assessment of non-inferiority for the primary endpoint were revised in 
consultation with the US FDA, in order to preserve data integrity and to ensure the safety of 
patients and study team by limiting further enrollment into the study. The justification for this 
NI margin is provided in the June 2018 (Revision 1) FDA Guidance “Complicated Urinary 
Tract Infections: Developing Drugs for Treatment”. This guidance demonstrates that the 
benefit of active antibacterial therapy over no treatment (M1) is estimated to be 30%. 
Therefore, an NI margin of -12.5% is deemed appropriate given the proposed margin is well 
below the M1 of 30% and retains greater than 50% of the clinical benefit (M1), whilst 
comparing TBPM-PI-HBr to an IV carbapenem comparator. 
9.10.2. 
Secondary Efficacy Variables 
Secondary Variables include: 
• Overall response (combined clinical cure plus microbiological eradication as 
defined above) at the TOC Visit in the ME population 
• Clinical cure at EOT, TOC, and LFU Visits in the micro-ITT, CE, and ME 
populations 
• By-subject and by-pathogen microbiological eradication at EOT, TOC, and LFU 
in the micro-ITT and ME populations 
• Overall response in subgroups, including: 
− Stratified infection category 
− Stratified age category 
− Country/Region 
• Time (days) to resolution or improvement of signs and symptoms of cUTI and AP 
present at baseline in the micro-ITT populations 
• Time (days) to defervescence in micro-ITT subjects with a documented fever at 
Screening or Day 1 
• Rate of clinical relapse at the LFU Visit in the micro-ITT population 
• Rates of superinfection and new infection in the micro-ITT population 
• Determine PK parameters (e.g., Vd, Cmax, AUC, T>MIC) in TBPM-PI-HBr 
recipients in the PK population 


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9.10.3. 
Exploratory Efficacy Variables 
Exploratory efficacy variables include: 
• Enteric colonization with antibiotic-resistant Enterobacteriaceae at the TOC Visit 
in the micro-ITT population 
• By-subject and by-pathogen microbiological eradication and clinical improvement 
at Day 5 in the micro-ITT, CE, and ME populations 
• Clinical, microbiological, and overall responses at TOC among subjects with 
cUTI/AP caused by ESBL-producing Enterobacteriaceae 
9.11. 
Safety Analyses 
All safety analyses will be summarized and listed using the Safety Analysis population. 
Primary assessments of safety will include assessments of treatment emergent adverse events 
(TEAEs), 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 
21.0. AEs will be recorded from the first dose of IP through LFU. TEAEs are defined as 
events that are newly occurring or worsening from the time of the first dose of IP 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 IP 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 subject more than once, the AE is counted only once for that 
preferred term and at the highest severity and strongest relationship to study drug. 
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 creatinine, 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. 


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Protocol Name: ADAPT-PO                                                                         
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9.12. 
Other Analyses 
9.12.1. 
Pharmacokinetic Analyses 
The PK population includes two sets of TBPM-PI-HBr-treated subjects, the Sentinel PK 
Analysis Group and the Sparse PK Analysis Group. 
The Sentinel PK Analysis Group is the first 35 TBPM-PI-HBr-treated subjects among the first 
70 subjects enrolled. Plasma and urine PK Assessments for this group will be performed as 
follows: 
• Plasma PK Assessments: Blood samples will be collected following an oral dose 
(first, second, or third) on Day 2 at the following time intervals after oral 
administration of study drug: 0.25 h (± 5 min); 0.5 h (± 5 min); 1 h (+ 15 min); 2 h 
(+ 15 min); and 8 h (+ 15 min but prior to the next scheduled dose); these samples 
will be used to estimate PK parameters, including AUC0-t, AUCextrap, AUC0-oo, λz, 
Vd, T>MIC, Cmax, Tmax, CL, t1/2, Cmin, and VSS 
• Urine PK Assessments: Twenty-four (24) hour urine collection will be collected 
roughly in three (3) 8-h aliquots starting on Day 1; TBPM concentrations will be 
measured and total 8-h, 16-h and 24-h urine elimination will be estimated 
The Sparse PK Analysis Group includes all subjects enrolled after the first 70 subjects.  
• Plasma PK Assessments: Blood samples, using sparse sampling 
(3 samples/subject), will be collected following an oral dose (first, second, or 
third) on Day 2 of treatment at the following time intervals after oral 
administration of  study drug: 1 h (+ 15 min); 4 h (+ 1 h); and 8 h (+ 30 min but 
prior to the next scheduled dose) 
• Urine PK Assessments will not be performed for this set of subjects 
Pharmacokinetic parameters will be estimated for each subject sample. The following 
parameters will be derived for the sentinel PK group: 
Parameter 
Definition 
Cmin 
The minimum observed concentration. 
Cmax 
The maximum observed concentration. 
Tmax 
The time at which Cmax was apparent. 
AUC0-t 
The area under the concentration versus time curve from time zero to the 
sampling time at the last quantifiable concentration (Ct) at the time of the last 
quantifiable concentration (tlast) calculated by the linear trapezoidal rule. 
AUCextrap 
The area under the plasma concentration-time curve extrapolated from time t to 
infinity as a percentage of total AUC. 
λz 
The apparent terminal rate constant, estimated using the negative slope of the 
least square regression analysis of the log concentration versus time data for the 
terminal linear portion of the curve. 


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Protocol Name: ADAPT-PO                                                                         
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Parameter 
Definition 
t1/2 
The apparent terminal half-life, calculated from Ln 2 / λz. 
AUC0-¥ 
The area under the concentration-time curve estimated from time zero to infinity 
as the sum of the 2 areas: AUC0-t and AUCextrap, where AUCextrap is calculated as 
Ct / λz. 
CL 
The systemic clearance calculated as: Dose/AUC0-¥. 
T>MIC 
The time above the minimum inhibitory concentration. 
Vd 
The apparent volume of distribution, calculated as the amount of drug in the body 
divided by the concentration of drug in the blood/plasma. 
Vss 
The apparent volume of distribution at steady state. 
 
Additional PK parameters may be calculated as appropriate. A separate PK SAP will be 
written providing full details of the parameter estimations and PK analyses. 
9.13. 
Sample Size Calculation and Power Considerations 
The sample size was determined based on the primary endpoint of overall response. Planned 
enrollment for this study is approximately 1200 subjects.  
Assuming a response rate of 70% for both treatment groups, a pre-specified NI margin of 
10%, a 1:1 randomization ratio, and a one-sided significance level of 0.025, a trial including 
884 evaluable subjects would have approximately 90% power to show NI within a 10% 
margin. This trial aims to recruit 884 subjects for inclusion in the micro-ITT population. 
Assuming 75% of randomized subjects are included in the micro-ITT population, 
approximately 1,180 subjects will be recruited to ensure 884 subjects in the micro-ITT 
population. This size study would also have 90% power for an analysis of the ME population, 
assuming a 75% response rate and 67% of randomized subjects are included in the ME 
population. A blinded assessment of overall evaluability rates (the proportion of randomized 
subjects in the micro-ITT and ME populations) and response rates (pooled across treatment 
groups) will be performed during the study, and if assumptions are very different to those 
expected the sample size may be increased up to a maximum of 1450 subjects according to 
pre-specified criteria (see Section 9.13 and 9.4 for details). 
9.13.1. 
Changes Due to the COVID-19 Pandemic 
At the time of the interim analysis (March 2020) the DRC performed the planned blinded 
sample size reassessment after response data at TOC was available for 70% of patients. Based 
on the preliminary review of blinded data, the DRC recommended continuing recruitment up 
to the protocol-allowed maximum of 1,450 patients (Section 9.4 ) in order to ensure inclusion 
of 884 eligible patients in the primary analysis population. 
Based on the DRC recommendation, enrollment in the study continued, however the rate of 
enrollment dramatically decreased in the setting of the global COVID-19 pandemic and 


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related impact at multiple sites in countries where the study is being conducted. The Sponsor 
performed a continuous risk assessment in order to determine which sites could continue 
enrollment with minimal impact to patient/staff safety and post-treatment data collection. This 
ongoing risk assessment identified potential for significant impact to study conduct and data 
integrity based on difficulties in conducting post-treatment follow-up visits necessary for 
assessment of the primary endpoint, along with data monitoring of case records. Ultimately 
these challenges suggested that a progressively increasing proportion of indeterminate 
outcomes for the primary endpoint is likely with continued enrollment, which could bias the 
study towards non-inferiority.  Therefore, the Sponsor, considered it in the best interest of the 
study, and study participants, to conclude enrollment and revise the planned analyses based on 
the available dataset. 
Thus, as detailed in Section 9.10.1 , the original NI margin of -10% was modified to -12.5% 
in consultation with FDA. Based on this modification, it is expected that at least 670 patients 
will be included in the micro-ITT population, which ensures that the study will have >90% 
power to show non-inferiority when using a -12.5% NI margin assuming a true response rate 
of at least 60% across both treatment groups. 


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Protocol Name: ADAPT-PO                                                                         
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10. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
This study is conducted in accordance with current applicable regulations, International 
Council on Harmonisation (ICH), EU and its updates, and local ethical and legal 
requirements. 
10.1. 
Sponsor’s Responsibilities 
10.1.1. 
Good Clinical Practice Compliance 
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 GCP Guideline E6 (1996) and 
EU Directive 2001/20/EC. 
Representatives of the study Sponsor and/or the company organizing/managing the research 
on behalf of the Sponsor to inspect study data, subjects’ 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 regulatory authority 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 regulatory authority approvals required prior 
to release of IP for shipment to the site. 
10.1.2. 
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. 
10.1.3. 
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.  
10.1.4. 
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Independent Ethics Committees 
The Sponsor will provide a summary of the Clinical Study Report within one year of the end 
of the study completion date to the competent authority of the Member State(s) concerned as 
required by regulatory requirement(s), and to comply with the community guideline on GCP.  
The Sponsor will provide the IECs with a copy of the same summary. 
10.1.5. 
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 


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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. 
The Sponsor will make an end of study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC. End of study is the time at which all 
required data has been collected to answer the research question(s) in the protocol.  
10.2. 
Investigator Responsibilities 
10.2.1. 
Good Clinical Practice Compliance 
The Investigator must undertake to perform the study in accordance with ICH GCP Guideline 
E6 (1996), EU Directive 2001/20/EC 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 subjects within the agreed recruitment period. 
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 subject has a primary care physician, the Investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study. 
10.2.2. 
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 subjects 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 IP, 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 (inter)national 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. 


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Protocol Name: ADAPT-PO                                                                         
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10.2.3. 
Documentation and Retention of Records 
10.2.3.1. Case Report Forms 
Electronic Case Report Forms (eCRF) 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.  
For electronic data capture studies the Investigator is responsible for maintaining adequate 
and accurate medical records from which accurate information is recorded onto 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. 
10.2.3.2. 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 
subject’s medical file, subject diary cards, original clinical laboratory reports, and histology 
and pathology reports. All key data must be recorded in the subject’s medical records. 
The Investigator must 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 
subject 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., subject’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 
Food and Drug Administration [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. 
10.2.3.3. 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 regulatory authorities), the EMA, other regulatory authorities, 
the Sponsor or its representatives, and the IRB/IEC for each site. 


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Protocol Name: ADAPT-PO                                                                         
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10.2.3.4. Financial Disclosure 
Upon submission of a marketing application to the FDA for any drug, Spero Therapeutics, 
Inc. 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. 
10.2.4. 
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. 
10.3. 
Ethical Considerations 
10.3.1. 
Informed Consent 
It is the responsibility of the Investigator to obtain written informed consent from all study 
subjects prior to any study-specific procedures including Screening assessments. All consent 
documentation must be in accordance with applicable regulations and GCP. Each subject or 
the subject’s legally-authorized representative is requested to sign the subject Informed 
Consent Form or a certified translation, after the subject has received and read (or been read) 
the written subject 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 subject’s rights and responsibilities. A copy of the informed consent documentation (e.g., 
a complete set of subject information sheets and fully executed signature pages) must be 
given to the subject or the legally-authorized representative of the subject. If applicable, a 
consent form provided in a certified translation of the local language. Signed consent forms 
must remain in each subject’s study file and must be available for verification at any time. 
If subjects 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 


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Coordinating PI) is responsible for this action. Additionally, if the IRB/IEC requires 
modification of the sample subject Information and Consent document provided by the 
Sponsor, the documentation supporting this requirement must be provided to the Sponsor. 
10.3.2. 
Institutional Review Board or Independent Ethics Committee 
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 subject recruitment information to the IRB/IEC for review, and 
all must be approved prior to site initiation. 
For sites within the EU, the applicant for an IEC opinion can be the Sponsor, the Investigator, 
or for multi-site studies the Coordinating PI or Sponsor, according to national provisions. 
Responsibility for coordinating with IRBs/IECs is defined in the Investigator Agreement. 
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 subject safety issue. 
IP 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. 
10.4. 
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 (GDPR) 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 Spero 
Therapeutics, Inc. for 15 years. Use of individual subject data and/or remaining samples may 
result in patents or have other monetary value. These patents or other products resulting from 
subject samples/data will be owned by Spero Therapeutics, Inc. There will be no financial 
benefit from the future research on subject data and samples. 
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines. 
After subjects have consented to take part in the study, the Sponsor and/or its representatives 
review their medical records and data collected during the study. Others, including the 


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following, may review these records and data: independent auditors who validate the data on 
behalf of the Sponsor; third parties with whom the Sponsor may develop, register, or market 
TBPM-PI-HBr; national or local regulatory authorities and the IRB(s)/IEC(s), which gave 
approval for the study to proceed. The Sponsor and/or its representatives accessing the 
records and data will take all reasonable precautions in accordance with applicable laws, 
regulations, and guidelines to maintain the confidentiality of subjects' identities. 
Subjects will be assigned a unique identifying number. However, their initials and date of 
birth may also be collected and used to assist the Sponsor to verify the accuracy of the data, 
for example, to confirm that laboratory results have been assigned to the correct subject. 
The results of studies containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth will be recorded. They may be transferred to, 
and used in, other countries that may not afford the same level of protection that applies 
within the countries where this study is conducted. The purpose of any such transfer would be 
to support regulatory submissions, to conduct new data analyses to publish or present the 
study results, or to answer questions asked by regulatory or health authorities. 
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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11. 
REFERENCES 
Patient CDC 2013. Antibiotic Resistance Threats in the Unites States. 
https://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf 
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976; 16(1):31–41. 
Doi Y, Park YS, Rivera JI, et al. (2013). Community-associated extended-spectrum beta-
lactamase-producing Escherichia coli infection in the United States. Clin Infect Dis 56: 641-
648. 
Fujimoto K., Takemoto K., Hatano K. Nakai T., Terashita S., Matsumoto M., Eriguchi Y., 
Eguchi K., Shimizudani T., Sato K., Katsunori Kanazawa K., Sunagawa M., Ueda Y. (2013). 
Novel Carbapenem Antibiotics for Parenteral and Oral Applications: In Vitro and In Vivo 
Activities of 2-Aryl Carbapenems and Their Pharmacokinetics in Laboratory Animals. 
Antimicrobial Agents and Chemotherapy. Vol 57, No. 2. 
Heang K., Grosser L., Farrington K., Cotroneo N., Jain A., Vacarro L., Corbett D., and Rubio 
A. (2018). In Vivo Characterization of Tebipenem-Pivoxil (SPR994) in a Murine Ascending 
Escherichia coli. Urinary Tract Infection Model. Spero Therapeutics, Cambridge, MA, USA; 
Evotec (UK) Ltd., Macclesfield, UK. 
Johnson JR, Tshesnokova V, Johnston B, Clabots C, Roberts PL, Billig M, Riddell K, Rogers 
P, Qin X, Butler-Wu S, Price LB, Aziz M, Nicolas-Chanoine MH, DebRoy C, Robicsek A, 
Hansen G, Urban C, Platell J, Trott DJ, Zhanel G, Weissman SJ, Cookson BT, Fang FC, 
Limaye AP, Scholes D, Chattopadhyay S, Hooper DC and Sokurenko EV (2013). Abrupt 
Emergence of a Single Dominant Multidrug-Resistant Strain of Escherichia coli. The Journal 
of Infectious Diseases, 207, 919-928. 
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 7 (5) 1747–1756. 
Meiji Seika Pharma Co., Ltd, Orapenem® J-NDA CTD Module 2.6.3 Pharmacology 
Tabulated Summary  
Mendes RE, Rhomberg PR, Watters A, Cotroneo N, Rubio A, and Flamm RK (2018). 
Antimicrobial Activity Assessment of Tebipenem (SPR859) against an Isolate Collection 
Causing Urinary Tract Infections. JMI Laboratories, North Liberty, Iowa, USA; Spero 
Therapeutics, Cambridge, Massachusetts, USA. 
Muratani T, Doi K, Kobayahi T, Nakamura T, and Matsumoto T. (2009). Antimicrobial 
Activity of Tebipenem Against Various Clinical Isolates from Various Specimen, Mainly 
Urinary Tract. The Japanese Journal of Antibiotics. 62-2, 1-13. 
Talan DA, Takhar SS, Krishnadasan A, Abrahamian FA, Mower WR, Moran GJ. (2016). 
Fluoroquinolone-Resistant and Extended-Spectrum β-Lactamase–Producing Escherichia coli 
Infections in Patients with Pyelonephritis, United States. Emerging Infectious Disease. (22)9. 


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Yao Q, Wang J, Cui T, Yang Z, Su M, Zhao P, Yan H, Zhan Y and Yang H (2016). 
Antibacterial Properties of Tebipenem Pivoxil Tablet, a New Oral Carbapenem Preparation 
against a Variety of Pathogenic Bacteria in Vitro and In Vivo. Molecules. 21, 62. 


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APPENDIX 1. SCHEDULE OF ASSESSMENTS 
Study Period 
Screening 
Treatment 
Follow-Up 
Visit or Study Day 
-1 or 1 
Days 1 through 14 
19 ± 2  
25 ± 2  
Study Day 
Screening a 
1 (Post-Rand.) 
2 – 14 
EOT b 
TOC c 
LFU 
Informed Consent 
X 
 
 
 
 
 
Medical & Surgical History d 
X 
 
 
 
 
 
Height and Weight  
X 
 
 
 
 
 
Complete Physical 
Examination e 
X 
 
 
X 
X 
X 
Focused Physical Examination 
e 
 
X 
X 
 
 
 
Vital Signs (T, P, RR, BP) f 
X 
X 
X 
X 
X 
X 
Collection of cUTI/ AP signs 
and symptoms 
X 
X 
X 
X 
X 
X 
12-lead ECG g 
X 
X 
 
X 
X 
 
Local labs for eligibility (safety 
and pregnancy testing) h 
X 
  
 
 
 
 
Local serum creatinine to 
assess renal function for dose 
adjustments h 
X 
X 
X 
 
 
 
Central labs (blood/urine for 
safety) i 
X 
X 
X 
X 
X 
X 
Urine culture j 
X 
 
X 
X 
X 
X 
Blood cultures k 
X 
<--------------------------------X-----------------------------> 
Rectal swab  
X 
 
 
 
X 
 
Study Drug Administration l 
 
X 
X 
 
 
Blood sample for plasma PK m 
 
X 
 
 
Urine collection for PK n 
 
X--------> 
 
 
 
 
Urinary tract instrumentation 
status o 
X 
 
X 
X 
X 
X 
Site of care p  
X 
X 
X 
X 
X 
X 
Investigator assessment of 
clinical outcome 
 
 
 
X 
X 
X 
Prior and concomitant 
medications 
X 
X 
X 
X 
X 
X 
Adverse Eventsq 
X 
X 
X 
X 
X 
AP= Acute Pyelonephritis ; BP = Blood Pressure; cUTI = Complicated Urinary Tract Infection; 
ECG = Electrocardiogram; EOT = End-of-Treatment Visit; LFU = Late Follow-up Visit; P = Pulse; 
PK = Pharmacokinetic; Rand= Randomization; RR= Respiratory Rate; T = Temperature; TOC = Test-of-Cure Visit  
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 hours of randomization) may be used to determine subject eligibility 
even if performed prior to signing the ICF; however, study-specific assessments, such as triplicate 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 (see Section 7.1.1  for detail). 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 


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  CONFIDENTIAL 
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Protocol Name: ADAPT-PO                                                                         
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Day 1 ECGs must be performed (i.e., Day 1 ECGs must be performed in triplicate 1h (±15 min) after the first oral 
dose administration) (see Section 7.1.2  for detail). 
b 
IP administration is 7-10 calendar days, or up to a maximum of 14 calendar days for subjects with a baseline blood 
culture that is positive for uropathogen growth. The EOT Visit occurs on the calendar day or the day following (+1 
day) the last dose of study drug. All EOT procedures may be performed the day following last dose of study drug 
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 be duplicated; for 
instance, if Day 7 and EOT occur on the same day, the EOT central lab assessment kit should be used in place of Day 
7 kit. 
c 
TOC Visit: Day 19 ± 2 days. The procedures at the TOC Visit should be performed for all subjects including those 
who prematurely discontinue study drug. 
d 
Obtain medical/surgical history, including urological history and any active or inactive conditions diagnosed within 
the previous 5 years. 
e 
Complete physical examinations at Screening, EOT, TOC, and LFU consist of skin, head and neck, heart, lung, 
abdomen (including suprapubic area), extremities, back/flank/costovertebral angle tenderness, and neuromuscular 
assessments. Focused physical examinations between Day 1 and EOT are symptom-based assessments. If Screening 
Visit and Day 1 occur on the same calendar day the focused physical exam on Day 1 is optional. 
f 
Vital signs include blood pressure, pulse, respiratory rate, and temperature. 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), TOC, and LFU. 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 subject’s body temperature 
should be used throughout the study. If Screening Visit and Day 1 occur on the same calendar day, repeated vital 
signs on Day 1 are optional. 
g 
At Screening, perform 12-lead ECGs in triplicate at 1-5 minute intervals (calculate mean QTcF value for 
eligibility). On Day 1, perform 12-lead ECGs in triplicate at 1-5 minute intervals 1h (±15 min) after the first oral dose 
administration. At EOT, perform 12-lead ECGs in triplicate at 1-5 minute intervals 1h (±15 min) after the final oral 
dose administration. At TOC, perform a single 12-lead ECG. 
h 
Results from the local blood and urine samples are used to determine eligibility (results can be from samples obtained 
up to 24 hours prior to randomization). Assessments include serum creatinine (for CrCl calculation), ALT, AST, total 
bilirubin, absolute neutrophil count, blood urea nitrogen (or blood urea), urinalysis (for LE and WBC in spun or 
unspun urine). A urine or serum beta human chorionic gonadotropin (β-HCG) pregnancy test (urine or serum 
according to local standard-of-care) is performed by the local laboratory on all FOCP at the Screening Visit, and if 
pregnancy is suspected at any time. Serum creatinine (for CrCl calculation) should be assessed every 3 days for 
subjects with normal renal function at baseline and at least once daily for subjects with moderate renal impairment 
from the time of first dose until the CrCl stabilizes. *If available, weight on the day of the serum creatinine 
measurement to be used for calculating CrCl. 
i 
The central safety laboratory will perform the following evaluations on blood and urine samples: hematology, 
coagulation, serum chemistry (including L-carnitine), and complete urinalysis. Central safety labs during treatment 
will be performed on Screening, Day 1 (if the Screening central safety labs are collected on Day 1, the Day 1 labs do 
not need to be repeated), Day 3, Day 5, Day 7, Day 9 (if still receiving IP), Day 11 (if still receiving IP), Day 13 (if 
still receiving IP), EOT, TOC, and LFU. In addition, serum β-HCG is performed on all FOCP at the Screening Visit 
and at the subject’s final visit (LFU Visit or time of early withdrawal from the study) by the central laboratory. 
j 
Obtain urine samples for culture at Screening (urine cultures collected per standard-of-care up to 24 h prior to 
randomization may be used for eligibility), Day 5, EOT, TOC, and LFU. At LFU, urine culture must be obtained in 
only subjects with a positive urine culture (growth of urine culture bacterial pathogen(s) ≥105 CFU/mL) after the 
TOC Visit. Urine culture must also be collected on any day a subject is deemed a clinical failure, prior to the start of 
non-study antibacterial rescue therapy.  
k 
Collect 2 sets of blood cultures (each set is 1 aerobic and 1 anaerobic blood culture bottle) from 2 separate 
venipuncture sites at Screening. Blood cultures should be repeated on the day that a previous (e.g., baseline) blood 


Spero Therapeutics, Inc. 
  CONFIDENTIAL 
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Protocol No: SPR994-301 
 
Version 4.0, Final 
Protocol Name: ADAPT-PO                                                                         
Page 94 of 96 
culture is determined to be positive (e.g., reveals growth of a uropathogen). Blood cultures should be repeated as 
necessary until negative blood cultures are obtained. 
l 
The TBPM-PI-HBr treatment group will be administered TBPM-PI-HBr 300 mg film-coated tablets orally 600mg 
q8h (±0.5h) plus a single dummy IV infusion over 30 min q24h (±0.5 h). The ertapenem treatment group will receive 
ertapenem for IV injection, administered as a 1-gram IV infusion over 30 min q24h (±0.5 h) plus dummy placebo 
tablets administered orally q8h (±0.5 h).  
m 
First approximately 70 subjects: Blood samples will be collected on following an oral dose (first, second, or third) on 
Day 2 at the following time intervals after oral administration of t study drug: 0.25 h (±5 min); 0.5 h (±5 min); 1 h 
(±15 min), 2 h (±15 min), 8 h (±15 min but prior to the next scheduled dose). For all subjects enrolled after the first 
70 subjects, blood samples using sparse sampling (3 samples/subject) will be collected following an oral dose (first, 
second, or third) on Day 2 at the following time intervals after oral administration of study drug: 1 h (±15 min), 4 h 
(±1h), and 8 h (±30 min but prior to the next scheduled dose). The exact dose time and the exact PK sample time 
should be collected for all subjects when collecting PK samples.  
n 
First approximately 70 subjects, a twenty-four (24) h urine collection will be collected in roughly three (3) 8-h 
aliquots after the first dose of the study drug on Day 1.  These collections should occur as close as possible to the 8 
hour time limit.  Deviations will only be documented for those collections that occur outside of a 7-9 hour window 
o 
Record all start times and end times of all urinary tract instrumentation, including but not limited to bladder catheters, 
stents, nephrostomy tubes, and other urological prosthetic material. 
p 
Record the site of care (e.g., acute care hospital ward, long-term care facility, outpatient infusion center). 
q 
AEs will be collected from the time of the first dose of IP. 


Spero Therapeutics, Inc. 
  CONFIDENTIAL 
    26May2020 
Protocol No: SPR994-301 
 
Version 4.0, Final 
Protocol Name: ADAPT-PO                                                                         
Page 95 of 96 
APPENDIX 2. LIST OF SHORT-ACTING ANTIBIOTICS 
Allowed vs. Disallowed Prior Antibiotics 
Receipt of any potentially effective systemic antibiotic with activity against Gram-negative 
uropathogens within the 72-h window prior to randomization is an exclusion criterion. 
However, subjects may be eligible for the study despite prior antimicrobial therapy if they 
received a single dose of a short-acting systemic antibiotic within 72 h prior to randomization. 
For the purposes of this study, a short-acting antibiotic is defined as having a dosage 
frequency of more than once daily (e.g., q12 h or more frequently). If a subject received a 
prior short-acting systemic antibiotic that is not listed below, the Investigator must contact the 
Medical Monitor to ensure subject eligibility.  
 
 



SAP_001.pdf: 
Offici al Titl e: 
A P h as e 3, R a n d o miz e d, D o u bl e -bli n d, D o u bl e -d u m m y, M ultic e nt er,  
Pr os p ecti v e St u d y t o Ass ess t h e Effic ac y, S af et y a n d P h ar m ac o ki n etics  
of Or all y A d mi nist er e d T e bi p e n e m Pi v o xil H y dr o br o mi d e ( S P R 9 9 4)  
C o m p ar e d t o I ntr a v e n o us Ert a p e n e m i n P ati e nts wit h C o m plic at e d Uri n ar y 
Tr act I nf ecti o n (c U TI) or Ac ut e P y el o n e p hritis ( A P)  
N C T N u m b er:  
N C T 0 3 7 8 8 9 6 7  
D oc u m e nt  D at e : 
S t atistic al A n al ysis Pl a n V ersi o n 1. 1 : 0 3 S e pt e m b er 2 0 2 0  


P a g e 1  of 3 9  
S per o  T her a pe utics, I nc.  
S T A TI S TI C A L A N A L Y SI S P L A N  
P R O T O C O L S P R 9 9 4 -3 0 1 
A P h ase 3, R a n d o mize d, D o u ble -bli n d, D o u ble -d u m m y, M ultice nter, Pr os pecti ve 
St u d y t o Assess t he Effic ac y, S afet y a n d P h ar m ac o ki netics of Or all y 
A d mi nistere d Te bi pe ne m Pi v o xil H y d r o br o mi de ( S P R 9 9 4) C o m p are d t o 
I ntr a ve n o us Ert a pe ne m i n S u bject s wit h C o m plic ate d Uri n ar y Tr act I nfecti o n 
(c U TI) or Ac ute P yel o ne p hritis ( A P)  
Pr ot oc ol c o de: 
S P R 9 9 4 -3 0 1  
S A P Versi o n:  
Fi nal versi o n 1. 1  
S A P D ate:  
0 3  Se pte m ber  2 0 2 0  
A ut h or:  
 


St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
 
P a g e 2 of 3 9  
 
 
S A P fi n al 1. 1: 0 3  S e pt e m b er  2 0 2 0  
C o nfi d e nti al  
D O C U M E N T HI S T O R Y  
V E R SI O N HI S T O R Y  
Versi o n #  
Versi o n D ate  
Fi nal  v 1. 0 
2 0 A u g ust 2 0 2 0  
Fi nal 1. 1  
0 3 Se pte m ber 2 0 2 0  
R E VI SI O N HI S T O R Y  
Versi o n #  
C h a pter  
Re visi o n S u m m ar y  
Re as o n(s) f or Re visi o n  
Fi nal v 1 . 0 
N/ A  
I nitial release 
N/ A  
Fi nal 1. 1  
7 
A d de d clarificati o n t o micr o -I T T 
p o p ulati o n defi niti o n t o i ncl u de pat h o ge ns 
i de ntifie d i n bl o o d i nt o c o nsi derati o n f or 
micr o -I T T assi g n me nt 
F ull rati o nal e is gi ve n i n secti o n 9  
Fi nal 1. 1  
9 
A d de d rati o nal e f or t he u p date i n secti o n 7 
Necessar y as t he clarificati o n i n Secti o n 7 
i m pacts t he defi niti o n pr o vi de d i n t he 
Pr ot oc ol  
 
 
 
 


St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
P a g e 3 of 3 9  
S A P fi n al 1. 1: 0 3  S e pt e m b er  2 0 2 0  
C o nfi d e nti al  
A P P R O V A L SI G N A T U R E S  
S T U D Y TI T L E: A P hase 3, Ra n d o mize d, D o u ble- bli n d, D o u ble- d u m m y, M ultice nter, 
Pr os pecti ve St u d y t o Assess t he Efficac y, Safet y a n d P ha r mac o ki netics of Orall y A d mi nistere d 
Te bi pe ne m Pi v o xil H y dr o br o mi de ( S P R 9 9 4) C o m pare d t o I ntra ve n o us Erta pe ne m i n S u bject s 
wit h C o m plicate d Uri nar y Tract I nfecti o n (c U TI) or Ac ute P yel o ne p hritis ( A P)  
P R O T O C O L N U M B E R: S P R 9 9 4 - 3 0 1 
S A P Fi nal  versi o n 1. 1, 0 3  Se pte m ber  2 0 2 0 
P SI  
A U T H O R:  
,  
 
 
Electr o nicall y si g ne d & date d 
R E V I E W E D B Y:  
,  
 
 
Electr o nicall y si g ne d & date d 
R E V I E W E D B Y:  
, 
 
 
Electr o nicall y si g n e d & date d 
R E V I E W E D B Y:  
,  
 
 
Electr o nicall y si g ne d & date d  
S per o  T hera pe utics, I nc. 
A P P R O V E D B Y:  
, M D,  
 
 
Electr o nicall y si g ne d & date d 
A P P R O V E D B Y:  
,  
 
 
Electr o nicall y si g ne d & date d 
A P P R O V E D B Y:  
, 
, 
 
Electr o nicall y si g ne d & date d 
A P P R O V E D B Y:  
, M D,  
 
 
Electr o nicall y si g ne d & date d 
A P P R O V E D B Y:  
,  
 
 
Si g n off s heet si g ne d a n d date d  






St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
 
P a g e 6 of 3 9  
 
S A P fi n al 1. 1: 0 3  S e pt e m b er  2 0 2 0  
C o nfi d e nti al  
LI S T O F  A B B R E VI A TI O N S  
A E  
A d verse e ve nt  
A P  
Ac ute p yel o ne p hritis  
A L P  
Al kali ne p h os p hatase  
A L T  
A la ni ne a mi n otra nsferase 
A S T  
A s partate a mi n otra nsferase 
A T C  
A nat o mical T hera pe utic C he mical  
B U N 
Bl o o d Urea Nitr o ge n 
C E 
Cli nicall y E val ua ble 
C F U 
C ol o n y- F or mi n g U nit 
CI  
C o nfi de nce i nter val  
C L SI  
Cli nical a n d La b orat or y Sta n dar ds I nstit ute  
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( Nati o nal Ca ncer 
I nstit ute) 
Cr  
Ser u m creati ni ne  
Cr Cl  
C reati ni ne cleara nce 
C R E  
C ar ba pe ne m-resista nt E nter o b acteri ace ae  
C R F  
Case re p ort f or m 
c U TI 
C o m plicate d uri nar y tract i nfecti o ns  
D S M B  
Data Safet y M o nit ori n g B oar d  
D R C  
Data Re vie w C o m mittee  
E C G  
Electr ocar di o gra m  
e C R F  
Electr o nic case re p ort f or m  
E O T  
E n d - of-Treat me nt  
E R P  
E val ua bil it y Re vie w Pla n  
E S B L  
E xte n de d S pectr u m Beta -Lacta mase  
H b  
He m o gl o bi n 
I P A 
Is o pr o p yl Alc o h ol 
I T T 
I nte nti o n-t o-Treat  
I V 
I ntra ve n o us 
L F U  
Late F oll o w -U p  
M E  
Micr o bi ol o gicall y E val ua ble  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
MI C  
Mi ni m u m I n hi bit or y C o nce ntrati o n  
M R S A  
Met hicilli n -resista nt St a p hyl oc occ us a ure us  


St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
 
P a g e 7 of 3 9  
 
S A P fi n al 1. 1: 0 3  S e pt e m b er  2 0 2 0  
C o nfi d e nti al  
NI  
N o n -i nferi orit y 
P D  
P har mac o d y na mics  
P E  
P h ysical E xa mi nati o n  
P K  
P har mac o ki netics  
p o p P K 
P o p ulati o n p har mac o ki netics 
P T  
Preferre d ter m  
Q Tc F  
Fri dericia’s f or m ula  
S A E  
Seri o us a d verse e ve nt  
S A P  
Statistical A nal ysis Pla n  
SI R S  
S yste mic i nfla m mat or y res p o nse s y n dr o me  
S O C  
S yste m Or ga n Class  
S R C  
Safet y Re vie w C o m mittee  
T E A E  
Treat me nt emer ge nt ad verse eve nt  
T L Fs  
Ta bles, listi n gs, a n d fi g ures  
T M P -S M X  
Tri met h o pri m -s ulfa met h o xaz ole 
T O C  
Test -of -C ure  
U L N  
U p per l i mit of n or mal  
W B C  
W hite Bl o o d Cells  
W H O  
W orl d Healt h Or ga nizati o n  
W H O D D  
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y 
 
 


St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
 
P a g e 8 of 3 9  
 
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C o nfi d e nti al  
1.  
I N T R O D U C TI O N 
T his Statistical A nal ysis Pla n ( S A P) descri bes t he statistical a nal ysis a n d re p orti n g f or t he st u d y 
pr ot oc ol S P R 9 9 4 - 3 0 1 ( versi o n 4. 0) date d 2 6 Ma y 2 0 2 0. It is base d o n t he fi nal electr o nic case 
re p ort f or ms (e C R Fs) date d 0 1 A pr  2 0 1 9. T his is a P hase 3, ra n d o mize d, d o u ble-bli n d, d o u ble -
d u m m y, m ultice nter, m ulti nati o nal, pr os pecti ve st u d y t o assess t he efficac y, safet y a n d 
p har mac o ki netics ( P K ) of te bi pe ne m pi v o xil h y dr o br o mi de ( T B P M -PI -H Br , als o k n o w n as 
S P R 9 9 4) a d mi nistere d orall y c o m pare d t o patie nts  recei vi n g erta pe ne m a d mi nistere d I V f or 
c o m plicate d uri nar y tract i nfecti o ns ( c U TI) or ac ute pyel o n e p hritis (A P ). 
T his S A P d oes n ot i ncl u de t he descri pti o n of t he P K a n d p har mac o d y na mic ( P D) a nal yses, 
w hic h are descri be d  i n a se parate sta n d-al o ne P K/ P D statistical a nal ysis pla n. 
2.  
S T U D Y O B J E C TI V E S  
2. 1  Pri m ar y  O bjecti ves  
•  T o assess t he o verall res p o nse (c o m bi ne d cli nical c ure pl us micr o bi ol o gical era dicati o n) 
of oral T B P M -PI -H Br  c o m pare d t o i ntra ve n o us (I V) erta pe ne m i n patie nts  ≥1 8 years of 
a ge wit h c U TI/ A P  
•  T o assess t he safet y  of oral T B P M -PI -H Br c o m pare d t o I V erta pe ne m i n patie nts  ≥1 8 years 
of a ge wit h c U TI/ A P . 
2. 2  Sec o n d ar y O bjecti ves  
•  T o c o m pare cli nical c ure rates bet wee n treat me nt gr o u ps 
•  T o c o m pare micr o bi ol o gical era dicati o n r ates bet wee n treat me nt gr o u ps 
•  T o  assess  t he  p o p ulati o n  p har mac o ki netics  ( p o p P K)  of  T B P M -PI -H Br  i n patie nts  wit h 
c U TI/ A P; t he d osa ge of T B P M -PI -H Br will be c o nfir me d base d off a bli n de d a nal ys is of 
P K data fr o m t he first a p pr o xi matel y 3 5 e nr olle d T B P M -PI -H B r patie nts.  
2. 3  E x pl or at or y O bjecti ves  
•  T o deter mi ne w het her treat me nt wit h T B P M -PI -H Br or erta pe ne m is ass ociate d wit h 
e nteric c ol o nizati o n wit h a nti bi otic -resista nt E nter o b acter ales  
•  T o c o m pare micr o bi ol o gical era dicati o n rates a n d cli nical i m pr o ve me nt at Da y  5 bet wee n 
treat me nt gr o u ps 
•  T o assess cli nical, micr o bi ol o gical, a n d o verall res p o nses i n patie nts  wit h c U TI/ A P ca use d 
b y E xte n de d S pectr u m Beta -Lacta mase  (E S B L )- pr o d uci n g E nter o b acter ales .  


St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
 
P a g e 9 of 3 9  
 
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C o nfi d e nti al  
3.  
S T U D Y  D E S C RI P TI O N 
3. 1  St u d y Desi g n , Pl a n ne d I nteri m A n al ysis, a n d Re v ie w C o m mittees 
T his is a P hase 3, ra n d o mize d, d o u ble- bli n d, d o u ble- d u m m y, m ultice nter, m ulti nati o nal, 
pr os pecti ve st u d y t o assess t he efficac y, safet y , a n d P K of T B P M -PI -H Br a d mi nistere d orall y 
c o m pare d wit h erta pe ne m a d mi nistere d I V f or  t he treat me nt of cU TI/ A P.  
T his st u d y will e nr oll a p pr o xi matel y 1, 2 0 0 patie nts, u p t o a ma xi m u m of 1, 4 5 0 patie nts 
(c o nti n ge nt u p o n a s ufficie nt n u m ber of e val ua ble patie nts). Sa m ple size deter mi nati o n details 
are pr o vi de d i n Secti o n  4 ; st u d y visits a n d all o we d ti me wi n d o ws are s pecifie d i n S ecti o n 8. 2 . 
3. 1. 1  
R a n d o mi z ati o n  
F or t his st u d y, e nr oll me nt occ urs at t he ti me of ra n d o mizati o n. All patie nts  wit h a cli nical 
dia g n osis of c U TI/ A P s ufficie nt t o start e m piric a nti bi otics a n d w h o are a ble t o t olerate oral 
me dicati o n will be ra n d o ml y assi g ne d t o  recei ve eit her T B P M -PI -H Br  or erta pe ne m i n a 1: 1 
rati o. 
Ra n d o mizati o n will be stratifie d b y: 
•  Baseli ne dia g n osis ( A P vs. c U TI)  
•  A ge at i nf or me d c o nse nt ( ≥1 8 t o < 6 5 years vs.  ≥6 5 years)  
N ote: Ac ute p yel o ne p hritis ( A P) i n t his st u d y refers t o A P wit h o ut c o m plicati n g fact ors. As per 
pr ot oc ol I ncl usi o n Criteri o n 4, patie nts  w h o meet t he disease  defi niti o n f or c U TI ( pr ot oc ol 
I ncl usi o n Criteri o n 4a) a n d w h o  als o ha ve fla n k pai n or c ost o verte bral te n der ness are t o be 
ra n d o mize d as c U TI rat her t ha n A P.  
3. 1. 2  
P K D at a R e vi e w C o m mitt e e  
Mas ke d i n di vi d ual a n d c o m p osite P K data fr o m t he Se nti nel P K A nal ysis Gr o u p ( first 
a p pr o xi matel y 3 5 T B P M- PI -H Br patie nts  e nr olle d a m o ng t he first a p pr o xi matel y 7 0 t otal 
pat ie nts e nr olle d) will be re vie we d b y a bli n de d, i n de pe n de nt P K Data Re vie w C o m mittee t o 
verif y t he T B P M -PI -H Br d ose.  T his re vie w will be bli n de d a n d will o nl y be a re vie w of i nteri m 
plas ma P K data; t his is n ot a f or mal re vie w of eit her safet y or efficac y. St u d y e nr oll me nt will 
c o nti n ue u ni nterr u pte d d uri n g t his bli n de d i nteri m P K data assess me nt, a n d t he re mai ni n g 
patie nts  will u n der g o s parse P K sa m pli n g. If T B P M-PI -H Br d ose alterati o n nee ds t o be 
c o nsi dere d, e nr oll me nt ma y be pa use d f or sa m ple size a dj ust me nt a n d pr ot oc ol a me n d me nt.  
A P K Data Re vie w C o m mittee  will verif y t he pr ot oc ol - defi ne d T B P M-PI - H Br d ose a n d ma ke 
rec o m me n dati o ns t o t he s p o ns or re gar di n g d ose a dj ust me nt, if a p plica ble. If a c ha n ge i n d ose is 
re q uire d, t he pla n ne d t otal e nr ollme nt ma y be a dj uste d as nee de d t o e ns ure s ufficie nt data are 
a vaila ble fr o m 8 8 4 e val ua ble patie nts  i nt o t he M icr o bi ol o gical I nte nt-t o- Treat (micr o -I T T) 
P o p ulati o n recei vi n g t he a me n de d d ose. All det ails re gar di n g P K Data Re vie w C o m mittee  will 
be pr o vi de d i n t he se para te c harter. 


St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
 
P a g e 1 0  of 3 9  
 
S A P fi n al 1. 1: 0 3  S e pt e m b er  2 0 2 0  
C o nfi d e nti al  
3. 1. 3  
D at a R e vi e w C o m mitt e e a n d S a m pl e Si z e R e a s s e s s m e nt  
A bli n de d sa m ple size reassess me nt will ta ke place after 7 0 % of t he patie nts  ha ve res p o nse data 
at t he Test-of - C ure visit (T O C ) a vaila ble a n d will be perf or me d b y t he bli n de d S p o ns or Data 
Re vie w C o m mittee  ( D R C). T he bli n de d sa m ple size re-esti mati o n will eit her c o nfir m t he i nitial 
sa m ple size esti mate is a de q uate or i ncrease t he sa m ple size ( n u m ber of ra n d o mize d patie nts ) t o 
e ns ure t he st u d y has a de q uate p o wer f or t he pri mar y o utc o me meas ure, u p t o a ma xi m u m of 
1, 4 5 0 patie nts . I n a d diti o n, t he sa m ple size ma y be i ncrease d base d o n a l o wer t ha n e x pecte d 
e val ua bilit y rate (t he pr o p orti o n of ra n d o mize d patie nts  i ncl u de d i n t he micr o-I T T P o p ulati o n). 
N o sa m ple size a dj ust me nt d o w n war ds will be perf or me d. 
T he sa m ple s ize re-esti mati o n will be base d o n a bli n de d re vie w of t he o verall res p o nse rate a n d 
e val ua bilit y rate f or t he micr o -I T T P o p ulati o n acc or di n g t o pre -s pecifie d criteria d oc u me nte d i n 
a sa m ple size reassess me nt d oc u me nt  ( D R C c harter, v. 1. 0 date d 1 3 M A R 2 0 2 0). N o al p ha 
a dj ust me nt will be ma de as t his will be a bli n de d reassess me nt , a n d n o treat me nt gr o u p 
c o m paris o n wil l be perf or me d f or a n y e n d p oi nt. 
3. 1. 4  
D at a S af et y M o nit ori n g C o m mitt e e  
T he D S M B will re vie w safet y data u p o n e nr ollme nt  of 2 5 % a n d 5 0 % of patie nts.  
Res p o nsi bilities of t he D S M B will be t he peri o dic re vie w of t he st u d y data b y perf or mi n g a 
q ualitati ve a n d q ua ntitati ve safet y assess me nt. I n a d diti o n, t he D S M B s h o ul d deter mi ne w het her 
t he basic st u d y ass u m pti o ns re mai n vali d a n d e val uate whet her t he o verall i nte grit y, scie ntific 
merit , a n d c o n d uct of t he st u d y are still acce pta ble.  
F ull details re gar di n g t he D S M B (e. g., c o m mittee c o m p ositi o n, ti mi n g a n d sc o pe of re vie w, data 
a nal yses, decisi o ns, etc., ) will be s pecifie d i n t he D S M B c harter . T he D S M B c harter will be 
a p pr o ve d a n d fi nalize d b y t he D S M B me m bers a n d s p o ns or pri or t o t he first D S M B meeti n g .  
3. 2  St u d y Tre at me nt  
P atie nts will be ra n d o mize d (e nr olle d) t o o ne of t w o treat me nt ar ms at a 1: 1 rati o , recei vi n g 
eit her: 
•  T B P M -PI - H Br 3 0 0 m g fil m-c oate d ta blet:  
o  F or patie nts wit h  n or mal  re nal  f u ncti o n  or  mil d  re nal  i ns ufficie nc y  ( Cr Cl  > 5 0 
m L/ mi n): 6 0 0 m g ( 2 ta blets) P O q 8 h ( ± 0. 5 h) pl us d u m m y I V i nf usi o n q 2 4 h ( ± 0. 5 
h)  
o  F or patie nts wit h m o derate re nal i ns ufficie nc y ( Cr Cl  > 3 0 t o ≤5 0 m L/ mi n): 3 0 0 m g 
( 1 ta blet) P O q 8 h ( ± 0. 5 h) pl us d u m m y I V i nf usi o n q 2 4 h ( ± 0. 5 h) 
•  Erta pe ne m: 1  gra m I V q 2 4 h ( ± 0. 5 h) f or all patie nts  ( Cr Cl > 3 0 m L/ mi n) 
o  Pl us 2 d u m m y oral ta blets q 8 h ( ± 0. 5 h) f or patie nts  wit h n or mal re nal f u ncti o n or 
mil d re nal i ns ufficie nc y ( Cr Cl > 5 0 m L/ mi n)  
o  Pl us 1 d u m m y oral ta blet q 8 h ( ± 0. 5 h) f or patie nts  wit h m o derate re nal i ns ufficie nc y 


St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
 
P a g e 1 1  of 3 9  
 
S A P fi n al 1. 1: 0 3  S e pt e m b er  2 0 2 0  
C o nfi d e nti al  
( Cr Cl > 3 0 t o ≤5 0 m L/ mi n) 
A d u m m y I V i nf usi o n of n or mal sali ne ( 0. 9 %) a n d d u m m y oral place b o ta blets will be use d t o 
mai ntai n t he bli n d . 
4.  
S A M P L E SI Z E A N D P O W E R C A L C U L A T I O N 
O ri gi n al ass u m pt i o ns 
Ass u mi n g a res p o nse rate of 7 0 % f or b ot h treat me nt gr o u ps, a pre- s pecifie d n o n- i nferi orit y ( NI) 
mar gi n of 1 0 % , a 1: 1 ra n d o mizati o n rati o, a n d a o ne-si de d si g nifica nce le vel of 0. 0 2 5, a trial 
i ncl u di n g 8 8 4 e val ua ble patie nts  i n t he micr o -I T T P o p ulati o n w o ul d ha ve a p pr o xi matel y 9 0 % 
p o wer t o s h o w NI wit hi n a 1 0 % mar gi n. T his trial ai ms t o recr uit 8 8 4  e val ua ble patie nts i nt o t he 
micr o -I T T P o p ulati o n. Ass u mi n g 7 5 % of ra n d o mize d patie nts  met t he criteria f or i ncl usi o n i n t he 
micr o -I T T P o p ulati o n, a p pr o xi matel y 1, 1 8 0 patie nts will be recr uite d t o e ns ure 8 8 4 e val ua ble 
patie nts  i nt o t he micr o-I T T P o p ulati o n. T his size st u d y w o ul d als o ha ve 9 0 % p o wer f or a n 
a nal ysis of t he  micr o bi ol o gicall y e val ua ble (M E ) P o p ulati o n, ass u mi n g a 7 5 % res p o nse rate a n d 
6 7 % of ra n d o mize d patie nts  are i ncl u de d i n t he M E P o p ulati o n. A bli n de d assess me nt of o verall 
e val ua bilit y rates (t he pr o p o rti o n of ra n d o mize d patie nts  i n t he micr o-I T T a n d M E P o p ulati o ns ) 
a n d res p o nse rates ( p o ole d acr oss treat me nt gr o u ps) will be perf or me d d uri n g t he st u d y, a n d if 
ass u m pti o ns are ver y differe nt t o t h ose e x pecte d, t he sa m ple size ma y be i ncrease d u p t o a 
ma xi m u m of 1 , 4 5 0 patie nts acc or di n g t o pre-s pecifie d criteria. 
C h a n ges D ue t o t he C O VI D- 1 9 P a n de mic 
At t he ti me of t he bli n de d assess me nt of res p o nse rate a n d e val ua bilit y rate  ( Marc h 2 0 2 0), t he 
D R C perf or me d t he pla n ne d bli n de d sa m ple size reassess me nt after res p o nse data at T O C was 
a vaila ble f or 7 0 % of patie nts. Base d o n t he preli mi nar y re vie w of bli n de d data, t he D R C 
rec o m me n de d co nti n ui n g recr uit me nt u p t o t he pr ot oc ol-all o we d ma xi m u m of 1, 4 5 0 patie nts i n 
or der t o e ns ure i ncl usi o n of 8 8 4 eli gi ble patie nts i n t he pri mar y a nal ysis p o p ulati o n. 
Base d o n t he D R C rec o m me n dati o n, e nr oll me nt i n t he st u d y c o nti n ue d; h o we ver, t he rate of 
e nr oll me nt dra maticall y decrease d i n t he setti n g of t he gl o bal C O VI D-1 9 pa n de mic  a n d relate d 
i m pact at m ulti ple sites i n c o u ntries w here t he st u d y is bei n g c o n d ucte d. T he S p o ns or perf or me d 
a c o nti n u o us ris k assess me nt i n or der t o deter mi ne w hic h sites c o ul d c o nti n ue e nr oll me nt wit h 
mi ni mal i m pact t o patie nt /staff safet y a n d p ost- treat me nt data c ollecti o n.   
T his o n g oi n g ris k assess me nt i de ntifie d p ote ntial  f or si g nifica nt i m pact t o st u d y c o n d uct a n d data 
i nte grit y base d o n diffic ulties i n c o n d ucti n g p ost-treatme nt f oll o w -u p visits necessar y f or 
assess me nt of t he pri mar y e n d p oi nt, al o n g wit h data m o nit ori n g of case rec or ds . Ulti matel y, 
t hese c halle n ges s u g geste d t hat a pr o gressi vel y  i ncreasi n g pr o p orti o n of i n deter mi nate res p o nse 
f or t he pri mar y e n d p oi nt is li kel y wit h c o nti n ue d e nr oll me nt, w hic h c o ul d bias t he st u d y t o war ds 
n o n- i nferi orit y. T heref ore, t he S p o ns or c o nsi dere d it i n t he best i nterest of t he st u d y , a n d st u d y 
partici pa nts, t o c o ncl u de e nr oll me nt  o n 0 5-Ma y - 2 0 2 0 a n d re vise t he pla n ne d a nal yses base d o n  
t he a vaila ble dataset.  


St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
 
P a g e 1 2  of 3 9  
 
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C o nfi d e nti al  
T h us, t he ori gi nal NI mar gi n of - 1 0 % was m o difie d t o - 1 2. 5 % i n c o ns ultati o n wit h U S F D A  (as 
detaile d i n Secti o n 8. 8. 1). Base d o n t his m o dificati o n, it is e x pecte d t hat at least 6 7 0 patie nts will 
be i ncl u de d i n t he micr o -I T T P o p ulati o n, w hic h e ns ures t hat t he st u d y will ha ve > 9 0 % p o wer t o 
s h o w n o n-i nferi orit y w he n usi n g a - 1 2. 5 % NI mar gi n, ass u mi n g a tr ue res p o nse rate of at least 
6 0 % acr oss b ot h treat me nt gr o u ps. 
5.  
A N A L Y SI S E N D P OI N T S  
5. 1  Pri m ar y E n d p oi nt s 
Effic ac y: O verall  res p o nse  (c o m bi ne d  cli nical  c ure  pl us  micr o bi ol o gical  era dicati o n)  at 
T O C  i n t he micr o-I T T P o p ulati o n . See S ecti o ns 6. 1 , 8. 2 , a n d 8. 8  f or f urt her details . 
S afet y:  Assess me nt of safet y a n d t olera bilit y u p t o t he Late F oll o w- Up v isit (L F U ) i n t he 
Safet y P o p ulati o n. See S ecti o ns 8. 2  a n d 8. 9  f or m ore details.  
5. 2  Sec o n d ar y E n d p oi nts  
•  O verall res p o nse (c o m bi ne d cli nical c ure pl us micr o bi ol ogical era dicati o n) at T O C i n t he 
M E P o p ulati o n. 
•  Cli nical c ure at E O T, T O C, a n d L F U Visits i n t he micr o -I T T, cli nicall y e val ua ble ( C E ), a n d 
M E P o p ulati o ns. 
•  Per  patie nt   a n d  b y-pat h o ge n  micr o bi ol o gical  era dicati o n  at  E O T , T O C ,  a n d  L F U i n  t he 
micr o -I T T a n d M E P o p ulati o ns. 
•  Se nsiti vit y  a nal yses  of  t he   pri mar y  efficac y  e n d p oi nt  ( overall  res p o nse  at  T O C  i n  t he 
micr o -I T T P o p ulati o n ) i n ke y s u b gr o u ps, i ncl u di n g: 
•  Stratifie d i nfecti o n cate g or y  
•  Stratifie d a ge cate g or y  
•  C o u ntr y/ Re gi o n. 
E n d p oi nts f or a nal yses i n a d diti o nal s u b gr o u ps of i nterest  are descri be d i n Secti o n  8. 8. 5  
•  Ti me ( da ys) t o res ol uti o n or i m pr o ve me nt of si g ns a n d s y m pt o ms of c U TI a n d A P prese nt 
at baseli ne i n t he micr o -I T T P o p ulati o n. 
•  Ti me ( d a ys) t o defer vesce nce i n micr o -I T T patie nts wit h a d oc u me nte d fe ver at Scree ni n g 
or Da y 1. 
•  Rate of cli nical rela pse at t he L F U Visit i n t he micr o -I T T P o p ulati o n. 
•  Rates of c ol o nizati o n, s u peri nfecti o n a n d ne w i nfecti o n i n t he micr o-I T T P o p ulati o n. 
•  Deter mi ne P K para meters (e. g., V d, C ma x, A U C, T > M I C) i n T B P M-PI -H Br reci pie nts i n 
t he P K P o p ulati o n i n t he first 7 0 patie nts e nr olle d ( Se nti nel P K Gr o u p). 
Detaile d descri pti o ns of P K a n d P D a nal yses are pr o vi de d i n a se parate P K/ P D S A P  a n d 
will be se parate l y re p orte d. 




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P a g e 1 4  of 3 9  
 
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C o nfi d e nti al  
6. 2  Cli nic al Res p o nse  
Cli nical res p o nse at E O T, T O C , a n d L F U are defi ne d  base d o n assess me nt b y t he I n vesti gat or of 
c ha n ge i n baseli ne si g ns a n d s y m pt o ms of c U TI/ A P . Cli nical res p o nse at Da y 5 are 
pr o gra m maticall y deri ve d base d o n t he case re p ort f or m  (C R F ) data.  
Cli nical res p o nse at Da y 5:  
•  Cli nical i m pr o ve me nt: Patie nt  is alive wit h res ol uti o n or i m pr o ve me nt b y at least o ne gra de 
i n  at least  1  baseli ne  si g n/s y m pt o m  A N D  n o  w orse ni n g  of a n y  baseli ne si g ns/s y m pt o ms 
A N D  de vel o p me nt of n o ne w si g ns/s y m pt o ms of c U TI/ A P re q uiri n g t he i nitiati o n of a n o n -
st u d y a nti bacterial t hera p y f or t he i n de x i nfecti o n ( defi ne d as n o c o nc o mita nt a nti bacterial 
me dicati o n f or pri mar y st u d y c o n diti o n pri or t o Da y 5) 
•  N o cli nical i m pr o ve me nt: Lac k of res ol uti o n or i m pr o ve me nt b y at least o ne gra de i n at least 
1 baseli ne si g n/s y m pt o m of c U TI /A P O R  de vel o pme nt of ne w si g ns/s y m pt o ms of c U TI/ A P  
re q uiri n g t he i nitiati o n of a n o n-st u d y a nti bacterial dr u g t hera p y, O R  deat h  
•  I n deter mi nate cli nical  res p o nse :  I ns ufficie nt  data  are  a vaila ble  t o  deter mi ne a  cli nical 
res p o nse at Da y 5 
Cli nical res p o nse at E O T, T O C:  
•  Cli nical c ure: Patie nt  is ali ve wit h c o m plete res ol uti o n or si g nifica nt i m pr o ve me nt of si g ns 
a n d s y m pt o ms of c U TI or A P t hat were prese nt at baseli ne a n d n o ne w s y m pt o ms, s uc h 
t hat n o f urt her a nti micr o bial t hera p y is warra nte d 
•  Cli nical fail ure:  
o  Persiste nce o r w orse ni n g of baseli ne si g ns/s y m pt o ms of c U TI or A P a n d/ or 
de vel o p me nt of ne w s y m pt o ms re q uiri n g t he i nitiati o n of a n o n-st u d y 
a nti bacterial dr u g t hera p y  
o  D eat h  
o  T O C  o nl y: Patie nt pre vi o usl y met criteria f or fail ure at E O T  
o  C o nti n uati o n of st u d y t hera p y be y o n d t he pr ot oc ol- s pecifie d 1 0 da ys of treat me nt 
( or m ore t ha n 1 4 da ys of treat me nt f or bactere mic patie nts) 
o  Cli nical i n deter mi nate: I ns ufficie nt data are a vaila ble t o deter mi ne if t he s u bject is a c ure or 
fail ure (e. g., patie nt is l ost t o f oll o w - u p or has missi n g data at t he  res pecti ve visit) 
Cli nical res p o nse at L F U are defi ne d as f oll o ws:  
•  S ustai ne d cli nical c ure : Met criteria f or cli nical c ure at T O C, a n d re mai ne d free of si g ns 
a n d s y m pt o ms of c U TI or A P at L F U Visit  
Cl arific ati o n: I ncl u des p atie nts w h o re m ai ne d free of ne w or rec urre nt si g ns a n d 
sy m pt o ms u p t o a n d i ncl u di n g t he L F U visit, s uc h t h at n o f urt her a nti micr o bi al t her a py 
f or t he tre at me nt of c U TI/ A P w as w arr a nte d. 
•  Cli nical rela pse: Met criteria f or cli nical c ure at T O C, b ut ne w si g ns a n d s y m pt o ms of 
c U TI or A P are prese nt at t he L F U a n d t he patie nt re q uires a nti bi otic t hera p y f or t he c U TI 
Cl arific ati o n:  I ncl u des p atie nts w h o devel o pe d ne w or rec urre nt si g ns a n d sy m pt o ms 


St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
 
P a g e 1 5  of 3 9  
 
S A P fi n al 1. 1: 0 3  S e pt e m b er  2 0 2 0  
C o nfi d e nti al  
a nyti me fr o m T O C a n d  u p t o a n d i ncl u di n g t he L F U re q uiri n g a d diti o n al a nti biotic 
t her a py f or t he tre at me nt of c U TI/ A P 
•  Cli nical i n deter mi nate: I ns ufficie nt data are a vaila ble t o deter mi ne if t he patie nt is a 
s ustai ne d cli nical c ure or cli nical rela pse 
•  Cli nical fail ure: P atie nt pre vi o usl y met criteria f or fail ure at E O T or T O C   
6. 3  Micr o bi ol o gic al Res p o nse  
Micr o bi ol o gical res p o nse will be deri ve d b y- pat h o ge n a n d per -patie nt  base d o n i n di vi d ual 
res p o nse f or eac h baseli ne ur o pat h o ge n is olate d fr o m a uri ne or bl o o d s o urce. A fa v ora ble b y-
pat h o ge n micr o bi ol o gic al res p o nse (era dicati o n  or pr es u me d era dicati o n)  will be deri ve d fr o m 
t he i n di vi d ual res p o nse f or eac h baseli ne ur o pat h o ge n. A fa v ora ble per -patie nt micr o bi ol o gical 
res p o nse re q uires a fa v ora ble res p o nse f or all baseli ne pat h o ge ns.  
B y - p at h o ge n micr o bi ol o gic al res p o nse  
T he b y- pat h o ge n micr o bi ol o gical res p o nse at Da y 5 , E O T a n d T O C are defi ne d as o utli ne d i n 
Ta ble 2  bel o w. Micr o bi ol o gical res p o nse at Da y 5 are prese nte d b y - patie nt o nl y usi n g t he 
assess me nt of is olates base d o n  Ta ble  2. 
T a ble 2 : Micr o bi ol o gic al res p o nse c ate g ories at D a y 5, E O T, a n d T O C f or e ac h p at h o ge n i de ntifie d at 
b aseli ne  
Res p o nse 
P at h o ge n f o u n d  i n uri ne 
o nl y at B L  
P at h o ge n f o u n d i n bl o o d  
o nl y at B L [ 1]  
P at h o ge n f o u n d i n uri ne 
a n d bl o o d at B L [ 1]  
Micr o bi ol o gic al 
er a dic ati o n 
•  B aseli ne pat h o ge n is 
re d uce d t o < 1 03 C F U/ m L 
o n uri ne c ult ure  
•  A bse nce of baseli ne 
pat h o ge n o n p ost -baseli ne 
bl o o d c ult ure  
 a n d 
•  S a me baseli ne pat h o ge n is 
< 1 0 3 C F U/ m L o n uri ne 
c ult ure or n ot prese nt  
•  A bse nce of baseli ne 
pat h o ge n o n m ost -rece nt 
p o st-baseli ne bl o o d c ult ure  
a n d 
•  B aseli ne pat h o ge n is < 1 0 3 
C F U/ m L o n uri ne c ult ure 
or n ot prese nt  
Pres u me d 
micr o bi ol o gic al  
er a dic ati o n 
(s pecific t o 
bl o o d 
p at h o ge ns)  
N/ A  
•  Cli nical res p o nse of c ure ( or  
cli nical i m pr o ve me nt 
res p o nse) w he n missi n g 
p ost -baseli n e bl o o d c ult ure 
 a n d 
•  B aseli ne pat h o ge n is < 1 0 3 
C F U/ m L o n uri ne c ult ure or 
n ot prese nt  
N/ A  
Micr o bi ol o gic al  
persiste nce [ 2]  
•  Is olati o n fr o m uri ne c ult ure 
of ≥1 0 3 C F U/ m L  
•  Is olati o n fr o m uri ne c ult ure 
of ≥1 0 3 C F U/ m L  
Or  
•  P rese nce of baseli ne 
pat h o ge n i n m ost -rece nt 
p ost -baseli ne bl o o d c ult ure  
•  Is olati o n fr o m uri ne c ult ure 
of ≥1 0 3 C F U/ m L  
Or  
•  P rese nce of baseli ne 
pat h o ge n i n m ost -rece nt 
p ost -baseli ne bl o o d c ult ure 
Pres u me d 
micr o bi ol o gic al  
persiste nce  
N A  
•  Patie nt res p o nse is cli nical fail ure or n o cli nical 
i m pr o ve me nt) a n d n o p ost-baseli ne bl o o d c ult ure is a vaila ble  


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P a g e 1 6  of 3 9  
 
S A P fi n al 1. 1: 0 3  S e pt e m b er  2 0 2 0  
C o nfi d e nti al  
Res p o nse 
P at h o ge n f o u n d  i n uri ne 
o nl y at B L  
P at h o ge n f o u n d i n bl o o d  
o nl y at B L [ 1]  
P at h o ge n f o u n d i n uri ne 
a n d bl o o d at B L [ 1]  
Micr o bi ol o gic al  
persiste nce wit h 
i ncre asi n g MI C 
[ 3] 
Pat h o ge n res p o nse is “ persiste nce” at E O T or T O C a n d p ost-baseli ne uri ne a n d/ or bl o o d 
is olate dis pla ys ≥4 f ol d hi g her MI C t o st u d y t hera p y recei ve d [ 4] 
Micr o bi ol o gic al  
i n deter mi n ate 
N o f oll o w -u p uri ne c ult ure is 
a vaila ble, or t he f oll o w -u p 
uri ne c ult ure ca n n ot be 
i nter prete d f or a n y reas o n 
(e. g., or t he f oll o w-u p uri ne 
c ult ure is c o nsi dere d 
c o nta mi nate d)  
Patie nt disc o nti n ue d pri or t o 
visit a n d n o c ult ures are 
a vaila ble. 
N o f oll o w -u p uri ne c ult ure is 
a vaila ble, or t he f oll o w -u p 
uri ne c ult ure ca n n ot be 
i nter prete d f or a n y reas o n 
(e. g., or t he f oll o w-u p uri ne 
c ult ure is c o nsi dere d 
c o nta mi nate d)  
B L = Baseli ne; MI C  =  Mi ni m u m I n hi bit or y C o nce ntrati o n ; E O T = E n d-of -Treat me nt; N/ A = N ot A p plica ble; 
T O C = Test- of -C ure, C F U = c ol o n y-f or mi n g u nit 
[ 1] P ost-baseli ne bl o o d c ult ures are t o be ta ke n o nl y if p ositi ve at baseli ne or as cli nicall y i n dicate d. P ost-baseli ne 
bl o o d c ult ures s h o ul d be re peate d u ntil ne gati ve. I n t he a bse nce of a p ost -baseli ne bl o o d c ult ure w he n o ne is 
e x pecte d, t he baseli ne bl o o d -pat h o ge n res p o nse  will be deri ve d or pres u me d fr o m t he cli nical res p o nse (i.e., 
pres u me d era dicati o n or pres u me d persiste nce). All cases i n v ol vi n g p ositi ve p ost -baseli ne bl o o d c ult ures will be 
ma n uall y re vie we d.  
[ 2] Pat h o ge ns wit h a micr o bi ol o gical pers iste nce res p o nse at E O T will be c o nsi dere d a persiste nce res p o nse at 
T O C 
[ 3] Deri ve d f or E O T a n d T O C o nl y 
[ 4] Te bi pe ne m a n d erta pe ne m MI Cs ha ve dil uti o ns u p t o 8 µ g/ m L ; t heref ore, MI C re p orte d as ‘ > 8’ will be 
c o nsi dere d as 1 6 µ g/ m L  w he n micr o bi ol o gic al per siste nce wit h i ncreasi n g MI C is deri ve d. F or baseli ne 
pat h o ge ns wit h MI C t o st u d y dr u g at baseli ne = 8 or ‘ > 8’ micr o bi ol o gic al persiste nce wit h i ncreasi n g MI C w o n’t 
be deri ve d.  
 
T he b y- pat h o ge n micr o bi ol o gical res p o nse at L F U is defi ne d as f oll o w s: 
•  S ustai ne d micr o bi ol o gic al era dicati o n: Micr o bi ol o gic al era dicati o n of baseli ne ur o pat h o ge n 
at T O C a n d n o s u bse q ue nt uri ne c ult ure at a n y ti me after T O C de m o nstrati n g rec urre nce of 
t he ori gi nal baseli ne ur o pat h o ge n at ≥1 05 C F U/ m L  
•  Micr o bi ol o gic al rec urre nce: Micr o bi ol o gical era dicati o n of baseli ne ur o pat h o ge n at T O C 
a n d  s u bse q ue nt  uri ne  c ult ure de m o nstrates  rec urre nce  of  baseli ne  ur o pat h o ge n  at ≥1 0 5 
C F U/ m L or i n bl o o d c ult ure at a n y ti me u p t o a n d i ncl u di n g t he L F U  
•  Micr o bi ol o gic al i n deter mi nate: T he f oll o w-u p  uri ne  c ult ure  (if  a vaila ble) ca n n ot  be 
i nter prete d f or a n y reas o n  (e. g., c ult ure is c o nsi dere d c o nta mi nate d), or ot her circ u msta nces 
precl u de classificati o n as era dicati o n or rec urre nce  
•  P at h o ge ns wit h a micr o bi ol o gic al persiste nce  ( or pres u me d persiste nce) res p o nse at E O T or 
T O C will be c o nsi dere d  as persiste nce at L F U  
W he n it is n ot p ossi ble t o pr o gra m maticall y assi g n b y- pat h o ge n micr o bi ol o gical res p o nse usi n g 
t he al g orit h ms descri be d a b o ve, b y- pat h o ge n micr o bi ol o gical res p o nse will be assi g ne d base d o n 
s p o ns or bli n de d re vie w of t he data. 
Per -p ati e nt micr o bi ol o gic al res p o nse : 
Per -patie nt micr o bi ol o gical res p o nse at eac h visit will be  cate g orize d as fa v ora ble, u nfa v ora ble 
or i n deter mi nate  as o utli ne d i n T a bles 3 a n d 4  a n d are pr o gra m maticall y deri ve d base d o n 


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C o nfi d e nti al  
micr o bi ol o gical res p o nse n ote d a b o ve f or all baseli ne ur o pat h o ge ns is olate d fr o m uri ne a n d/ or 
bl o o d.  
A fa v ora ble per- patie nt  micr o bi ol o gical res p o nse re q uires a fa v ora ble res p o nse f or all baseli ne 
pat h o ge ns (era dicati o n or pres u me d era dicati o n  f or Da y 5, E O T a n d T O C; sustai ne d 
micr o bi ol o gic al era dicati o n f or L F U ) is olate d fr o m uri ne a n d/ or bl o o d. If at least o ne baseli ne 
pat h o ge n has micr o bi ol o gic al res p o nse of persiste nce (f or Da y 5, E O T, or T O C) or rec urre nce 
f or L F U, a per-patie nt micr o bi ol o gic al res p o nse will be assi g ne d as u nfa v ora ble.  
Per -patie nt  micr o bi ol o gical res p o nses at Da y 5, E O T a n d T O C are defi ne d as o utli ne d i n  T a ble 
3 . Per -patie nt micr o bi ol o gical res p o nse at L F U is defi ne d as o utli ne i n  Ta ble 4 . 
T a ble 3 : Per -p atie nt m icr o bi ol o gic al res p o nse o utc o mes  at D a y 5, E O T, a n d T O C  
E O T = E n d of Treat me nt, T O C = T est-of -C ure.  
T a ble 4 : Per -p atie nt m icr o bi ol o gic al res p o nse o utc o mes  at L F U  
C ate g or y  
Criteri a  
Fa v ora ble  
T he res p o nse of all baseli ne pat h o ge ns m ust be s ustai ne d micr o bi ol o gic era dicati o n  
U nfa v ora ble  
•  
T he res p o nse of at least 1 baseli ne pat h o ge n is micr o bi ol o gic rec urre nce 
•  
S u bjects wit h a n u nfa v ora ble micr o bi ol o gic al res p o nse at T O C will be c o nsi dere d 
u nfa v ora ble res p o nse at L F U  
I n deter mi nate 
T he res p o nse of at least 1 baseli ne  pat h o ge n is i n deter mi nate a n d t here is n o o utc o me of 
rec urre nce or  persiste nce f or a n y baseli ne pat h o ge n 
T O C = T est-of -C ure, L F U = Late F oll o w -u p.  
A d diti o nal micr o bi ol o gic al res p o nse f or p ost-baseli ne pat h o ge ns i ncl u de t he f oll o wi n g: 
•  C ol o nizati o n:  Is olat i o n  of  a  ne w ur o pat h o ge n  at ≥1 0 5 C F U/ m L  ( ot her  t ha n  t he  ori gi nal 
baseli ne  pat h o ge n[s]  fr o m  bl o o d  a n d/ or  uri ne)  fr o m  a  uri ne  c ult ure  i n  a patie nt w h o  is 
assesse d  as  a  cli nical  c ure  or  s ustai ne d  cli nical  c ure  (e. g.,  re q uires  n o  a d diti o nal  or 
alter nati ve a nti micr o bial t hera p y)  
•  S u peri nfe cti o n: Is olati o n of a ne w ur o pat h o ge n at ≥1 0 5 C F U/ m L ( ot her t ha n t he ori gi nal 
baseli ne pat h o ge n[s]  fr o m bl o o d a n d/ or uri ne ) fr o m a uri ne c ult ure t hat is acc o m pa nie d b y 
cli nical si g ns a n d s y m pt o ms of i nfecti o n re q uiri n g alter nati ve a nti micr o bial t hera p y (e. g., 
t he patie nt is assesse d b y t he I n vesti gat or as a cli nical fail ure) d uri n g t he peri o d u p t o a n d 
i ncl u di n g E O T 
C ate g or y  
Criteri a  
Fa v ora ble  
All  baseli ne ur o pat h o ge n(s) ha ve  a res p o nse of era dicati o n or pres u me d era diati o n 
at t he s pecifie d visit ( Da y 5, E O T or T O C)  
U nfa v ora ble  
•  
T he res p o nse of at least 1 baseli ne pat h o ge n is  persiste nce  or pres u me d 
persiste nce.  
•  
S u bjects wit h a n u nfa v ora ble micr o bi ol o gical res p o nse  at E O T will be 
c o nsi dere d u nfa v ora ble  at T O C  
I n deter mi nate 
T he res p o nse of at least 1 baseli ne pat h o ge n is i n deter mi nate a n d t here is n o 
res p o nse of persiste nce  or pres u me d persiste nce f or a n y baseli ne pat h o ge n 


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P a g e 1 8  of 3 9  
 
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C o nfi d e nti al  
•  Ne w  i nfecti o n: Is olati o n of a ne w ur o pat h o ge n at ≥1 0 5 C F U/ m L ( ot her t ha n t he ori gi nal 
baseli ne pat h o ge n[s]  fr o m bl o o d a n d/ or uri ne) fr o m a uri ne c ult ure t hat is acc o m pa nie d b y 
cli nical si g ns a n d s y m pt o ms of i nfecti o n re q uiri n g alter nati ve a nti micr o bial t hera p y (e. g., 
t he patie nt is assesse d b y t he I n vesti gat or as a cli nical fail ure) i n t he peri o d after E O T. 
6. 4  E x pl or at or y res p o nse defi niti o ns  
E nteri c c ol o nizati o n will be defi ne d as n e w p ost-baseli ne detecti o n  of car ba pe ne m- resista nt 
E nter o b acter ales  fr o m a p ost- baseli ne rectal s wa b  i n patie nts w h o were ne gati ve at baseli ne.  
C R E C ol o nizati o n at T O C will be defi ne d as per al g orit h m descri be d i n  Ta ble 5 . 
T a ble 5 : C R E C ol o niz ati o n at T O C  
C R E 
C ol o niz ati o n 
at T O C  
Scree ni n g Visit  
T O C Visit  
E x pl a n ati o n  
N O  
Rectal s wa b c ult ure i de ntifie d as 
Mer o pe ne m -resist a nt 
E nter o b acter ales  ( Mer o pe ne m MI C ≥ 
4 µ g/ m L) at scree ni n g visit [ C R E 
p ositi ve at scree ni n g visit ] 
Rect al s wa b wit h eit her t he 
s a me ge n us a n d s pecies of 
mer o pe ne m -resista nt 
E nter o b acter ales  i de ntifie d at 
scree ni n g visit or  ne gati ve 
rectal s wa b c ult ure 
C R E was alrea d y 
prese nt at baseli ne 
scree ni n g a n d n o 
i n dicati o n eit her st u d y 
dr u g pr o m ote d C R E 
c ol o nizati o n 
Y E S  
Eit her  n o E nter o b acter ales  ( n o 
or ga nis m) or  mer o pe ne m -s usce pti ble 
E nter o b acter ales  ( mer o pe ne m MI C ≤ 
1 µ g/ m L) i de ntifie d at scree ni n g visit 
[ C R E ne gati ve at scree ni n g visit] 
Rectal s wa b t hat yiel ds a 
mer o pe ne m -resist a nt 
E nter o b acter ales  
( mer o pe ne m MI C ≥ 4 µ g/ ml) 
at T O C visit [ C R E p ositi ve 
at T O C visit ] 
Ne w C R E at T O C t hat  
was n ot prese nt  at 
scree ni n g 
C R E = car ba pe ne m-resista nt E nter o b acter ales , MI C = Mi ni m u m i n hi bit or y c o nce ntrati o n, T O C = T est-of - Cure . 
7.  
A N A L Y SI S P O P U L A TI O N S  
T he a nal ysis p o p ulati o n s f or t he st u d y are defi ne d as f oll o ws: 
•  I nte nt-t o-Tre at (I T T) P o p ul ati o n : All patie nts w h o w ere ra n d o mize d, re gar dless of 
w het her t he y recei ve d a n y st u d y dr u g. Patie nts  will be s u m marize d b y t he treat me nt t o 
w hic h t he y were ra n d o mize d. 
•  S afet y A n al ysis P o p ul ati o n : Ra n d o mize d patie nts  w h o recei ve d a n y a m o u nt of st u d y 
dr u g. Patie nts  will be s u m mariz e d b y t he treat me nt w hic h t he y recei ve d.  
•  Micr o bi ol o gic al I nte nt -t o-Tre at ( micr o -I T T) P o p ul ati o n: All ra n d o mize d patie nts  
wit h a c o nfir me d dia g n osis of c U TI or A P (I ncl usi o n Criteri o n  4) a n d a p ositi ve 
Scree ni n g uri ne c ult ure defi ne d as gr o wt h of o ne or t w o ur o pat h o ge ns at ≥1 0 5 C F U/ m L  
a n d/ or p ositi ve Scree ni n g bl o o d c ult ure wit h is olati o n of  o ne or m ore  ur o pat h o ge ns.  
Patie nts wit h Scree ni n g uri ne  c ult ure gr o wt h of m ore t ha n 2 s pecies of ur o pat h o ge ns will 
be e xcl u de d fr o m t he micr o -I T T P o p ulati o n, re gar dless of c ol o n y c o u nt u nless a 
ur o pat h o ge n was als o is olate d fr o m bl o o d. A n y patie nt wit h c U TI or A P ca use d b y a 
pat h o ge n t hat is t y picall y n ot e x pecte d t o res p o n d t o st u d y dr u g e. g., Aci net o b acter  s p p., 
Ste n otr o p h o m o n as  s p p., Pse u d o m o n as aer u gi n os a , met hicillin- resista nt St a p hyl oc occ us 


St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
 
P a g e 1 9  of 3 9  
 
S A P fi n al 1. 1: 0 3  S e pt e m b er  2 0 2 0  
C o nfi d e nti al  
a ure us  (M R S A ) as o utli ne d i n t he S P R 9 9 4 E val ua bilit y Re vie w Pla n ( E R P , v. 3 date d 2 0 
A u g 2 0 2 0) will be e xcl u de d fr o m t his a nal ysis p o p ulati o n. I n a d diti o n t o n o n- fer me nti n g 
Gra m - ne gati ve bacilli a n d M R S A, baseli ne ur o pat h o ge ns t hat are n o n-s usce pti ble t o 
mer o pe ne m will be e xcl u de d fr o m t he micr o -I T T P o p ulati o n.  
•  C li nic all y E v al u a ble ( C E) P o p ul ati o n  ( defi ne d i n detail i n S P R 9 9 4 - 3 0 1 E R P  v. 3 date d 
2 0 A u g 2 0 2 0) : T he C E P o p ulati o n will be defi ne d f or eac h visit ( C E -E O T, C E -T O C , a n d 
C E - LF U) f or t he a nal yses i n t he C E P o p ulati o n at eac h res pecti ve visit  a n d is a s u bset of 
t he I T T P o p ulati o n a n d i ncl u des patie nts w h o ha ve n o i m p orta nt pr ot oc ol de viati o ns t hat 
w o ul d affect t he assess me nt of efficac y a n d ha d a n res p o nse assesse d as cli nical c ure or 
cli nical fail ure at E O T, T O C, a n d/ or L F U. S pecific criteria f or e xcl usi o n fr o m t he C E 
P o p ulati o n are s pecifie d i n t he E R P v. 3 date d 20 A u g 2 0 2 0.  
•  M icr o bi ol o gic all y E v al u a ble  ( M E ) P o p ul ati o n : T he  M E P o p ulati o n i ncl u des patie nts 
w h o meet t he defi niti o ns of b ot h t he micr o -I T T P o p ulati o n a n d C E P o p ulati o n a n d will be 
defi ne d  f or  eac h  visit ( M E-E O T,  M E -T O C , a n d  M E-L F U)  f or  t he  a nal yses  i n  t he  M E 
P o p ulati o n at eac h res pecti ve visit  as o utli ne d i n t he E R P v. 3 date d 2 0 A u g 2 0 2 0.  
•  P K P o p ul ati o n:  All patie nts treate d wit h at least o ne d ose of T B P M -PI -H Br wit h at least 
o ne a nal yza ble plas ma or uri ne P K sa m ple. T he P K P o p ulati o n i ncl u des t w o sets of T B P M-
PI -H Br -treate d patie nts . T he Se nti nel P K A nal ysis Gr o u p i ncl u des t he first a p pr o xi matel y 
3 5 T B P M -PI -H Br -treated patie nts a m o n g t he first a p pr o xi matel y 7 0 patie nts e nr olle d, a n d 
t he S parse P K A nal ysis Gr o u p i ncl u des all patie nts e nr olle d t hereafter. P K data f or b ot h 
gr o u ps i n t he  P K P o p ulati o n will be use d f or all P K a nal yses as descri be d i n t he se parate 
P K S A P.     
8.  
A N A L Y TI C A L  P L A N A N D S T A TI S TI C A L M E T H O D S  
8. 1  Ge ner al C o n ve nti o ns a n d St atistic al C o nsi der ati o ns  
All a nal yses will be perf or me d usi n g S A S ®  statistical a nal ysis s oft ware ( S A S, S A S/ G R A P H a n d 
S A S/ S T A T; versi o n 9. 4 or hi g her of S A S f or Wi n d o ws [ S A S I nstit ute I nc.; Car y, N C, U S A]).  
Descri pti ve statistics f or c o nti n u o us varia bles (if n ot state d ot her wise) will i ncl u de t he n u m ber of 
patie nts , mea n a n d sta n dar d de viati o n, me dia n, a n d mi ni m u m a n d ma xi m u m val ues. All ra w data 
will be prese nte d t o t he ori gi nal n u m ber of de ci mal places. Mea ns, me dia ns, a n d c o nfi de nce 
i nter vals will be prese nte d t o 1 m ore deci mal place t ha n i n t he ra w data. Sta n dar d de viati o ns will 
be prese nte d t o 2 m ore deci mal places t ha n i n t he ra w  data. S u m mar y statistics f or cate g orical 
varia bles will c o ntai n c o u nt a n d perce nta ge. Perce nta ges will be prese nte d t o o ne deci mal, e xce pt 
f or o ne h u n dre d perce nt, w hic h will be prese nte d as 1 0 0 %. U nless ot her wise s pecifie d, 
perce nta ges f or baseli ne s u m ma ries will be base d o n t he t otal n u m ber of patie nts i n t he treat me nt 
ar m or o verall f or t he i n dicate d p o p ulati o n ( de pe n de nt o n ta ble c ol u m n hea di n g); perce nta ges f or 
p ost- baseli ne s u m maries will be base d o n t he t otal n u m ber of patie nts  wit h n o n- missi n g val ues i n 
t he treat me nt ar m or o verall.  
D ata will be liste d i n di vi d uall y b y patie nt . 


St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
 
P a g e 2 0  of 3 9  
 
S A P fi n al 1. 1: 0 3  S e pt e m b er  2 0 2 0  
C o nfi d e nti al  
Ta bles f or t he I T T, micr o-I T T, M E, a n d C E P o p ulati o ns will be pr o d uce d usi n g ra n d o mize d 
treat me nt gr o u ps. Ta bles f or t he Safet y P o p ulati o n will be pr o d uce d  usi n g act ual treat me nt 
recei ve d b y a patie nt. 
8. 2  Defi niti o n of B aseli ne, St u d y V isits, a n d Visit Wi n d o ws 
Ge nerall y , baseli ne is defi ne d as t he m ost rece nt val ue pri or t o t he start of treat me nt wit h st u d y 
dr u g, wit hi n 4 8 h o urs pri or t o t he first d ose of st u d y me dicati o n wit h t he e xce pti o n of: 
•  Baseli ne pat h o ge n ma y ori gi nate fr o m a n y c ult ure ta ke n wit hi n 4 8 h o urs pri or t o first d ose  
or o n st u d y da y 1. 
•  E C G will  be  perf or me d  i n  tri plicate.  A vera ge  of  t he  tri plicate  is  use d  i n  t he  a nal ysis. 
Baseli ne E C G val ue is defi ne d as a vera ge of t hree latest assess me nts pri or t o first d ose.  
•  Ma xi m u m dai l y te m perat ure will be prese nte d i n t he ta bles. Acc or di n g t o t he pr ot oc ol, if 
scree ni n g a n d st u d y D a y 1 visit occ urre d o n sa me c ale n dar da y , o nl y o ne rec or d will be 
mar ke d as ma xi m u m dail y te m perat ure. F or t hese cases , t he baseli ne val ue will be defi ne d 
as ma xi m u m te m perat ure fr o m pre -d ose assess me nts a n d val ue f or st u d y D a y 1 will be 
e q ual t o ma xi m u m p ost- d ose te m perat ure fr o m t hi s cale n dar da y. 
Safet y a n d efficac y data will be a nal yze d acc or di n g t o t he visits rec or de d i n t he e C R F . O ut - of-
wi n d o w visits wil l affect e val ua bilit y i n C E p o p ulati o ns as detaile d i n t he S P R 9 9 4- 3 0 1 E R P ( v. 3 
date d 2 0 A u g 2 0 2 0). Pr ot oc ol- defi ne d ti mi n g of visit s a n d wi n d o ws are o utli ne d as f oll o ws: 
•  E O T : O cc urs o n t he cale n dar da y or t he da y f oll o wi n g ( + 1 da y) t he last d ose of st u d y dr u g  
•  T O C : Da y 1 9 ± 2 da ys  
•  L F U : Da y 2 5  ± 2 da ys. 
8. 3  Micr o bi ol o gic al  d at a defi niti o ns  
T he pr ocess of deter mi nati o n of ur o pat h o ge n fr o m scree ni n g uri ne a n d bl o o d c ult ures is 
s pecifie d i n t he S P R 9 9 4 - 3 0 1 E R P  ( v. 3 date d 2 0 A u g 2 0 2 0).  
B y - pat h o ge n micr o bi ol o gical res p o nses f or baseli ne pat h o ge ns will be deri ve d pr o gra m maticall y  
(as s pecifie d i n Secti o n  6. 3 ) base d o n t he fi nal o ut p ut pr o vi de d b y S per o fr o m t he bli n de d 
micr o bi ol o gical a n d cli nical e val ua bilit y re vie w  a n d cli nical res p o nse fr o m t he clinical data base.   
T h e fi nal o ut p ut will be i n t he f or m of a S A S dataset w here pat h o ge ns f or eac h patie nt at eac h 
visit will be i de ntifie d after a dj u dicati o n . T he dataset will als o mar k patie nts w h o are t o be 
e xcl u de d fr o m t he micr o -I T T P o p ulati o n d ue t o car ba pe ne m- resista nt pat h o ge ns. 
8. 4  H a n dli n g of Missi n g D at a  
I m p utati o n met h o ds will be use d f or missi n g dates as liste d bel o w. Ori gi nal, n o n- i m p ute d dates 
will be pr o vi de d i n all listi n gs.  


St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
 
P a g e 2 1  of 3 9  
 
S A P fi n al 1. 1: 0 3  S e pt e m b er  2 0 2 0  
C o nfi d e nti al  
N o ot her met h o ds will be utilize d f or ha n dli n g missi n g data.  
8. 4. 1  
A dverse Eve nts  
F or a d verse e ve nts ( A Es), i m p utati o n r ules will be use d t o ha ve a n y A Es wit h missi n g dates be 
classifie d as treat me nt -e mer ge nt if t here is a n y p ossi bilit y f or t hat t o be t he case. T heref ore, t he 
f oll o wi n g will be use d f or i m p utati o n of i nc o m plete A E dates.  
F or start dat e, 
•  If o nl y t he da y c o m p o ne nt is missi n g a n d t he year a n d m o nt h of t he A E start  are n ot t he 
sa me as t he year a n d m o nt h of t he treat me nt start, t he n t he A E start date will be i m p ute d 
as t he first da y of t he m o nt h. If t he year a n d m o nt h of t he A E start matc h t he year a n d 
m o nt h of t he treat me nt start, t he n t he treat me nt start date will be use d t o i m p ute t he start 
date of t he A E.  
•  If b ot h da y a n d m o nt h c o m p o ne nts are missi n g  a n d t he year d oes n ot e q ual t he year of 
treat me nt start, t he n use Ja n uar y 0 1. If t he year matc hes t he year of treat me nt start, t he n 
use t he treat me nt start date as t o i m p ute t he start date of t he A E.  
F or e n d date,  
•  If o nl y t he da y c o m p o ne nt is missi n g, t he n use t he last da y of t he m o nt h.  
•  If b ot h da y a n d m o nt h c o m p o ne nts are missi n g, t he n use Dece m ber 3 1. 
•  St o p dates will n ot be i m p ute d if A E is liste d as o n g oi n g.  
If b ot h start a n d e n d dates are co m pletel y missi n g , t he y will n ot be i m p ute d , a n d A Es will be 
c o nsi dere d treat me nt -e mer ge nt. 
8. 4. 2  
Pri or a n d C o nc o mit a nt Me dic ati o n  
I n or der t o si m plif y t he pr ocess of differe ntiati o n bet wee n t he pri or a n d c o nc o mita nt me dicati o ns 
( defi ne d i n Secti o n  8. 7. 2 ), t he f oll o wi n g will be use d f or i m p utati o n of i nc o m plete me dicati o n 
dates:  
F or start date,  
•  If o nl y t he da y c o m p o ne nt is missi n g, t he n use t he first da y of t he m o nt h;  
•  If b ot h da y a n d m o nt h c o m p o ne nts are missi n g, t he n use Ja n uar y 0 1. 
F or e n d date,  
•  If o nl y t he da y c o m p o ne nt is missi n g, t he n use t he last da y of t he m o nt h. 
•  If b ot h da y a n d m o nt h c o m p o ne nts are missi n g, t he n use Dece m ber 3 1.  
St o p dates will n ot be i m p ute d if me dicati o n is  o n g oi n g at L F U or disc har ge fr o m t he st u d y.  


St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
 
P a g e 2 2  of 3 9  
 
S A P fi n al 1. 1: 0 3  S e pt e m b er  2 0 2 0  
C o nfi d e nti al  
If b ot h start a n d e n d dates are co m pletel y missi n g , t he y will n ot be i m p ute d , a n d me dicati o n will 
be c o nsi dere d b ot h pri or a n d c o nc o mita nt. 
8. 5  P atie nt  Dis p osi ti o n 
T he n u m ber a n d perce nta ge of patie nts  ra n d o mize d will be prese nte d. T he s u m m aries will be 
ge nerate d b y c o u ntr y a n d re gi o n a n d b y ce nter. 
T he  n u m ber a n d perce nta ge of patie nts  i n eac h a nal ysis p o p ulati o n t o get her wit h reas o ns f or 
e xcl usi o n fr o m eac h p o p ulati o n will be pr o vi de d.  
Patie nts  recei vi n g treat me nt, c o m plete d t he treat me nt peri o d, disc o nti n ue d pre mat urel y fr o m t he 
st u d y treat me nt al o n g wit h t he reas o n f or disc o nti n uati o n, c o m plete d t he p ost-treat me nt peri o d, 
a n d disc o nti n ue d fr o m t he p ost- treat me nt al o n g wit h t he reas o n f or disc o nti n uati o n will be 
s u m marize d b y n u m ber a n d perce nta ge f or all patie nts i n t he Safet y , I T T, a n d micr o -I T T 
P o p ulati o ns , b y treat me nt a n d o verall. S u m maries will i ncl u de C O VI D-1 9 as a se parate reas o n 
f or treat me nt/st u d y disc o nti n uati o n. 
Listi n gs will be pr o vi de d f or st u d y dis p ositi o n, i ncl u di n g reas o ns f or e xcl usi o n a n d 
disc o nti n uati o n fr o m t he st u d y. 
8. 6  Pr ot oc ol De vi ati o ns  
Pr ot oc ol de viati o ns will be ta b ulate d i n I T T P o p ulati o n. T he s u m mar y will i ncl u de n u m ber a n d 
perce nta ge o f patie nts wit h at least o ne maj or de viati o n, at least o ne mi n or de viati o n a n d at least 
o ne maj or de viati o n of eac h cate g or y. A si milar s u m mar y of pr ot oc ol de viati o ns will be 
pr o d uce d f or t h ose de viati o ns relate d t o C O VI D - 1 9 a n d will be s u m marize d f or t he I T T 
P o p ulati o n.  
A listi n g of all pr ot oc ol de viati o ns, al o n g wit h t heir cate g orizati o n as maj or or mi n or,  will be 
pr o vi de d f or all patie nts i n t he I T T P o p ulati o n. Pr ot oc ol de viati o ns relate d t o C O VI D -1 9 will be 
fla g ge d i n t his listi n g. 
8. 7  P atie nt  C h ar acteristics  
All ta bles i n t his secti o n will be r u n f or t he Safet y  a n d micr o-I T T P o p ulati o ns.  
Baseli ne de m o gra p hics will be s u m marize d b y treat me nt gr o u p a n d o verall t o i ncl u de a ge a n d 
a ge cate g or y at ti me of i nf or me d c o nse nt  i n years as rec or de d o n C R F ( ≥1 8 t o < 6 5 years, ≥6 5 t o 
< 7 5, ≥7 5 years), se x, race ( A merica n I n dia n or Alas ka Nati ve / Asia n/ Blac k or Africa n 
A merica n/ Nati ve Ha waiia n or Ot her Pacific Isla n der/ W hite/ Ot her/ N ot Re p orte d; n ote t hat t he 
cate g ories of Ot her/ N ot Re p orte d / America n I n dia n or Alas ka Nati ve /Nati ve Ha waiia n or Ot her 
Pacific Isla n der race cate g ories will be gr o u pe d i nt o Ot her f or s u b gr o u p a nal ysis), et h nicit y 
( His pa nic or Lati n o/ N ot His pa nic or Lati n o/ N ot Re p orte d), re gi o n ( Ce ntral a n d Easter n E ur o pe, 
S o ut h Afri ca, U nite d States) , B MI at scree ni n g ( k g/c m 2).  


St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
 
P a g e 2 3  of 3 9  
 
S A P fi n al 1. 1: 0 3  S e pt e m b er  2 0 2 0  
C o nfi d e nti al  
Baseli ne cli nical  c haracteristics will be s u m marize d b y treat me nt gr o u p a n d o verall t o i ncl u de 
b aseli ne dia g n osis [A P vs. c U TI ]; esti mate d creati ni ne cleara nce [Cr Cl ], ce ntral la b val ues or if 
missi n g, E D C ca lc ulate d l ocal la b val ues) as calc ulate d b y C oc kcr oft Ga ult met h o d ( C oc kcr oft 
a n d Ga ult 1 9 7 6) ( ≤3 0, > 3 0 t o ≤5 0, > 5 0 m L/ mi n ), bactere mia at baseli ne ( Y/N), recei pt of pri or 
s yste mic a nti bi otics (Y/ N ), m o difie d s yste mic i nfla m mat or y res p o nse s y n dr o me (SI R S ) criteria, 
i nfecti o n d ue t o resista nt G ra m- ne gati ve ur o pat h o ge n ( E S B L- p he n ot ype, F Q -N S, T M P/ S X - R); 
per criteria o utli ne d i n  Ta ble 6  (S ecti o n 8. 7. 3 ).  
T he s u m mar y of baseli ne dia g n osis will als o i ncl u de s u bsets of c U TI s plit b y c UTI wit h a n d 
wit h o ut A P, as detecte d b y t he prese nce or a bse nce of a n y se verit y of c ost o verte bral a n gle 
te n der ness or fla n k pai n at baseli ne . S pecificall y, a patie nt wit h c U TI w h o has c ost o verte bral 
a n gle te n der ness or fla n k pai n at baseli ne  (a n y se verit y) re p orte d o n C R F at baseli ne is 
c o nsi dere d t o ha ve c U TI wit h A P, w hile a patie nt wit h c U TI w h o d oes n ot ha ve c ost o verte bral 
a n gle te n der ness or fla n k pai n at baseli ne  re p orte d o n C R F at baseli ne is c o nsi dere d t o ha ve c U TI 
wit h o ut A P (i.e., c o m plicate d c ystitis).  
M o difie d SI R S criteria at baseli ne will be deri ve d pr o gra m maticall y.  A patie nt  is c o nsi dere d t o 
ha ve SI R S at baseli ne if t w o or m ore of t he f oll o wi n g s y m pt o ms are prese nt at baseli ne:  
•  B o d y te m perat ure  < 3 6° C or > 3 8° C  
•  Heart rate  > 9 0 beats per mi n ute 
•  Res pira t or y rate > 2 0 breat hs per mi n ute 
•  W hite bl o o d cell c o u nt  < 4 x 1 09 cells/ L or > 1 2 x 1 09 cells/ L 
Listi n gs will be pr o vi de d f or all de m o gra p hic a n d baseli ne varia bles f or t he I T T P o p ulati o n . 
8. 7. 1  
Me dic al  a n d S ur gic al Hist ory a n d C urre nt Me dic al C o n diti o ns 
Uri nar y tract si g ns a n d s y m pt o ms ( ter m a n d se verit y)  will be s u m marize d f or eac h visit b y 
treat me nt ar m a n d o verall f or all patie nts  i n t he Safet y a n d micr o -I T T P o p ulati o ns. 
Me dical a n d sur gical hist or y ( b ot h pri or a n d c o nc urre nt c o n diti o ns a n d pr oce d ures ) will be c o de d 
usi n g t he Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A; versi o n 2 1. 0 or later). F or 
eac h S yste m Or ga n Class ( S O C) a n d preferre d ter m ( P T) , s u m maries will be prese nte d b y 
n u m ber a n d perce nta ge of s u bjects ha vi n g at least o ne occ urre n ce of a disease. S u m maries will 
be prese nte d b y treat me nt a n d o verall, f or all s u bjects i n t he Safet y a n d I T T P o p ulati o ns. 
L isti n gs will be pr o vi de d f or all patie nts’  me dical hist or y  a n d c urre nt me dical c o n diti o ns  a n d 
pr oce d ures f or t he I T T P o p ulati o n. 
8. 7. 2  
Pri or a n d C o nc o mit a nt Me dic ati o n  
All pri or a n d c o nc o mita nt me dicati o ns will be c o de d usi n g t he W orl d H ealt h O r ga nizati o n Dr u g 
Dicti o nar y ( W H O D D ; W H O D R U G/ 2 0 0 6 Q A or ne wer versi o n).  A me dicati o n is  c o nsi dere d 


St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
 
P a g e 2 4  of 3 9  
 
S A P fi n al 1. 1: 0 3  S e pt e m b er  2 0 2 0  
C o nfi d e nti al  
pri or if a d mi nistere d wit hi n 3 0 da ys ( or p har mac o ki n etic e q ui vale nt of  5 half -li ves, w hic he ver is 
l o n ger) of  t he date of first d ose of st u d y dr u g. A c o nc o mita nt me dicati o n is defi ne d as a n y 
me dic ati o n ta ke n d uri n g t he peri o d fr o m t he date of first d ose of st u d y dr u g t hr o u g h t he late 
f oll o w- u p visit. A me dicati o n t hat was starte d bef ore  t he date  of first  d ose a n d c o nti n ues after t he 
first d ose will be i ncl u de d as b ot h a pri or a n d c o nc o mita nt  me dicati o n . 
Pri or  a nti bi otics a n d c o nc o mita nt ( b ot h a nti bi otic a n d n o n-a nti bi otic) me dicati o n s will be 
s u m marize d b y t he A nat o mical T hera pe utic C he mical ( A T C) class ( A T C 2 a n d A T C 4) a n d P T . 
A nti bi otic a n d n o n- a nti bi otic treat me nts w ill be s u m marize d se paratel y. T he s u m mar y f or 
c o nc o mita nt a nti bi otics treat me nt will be f urt her s plit t o: a n y c o nc o mita nt a nti bi otic, c o nc o mit a nt 
a nti bi otics f or c U T I/ A P, a n d c o nc o mita nt a nti bi otics gi ve n f or ot her i nfecti o ns. S u m maries will 
be prese nte d b y treat me nt a n d o verall, f or all patie nts i n t he Safet y a n d micr o -I T T P o p ulati o ns.  
L isti n gs of all pri or a n d c o nc o mita nt me dicati o ns (a nti bi otic a n d n o n-a nti bi otic se paratel y), pri or 
a n d c o nc o mita nt n o n- dr u g t hera pies will be pr o vi de d f or all patie nts i n t he I T T P o p ulati o n.  
8. 7. 3  
B aseli ne p at h o ge ns 
All s u m maries s pecifie d i n t his secti o n will be d o ne se paratel y f or baseli ne pat h o ge ns is olate d 
fr o m uri ne a n d/ or bl o o d a n d f or baseli ne pat h o ge ns is olate d fr o m bl o o d (if n ot n ote d ot her wise i n 
t he secti o n te xt). All s u m maries will be prese nte d  i n micr o-I T T a n d M E- T O C p o p ulati o ns. 
Q ualif yi n g bl o o d a n d/ or ur o pat h o ge ns is olate d at ≥1 0 5 C F U/ m L fr o m baseli ne uri ne c ult ures will 
be s u m marize d b y treat me nt gr o u p a n d o verall f or patie nts i n t he micr o- I T T a n d M E-T O C  
P o p ulati o ns. Baseli ne pat h o ge n s u m maries will be prese nte d b y ge n us a n d s pecies wit hi n eac h 
gr o u p of pat h o ge ns f or ur o pat h o g e ns is olate d fr o m uri ne a n d/ or bl o o d a n d se paratel y f or 
ur o pat h o ge ns is olate d fr o m bl o o d.  
T he n u m ber of patie nts wit h E nter o b acter ales  pat h o ge ns will be prese nte d i n- micr o -I T T a n d 
M E P o p ulati o ns. 
All pat h o ge ns is olate d fr o m uri ne a n d/ or bl o o d c ult ures will u n der g o i de ntificati o n a n d 
s usce pti bilit y testi n g at b ot h t he l ocal a n d ce ntral la b orat or y. I de ntificati o n a n d s usce pti bilit y 
res ults fr o m t he ce ntral la b orat or y will be use d b y defa ult f or e val ua bilit y a n d res p o nse 
assess me nts w here a vaila ble as descri be d i n t he E R P ( v 3, date d 2 0 A u g 2 0 2 0). H o we ver, w here 
ce ntral la b orat or y data are n ot a vaila ble, l ocal la b orat or y data ma y be utilize d  as defi ne d i n t he 
E R P  ( v 3, date d 2 0 A u g 2 0 2 0).  
I n vitr o testi n g res ults of baseli ne pat h o ge n s usce pti bilit y t o te bi pe nem, erta pe ne m , ceftazi di me, 
le v ofl o xaci n a n d tri met h o pri m/s ulfa met h o xaz ole will be se paratel y s u m marize d f or all pat h o ge ns 
b y treat me nt gr o u p a n d o verall f or t he micr o -I T T a n d M E-T O C P o p ulati o ns . F or erta pe ne m, 
le v ofl o xaci n a n d tri met h o pri m/s ulfa met h o xaz ole  res ults will be prese nte d as “s usce pti ble ” a n d 
“ no ns usce pti ble ” (i ncl u di n g s u bsets of ‘i nter me diate’ or “resista nt”  or “ u n k n o w n”); f or T B P M-
PI -H Br, res ults will be prese nte d b y te bi pe ne m MI C c ate g or y as ≤0. 2 5 m g/ L, > 0. 2 5 m g/ L a n d 
‘ missi n g’.  


St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
 
P a g e 2 5  of 3 9  
 
S A P fi n al 1. 1: 0 3  S e pt e m b er  2 0 2 0  
C o nfi d e nti al  
Tar get a nti bi otic -resista nt p he n ot y pes of i nterest f or baseli ne E nter o b acter ale s is olates will be 
i de ntifie d base d o n t he s usce pti bilit y criteria o utli ne d i n Ta ble 6 .  
T a ble 6 . Resist a nt p at h o ge n p he n ot y pes f or E nter o b acter ales  is ol ates 
P he n ot y pe  
Criteri a  
C o m me nt  
E S B L -p he n ot y pe  
Ceftazi di me MI C ≥2 µ g/ m L  
(or ceftria x o ne MI C  ≥2 
µ g/ m L if ceftazi di me 
s usce pti bilit y is n ot a vaila ble) 
Criteria f or selecti n g is olates 
f or m olec ular c haracterizati o n 
of β- lacta mase ge nes 
Fl u or o q ui n ol o ne -n o ns usce pti ble  
Le v ofl o xaci n MI C ≥1 µ g/ m L  
C L SI brea k p oi nt f or 
i nter me diate a n d resista nt 
s usce pti bilit y 
Tri met h o pri m -s ulfa met h o xaz ole-
resista nt  
T M P -S M X MI C ≥4  µ g/ m L  
C L SI brea k p oi nt f or 
resista nce 
E S B L = E xte n de d S pectr u m Beta -Lacta mase ; MI C = Mi ni m u m I n hi bit or y C o nce ntrati o n ; C L SI = Cli nical a n d 
La b orat or y S ta n dar ds I nstit ute; T M P-S M X  = Tri met h o pri m -s ulfa met h o xaz ole   
If m ore t ha n o ne pat h o ge n of t he sa me s pecies is is olate d i n a patie nt, t he pat h o ge n wit h t he 
hi g hest Mi ni m u m I n hi bit or y C o nce ntrati o n ( MI C ) val ue f or t hat p he n o t y pic criteria will be 
selecte d. 
Baseli ne pat h o ge n s usce pti b ilit y p he n ot y pes will be s u m marize d o n a b y- pat h o ge n a n d per-
patie nt  basis  as o utli ne d bel o w (t hese s u m maries will o nl y be d o ne base d o n pat h o ge ns is olate d 
fr o m uri ne a n d/ or bl o o d): 
•  
B y- p at h o ge n  s u m mar y  ta bles  will  prese nt  t he t otal n u m ber  of  pat h o ge ns  of  eac h  p he n ot y pe  
prese nte d b y ge n us a n d s pecies . E S B L, F Q a n d T M P/ S M X cate g ories are n ot m ut uall y e xcl usi ve 
(e. g., a  pat h o ge n  t hat  is  E S B L -p he n ot y pe  b ut  F Q -s usce pti ble  s h o ul d  still  be  co u nte d  i n  b ot h 
s u m mar y r o ws). H o we ver, a patie nt wit h 2 E. c oli  is olates, o ne F Q-N S a n d o ne F Q -S w o ul d be 
c o u nte d o nl y o nce i n t he s u m mar y r o ws f or F Q p he n ot y pe b y t he hi g hest le v ofl o xaci n MI C. 
•  
Per -p atie nt s u m mar y ta bles will prese nt t he t otal n u m ber patie nts wit h a n y resista nt pat h o ge n i n 
eac h p he n ot y pe  cate g or y  base d o n is olate wit h hi g hest MI C f or t he p he n ot y pe cate g or y ; e. g., if at 
least o ne pat h o ge n is olate d i n a patie nt is c o nsi dere d E S B L-p he n ot y pe, a patie nt will be c o nsi dere d 
E S B L -p he n ot y pe ).  
T he d istri b uti o n of baseli ne pat h o ge n MI C t o st u d y dr u gs a n d/ or t h ose o utli ne d f or resista nce 
selecti o n (Ta ble 6 ) will be prese nte d  b y treat me nt gr o u p a n d o verall f or eac h pat h o ge n/ pat h o ge n 
cate g or y  f or t he micr o -I T T a n d M E- T O C P o p ulati o ns. T he f oll o wi n g s u m maries will be 
perf or me d : 
•  Distri b uti o n  of te bi pe ne m,  erta pe ne m,  ceftazi di me, le v ofl o xaci n, a n d tri met h o pri m-
s ulfa met h o xaz ole MI C of baseli ne E nter o b acter ales  pat h o ge ns 


St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
 
P a g e 2 6  of 3 9  
 
S A P fi n al 1. 1: 0 3  S e pt e m b er  2 0 2 0  
C o nfi d e nti al  
•  Distri b uti o n  of te bi pe ne m  a n d  erta pe ne m  MI C s  of E nter o b acter ales  pat h o ge ns  b y 
resista nce- pat h o ge n p he n ot y pe: 
o  E S B L - p he n ot y pe vs. n o n -E S B L - p he n ot y pe 
o   Fl u or o q ui n ol o ne- n o ns usce pti ble vs. Fl u or o q ui n ol o ne-s usce pti ble 
o  Tri met h o pri m -s ulfa met h o xaz ole (T M P -S M X )-resista nt vs. T M P-S M X -s usce pti ble 
I n a d diti o n, MI C distri b uti o n s u m maries will i ncl u de s usce pti bilit y cate g ories ( w here 
a p plica ble), MI C fre q ue ncies a n d s u m mar y statisti cs i ncl u di n g mi ni m u m a n d ma xi m u m val ues 
as well as MI C 5 0 a n d MI C9 0 val ues a n d ra n ge.  Pat h o ge ns will be gr o u pe d t o E nter o b acter ales  
a n d N o n- fer me nti n g Gra m-ne gati ve Bacilli i n t he s u m mar y ta ble . 
MI C  val ues will be deri ve d pr o gra m maticall y: MI C val ues will be or dere d fr o m l o west t o 
hi g hest wit h a greater t ha n si g n ta ki n g a hi g her val ue (e. g., 8 is first t he n > 8 is ne xt). C u m ulati ve 
perce nta ge will be deter mi ne d fr o m l o west t o hi g hest val ue. MI C 5 0 will  be selecte d as t he first 
val ue e q ual t o or greater t ha n 5 0 %. MI C 9 0 will be deri ve d  i n a si milar wa y. T he MI C 5 0 will o nl y 
be calc ulate d w he n ≥5 is olates are a vaila ble, w hilst t he MI C 9 0 will o nl y be calc ulate d w he n ≥1 0 
is olates are a vaila ble. 
C ult ure res ults a n d s usce pti bilit y testi n g res u lts f or eac h baseli ne pat h o ge n will be liste d b y 
patie nt a n d treat me nt gr o u p f or t he I T T P o p ulati o n ( patie nts i ncl u de d i nt o t he micr o-I T T 
P o p ulati o n will be fla g ge d) . 
8. 8  
Effic ac y A n al ysis  
8. 8. 1  
A n al y si s of Pri m ar y Effi c a c y E n d p oi nt  
T he p ri mar y efficac y e n d p oi nt is o verall res p o nse (c o m bi ne d cli nical c ure a n d micr o bi ol o gical 
era dicati o n) at T O C i n t he micr o-I T T P o p ulati o n. Patie nts wit h  a n i n deter mi nate o utc o me at 
T O C f or eit her t he cli nical or micr o bi ol o gic al res p o nse at T O C will be defi ne d as i n deter mi nate 
f or t he pri mar y a nal ysis (Ta ble 1 ) a n d will be i ncl u de d i n t he de n o mi nat or f or t he calc ulati o n of 
o verall res p o nse rate  a n d c o nfi dence i nter vals . 
T he n u m ber a n d  perce nta ge of patie nts i n eac h treat me nt gr o u p i n eac h res p o nse cate g or y 
(s uccess, fail ure, or i n deter m i nate) at T O C will be  re p orte d. 
T he n ull a n d alter nati ve h y p ot hese s are t he f oll o wi n g: 
H 0: P 1 − P 2 ≤ - Δ 
H 1: P 1 – P 2 > - Δ 
W here:  
P 1 = o verall res p o n der (s uccess) rate i n t he T B P M -PI - H Br gr o u p, 
P 2 = o verall res p o n der (s ucces s) rate i n t he erta pe ne m gr o u p, 
Δ = t he n o n -i nferi orit y mar gi n 


St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
 
P a g e 2 7  of 3 9  
 
S A P fi n al 1. 1: 0 3  S e pt e m b er  2 0 2 0  
C o nfi d e nti al  
T he n o n- i nferi orit y h y p ot hesis test is a 1-si de d h y p ot hesis test perf or me d at t he 2. 5 % le vel of 
si g nifica nce. T he 9 5 % CI will be calc ulate d usi n g t he met h o d of Mietti ne n  a n d N ur mi ne n 
( Stratifie d Mietti ne n  a n d N ur mi ne n CIs wit h C oc hra n- Ma ntel -Hae nszel wei g hts will be use d. 
Stratificati o n varia bles will be b aseli ne dia g n osis ( A P vs. c U TI)  a n d a ge at i nf or me d c o nse nt 
( ≥1 8 t o < 6 5 years vs. ≥6 5 years) ). If t he l o wer li mit of t he 9 5 % CI f or t he differe nce bet wee n 
treat me nt gr o u ps i n o verall res p o nse (res p o n der) is greater t ha n - 1 2. 5%,  n o n -i nferi orit y will be 
declare d.   
Reas o ns f or n o n -res p o n ders a nd i n deter mi nate  at T O C will be s u m marize d i n  t he micr o-I T T 
usi n g n u m ber a n d perce nta ges.  
8. 8. 2  
A n al y si s of S e c o n d ar y Effi c a c y E n d p oi nt s 
T o a v oi d re petiti o n i n t he A nal ysis of A d diti o nal Efficac y E n d p oi nts secti o n bel o w ( Secti o n 
8. 8. 4 ), a n d si nce t he a d diti o nal efficac y e n d p oi nts liste d bel o w are t o be a nal yze d i n t he sa me 
ma n ner as s o me sec o n dar y efficac y e n d p oi nts, t he f oll o wi n g a d diti o nal efficac y e n d p oi nts are 
i ncl u de d i n t his secti o n: 
•  O verall res p o nse at E O T i n t he micr o -I T T a n d M E P o p ulati o ns.  
•  Cli nical c ure at E O T  a n d T O C b y baseli ne pat h o ge n i n t he micr o -I T T a n d M E P o p ulati o ns 
O verall res p o nse at E O T i n t he micr o -I T T P o p ulati o n a n d t he o verall res p o nse at E O T a n d T O C 
i n t he M E P o p ulati o n will be defi ne d si milarl y t o t he pri mar y e n d p oi nt a n d s u m marize d usi n g 
n u m ber a n d perce nta ges. Ris k differe nce bet wee n t he t w o treat me nt ar ms will be calc ulate d  
al o n g wit h 9 5 % C Is i n t he sa me wa y as f or t he pri mar y e n d p oi nt. 
If a patie nt is assesse d as a cli nical fail ure at E O T or T O C, t he patie nt is a ut o maticall y 
c o nsi dere d a fail ure at s u bse q ue nt visits, a n d will be pr o gra m maticall y deri ve d as a cli nical 
fail ure w here cli nical res p o nse is missi n g d ue t o misse d visit. Ot her wise cli nical res p o nse will be 
pr o gra m maticall y deri ve d as i n deter mi nate if cli nical res p o nse is missi n g d ue t o misse d visit. 
Patie nts wit h missi n g visits will be e xcl u de d fr o m c orres p o n di n g C E p o p ulati o n d ue t o cli nical 
i n deter mi nate ( d ue t o misse d visits) re gar dless of pr o gra m maticall y assi g ne d cli nical fail ure 
res p o nse. 
A nal yses i n t he M E a n d C E p o p ulati o ns wil l be perf or me d usi n g t he M E a n d C E p o p ulati o ns 
deri ve d f or eac h res pecti ve visit ( e. g., M E -E O T, M E -T O C, M E -L F U) . 
Cli nical res p o nse at E O T, T O C, a n d L F U will be s u m marize d b y n u m ber a n d perce nta ges  i n t he 
micr o -I T T, C E, a n d M E P o p ulati o ns. T he ris k differe nce a n d 9 5 % CI s will be calc ulate d as for 
t he pri mar y e n d p oi nt. Reas o ns f or cli nical fail ure res p o nse will be prese nte d b y visit i n t he 
micr o -I T T P o p ulati o n.  
Cli nical res p o nse b y pat h o ge n f or t he E O T a n d T O C will als o be s u m marize d i n t he micr o -I T T 
a n d M E P o p ulati o ns. 


St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
 
P a g e 2 8  of 3 9  
 
S A P fi n al 1. 1: 0 3  S e pt e m b er  2 0 2 0  
C o nfi d e nti al  
Per -patie nt micr o bi ol o gical res p o nse at E O T, T O C, a n d L F U will be s u m marize d b y n u m ber a n d 
perce nta ges i n t he micr o -I T T a n d M E P o p ulati o n s. T he ris k differe nce a n d 9 5 % CIs will be 
calc ulate d as f or t he pri mar y e n d p oi nt.  
B y - pat h o ge n micr o bi ol o gical res p o nse at E O T, T O C, a n d L F U will be s u m marize d b y c o u nts 
a n d perce nta ges i n t he micr o -I T T a n d M E P o p ulati o n s. 
All b y -pat h o ge n s u m maries will be prese nte d se paratel y f or is olates fr o m uri ne a n d/ or bl o o d a n d 
f or is olates fr o m bl o o d. 
Ti me ( da ys) t o res ol uti o n or i m pr o ve me nt of si g ns a n d s y m pt o ms of c U TI a n d A P prese nt at 
baseli ne will be defi ne d as f oll o ws: date of first visit at w hic h all baseli ne si g n/s y m pt o ms ha ve 
i m pr o ve d b y at least o ne gra de wit h w orse ni n g of n o ne or de vel o p me nt of n o ne w 
si g ns/s ym pt o ms of t he i n de x i nfecti o n – date of ra n d o mizati o n. If t he res ol uti o n/i m pr o ve me nt di d 
n ot occ ur, t he n t he data is ce ns ore d at t he date of t he last n o n- missi n g s y m pt o m assess me nt. T he 
a nal ysis will be perf or me d i n t he micr o -I T T P o p ulati o n. 
Ti me ( da ys) t o defer vesce nce i n micr o -I T T patie nts wit h a d oc u me nte d fe ver at Scree ni n g or 
Da y 1  will be defi ne d as f oll o ws: date of first p ost -baseli ne te m perat ure meas ure  wit h ma xi m u m 
dail y t e m perat ure ≤3 8° C – ra n d o mizati o n date. If t he te m p erat ure d oes n ot e ver fall bel o w t he 
t hres h ol d, t he patie nt will be c o nsi dere d ce ns ore d at t he date of t he last te m p erat ure assess me nt. 
Patie nts wit h o ut fe ver ( defi ne d as te m perat ure ≤3 8. 0° C) at baseli ne will be e xcl u de d fr o m t his 
a nal ysis. 
Ti me t o res ol uti o n or i m pr o ve me nt of si g n s a n d s y m pt o ms a n d ti me t o first defer vesce nce will 
be s u m marize d usi n g a Ka pla n -Meier pl ot i ncl u di n g t he si g nifica nce le vel fr o m t he l o g ra n k test, 
a n d als o as t he mea n, me dia n, mi ni m u m, a n d ma xi m u m n u m ber of da ys a n d n u m b er of patie nts.    
Rate s of s u peri nfecti o n, c ol o nizati o n, a n d ne w i nfecti o n at res pecti ve visits will be s u m marize d 
i n t he micr o-I T T P o p ulati o n. 
S u b gr o u p a nal ysis is descri be d i n Secti o n  8. 8. 5 . 
8. 8. 3  
A n al y si s of E x pl or at or y Effi c a c y E n d p oi nt s  
Rate of enteric c ol o nizati o n wit h a nti bi otic  (car ba pe ne m)-resista nt E nter o b acter ales  at T O C will 
be s u m marize d b y treat me nt ar m a n d o verall i n t he micr o-I T T P o p ulati o n a n d will be 
s u m marize d b y pat h o ge n, if a vaila ble. 
Per -patie nt  micr o bi ol o gical res p o nse a n d per- patie nt cli nical i m pr o ve me nt at Da y 5 will be 
s u m marize d f or t he micr o-I T T P o p ulati o n.  
Reas o ns f or cli nical n o n -res p o nse a n d i n deter mi nate (s uc h as deat h, ne w si g ns a n d s y m pt o ms 
re q uiri n g a nti bi otic t hera p y, lac k of i m pr o ve me nt, si g ns a n d s y m pt o ms are n ot assesse d) at t he 
Da y 5 will be s u m marize d i n t he micr o -I T T P o p ulati o n. 


St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
 
P a g e 2 9  of 3 9  
 
S A P fi n al 1. 1: 0 3  S e pt e m b er  2 0 2 0  
C o nfi d e nti al  
Per -patie nt  cli nical res p o nse, micr o bi ol o gical res p o nse, a n d o verall res p o nses at T O C a m o n g 
patie nts wit h c U TI/ A P  ca use d b y resista nt pat h o ge n p he n ot y pes ( Ta ble 6, p he n ot y pe 
cate g orizat i o n f or a patie nt will be deter mi ne d base d o n baseli ne pat h o ge ns is olate d fr o m uri ne 
a n d/ or bl o o d) will be s u m marize d i n t he sa me ma n ner as f or t he pri mar y e n d p oi nt  i n micr o-I T T 
a n d M E P o p ulati o ns, a n d t he 9 5 % CI will be pr o d uce d usi n g t he sa me met h o d as for t he pri mar y 
a nal ysis. If t he re are i ns ufficie nt patie nts i n eac h strata i n or der t o perf orm t he stratifie d a nal ysis, 
t he ( u nstratifie d) met h o d of Mietti ne n  a n d N ur mi ne n will be use d .  
F or a s u bset of Gra m - ne gati ve pat h o ge ns meeti n g p he n ot y pic ( MI C) scree ni n g criteria f or t he 
prese nce of a β- lacta mase, m olec ular c haracterizati o n of β-lacta m resista nce mec ha nis ms will be 
e val uate d i n vitr o, all o wi n g f or t he a nal yses of res p o nse b y resista nce mec ha nis m a m o n g patie nts 
wit h c U TI/ A P ca use d  b y ca use d E S B L - pr o d uci n g E nter o b acter ales . T he per- patie nt  a n d b y- 
pat h o ge n micr o bi ol o gical res p o nse at T O C, a n d cli nical res p o nse at T O C b y resista nce ge n ot y pe 
will be ge nerate d se paratel y fr o m o ut p ut f or fi nal a nal ysis a n d re p orte d i n a n a d de n d u m t o t he 
C S R .  
8. 8. 4  
A n alysis of A d diti o n al Effic acy E n d p oi nts 
T he per- patie nt cli nical res p o nse b y pat h o ge n a n d b y- pat h o ge n micr o bi ol o gic al res p o nse at E O T 
a n d T O C will be s u m marize d b y resista nt pat h o ge n p he n ot y pes (as o utli ne d i n Ta ble 6 , 
p he n ot y pe cate g orizati o n f or a patie nt will be deter mi ne d base d o n baseli ne pat h o ge ns is olate d 
fr o m uri ne a n d/ or bl o o d) f or t he micr o-I T T a n d M E P o p ulati o ns.  
I n a d diti o n, b y- pat h o ge n micr o bi ol o gical res p o nse at T O C will be s u m marize d b y te bi pe ne m 
MI C a n d erta pe ne m MI C f or t he micr o -I T T P o p ulati o n . Si milar a nal yses will be perf or me d eac h 
s u bset of resista nt pat h o ge ns is olate d fr o m uri ne a n d/ or bl o o d (as o utli ne d i n T a ble 6 ). 
I n a d diti o n t he o verall res p o nse a n d per-patie nt cli nical a n d micr o bi ol o gic al res p o nse will be 
s u m marize d f or patie nts wit h bactere mia at baseli ne.  
8. 8. 5  
S u b gr o u p a n alyses 
S u b gr o u p a nal yses of t he pri mar y efficac y e n d p oi nt ( o verall res p o nse at T O C i n t he micr o- I T T 
P o p ulati o n) will als o be c o n d ucte d. Descri pti ve statistics al o n g wit h treat me nt differe nce a n d 
9 5 % CI ( deri ve d usi n g t he u nstrat ifie d met h o d of Mietti ne n a n d N ur mine n)  will be prese nte d i n 
ta bles as well as i n f orest pl ot f or t he f oll o wi n g s u b gr o u ps usi n g baseli ne data:  
•  
I nfecti o n cate g or y (c U TI, c U TI wit h/ wit h o ut A P, A P)  
•  
A ge cate g or y ( ≥1 8 t o < 6 5 years, ≥6 5 t o < 7 5, ≥7 5 years ) 
•  
Re gi o n  
•  
Se x  
•  
Race  ( Asia n/ Blac k or Africa n A merica n/ W hite/ Ot her *) 


St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
 
P a g e 3 0  of 3 9  
 
S A P fi n al 1. 1: 0 3  S e pt e m b er  2 0 2 0  
C o nfi d e nti al  
•  
Et h nicit y  ( His pa nic or Lati n o/ N ot His pa nic or Lati n o/ N ot Re p orte d) 
•  
Creati ni ne cleara nce ( ≤3 0, > 3 0 t o ≤ 5 0, > 5 0 m L/ mi n)  
•  
Pri or a nti bi otics ( Y/ N)  
•  
Bactere mia at baseli ne ( Y/ N)  
•  
M o difie d SI R S  at b aseli ne ( Y/ N)  * *  
•  
Baseli ne  E nter o bacterales  pat h o ge n  s usce pti bilit y  p he n ot y pe  ( base d  o n  t he  s usce pti bilit y  of  t he 
pat h o ge ns is olate d fr o m uri ne a n d / or bl o o d at baseli ne  a n d criteria o utli ne d i n  Ta ble 6 ; pat h o ge n 
wit h hi g hest MI C is c o nsi dere d)   
o  E S B L -p he n ot y pe baseli ne pat h o ge ns  
o  F Q -n o n -s usce pti ble ( N S) baseli ne pat h o ge ns  
o  T M P -S M X -resista nt baseli ne pat h o ge ns 
* I ncl u des ‘ Ot her’, ‘ N ot Re p orte d’, ‘A merica n I n dia n or Alas ka Nati ve ’, ‘Nati ve Ha waiia n or 
Ot her Pacific Isla n de r’ race cate g ories t o be c o m bi ne d t o get her f or s u b gr o u p a nal ysis 
* * SI R S criteria are m o difie d t o c o nsi der o nl y te m perat ure, heart rate, res pirat or y rate , a n d w hite 
bl o o d cells ; i m mat ure ne utr o p hils c o u nts are n ot i ncl u de d (as defi ne d i n S ecti o n 8. 7 )  
8. 9  S afet y A n al ysis  
All t he a nal yses i n t his secti o n will be r u n o n Safet y P o p ulati o n. N o h y p ot hesis testi n g will be 
perf or me d ; all a nal yses will be descri pti ve i n nat ure.  
8. 9. 1  
A dverse Eve nts  
All A Es will be c o de d usi n g Me d D R A versi o n 2 1. 0 or later. All A Es occ urri n g d uri n g t his trial 
f or a gi ve n patie nt  will be rec or de d fr o m t he first d ose of st u d y dr u g t hr o u g h t he late f oll o w- u p 
visit; t heref ore , all A Es will be dee me d as T E A Es .  
S u m maries of A Es will be pr o vi de d b y treat me nt a n d o verall f or t he Safet y P o p ulati o n.  
A n o verall s u m mar y of A Es will be prese nte d , w hic h will i ncl u de t he n u m ber a n d perce nta ge of 
patie nts  wit h at least o ne T E A E, Seri o us A d verse E ve nt ( S A E ), dr u g-relate d T E A E, seri o us 
dr u g- relate d T E A E, T E A E lea di n g t o disc o nti n uati o n fr o m treat me nt, a n d T E A E lea di n g t o 
deat h, al o n g wit h t he t otal n u m ber of e ve nts.  
T he i n cide nce a n d fre q ue nc y of T E A Es , S A Es, A Es relate d t o st u d y dr u g ( e ve nts classifie d as 
p ossi ble or pr o ba ble, or wit h missi n g relati o ns hi p stat us, wil l be classifie d as relate d t o st u d y 
dr u g), A Es lea di n g t o st u d y dr u g wit h dra wal, A Es lea di n g t o t he st u d y disc o nti n uati o n, a n d A Es 
lea di n g t o deat h will be prese nte d b y s yste m or ga n class ( S O C) a n d preferre d ter m ( P T), b y 
treat me nt a n d o verall. A s u m mar y of T E A Es  a n d SA Es b y C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E ve nts ( C T C A E; versi o n 5. 0) se verit y gra de (se vere, life-t hreate ni n g or disa bli n g a n d 


St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
 
P a g e 3 1  of 3 9  
 
S A P fi n al 1. 1: 0 3  S e pt e m b er  2 0 2 0  
C o nfi d e nti al  
deat h ) will be prese nte d t o get her i n s u m mar y ta bles , b y S O C a n d P T, will als o be pr o vi de d b y 
treat me nt a n d o verall.  
S u m mar ies of T E A Es a n d S A Es b y decreasi n g fre q ue nc y of P T f or T B P M -PI -H Br  a n d f or 
erta pe ne m will als o be pr o vi de d b y treat me nt a n d o verall. Base d o n t he latest versi o n of 
Me d D R A, A Es  re p orte d d ue t o C O VI D- 1 9 will be a p pr o priatel y c o de d i n t he listi n gs a n d 
i de ntifia ble i n t he s u m mar y ta bles a n d listi n gs b y S O C a n d P T.   
F or all s u m maries, patie nts  will be c o u nte d o nce f or eac h A E cate g or y, S O C, or i n di vi d ual A E 
P T. F or t he s u m maries b y se verit y gra de, e ver y patie nt  will be c o u nte d o nce  f or eac h A E at t he 
hi g hest se verit y.  
S u m mar y ta bles a n d listi n gs f or T E A E s relate d t o tar get or ga n t o xicit y a n d f or T E A Es of s pecial 
i nterest will be pr o vi de d if dee me d a p pr o priate base d o n the bli n de d re vie w of t he A Es  
perf or me d b y s p o ns or. 
A E s u m maries will i ncl u de n u m ber of patie nts wit h a gi ve n A E, as well as n u m ber of A Es 
t he msel ves. 
All A E s u m maries will be re peate d s u m mari zi n g a d verse e ve nts w hic h occ urre d starti n g fr o m 
first d ose t o e n d of treat me nt visit.  
Listi n gs will be pr o vi de d f or all T E A Es, S A Es, T E A Es rela te d t o st u d y dr u g, T E A Es lea di n g t o 
disc o nti n uati o n fr o m t he st u d y, T E A Es lea di n g t o st u d y dr u g wit h dra wal, a n d T E A Es lea di n g t o 
deat h f or all patie nts  i n t he Safet y P o p ulati o n. A d verse e ve nts of C O VI D - 1 9 will be c o de d as a 
s pecific preferre d ter m i n t hese listi n gs. 
A listi n g of all deat hs, i ncl u di n g t he date of deat h a n d pri mar y ca use of deat h , will be prese nte d 
f or all patie nts i n t he Safet y  P o p ulati o n.   
8. 9. 2  
L a b or at ory D at a  
La b orat or y pa nels ( he mat ol o g y, c he mistr y, c oa g ulati o n, a n d uri nal ysis) will be s u m marize d b y 
visit , al o n g wit h c ha n ges fr o m baseli ne t o eac h p ost-baseli ne ti me p oi nt, f or eac h test. All 
s u m mar y ta bles will be prese nte d b y treat me nt a n d o verall, f or t he Safet y P o p ulati o n .  
Descri pti ve statistics will be pr o vi de d f or c o nti n u o us varia bles; f o r cate g orical varia bles, n u m ber 
a n d perce nta ge will be s u m marize d. O nl y data fr o m t he ce ntral la borat or y  will be s u m marize d.  
Se parate ta bles will be prese nte d f or eac h la b orat or y pa nel .  
S hift ta bles ( n u m ber a n d perce nta ge) will be pr o vi de d b y C T C A E 5. 0 g ra des fr o m baseli ne t o t he 
w orst p ost- baseli ne assess me nt a n d will be s u m marize d b y treat me nt a n d o verall f or eac h 
la b orat or y test. T he n u m ber of patie nts  i n a partic ular treat me nt ar m ha vi n g b ot h baseli ne a n d 
p ost- baseli ne res ults a vaila ble will be use d a s t he de n o mi nat or.  


St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
 
P a g e 3 2  of 3 9  
 
S A P fi n al 1. 1: 0 3  S e pt e m b er  2 0 2 0  
C o nfi d e nti al  
A d diti o nal a nal ysis of la b orat or y para meters (c he mistr y a n d he mat ol o g y para meters will  be 
s u m marize d se paratel y) will be c o n d ucte d i n t he Safet y P o p ulati o n a n d will i ncl u de fre q ue ncies 
f or w orst p ost-baseli ne val ues :  
•  
Patie nts  wit h at l east a 2- gra de i ncrease i n C T C A E t o xicit y gra de fr o m baseli ne i n a n y para meters  
•  
Patie nts  wit h  C T C A E t o xicit y gra de ≥ 4 i n a n y para meters  
A nal ysis of patie nts  wit h p ost- b aseli ne ami n otra nsferase ele vati o ns a n d t otal bilir u bi n b y 
cate g or y will be d o ne f or w orst p ost- baseli ne val ues  i n t he Safet y P o p ulati o n a n d defi ne d as:  
o  A L T > 3 x, > 5 x, > 1 0 x u p per li mit of n or mal ( U L N )  
o  A S T > 3 x, > 5 x, > 1 0 x U L N  
o  A L T a n d A S T > 3 x, > 5 x, a n d > 1 0 x U L N  
o  T otal b ilir u bi n > 2 x U L N 
o  A L T a n d A S T > 3 x U L N a n d  total b ilir u bi n >2 x U L N  
A patie nt wit h ele vate d la b para meter s ma y bel o n g t o m ore t ha n o ne cate g or y (e. g., if a patie nt 
has a n A L T val ue = 6 x U L N, t his patie nt will be p rese nte d u n der b ot h > 3 x U L N a n d > 5 xU L N ). 
Patie nts w h o meet p ote ntial H y’s  La w la b orat or y criteria will be liste d. H y ’s L a w la b orat or y 
criteria are  defi ne d as a n y ele vate d A L T a n d/ or A S T of > 3 x U L N t hat is ass ociate d wit h b ot h a n 
A L P  < 2 x U L N a n d a n i ncrease i n bilir u bi n > 2 x U L N.  
All la b orat or y data will be liste d f or all patie nts  i n t he Safet y P o p ulati o n, i ncl u di n g t o xicit y 
gra des, n or mal ra n ges, a n d cli nicall y si g nifica nce fla gs; val ues o utsi de t heir n or mal ra n ge will be 
fla g ge d as H ( hi g h, a bo ve n or mal) or L (l o w, bel o w n or mal).   
A listi n g of all pre g na nc y test res ults will be pr o vi de d f or all fe male patie nts i n t he Safet y  
P o p ulati o n , w here a p plica ble. 
B o x pl ots of la b orat or y val ues  ( A L T, A S T, bilir u bi n, G G T, he mat ocrit, platelets, ne utr o p hils, 
W B C, differe ntial c o u nts , t otal/free car niti ne, B U N, creati ni ne, calci u m, t otal/ direct bilir u bi n, 
he m o gl o bi n ) vers us visit will als o be pr o vi de d  b y treat me nt gr o u p . 
8. 9. 3  
Vit al Si g ns  a n d Ot her S afety E n d p oi nts 
Vital si g ns i ncl u de s yst olic a n d diast olic bl o o d p ress ure ( m m H g), wei g ht ( k g), p ulse rate ( beats 
per mi n ute [ b p m]), res pirat or y rate ( breat hs per mi n ute), a n d ma xi m u m dail y te m perat ure 
( de gree C).   
S u m mar y ta bles of vital si g ns o bser ve d val ues a n d c ha n ges fr o m baseli ne t o sc he d ule d p ost-
baseli ne visits  will be prese nte d b y treat me nt a n d o verall , f or t he Safet y P o p ulati o n, f or eac h 
vital si g n c ollecte d. Si milar ta bles will be create d f or eac h E C G para meter.  W he n E C G  data are 
c ollecte d i n tri plicates, t he a vera ge val ue a m o n g t hree meas ure me nts will be s u m marize d. 


St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
 
P a g e 3 3  of 3 9  
 
S A P fi n al 1. 1: 0 3  S e pt e m b er  2 0 2 0  
C o nfi d e nti al  
Electr ocar di o gra m s u m maries  i ncl u de h eart rate ( b p m), P R i nter val ( msec), Q R S d urati o n 
( msec), Q T inter val ( msec), R R inter val ( msec), Q Tc F inter val ( msec).  
Electr ocar di o gra m val ues (t he w orst i nter pretati o n val ue of t he tri plicate) will be s u m marize d b y 
t he n u m ber a n d perce nta ge classifie d as n or mal, a b n or mal – n ot cli nicall y si g nifica nt, a b n or mal 
– cli nicall y si g nifica nt, or n ot d o ne at eac h sc he d ule d visit, b y treat me nt a n d o verall, f or t he 
Safet y P o p ulati o n. 
W orst p ost- baseli ne ca te g orize d Q Tc F val ues will be prese nte d i n t he Safet y P o p ulati o n as 
f oll o ws: 
•  Q Tc F > 5 0 0 msec a n d baseli ne ≤5 0 0 msec  
•  Q Tc F > 4 8 0 – ≤5 0 0 msec a n d baseli ne ≤4 8 0 msec  
•  Q Tc F > 4 5 0 – ≤4 8 0 msec a n d baseli ne ≤4 5 0 msec  
•  Q Tc F c ha n ge fr o m baseli ne > 3 0 – ≤6 0 msec  
•  Q Tc F c ha n ge fr o m baseli ne > 6 0 msec  
•  P ost -baseli ne Q Tc F > 5 0 0 msec a n d Q Tc F c ha n ge fr o m basel i ne > 3 0 –≤6 0 msec  
•  P ost -baseli ne Q Tc F > 5 0 0 msec a n d Q Tc F c ha n ge fr o m baseli ne > 6 0 msec  
•  P ost -baseli ne Q Tc F > 4 8 0 – ≤5 0 0 msec a n d Q Tc F c ha n ge fr o m baseli ne > 3 0 – ≤6 0 msec 
•  P ost -baseli ne Q Tc F > 4 8 0 – ≤5 0 0 msec a n d Q Tc F c ha n ge fr o m baseli ne > 6 0 msec 
Listi n gs of vital si g ns data a n d E C G data ( o bser ve d a n d c ha n ge fr o m baseli ne) will be prese nte d 
f or all patie nts i n t he Safet y P o p ulati o n ; t he listi n gs will state all para meters i n t heir ori gi nal 
c ollecti o n u nits. 
A b n or mal p h ysical e xa mi nati o n  ( P E) res ults will be rec or de d at baseli ne a n d will be liste d. P ost-
baseli ne a b n or mal P E val ues will be rec or de d as A Es a n d s u m marize d a n d liste d as A Es . N o 
s pecific s u m maries f or t he P E val ues will be create d. 
Uri nar y tract si g ns a n d s y m pt o ms ( ter m a n d se verit y) will be liste d a n d als o s u m marize d b y visit 
i n t he Safet y P o p ulati o n.  
8. 9. 4  
Ex p os ure t o St u dy Dr u g  
T he f oll o wi n g para meters will be calc ulate d f or t he e x p os ure data:  
•  Act ual t otal I V d ose  (i n m L) recei ve d t hr o u g h o ut t he st u d y, defi ne d as t he s u m of all t he 
I V d oses recei ve d b y t he patie n t. 
•  Act ual t otal oral d ose recei ve d t hr o u g h o ut t he st u d y ( m g), defi ne d as t he s u m of all t he 
oral d oses recei ve d b y t he patie nt.  
•  D urati o n of t he I V treat me nt ( da ys ), defi ne d as ( n u m ber of h o urs bet wee n last a n d first 
i njecti o n + 1)/ 2 4 h o urs.  


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P a g e 3 4  of 3 9  
 
S A P fi n al 1. 1: 0 3  S e pt e m b er  2 0 2 0  
C o nfi d e nti al  
•  D urati o n of t he oral treat me nt ( da ys), defi ne d as (n u m ber of h o urs bet wee n last a n d first 
oral i nta ke + 1)/ 2 4 h o urs.  
•  C o m plia nce will be defi ne d se paratel y f or oral a n d I V dr u g. C o m plia nce f or oral dr u g will 
be calc ulate d as act ual n u m ber of ta blets ta ke n/ pla n ne d n u m ber of ta blets . Act ual n u m ber 
of ta blets = all ta blets ta ke n b y a patie nt. Pla n ne d n u m ber of ta blets will be calc ulate d a s a 
s u m of all pla n ne d d oses per i nta ke f or a patie nt. Pla n ne d d ose per i nta ke will be 2 or 1 (if 
creati ni ne cleara nce val ues re q uire d ose a dj ust me nt as rec or de d o n C R F data). C o m plia nce 
wit h I V dr u g will be defi ne d i n a si milar wa y . 
T he a b o ve- defi ne d para met ers will be s u m marize d  i n t he Safet y P o p ulati o n b y treat me nt ar m . 
D urati o n of t he I V a n d oral treat me nt will be s u m marize d b ot h cate g oricall y a n d usi n g mea ns. 
C o m plia nce will be s u m marize d as  a c o nti n u o us varia ble.  
Listi n gs will be create d f or all oral a n d  I V d oses a d mi nistere d a n d c o m plia nce ( oral a n d I V). 
8. 1 0  O t her E n d p oi nts  
8. 1 0. 1  P h ar m ac oki netic D at a 
Descri pti ve statistics of i n di vi d ual plas ma c o nce ntrati o ns f or T B P M will be s u m marize d a n d 
liste d acc or di n g t o t he n o mi nal sa m pli n g wi n d o ws p ost d osi n g f or t he P K P o p ulati o n a n d will be 
re p orte d i n t he C S R. S u m maries f or P K plas ma c o nce ntrati o n will i ncl u de n, mea n, sta n dar d 
de viati o n, mi ni m u m, m a xi m u m, me dia n as well as ge o metric mea n a n d c oefficie nt of variati o n, 
T B P M bl o o d c o nce ntrati o ns were c o n verte d t o plas ma c o nce ntrati o ns usi n g t he f oll o wi n g 
e q uati o n: T B P M plas ma c o nce ntrati o n = re p orte d bl o o d c o nce ntrati o n x 3. 6; w here 3. 6 
re prese nts a pro d uct of he mat ocrit val ue of 1. 8 a n d dil uti o n fact or of 2 b y a d diti o n of 1: 1 
is o pr o p yl alc o h ol (I P A): Bl o o d v ol u me.  I P A was a d de d as a sta bilizer d uri n g bl o o d sa m ple 
c ollecti o ns t o pre ve nt c o n versi o n of T B P M- PI t o T B P M p ost sa m ple c ollecti o n.  T B P M 
c o m part me ntal p har mac o ki netic ( P K) para meters deri ve d fr o m P o p ulati o n P K a nal ysis, a n d 
p ote ntial P K/ p har mac o d y na mic ( P D) relati o ns hi ps will be re p orte d se paratel y.  
9.  
D E VI A TI O N S F R O M A N A L Y SI S  A S D E S C RI B E D I N T H E 
P R O T O C O L  
T he f oll o wi n g u p dates were ma de t o t he pla n ne d a nal ysis: 
•  
T he  defi niti o n of s ustai ne d cli nical c ure at L F U was clarifie d , i n t hat a patie nt s h o ul d 
meet  criteria f or cli nical c ure at T O C a n d re mai n free of ne w si g ns a n d s y m pt o ms of 
c U TI or A P at L F U.   
o  J ustificati o n: S o me si g ns a n d s y m pt o ms ma y be mi nimal a n d n ot re q uire t hera p y 
at L F U, a n d t he patie nt is still a s ustai ne d c ure wit h o ut t he nee d f or resc ue 
a nti bi otics. T he i nte nt of t he pr ot oc ol was t o use t he ter m “ ne w” si g ns a n d 
s y m pt o ms f or s ustai ne d c ure at L F U, t o e ns ure a c o nsiste nt a p pr oac h t o t he 


St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
 
P a g e 3 5  of 3 9  
 
S A P fi n al 1. 1: 0 3  S e pt e m b er  2 0 2 0  
C o nfi d e nti al  
ha n dli n g of “ ne w” si g ns a n d s y m pt o ms as t he y are d efi ne d f or s uccess a n d fail ure 
at L F U. 
•  
T he d efi niti o n of micr o -I T T P o p ulati o n was m o difie d t o e xcl u de patie nts w h o ha ve n o n-
fer me nti n g Gra m-ne gati ve bacilli, M R S A  a n d/ or pat h o ge ns n o n-s usce pti ble t o 
mer o pe ne m . 
o  J ustificati o n: T he i nte nt is t o e xcl u de t he t otalit y of pat h o ge ns n ot e x pecte d t o 
res p o n d t o st u d y dr u gs i ncl u di n g car ba pe ne mase - pr o d uci n g E nter o b acter ales  
usi n g mer o pe ne m as t he m ost a p pr o priate s urr o gate f or resista nce via 
car ba pe ne mase pr o d ucti o n.  
•  T he defi niti o n of t he micr o -I T T P o p ulati o n was clarifie d t o n ote t hat patie nts wit h o ne or 
m ore ur o pat h o ge ns is olate d fr o m bl o o d at baseli ne/ Scree ni n g w o ul d be i ncl u de d i n the 
micr o -I T T P o p ulati o n as o utli ne d i n t he E R P ( v. 3 date d 2 0 A u g 2 0 2 0).  
o  J ustificatio n: La n g ua ge clarifie d t o be c o nsiste nt wit h t he i n d ustr y st u d y sta n dar d 
a n d t he a p pr oac h f oll o we d t hr o u g h o ut t he st u d y as d oc u me nte d i n t he E R P  v. 3 
date d 2 0 A u g 2 0 2 0 a n d D R C meeti n g mi n utes. I n or der t o e ns ure tra ns pare nc y , 
t he clarificati o n pr o vi de d i n t hese d oc u me nts was als o a d de d t o t he S A P 
defi niti o n .  
•  T he defi niti o n of baseli ne c ult ure or baseli ne pat h o ge n was u p date d t o n ote t hat t he 
baseli ne pat h o ge n c o ul d be i de ntifie d fr o m a n y c ult ure c ollecte d wit hi n 4 8 h o urs pri or t o 
t he first d ose or p ost- d ose  if o n t he sa me cale n dar da y as da y 1. 
o  J ustificati o n: It w o ul d be i n a p pr o priate t o e xcl u de a pat h o ge n is olate d at t he 
re q uire d > 1 05 C F U/ ml  o n t he sa me cale n dar da y as t he start of st u d y t hera p y.  
•  
Prese ntati o ns f or o verall res p o nse at E O T will be pr o vi de d i n t he micr o -I T T a n d M E 
P o p ulati o ns, a n d prese ntati o ns of c li nical c ure at E O T a n d  T O C b y baseli ne pat h o ge n 
will be pr o vi de d i n t he micr o-I T T a n d M E P o p ulati o n s. 
o  J ustificati o n: T hese a d diti o nal data are t o be prese nte d t o pr o vi de a c o m plete 
re vie w of t he cli nical trial res ults f or t he ke y e n d p oi nts at ke y ti me p oi nts. 
•  
Defi niti o n s of t he C E a n d M E P o p ulati o ns w ere clarifie d t o i ncl u de b y-visit C E  a n d M E 
P o p ulati o ns, a n d criteria f or i ncl usi o n i n t hese p o p ulati o ns were als o u p date d. 
o  J ustificati o n: T he patie nts i ncl u de d i n t he C E a n d M E P o p ulati o ns will var y b y 
visit as t his will de pe n d u p o n t he data a vaila ble.  
•  
Pr ot oc ol re q uires de m o gra p hics a n d baseli ne c haracteristics t o be s u m marize d i n I T T a n d 
Safet y P o p ulati o ns; h o we ver, t he I T T P o p ulati o n will n ot be use d.  
o  J ustificati o n: T he S afet y P o p ulati o n is use d t o s u p p ort safet y s u m maries, w hilst 
t he I T T P o p ulati o n is n ot re q uire d as t his will be a ver y si milar p o p ulati o n.  


St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
 
P a g e 3 6  of 3 9  
 
S A P fi n al 1. 1: 0 3  S e pt e m b er  2 0 2 0  
C o nfi d e nti al  
•  
Pat h o ge n s u m maries f or E nter o b acteri a ce ae ha ve bee n u p date d t o t he or der 
“E nter o b acter ales ” based o n c urre nt ta x o n o m y.  
o  J ustificati o n: E nter o b acter ales is t he c urre nt a p pr o priate ta x o n o mic ter m f or t his 
gr o u p of bacteria.  
•  
Da y 5 micr o bi ol o gical res p o nse rates b y- pat h o ge n were re m o ve d fr o m t he Da y 5 
e x pl orat or y e n d p oi nt . 
o  J ustificati o n: The i nte nt was t o  pr o vi de a n o verall per -patie nt assess me nt a n d t he 
o utc o mes b y- pat h o ge n are li kel y t o be n o n- mea ni n gf ul at Da y 5 a n d u nli kel y t o be 
differe nt t ha n t he a nal ysis of b y - pat h o ge n o utc o mes at E O T. 
1 0.  P R O G R A M MI N G S P E CI FI C A TI O N S  
All o ut p uts will be pr o d uce d usi n g S A S versi o n 9 . 4 or a later versi o n.  
T he mar gi ns s h o ul d be at least 1. 5 0 i nc hes f or t he bi n di n g e d ge a n d 1. 0 i nc hes f or all ot hers.  
I n t he t o p left p orti o n of eac h ta ble/listi n g, t he S p o ns or c o m pa n y a n d pr ot oc ol n u m ber will be 
prese nte d. O n t he ne xt li ne, a ta ble/listi n g n u m ber f oll o we d b y the title of t he ta ble/listi n g a n d 
p o p ulati o n i nf or mati o n will be dis pla ye d. H oriz o ntal li nes will a p pear after t he c ol u m n hea di n g 
of t he ta ble/listi n g. F o ot n otes will be p ut u n der t he mai n b o d y of te xt at t he b ott o m of t he pa ge.. 
T he s o urce listi n g n u m ber a n d t he A Da M dataset use d, al o n g wit h t he date of t he data s na ps h ot 
or t he date of data base l oc k , will be dis pla ye d f or all ta bles. T he S A S pr o gra m na me (i ncl u di n g 
l ocati o n) a n d t he pr o gra m mer I D will a p pear b ott o m left i n a stri n g, a n d t he date a n d ti me of 
creati o n of ta ble/listi n g will a p pear b ott o m ri g ht. T he pa ge n u m ber will a p pear o n t he t o p ri g ht 
c or ner of eac h ta ble/listi n g.  
C o urier Ne w 8 - p oi nt b ol d f o nt will be use d f or all ta bles a n d listi n gs. Us uall y, a la n dsca pe la y o ut 
is s u g geste d f or b ot h ta bles a n d listi n gs, b ut it is n ot ma n dat or y. A n y date i nf or mati o n i n t he 
listi n g will use t he date 9 f or mat ( D D M M M Y Y Y Y). 
1 1.  T A B L E S , LI S TI N G S , A N D  FI G U R E S 
T he T L Fs will be pr o vi de d i n a se parate M oc k -U p T L Fs d oc u me nt , w hic h will be fi nalize d 
se paratel y fr o m t his S A P. 
 


St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
 
P a g e 3 7  of 3 9  
 
S A P fi n al 1. 1: 0 3  S e pt e m b er  2 0 2 0  
C o nfi d e nti al  
1 2.  A P P E N DI X 1 : S C H E D U L E O F A S S E S S M E N T S  
St u d y Peri o d  
Scree ni n g  
Tre at me nt  
F oll o w -U p  
Visit or St u d y D a y  
-1 or 1  
D a ys 1 t hr o u g h 1 4  
1 9 ± 2  
2 5 ± 2  
St u d y D a y  
Scree ni n g a 
1 ( P ost -R a n d.)  
2 –  1 4  
E O T  b 
T O C c 
L F U  
I nf or me d C o nse nt 
X  
 
 
 
 
 
Me dical & S ur gical Hist or y 
d 
X  
 
 
 
 
 
Hei g ht a n d Wei g ht *  
X  
 
 
 
 
 
C o m plete P h ysical E xa mi nati o n e 
X  s 
 
 
X  
X  
X  
F oc use d P h ysical E xa mi nati o n e 
 
X  
X  
 
 
 
Vita l Si g ns ( T, P, R R, B P) f 
X  s 
X  
X  
X  
X  
X  
C ollecti o n of c U TI/ A P  si g ns 
a n d s y m pt o ms 
X  s 
X r 
X 
X 
X 
X 
1 2 -lea d E C G g 
X  
X  
 
X  
X  
 
L ocal la bs f or eli gi bilit y (safet y 
a n d pre g na nc y testi n g)  h 
X 
  
 
 
 
 
L ocal ser u m creati ni ne t o assess 
re nal f u ncti o n f or d ose 
a dj ust me nts  h 
X  s 
X 
X 
 
 
 
Ce ntral la bs ( bl o o d/ uri ne f or 
safet y)  i 
X 
X 
X 
X 
X 
X 
Uri ne c ult ure j 
X  
 
X  
X  
X  
X  
Bl o o d c ult ures  k 
X  s 
< --------------------------------X ----------------------------->  
Rectal s wa b  
X  
 
 
 
X  
 
St u d y Dr u g A d mi nistrati o n  l 
 
X  
X  
 
 
 
Bl o o d sa m p le f or plas ma P K m  
 
 
X  
 
 
 
Uri ne c ollecti o n f or P K n 
 
X -------->  
 
 
 
 
Uri nar y tract i nstr u me ntati o n 
stat us o 
X 
 
X 
X 
X 
X 
Site of care  p  
X  
X  
X  
X  
X  
X  
I n vesti gat or assess me nt of 
cli nical o utc o me  
 
 
 
X 
X 
X 
Pri or a n d c o nc o mita nt 
me dicati o ns  
X 
X 
X 
X 
X 
X 
A d ver se E ve ntsq 
 
X  
X  
X  
X  
X  
A P = Ac ute P yel o ne p hritis ; B P = Bl o o d Press ure; c U TI = C o m plicate d Uri nar y Tract I nfecti o n; E C G  = Electr ocar di o gra m; 
E O T = E n d -of -Treat me nt Visit; L F U  = Late F oll o w -u p Visit; P = P ulse; P K  = P har mac o ki netic; Ra n d = Ra n d o mizati o n; R R = 
Res pirat or y Rate; T = T e m perat ure; T O C = Test -of -C ure Visit  


St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
 
P a g e 3 8  of 3 9  
 
S A P fi n al 1. 1: 0 3  S e pt e m b er  2 0 2 0  
C o nfi d e nti al  
a 
Scree ni n g pr oce d ures m ust be c o m plete d wit hi n 2 4 h pri or t o ra n d o mizati o n o n Da y 1. Scree ni n g la b orat or y assess me nts 
f or eli gi bilit y will be perf or me d at t he l ocal/re gi o nal la b orat or y. Sta n dard- of -care assess me nts p erf or me d at t he site 
wit hi n t he Scree ni n g peri o d ( wit hi n 2 4 h o urs of ra n d o mizati o n) ma y be use d t o deter mi ne s u bject eli gi bilit y e ve n if 
perf or me d pri or t o si g ni n g t he I C F; h o we ver, st u d y -s pecific assess me nts, s uc h as tri plicate E C Gs, bl o o d c ult ures (if usi n g 
a st u d y-s pecific re gi o nal la b orat or y), a n d Scree ni n g safet y la bs c ollecte d f or a nal ysis b y t he ce ntral la b orat or y, m ust be 
perf or me d after si g ni n g t he I C F (see Pr ot oc ol Secti o n 7. 1. 1 f or detail). If Scree ni n g Visit a n d Da y 1 occ u r o n t he sa me 
cale n dar da y: C o m plete p h ysical e xa m at Scree ni n g is re q uire d, w hile Da y 1 f oc use d p h ysical e xa m is o pti o nal; vital 
si g ns at Scree ni n g are re q uire d, w hile re peate d Da y 1 vital si g ns are o pti o nal (if re peate d vital si g ns are c ollecte d, rec or d  
t he hi g hest dail y te m perat ure i n t he e C R F); assess me nt of c U TI/ A P cli nical si g ns a n d s y m pt o ms at Scree ni n g is re q uire d, 
w hile Da y 1 assess me nt of cli nical si g ns a n d s y m pt o ms is o pti o nal; a n d se parate Scree ni n g a n d Da y 1 E C Gs m ust be 
perf or me d (i.e., Da y 1 E C Gs m ust be perf or me d i n tri plicate 1 h ( ± 1 5 mi n) after t he first oral d ose a d mi nistrati o n) (see 
Pr ot oc ol Secti o n 7. 1. 2 f or detail).  
b 
I P a d mi nistrati o n is 7-1 0 cale n dar da ys, or u p t o a ma xi m u m of 1 4 cale n dar da ys f or s u bjects wit h a baseli ne bl o o d 
c ult ure t hat is p ositi ve f or ur o pat h o ge n gr o wt h. T he E O T Visit occ urs o n t he cale n dar da y or t he da y f oll o wi n g ( + 1 da y) 
t he last d ose of st u d y dr u g. All E O T pr oce d ures ma y be perf or me d t he da y f oll o wi n g last d ose of st u d y dr u g wit h t he 
e xce pti o n of t he E O T E C Gs , w hic h m ust be perf or me d 1 h o ur ( ± 1 5 mi n) after t he last d ose rat her t ha n t he f oll o wi n g da y. 
La b assess me nts t hat are re q uire d o n t he da y of last d ose a n d E O T d o n ot nee d t o be d u plicate d; f or i nsta nce, if Da y 7 a n d 
E O T occ ur o n t he sa me da y, t he E O T ce nt ral la b assess me nt kit s h o ul d be use d i n place of Da y 7 kit. 
c 
T O C Visit:  Da y 1 9 ± 2 da ys. T he pr oce d ures at t he T O C Visit s h o ul d be perf or me d f or all s u bjects i ncl u di n g t h ose w h o 
pre mat urel y disc o nti n ue st u d y dr u g.  
d 
O btai n me dical/s ur gical hist or y, i nc l u di n g ur ol o gical hist or y a n d a n y acti ve or i nacti ve c o n diti o ns dia g n ose d wit hi n t he 
pre vi o us 5 years.  
e 
C o m plete p h ysical e xa mi nati o ns at Scree ni n g, E O T, T O C, a n d L F U c o nsist of s ki n, hea d a n d nec k, heart, l u n g, a b d o me n 
(i ncl u di n g s u pra p u bic area), e xtremities, bac k/fla n k/c ost o verte bral a n gle te n der ness, a n d ne ur o m usc ular assess me nts. 
F oc use d p h ysical e xa mi nati o ns bet wee n Da y 1 a n d E O T are s y m pt o m -base d assess me nt s. If Scree ni n g Visit a n d Da y 1 
occ ur o n t he sa me cale n dar da y t he f oc use d p h ysical e xa m  o n D a y 1 is o pti o nal.  
f 
Vital si g ns i ncl u de bl o o d press ure, p ulse, res pirat or y rate, a n d te m perat ure. Ma xi m u m dail y te m perat ure ( defi ne d as t he 
ma xi m u m te m perat ure re p orte d o n a si n gle cale n dar da y) will be c ollecte d at Scree ni n g, dail y Da y 1 t hr o u g h E O T  ( prior 
t o dail y I V i nf usi o ns), T O C, a n d L F U. B o d y te m perat ure ma y be ta ke n per t he site’s preferre d met h o d b ut li mite d t o oral, 
t y m pa nic, rectal, or c ore meas ure me nts. T he sa me met h o d of meas uri n g a s u bject’s b o d y te m perat ure s h o ul d be use d 
t hr o u g h o ut t he st u dy. If Scree ni n g Visit a n d Da y 1 occ ur o n t he sa me cale n dar da y, re peate d vital si g ns o n Da y 1 are 
o pti o nal.  
g 
At Scree ni n g, perf or m 1 2 -lea d E C Gs i n tri plicate at 1-5 mi n ute i nter vals (calc ulate mea n Q Tc F val ue f or eli gi bilit y).  O n 
Da y 1, perf or m 1 2 -lea d EC Gs i n tri plicate at 1 -5 mi n ute i nter vals 1 h ( ± 1 5 mi n) after t he first oral d ose a d mi nistrati o n. At 
E O T, perf or m 1 2 -lea d E C Gs i n tri plicate at 1-5 mi n ute i nter vals 1 h ( ± 1 5 mi n) after t he fi nal oral d ose a d mi nistrati o n. At 
T O C, perf or m a si n gle 1 2 -lea d E C G.  
h 
Res ults fr o m t he l ocal bl o o d a n d uri ne sa m ples are use d t o deter mi ne eli gi bilit y (res ults ca n be fr o m sa m ples o btai ne d u p 
t o 2 4 h o urs pri or t o ra n d o mizati o n). Assess me nts i ncl u de ser u m creati ni ne (f or Cr Cl calc ulati o n), A L T, A S T, t otal 
bilir u bi n, a bs olute ne utr o p hil c o u nt, bl o o d urea nitr o ge n ( or bl o o d urea), uri nal ysis (f or L E a n d W B C i n s p u n or u ns p u n 


St ati sti c al A n al y si s Pl a n S P R 9 9 4 -3 0 1 
 
P a g e 3 9  of 3 9  
 
S A P fi n al 1. 1: 0 3  S e pt e m b er  2 0 2 0  
C o nfi d e nti al  
uri ne). A uri ne or ser u m beta h u ma n c h ori o nic g o na d otr o pi n ( β -H C G) pre g na nc y test ( uri ne or ser u m acc or di n g t o l ocal 
sta n dar d-of -care) is perf or me d  b y t he l ocal la b orat or y o n all F O C P at t he Scree ni n g Visit, a n d if pre g na nc y is s us pecte d 
at a n y ti me. Ser u m creati ni ne (f or Cr Cl calc ulati o n) s h o ul d be assesse d e ver y 3 da ys f or s u bjects wit h n or mal re nal 
f u ncti o n at baseli ne a n d at least o nce dail y f or s u bjects wit h m o derate re nal i m pair me nt fr o m t he ti me of first d ose u ntil 
t he Cr Cl sta bilizes. *If a vaila ble, wei g ht o n t he da y of t he ser u m creati ni ne meas ure me nt t o be use d f or calc ulati n g Cr Cl. 
i 
T he ce ntral safet y la b orat or y will perf or m t he f oll o wi n g  e valuati o ns o n bl o o d a n d uri ne sa m ples: he mat ol o g y, 
c oa g ulati o n, ser u m c he mistr y (i ncl u di n g L -car niti ne), a n d c o m plete uri nal ysis. Ce ntral safet y la bs d uri n g treat me nt will 
be perf or me d o n Scree ni n g, Da y 1 (if t he Scree ni n g ce ntral safet y la bs are c ollecte d o n  Da y 1, t he Da y 1 la bs d o n ot nee d 
t o be re peate d), Da y 3, Da y 5, Da y 7, Da y 9 (if still recei vi n g I P), Da y 1 1 (if still recei vi n g I P), Da y 1 3 (if still recei vin g 
I P), E O T, T O C, a n d L F U. I n a d diti o n, ser u m β-H C G is perf or me d o n all F O C P at t he Scree ni n g Vi sit a n d at t he s u bject’s 
fi nal visit ( L F U Visit or ti me of earl y wit h dra wal fr o m t he st u d y) b y t he ce ntral la b orat or y. 
j 
O btai n uri ne sa m ples f or c ult ure at Scree ni n g ( uri ne c ult ures c ollecte d per sta n dar d -of -care u p t o 2 4 h pri or t o 
ra n d o mizati o n may be use d f or eli gi bilit y), Da y 5, E O T, T O C, a n d L F U. At L F U, uri ne c ult ure m ust be o btai ne d i n o nl y 
s u bjects wit h a p ositi ve uri ne c ult ure ( gr o wt h of uri ne c ult ure bacterial pat h o ge n(s) ≥1 0 5 C F U/ m L) after t he T O C Visit. 
Uri ne c ult ure m ust als o be c ollecte d o n a n y da y a s u bject is dee me d a cli nical fail ure, p ri or t o t he start of n o n-st u d y 
a nti bacterial resc ue t hera p y.   
k 
C ollect 2 sets of bl o o d c ult ures (eac h set is 1 aer o bic a n d 1 a naer o bic bl o o d c ult ure b ottle) fr o m 2 se parate ve ni p u nct ure 
sites at Scree ni n g. Bl o o d c ult ures s h o ul d be re peate d o n t he da y t hat a pre vi o us (e. g., baseli ne) bl o o d c ult ure is 
deter mi ne d t o be p ositi ve (e. g., re veals gr o wt h of a ur o pat h o ge n). Bl o o d c ult ures s h o ul d be re peate d as necessar y u ntil 
ne gati ve bl o o d c ult ures are o btai ne d.  
l 
T he T B P M -PI -H Br  treat me nt gr o u p will be a d mi nistere d T B P M -PI -H Br 3 0 0 m g fil m -c oate d  ta blets orall y 6 0 0 m g q 8 h 
( ± 0.5 h) pl us a si n gle d u m m y I V i nf usi o n o ver 3 0 mi n q 2 4 h ( ± 0. 5 h). T he erta pe ne m treat me nt gr o u p will recei ve 
erta pe ne m f or I V i njecti o n, a d mi nistere d as a 1 -gra m I V i nf usi o n o ver 3 0 mi n q 2 4 h ( ± 0 . 5 h) pl us d u m m y place b o ta blets 
a d mi nistere d orall y q 8 h ( ± 0. 5 h) .  
m 
First a p pr o xi matel y 7 0 s u bjects: Bl o o d sa m ples will be c ollecte d o n f oll o wi n g a n oral d ose (first, sec o n d, or t hir d) o n Da y 
2 at t he f oll o wi n g ti me i nter vals after oral a d mi nistrati o n o f t st u d y dr u g: 0. 2 5 h ( ± 5 mi n); 0. 5 h ( ± 5 mi n); 1 h ( ± 1 5 mi n), 
2 h ( ± 1 5 mi n), 8 h ( ± 1 5 mi n b ut pri or t o t he ne xt sc he d ule d d ose). F or all s u bjects e nr olle d after t he first 7 0 s u bjects, 
bl o o d sa m ples usi n g s parse sa m pli n g ( 3 sa m ples/s u bject) will be c ollec te d f oll o wi n g a n oral d ose (first, sec o n d, or t hir d) 
o n Da y 2 at t he f oll o wi n g ti me i nter vals after oral a d mi nistrati o n of st u d y dr u g: 1 h ( ± 1 5 mi n), 4 h ( ± 1 h), a n d 8 h ( ± 3 0 
mi n b ut pri or t o t he ne xt sc he d ule d d ose). T he e xact d ose ti me a n d t he e xact P K sa m ple ti me s h o ul d be c ollecte d f or all 
s u bjects w he n c ollecti n g P K sa m ples.  
n 
First a p pr o xi matel y 7 0 s u bjects, a t we nt y -f o ur ( 2 4) h uri ne c ollecti o n will be c ollecte d i n r o u g hl y t hree ( 3) 8-h ali q u ots 
after t he first d ose of t he st u d y dr u g o n Da y 1.  T hese c ollecti o ns are i nte n de d t o occ ur wit hi n t he first 8 h o urs after  d osi n g  
o 
Rec or d all start ti mes a n d e n d ti mes of all uri nar y tract i nstr u me ntati o n, i ncl u di n g b ut n ot li mite d t o bla d der cat heters, 
ste nts, ne p hr ost o m y t u bes, a n d ot her ur ol o gical pr ost hetic material. 
p 
Rec or d t he site of care (e. g., ac ute care h os pital  war d, l o n g -ter m care facilit y, o ut patie nt i nf usi o n ce nter). 
q 
A Es will be c ollecte d fr o m t he ti me of t he first d ose of I P.