Clinical trial NCT03425396
Conditions: Uncomplicated Urinary Tract Infection Cystitis
Sponsor: Paratek Pharmaceuticals Inc
Start date: 2018-01-04; Completion date: 2019-06-05
Enrollment: 225 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of oral omadacycline as compared to oral nitrofurantoin in the treatment of female adults with cystitis.

Detailed description:
Participants were randomized to receive 7 days of treatment of either omadacycline or nitrofurantoin. The End of Treatment visit, Post Therapy Evaluation visit, and Final Follow-up visit was planned within 2 days following the last dose of study drug, on Day 14 (+/- 2 days) after the first dose of study drug, and within 30 to 37 days following the first dose of study drug, respectively. The study followed a double-dummy design. To maintain the study blinding, participants assigned to omadacycline received active omadacycline tablets and over-encapsulated nitrofurantoin placebo tablets. Participants assigned to the nitrofurantoin arm received omadacycline placebo tablets and over-encapsulated active nitrofurantoin capsules.

Arms: arm 1: Participants received omadacycline 300 milligrams orally, once every 12 hours, fed on Day 1 and omadacycline 300 milligrams orally, once every 24 hours on Days 2 through 7. Odd doses on Days 2 to 7 were administered in a fasted state. Even doses on Days 2 to 7 were administered approximately 2 hours following a light meal. arm 2: Participants received omadacycline 450 milligrams orally, once every 12 hours, fed on Day 1 and omadacycline 300 milligrams orally, once every 24 hours on Days 2 through 7. Odd doses on Days 2 to 7 were administered in a fasted state. Even doses on Days 2 to 7 were administered approximately 2 hours following a light meal. arm 3: Participants received omadacycline 450 milligrams orally, once every 12 hours, fed on Day 1 and omadacycline 450 milligrams orally, once every 24 hours on Days 2 through 7. Odd doses on Days 2 to 7 were administered in a fasted state. Even doses on Days 2 to 7 were administered approximately 2 hours following a light meal. arm 4: Participants received omadacycline 450 milligrams orally, once every 12 hours, fed on Day 1 and omadacycline 450 milligrams orally, once every 12 hours on Days 2 through 7. Odd doses on Days 2 to 7 were administered in a fasted state. Even doses on Days 2 to 7 were administered approximately 2 hours following a light meal. arm 5: Participants received nitrofurantoin 100 milligrams orally, once every 12 hours, fed on Day 1 and nitrofurantoin 100 milligrams orally, once every 12 hours on Days 2 through 7. Odd doses on Days 2 to 7 were administered in a fasted state. Even doses on Days 2 to 7 were administered approximately 2 hours following a light meal.
Interventions: intervention 1: Omadacycline tablets intervention 2: Nitrofurantoin capsules
Intervention descriptions: intervention 1: Oral Omadacycline intervention 2: Oral Nitrofurantoin

Protocol documents:
Prot_000.pdf: 
Omadacycline  
 Paratek Pharmaceuticals, LLC 
PTK0796-UUTI-17201-Version 3.0 FINAL; 18-FEB-2019 
IND # 75,928 IND # 73,431 
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Clinical Trial Protocol:  PTK0796-UUTI-17201
Study Title: 
A Randomized, Double-Blinded, Adaptive Phase 2 Study to Evaluate the 
Safety and Efficacy of Oral Omadacycline and Oral Nitrofurantoin in the 
Treatment of Female Adults with Cystitis  
Study Number: 
PTK0796-UUTI-17201 
Study Phase: 
2 
Product Name: 
Omadacycline (PTK 0796) 
IND Number: 
75,928 
73,431 
Indication: 
Uncomplicated Urinary Tract Infection (Cystitis) 
Investigators: 
Multicenter 
Sponsor: 
Paratek Pharma, LLC  
A wholly-owned subsidiary of Paratek Pharmaceuticals, Inc. 
75 Park Plaza, 4th Floor 
Boston, MA 02116  
1000 First Ave  
Suite 200  
King of Prussia, PA 19406  
Sponsor Contact: 
Tel: +1 617-275-0040 
Medical Monitor: 
 
Protocol Amendment 2, Version 3: 
Protocol Amendment 1, Version 2: 
Original Protocol Version 1: 
18 February 2019 
29 October 2018 
20 October 2017 
Confidentiality Statement 
The concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without the expressed, 
written consent of Paratek Pharma, LLC. 
The study was in accordance with the International Conference on Harmonisation 
Harmonised Tripartite Guidelines for Good Clinical Practice. 
NCT Number: NCT03425396
This NCT number has been applied to the document for
purposes of posting on clinicaltrials.gov


Omadacycline  
 Paratek Pharmaceuticals, LLC 
PTK0796-UUTI-17201-Version 3.0 FINAL; 18-FEB-2019 
IND # 75,928 IND # 73,431 
 
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SYNOPSIS 
Sponsor: 
Paratek Pharma, LLC 
A wholly-owned subsidiary of Paratek Pharmaceuticals, Inc.  
 
Name of Finished Product: 
Omadacycline oral tablet, 150 mg 
 
Name of Active Ingredient: 
Omadacycline  
 
Study Title:  
A Randomized, Double-Blinded, Adaptive Phase 2 Study to Evaluate the Safety and Efficacy of Oral 
Omadacycline and Oral Nitrofurantoin in the treatment of Female Adults with Cystitis  
 
Study Number: 
PTK0796-UUTI-17201 
 
Study Phase:  2 
 
Study Rationale: 
Omadacycline is the first member of the aminomethylcycline class of antibiotics, which are 
semisynthetic derivatives of the tetracycline class.  Omadacycline- has in vitro activity against the 
most common bacterial pathogens associated with cystitis.  Omadacycline has been shown to have a 
significant fraction of the administered dose excreted by the kidneys and is present as active drug in 
the urine.  The safety, efficacy and pharmacokinetics (PK) of omadacycline have been evaluated in a 
limited number of adults with cystitis. 
 
Primary Objective:  
To evaluate the efficacy of omadacycline and nitrofurantoin in the treatment of female adults with 
cystitis. 
 
Secondary Objectives: 
• To evaluate the safety of omadacycline in the treatment of female adults with cystitis.   
• To evaluate the clinical and microbiologic response according to the identified causative 
pathogen.  
• To evaluate the pharmacokinetics of omadacycline in female adults with cystitis.  
 
Study Design: 
This is a randomized, double-blinded, adaptive designed Phase 2 study evaluating 4 dosing regimens 
of omadacycline compared to nitrofurantoin in the treatment of female adults with cystitis.  The 


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planned length of subject participation in the study is up to 37 days which includes a total duration of 
study therapy for 7 days.   
 
Following a Screening period of up to 24 hours, eligible subjects will be randomly assigned to receive 
one of 3 dosing regimens of once-daily omadacycline treatment, 1 dosing regimen of twice-daily 
omadacycline, or a twice-daily regimen of nitrofurantoin.  Treatment will be double-blinded and 
double-dummy. 
Subjects will be randomized to the following treatment groups: 
Group 
Test Article 
Study Day 
1 
Study Days 
2-7* 
1 
Omadacycline 
300 mg po q12h, fed 
300 mg po q24h 
2 
Omadacycline 
450 mg po q12h, fed 
300 mg po q24h  
3 
Omadacycline 
450 mg po q12h, fed 
450 mg po q24h 
4 
Omadacycline 
450 mg po q12h, fed 
450 mg po q12h 
5 
Nitrofurantoin 
100 mg po q12h, fed 
100 mg po q12h 
q12h= every 12 hours, q24h= every 24 hours 
*Odd doses on Study Days 2-7 should be taken in a fasted state. Even doses on Study Days 2-7 will be 
administered approximately 2 hours following a light meal  
 
 
 


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Dosing double-blind, double-dummy design: 
 
Dosing 
Group 1 
Group 2 
Group 3 
Group 4 
Group 5 
Dosing 
Condition 
omadacycline 
omadacycline 
omadacycline  
omadacycline 
nitrofurantoin 
Day 1 
 
 
 
 
 
Dose 1 
Two 150 mg 
omadacycline 
tablets, one 
placebo tablet 
resembling 
omadacycline  
Three 150 mg 
omadacycline 
tablets  
Three 150 mg 
omadacycline 
tablets 
Three 150 mg 
omadacycline 
tablets 
Three placebo 
tablets 
resembling 
omadacycline  
 
 
 
 
2 hours after 
light meala 
 
One placebo 
capsule 
resembling 
nitrofurantoin 
One placebo 
capsule 
resembling 
nitrofurantoin 
One placebo 
capsule 
resembling 
nitrofurantoin 
One placebo 
capsule 
resembling 
nitrofurantoin 
One 100 mg 
nitrofurantoin 
capsule 
 
 
 
 
 
Dose 2b 
Two 150 mg 
omadacycline 
tablets, one 
placebo tablet 
resembling 
omadacycline  
Three 150 mg 
omadacycline 
tablets  
Three 150 mg 
omadacycline 
tablets 
Three 150 mg 
omadacycline 
tablets 
Three placebo 
tablets 
resembling 
omadacycline  
 
 
 
 
2 hours after 
light meala  
 
One placebo 
capsule 
resembling 
nitrofurantoin 
One placebo 
capsule 
resembling 
nitrofurantoin 
One placebo 
capsule 
resembling 
nitrofurantoin 
One placebo 
capsule 
resembling 
nitrofurantoin 
One 100 mg 
nitrofurantoin 
capsule 
Days    
2-7 
 
 
 
Dose 3 
and 
odd 
doses 
Two 150 mg 
omadacycline 
tablets, one 
placebo tablet 
resembling 
omadacycline  
Two 150 mg 
omadacycline 
tablets, one 
placebo tablet 
resembling 
omadacycline  
Three 150 mg 
omadacycline 
tablets 
Three 150 mg 
omadacycline 
tablets 
Three placebo 
tablets 
resembling 
omadacycline  
 
 
 
 
Fastingc 
 
One placebo 
capsule 
resembling 
nitrofurantoin 
One placebo 
capsule 
resembling 
nitrofurantoin 
One placebo 
capsule 
resembling 
nitrofurantoin 
One placebo 
capsule 
resembling 
nitrofurantoin 
One 100 mg 
nitrofurantoin 
capsule   
 
 
Dose 4 
and 
even 
doses 
Three placebo 
tablets 
resembling 
omadacycline 
Three placebo 
tablets 
resembling 
omadacycline 
Three placebo 
tablets 
resembling 
omadacycline 
Three 150 mg 
omadacycline 
tablets 
Three placebo 
tablets 
resembling 
omadacycline 
 
 
2 hours after 
light meald  
 
One placebo 
capsule 
resembling 
nitrofurantoin  
One placebo 
capsule 
resembling 
nitrofurantoin 
One placebo 
capsule 
resembling 
nitrofurantoin 
One placebo 
capsule 
resembling 
nitrofurantoin 
One 100 mg 
nitrofurantoin 
capsule 
Day is defined as the 24-hour period, not calendar day.  All subjects will be dosed twice daily, ~12 hours apart, except where 
noted.  
 
a 
Doses 1 & 2 of the omadacycline tablets or placebo tablets resembling omadacycline and nitrofurantoin or placebo 
capsules resembling nitrofurantoin should be taken approximately 2 hours after a light meal on Day 1.  After dosing, no 
food for 2 hours and no dairy products, antacids or multivitamins containing multivalent cations (eg, aluminum, 
magnesium, calcium, bismuth, iron, or zinc) for 4 hours. 
b Dose 2 can be taken a minimum of 8 hours and up to 12 hours after Dose 1.  Dose 3 should be taken a minimum of 8 hours 
after Dose 2. 


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c      Beginning with Dose 3, all consecutive odd numbered doses of the omadacycline tablets and placebo tablets resembling 
omadacycline should be taken in a fasted state.  Fasting is defined as no food, antacids or multivitamins containing 
multivalent cations (eg, aluminum, magnesium, calcium, bismuth, iron, or zinc) or drink except water for at least 6 hours 
before dosing.  After dosing, no food for 2 hours, no dairy products, antacids or multivitamins containing multivalent 
cations (eg, aluminum, magnesium, calcium, bismuth, iron, or zinc) for 4 hours. 
d    Beginning with Dose 4, all even numbered doses should be taken approximately 2 hours after a light meal. 
 


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During the study treatment period, blood samples will be collected for safety analysis and for 
PK analysis of omadacycline.  Urine samples will be collected during the study period for 
safety, PK analysis, and microbiological analysis.  Safety assessments will include monitoring 
of adverse events (AEs), concomitant medications, clinical laboratory test results, vital sign 
measurements, pregnancy testing and physical examination findings. 
Subjects will return to the clinical site for visits on Day 1, Day 3, Day 5, and for an End of 
Treatment (EOT)/Day 7 visit on the day of or within the 2 days following the last dose of test 
article.  Subjects will return to the study site for a Post Therapy Evaluation (PTE) on Day 14 
(+/- 2 days) after the subject’s first dose of test article.  A Final Follow-up assessment will be 
conducted within 30 to 37 days following the first dose of test article.  The Final Follow-up 
assessment may be conducted via telephone contact or by another interactive technology for 
subjects who are not having any symptoms and had no AEs or clinically significant laboratory 
abnormalities noted at or after the PTE visit.  Otherwise, this assessment is to be performed 
with an in-person study visit.  During the Follow-up call/visit if the subject reports symptoms 
of potential recurrence, additional procedures will be performed.   
Rationale for Omadacycline Dose Regimen Selection: 
The dosing regimen of omadacycline selected for this study is based on the nonclinical and 
clinical experience to date, including in vitro antibacterial activity, PK characteristics, clinical 
efficacy in prior studies, and the overall safety and tolerability profile.  Key considerations in 
dose selection are summarized below: 
• While the driver of efficacy for omadacycline in UTI is not known, a pragmatic 
assumption was made that maximizing the time of urine concentration above 
pathogen MIC (ideally, throughout the dosing interval) would be desirable. 
• In PTK0796-UUTI-15103, omadacycline dosed as 300 mg po  every 12 hours 
(q12h) on Day 1 followed by 300 mg po daily for 5 days and 450 mg po q12h on 
Day 1 followed by 450 mg po daily for 5 days both demonstrated high urinary 
concentrations on Day 1 and Day 5.  For the 300 mg dosing group, over the 24 
hour dosing period, mean urinary concentrations ranged from 14 to 20 µg/mL on 
Day 1 and 17 to 30 µg/mL on Day 5.  For the 450 mg dosing group, over the 24 
hour dosing period, mean urinary concentrations ranged from 11 to 25 µg/mL on 
Day 1 and 30 to 48 µg/mL on Day 5. 
• In PTK0796-UUTI-15103, both the 300 mg and 450 mg omadacycline treatment 
groups had nausea reported in 60% of subjects.  Vomiting occurred in 40% and 
20% of the 300 mg and 450 mg treatment groups, respectively.  In the recently 
completed PTK0796-ABSI-16301 study which compared omadacycline 450 mg 
po every 24 hours (q24h) for 2 doses followed by 300 mg po q24h for a total of 7 
to 14 days to linezolid 600 mg po every 12 hours for a total of 7 to 14 days, 
nausea and vomiting rates of 30.2% and 16.8% were observed.  In both studies, 
most events of nausea and vomiting occurred early in the treatment associated 
with the loading doses of omadacycline. 
• The effect of a light meal administered approximately 1.5 hours before dosing 
was evaluated using the free base formulation of omadacycline and resulted in 
approximately 20% decrease in exposure.  In the recently completed study 


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PTK0796-DDI-17106, the effect of a light meal administered approximately 1.5 
hours before dosing with the same formulation of omadacycline used in the 
pivotal Phase 3 studies was evaluated.  The results demonstrated an 
approximately 19% to 25% reduction in exposure when a light meal was 
administered 1.5 hours before dosing. 
• The Sponsor has decided to add an omadacycline treatment group dosed at 450 
mg twice daily for 7 days. The rationale for the change includes: 
1)    Since the driver of efficacy is unknown and the mean renal excretion of a 300 
mg oral dose is 14.4%,  a regimen that maximizes the tolerated dose of 
omadacycline may provide additional information on the dose necessary for 
clinical and microbiologic success in uUTI and allow comparison to the daily 
dosed omadacycline treatment groups. 
2) The proposed dosing of 450mg twice daily for 7 days will provide 
approximately 2x or greater the amount of omadacycline that is excreted into 
the urine compared to the daily omadacycline treatment groups.   
3) Blinded review of the first 145 subjects reveals good tolerability. Nausea has 
occurred in approximately 10% of all subjects with only a single subject 
(0.7%) reporting vomiting. There has been only one treatment discontinuation 
due to adverse events of nausea and/or vomiting reported. Therefore, even if 
all cases of nausea and vomiting were in a single omadacycline treatment 
group, nausea and vomiting appears lower than observed in  PTK0796-UUTI-
15103 study. 
4) Dose-limiting transaminase increases were seen in Phase 1 studies at 600mg 
IV which is higher than the exposure at 450mg PO twice daily. 
5) Increases in heart rate following omadacycline are Cmax associated. Cmax 
concentrations with the 450mg PO dose (1077 ng/mL) at steady state are 
approximately one-half the Cmax concentration with the 100mg IV dose 
(2120 ng/mL) suggesting that heart rate increases above 12-17 bpm observed 
with 100-200mg IV doses in healthy patients is unlikely following 450mg 
twice daily dosing. 
Therefore based on the pharmacokinetic, clinical, and safety data, the 450mg 
twice daily dose will increase urinary concentration, may provide additional 
clinical and microbiologic benefit while maintaining the safety profile observed 
with daily dosing. 
 
In order to minimize the effect of food on exposure and to potentially minimize the impact of 
nausea and vomiting during the omadacycline loading dose, omadacycline will be dosed twice 
on Day 1 with each dose administered 2 hours following a light meal, and all even numbered 
doses will be administered approximately 2 hours following a light meal.Given the urinary 
concentrations observed in PTK0796-UUTI-15103 and the expected impact of a light meal, 
urinary concentrations should remain above the typical omadacycline MIC90 of 2 µg/mL for 
Escherichia coli, the most common uropathogen in uncomplicated cystitis. 
Study Population:  


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Approximately 225 female subjects will be enrolled at up to 25 sites.  Subjects will be 
randomized (1:1:1:1:1) to five treatment groups.  
Adaptive design:  
This is an adaptive dose-response finding study.  During the course of the study, a Bayesian 
analysis will be used to adaptively allocate new subjects to one of the treatment arms, 
conditional on the availability of primary efficacy endpoint data (investigator assessment of 
clinical response at PTE).  When there is sufficient information available about the dose-
response, results from the Bayesian analysis will be reviewed by a DMC to determine if 
enrollment in any omadacycline treatment arms should be stopped or modified. Modifications 
to omadacycline dosing regimens/treatment arms may also be based on safety and tolerability. 
Bayesian analyses will be conducted after efficacy data (investigator assessment of clinical 
response at PTE) are available for approximately 40, 80, and 100 subjects in order to:  
• Determine omadacycline dose group(s) that can be dropped from the trial, or  
• Modify the randomization ratios among the dose groups to improve the precision 
of the selected dose groups comparison of clinical success to the that of the 
nitrofurantoin group.   
 
Additional analyses may be carried out for the same two purposes.  Response criteria are 
targeted toward estimating the probability that the clinical success rate (proportion of 
subjects) for each dose group is within 10% of that of the nitrofurantoin group.  If at the 
analyses, that probability falls below 30% for a particular dose group, recruitment for that 
dose group may be stopped or curtailed.  If that probability exceeds 80% for a particular dose 
group, recruitment for that dose group may be increased to improve the precision of the 
estimate. 


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Main Criteria for Inclusion: 
1. Written and signed informed consent must be obtained before any assessment is 
performed 
2. Females age 18 years or older 
3. Onset of TWO or more of the following clinical signs and symptoms of cystitis within 
96 hours prior to randomization:  
• Dysuria 
• Frequency 
• Urgency 
• Suprapubic pain 
NOTE: symptoms should be continuing at the time of randomization 
4. A clean-catch midstream urine sample with pyuria (white blood cell [WBC] count >10/μL 
in unspun urine or ≥10 per high power field in spun urine) or dipstick analysis positive (at 
least ++) for leukocyte esterase.  Urine sample must also be sent for microbiologic culture 
prior to randomization. 
5. Must have a negative pregnancy test at Screening, and agree to comply with using an 
acceptable form of birth control (eg, abstinence, oral contraceptive, intrauterine device 
[IUD], barrier contraception [condom], tubal ligation, hysterectomy, bilateral 
oophorectomy, postmenopausal or vasectomized partner) from Screening through PTE 
6. Ability to swallow 4 tablets/capsules in succession  
7. Ability to communicate well with the investigator, to understand and comply with the 
requirements of the study 
Main Criteria for Exclusion: 
1. Males 
2. Pregnant or nursing (breastfeeding) women 
3. Criterion no longer applicable as per Protocol Amendment #1 
4. Criterion no longer applicable as per Protocol Amendment #1 
5. Receipt of any dose of a potentially therapeutic antibacterial agent (with potential activity 
against uropathogens in the urinary tract) from 72 hours prior to randomization until the 
first dose of test article. [NOTE: Subjects who developed the current cystitis while 
receiving prophylactic antibacterial therapy (for any reason) may be eligible if all 
prophylactic antibacterials are stopped (no further dosing after randomization) and 
approved by the study medical monitor.] 
6. Anticipated need for systemic antibacterial therapy other than test article (for treatment or 
prophylaxis) during the study period 
7. Has a suspected upper UTI (eg, fever [≥ 38°C, ≥ 100.4°F], chills, rigors, flank pain, or 
costovertebral angle tenderness) 
8. Symptoms/signs suggestive of vaginitis or sexually transmitted infection (eg, vaginal 
discharge or vaginal irritation) 
9. Known prior UTI caused by Pseudomonas aeruginosa or Proteus spp., or suspected 
current infection with P. aeruginosa or Proteus spp. or nitrofurantoin-resistant pathogen 
10. Has a confirmed or suspected complicated UTI, defined as: 
• Use of an indwelling urinary catheter, nephrostomy tubes or other indwelling urinary 
tract device within the 30 days prior to randomization or scheduled to be used during 


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the study period 
• Known urinary retention (≥100 mL of residual urine after voiding) within the 30 days 
prior to randomization 
• History of surgically modified or abnormal urinary tract anatomy (eg, bladder 
diverticula or redundant urine collection system) 
• Complete or partial obstruction of the urinary tract, or obstructive uropathy that is 
scheduled to be medically or surgically relieved during the study therapy period 
• History of renal transplant or a surgically created intestinal conduit for urinary 
diversion 
• Suspected or confirmed renal calculi, stricture, primary renal disease (eg, polycystic 
renal disease), neurogenic bladder, or other anatomical or functional abnormalities 
predisposing to UTI 
• Had an overnight stay in the hospital within the past 6 months 
11. Screening calculated creatinine clearance (CrCl) < 60 mL/minute, using the Cockcroft-
Gault equation (see equation in Appendix 2), requires any form of dialysis (eg, 
hemodialysis, peritoneal dialysis), or other evidence of severe renal disease 
12. Has any of the following at Screening: 
• alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3 × Upper 
Limit of Normal (ULN)  
• total bilirubin > 1.5 × ULN 
• suspected or confirmed clinical evidence of end-stage liver disease (eg, ascites, hepatic 
encephalopathy) 
13. History of having experienced unstable cardiac disease (eg, unstable angina, myocardial 
infarction, acute congestive heart failure, unstable cardiac arrhythmia, etc.) within the 
3 months prior to randomization 
14. Significant immunological disease determined by any of the following: 
• Current or anticipated neutropenia defined as less than 500 neutrophils/mm3 
• Known infection with Human Immunodeficiency Virus (HIV) and a cluster of 
differentiation 4 (CD4) count that is unknown or documented to be less 
than 200 cells/mm3 within the last year, or other Acquired Immune Deficiency 
Syndrome (AIDS)-defining illness as determined by the investigator 
15. Receipt of 40 mg of prednisone per day (or equivalent) or receipt of 40 mg of prednisone 
per day (or equivalent) for more than 14 days in the 30 days prior to randomization  
16. History of hypersensitivity or allergic reaction (eg, anaphylaxis, urticaria, other significant 
reaction) to any tetracycline (eg, minocycline, doxycycline or tigecycline) or nitrofurans 
(nitrofurantoin) 
17. History of pseudotumor cerebri, or prior (within 2 weeks prior to randomization) or 
planned concomitant use of isotretinoin 
18. History of systemic lupus erythematosus or lupus-like syndrome 
19. Has current evidence of pancreatitis 
20. History of known glucose-6-phosphate dehydrogenase deficiency or hemolytic anemia 
21. History of adverse reaction to nitrofurantoin (eg, lung or liver reaction or peripheral 
neuropathy) after use of nitrofurantoin or other nitrofurans in the past 


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22. Need for concurrent use of uricosuric drugs (eg, probenecid, colchicine, sulfinpyrazone) 
23. Use of other investigational drugs within 5 half-lives or 30 days prior to randomization, 
whichever is longer 
24. Has previously been treated with omadacycline or previously enrolled in this study 
25. Unable or unwilling, in the opinion of the investigator, to comply with the protocol 
requirements, or has any concomitant condition or planned medical intervention that, in 
the opinion of the investigator, is likely to interfere with evaluation of the response of the 
infection under study, determination of AEs, or completion of the expected course of 
treatment. 
Test Article; Dose; and Mode of Administration:  
Group 1: Omadacycline 300 mg po q12h x 1 day followed by 300 mg po q24h  
Group 2: Omadacycline 450 mg po q12h x 1 day followed by 300 mg po q24h  
Group 3: Omadacycline 450 mg po q12h x 1 day followed by 450 mg po q24h 
Group 4: Omadacycline 450 mg po q12h  
Group 5: Nitrofurantoin 100 mg po q12h  
 
Duration of Treatment:  
The total duration of therapy for all subjects will be 7 days.  
 
Pharmacokinetic Assessments 
• Blood Collection (plasma); 
• 
Urine Collection 
 
Safety Assessments: 
• Physical examinations; 
• Vital signs (body weight, body temperature, blood pressure [BP], heart rate); 
• Laboratory tests (Hematology, serum chemistry, urinalysis); 
• AEs and Serious Adverse Events (SAEs); 
• AEs of Interest (nausea and vomiting); 
• Concomitant medications; 
• Pregnancy assessments. 
Efficacy Assessments: 
• Investigator’s assessment of clinical response.  Clinical success is defined as 
resolution of signs and symptoms of the infection to the extent that further 
antibacterial therapy is not necessary;  
• Microbiological assessment of the infection;  
• Subject assessment of UTI signs and symptoms severity (via the UTI Symptoms 
Assessment [UTISA] questionnaire). 


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Statistical Methods:  
Enrollment of a total of approximately 225 subjects is planned.  The Bayesian posterior 
probability that the clinical success rate at the PTE Visit is within 0.10 of that of the 
nitrofurantoin group will be estimated for each omadacycline dose group.  The target 
probability is 0.80.  If the true underlying clinical success rates for the nitrofurantoin and 
omadacycline dose groups are 0.82, then the sample size of N=50 per treatment has 
approximately 79% power/probability to yield the target probability (N=53 per treatment for 
80% power). The sample size may be increased for a particular omadacycline dosing group by 
changing the randomization ratio and/or dropping a dose group to achieve improved power / 
probability of achieving the target probability that clinical success rates for a dose group is 
within 0.10 of that of the nitrofurantoin group. If required to improve the precision of the 
interim or projected final analyses estimates of response rates or posterior probabilities, 
sample size may be increased to a maximum sample size provided in the statistical analysis 
plan (SAP).  Subjects will be randomized (1:1:1:1:1) to five treatment groups.  
 
The following subject analysis populations have been defined: 
• Intent-to-treat (ITT):  all randomized subjects. 
• Safety:  all randomized subjects who receive any amount of test article.   
• The microbiological ITT (micro-ITT) population will consist of subjects in the 
ITT population who have a study-qualifying pre-treatment positive Baseline urine 
culture with 1 or 2 uropathogens at ≥105 Colony Forming Units (CFU)/mL. (ME) 
population will include subjects in the CE population who have a study-qualifying 
pre-treatment Baseline urine culture with 1 or 2 uropathogens at ≥105 CFU/mL.   
• The clinically evaluable (CE) population will consist of all ITT subjects who 
received test article, have a qualifying infection, an assessment of outcome, and 
meet all other evaluability criteria detailed in the SAP. 
• The microbiologically evaluable (ME) population will include subjects in the CE 
population who have a study-qualifying pre-treatment Baseline urine culture with 
1 or 2 uropathogens at ≥ 105 CFU/mL.   
 
All safety data will be summarized by treatment groups and the incidence of AEs will be 
presented by system organ class (SOC) and preferred term (PT) according to the Medical 
Dictionary for Regulatory Affairs (MedDRA®), relationship to the test article, and severity.  
Descriptive statistics of clinical laboratory results and vital signs and the change from 
Baseline will be presented as will a summary of clinically notable values. 
The number and percentage of subjects with investigator’s assessment of clinical response 
and a microbiological response will be presented at each time point measured by treatment 
group.  Exact 95% confidence intervals will be determined for the point estimates of the 
clinical success rates and the microbiological success.  A comparison of the clinical success 
rate at PTE between each omadacycline dose group and the nitrofurantoin group will be 
conducted using a beta distribution with an uninformative Bayesian prior distribution. 


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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
TABLE OF CONTENTS .........................................................................................................13 
LIST OF IN-TEXT TABLES ..................................................................................................16 
LIST OF APPENDICES ..........................................................................................................16 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................17 
1 
DISCLOSURE STATEMENT ........................................................................................19 
2 
CONTACTS ....................................................................................................................20 
 
Emergency Contacts ..............................................................................................20 
 
Additional Contacts ...............................................................................................20 
3 
INTRODUCTION ...........................................................................................................21 
 
Uncomplicated Urinary Tract Infection (UTI) ......................................................21 
 
Omadacycline ........................................................................................................21 
4 
STUDY OBJECTIVES ....................................................................................................23 
 
Primary Objective ..................................................................................................23 
 
Secondary Objectives .............................................................................................23 
5 
INVESTIGATIONAL PLAN ..........................................................................................24 
 
Overall Study Description ......................................................................................24 
5.1.1 
Adaptive Design ...........................................................................................24 
 
Rationale for Study Design ....................................................................................25 
 
Rationale for Control Group ..................................................................................25 
 
Approximate Duration of Subject Participation ....................................................25 
 
Approximate Duration of Study .............................................................................26 
 
Approximate Number of Subjects .........................................................................26 
6 
STUDY POPULATION SELECTION ...........................................................................27 
 
Study Population ....................................................................................................27 
 
Inclusion Criteria ...................................................................................................27 
 
Exclusion Criteria ..................................................................................................27 
 
Screen Failures .......................................................................................................29 
7 
STUDY TREATMENT(S) ..............................................................................................30 
 
Treatments Administered .......................................................................................30 
 
Identity of the Investigational Product:  Omadacycline ........................................30 
 
Comparator Test Article:  Nitrofurantoin ..............................................................30 
 
Dose Selection Rationale .......................................................................................31 
 
Description of Treatments ......................................................................................32 
 
Test Article Administration – Fed and Fasting State .............................................33 
 
Dose Adjustments and Interruptions of Test Article .............................................35 


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Method of Assigning Patients to Treatment Groups ..............................................35 
7.8.1 
Subject Numbering ......................................................................................35 
 
Dispensing Test Article..........................................................................................35 
 
Blinding..................................................................................................................36 
 
Emergency Unblinding of Treatment Assignment ................................................36 
 
Prior & Concomitant Therapy ...............................................................................37 
 
Prohibited Therapy .................................................................................................37 
7.13.1 
Concomitant Medications That May Interact with Nitrofurantoin ..............37 
 
Permitted Treatments .............................................................................................37 
 
Treatment Compliance ...........................................................................................38 
 
Packaging and Labeling .........................................................................................38 
 
Storage and Accountability ....................................................................................38 
 
Investigational Product Retention at Study Site ....................................................38 
8 
STUDY PROCEDURES .................................................................................................39 
 
Informed Consent...................................................................................................39 
 
Subject Demographics/Other Baseline Characteristics .........................................39 
 
Medical History .....................................................................................................39 
 
Physical Examination.............................................................................................39 
 
Vital Signs ..............................................................................................................40 
 
Clinical Laboratory Tests .......................................................................................40 
8.6.1 
Central Laboratory Parameters ....................................................................40 
8.6.2 
Local Laboratory Parameters .......................................................................41 
 
Pregnancy Assessments .....................................................................41 
 
Urine Culture and Dipstick Tests .......................................................42 
 
Efficacy assessments ..............................................................................................43 
8.7.1 
Investigator’s Assessment of Clinical Response .........................................43 
 
Investigator’s Assessment of Clinical Response at EOT ...................43 
 
Investigator’s Assessment of Clinical Response at PTE ...................43 
 
Investigator’s Assessment of Clinical Response at Final Follow-
up........................................................................................................43 
 
Subject Assessment of UTI Signs and Symptoms Severity...................................44 
 
Pharmacokinetic Assessments ...............................................................................44 
8.9.1 
PK Blood Collection and Processing ...........................................................44 
8.9.2 
PK Urine Collection and Processing............................................................44 
8.9.3 
Storing and Shipping of PK Samples...........................................................44 
 
Adverse Events ......................................................................................................44 
 
Serious Adverse Events .........................................................................................45 
 
Other Reportable Information ................................................................................46 
 
Overdose ................................................................................................................46 


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Medication Errors ..................................................................................................46 
 
Recording and Reporting .......................................................................................47 
8.15.1 
Serious Adverse Event Reporting ................................................................47 
8.15.2 
Assessment of Relatedness ..........................................................................48 
8.15.3 
Assessment of Severity ................................................................................48 
8.15.4 
Laboratory Findings .....................................................................................48 
8.15.5 
Worsening or Progression of Disease Under Study .....................................49 
8.15.6 
Pregnancies ..................................................................................................49 
 
Concomitant Medication Assessments ..................................................................49 
 
Subject Discontinuation or Withdrawal .................................................................49 
9 
STUDY ACTIVITIES .....................................................................................................51 
 
Screening Phase .....................................................................................................51 
 
Double-Blind Treatment Phase (Day 1, Day 3 and Day 5 In-Office Visits) .........51 
9.2.1 
Day 1 Visit Procedures ................................................................................51 
9.2.2 
Day 3 Visit Procedures ................................................................................52 
9.2.3 
Day 5 Visit Procedures ................................................................................52 
 
Double-Blind Treatment Phase (Day 2, Day 4 and Day 6 At-Home 
Requirements) ........................................................................................................52 
 
End of Treatment/Day 7 Visit Procedures .............................................................52 
 
Follow-up Phase.....................................................................................................53 
9.5.1 
Post-Treatment Evaluation (PTE) Visit .......................................................53 
9.5.2 
Final Follow-up ............................................................................................53 
10 STUDY SUSPENSION, TERMINATION, AND COMPLETION ................................55 
 
Study Completion and Post-Study Test Article .....................................................55 
 
Study Suspension or Termination ..........................................................................55 
11 QUALITY CONTROL AND ASSURANCE .................................................................56 
12 PLANNED STATISTICAL METHODS ........................................................................57 
 
General Considerations ..........................................................................................57 
 
Determination of Sample Size ...............................................................................57 
 
Analysis Populations ..............................................................................................57 
 
Demographics and Baseline Characteristics ..........................................................58 
 
Primary Endpoint(s) ...............................................................................................58 
12.5.1 
Efficacy Endpoint ........................................................................................58 
 
Secondary Endpoint(s) ...........................................................................................58 
12.6.1 
Safety Endpoint(s) .......................................................................................58 
12.6.2 
Efficacy Endpoint(s) ....................................................................................59 
 
Interim Analysis .....................................................................................................59 
 
Data Monitoring Committee ..................................................................................60 


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13 ADMINISTRATIVE CONSIDERATIONS ....................................................................61 
 
Investigators and Study Administrative Structure .................................................61 
 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ................................................................................................................61 
 
Ethical Conduct of the Study .................................................................................61 
 
Patient Information and Consent ...........................................................................61 
 
Direct Access, Data Handling, and Record Keeping .............................................62 
13.5.1 
Investigator ..................................................................................................62 
13.5.2 
Sponsor ........................................................................................................62 
 
Protocol Adherence ................................................................................................62 
13.6.1 
Violations/Deviations ..................................................................................62 
13.6.2 
Protocol Amendments ..................................................................................62 
 
Subject Injury .........................................................................................................63 
 
Pre-Study Documentation ......................................................................................63 
 
Retention of Data ...................................................................................................64 
 Publication and Disclosure Policy .........................................................................64 
14 REFERENCE LIST .........................................................................................................65 
APPENDIX 1 
SCHEDULE OF EVENTS ..........................................................................66 
APPENDIX 2 
EQUATIONS AND CONVERSION FACTORS .......................................68 
APPENDIX 3 
SPONSOR SIGNATURE ............................................................................69 
APPENDIX 4 
INVESTIGATOR’S SIGNATURE .............................................................70 
 
LIST OF IN-TEXT TABLES 
Table 1. Description of Treatment groups ............................................................................33 
Table 2. Dosing:  Double-Blind, Double-Dummy Design ...................................................34 
Table 3. Clinical Laboratory Tests (Central) ........................................................................41 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events .......................................................................................66 
Appendix 2 
Equations and Conversion Factors...............................................................68 
Appendix 3 
Sponsor Signature ........................................................................................69 
Appendix 4 
Investigator’s Signature ...............................................................................70 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
 
 
ABSSSI 
Acute Bacterial Skin and Skin Structure Infection 
AE 
Adverse Event 
AIDS 
Auto-Immune Deficency Syndrome 
ALT 
Alanine Aminotransferase (SGPT) 
AST 
Aspartate Aminotransferase (SGOT) 
B hCG 
Serum β-human chorionic gonadotropin 
BP 
Blood Pressure 
CABP 
Community-Aquired Bacterial Pneumonia 
CD4 
Cluster of Differentiation 4 
CE 
Clinically Evaluable 
CFR 
Code of Federal Regulations 
CFU 
Colony Formimg Units 
CI 
Confidence Interval  
CrCl 
Creatinine Clearance 
CSA 
Clincial Study Agreement 
CSR 
Clinical Study Report 
DMC 
Data Monitoring Committee 
EBSL 
Extended Spectrum Beta-Lactamase 
eCRF 
Electronic Case Report Form 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
ICH 
International Conference foron Harmonisation  
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug  


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IRB 
Institutional Review Board 
ITT                      Intent-to-Treat 
iv 
Intravenous 
IxRS 
Interactive Voice/Web Response System 
ME 
Microbiologically Evaluable 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
Minimum Inhibitory Concentration 
Micro-ITT 
Microbiological modified Intent-to-Treat 
NSAID 
Nonsteroidal anti-inflammatory 
OTC 
Over the Counter 
PI 
Package Insert 
PK 
Pharmacokinetics 
po 
by mouth 
PT 
Preferred Term 
PTE 
Post Treatment Evaluation 
q24h 
Every 24 hours 
q12h 
Every 12 hours 
REB 
Research Ethics Board 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TFL 
Tables, Figures and Listings 
ULN 
Upper Limit of Normal 
US 
United States 
UTI  
Urinary Tract Infection  
UTISA 
Urinary Tract Infection Symptoms Assessment  
WBC 
White Blood Cell (Count) 


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1 
DISCLOSURE STATEMENT 
Restricted Distribution of Documents 
This document contains information that is confidential and proprietary to the sponsor.  This 
information is being provided to you solely for the purpose of evaluating and/or conducting a 
clinical study for the sponsor.  You may disclose the contents of this document only to study 
personnel under your supervision, institutional review boards (IRBs)/independent ethics 
committees (IECs)/research ethics boards (REBs), or duly authorized representatives of 
regulatory agencies for this purpose under the condition that they maintain confidentiality.  
The contents of this document may not be used in any other clinical study, disclosed to any 
other person or entity, and/or published without the prior written permission of the sponsor.  
The foregoing shall not apply to disclosure required by any regulations; however, you will 
give prompt notice to the sponsor of any such disclosure.  All other nonpublic information 
provided by the sponsor and any information that may be added to this document also is 
confidential and proprietary to the sponsor and must be kept in confidence in the same 
manner as the contents of this document. 


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2 
CONTACTS 
 
Emergency Contacts 
Name/Title: 
 
 
 
 
 
 
Phone (during business hours): 
 
Phone (after business hours):  
 
E-mail (not for emergencies):  
 
Address:  
 
 
 
 
 
 
 
Name/Title:   
 
 
 
 
 
Phone (during business hours): 
 
Phone (after business hours): 
 
E-mail (not for emergencies): 
 
Address: 
 
Paratek Pharmaceuticals 
 
1000 First Ave 
Suite 200 
King of Prussia, PA, 19406 
 
 
Additional Contacts 
SAE contact information: 
E-Mail: 
 
 
 
 
 
 
 


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3 
INTRODUCTION 
 
Uncomplicated Urinary Tract Infection (UTI) 
Uncomplicated Urinary tract infection (UTI) or acute cystitis is characterized by dysuria, 
frequency and urgency with pyuria, and bacteriuria in a person without underlying urologic 
or renal abnormalities. The burden of UTI is high in women; up to 60% of women have an 
episode during their lifetime.1,2,3,4 Long-term morbidity is low; however, the 30% to 40% 
recurrence rate is significant.1,2,5  Short-term morbidity has been described in female college 
students who experienced a mean of 6.1 symptomatic days and 2.4 days of restricted activity 
per episode.1,3 Recieveing no treatment or an ineffective treatment for an uUTI increases the 
duration of symptoms and can be complicated by pyelonephritis in approximately 2.6% of 
women.6,7  
Uncomplicated UTIs are predominately caused by E. coli (80% to 85%) and 
Staphylococcus saprophyticus (5% to 15%) with a small minority caused by 
Klebsiella pneumoniae, Proteus mirabilis, and other uropathogens.1,6  Increasing rates of 
resistance among UTI pathogens to trimethoprim/sulfamethoxazole, beta-lactams and 
fluoroquinolones, as well as, a recent safety warning to previously recommended first-line 
antibiotics (fluoroquinolone Food and Drud Adminstration [FDA] safety alert and black box 
warnings) has necessitated reconsideration of antibiotic treatment recommendations. 
Fosfomycin and nitrofurantoin are now considered first-line agents in the treatment of UTI. 
Resistance is generally low however emerging resistance has been observed in multi-drug 
resistant isolates. As a result, there is a need for new agents with efficacy against resistant 
uropathogens including extended-spectrum β-lactamase (ESBL) producing E. coli.8 
 
Omadacycline 
The investigational product, omadacycline (formerly named PTK 0796), is the first member 
of the aminomethylcycline class of antibiotics, which are semi synthetic derivatives of the 
tetracycline class.  As a class, the tetracyclines have been in use for approximately 70 years. 
They are well-tolerated, and have proven effective in the treatment of a variety of bacterial 
infections. Omadacycline is being developed for clinical use by both intravenous (iv) and 
per oral (po) administration. The targeted indications include community-acquired bacterial 
pneumonia (CABP), acute bacterial skin and skin structure infections (ABSSSI), and UTI. 
Omadacycline has been evaluated in a global Phase 3 study comparing the safety and 
efficacy of iv and po omadacycline to iv and po linezolid in the treatment of adult subjects 
with ABSSSI (PTK0796-ABSI-1108).  In addition, a global Phase 3 study has been 
conducted to evaluate the safety and efficacy of iv and po omadacycline compared to iv and 
po moxifloxacin in the treatment of adult subjects with CABP (PTK0796-CABP-1200).  The 
latest United States (US)-only Phase 3 study compared the safety of po only omadacycline to 
po only linezolid in the treatment of adult subjects with ABSSSI (PTK0796-ABSI-16301).  
In all three studies, omadacycline was well-tolerated and demonstrated non-inferiority to its 
respective comparator. Omadacycline (IV and PO) has recently been approved by US FDA 
for the treatment of adults with ABSSSI and CABP infections. 


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The drug is active against strains expressing both mechanisms of tetracycline 
resistance,namely efflux and ribosomal protection.9  Omadacycline has in vitro activity 
against the most common uUTI uropathogens including E. coli and S. saprophyticus. 
Resistance to other antibiotics does not affect omadacycline activity. Omadacycline is not 
affected by tetracycline-resistance, presence of ESBL, or other common resistance 
mechanisms.  Omadacycline is active against the Enterobacteriaceae with a significant 
proportion of isolates having an  minimum inhibitory concentration (MIC) < 2.0 μg/ml.  The 
minimum inhibitory concentrations for at least 90% of the common uUTI pathogens tested 
(MIC90) for omadacycline are 0.5 µg/mL for S. saprophyticus, 2 µg/mL for ESBL-negative 
E. coli, and 2 µg/mL for ESBL-producing E. coli.9 
Study PTK0796-UUTI-15103 was a randomized (1:1:1), open-label, parallel-designed 
Phase 1b study evaluating 3 dosing regimens of omadacycline in 31 female adults with 
cystitis. During the treatment period, serial blood and urine samples were collected for safety, 
microbiological, and pharmacokinetic (PK) analyses of omadacycline. In this study, the PK 
of omadacycline in women with cystitis was found to be similar to the PK in healthy 
subjects. At steady-state, 10% to 13% of a po omadacycline dose is excreted in the urine, 
resulting in high urine concentrations. With the treatment regimens studied, observed urine 
concentrations of omadacycline compared favorably with MIC values for common UTI 
pathogens, and a high percentage of subjects achieved clinical success and favorable 
microbiological responses. There was a higher than expected incidence of nausea and 
vomiting, which contrasts with the notably lower rates of nausea and vomiting observed in 
other omadacycline studies using comparable dosing regimens and active controls. The 
reason(s) for the increased incidences in nausea and vomiting are difficult to ascertain given 
the open-label study design, small sample size, and lack of prior experience with 
omadacycline in the cystitis study population.  
This study is intended to evaluate the efficacy and safety of oral omadacycline as compared 
to oral nitrofurantoin in the treatment of adult female subjects with cystitis. These data will 
be important to determine the potential utility of omadacycline for the treatment of UTI and 
will help in selection of dosing regimens that may be used in future UTI studies. 
It is expected that the dosing regimens evaluated in this study will provide urine 
concentrations of omadacycline that will exceed the MIC90 for the common uncomplicated 
UTI pathogens (see dose selection discussion in Section 7.4). 
Please refer to the current version of the Investigator's Brochure10 for additional information 
on omadacycline.  
 
 


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4 
STUDY OBJECTIVES 
 
Primary Objective  
The primary objective of this study is: 
To evaluate the efficacy of omadacycline and nitrofurantoin in the treatment of female adults 
with cystitis. 
 
Secondary Objectives  
The secondary objectives of this study are: 
• To evaluate the safety of omadacycline in the treatment of female adults with cystitis.   
• To evaluate the clinical and microbiologic response according to the identified causative 
pathogen.  
• To evaluate the pharmacokinetics of omadacycline in female adults with cystitis. 


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5 
INVESTIGATIONAL PLAN 
 
Overall Study Description 
This is a randomized, double-blinded, adaptive designed Phase 2 study evaluating 3 dosing 
regimens of once-daily omadacycline, 1 dosing regimen of twice-daily omadacycline 
compared to twice-daily nitrofurantoin in the treatment of female adults with cystitis.  The 
planned length of subject participation in the study is up to 37 days which includes a total 
duration of study therapy for 7 days.   
The study will consist of 3 protocol-defined phases:  Screening, double-blind treatment and 
follow-up.  All Screening evaluations should be completed within the 24 hours prior to 
randomization.  Subjects who meet inclusion criteria, and do not meet exclusion criteria will 
be randomly assigned to 1 of 3 oral omadacycline dosing regimens or a twice-daily regimen 
of oral nitrofurantoin (see Table 1 and Table 2).  Subjects should receive their first dose of 
test article at the site within 4 hours after randomization.  Treatment will be double-blinded 
and double-dummy (see Table 2). Please refer to Section 9 of the protocol for further details 
on study phases and required assessments/procedures per phase. 
During the study treatment period, blood samples will be collected for safety analysis and for 
PK analysis of omadacycline.  Urine samples will be collected during the study period for 
safety, PK analysis, and microbiological analysis.  Safety assessments will include 
monitoring of adverse events (AEs), concomitant medications, clinical laboratory test results, 
vital sign measurements, pregnancy testing and physical examination findings. 
Subjects will return to the clinical site for visits on Day 1, Day 3, Day 5, and for an End of 
Treatment (EOT)/Day 7 visit on the day of or within 2 days following the last dose.  Subjects 
will also return to the study site for a Post Therapy Evaluation (PTE) on Day 14 (+/- 2 days) 
after the subject’s first dose of test article.  A Final Follow-up assessment will be conducted 
within 30 to 37 days following the first dose of test article.  The Final Follow-up assessment 
may be conducted via telephone contact or by another interactive technology for subjects 
who are not having any symptoms and had no AEs or clinically significant laboratory 
abnormalities noted at or after the PTE visit.  Otherwise, this assessment is to be performed 
with an in-person study visit. During the Follow-up call/visit if the subject reports symptoms 
of potential recurrence, additional procedures will be performed.   
See Appendix 1 for the full Schedule of Events. 
5.1.1 
Adaptive Design 
This is an adaptive dose-response finding study. Initially, subjects will be randomized 
(1:1:1:1:1) to five treatment groups. During the course of the study, a Bayesian analysis will 
be used to adaptively allocate new subjects to one of the treatment arms, conditional on the 
availability of primary efficacy endpoint data (investigator assessment of clinical response at 
PTE). When there is sufficient information available about the dose-response, results from 
the Bayesian analysis will be reviewed by a DMC to determine if enrollment in any 


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omadacycline treatment arms should be stopped or modified. Modifications to omadacycline 
dosing regimens/treatment arms may also be based on safety and tolerability. 
Bayesian analyses will be conducted after efficacy data (investigator assessment of clinical 
response at PTE) are available for approximately 40, 80, and 100 subjects in order to:  
1. Determine omadacycline dose group(s) that can be dropped from the trial, or  
2. Modify the randomization ratios among the dose groups to improve the precision of the 
selected dose groups comparison of clinical success to that of the nitrofurantoin group.   
Additional analyses may be carried out for the same two purposes.  Response criteria are 
targeted toward estimating the probability that the clinical success rate (proportion of 
subjects) for each omadacycline dose group is within 10% of that of the nitrofurantoin group.  
If at the analyses, that probability falls below 30% for a particular dose group, recruitment 
for that dose group may be stopped or curtailed.  If that probability exceeds 80% for a 
particular omadacycline dose group, recruitment for that dose group may be  increased to 
improve the precision of the estimate.  
 
Rationale for Study Design  
Omadacycline is the first member of the aminomethylcycline class of antibiotics, which are 
semisynthetic derivatives of the tetracycline class.  Omadacycline- has in vitro activity 
against the most common bacterial pathogens associated with cystitis.  Omadacycline has 
been shown to have a significant fraction of the administered dose excreted by the kidneys 
and is present as active drug in the urine.  The safety, efficacy and pharmacokinetics (PK) of 
omadacycline have been evaluated in a limited number of adults with cystitis. 
 
Rationale for Control Group 
Nitrofurantoin (Macrobid) is approved in the US for the treatment of acute uncomplicated 
urinary tract infection (acute cystitis) at a dose of 100 mg administered orally every 12 hours 
(q12h) for 7 days.11  It is recommended as a first line treatment by the Infectious Disease 
Society of America and the European Society of Microbiology and Infectious Diseases.6  
Clinical studies have demonstrated equivalent microbiologic eradication with other 
nitrofurantoin formulations (Macrodantin).11  Equivalent early and late clinical efficacy and 
early bacterial cure with other commonly used first line therapies for uUTI including 
trimethoprim-sulfamethoxazole, fosfomycin, and ciprofloxacin have been demonstrated in 
four randomized clinical trials.6  Resistance to nitrofurantoin is low and the therapy is 
generally well tolerated.6  The most frequently reported AEs that are possibly or probably 
drug related include nausea, headache, and flatulence.11 
 
Approximate Duration of Subject Participation 
Subjects will participate in the study for up to 37 days.  Following Screening, eligible 
subjects will be randomly assigned to receive 7 days of po treatment of either omadacycline 
or nitrofurantoin.  Subjects will return to the site for an EOT visit within 2 days following the 
last dose of test article, and then again for a PTE visit on Day 14 (+/- 2 days) after the 


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subject’s first dose of test article.  A final follow-up assessment will be conducted within 30 
to 37 days following the first dose of test article. 
 
Approximate Duration of Study 
The study is expected to be clinically complete in approximately 24 months. 
 
Approximate Number of Subjects 
Approximately 225 subjects will participate in this study at up to 25 sites. 


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6 
STUDY POPULATION SELECTION 
Each subject must participate in the informed consent process and sign and date an IRB/IEC/ 
REB approved informed consent form (ICF) before any procedures specified in this protocol 
are performed. 
 
Study Population 
Approximately 225 female subjects will be enrolled at up to 25 sites.  Initally, subjects will 
be randomized (1:1:1:1:1) to five treatment groups (see Table 1).   
 
Inclusion Criteria 
Each subject must meet all of the following criteria to be enrolled in this study: 
Main Criteria for Inclusion: 
1. Written and signed informed consent must be obtained before any assessment is 
performed  
2. Females age 18 years or older 
3. Onset of 2 or more of the following clinical signs and symptoms of cystitis within 
96 hours prior to randomization:  
• Dysuria 
• Frequency 
• Urgency 
• Suprapubic pain 
NOTE: symptoms should be continuing at the time of randomization 
4. A clean-catch midstream urine sample with pyuria (white blood cell [WBC] count 
> 10/μL in unspun urine or ≥ 10 per high power field in spun urine) or dipstick analysis 
positive (at least ++) for leukocyte esterase.  Urine sample must  be sent for 
microbiologic culture prior to randomization. 
5. Must have a negative pregnancy test at Screening, and agree to comply with using an 
acceptable form of birth control (eg, abstinence, oral contraceptive, intrauterine device 
[IUD], barrier contraception [condom], tubal ligation, hysterectomy, bilateral 
oophorectomy, postmenopausal or vasectomized partner) from Screening through PTE 
6. Ability to swallow 4 tablets/capsules in succession 
7. Ability to communicate well with the investigator, to understand and comply with the 
requirements of the study 
 
Exclusion Criteria 
Patients who meet any of the following exclusion criteria will be excluded from the study: 
Main Criteria for Exclusion: 


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1. Males 
2. Pregnant or nursing (breastfeeding) women 
3. Criterion no longer applicable as per Protocol Amendment #1 
4. Criterion no longer applicable as per Protocol Amendment #1  
5. Receipt of any dose of a potentially therapeutic antibacterial agent (with potential activity 
against uropathogens in the urinary tract) from 72 hours prior to randomization until the 
first dose of test article. [NOTE:  Subjects who developed the current cystitis while 
receiving prophylactic antibacterial therapy (for any reason) may be eligible if all 
prophylactic antibacterials are stopped (no further dosing after randomization) and 
approved by the study medical monitor] 
6. Anticipated need for systemic antibacterial therapy other than test article (for treatment or 
prophylaxis) during the study period 
7. Has a suspected upper UTI (eg, fever [≥ 38°C, ≥ 100.4°F], chills, rigors, flank pain, or 
costovertebral angle tenderness) 
8. Symptoms/signs suggestive of vaginitis or sexually transmitted infection (eg, vaginal 
discharge or vaginal irritation) 
9. Known prior UTI caused by P. aeruginosa or Proteus spp., or suspected current infection 
with P. aeruginosa or Proteus spp. or nitrofurantoin-resistant pathogen 
10. Has a confirmed or suspected complicated UTI, defined as: 
• Use of an indwelling urinary catheter, nephrostomy tubes or other indwelling urinary 
tract device within the 30 days prior to randomization or scheduled to be used during 
the study period 
• Known urinary retention (≥ 100 mL of residual urine after voiding) within the 30 days 
prior to randomization 
• History of surgically modified or abnormal urinary tract anatomy (eg, bladder 
diverticula or redundant urine collection system) 
• Complete or partial obstruction of the urinary tract, or obstructive uropathy that is 
scheduled to be medically or surgically relieved during the study therapy period 
• History of renal transplant or a surgically created intestinal conduit for urinary 
diversion 
• Suspected or confirmed renal calculi, stricture, primary renal disease (eg, polycystic 
renal disease), neurogenic bladder, or other anatomical or functional abnormalities 
predisposing to UTI 
• Had an overnight hospital stay within the past 6 months 
11. Screening calculated creatinine clearance (CrCl) < 60 mL/minute, using the Cockcroft-
Gault equation (see equation in Appendix 2), requires any form of dialysis (eg, 
hemodialysis, peritoneal dialysis), or other evidence of severe renal disease 
12. Has any of the following at Screening: 
• alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3 × Upper 
Limit of Normal (ULN)  
• total bilirubin > 1.5 × ULN 
• suspected or confirmed clinical evidence of end-stage liver disease (eg, ascites, 
hepatic encephalopathy) 


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13. History of having experienced unstable cardiac disease (eg, unstable angina, myocardial 
infarction, acute congestive heart failure, unstable cardiac arrhythmia, etc.) within the 
3 months prior to randomization 
14. Significant immunological disease determined by any of the following: 
• Current or anticipated neutropenia defined as less than 500 neutrophils/mm3 
• Known infection with Human Immunodeficiency Virus (HIV) and a cluster of 
differentiation 4 (CD4) count that is unknown or documented to be less 
than 200 cells/mm3 within the last year, or other Acquired Immune Deficiency 
Syndrome (AIDS)-defining illness as determined by the investigator 
15. Receipt of 40 mg of prednisone per day (or equivalent) or receipt of 40 mg of prednisone 
per day (or equivalent) for more than 14 days in the 30 days prior to randomization (see 
Appendix 2)  
16. History of hypersensitivity or allergic reaction (eg, anaphylaxis, urticaria, other 
significant reaction) to any tetracycline (eg, minocycline, doxycycline or tigecycline) or 
nitrofurans (nitrofurantoin) 
17. History of pseudotumor cerebri, or prior (within 2 weeks prior to randomization) or 
planned concomitant use of isotretinoin 
18. History of systemic lupus erythematosus or lupus-like syndrome 
19. Has current evidence of pancreatitis 
20. History of known glucose-6-phosphate dehydrogenase deficiency or hemolytic anemia 
21. History of adverse reaction to nitrofurantoin (eg, lung or liver reaction or peripheral 
neuropathy) after use of nitrofurantoin or other nitrofurans in the past 
22. Need for concurrent use of uricosuric drugs (eg, probenecid, colchicine, sulfinpyrazone) 
23. Use of other investigational drugs within 5 half-lives or 30 days prior to randomization, 
whichever is longer 
24. Has previously been treated with omadacycline or previously enrolled in this study 
25. Unable or unwilling, in the opinion of the investigator, to comply with the protocol 
requirements, or has any concomitant condition or planned medical intervention that, in 
the opinion of the investigator, is likely to interfere with evaluation of the response of the 
infection under study, determination of adverse events (AEs), or completion of the 
expected course of treatment 
 
Screen Failures 
Subjects who sign the ICF but withdraw or are withdrawn from the study before random 
assignment to double-blind treatment are defined as screen failures.  All screen failures 
should be recorded on the subject master list.  Limited information including reason for 
screen failure will be recorded on the electronic case report form (eCRF) or interactive 
voice/web response system (IxRS) system for screen failures. Screen failure subjects may be 
re-screened at the discretion of the investigator and in consultation with the medical monitor 
as needed.  


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7 
STUDY TREATMENT(S) 
 
Treatments Administered 
Test articles will be supplied by Paratek Pharma, LLC (the sponsor).  Test articles will be 
labeled according to regulations. 
The test articles should be administered only to subjects who have provided informed 
consent and who meet all of the inclusion criteria and none of the exclusion criteria.  Once 
the test article has been assigned to a subject, it must not be reassigned to another subject. 
Following a Screening period of up to 24 hours, eligible subjects will be randomly assigned 
to receive 1 of 3 once-daily dosing regimens of omadacycline treatment, 1 dosing regimen of 
twice-daily omadacycline, or a twice-daily regimen of nitrofurantoin.  Treatment will be 
double-blind and double-dummy.  
 
Identity of the Investigational Product:  Omadacycline 
Oral Formulation 
Name 
Omadacycline Tablet, 150 mg 
Excipients 
Lactose monohydrate, microcrystalline cellulose, sodium stearyl fumarate, crospovidone, 
colloidal silicone dioxide, sodium bisulfite, polyvinyl alcohol, titanium dioxide, talc, 
glycerol monocaprylocaprate, sodium lauryl sulfate, iron oxide yellow 
How supplied 
High-Density Polyethylene (HDPE) bottles with induction seal, child resistant closure and 
desiccant 
Storage 
Do not store above 25°C (77°F).  Protect from moisture 
Preparation and 
handling 
No special requirements 
Administration 
Please reference Table 2 in Section 7.6  
 
 
Comparator Test Article:  Nitrofurantoin 
Oral Formulation 
Name 
Macrobid 100 mg capsules (nitrofurantoin Monohydrate/macrocrystals) 
How supplied 
High-Density Polyethylene (HDPE) bottles with induction seal, child resistant closure and 
desiccant 
Storage 
Do not store above 25°C (77°F).  Protect from moisture 
Preparation and 
handling 
No special requirements 
Administration 
Please reference Table 2 in Section 7.6  


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HDPE = High-Density Polyethylene; PVC = Polyvinyl Chloride;  DBAA=Double-Blind size AA 
The comparator drug, nitrofurantoin, is an antibacterial agent specific for urinary tract 
infections.  It has an acceptable and well-defined safety profile.  Nitrofurantoin is 
well-tolerated, can be administered orally, is well-concentrated in the urine and is shown to 
be effective against common uncomplicated UTI uropathogens including E. coli and 
Staphylococcus saprophyticus.  
 
Dose Selection Rationale 
The dosing regimen of omadacycline selected for this study is based on the nonclinical and 
clinical experience to date, including in vitro antibacterial activity, PK characteristics, 
clinical efficacy in prior studies, and the overall safety and tolerability profile.  Key 
considerations in dose selection are summarized below: 
• While the driver of efficacy for omadacycline in UTI is not known, a pragmatic 
assumption was made that maximizing the time of urine concentration above pathogen 
MIC (ideally, throughout the dosing interval) would be desirable. 
• In PTK0796-UUTI-15103, omadacycline dosed as 300 mg po q12h on Day 1 followed by 
300 mg po daily for 5 days and 450 mg po q12h on Day 1 followed by 450 mg po daily 
for 5 days both demonstrated high urinary concentrations on Day 1 and Day 5.  For the 
300 mg dosing group, over the 24-hour dosing period, mean urinary concentrations 
ranged from 14 to 20 µg/mL on Day 1 and 17 to 30 µg/mL on Day 5.  For the 450 mg 
dosing group, over the 24-hour dosing period, mean urinary concentrations ranged from 
11 to 25 µg/mL on Day 1 and 30 to 48 µg/mL on Day 5. 
• In PTK0796-UUTI-15103, both the 300 mg and 450 mg omadacycline treatment groups 
had nausea reported in 60% of subjects.  Vomiting occurred in 40% and 20% of the 
300 mg and 450 mg treatment groups, respectively.  In the recently completed 
PTK0796-ABSI-16301 study which compared omadacycline 450 mg po every 24 hours 
(q24h) for 2 doses followed by 300 mg po q24h for a total of 7 to 14 days to linezolid 
600 mg po q12h for a total of 7 to 14 days, nausea and vomiting rates of 30.2% and 
16.8% were observed.  In both studies, most events of nausea and vomiting occurred 
early in the treatment associated with the loading doses of omadacycline. 
• The effect of a light meal administered approximately 1.5 hours before dosing was 
evaluated using the free base formulation of omadacycline and resulted in approximately 
20% decrease in exposure.  In the recently completed study PTK0796-DDI-17106, the 
effect of a light meal administered approximately 1.5 hours before dosingwith  the same 
formulation of omadacycline used in the pivotal Phase 3 studies was evaluated.  The 
results demonstrated an approximately 19% to 25% reduction in exposure when a light 
meal was administered 1.5 hours before dosing. 
• The Sponsor has decided to add an omadacycline treatment group dosed at 450 mg twice 
daily for 7 days. The rationale for the change includes: 
1)    Since the driver of efficacy is unknown and the mean renal excretion of a 300 
mg oral dose is 14.4%,  a regimen that maximizes the tolerated dose of 
omadacycline may provide additional information on the dose necessary for 


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clinical and microbiologic success in uUTI and allow comparison to the daily 
dosed omadacycline treatment groups. 
6) The proposed dosing of 450mg twice daily for 7 days will provide 
approximately 2x or greater the amount of omadacycline that is excreted into 
the urine compared to the daily omadacycline treatment groups.   
7) Blinded review of the first 145 subjects reveals good tolerability. Nausea has 
occurred in approximately 10% of all subjects with only a single subject 
(0.7%) reporting vomiting. There has been only one treatment 
discontinuation due to adverse events of nausea and/or vomiting reported. 
Therefore, even if all cases of nausea and vomiting were in a single 
omadacycline treatment group, nausea and vomiting appears lower than 
observed in  PTK0796-UUTI-15103 study. 
8) Dose-limiting transaminase increases were seen in Phase 1 studies at 600mg 
IV which is higher than the exposure at 450mg PO twice daily. 
9) Increases in heart rate following omadacycline are Cmax associated. Cmax 
concentrations with the 450mg PO dose (1077 ng/mL) at steady state are 
approximately one-half the Cmax concentration with the 100mg IV dose 
(2120 ng/mL) suggesting that heart rate increases above 12-17 bpm observed 
with 100-200mg IV doses in healthy patients is unlikely following 450mg 
twice daily dosing. 
Therefore based on the pharmacokinetic, clinical, and safety data, the 450mg 
twice daily dose will increase urinary concentration, may provide additional 
clinical and microbiologic benefit while maintaining the safety profile observed 
with daily dosing. 
 
In order to minimize the effect of food on exposure and to potentially minimize the impact of 
nausea and vomiting during the omadacycline loading dose, omadacycline will be dosed 
twice on Day 1 with each dose administered approximately 2 hours following a light meal. In 
addition, all even numbered doses will also be administered approximately 2 hours following 
a light meal. Given the urinary concentrations observed in PTK0796-UUTI-15103 and the 
expected impact of a light meal, urinary concentrations should remain above the typical 
omadacycline MIC90 of 2 µg/mL for E.coli, the most common uropathogen in uncomplicated 
cystitis. 
 
Description of Treatments 
Subjects will be randomized (1:1:1:1:1) to 1 of the following 5 treatment groups: 


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Table 1. 
Description of Treatment groups 
Group 
Test Article 
Study Day 
1 
Study Days 
2-7* 
1 
Omadacycline 
300 mg po q12h, fed 
300 mg po q24h 
2 
Omadacycline 
450 mg po q12h, fed 
300 mg po q24h  
3 
Omadacycline 
450 mg po q12h, fed 
450 mg po q24h 
4 
Omadacycline 
450 mg po q12h, fed 
450 mg po q12h 
5 
Nitrofurantoin 
100 mg po q12h, fed 
100 mg po q12h 
q12h= every 12 hours, q24h= every 24 hours 
*Odd doses on Study Days 2-7 should be taken in a fasted state. Even doses on Study Days 2-7 
will be administered approximately 2 hours following a light meal  
 
 
 
Test Article Administration – Fed and Fasting State 
All doses of test article should be taken with water.  There are fed and fasting requirements 
for test article administration of the odd numbered doses due to effects of food on oral 
omadacycline (see Table 2). 
Doses 1 & 2 of the omadacycline tablets or placebo tablets resembling omadacycline and 
nitrofurantoin or placebo capsules resembling nitrofurantoin should be taken approximately 2 
hours after a light meal on Day 1 (24-hour period after randomization).  In addition, all even 
numbered doses beginning with Dose 4 will also be administered approximately 2 hours 
following a light meal. A light meal is defined in general as a meal of < 300 calories (ie, tea 
or non-calcium fortified orange juice and toast) with no calcium containing products. After 
dosing, no food is permitted for 2 hours as well as no dairy products, antacids or 
multivitamins containing multivalent cations (eg, aluminum, magnesium, calcium, bismuth, 
iron, or zinc) for 4 hours. 
Beginning with Dose 3, all consecutive odd numbered doses of the omadacycline tablets and 
placebo tablets resembling omadacycline should be taken in a fasted state.  Fasting is defined 
as no food, antacids or multivitamins containing multivalent cations (eg, aluminum, 
magnesium, calcium, bismuth, iron, or zinc) or drink except water for at least 6 hours before 
dosing.  After dosing, no food is permitted for 2 hours as well as no dairy products, antacids 
or multivitamins containing multivalent cations (eg, aluminum, magnesium, calcium, 
bismuth, iron, or zinc) for 4 hours. 


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Table 2. 
Dosing:  Double-Blind, Double-Dummy Design 
Dosing 
Group 1 
Group 2 
Group 3 
Group 4 
Group 5 
Dosing 
Condition 
omadacycline 
omadacycline 
omadacycline  
omadacycline 
nitrofurantoin 
Day 1 
 
 
 
 
 
Dose 1 
Two 150 mg 
omadacycline 
tablets, one 
placebo tablet 
resembling 
omadacycline  
Three 150 mg 
omadacycline 
tablets  
Three 150 mg 
omadacycline 
tablets 
Three 150 mg 
omadacycline 
tablets 
Three placebo 
tablets 
resembling 
omadacycline  
 
 
 
 
2 hours after 
light meala 
 
One placebo 
capsule 
resembling 
nitrofurantoin 
One placebo 
capsule 
resembling 
nitrofurantoin 
One placebo 
capsule 
resembling 
nitrofurantoin 
One placebo 
capsule 
resembling 
nitrofurantoin 
One 100 mg 
nitrofurantoin 
capsule 
 
 
 
 
 
Dose 2b 
Two 150 mg 
omadacycline 
tablets, one 
placebo tablet 
resembling 
omadacycline  
Three 150 mg 
omadacycline 
tablets  
Three 150 mg 
omadacycline 
tablets 
Three 150 mg 
omadacycline 
tablets 
Three placebo 
tablets 
resembling 
omadacycline  
 
 
 
 
2 hours after 
light meala  
 
One placebo 
capsule 
resembling 
nitrofurantoin 
One placebo 
capsule 
resembling 
nitrofurantoin 
One placebo 
capsule 
resembling 
nitrofurantoin 
One placebo 
capsule 
resembling 
nitrofurantoin 
One 100 mg 
nitrofurantoin 
capsule 
Days    
2-7 
 
 
 
Dose 3 
and 
odd 
doses 
Two 150 mg 
omadacycline 
tablets, one 
placebo tablet 
resembling 
omadacycline  
Two 150 mg 
omadacycline 
tablets, one 
placebo tablet 
resembling 
omadacycline  
Three 150 mg 
omadacycline 
tablets 
Three 150 mg 
omadacycline 
tablets 
Three placebo 
tablets 
resembling 
omadacycline  
 
 
 
 
Fastingc 
 
One placebo 
capsule 
resembling 
nitrofurantoin 
One placebo 
capsule 
resembling 
nitrofurantoin 
One placebo 
capsule 
resembling 
nitrofurantoin 
One placebo 
capsule 
resembling 
nitrofurantoin 
One 100 mg 
nitrofurantoin 
capsule   
 
 
Dose 4 
and 
even 
doses 
Three placebo 
tablets 
resembling 
omadacycline 
Three placebo 
tablets 
resembling 
omadacycline 
Three placebo 
tablets 
resembling 
omadacycline 
Three 150 mg 
omadacycline 
tablets 
Three placebo 
tablets 
resembling 
omadacycline 
 
 
2 hours after 
light meald  
 
One placebo 
capsule 
resembling 
nitrofurantoin  
One placebo 
capsule 
resembling 
nitrofurantoin 
One placebo 
capsule 
resembling 
nitrofurantoin 
One placebo 
capsule 
resembling 
nitrofurantoin 
One 100 mg 
nitrofurantoin 
capsule 
Day is defined as the 24-hour period, not calendar day.  All subjects will be dosed twice daily, ~12 hours apart, except where 
noted.  
a Doses 1 & 2 of the omadacycline tablets or placebo tablets resembling omadacycline and nitrofurantoin or placebo capsules 
resembling nitrofurantoin should be taken approximately 2 hours after a light meal on Day 1.  After dosing, no food for 
2 hours and no dairy products, antacids or multivitamins containing multivalent cations (eg, aluminum, magnesium, 
calcium, bismuth, iron, or zinc) for 4 hours. 
b    Dose 2 can be taken a minimum of 8 hours and up to 12 hours after Dose 1.  Dose 3 should be taken a minimum of 8 hours 
after Dose 2. 


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c Beginning with Dose 3, all consecutive odd numbered doses of the omadacycline tablets and placebo tablets resembling 
omadacycline should be taken in a fasted state.  Fasting is defined as no food, antacids or multivitamins containing 
multivalent cations (eg, aluminum, magnesium, calcium, bismuth, iron, or zinc) or drink except water for at least 6 hours 
before dosing.  After dosing, no food for 2 hours, no dairy products, antacids or multivitamins containing multivalent 
cations (eg, aluminum, magnesium, calcium, bismuth, iron, or zinc) for 4 hours. 
d   Beginning with Dose 4, all even numbered doses should be taken approximately 2 hours after a light meal. 
 
 
Dose Adjustments and Interruptions of Test Article 
No dose adjustments or interruptions of test article will be permitted during this study. 
 
Method of Assigning Patients to Treatment Groups 
Initially, all eligible subjects will be randomized via an IxRS that assigns them to 1 of the 
5 treatment arms (in a 1:1:1:1:1 ratio).  The site delegate will contact the IxRS (via phone or 
web) after confirming that the subject fulfills all the inclusion criteria and none of the 
exclusion criteria.  The IxRS will assign a test article to the subject based on a 
computer-generated randomization schedule.  The randomization will be a blocked 
randomization sequence as defined in the IxRS specifications and Statistical Analysis Plan 
(SAP).  Subjects randomized into the study will be assigned the treatment corresponding to 
the next available number from the computer-generated randomization schedule.  The subject 
is considered randomized when the IxRS provides the test article assignment, regardless of 
whether the subject actually receives any medication.  As this is an adaptive design trial, any 
updates to the randomization schedule based upon the Bayesian analysis will be incorporated 
into the IxRS system. 
 
7.8.1 
Subject Numbering 
Upon signing the informed consent, the subject will be assigned a unique subject number. 
Subject number ranges will be provided by the sponsor.  Subjects who have been 
pre-screened on the telephone but who do not sign an ICF will not be assigned a subject 
number.  A subject who discontinues participation or is withdrawn before receiving a 
treatment assignment, and who is re-screened at a later time will be assigned a new subject 
number and recorded as re-screened at the discretion of the investigator and in consultation 
with the sponsor as necessary.  The investigator will maintain a subject master list to 
document every subject who has signed an ICF.  A copy of this list should be retained in the 
investigator’s study files.    
 
Dispensing Test Article 
Each study site will be supplied by the sponsor with the investigational product and 
comparator.  Test articles will be supplied to the sites in kits that contain active omadacycline 
tablets or matched placebo tablets, and active nitrofurantoin over-encapsulated capsules or 
matched placebo over-encapsulated capsules.  Oral test article supplies are completely 
blinded and blinded study personnel can conduct storage, dispensation, and reconciliation.  
The IxRS will  assign the test article kit to be given to the subject.  The study 
coordinator/staff will instruct the subject on the use of po test article.   


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 Blinding 
The investigator and sponsor will be blinded to treatment group assignments throughout the 
study.  The sponsor designee (eg, study statistical team, IxRS vendor, etc.) will have a 
designated randomization administrator who will maintain the randomization codes in 
accordance with standard operating procedures to ensure the blind is properly maintained, 
and that only sponsor personnel who require knowledge of treatment assignments will be 
unblinded (eg, staff involved in maintaining the randomization codes).  The DMC will 
review safety data and the results from the Bayesian analysis of efficacy based on masked 
(treatments groups 1 to 4) treatment assignments.  Based on this analysis, modifications may 
be made to the omadacycline treatment groups. 
The study will follow a double-dummy design.  Subjects assigned to omadacycline will 
receive active omadacycline tablets and over-encapsulated nitrofurantoin placebo capsules.  
Subjects assigned to the nitrofurantoin arm will receive omadacycline placebo tablets and 
over-encapsulated active nitrofurantoin capsules.  
Randomization data are kept strictly confidential until the time of database lock and 
unblinding at the end of the study.  
Unblinding is only to occur in the case of subject emergencies (see Section 7.11, below) and 
at the conclusion of the study.  
 Emergency Unblinding of Treatment Assignment 
Emergency unblinding should only be undertaken when it is essential to treat the subject 
safely and efficaciously.  Most often, test article discontinuation and knowledge of the 
possible treatment assignments are sufficient to treat a study subject who presents with an 
emergency condition.  It is encouraged for the investigator, when contemplating unblinding, 
to contact the sponsor or sponsor’s designated Medical Monitor or designee to confirm the 
need to unblind, prior to unblinding (see Section 2 for contact information).  However, if 
required, the investigator can unblind without consulting the Medical Monitor. 
Emergency code breaks are performed using the IxRS.  When the investigator contacts the 
system to unblind a subject, he/she must provide the requested subject identifying 
information and confirm the necessity to unblind the subject.  The investigator will then 
receive details of the drug treatment for the specified subject and a fax or e-mail confirming 
that the treatment assignment of the subject was unblinded.  The system will automatically 
inform the sponsor’s monitor for the site and the sponsor that the code has been broken. 
It is the investigator’s responsibility to ensure that there is a procedure in place at their site to 
allow access to the IxRS code break information in case of emergency.  The investigator will 
inform the subject how to contact his/her backup in cases of emergency when he/she is 
unavailable.  The investigator will provide protocol number, test article name if available, 
subject number, and instructions for contacting the sponsor (or any entity to which it has 
delegated responsibility for emergency code breaks) to the subject in case emergency 
unblinding is required at a time when the investigator and backup are unavailable. 


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All steps outlined above will be followed, including contacting the Medical Monitor as soon 
as possible and not more than 24 hours afterwards.  It will be the responsibility of all study 
personnel to ensure that, except for the above procedure, investigator blinding is maintained 
until after study completion. 
 Prior & Concomitant Therapy 
Treatments that have been administered within the 7 days prior to the date of informed 
consent, or during the Screening phase, will be recorded in the eCRF.  The investigator is to 
instruct the subject to notify the study site about any new medications he/she takes after the 
start of the test article.  All medications and significant non-drug therapies (including 
physical therapy and blood transfusions) administered after the subject starts treatment with 
test article must be listed in the eCRF (see Section 9).  In addition, for antibacterial agents 
and anti-emetics administered, the dose, unit, frequency and route must be entered in the 
eCRF. 
 Prohibited Therapy  
• All investigational medications or devices used during the 30 days prior to Screening are 
prohibited.   
All of the following therapies are excluded starting from the time of consent through EOT 
visit: 
• Potentially therapeutic antibacterial agents (with potential activity against uropathogens 
responsible for UTI) are prohibited for 72 hours prior to randomization through EOT, 
with the exception of cases where a subject is deemed a clinical failure during the course 
of the study and requires treatment with an additional antibacterial agent  
• Subjects will be instructed to avoid taking antacids and multivitamins containing 
multivalent cations (eg, aluminum, magnesium, calcium, bismuth, iron, or zinc) for 
6 hours before and within 4 hours after doses 1, 2 and all subsequent odd numbered doses 
• Non-steroidal anti-inflammatory drugs (NSAIDs) are prohibited  
• Anti-spasmodic medications are prohibited  
• Consumption of cranberry juice and/or cranberry pills and over-the-counter (OTC) 
D-mannose-containing products are also prohibited 
• Any other treatments used to treat the symptoms of UTI 
7.13.1 
Concomitant Medications That May Interact with Nitrofurantoin 
Use of uricosuric drugs (eg, probenecid, colchicine, sulfinpyrazone) are prohibited from the 
time of consent through EOT visit.  
 Permitted Treatments 
All other treatments not specified as prohibited are permitted during the study.  Subjects 
requiring additional or alternative antibacterial therapy for their cystitis will be judged as 
Clinical Failures and test article will be discontinued.  Further treatment for their infection is 


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at the discretion of the investigator or the subject’s health care provider and will be 
considered as a concomitant medication. 
Subjects should be encouraged to contact site personnel before starting any new treatment. 
For all treatments received by the subject during the study, relevant information must be 
recorded on the subject’s eCRF. 
 Treatment Compliance 
 
Study personnel at the site should monitor po test article compliance at each study visit by 
comparing the returned test article with the dosing information reported by the subject.  
Compliance and any unresolved discrepancies will be documented in the source document 
and on the drug inventory record.  The test article eCRF should reflect the reconciled dosing 
information provided by the subject. 
 Packaging and Labeling 
The investigational test article, omadacycline, will be packaged by the sponsor and supplied 
to the investigator.  This includes:  omadacycline 150-mg oral tablets and matching placebo.  
The comparator test article, nitrofurantoin, will be packaged by the sponsor and supplied to 
the investigator.  This includes:  nitrofurantoin 100-mg oral capsules and matching placebo. 
 Storage and Accountability 
Test article must be received at the study site by a designated person, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designated staff have access.  Upon receipt, the test article should be stored according to the 
instructions specified on the drug labels.  Storage conditions must be adequately monitored 
and appropriate temperature logs maintained as source data. 
The designated study personnel must maintain an accurate record of the shipment and 
dispensing of test articles in the study specific medication accountability ledger.  Test article 
supplies are completely blinded.  Subjects will be asked to return all unused test article and 
packaging at each visit and at the end of the study, last study visit or at the time of test article 
discontinuation. Monitoring of oral medication accountability will be performed by the field 
monitor during site visits and at the completion of the study.   
 Investigational Product Retention at Study Site 
At the conclusion of the study, and as appropriate during the course of the study, with 
instruction from the sponsor, the designated study personnel will destroy on site as permitted 
by local site operating procedures, or return all unused test articles, packaging, and drug 
labels.  Destruction/return of all test article will be documented and maintained in the site 
files. 


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8 
STUDY PROCEDURES 
Written, signed, and dated informed consent will be obtained before any study-related 
procedures have been performed.  Upon signing the informed consent, the subject will then 
be assigned a study subject number.  Adverse events must be recorded from the time the ICF 
is signed.  Subjects who have been pre-screened on the telephone but who do not sign an ICF 
will not be assigned a subject number.  The investigator will maintain a subject master list to 
document every subject who has signed an ICF.  A copy of this list should be retained in the 
investigator’s study files. 
 
Informed Consent 
The investigator will provide for the protection of the subjects by following all applicable 
regulations.  These regulations are available upon request from the sponsor.  The ICF must 
be reviewed by the sponsor and approved by the IRB/IEC/REB. 
Before any procedures specified in the protocol are performed, a subject must: 
• Be informed of all pertinent aspects of the study and all elements of informed consent  
• Be given time to ask questions and time to consider the decision to participate 
• Voluntarily agree to participate in the study 
• Sign and date an IRB/IEC/REB approved ICF 
 
Subject Demographics/Other Baseline Characteristics 
Subject demographic and Baseline characteristic data to be collected on all subjects include:  
date of birth, gender, and race/ethnicity.   
 
Medical History 
The investigator will perform a comprehensive history at the Screening visit.  Significant 
medical history (at any time) and any medical history within the past 6 months including 
ongoing medical conditions at the time of signing of the ICF will be recorded.  In addition, 
subject history of prior UTIs will be captured.  Where possible, diagnoses are to be recorded.  
Any event or change in the subject’s condition or health status occurring after signing the 
ICF will be reported as an AE. 
 
Physical Examination 
At Screening, a full physical examination will include the examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, 
back, lymph nodes, extremities, and vascular and neurological systems.  If indicated based on 
medical history and/or symptoms, rectal, external genitalia, breast, and/or pelvic exams may 
be performed.   
Information for all physical examinations must be included in the source documentation at 
the study site.  Significant and relevant findings that are present prior to the start of test 


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article must be included in the subject’s eCRF.  Relevant findings that are present prior to the 
start of test article must be included in the relevant medical history/current medical 
conditions screen on the subject’s eCRF.  Significant findings made after the start of test 
article which meet the definition of an AE must be recorded on the Adverse Event screen of 
the subject’s eCRF. 
 
Vital Signs 
Vital signs include blood pressure (BP), heart rate, body temperature, height and body 
weight. 
• Blood pressure and heart rate should be measured within 30 min before, and 
approximately (± 15 minutes) 1 hour after and 3 hours after the completion of the first 
dose.  
The subject’s vital signs should be captured after at least 5 minutes (+ 5 minutes) of rest 
while in a non-standing position (supine or semi-recumbent, head of bed from 0° to 90°).  
Subsequent vital sign measurements should be captured in the same non-standing position. 
Systolic and diastolic BP will be measured using an automated validated device, with an 
appropriately sized cuff.  
Heart rate will be measured using an automated validated device, when available.  If not 
available, heart rate will be measured manually.  
Temperature will be obtained using an electronic (rapid reading) device whenever possible.   
 
Clinical Laboratory Tests 
Clinical laboratory tests to be performed include hematology (including coagulation), serum 
chemistry, urine or serum pregnancy assessments, and urinalysis.  The Central Laboratory 
will be used for safety analysis of all specimens collected.  Details on the collection tubes 
and containers, shipment of samples and reporting of results by the Central Laboratory are 
provided to investigators in the Central Laboratory Manual.  
Because subject enrollment will not permit using Central Laboratory results to assess a 
subject’s meeting inclusion/exclusion criteria, it is expected that local laboratory testing will 
be used in circumstances where this testing is needed to assess a subject’s WBC count or 
differential, serum transaminase or bilirubin levels, serum creatinine or pregnancy testing.  
The total volume of blood collected from each subject will be approximately 4 – 14 mL per 
visit, or approximately 48 mL (3 tablespoons) over the course of the study. 
8.6.1 
Central Laboratory Parameters 
Clinical laboratory tests will include the following:  


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Table 3. 
Clinical Laboratory Tests (Central) 
Hematology: 
Hematocrit (Hct) 
• 
Hemoglobin (Hgb) 
• 
Mean corpuscular hemoglobin (MCH) 
• 
Mean corpuscular hemoglobin concentration 
(MCHC) 
• 
Mean corpuscular volume (MCV) 
• 
Platelet count 
• 
Red blood cell (RBC) count  
• 
White blood cell (WBC) count with 
differential 
 
Coagulation:  
• 
Ratio of prothrombin time (PT) and 
international normalized ratio (INR) 
 
Pregnancy (all subjects): 
• 
Serum β-human chorionic gonadotropin 
(β-HCG) 
 
Urinalysis:  
• 
Bilirubin 
• 
Glucose 
• 
Ketones 
• 
Leukocyte esterase 
• 
Microscopic examination of sediment with 
WBC count  
• 
Nitrites 
• 
Occult blood 
• 
potential of hydrogen (pH) 
• 
Protein 
• 
Specific gravity 
• 
Urobilinogen 
Serum Chemistry: 
• 
Albumin (ALB) 
• 
Alkaline phosphatase (ALP) 
• 
Alanine aminotransferase (ALT) 
• 
Amylase 
• 
Aspartate aminotransferase (AST) 
• 
Blood urea nitrogen (BUN) 
• 
Calcium (Ca) 
• 
Carbon dioxide (CO2) 
• 
Chloride (Cl) 
• 
Creatinine 
• 
Creatine phosphokinase (CK) 
• 
Gamma-glutamyl transpeptidase (GGT) 
• 
Glucose 
• 
Lactate dehydrogenase (LDH) 
• 
Lipase 
• 
Magnesium 
• 
Phosphorus (P) 
• 
Potassium (K) 
• 
Sodium (Na) 
• 
Total bilirubin 
• 
Total protein 
• 
Uric acid 
8.6.2 
Local Laboratory Parameters 
 
Pregnancy Assessments  
All subjects will have a local urine or serum pregnancy test at the site at the Screening and 
PTE visits.  Urine pregnancy test kits will be provided by the sponsor through the Central 
Laboratory.  If a positive urine or serum pregnancy test result is obtained at the site during 
Screening, the subject is not to be randomized.  A serum sample for Serum β-human 
chorionic gonadotropin (β-hCG) testing will be collected at the Screening visit and sent to the 
Central Laboratory for confirmation of the local urine or serum pregnancy test results as well 
as at EOT.  If a positive β-hCG result is reported by the Central Laboratory after a subject is 
enrolled, test article administration should be discontinued (see Section 8.15.6). 


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Urine Culture and Dipstick Tests 
A clean-catch midstream urine sample should be collected and immediately sent to the local 
microbiology laboratory for microscopic examination and culture.  The sample should be 
analyzed for pyuria microscopically (WBC count greater than 10/μL in unspun urine or 
greater than or equal to 10 per high power field in spun urine) or by urine dipstick test for 
leukocyte esterase.  Results will be recorded on the eCRF.   
Quantitative urine culture by appropriate methods should be performed using a calibrated 
loop that would identify bacteria at a lower limit of 1.0 × 103 colony forming units 
(CFU)/mL.  A study-qualifying pretreatment Baseline culture must grow at least 1 and no 
more than 2 bacterial isolates at ≥ 1.0 × 105 CFU/mL each.  If more than two bacterial 
isolates are identified, the culture will be considered contaminated.  In general, at any visit, 
bacteria identified at 1.0 × 105 CFU/mL or greater should be considered a bacterial pathogen 
(probability of true pathogen is greater than probability of contamination).  At any visit after 
Screening, a pathogen the same species as the Baseline pathogen with a CFU count of 
≥ 1 × 104 CFU/mL should be considered a persisting pathogen.  At any visit after Screening, 
any culture with a CFU count of < 104 CFU/mL should be considered a negative culture. 
Culture results are to include identification of all pathogens to the level of genus and species.  
In vitro antimicrobial susceptibility testing of the isolates to antimicrobial drugs that may be 
used to treat UTIs can be performed locally using a standard method chosen by the 
laboratory.  
All bacterial isolates that grow ≥ 103 CFU/mL (whether at Baseline or post-Baseline) 
identified by the local laboratory from urine culture will be submitted to the Central 
Laboratory for verification of genus and species and for standardized MIC testing performed 
for omadacycline, nitrofurantoin and a panel of other antibiotics.  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 Laboratory.   
Details concerning cultures and shipment to the Central Laboratory will be provided in a 
Clinical Microbiology Laboratory Manual.  
The investigator may use the culture and susceptibility results from the local microbiology 
laboratory to help guide therapy; however, decisions to continue or discontinue test article 
should be based on clinical response rather than susceptibility results (as omadacycline 
susceptibility testing is not available at the local site).  The decision to continue or 
discontinue study treatment should be based on the subject's clinical course and the 
investigator’s clinical judgment.  The rationale for this decision should be recorded in source 
documents.  


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Efficacy assessments 
8.7.1 
Investigator’s Assessment of Clinical Response 
 
Investigator’s Assessment of Clinical Response at EOT 
The investigator will determine whether or not the subject meets the criteria of 1 of the 
following clinical outcomes: 
• Clinical Success:  Sufficient resolution of signs and symptoms at the EOT visit such that 
no additional systemic antimicrobial therapy is required for the current infection. 
• Clinical Failure:  No apparent response to therapy or persistence of signs and symptoms 
of infection at the EOT visit such that use of additional systemic antimicrobial therapy for 
the current infection is required. 
• Indeterminate:  EOT visit not completed. 
 
Investigator’s Assessment of Clinical Response at PTE 
The investigator will determine whether or not the subject meets the criteria of 1 of the 
following clinical outcomes: 
• Clinical Success:  Sufficient resolution of signs and symptoms at the PTE such that no 
additional systemic antimicrobial therapy is required for the current infection. 
• Clinical Failure:  No apparent response to therapy or persistence of signs and symptoms 
of infection or reappearance of signs and symptoms at or before the PTE visit such that 
use of additional systemic antimicrobial therapy for the current infection is required. 
• Indeterminate:  PTE visit not completed. 
 
Investigator’s Assessment of Clinical Response at Final Follow-up 
The investigator will determine whether or not the subject meets the criteria of 1 of the 
following clinical outcomes: 
• Clinical Success:  Sufficient resolution of signs and symptoms at the Final Follow-up 
visit such that no additional systemic antimicrobial therapy is required for the current 
infection. 
• Clinical Failure:  No apparent response to therapy or persistence of signs and symptoms 
of infection or reappearance of signs and symptoms at or before the Final Follow-up visit 
such that use of additional systemic antimicrobial therapy for the current infection is 
required. 
• Indeterminate:  Final Follow-up visit not completed. 


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Subject Assessment of UTI Signs and Symptoms Severity 
The subject will record her assessment of UTI signs and symptoms severity using the UTI 
Symptoms Assessment questionnaire (UTISA).  The UTISA is a 14-item instrument asking 
about the severity and bothersomeness of seven key uUTI symptoms, and applies a 4-point 
scale:  No Symptoms, Mild, Moderate, Severe. 
The investigator must review subject’s responses to the questionnaire and record any AEs as 
appropriate (please refer to section 8.15.5). 
 
Pharmacokinetic Assessments 
Instructions will be provided to sites with detailed information on sample collection, 
handling, and shipment requirements.  All samples will be given a unique identifier.  The 
exact clock time of dosing, as well as actual sample collection date and time will be entered 
on the eCRF. 
8.9.1 
PK Blood Collection and Processing 
Blood samples will be collected and analyzed for omadacycline concentration at the 
following times:  
• Day 1:  2 hours after the first odd-numbered dose 
• Day 5:  During study visit  
8.9.2 
PK Urine Collection and Processing 
Urine will be collected and analyzed for omadacycline concentration at the following times: 
• Day 3:  During study visit 
• Day 5:  During study visit 
8.9.3 
Storing and Shipping of PK Samples 
After all PK samples from a single subject have been collected and frozen at - 20°C or 
colder, the primary samples from each time point can be batched together and carefully 
packaged and shipped frozen at - 20°C or colder to the central laboratory designated by the 
sponsor.  Samples are to be shipped with sufficient dry ice to remain frozen during overnight 
transit.  For each subject and time point, the remaining stored aliquots will be retained on site 
at - 20°C or colder until released or requested by the sponsor. 
 Adverse Events  
An AE is any untoward, undesired, or unplanned event in the form of signs, symptoms, 
disease, or laboratory or physiologic observations occurring in a person given a test article or 
in a clinical study.  The event does not need to be causally related to the test article or clinical 
study.  An AE includes, but is not limited to, the following: 


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• Any clinically significant worsening of a preexisting condition. 
• An AE occurring from overdose of a test article, whether accidental or intentional.  
Overdose is a dose greater than that specified in the protocol. 
• An AE occurring from abuse (eg, use for nonclinical reasons) of a test article 
• An AE that has been associated with the discontinuation of the use of a test article 
 Serious Adverse Events 
A Serious Adverse Event (SAE) is an AE that: 
• Results in death 
• Is life-threatening (see below) 
• Requires hospitalization or prolongation of an existing hospitalization (see below) 
• Results in a persistent or significant disability or incapacity (see below) 
• Results in a congenital anomaly or birth defect 
• Additionally, important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered SAEs when, based on appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent any one (1) of the outcomes listed above in this definition.  
Examples of such events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. 
Life-threatening refers to immediate risk of death as the event occurred per the reporter.  A 
life-threatening experience does not include an experience, had it occurred in a more severe 
form, might have caused death, but as it actually occurred, did not create an immediate risk 
of death.  For example, hepatitis that resolved without evidence of hepatic failure would not 
be considered life-threatening, even though hepatitis of a more severe nature can be fatal.  
Similarly, an allergic reaction resulting in angioedema of the face would not be 
life-threatening, even though angioedema of the larynx, allergic bronchospasm, or 
anaphylaxis can be fatal. 
Hospitalization is official admission to a hospital.  Hospitalization or prolongation of a 
hospitalization constitutes criteria for an AE to be serious; however, it is not in itself 
considered an SAE.  In absence of an AE, a hospitalization or prolongation of a 
hospitalization should not be reported as an SAE by the participating investigator.  This is the 
case in the following situations: 
• The hospitalization or prolongation of hospitalization is needed for a procedure required 
by the protocol 
• The hospitalization or prolongation of hospitalization is part of a routine procedure 
followed by the center (eg, stent removal after surgery).  This should be recorded in the 
study file. 
• A hospitalization for a preexisting condition that has not worsened  


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Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions. 
If there is any doubt about whether the information constitutes an SAE, the information is 
treated as an SAE. 
 Other Reportable Information  
Certain information, although not considered an SAE, must be recorded, reported, and 
followed up as indicated for an SAE.  This includes: 
• Pregnancy exposure to a test article:  If a pregnancy is confirmed, use of the test article 
must be discontinued immediately.  Information about pregnancy exposure includes the 
entire course of pregnancy and delivery, and perinatal and neonatal outcomes, even if 
there are no abnormal findings.   
• Lactation exposure to a test article with or without an AE 
• Overdose of a test article as specified in this protocol with or without an AE 
• Inadvertent or accidental exposure to a test article with or without an AE 
 
 Overdose 
Any administration of omadacycline of greater than 1350 mg within a 24-hour period will be 
an overdose, regardless of whether the overdose is intentional or accidental, it is a reportable 
event and the sponsor must be notified within 1 business day.  Any administration of greater 
than 300 mg of nitrofurantoin within a 24-hour period will be an overdose.  In the event that 
a study subject takes an overdose of test article, the investigator may obtain the subject’s 
treatment assignment by contacting the IxRS.  Interactive Response System will also provide 
a confirmation report of the drug assignment to site personnel.  The site personnel will retain 
this confirmation report.  In the case of a potential overdose, the subject should maintain a 
high level of fluid intake to promote urinary excretion (as recommended in the nitrofurantoin 
USPI11). 
The physician managing the overdose may order any test he/she thinks is necessary to 
manage the subject properly. 
 Medication Errors 
Medication errors are the result of administration or consumption of the wrong product, by 
the wrong subject, at the wrong time, and/or by the wrong administration route, due to human 
error.   
Medication errors include, but are not limited to, the following: 
• The administration and/or consumption of test article that has not been assigned to the 
subject 
• Administration of expired test article 


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All AEs and SAEs must be handled as specified in this protocol whether or not they are 
associated with a medication error.  A medication error associated with an SAE (including 
overdose, inadvertent exposure, and/or accidental exposure) will be reported with the SAE on 
the SAE Report Form.  All other medication errors will be reported by e-mailing the Clinical 
Test Article Error Incident Report Form as indicated in the Emergency Contacts (see 
Section 2). 
 Recording and Reporting 
A subject’s AEs and SAEs will be recorded and reported from the signing of the ICF to the 
time of the Final Follow-up assessment.  The investigator must instruct the subject to report 
AEs and SAEs during this time period.  Reports of death within 30 days after the last contact 
with the subject will be reported to the sponsor and additional information relative to the 
cause of death will be sought and documented.   
All AEs and SAEs must be recorded on source documents.  All AEs and SAEs for subjects 
who receive a treatment assignment will be recorded in the eCRFs. 
The investigator must follow-up as medically necessary on all AEs and SAEs until the events 
have subsided, the condition has returned to Baseline, or in case of permanent impairment, 
until the condition stabilizes. 
AEs should be based on the signs or symptoms detected during the physical examination and 
on clinical evaluation of the subject.  In addition to the information obtained from those 
sources, the subject should be asked the following nonspecific question:  "How have you 
been feeling since your last visit?"  Whenever possible, AEs should be reported as a 
diagnosis rather than individual signs and symptoms.  If a definitive diagnosis is not possible, 
the individual signs and symptoms should be recorded using standard medical terminology. 
If an AE requires a surgical or diagnostic procedure, the illness leading to the procedure 
should be recorded as the AE, not the procedure itself. 
Death should be recorded in the eCRF as an outcome of an AE.  Any unanticipated risks to 
the subjects must be reported promptly to the IRB/IEC/REB.  
8.15.1 
Serious Adverse Event Reporting 
All SAEs and follow-up information must be reported within 1 business day or 24 hours as 
required by local regulations by emailing a completed SAE Report to the email address 
below.  
Serious Adverse Event (SAE) contact information: 
E-Mail: 
 


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8.15.2 
Assessment of Relatedness 
The investigator will assess causality (ie, whether there is a reasonable possibility that test 
article caused the event) for all AEs and SAEs.  The relationship will be characterized using 
the following classification: 
• Not related:  This relationship suggests that there is no association between test article 
and the reported event.  The event can be explained by other factors such as an 
underlying medical condition, concomitant therapy, or accident, and no plausible 
temporal or biologic relationship exists between test article and the event. 
• Related:  This relationship suggests that a definite causal relationship exists between test 
article administration and the AE, or there is a reasonable possibility that the event was 
caused by the study medication, and other conditions (concurrent illness, 
progression/expression of disease state, or concurrent medication reaction) do not appear 
to explain the event. 
AEs and SAEs also will be assessed for their potential relationship to the protocol.  A 
protocol-related adverse event is one that is not related to the test article, but is considered by 
the investigator or the medical monitor (or designee) to be related to the research conditions, 
ie, related to the fact that a subject is participating in the study.  For example, a protocol-
related AE may be an untoward event related to a medical procedure required by the 
protocol. 
8.15.3 
Assessment of Severity 
The severity (or intensity) of an AE will be classified using the following criteria: 
• Mild:  These events are usually transient, require minimal or no treatment, and do not 
interfere with the subject’s daily activities. 
• Moderate:  These events result in a low level of inconvenience or concern with the 
therapeutic measures.  Moderate events may cause some interference with normal 
functioning but pose no significant or permanent risk of harm. 
• Severe:  These events interrupt a subject’s usual daily activity and may require systemic 
drug therapy or other treatment.  Severe events are usually incapacitating. 
Changes in the severity of an AE should be documented as a new event to allow an 
assessment of the duration of the event at each level of intensity to be performed. 
8.15.4 
Laboratory Findings 
Protocol-defined safety laboratory test results will be analyzed as part of specific laboratory 
safety analyses.  Additional laboratory test results at other time points may be available to the 
investigator as part of standard clinical practice.  Throughout the study, laboratory-related 
abnormalities should be recorded as AEs only if considered clinically significant, outside the 
range of expected values given the subject’s Baseline assessments and clinical course, and 
not known to be part of another AE diagnosis. 


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8.15.5 
Worsening or Progression of Disease Under Study 
Worsening or progression of the qualifying UTI should be recorded as a clinical failure (as 
part of the efficacy assessment), rather than an AE, unless the worsening/progression also 
meets the criteria for a serious AE (in which case the event also should be reported as an 
SAE).  In contrast, any new or secondary infections that the investigator considers to be 
distinct from the qualifying UTI should be reported as AEs in all cases, whether non-serious 
or serious. 
8.15.6 
Pregnancies 
To ensure subject safety, each pregnancy in a subject on test article must be reported to the 
sponsor within 1 business day of learning of its occurrence.  Test article should be 
discontinued immediately and the pregnancy should be followed up to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the sponsor.  Pregnancy follow-up should be recorded on the same form and 
should include an assessment of the possible relationship to the test article of any pregnancy 
outcome.  Any SAE experienced during pregnancy must be reported on the SAE Report 
Form. 
 Concomitant Medication Assessments 
The investigator should instruct the subject to notify the study site about any new 
medications she takes after the start of the test article.   
All prescription medications, OTC drugs, and recreational drugs taken within the timeframe 
defined in the entry criteria prior to the start of the study and during the study, must be 
recorded on the Prior/Concomitant Medications page of the eCRF.  Medication entries 
should be specific to trade name, the single dose and unit, the frequency and route of 
administration, the start and discontinuation dates, and the reason for therapy. 
 Subject Discontinuation or Withdrawal 
Reasons why a subject may discontinue or be withdrawn from the study include, but are not 
limited to, AE, lost to follow up, withdrawal by subject, physician decision, death, and other 
(specify reason eg, subject non-compliance or study termination by the sponsor).  Subjects 
may voluntarily withdraw from the study for any reason at any time.  Subjects are considered 
withdrawn from the study if they state an intention to withdraw, or fail to return for visits, or 
become lost to follow up for any other reason.  If premature withdrawal from the study 
occurs for any reason, the investigator should determine the primary reason for a subject’s 
premature withdrawal from the study and record this information on the eCRF. 
Subjects who discontinue study treatment should not be considered withdrawn from the study 
(unless the subject withdraws informed consent).  The date and primary reason for 


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discontinuation of study treatment should be recorded.  Subjects who discontinue study 
treatment prematurely should complete the EOT visit, PTE visit and Final Follow-up 
Assessment, if possible (see Schedule of Events - Appendix 1).  The site should also collect 
subject safety information through the Final Follow-up assessment.   
Site personnel should also contact the IxRS to register the subject’s discontinuation from test 
article.   
For subjects who are lost to follow up, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, eg, dates of 
telephone calls, registered letters, etc. 


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9 
STUDY ACTIVITIES 
The full assessment schedule is presented in the Schedule of Events (see Appendix 1).  
Subjects should be seen for all visits on the designated day.   
 
Screening Phase 
The Screening visit should be completed within a 24-hour period prior to randomization.  
The Screening procedures will be used to establish subject eligibility and Baseline 
characteristics for each subject.  Following the signing of an ICF, the site staff will 
collect/perform the following: 
• Demographics 
• Medical history 
• Physical examination 
• Vital signs:  body weight & height, body temperature, blood pressure, heart rate 
• Review of inclusion/exclusion criteria 
• Laboratory tests (blood):   
– hematology (includes coagulation) 
– chemistry 
– serum pregnancy test 
• Laboratory tests (urine): 
– Urinalysis via dipstick with optional microscopic exam_ 
– Urine culture 
– Urine pregnancy test 
• Concomitant medications (past 7 days) 
• AEs since the signing of the ICF 
Subject assessment of UTI signs and symptoms severity (UTISA questionnaire) 
 
Double-Blind Treatment Phase (Day 1, Day 3 and Day 5 In-Office Visits) 
The double-blind treatment period is 7 days in duration.  Subjects who meet all of the 
inclusion criteria and none of the exclusion criteria may be randomized. 
9.2.1 
Day 1 Visit Procedures 
The following assessments will be performed: 
• Review of inclusion/exclusion criteria 
• Randomization 
• Concomitant medications 
• Vital signs:  body temperature, blood pressure, heart rate 
• AEs  
• Dispensation and Administration of test article (2 hours after light meal) 
• PK blood collection (2 hours after first odd numbered dose of test article) 
• Subject assessment of UTI signs and symptoms severity (UTISA questionnaire) 


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9.2.2 
Day 3 Visit Procedures 
The following assessments will be performed: 
• Subject assessment of UTI signs and symptoms severity (UTISA questionnaire) 
• Concomitant medications 
• Laboratory tests (urine): 
– Urinalysis via dipstick with optional microscopic exam  
– Urine culture 
• Vital signs:  body temperature, blood pressure, heart rate 
• AEs  
• PK urine collection 
• Administration and accountability of test article 
9.2.3 
Day 5 Visit Procedures 
The following assessments will be performed: 
• Subject assessment of UTI signs and symptoms severity (UTISA questionnaire) 
• Concomitant medications 
• Laboratory tests (urine): 
– Urinalysis via dipstick with optional microscopic exam  
– Urine culture 
• Vital signs:  body temperature, blood pressure, heart rate 
• AEs  
• PK blood collection 
• PK urine collection 
• Administration and accountability of test article 
 
Double-Blind Treatment Phase (Day 2, Day 4 and Day 6 At-Home 
Requirements) 
• Administration of test article 
• Subject assessment of UTI signs and symptoms severity (UTISA questionnaire) 
 
 
End of Treatment/Day 7 Visit Procedures 
The End of Treatment (EOT)/Day 7 evaluation should be conducted on the day of or within 
the 2 days following the last dose of test article.  If the subject voluntarily withdraws or is 
discontinued from her dosing regimen, these procedures should be performed on that day: 
• Subject assessment of UTI signs and symptoms severity (UTISA questionnaire) 
• Concomitant medications 
• Physical Examination 
• Vital signs:  body weight, body temperature, blood pressure, heart rate 
• Laboratory tests (blood):   


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– hematology (includes coagulation) 
– chemistry 
– serum pregnancy test 
• Laboratory tests (urine): 
– Urinalysis via dipstick with optional microscopic exam   
– Urine culture 
• AEs  
• Investigator’s assessment of clinical response  
• Accountability of test article 
 
Follow-up Phase 
9.5.1 
Post-Treatment Evaluation (PTE) Visit 
The PTE visit should be conducted on Day 14 (+/- 2 days) after the subject’s first dose of test 
article.  This evaluation should also be conducted for any prematurely withdrawn subject.  
The following assessments will be performed at the PTE visit: 
• Subject assessment of UTI signs and symptoms severity (UTISA questionnaire) 
• Physical examination 
• Concomitant medications 
• Laboratory tests (urine): 
– Urinalysis via dipstick with optional microscopic exam 
– Urine culture 
• Vital signs:  body temperature, blood pressure, heart rate 
• Laboratory tests (blood):   
– hematology (includes coagulation) * 
– chemistry * 
– serum pregnancy test 
*Note:  hematology & chemistry will be performed only if clinically significant 
abnormalities were noted at EOT 
• AEs 
• Investigator’s assessment of clinical response  
9.5.2 
Final Follow-up 
The Final Follow-up assessment should be conducted 30 to 37 days following the subject’s 
first dose of test article.  This evaluation should also be conducted for any prematurely 
withdrawn subject with the exception of subjects who withdraw consent.  The Final Follow-
up assessment may be conducted via telephone contact or by another interactive technology 
for subjects who are not having any symptoms and had no AEs or clinically significant 
laboratory abnormalities noted at or after the PTE visit.  Otherwise, the visit must be 
conducted in person.  
The standard procedures for final follow-up call/visit are as follows: 


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• Subject assessment of UTI signs and symptoms severity (UTISA questionnaire) 
• Concomitant medications 
• AEs 
• Investigator’s assessment of clinical response 
 
If during the final follow-up visit or call the subject reports symptoms of potential 
recurrence, the following additional procedures will be performed in clinic:  
• Laboratory tests (urine): 
– Urinalysis via dipstick with optional microscopic exam  
– Urine culture 
• Vital signs:  body temperature, blood pressure, heart rate 


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10 STUDY SUSPENSION, TERMINATION, AND COMPLETION 
 Study Completion and Post-Study Test Article 
A subject will have successfully completed the study after the planned test article regimen 
has been administered, and all assessments and visits have been performed up through the 
final follow-up assessment (Final Follow-up).  The study will be completed when the last 
subject has either discontinued or completed the Final Follow-up assessment.   
No long-term follow-up of subjects is planned, with the exception of pregnancies, as 
described in Section 8.15.6, and SAEs described in Section 8.15.1. 
Sites will be notified by either the Sponsor or IxRS to stop enrollment when the desired 
number of treated subjects have been enrolled.  Subjects already consented, but not yet 
randomized will be allowed to continue Screening procedures. 
Upon study completion, the investigator will provide the sponsor, IRB/IEC/REB, and 
regulatory agency with final reports and summaries as required by regulations.  The 
investigator must submit a written report to the sponsor and the IRB/IEC/REB within 
3 months after the completion or termination of the study. 
 Study Suspension or Termination 
The sponsor may suspend or terminate the study or part of the study at any time for any 
reason.  Should this be necessary, subjects should be seen as soon as possible and treated as 
described in Section 9.3 for prematurely withdrawn subjects.  The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the subject’s interests.  The investigator will be 
responsible for informing Institutional Review Boards (IRBs) and/or Ethics Committees 
(ECs) of the early termination of the study. 
If the investigator suspends or prematurely terminates their participation in the study, the 
investigator will promptly inform the sponsor and the IRB/IEC/REB and provide them with a 
detailed written explanation.  Subjects should be seen as soon as possible and treated as 
described in Section 9.3 for prematurely withdrawn subjects.  The investigator will also 
return all test articles, containers, and other study materials to the sponsor. 


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11 QUALITY CONTROL AND ASSURANCE 
The sponsor performs quality control and assurance checks on all clinical studies that it 
sponsors.  Before enrolling any subjects in this study, sponsor personnel and the investigator 
review the protocol, the Investigator’s Brochure, the case report forms (CRFs) and 
instructions for their completion, the procedure for obtaining informed consent, and the 
procedure for reporting AEs and SAEs.  A qualified representative of the sponsor monitors 
the conduct of the study by visiting the site and by contacting the site by telephone and e-
mail.  During these site visits, information recorded in the CRFs is verified against source 
documents. 


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12 PLANNED STATISTICAL METHODS 
 General Considerations 
All analyses of data for this study will comply with International Conference on 
Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for 
Human Use (ICH-E9) and the sponsor’s guidance documents and standards.  Statistical 
analyses will be performed using Statistical Analysis Software (SAS®). 
A Statistical Analysis Plan incorporating the sections below and with mock table, figure, and 
listing (TFL) shells will be prepared, approved and finalized by the sponsor prior to database 
lock.  This plan will define populations for analysis, outline all data handling conventions, 
and specify statistical methods to be used for analysis of safety and efficacy.  Analyses of PK 
endpoints will be described in a separate analysis plan. 
Descriptive statistics, including the numbers and percentages for categorical variables, and 
the numbers, means, standard deviation (SD), medians, minimums, and maximums for 
continuous variables will be provided.  Exploratory analyses may also be performed.  
Listings of individual subject’s data will be produced. 
All eCRFs must be completed, entered and checked; all safety laboratory results must have 
been reported; all AEs must have been fully characterized (eg, relationship to test article 
determined) and coded; and all queries must have been resolved prior to database lock and 
unblinding.  Determination of inclusion in the analysis populations, characterization of 
protocol deviations as major/minor and final approval of the SAP will also be completed 
prior to database lock. 
 Determination of Sample Size 
Enrollment of a total of approximately 225 subjects is planned.  The Bayesian posterior 
probability that the clinical success rate at the PTE Visit is within 0.10 of that of the 
nitrofurantoin group will be estimated for each omadacycline dose group.  The target 
probability is 0.80.  If the true underlying clinical success rates for the nitrofurantoin and 
omadacycline dose groups are 0.82, then the sample size of N = 50 per treatment has 
approximately 79% power/probability to yield the target probability (N = 53 pertreatment for 
80% power).  The sample size may be increased for a particular omadacycline dose group by 
changing the randomization ratio and/or dropping a dose group to achieve improved 
power/probability of achieving the target probability that clinical success rates for a dose 
group is within 0.10 of that of the nitrofurantoin group.  If required to improve the precision 
of the interim or projected final analyses estimates of response rates or posterior 
probabilities, sample size may be increased to a maximum sample size provided in the SAP. 
 Analysis Populations  
The following subject analysis populations have been defined: 
• Intent-to-treat (ITT):  all randomized subjects. 


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• Safety:  all randomized subjects who receive any amount of test article.   
• The microbiological ITT (micro-ITT) population will consist of subjects in the ITT 
population who have a study-qualifying pre-treatment Baseline urine culture with 1 or 2 
uropathogens at ≥ 105 CFU/mL.   
• The clinically evaluable (CE) population will consist of all ITT subjects who received 
test article, have a qualifying infection, an assessment of outcome, and meet all other 
evaluability criteria detailed in the SAP 
• The microbiologically evaluable (ME) population will include subjects in the CE 
population who have a study-qualifying pre-treatment Baseline urine culture with 1 or 
2 uropathogens at ≥ 105 CFU/mL.   
 Demographics and Baseline Characteristics 
Demographics (including age, ethnicity and race) and Baseline characteristics will be 
summarized in the ITT population by treatment group.  
Descriptive statistics of the duration of test article treatment will be provided by treatment 
group.  The number and percentage of subjects who prematurely discontinued test article and 
the reason for discontinuation and the number and percentage of subjects prematurely 
discontinuing the study and the primary reason for discontinuation will be presented by 
treatment group. 
 Primary Endpoint(s) 
12.5.1 
Efficacy Endpoint 
The primary efficacy endpoint is the Investigator’s assessment of clinical success at PTE in 
the ITT population.  The number and percentage of subjects with an Investigator’s 
assessment of clinical success, clinical failure and indeterminate response at the PTE visit 
will be determined by treatment group in the ITT population.  Exact 95% confidence 
intervals will be determined for the point estimates of the clinical success rates in each 
treatment group. 
A comparison of the clinical success rate at the PTE Visit between each omadacycline dose 
group and the nitrofurantoin group will be conducted using a beta distribution with an 
uninformative Bayesian prior distribution.  Additional analyses on the primary efficacy 
endpoint will be performed using Bayesian modeling.  Details are described in SAP.  
 Secondary Endpoint(s) 
12.6.1 
Safety Endpoint(s) 
All safety analyses will utilize the Safety population.  Summary tables will be provided for 
all treatment-emergent adverse events (TEAEs).  A TEAE is defined as an AE with a start 
date and time on or after the first dose of test article.  AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) and will be summarized by presenting the 
number and percentage of subjects having each TEAE for each treatment group by system 


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organ class (SOC) and preferred term (PT), by SOC, PT and severity, and by SOC, PT and 
relationship to test article.  Additional tabulations will provide summaries by SOC and PT of 
subjects experiencing SAEs and TEAEs judged to be related to test article. 
The following variables will be analyzed descriptively by treatment group in the Safety 
population: 
• Vital signs (systolic and diastolic BP, heart rate, body temperature), including change 
from Baseline by visit and time point measured 
• Clinically notable vital signs (meeting predefined criteria as specified in the SAP) by visit 
and time point measured 
• Laboratory parameters, including change from Baseline by visit 
• Clinically notable laboratory parameters (meeting predefined criteria s specified in the 
SAP) by visit  
12.6.2 
Efficacy Endpoint(s) 
The number and percentage of subjects with an Investigator’s assessment of clinical success, 
clinical failure and indeterminate response at the EOT Visit (ITT and CE populations; by 
definition subjects in the CE population cannot have an indeterminate response) and PTE 
visit (CE and micro-ITT population) will be determined by treatment group.  Exact 95% 
confidence intervals will be determined for the point estimates of the clinical success rates in 
each treatment group. 
The number and percentage of subjects with a microbiologic failure, success and 
indeterminate response at the EOT and PTE Visits (micro-ITT and ME populations; by 
definition subjects in the ME population cannot have an indeterminate response) will be 
determined by treatment group.  Exact 95% confidence intervals will be determined for the 
point estimates of the microbiologic success rates in each treatment group. 
 Interim Analysis 
This is an adaptive dose-response finding study. Bayesian analysis will be conducted when 
primary efficacy endpoint data (investigator assessment of clinical response at PTE) is 
available from 40, 80 and 100 subjects in order to: 
• Determine if omadacycline dose group(s) that can be dropped from the trial, or 
• Modify the randomization ratios among the omadacycline dose groups to improve the 
precision of the selected dose group comparison of clinical success to that of the 
nitrofurantoin group. 
Additional analyses may be carried out for these same two purposes.  Response criteria are 
targeted toward estimating the probability that the clinical success rate (proportion of 
subjects) for each dose group is within 10% of that of the nitrofurantoin group.  If at the 
specified analysis time point, that probability falls below 30% for a particular omadacycline 
dose group, recruitment for that omadacycline dose group may be stopped or curtailed by 
changing the randomization ratio.  If that probability exceeds 80% for a particular 


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omadacycline dose group, recruitment for that dose group may be increased by changing the 
randomization ratio to improve the precision of the estimate.    
Results from the Bayesian analysis will be reviewed by a DMC to determine if enrollment in 
any omadacycline treatment arms should be stopped or modified.  Modifications to 
omadacycline dosing regimens/treatment arms may also be based on safety and tolerability.  
A DMC charter describing the composition of the DMC, roles and responsibilities, and 
statistical parameters will be developed and finalized prior to the first data review. 
 Data Monitoring Committee 
A DMC will provide ongoing monitoring of data.  The charter for the DMC will clearly 
outline membership, all roles, responsibilities, and decision-making criteria.  This will 
include a detailed description of the manner in which security and blinding of the data for the 
study management team will be maintained, in addition to the procedures that ensure the 
independence and objectivity of the DMC’s activities.  As the DMC will be reviewing data 
for this study, it may require reports indicating treatment assignment to assist in clinical 
interpretation of its findings.  Therefore, the DMC charter will provide a detailed explanation 
of the processes by which the DMC will obtain the information necessary for its operation 
that will not prejudice or create any potential source of bias in the conduct of the study. 


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13 ADMINISTRATIVE CONSIDERATIONS 
 Investigators and Study Administrative Structure 
The investigator will permit study-related monitoring, audits, IRB/IEC/REB review, and 
regulatory inspections by providing direct access to source data and documents. 
All information will be recorded on source documents.  All required data will be recorded in 
the eCRFs. 
If an investigator retires, relocates, or otherwise withdraws from conducting the study, the 
investigator must notify the sponsor to agree upon an acceptable storage solution.  
Regulatory agencies will be notified with the appropriate documentation. 
An updated form 1572 will be filed with the sponsor for any changes in the study personnel 
reported in the current form 1572. 
 Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval 
The protocol and the proposed ICF must be reviewed and approved by a properly constituted 
IRB/IEC/REB before study start.  A signed and dated statement that the protocol and ICF 
have been approved by the IRB/IEC/REB must be given to the sponsor before study 
initiation.  Prior to study start, the investigator is required to sign a protocol signature page 
confirming his/her agreement to conduct the study in accordance with these documents and 
all of the instructions and procedures found in this protocol and to give access to all relevant 
data and records to the sponsor monitors, auditors, designated agents of the sponsor, 
IRBs/IECs/REBs, and regulatory authorities as required.  If an inspection of the clinical site 
is requested by a regulatory authority, the investigator must inform the sponsor immediately 
that this request has been made.   
 Ethical Conduct of the Study 
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice (GCP), with applicable 
local regulations (including European Directive 2001/20/EC, US 21 Code of Federal 
Regulations (CFR), and Japanese Ministry of Health, Labor, and Welfare), and with the 
ethical principles laid down in the Declaration of Helsinki. 
 Patient Information and Consent 
The investigator will provide for the protection of the subjects by following all applicable 
regulations.  These regulations are available upon request from the sponsor.  The ICF must 
be reviewed by the sponsor and approved by the IRB/IEC/REB. 
Before any procedures specified in the protocol are performed, a subject must: 
• Be informed of all pertinent aspects of the study and all elements of informed consent; 


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• Be given time to ask questions and time to consider the decision to participate; 
• Voluntarily agree to participate in the study; 
• Sign and date an IRB/IEC/REB-approved ICF. 
 Direct Access, Data Handling, and Record Keeping 
13.5.1 
Investigator 
The investigator will permit study-related monitoring, audits, IRB/IEC/REB review, and 
regulatory inspections by providing direct access to source data and documents. 
All information will be recorded on source documents.  All required data will be recorded in 
the eCRFs. 
If an investigator retires, relocates, or otherwise withdraws from conducting the study, the 
investigator must notify the sponsor to agree upon an acceptable storage solution.  
Regulatory agencies will be notified with the appropriate documentation. 
An updated form 1572 will be filed with the sponsor for any changes in the study personnel 
reported in the current form 1572. 
13.5.2 
Sponsor 
The data is entered into an electronic database via eCRFs.  The Sponsor Medical Monitor 
reviews the data for safety information.  The data is reviewed for completeness and logical 
consistency.  Automated validation checks identify missing data, out-of-range data, and other 
data inconsistencies.  The central safety and microbiology data will be processed 
electronically.  Requests for data clarification are forwarded to the investigative site for 
resolution. 
 Protocol Adherence 
13.6.1 
Violations/Deviations 
Investigators will agree to apply due diligence to avoid protocol deviations.  Under no 
circumstances should the investigator contact the sponsor or its agents to request approval of 
a prospective protocol deviation, as no authorized deviations are permitted.  If the 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by the 
sponsor and approved by the IRB/IEC/REB, it cannot be implemented.  All significant 
protocol deviations will be recorded and reported in the clinical study report (CSR). 
13.6.2 
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment 
that must be approved by the sponsor, Health Authorities where required, and the 
IRB/IEC/REB.  Only amendments that are required for subject safety may be implemented 
prior to IRB/IEC/REB approval.  Notwithstanding the need for approval of formal protocol 


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amendments, the investigator is expected to take any immediate action required for the safety 
of any subject included in this study, even if this action represents a deviation from the 
protocol.  In such cases, the sponsor should be notified of this action and the IRB/IEC/REB 
at the study site should be informed within 10 working days. 
 Subject Injury 
In general, subject to specific provisions in the clinical study agreement (CSA), if a subject is 
injured as a direct result of a test article, the sponsor will pay for reasonable and necessary 
medical treatment for the injury, to the extent that such expenses are not covered by the 
subject’s medical insurance, a government program, or other responsible third party.  If laws 
or regulations of the locality in which the study is taking place require additional payment of 
expenses, the sponsor shall comply with such laws or regulations.  Where applicable, the 
sponsor has taken specific national insurance. 
 Pre-Study Documentation 
The investigator must provide the sponsor with the following documents BEFORE enrolling 
any subjects: 
• Completed and signed form 1572 
• All applicable country-specific regulatory forms 
• Current signed and dated curricula vitae for the investigator, sub-investigators, and other 
individuals having significant investigator responsibility who are listed on the 
form 1572 or equivalent, or the clinical study information form 
• Copy of the IRB/IEC/REB approval letter for the protocol and informed consent.  All 
advertising, recruitment, and other written information provided to the subject must be 
approved by the IRB/IEC/REB.  Written assurance of continuing approval (at least 
annually) as well as a copy of the annual progress report submitted to the IRB/IEC/REB 
must also be provided to the sponsor.   
• Copy of the IRB/IEC/REB-approved informed consent document to be used 
• Where applicable, a list of the IRB/IEC/REB members and their qualifications, and a 
description of the committee’s working procedure 
• Copy of the protocol sign-off page signed by the investigator 
• Fully executed CSA 
• Where applicable, a financial disclosure form 
• A written document containing the name, location, certification number, and date of 
certification of the laboratories to be used for laboratory assays and those of other 
facilities conducting tests.  This document should be returned along with the statement of 
investigator form.  The sponsor must be notified if the laboratory is changed or if any 
additional laboratory is to be used.  
• List of normal laboratory values and units of measure for all laboratory tests required by 
the protocol.  This is required for each laboratory to be used during the study.  The 
sponsor must be notified if normal values or units of measurement change. 


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 Retention of Data 
The investigator shall retain and preserve 1 copy of all data generated in the course of the 
study, specifically including but not limited to those defined by GCP as essential, for the 
longer of: (a) 2 years after the last marketing authorization for the investigational test article 
has been approved or the sponsor has discontinued its research with respect to such 
investigational test article or (b) such longer period as required by applicable global 
regulatory requirements.  At the end of such period, the investigator shall notify the sponsor 
in writing of its intent to destroy all such material.  The sponsor shall have 30 days to 
respond to the investigator’s notice, and the sponsor shall have a further opportunity to retain 
such materials at the sponsor’s expense. 
 Publication and Disclosure Policy 
The sponsor assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov.  In addition, upon study completion and 
finalization of the study report, the results of this study will be either submitted for 
publication and/or posted in a publicly accessible database of clinical study results. 
Upon completion of the study, the investigator may publish the results in recognized 
(refereed) scientific journals subject to the provisions of the CSA.  Unless otherwise 
specified in the CSA, the following process shall occur: 
The institution and Principal Investigator (PI) shall not publish or present data from an 
individual study center until the complete multi-center study has been presented in full or for 
2 years after the termination of the multi-center study, whichever occurs first.  Subsequent 
publications must refer to the multi-center findings.  Thereafter, if the PI expects to 
participate in the publication of data generated from this site, the institution and PI shall 
submit reports, abstracts, manuscripts, and/or other presentation materials to the sponsor for 
review before submission for publication or presentation.  The sponsor shall have 60 days to 
respond with any requested revisions, including, without limitation, the deletion of 
confidential information.  The PI shall act in good faith upon requested revisions, except that 
the PI shall delete any confidential information from such proposed publication.  The PI shall 
delay submission of such publication or presentation materials for up to an additional 90 days 
in order to have a patent application(s) filed. 


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14 REFERENCE LIST
                                                 
1 Hooton TM, Besser R, Foxman B, Fritsche TR, Nicolle LE.  Acute uncomplicated cystitis 
in an era of increasing antibiotic resistance: a proposed approach to empirical therapy. Clin 
Infect Dis.  2004 Jul 1;39(1):75-80.  Epub 2004 Jun 14. 
2 Foxman B, Barlow R, D'Arcy H, Gillespie B, Sobel JD.  Urinary tract infection: self-
reported incidence and associated costs.  Ann Epidemiol.  2000 Nov;10(8):509-15. 
3 Foxman B.  Epidemiology of urinary tract infections: incidence, morbidity, and economic 
costs.  Am J Med.  2002 Jul 8;113 Suppl 1A:5S-13S 
4 Simmering JE, Tang F, Cavanaugh JE, Polgreen LA, Polgreen PM.  The Increase in 
Hospitalizations for Urinary Tract Infections and the Associated Costs in the United 
States,1998-2011.  Open Forum Infect Dis.  2017 Feb 24;4(1): ofw281. doi: 
10.1093/ofid/ofw281. eCollection 2017 Winter. 
5 Ikäheimo R, Siitonen A, Heiskanen T, Kärkkäinen U, Kuosmanen P, Lipponen P, et al.  
Recurrence of urinary tract infection in a primary care setting: analysis of a 1-year follow-
up of 179 women.  Clin Infect Dis.  1996 Jan;22(1):91-9. 
6 Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG, et al.  International 
clinical practice guidelines for the treatment of acute uncomplicated cystitis and 
pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America 
and the European Society for Microbiology and Infectious Diseases.  Clin Infect Dis.  2011 
Mar 1;52(5): e103- 20. doi: 10.1093/cid/ciq257. 
7 Christiaens TC, De Meyere M, Verschraegen G, Peersman W, Heytens S, De Maeseneer 
JM.  Randomised controlled trial of nitrofurantoin versus placebo in the treatment of 
uncomplicated urinary tract infection in adult women.  Br J Gen Pract.  
2002 Sep;52(482):729-34. 
8 Sanchez GV, Master RN, Karlowsky JA, Bordon JM.  In vitro antimicrobial resistance of 
urinary Escherichia coli isolates among U.S. outpatients from 2000 to 2010.  Antimicrob 
Agents Chemother.  2012;56:2181-3. 
9 Doi Y, Park YS, Rivera JI, Adams-Haduch JM, et al.  Community-Associated Extended-
Spectrum Beta-Lactamase-Producing Escherichia coli Infection in the United States. Clin 
Infect Dis.  2012;56(5):641-8. 
10 Paratek Pharmaceuticals, Inc.  Omadacycline/PTK 0796 Investigator's Brochure, Edition 
10.0.  2016. 
11 Macrobid, US Package Insert. 


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PTK0796-UUTI-17201-Version 3.0 FINAL; 18-FEB-2019 
IND # 75,928 IND # 73,431 
Confidential and Proprietary 
Page 66 of 70 
Appendix 1 
Schedule of Events  
Study Phase 
Screeninga 
Treatment Phase 
Follow-up Phase 
Evaluation 
 
Day 1b 
Day 3 
Day 5 
EOTc 
PTEr 
Final Follow-ups 
Signed Informed Consentd 
X 
 
 
 
 
 
 
Subject assessment of UTI symptomse 
X 
      X-------------------------------------------X 
X 
X 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Prior & Concomitant Medicationsf 
X 
      X-----------------------------------------------------------------------------------X 
Clean-catch, midstream urine sample: 
 
       Urine dipstick for nitrites and leukocyte esterase (or 
microscopic evaluation for white blood cells)g 
X 
 
X 
X 
X 
X 
Xt 
 
Urine cultureh  
X 
 
X 
X 
X 
X 
Xt 
Physical examinationi 
X 
 
 
 
X 
X 
 
Vital signs: 
 
       Body weight (in kg) 
X 
 
 
 
X 
 
 
 
Body temperature 
X 
X 
X 
X 
X 
X 
Xt 
 
Blood pressure 
X 
Xj 
X 
X 
X 
X 
Xt 
       Heart rate 
X 
Xj 
X 
X 
X 
X 
Xt 
Hematologyk 
X 
 
 
 
X 
Xu 
 
Serum chemistry 
X 
 
 
 
X 
Xu 
 
Local urine or serum pregnancy testl 
X 
 
 
 
 
X 
 
Central serum pregnancy testm 
X 
 
 
 
X 
 
 
Adverse Eventsn 
X 
      X-----------------------------------------------------------------------------------X 
Review of Inclusion and Exclusion Criteria  
X 
X 
 
 
 
 
 
Randomization (if eligible) 
 
X 
 
 
 
 
 
Test Article  
 
        Test Article Dispensation 
 
X 
 
 
 
 
 
        Test Article Administration – 2 hours after light 
         mealo,p 
 
X 
 
 
 
 
 
        Test Article Administrationo 
 
 
X----------------------------X 
 
 
        Test Article Accountabilityo 
 
 
X 
X 
X 
 
 
PK blood collectionq 
 
X 
 
X  
 
 
 
PK urine collection  
 
 
X 
X 
 
 
 
Investigator’s Assessment of Clinical Response 
 
 
 
 
X 
X 
X 


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Confidential and Proprietary 
Page 67 of 70 
Study Phase 
Screeninga 
Treatment Phase 
Follow-up Phase 
Evaluation 
 
Day 1b 
Day 3 
Day 5 
EOTc 
PTEr 
Final Follow-ups 
AE = adverse event; β-hCG = β-human chorionic gonadotropin; BP = blood pressure; CFU = colony forming unit; eCRF = electronic case report form; 
EOT = end of treatment; ICF = informed consent form; PK = pharmacokinetics; PTE = post therapy evaluation; SAE = serious adverse event; UTI = 
urinary tract infection; UTISA= urinary tract infection system assessment; WBC = white blood cell. 
a 
Following the signing of an ICF, all Screening evaluations should be completed within the 24 hours prior to randomization.  
b 
Study Day 1 is the first day of test article administration. 
c 
To be conducted on the day of or within the 2 days following the last dose of test article.  This evaluation should also be conducted for any prematurely 
withdrawn subject on the day treatment ends. 
d 
Written and signed ICF must be obtained before any study-related assessment is performed. 
e 
Subject assessment of UTI signs and symptoms severity will be collected daily through EOT (including self-completion by subject at home on Days 2, 4 and 
6), at PTE and at Final Follow-up via the UTISA questionnaire. 
f 
Treatments that have been administered within the 7 days prior to the date of signing the ICF or during the Screening phase will be recorded in the eCRF.  All 
medications and significant non-drug therapies administered after the first dose of test article must be recorded in the eCRF. 
g 
A clean-catch, midstream urine sample should be collected and immediately sent to the local microbiology laboratory for microscopic evaluation and culture.  
Quantitative urine culture by appropriate methods should be performed using a calibrated loop that would identify bacteria at a lower limit of 103 CFU/mL.  
White blood cell counts should be measured by microscopy from spun or unspun urine or dipstick analysis for leukocyte esterase and nitrites. The 
statement “or microscopic evaluation for white blood cells” refers to the alternative method to assess for the presence of pyuria (inclusion #4), but the 
dipstick assessment is required regardless of how inclusion is assessed.  
h 
Urine isolates that grow ≥ 103 CFU/mL (whether at Baseline or post-Baseline) and are not deemed to be a contaminant as detailed in the Micro Manual, 
are to be sent from the local lab to the Central Lab for further analysis. 
i 
A full physical examination will be completed at Screening, thereafter only changes from Screening assessments should be recorded as AEs in the eCRFs. 
j 
BP and heart rate should be measured within 30 min before, and approximately 1 hour (± 15 minutes) after and 3 hours (± 15 minutes) after the 
completion of the first dose on Day 1.   
k 
Hematology includes coagulation. 
l 
All subjects will have a local urine or serum pregnancy test at Screening which results will be used to confirm eligibility. 
m 
All subjects will have blood collected for a serum β-hCG pregnancy test at the Central Laboratory at the Screening and EOT visits.   
n 
A subject’s AEs and SAEs will be recorded and reported from signing of the ICF to the Final Follow-up assessment. 
o 
Subjects should receive their first dose of test article within 4 hours after randomization in the office with a light meal. All other doses can be administered 
by subject at home. Beginning with Dose 3, all consecutive odd numbered doses of the omadacycline tablets and placebo tablets resembling omadacycline 
should be taken in a fasted state. Beginning with Dose 4, all even numbered doses should be taken approximately 2 hours after a light meal.  The total 
duration of po test article therapy for all subjects will be 7 days.  At the EOT visit, subjects will return any remaining unused po test article and site staff will 
perform accountability. 
p 
Dose 2 can be taken a minimum of 8 hours and up to 12 hours after Dose 1.  Dose 3 should be taken a minimum of 8 hours after Dose 2. 
q 
PK blood collection to occur on Day 1 (2 hours after first dose of test article) and Day 5.  
r 
A PTE will occur on Day 14 (+/- 2 days) after the subject’s first dose of test article.  
s 
A Final Follow-up will occur 30 to 37 days following the first dose of test article.  The Final Follow-up may be performed via phone call or another 
interactive technology.  
t 
During the Follow-up call/visit if the subject reports symptoms of potential recurrence, additional procedures will be performed. 
u 
Hematology and serum chemistry will be repeated if any clinically significant abnormalities are noted at the EOT visit.  
 


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IND # 75,928 IND # 73,431 
 
Confidential and Proprietary 
Page 68 of 70 
Appendix 2 
Equations and Conversion Factors 
1. Cockcroft-Gault equation to calculate creatinine clearance (CrCl) (relevant to Exclusion 
criterion number 11): 
(140-age [yrs]) * weight (kg) * (Z) 
Z = 0.85, if Female 
Cr (mg/dL) * 72 
 
2. Corticosteroid conversions (relevant to Exclusion criterion number 15): 
The following have equivalent glucocorticoid activitya 
Hydrocortisone 
160 mg 
Prednisone 
40 mg 
Prednisolone 
40 mg 
Methylprednisolone 
32 mg 
Triamcinolone 
32 mg 
Dexamethasone 
6 mg 
 a 
Axelrod L.  Glucocorticoid therapy.  In: Jameson JL & De Groot LJ, eds. Endocrinology. 6th ed. 
Philadelphia, PA: Saunders; 2010:1840. 


Omadacycline  
 Paratek Pharmaceuticals, LLC 
PTK0796-UUTI-17201-Version 3.0 FINAL; 18-FEB-2019 
IND # 75,928 IND # 73,431 
 
Confidential and Proprietary 
Page 69 of 70 
Appendix 3 
Sponsor Signature 
Study Title: 
A Randomized, Double-Blinded, Adaptive Phase 2 Study to 
Evaluate the Safety and Efficacy of Oral Omadacycline and Oral 
Nitrofurantoin in the Treatment of Female Adults with Cystitis 
Study Number: 
PTK0796-UUTI-17201 
Protocol 
Amendment #2 
Final Date: 
18 February 2019 
 
 
 
This clinical study protocol was subject to critical review and has been approved by the 
sponsor.  The following personnel contributed to writing and/or approving this protocol: 
 
Signed: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date:  
 
 
 
 
 
 
Paratek Pharma, LLC 
 


Omadacycline  
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PTK0796-UUTI-17201-Version 3.0 FINAL; 18-FEB-2019 
IND # 75,928 IND # 73,431 
 
Confidential and Proprietary 
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Appendix 4 
Investigator’s Signature 
Study Title: 
A Randomized, Double-Blinded, Adaptive Phase 2 Study to 
Evaluate the Safety and Efficacy of Oral Omadacycline and Oral 
Nitrofurantoin in the Treatment of Female Adults with Cystitis 
Study Number: 
PTK0796-UUTI-17201 
Protocol 
Amendment #2 Final 
Date: 
18 February 2019 
 
 
I have read the protocol described above.  I agree to comply with all applicable regulations 
and to conduct the study as described in the protocol.  
 
 
Signed: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date:  
 
 
 
 
 
 
Investigator Name:___________________________________ 
Investigator Title:____________________________________  
Investigator Affiliation:_______________________________ 
Investigator Address:_________________________________ 
Investigator Phone Number:____________________________ 
 


 
Omadacycline                                                                                                                   Paratek Pharmaceuticals, LLC 
PTK0796-UUTI-17201-Version 3.0 FINAL; 18-FEB-2019 
  IND # 75,928 IND # 73,431 
Confidential and Proprietary 
 
Page 1 of 1 
 
A Randomized, Double-Blinded, Adaptive Phase 2 Study to Evaluate the 
Safety and Efficacy of Oral Omadacycline and Oral Nitrofurantoin in the 
Treatment of Female Adults with Cystitis 
SUMMARY OF CHANGES 
Product Name: Omadacycline (PTK 0796) 
Study Number: PTK0796-UUTI-17201 
Date and Version: Version 3, 18 February 2019 
Change 
Rationale for Change 
Addition of 450mg BID omadacycline 
treatment arm, to be dosed 
approximately 2 hours after a light 
meal.  
Based on the pharmacokinetic, clinical, and safety 
data, the 450mg twice daily dose will increase 
urinary concentration, may provide additional 
clinical and microbiologic benefit while maintaining 
the safety profile observed with daily dosing. Refer 
to the protocol for additional/detailed rationale 
supporting this change.  
Increased sample size to approximately 
225 subjects (previously approximately 
200 subjects).  
The approximate total enrollment will increase to 
accommodate the addition of the 450mg BID 
treatment arm. The initial goal was to enroll at least 
n=53 subjects per arm for final analysis. Sample size 
may be increased for a particular omadacycline dose 
group, based on recommendations from DMC to 
change randomization ratio and/or drop a dose group 
to achieve improved power/probability of achieving 
the target probability that clinical success rates for a 
dose group is within 0.10 of that of the nitrofurantoin 
group.   
Addition of statement regarding 
omadacycline approved uses  
Omadacycline has recently been FDA-approved for 
CABP & ABSSSI (since original version of protocol 
was written) 
Increased the approximate duration of 
the study to 24 months 
Due to enrollment progressing slower than originally 
projected and the addition of 25 subjects to overall 
sample size 
Indicated that additional analyses on 
the primary efficacy endpoint will be 
performed using Bayesian modeling.  
An additional sensitivity analysis will be conducted 
on the efficacy endpoints to ensure improved 
interpretation and precision of estimates of efficacy 
analysis for dose selection. 
 


Omadacycline 
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PTK0796-UUTI-17201-Version 2.0 FINAL; 29-OCT-2018 
  IND # 75,928 IND # 73,431 
Confidential and Proprietary 
Page 1 of 1 
A Randomized, Double-Blinded, Adaptive Phase 2 Study to Evaluate the 
Safety and Efficacy of Oral Omadacycline and Oral Nitrofurantoin in the 
Treatment of Female Adults with Cystitis 
SUMMARY OF CHANGES 
Product Name: Omadacycline (PTK 0796) 
Study Number: PTK0796-UUTI-17201 
Date and Version: Version 2, 29 October 2018 
Protocol Section 
Change 
Synopsis 
Reference to ECG removed as this is not a required study 
procedure and was included in error 
Synopsis & Exclusion Criteria 
Exclusion criterion #4 removed (in alignment with current 
FDA UUTI guidance) & marked as not applicable  
Synopsis & Exclusion Criteria 
Inclusion criteria #3 timepoint for onset of symptoms 
related to randomization clarified & Exclusion criterion #3 
removed/marked as not applicable 
Synopsis & Exclusion Criteria 
Exclusion criteria #7 temperature parameters for fever 
slightly modified to align with current UUTI FDA 
Guidance 
Synopsis & Exclusion Criteria 
Exclusion criteria #10 updated to specify for a 'confirmed 
or suspected complicated UTI' 
Study Procedures & Schedule of 
Assessments  
Clarified timing of Day 1/Dose 1 PK collection 
Efficacy Assessments 
New section 8.7.1.3 added to collect Investigators 
Assessment of Clinical Response at Final Follow-up visit 
(per previously issued protocol clarification letter) 
Concomitant Medication 
Assessments 
updated title of eCRF page 
Adaptive Design, Interim 
Analysis, Statistical Methods 
probability % updated 
Other Reportable Information 
Removed references to paternal/male subject reporting as 
this is N/A for this study 
UTISA 
added reference to section 8.15.5 which discusses handling 
of worsening of disease under study and AE reporting 
Multiple 
Several section hyperlinks corrected 
Schedule of Assessments 
Typos corrected & footnotes G & U clarified 

SAP_001.pdf: 
Omadacycline (PTK 0796) 
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PTK0796-UUTI-17201 Statistical Analysis Plan 
Page 1 of 45 
Confidential 
STATISTICAL ANALYSIS PLAN 
Sponsor: 
Paratek Pharma, LLC 
Protocol No: 
PTK0796-UUTI-17201 
PRA Project Id: 
PTK162IC-P162IC 
Title: 
A Randomized, Double-Blinded, Adaptive Phase 2 Study to Evaluate the 
Safety and Efficacy of Oral Omadacycline and Oral Nitrofurantoin in the 
Treatment of Female Adults with Cystitis 
SAP Version 
No./Date: 
22 May 2019 
APPROVALS 
Representative/ Title: 
Signature /Date: 
Representative/ Title: 
Signature /Date: 
Representative/ Title: 
Signature /Date: 
Biostatistician / 
Title (Owner): 
Number: GEN-STP-0292               Version: 1.0               Status: Approved    Approved Date:
PTK0796-UUTI-17201 Statistical Analysis Plan
This copy of the document was retrieved from the system by 
 on 4/23/2020
NCT Number: NCT03425396
This NCT number has been applied to the document for
purposes of posting on clinicaltrials.gov


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Confidential 
 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................1 
APPROVALS ..................................................................................................................................1 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF TABLES ...........................................................................................................................4 
LIST OF FIGURES .........................................................................................................................4 
GLOSSARY OF ABBREVIATIONS .............................................................................................5 
1 
INTRODUCTION ....................................................................................................................7 
2 
STUDY OBJECTIVES, ENDPOINTS, AND MEASURES ...................................................7 
3 
STUDY DESIGN .....................................................................................................................8 
3.1 
Sample Size Considerations .................................................................................................8 
3.2 
Randomization and Blinding ...............................................................................................9 
3.3 
Data Monitoring Committee ................................................................................................9 
3.4 
Interim Analyses ................................................................................................................10 
3.5 
Final Analyses and Reporting ............................................................................................10 
4 
ANALYSIS POPULATIONS ................................................................................................10 
4.1 
Intent-to-Treat Population ..................................................................................................10 
4.2 
Safety Population ...............................................................................................................10 
4.3 
Microbiological Intent-to-Treat Population .......................................................................11 
4.4 
Clinically Evaluable Population ........................................................................................11 
4.5 
Microbiologically Evaluable Populations ..........................................................................13 
4.6 
Additional Populations.......................................................................................................13 
5 
OVERALL STATISTICAL CONSIDERATIONS ................................................................14 
5.1 
General ...............................................................................................................................14 
5.1.1 
Definitions....................................................................................................................14 
5.1.2 
Missing Data and Data Imputation Methods ...............................................................14 
5.1.3 
Visit Windows .............................................................................................................16 
5.1.4 
Multiple Comparison and Multiplicity ........................................................................17 
6 
POPULATION SUMMARIES ..............................................................................................17 
6.1 
Subject Disposition ............................................................................................................17 
6.2 
Demographic and Baseline Characteristics .......................................................................18 
6.3 
Baseline Microbiology .......................................................................................................18 
6.4 
Medical and UTI History ...................................................................................................19 
6.5 
Prior and Concomitant Medications ..................................................................................19 
6.6 
Protocol Deviations ............................................................................................................20 
6.7 
Other Baseline Summaries .................................................................................................20 
7 
EFFICACY ENDPOINTS AND ANALYSES ......................................................................21 
7.1 
Efficacy Endpoints .............................................................................................................21 
7.1.1 
Investigator’s assessment of clinical response .............................................................22 
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7.1.1.1 
EOT Visit Clinical Response Assessment .............................................................22 
7.1.1.2 
PTE Visit Clinical Response Assessment ..............................................................22 
7.1.1.3 
FFU Visit Clinical Response Assessment .............................................................23 
7.1.2 
Microbiologic response ................................................................................................24 
7.1.2.1 
Pathogen Determination.........................................................................................24 
7.1.2.2 
Microbiologic Response ........................................................................................24 
7.1.2.3 
Other microbiological endpoints............................................................................26 
7.1.3 
UTI Signs and Symptoms Assessment ........................................................................26 
.......................................27 
7.2 
Primary Efficacy Endpoint Analysis .................................................................................28 
7.3 
Secondary Efficacy Endpoint Analysis .............................................................................28 
7.3.1 
Investigator’s Assessment of Clinical Success ............................................................28 
7.3.2 
Per-Subject Microbiological Response ........................................................................29 
........29 
........29 
........29 
........29 
7.4 
Exploratory Analyses .........................................................................................................30 
7.4.1 
UTI signs and symptoms assessment ...........................................................................30 
7.5 
Efficacy Sensitivity Analysis .............................................................................................30 
.......................30 
.......................30 
.......................34 
.......................34 
8 
SAFETY ANALYSES ...........................................................................................................35 
8.1 
General ...............................................................................................................................35 
8.2 
Duration of Exposure to Test Article and Compliance ......................................................35 
8.3 
Concomitant Medications ..................................................................................................36 
8.4 
Adverse Events ..................................................................................................................36 
8.5 
Clinical Laboratory Results ...............................................................................................37 
8.6 
Vital Signs ..........................................................................................................................38 
8.7 
Pregnancies ........................................................................................................................39 
9 
CHANGES FROM PROTOCOL ...........................................................................................40 
10 REFERENCES .......................................................................................................................40 
APPENDIX 1 CLINICAL LABORATORY TESTS (CENTRAL) ..............................................41 
APPENDIX 2 DIRECTIONALITY OF WORST LABORATORY PARAMETERS .................42 
APPENDIX 3 MODIFIED DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES ADULT TOXICITY TABLE .............................................................................43 
APPENDIX 4 CONCOMITANT MEDICATION START DATE IMPUTATION .....................45 
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LIST OF TABLES 
Table 1 
Description of Treatment groups .............................................................................9 
Table 2 
General Definitions ................................................................................................14 
Table 3 
Adverse Event Start/Stop Date Imputation ............................................................15 
Table 4 
Scheduled Study Visits ..........................................................................................17 
Table 5 
Overall Investigator's Assessment of Clinical Response at PTE Visit ..................23 
Table 6 
Overall Investigator's Assessment of Clinical Response at FFU Visit ..................24 
Table 7 
Pathogen Microbiological Outcome Categories at EOT and PTE.........................25 
Table 8  
Per-Subject Microbiologic Response .....................................................................25 
Table 9 
Microbiologic Response at PTE ............................................................................26 
27 
Table 11 
Criteria for Clinically Notable Vital Signs ............................................................38 
Table 12 
Clinical Laboratory Tests (Central) .......................................................................41 
 
LIST OF FIGURES 
......32 
......33 
......33 
 
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Confidential 
 
GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
BID 
twice daily 
BMI 
Body Mass Index 
CE 
clinically evaluable 
CE-EOT 
clinically evaluable at the end of treatment 
CE-FFU 
clinically evaluable at the final follow-up 
CE-PTE 
clinically evaluable at the post-therapy evaluation 
CFU 
colony forming unit 
CN 
clinically notable 
CrCl 
Creatinine Clearance 
DMC 
Data Monitoring Committee 
DMID 
Division of Microbiology and Infectious Diseases 
eCRF 
electronic case report form 
EOT 
end of treatment 
FFU 
final follow-up 
ITT 
Intent-to-treat 
IxRS 
Interactive Response System 
ME 
microbiologically evaluable 
MedDRA 
Medical Dictionary for Regulatory Activities 
ME-EOT 
microbiologically evaluable at the end of treatment 
ME-PTE 
microbiologically evaluable at the post therapy evaluation 
Mg 
milligram 
MIC 
minimum inhibitory concentration 
micro-ITT 
microbiological intent to treat 
micro-m1ITT 
modified microbiological intent to treat 1 
micro-m2ITT 
modified microbiological intent to treat 2 
OMC 
omadacycline  
po 
orally 
PT 
preferred term 
PTE 
post therapy evaluation 
q12h 
every 12 hours 
q24h 
every 24 hours 
QTc 
QT, corrected 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SI 
International System of Units 
SOC 
system organ class  
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
UTI 
urinary tract infection 
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Abbreviation 
Definition 
UTISA 
UTI Symptoms Assessment 
WBC 
white blood cell 
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1 INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for Paratek 
Pharma Protocol PTK0796-UUTI-17201 (A Randomized, Double-Blinded, Adaptive Phase 2 
Study to Evaluate the Safety and Efficacy of Oral Omadacycline and Oral Nitrofurantoin in the 
Treatment of Female Adults with Cystitis). 
The reader of this SAP is encouraged to read the study protocol for details on the conduct of this 
study, the operational aspects of clinical assessments, and the timing for completing the 
participation of a patient in this study.  
The SAP is intended to be in agreement with the protocol, especially with regards to the primary 
and all secondary endpoints and their respective analyses. However, the SAP may contain more 
details regarding these particular points of interest, or other types of analyses (eg, other 
endpoints). When differences exist in descriptions or explanations provided in the study protocol 
and this SAP, the SAP prevails; the differences will be explained in the Clinical Study Report. 
Methods of reporting of pharmacokinetic data and details pertaining to interim analyses within 
the scope of Data Monitoring Committee (DMC) are outside of scope of this SAP. 
2 STUDY OBJECTIVES, ENDPOINTS, AND MEASURES 
The primary objective of this study is to evaluate the efficacy of omadacycline and nitrofurantoin 
in the treatment of female adults with cystitis. 
The primary efficacy endpoint is investigator’s assessment of clinical response at Post Therapy 
Evaluation (PTE) in the intent-to-treat (ITT) population, as measured by the number of subjects 
in each treatment group. The primary efficacy outcome is the percentage of subjects with an 
overall clinical success at the PTE Assessment in the ITT population. For further details refer to 
Section 7.1.1.2 (PTE Visit Clinical Response Assessment) and Section 7.2 (Primary Efficacy 
Endpoint Analysis). 
The secondary objectives of this study are: 
 To evaluate the safety of omadacycline in the treatment of female adults with cystitis.   
 To evaluate the clinical and microbiologic response according to the identified causative 
pathogen.  
 To evaluate the pharmacokinetics of omadacycline in female adults with cystitis. 
 
The secondary safety endpoints include adverse events (AEs), vital signs, clinically notable 
events, and laboratory assessments, as measured by number and percentage for discrete data, and 
changes from baseline for continuous data. Exposure to study medication, compliance, and 
protocol deviations will also be evaluated. All subjects from safety analyses set are included in 
these assessments. For further details refer to Section 8. 
Number: GEN-STP-0292               Version: 1.0               Status: Approved    Approved Date:
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3 STUDY DESIGN 
This is a randomized, double-blinded, adaptive designed Phase 2 study evaluating 3 dosing 
regimens of once-daily omadacycline and 1 dosing regimen of twice-daily omadacycline 
compared to nitrofurantoin twice daily in the treatment of female adults with cystitis.  The 
planned length of subject participation in the study is up to 37 days, which includes a total 
duration of study therapy for 7 days. Approximately 225 subjects will participate in this study at 
up to 25 sites within the United States. 
The study will consist of 3 protocol-defined phases: screening, double-blind treatment and 
follow-up.   
Following a Screening period of up to 24 hours, eligible subjects will be randomly assigned to 
receive one of 3 dosing regimens of once-daily omadacycline treatment, 1 dosing regimen of 
twice-daily omadacycline, or a twice-daily regimen of nitrofurantoin.  Treatment will be double-
blinded and double-dummy. 
Subjects will return to the clinic site for visits on Day 1, Day 3, Day 5, and for an End of 
Treatment (EOT)/Day 7 visit on the day of or within 2 days following the last dose.  Subjects 
will also return to the study site for a PTE on Day 14 (± 2 days) after the subject’s first dose of 
test article.  A Final Follow-up (FFU) assessment will be conducted within 30 to 37 days 
following the first dose of test article. 
A study schedule of events is provided in tabular form in the protocol (Appendix 1: Schedule of 
Events). 
This is an adaptive dose-response finding study. During the course of the study, a Bayesian 
analysis will be used to adaptively allocate new subjects to one of the treatment arms, conditional 
on the availability of primary efficacy endpoint data (investigator assessment of clinical response 
at PTE). When there is sufficient information available about the dose-response, results from the 
Bayesian analysis will be reviewed by DMC to determine if enrollment in any Omadacycline 
treatment arms should be stopped or modified. Modifications to Omadacycline dosing 
regimens/treatment arms may also be based on safety and tolerability. 
3.1 
Sample Size Considerations 
Enrollment of a total of approximately 225 subjects is planned. The Bayesian posterior 
probability that the clinical success rate at the PTE Visit is within 0.10 of that of the 
nitrofurantoin group will be estimated for each omadacycline dose group. The target probability 
is 0.80. If the true underlying clinical success rates for the nitrofurantoin and omadacycline dose 
groups are 0.82, then the sample size of N = 50 per treatment has approximately 79% 
power/probability to yield the target probability (N = 53 per treatment for 80% power).  
The sample size may be increased for a particular omadacycline dose group by changing the 
randomization ratio and/or dropping a dose group to achieve improved power/probability of 
achieving the target probability that clinical success rates for a dose group is within 0.10 of that 
of the nitrofurantoin group. If required to improve the precision of the interim or projected final 
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analyses estimates of response rates or posterior probabilities, sample size may be increased to a 
maximum sample size of 300 patients.  
The decisions affecting changes of randomization to treatment groups, hence affecting total 
sample size, will be based on the recommendation of the DMC at interim analyses in an 
unblinded manner. Statistical details relevant to pre-defined decision rules for the DMC are 
documented in the DMC SAP(1).   
3.2 
Randomization and Blinding 
Approximately 225 female subjects will be enrolled at up to 25 sites. Subjects will be 
randomized (1:1:1:1:1) to five treatment groups (see Table 1). 
 
Table 1 
Description of Treatment groups 
Group 
Test Article 
Study Day 
1 
Study Days 
2-7* 
1 
omadacycline 
300 mg po q12h, fed 
300 mg po q24h 
2 
omadacycline 
450 mg po q12h, fed 
300 mg po q24h 
3 
omadacycline 
450 mg po q12h, fed 
450 mg po q24h 
4 
omadacycline 
450 mg po q12h, fed 
450 mg po q12h 
5 
nitrofurantoin 
100 mg po q12h, fed 
100 mg po q12h 
q12h= every 12 hours, q24h= every 24 hours 
*Odd doses on Study Days 2-7 should be taken in a fasted state. Even doses on Study Days 2-7 will be administered 
approximately 2 hours following a light meal  
 
The site delegate will contact the Interactive Response System (IxRS) after confirming that the 
subject fulfills all the inclusion criteria and none of the exclusion criteria. The IxRS will assign a 
test article to the subject based on a computer-generated randomization schedule. The 
randomization will be a blocked randomization sequence and centrally balanced as defined in the 
IxRS specifications. Subjects randomized into the study will be assigned the treatment 
corresponding to the next available number from the computer-generated randomization 
schedule. The subject is considered randomized when the IxRS provides the test article 
assignment, regardless of whether the subject actually receives any medication. As this is an 
adaptive design trial, any updates to the randomization schedule based upon the Bayesian 
analysis will be incorporated into the IxRS system. 
3.3 
Data Monitoring Committee 
A DMC will provide ongoing monitoring of data in an unblinded manner. The charter for the 
DMC will outline membership, roles, and responsibilities. This will include a detailed 
description of the manner in which security and blinding of the data for the study blinded 
management team will be maintained, in addition to the procedures that ensure the independence 
and objectivity of the DMC’s activities. The purpose of DMC is to monitor safety, tolerability, 
and to provide efficacy decisions based on the Interim Analyses as described in Section 3.4, for 
further details please refer to DMC Charter. 
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3.4 
Interim Analyses 
This is an adaptive dose-response finding study. Bayesian efficacy analyses will be conducted 
when data is available from 40, 80 and 100 subjects for the DMC to: 
 Determine if omadacycline dose group(s) can be dropped from the trial, or 
 Modify the randomization ratios among the omadacycline dose groups to improve the 
precision of the selected dose group comparison of clinical success to that of the 
nitrofurantoin group. 
Detailed description of the analyses and decision rules related to efficacy are included in the 
DMC SAP.1  
Interim analyses will be performed by an independent unblinded statistician. Results will be 
reviewed by the DMC in closed session. Of note, modifications to omadacycline dosing 
regimens/treatment arms may also be based on safety and tolerability. The DMC’s decisions will 
be documented in meeting minutes. 
PRA Health Sciences and Sponsor’s study teams will remain blinded throughout the course of 
the study. 
3.5 
Final Analyses and Reporting 
All analyses identified in this SAP will be performed after the end of study as defined in the 
study protocol.  
This SAP and any corresponding amendments will be approved before database lock. 
The randomization codes will not be unblinded until this SAP has been approved and issued. 
4 ANALYSIS POPULATIONS 
4.1 
Intent-to-Treat Population 
The intent-to-treat (ITT) population will consist of all randomized subjects regardless of whether 
or not the subject received test article.  
A subject is considered randomized when the IxRS provides the test article assignment by 
providing the kit number (ie, completes a randomization transaction). Subjects in this population 
will be summarized according to randomized test article assignment. 
4.2 
Safety Population 
The Safety population will consist of all randomized subjects who receive any amount of test 
article. All safety analyses will be conducted in this population. Subjects in this population will 
be summarized according to actual test article received. 
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4.3 
Microbiological Intent-to-Treat Population 
The microbiological Intent-to-treat (micro-ITT) population will consist of subjects in the ITT 
population who have a study-qualifying pre-treatment Baseline urine culture with 1 or 
2 uropathogens at ≥ 105 colony forming unit (CFU)/mL.  
If more than two bacterial isolates are identified, the culture will be considered contaminated. 
Rules for Sponsor’s determination of qualifying pathogens are described in the Pathogen and CE 
Review Plan: PTK0796-uUTI-172012. 
4.4 
Clinically Evaluable Population 
The clinically evaluable (CE) population will consist of all ITT subjects who received test 
article, have a qualifying infection, an assessment of outcome, and meet all other evaluability 
criteria as described below. 
Inclusion into the CE populations will be determined programmatically based on the data on the 
electronic case report form (eCRF) and a manual review by the Sponsor as necessary prior to 
unblinding. Details on allocation to each CE population are described in the Pathogen and CE 
Review Plan: PTK0796-uUTI-172012. 
Since patient count may differ depending on timepoint, CE populations will be defined by 
milestone visit (CE-EOT, CE-PTE and CE-FFU). 
To be included in the CE populations, subjects must meet all criteria defined below:   
1. Qualifying infection:  
 Exclusion Criterion #2, 3, and 4; Note: for subjects randomized after amendment 
1 or later exclusions 3 and 4 are not applicable. 
2. Assessment of outcome for CE population: 
Subjects must meet all of the following to be included in any CE populations: 
 Subject did not meet any of the exclusion criteria 1 and 7 through 10 in the 
protocol (Baseline event exclusion). 
 Received the randomized test article and was at least 80% compliant with the 
dosing regimen (Compliance to test article intake). 
 Study personnel involved in the assessment of efficacy remained blinded to study 
treatment, unless a treatment limiting AE occurred that required emergency 
unblinding. 
In addition, for each endpoint the following needs to be satisfied, as appropriate: 
a. For the CE-EOT population: 
i. Completed the investigator’s assessment of clinical response (ie, was not 
deemed an indeterminate outcome) at the EOT visit  
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ii. The EOT visit occurred on the day of, or within +2 days following the last 
dose of test article (3-day window).    
b. For the CE-PTE population: 
i. The Overall Clinical Response (based on the investigator's assessment) at 
the PTE Visit is not Indeterminate (see Table 5) 
ii. The PTE Visit occurred on Day 14 (± 2 days) after the subject’s first dose 
of test article, unless the subject was considered to be a Clinical Failure 
based on the investigator’s assessment at the EOT visit.   
c. For the CE-FFU population: 
i. The Overall (Sustained) Clinical Response (based on the investigator's 
assessment) at the FFU Visit is not Indeterminate (see Table 6) 
ii. The FFU Visit/Call occurred 30 to 37 days from the first dose of test 
article, unless the subject was considered to be a Clinical Failure based on 
the investigator’s assessment at the PTE visit. 
3. Other Evaluability Criteria 
a. Prior Antibiotic Therapy: 
Exclusion Criterion #5: Receipt of any dose of a potentially therapeutic antibacterial 
agent (with potential activity against uropathogens in the urinary tract) from 72 hours 
prior to randomization until the first dose of test article [Note: subjects who 
developed current cystitis while receiving prophylactic antibacterial therapy may be 
eligible if all prophylactic antibacterials are stopped]. Subjects who meet exclusion 
criteria #5 will be excluded from the CE populations. 
b. Concomitant Antibiotic Therapy: 
Subjects who receive any systemic concomitant antibiotic therapy that is potentially 
effective against the baseline pathogen from the start of administration of the first 
dose of test article through the EOT visit (CE-EOT population), PTE visit (CE-PTE 
population) or FFU visit (CE-FFU population) will be excluded from the CE 
populations.  If no pathogen is isolated and the systemic concomitant antibiotic is 
effective against Gram-negative uropathogens, the subject will be excluded from the 
respective CE population. Subjects, who are a clinical failure on the particular visit 
and received non-study antibiotics for insufficient therapeutic effect of the test article, 
will not be excluded from the CE populations assuming they meet all other CE 
criteria. Subjects who receive a systemic concomitant antibiotic that is not potentially 
effective against the baseline pathogen will be included in the CE populations. 
c. Evaluable Success and Failure 
Evaluable success:  The subject received at least 4 doses of active test article 
(omadacycline groups 1, 2, and 3) at least 6 doses of active test article (nitrofurantoin 
and omadacycline group 4) and the investigator classifies the subject as a Clinical 
Success at the EOT Visit (CE EOT population) or the overall Clinical Response 
(based on the investigator's assessment) at the PTE Visit (CE-PTE population) is 
Clinical Success. 
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Evaluable failure:  The subject received at least 3 doses of active test article 
(omadacycline groups 1, 2, and 3) or at least 4 doses of active test article 
(nitrofurantoin and omadacycline group 4) and the investigator classifies the subject 
as a Clinical Failure at the EOT Visit (CE EOT population) or the overall Clinical 
Response (based on the investigator's assessment) at the PTE Visit (CE-PTE 
population) is Clinical Failure. 
 
4.5 
Microbiologically Evaluable Populations 
The microbiologically evaluable (ME) population will include subjects in the CE population who 
have a study-qualifying pre-treatment Baseline urine culture with 1 or 2 uropathogens at ≥ 105 
CFU/mL. 
Since patient count may differ depending on timepoint, ME populations will be defined by 
milestone visit (ME-EOT and ME-PTE).  
The ME populations consist of subjects in the micro-ITT population and the CE-EOT and CE-
PTE populations, respectively who also have:   
 A clean-catch urine specimen at the EOT and PTE visits, and  
 Interpretable urine culture results at the EOT and PTE visits. 
An interpretable post-baseline urine culture is one that has a clearly identified pathogen or one 
where the baseline pathogen(s) can be excluded (ie, there is no growth of the baseline pathogen), 
for further details refer to Pathogen and CE Review Plan: PTK0796-uUTI-172012. 
Subjects with an unfavorable microbiological outcome at EOT will be included as 
microbiological failures in the ME-PTE population, regardless of whether they provide a urine 
culture at the PTE visit.   
At any visit after Screening, a pathogen the same species as the Baseline pathogen with a CFU 
count of ≥ 1 × 104 CFU/mL should be considered a persisting pathogen.  
At any visit after Screening, any culture with a CFU count of < 104 CFU/mL should be 
considered a negative culture. 
4.6 
Additional Populations 
For the purpose of sensitivity analyses described in Section 7.5.1, the following modified micro-
ITT populations are defined. 
The modified microbiological ITT 1 (micro-m1ITT) population will consist of subjects in the 
ITT population who have a study-qualifying pre-treatment Baseline urine culture with 1 or 2 
uropathogens at ≥ 104 CFU/mL. 
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The modified microbiological ITT 2 (micro-m2ITT) population will consist of subjects in the 
ITT population who have a study-qualifying pre-treatment Baseline urine culture with 1 or 2 
uropathogens ≥ 103 CFU/mL. 
5 
OVERALL STATISTICAL CONSIDERATIONS  
5.1 
General 
All analyses will use SAS version 9.4 or higher. Results will be reported by treatment group. 
Unless otherwise noted, categorical variables will be summarized using counts and percentages. 
Percentages will be rounded to one decimal place except for 100%, which will be displayed 
without any decimal places. In addition, percentages will not be displayed for zero counts.  
Continuous variables will be summarized using the number of observations (n), mean, standard 
deviation (SD), median, minimum and maximum.  
5.1.1 Definitions 
In Table 2 the general definitions provided are used in the statistical analysis. 
Table 2 
General Definitions 
Variable 
Definition 
Baseline 
 
Unless otherwise stated, baseline is defined as the value closest to but prior to the 
initiation of test article administration.   
Change from baseline 
Change from baseline will be defined as the post-baseline value minus the baseline 
value (on a subject level). Change from baseline will only be calculated for subjects 
who have both baseline and at least one post-baseline value for any parameter.  
Duration Variables 
Duration variables will be calculated using the general formula: 
   Duration (days) = End date - Start date + 1 
If applicable, where time is collected: 
   Duration (hh:mm) = End datetime - Start datetime 
Calculated Creatinine 
Clearance (mL / min), 
Cockcroft-Gault equation 
(140 – age [yrs]) * weight [kg] * Z 
Creatinine [mg/dL] * 72 
   Z = 0.85 for Female subjects 
Body Mass Index (BMI) 
BMI = Weight (kg) / Height (m)2 
 
 
5.1.2 Missing Data and Data Imputation Methods 
Missing data will be handled as outlined below  
1. Adverse Events and Safety Data: 
 All missing and partial dates for AEs will be queried for a value. If no value can be 
obtained, substitutions will be made as detailed in Section 8.4 (Adverse Events). These 
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substitutions will be used in calculations; however, the actual value recorded on the eCRF 
will be used in all listings. 
 If the time of the first dose of test article is missing, it will be imputed with time of 
randomization + 1 minute. If time is missing for other doses it will be imputed with time 
of previous dose + 12 h. 
 An AE is considered treatment emergent if the AE start date and time is on or after the 
start date and time of the first dose of test article.   
If time of the AE is missing and it occurred on the same date as the first dose of test article, the 
AE will be defined as treatment emergent. If the start date of the AE is partial or missing and it 
cannot be determined if the AE occurred prior to or after the first dose of test article, the AE 
should be defined as treatment emergent. Table 3 provides imputation for partial or missing date 
information. For AE listings, all dates and times will be displayed as reported on the Case Report 
Forms. 
Table 3 
Adverse Event Start/Stop Date Imputation 
Parameter 
Missing 
Additional Conditions 
Imputation 
Start date 
for AEs 
 
D 
M and Y same as M and Y of first dose of test article 
Date of first dose of test article 
M and/or Y not same as date of first dose of test article 
First day of month 
D and M 
Y same as Y of first dose of test article 
Date of first dose of test article 
Y prior to Y of first dose of test article but same as Y 
of screening date 
Date of screening date 
D, M, Y 
None - date completely missing 
Date of first dose of test article 
Stop date 
for AEs 
 
D 
M and Y same as M and Y of last dose of test article 
Date of last dose of test article 
M and/or Y not same as date of last dose of test article 
Use last day of month 
D and M 
Y same as Y of last dose of test article 
Date of last dose of test article 
Y not same as Y of last dose of test article 
Use Dec 31 
D, M, Y 
None - date completely missing 
No imputation, but assume 
ongoing 
D=day, M=month, Y=year 
Note:  In all cases, if an estimated start date is after a complete stop date, use the first day of the stop date month. 
Similarly, if the estimated stop date is before a complete or imputed start date, use the last day of the start day 
month. 
In all cases, if it cannot be determined if the adverse event occurred prior to or after the first dose of test article, the 
adverse event should be defined as treatment emergent. 
 
 If no value can be obtained for all other times for events and assessments occurring after 
randomization, the time will not be imputed but will remain missing.   
 The severity and causality assessment for AEs cannot be missing.  Missing data will be 
queried for a value. The highest severity and most related causality should be used if 
query is missing. If query will return missing, then the highest severity and most related 
causality will be used for the purpose of summaries.   
 If the reported value of a clinical laboratory parameter cannot be used in a statistical 
summary table (eg, a character string is reported for a parameter of the numerical type), a 
coded value must be appropriately determined and used in the statistical analyses. A 
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value or lower limit of normal range (eg will be calculated as 99.99% of the value if it is 
reported as “<” (eg <5 will be converted to 5*0.99=4.9995). The upper normal range of a 
value will be converted to 100.01% if it is reported as “>” (eg >7 will be converted to 
7*1.001=7.007). However, the actual values as reported in the database will be presented 
in data listings.  
 Prior and Concomitant Medication Start Date Imputation will be imputed according to 
table in Appendix 4 Concomitant Medication Start Date Imputation. 
2. Efficacy Data 
 Analysis of efficacy data will be based on the available data, unless otherwise stated. 
 Missing data for clinical and microbiological outcomes will be denoted “indeterminate” 
unless otherwise stated. 
 Missing microbiological outcomes at EOT will be imputed by last day of test article 
intake.  
 The Overall Clinical Response at PTE and FFU visits are derived based on the “worst 
case scenario” to accommodate for missing visit assessments and intercurrent events (eg 
rescue medication at EOT visit). Similar imputations were applied to microbiological 
response endpoints. Details are described in Section 7.   
 UTISA data for bothersome score will be imputed with score of 0 for each question for 
which severity is answered “Did not have”. 
 Missing UTISA responses at baseline will be imputed with Day 1 responses. 
 
5.1.3 Visit Windows 
For efficacy outcomes, the data collected at the EOT, PTE and FFU visits, regardless of when 
these occur will be utilized in the analysis of the ITT and micro-ITT populations. The CE and 
ME populations exclusions due to windowing are outlined in Sections 4.4 and 4.5. 
For each safety outcome and UTISA data, analyses will utilize assessments occurring during the 
scheduled visit windows (provided in Table 4). Thus, if a subject has a visit outside the 
scheduled visit window, for example, a PTE Visit occurred 20 days after the subject's last day of 
therapy, the assessment will not be summarized with the PTE Visit but will be considered an 
unscheduled assessment. If a subject does not have an assessment at a scheduled visit and an 
unscheduled assessment was taken within the window for the time point (for example, 14 days [± 
2 days] after the subject's first day of therapy for PTE), these assessments will be summarized in 
the by time point analyses. If more than one measurement is taken during the visit window, the 
value taken on the scheduled visit will be utilized or if no scheduled visit was done, the first 
(earliest) measurement in the visit window will be used. If more than one measurement is taken 
on the same day, the assessment closest to the start of the dose will be used for on-treatment 
values and the last measurement on the day will be used for post-treatment values. For worst 
overall post-baseline analyses, all assessments including those obtained from unscheduled visits 
will be included. 
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Table 4 
Scheduled Study Visits 
Study Visit 
Study Day 
Notes 
Baseline 
Day -1 or Day 1 
Except where indicated, last measurement prior to the first dose 
of test article.  Screening assessments are to be taken within 
24 hours prior to randomization if no test article is taken, the 
date and time of randomization is used in place of 
randomization date. 
On Treatment (note:  
analysis visit will be 
each Study Day) 
Day 1- 6 
As entered in the eCRF* for these visits 
EOT 
Day 7 
Within 2 days following the last dose of test article 
PTE 
Day 14 
14 ± 2 days after the subject's first dose of test article 
Final Follow-up (FU) 
Day 30 to 37 
30 to 37 days after the start of the first dose of test article 
Study Day is calculated relative to the first dose of test article (Day 1); there is no Day 0 – the day prior to the first 
dose of test article is Day -1.  If no test article is taken, study day is calculated relative to the date of 
randomization. *Days 2, 4, 6 are completed at home. 
 
5.1.4 Multiple Comparison and Multiplicity  
No adjustment for multiplicity will be applied to any endpoints, thus any inferential statistics will 
be nominal.  
6 POPULATION SUMMARIES 
Unless otherwise stated, listings corresponding to all summaries in this section will be provided 
for all randomized subjects (ITT population). 
6.1 
Subject Disposition 
The number of subjects included in each of the analysis populations defined in this SAP and the 
reasons for exclusion will be summarized by treatment group. A listing will be provided to 
indicate each subject’s inclusion/exclusion from the populations, and the reason for exclusion 
from a population will be presented. 
A list of randomized subjects who did not meet all inclusion/exclusion criteria, and which 
criteria were not met will be presented.   
The number and percentage of subjects completing the study (defined as completing the EOT, 
PTE and FFU visits, as reported on CRF), as well as the completion status of EOT, PTE, and 
FFU visits will be presented. Reasons for not completing the study and for missing visits, as 
recorded on the eCRF, will be summarized (number and percentage) by treatment group for ITT, 
CE and PTE populations.   
The number and percentage of subjects completing and prematurely discontinuing test article and 
the reasons for discontinuation will be presented by treatment group.  A listing of all subjects 
who prematurely discontinued from test article or who did not complete the study will be 
presented, along with the primary reason for discontinuation of test article or not completing the 
study for ITT, micro-ITT, CE-PTE, and ME-PTE.  
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The number of screen failures and reason for screen failure will be presented overall. For 
randomized subjects, a listing will be provided that indicates the date and time of randomization, 
randomization number, randomized treatment assignment, drug unit identifications, and 
corresponding drug codes. 
6.2 
Demographic and Baseline Characteristics 
Demographic characteristics will be summarized for ITT, micro-ITT, CE-PTE, and ME-PTE 
populations. The summary table will include age, race, and ethnicity, along with baseline 
characteristics for height, weight, body mass index (BMI), number of prior urinary tract 
infections (UTIs) (lifetime), and renal function. Age will be summarized as a continuous variable 
and as categorical, based on the following groups: 18 to 45 years, >45 to 65 years, >65 years.  
Renal function will be categorized as normal (creatinine clearance [CrCl] > 89 mL/min), mild 
renal impairment (CrCl > 60 to 89 mL/min), moderate renal impairment (CrCl 30 to 60 mL/min) 
and severe renal impairment (CrCl < 30 mL/min). Creatinine clearance will be calculated from 
the local laboratory data and will be determined from the Cockcroft-Gault equation, for female 
subjects:  
 
 
Gender will not be included in the summary, as all subjects enrolled in this study will be female, 
per inclusion criteria.  
General medical history and will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) and summarized by system organ class (SOC) and preferred term (PT). 
Results of the UTI Symptoms Assessment (UTISA) questionnaire will be as the number and 
percentage of subjects responding to each item, including individual severity scores, individual 
bothersome scores, and overall severity (ITT, micro-ITT, CE populations). 
6.3 
Baseline Microbiology 
The microbiological assessment of the urine culture by the local laboratory will be summarized 
by treatment group for the ITT, micro-ITT, micro-m1ITT, and micro-m2ITT populations and 
will include as follows:   
 The number of subjects with local urine culture performed 
 The number of subjects with a clean catch sample 
 The number of subjects with urine culture growth  
 The number of isolates per subject where CFU count ≥105 CFU/mL.  
 Each isolate identified will also be reported and will include the CFU counts as recorded 
on the CRF (< 103 CFU/mL, 103 ≤ and < 104 CFU/mL, 104 ≤ and < 105 CFU/mL, and 
≥ 105 CFU/mL).   
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Test article received disk diffusion (mm) to baseline pathogen will be provided for micro-ITT 
population. 
All of the below reports will be provided for micro-ITT and ME populations. 
 The number and percentage of subjects with a positive urine culture by pathogenic organism 
will be provided.   
 The number and percentage of subjects with a Gram-positive organism (aerobes and 
anaerobes) and with a Gram-negative organism (aerobes and anaerobes) will be presented by 
genus and species.  
The number and percentage for minimum inhibitory concentration (MIC) data will be provided 
as:  
 The MIC distribution to omadacycline and nitrofurantoin, across treatment groups 
 The MIC distribution to the test article received, by treatment group  
MIC summary statistics (ie, range, MIC50, and MIC90) to the test article received.  The MIC 
range will be provided for all baseline pathogens.  The MIC50 and MIC90 will be provided only 
for those pathogens isolated at least 10 times in a treatment group. MIC50 and MIC90 values are 
defined as the lowest concentration of the antibiotic at which 50% and 90% of the isolates were 
inhibited. 
MIC summary statistics (ie, range, MIC50, and MIC90) to the test article received for each 
pathogen at baseline. 
A listing will be provided that includes for each subject all baseline and post-baseline isolates 
identified by Genus and species from the local and central urine culture including the CFU count 
and whether or not the isolate is a pathogen.   
6.4 
Medical and UTI History 
Significant medical history (at any time) and any medical history within the past 6 months 
including ongoing medical conditions at the time of signing of the ICF will be recorded.  
In addition, subject history of prior UTI infection will be captured. Where possible, diagnoses 
are to be recorded. Of note, any event or change in the subject’s condition or health status 
occurring after signing the ICF will be reported as an AE. All medical history will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). 
The incidence of medical history abnormalities will be summarized using descriptive statistics by 
system organ class (SOC) and preferred term. Patients are counted only once in each preferred 
term and SOC category. Summaries will be presented by treatment group and for all patients. 
6.5 
Prior and Concomitant Medications 
Treatments that have been administered within the 7 days prior to the date of informed consent, 
or during the Screening phase, will be recorded in the eCRF. The investigator is to instruct the 
subject to notify the study site about any new medications he/she takes after the start of the test 
article. All medications and significant non-drug therapies (including physical therapy and blood 
transfusions) administered after the subject starts treatment with test article must be listed in the 
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eCRF. In addition, for antibacterial agents and anti-emetics administered, the dose, unit, 
frequency and route must be entered in the eCRF. 
If a medication is taken prior to the first dose of test article or if their start date is unknown, it 
will be summarized as a prior medication. Medications are considered concomitant if taken on or 
after the first dose of test article, or if their stop date is unknown or marked as continuing. Thus, 
in cases where a medication starts prior to the first dose, and continues throughout the treatment 
period, the medication will be summarized as both prior and concomitant.  
Summary of prior antiemetic and antibiotic medications will also be provided for ITT and micro-
ITT populations.  
6.6 
Protocol Deviations 
Deviations will be reviewed in a blinded manner by the sponsor and categorized into general 
categories (eg. inclusion/exclusion criteria).  The sponsor will also categorize the protocol 
deviations as major and minor.  Review of deviations will be conducted and finalized prior to 
unblinding the database. A major deviation is defined as one that potentially affects the efficacy 
and/or safety analyses. 
The number and percentage of subjects with at least one major protocol deviation or at least one 
minor protocol deviation will be summarized for the ITT, micro-ITT, and CE-PTE populations. 
The summaries of major deviations will also be presented by category.  
6.7 
Other Baseline Summaries 
Abnormal laboratory results and abnormal vital signs at baseline will be reported. For further 
details refer to Section 8.5. 
At Screening a full physical examination will include the examination of general appearance, 
skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph 
nodes, extremities, and vascular and neurological systems. Only changes from Screening 
assessments will be recorded as AEs in the eCRFs. If indicated based on medical history and/or 
symptoms, rectal, external genitalia, breast, and/or pelvic exams may be performed. Subject 
listings of all physical examination results by body system will be provided. Any changes from 
baseline will be recorded as AEs. 
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7 EFFICACY ENDPOINTS AND ANALYSES 
7.1 
Efficacy Endpoints 
The efficacy endpoints are as follows: 
 
Endpoint 
Visit 
Population 
Primary 
Overall Investigator’s assessment of clinical response 
PTE 
ITT 
Secondary 
Investigator’s assessment of clinical response 
EOT 
ITT 
CE-EOT 
micro-ITT 
 
Overall Investigator’s assessment of clinical response 
PTE 
CE-PTE 
micro-ITT 
 
Overall (Sustained) Investigator’s assessment of clinical 
response 
FFU 
ITT 
CE-FFU 
micro-ITT 
 
Microbiologic response  
 
EOT 
micro-ITT 
ME-EOT 
 
Overall Microbiologic response 
PTE 
micro-ITT 
ME-PTE 
Explorato
ry 
UTISA 
by timepoint 
ITT, micro-ITT, CE-
EOT, CE-PTE, CE-FFU 
Sensitivity 
 
 
 
 
 
 
Note: Microbiological response is summarized both by patient and by pathogen  
 
 
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7.1.1 
Investigator’s assessment of clinical response 
The primary efficacy endpoint is the investigator’s assessment of clinical success at the PTE visit 
in the ITT population. Detailed definition is included in Section 7.1.1.2. 
Additional efficacy endpoints are described below. 
7.1.1.1 
EOT Visit Clinical Response Assessment 
At the EOT visit (on the day of or within 2 days following the last dose of test article) the 
investigator will determine whether the subject meets the criteria of 1 of the following clinical 
outcomes: 
 Clinical Success:  Sufficient resolution of signs and symptoms at the EOT visit such that 
no additional systemic antimicrobial therapy is required for the current infection. 
 Clinical Failure:  No apparent response to therapy or persistence of signs and symptoms 
of infection at the EOT visit such that use of additional systemic antimicrobial therapy for 
the current infection is required. 
 Indeterminate: EOT visit not completed, due to the subject being lost to follow-up or 
the subject withdrawing consent, or other specified reason.  
7.1.1.2 
PTE Visit Clinical Response Assessment 
At the PTE visit (Day 14 (± 2) days after the subject's first dose of test article), the investigator 
will determine whether or not the subject meets the criteria of 1 of the following clinical 
outcomes: 
 Clinical Success:  Sufficient resolution of signs and symptoms at the PTE such that no 
additional systemic antimicrobial therapy is required for the current infection. 
 Clinical Failure:  No apparent response to therapy or persistence of signs and symptoms 
of infection or reappearance of signs and symptoms at or before the PTE visit such that 
use of additional systemic antimicrobial therapy for the current infection is required. 
 Indeterminate: PTE visit not completed.  
For the purpose of analysis, Overall Clinical Response at PTE is determined as follows (Table 5) 
from the investigator's assessments at the EOT and PTE Visits as per the CRF: 
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Table 5 
Overall Investigator's Assessment of Clinical Response at PTE Visit 
EOT Visit 
PTE Visit 
Overall Clinical Response at PTE Visit  
Success 
Success 
Success 
Success 
Failure 
Failure 
Success 
Indeterminate 
Indeterminate 
Failure 
Success 
Failure 
Failure 
Failure 
Failure 
Failure 
Indeterminate 
Failure 
Indeterminate 
Success 
Indeterminate 
Indeterminate 
Failure 
Failure 
Indeterminate 
Indeterminate 
Indeterminate 
EOT = end of treatment; PTE = post-therapy evaluation. 
 
The Overall Clinical Response is derived based on the “worst case scenario” to accommodate for 
missing visit assessment and intercurrent events (eg rescue medication at EOT visit). For the ITT 
and micro-ITT populations, the proportion of subjects with a Clinical Success is defined using 
the following formula (missing information at the PTE visit will be counted as Indeterminate): 
# of subjects with Clinical Success 
_____________________________________________________________________________________________________________________________________________________________________________________________________________________________ 
(# of subjects with Clinical Success + # of subjects with Clinical Failure + # of subjects with 
Indeterminate response) 
 
By definition, subjects in the CE-PTE population cannot have an Indeterminate response.  Thus, 
for the CE population, the proportion of subjects with a Clinical Success is defined using the 
following formula: 
# of subjects with Clinical Success 
_____________________________________________________________________________________________________________________________________________________________________________________________________________________________ 
(# of subjects with Clinical Success + # of subjects with Clinical Failure) 
 
7.1.1.3 
FFU Visit Clinical Response Assessment 
At the follow-up assessment (FFU), subjects will be re-evaluated by the Investigator for clinical 
response and will be reported for the micro-ITT and CE-FFU population by treatment group.  
The investigator will determine whether or not the subject meets the criteria of 1 of the following 
clinical outcomes: 
 Clinical Success: Sufficient resolution of signs and symptoms at the Final Follow-up 
visit such that no additional systemic antimicrobial therapy is required for the current 
infection. 
 Clinical Failure: No apparent response to therapy or persistence of signs and symptoms 
of infection or reappearance of signs and symptoms at or before the Final Follow-up visit 
such that use of additional systemic antimicrobial therapy for the current infection is 
required. 
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 Indeterminate: Final Follow-up visit not completed. 
Overall (Sustained) Response (based on the investigator’s assessment) at FFU is determined as 
defined in Table 6. 
Table 6 
Overall Investigator's Assessment of Clinical Response at FFU Visit 
Overall Clinical Response at  
PTE Visit 
Clinical Response at  
FFU Visit 
Overall Clinical Response  
at FFU Visit 
Success 
Success 
(Sustained) Clinical Cure 
Success 
Failure 
Clinical Failure 
Success 
Indeterminate 
Indeterminate 
Failure 
Success 
Clinical Failure 
Failure 
Failure 
Clinical Failure 
Failure 
Indeterminate 
Clinical Failure 
Indeterminate 
Success 
Indeterminate 
Indeterminate 
Failure 
Clinical Failure 
Indeterminate 
Indeterminate 
Indeterminate 
PTE = post-therapy evaluation; FFU = Final Follow-up 
 
7.1.2 
Microbiologic response 
Per-pathogen and per-subject microbiologic response will be programmatically determined at the 
EOT and PTE Visits in the micro-ITT and ME populations (by definition subjects in the ME 
population cannot have an indeterminate response). 
Microbiological response will be derived using electronically transferred microbiology data from 
the central laboratory (or local laboratory if central data are not available).   
Overall per-pathogen microbiological response at PTE is determined as follows (Table 7) from 
the per-pathogen microbiological responses at the EOT and PTE Visits. 
7.1.2.1 
Pathogen Determination 
A pathogen is defined as bacteria implicated as causative in a subject’s cystitis.  Baseline 
pathogens and post-baseline pathogens will be identified for each patient programmatically with 
a manual review and confirmation. Sponsor determination review will be performed in a blinded 
manner by Sponsor’s internal microbiology review committee. Details are documented in the 
Pathogen and CE Review Plan: PTK0796-uUTI-172012. 
7.1.2.2 
Microbiologic Response 
Per-pathogen microbiological response will be programmatically determined at the EOT and 
PTE Visits in the micro-ITT and ME populations (by definition subjects in the ME population 
cannot have an indeterminate response). 
Pathogen microbiological outcome categories are: eradication, persistence, and indeterminate 
and these are defined in Table 7. Favorable microbiological outcomes include eradication. 
Unfavorable microbiological outcomes include persistence or indeterminate.  
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Table 7 
Pathogen Microbiological Outcome Categories at EOT and PTE  
Category  
Criteria  
Interpretation  
Eradication  
Urine specimen shows absence of the original 
baseline pathogen or the baseline 
pathogen grew at <104 CFU/mL at visit.  
Favorable  
Persistence  
Urine culture shows continued 
presence (defined as ≥104 CFU/mL) of the 
original baseline pathogen(s) at visit.  
Unfavorable  
Indeterminate  
Urine specimen was not available to 
culture (or the culture result was not 
interpretable).  
Unfavorable  
*for PTE visit use Overall Clinical Response at PTE  
 
Per-subject microbiological responses will be based on per-pathogen outcomes. To have an 
overall per subject favorable microbiologic response, the outcome for each baseline pathogen 
must be favorable. If the outcome for any baseline pathogen is unfavorable, the subject will be 
considered to have an unfavorable per-subject microbiologic response. Subjects with an 
indeterminate response for all baseline pathogens will be considered to have an indeterminate 
per-subject microbiologic response. Subjects with at least one indeterminate response for a 
baseline pathogen when all other baseline pathogens have a favorable response will be 
considered to have an indeterminate per-subject microbiologic response. 
Table 8  
Per-Subject Microbiologic Response  
Condition 
Microbiologic Response at 
Visit 
Per-Subject Microbiologic Response 
at Visit 
All per-pathogen microbiological 
responses at visit 
 
Favorable (Eradication)  
Favorable 
Any per-pathogen 
microbiological response at visit 
 
Unfavorable (Persistence) 
Unfavorable 
All per-pathogen microbiological 
responses at visit 
 
Indeterminate 
Indeterminate 
At least one per-pathogen 
microbiological response at visit 
when other responses are 
Favorable (Eradication)  
Indeterminate 
Indeterminate 
 
Per-pathogen and per-subject overall microbiological responses at PTE are determined as 
follows (Table 9) from the per-pathogen and per-subject microbiological responses at the EOT 
and PTE Visits: 
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Table 9 
Microbiologic Response at PTE  
Microbiologic Response at 
EOT Visit 
Microbiologic Response at 
PTE Visit 
Overall Microbiologic Response at 
PTE 
Favorable 
Favorable 
Favorable 
Favorable 
Unfavorable 
Unfavorable 
Favorable 
Indeterminate 
Indeterminate 
Unfavorable 
Favorable 
Unfavorable 
Unfavorable 
Unfavorable 
Unfavorable 
Unfavorable 
Indeterminate 
Unfavorable 
Indeterminate 
Favorable 
Indeterminate 
Indeterminate 
Unfavorable 
Unfavorable 
Indeterminate 
Indeterminate 
Indeterminate 
Favorable is defined as the eradication  of the baseline pathogen. 
Unfavorable is defined as the persistence of a baseline pathogen 
EOT = end of treatment; PTE = post-therapy evaluation. 
 
7.1.2.3 
Other microbiological endpoints 
7.1.3 
UTI Signs and Symptoms Assessment 
Subject assessment of UTI signs and symptoms severity will be collected at Screening, and daily 
through EOT (including self-completion by subject at home on Days 2, 4 and 6), at PTE and at 
FFU via the UTISA questionnaire. 
The UTISA is a subject completed, 14-item questionnaire that assesses the levels of ‘severity’ 
and ‘bothersomeness’ for each of the seven most frequently reported symptoms and signs of 
UTI: 
 Frequency 
 Urgency  
 Pain/burning on urination 
 Incomplete voiding 
 Pain in pelvic area 
 Low back pain 
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 Blood in urine 
 
Each item has a Likert-type response scale, the ‘severity’ item response options being ‘did not 
have’, ‘mild’, ‘moderate’, ‘severe’, scored 0–3; and the bothersomeness item response options 
being ‘not at all’, ‘a little’, ‘moderately’, ‘a lot’, scored 0–3. 
Total scores of the 7 items for the severity of signs and symptoms scores and total scores for the 
7 items related to the bothersomeness will be calculated for each subject and visit. The total 
scores for severity and bothersomeness will be between 0 and 21. The total score 0 is indicating 
the least severity of signs and symptoms and a total score of 21 is indicating the worst severity. 
For bothersomeness, the total score 0 is indicating the least bothersome score and a total score of 
21 is indicating the most bothersome score. 
The bothersomeness questions are only answered if the subject reported presence of the 
sign/symptom, otherwise this answer is omitted by design. 
For calculating the individual total subject score by timepoint for both sub-scales, the scores of 
non-missing item scores are summed up and divided by the number of non-missing items and 
then multiplied by 7. If less than 4 items are answered for each sub-scale, the total score is set to 
‘missing’ for the sub-scale of the subject. 
Frequency of subjects with resolution of all symptoms, without occurrence of new symptoms (in 
comparison to baseline), and no worsening of baseline symptoms will be provided by timepoint.  
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7.2 
Primary Efficacy Endpoint Analysis 
The primary efficacy endpoint is investigator’s assessment of clinical response at PTE in the ITT 
population, as measured by the number of subjects in each treatment group.  
The primary efficacy outcome is the percentage of subjects with an overall clinical success at the 
PTE Assessment in the ITT population. Each omadacycline treatment group will be compared to 
nitrofurantoin group for non-inferiority (pairwise). This non-inferiority test will be based on the 
lower limit of the 2-sided exact 95% confidence interval (CI). 
The null and alternative hypotheses are as follows for overall clinical success: 




2
1
0 :
p
p
H
 and 




2
1
1 :
p
p
H
, 
 
 
where p1 is the primary efficacy success rate in each of the omadacycline treatment group, p2 is 
the primary efficacy success rate of nitrofurantoin group, and Δ is the non-inferiority margin of 
10%. No multiplicity adjustment will be used to account for multiple doses being compared to 
levofloxacin. 
To test the null hypothesis, a 2-sided 95% CI for the observed difference in primary outcome 
rates (omadacycline group minus nitrofurantoin group) will be calculated. If the lower limit of 
the 95% CI for the difference exceeds –10%, then the null hypothesis will be rejected and the 
non-inferiority of omadacycline to nitrofurantoin will be declared for that dose.   
The number and percentage of subjects in each treatment group defined as an overall clinical 
success, failure and indeterminate (subjects with missing data or who are lost to follow-up) will 
be tabulated, as will the overall category combining failure and indeterminate. 
In addition, 95% credible intervals will be provided for the difference in success rates using the 
modeling as follows. Assuming the likelihood for number of responders to have binomial 
distribution [𝑌i~𝐵𝑖𝑛(𝑛i, 𝑝i)] and non-informative beta priors [pi ~ Beta(0.5, 0.5)]. The posterior 
probability of non-inferiority will be computed as P(pOMC – pN > -0.1 | data) for assessment. 
Additional sensitivity analyses are described in Section 7.5.2. 
7.3 
Secondary Efficacy Endpoint Analysis 
7.3.1 
Investigator’s Assessment of Clinical Success 
The number and percentage of subjects with an (overall) investigator’s assessment of clinical 
success, clinical failure and indeterminate response at the EOT, PTE, and FFU visits (ITT, 
micro-ITT, and CE populations; by definition subjects in the CE population cannot have an 
indeterminate response) will be determined by treatment group. Exact 95% confidence intervals 
will be determined for the point estimates of the clinical success rates in each treatment group 
and for difference from nitrofurantoin (omadacycline - nitrofurantoin). 
 
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Reasons for investigator assessment of clinical failure and indeterminate at EOT and for overall 
assessment at PTE and FFU visits will be tabulated. 
 
7.3.2 
Per-Subject Microbiological Response 
The per-subject microbiological (overall) response at the EOT and PTE Visits in the micro-ITT, 
ME-EOT and ME-PTE populations will be determined to support the clinical findings.  
The number and percentage of subjects classified with a favorable (eradication) and unfavorable 
(persistence and indeterminate) microbiological response (by definition, indeterminates are 
excluded from the ME population) will be tabulated for both treatment groups. Exact 95% 
confidence intervals will be determined for the point estimates of the favorable microbiologic 
outcome rates in each treatment group and for difference from nitrofurantoin (omadacycline - 
nitrofurantoin). 
Concordance of microbiological outcome with clinical outcome at EOT and PTE visits for the 
micro-ITT and ME populations will be provided. 
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7.4 
Exploratory Analyses 
7.4.1 
UTI signs and symptoms assessment 
Results of the UTISA questionnaire will be summarized in the ITT, micro-ITT, and CE 
populations. Summaries will be based on the available data; no imputations will be applied to 
missing values.  
Shifts from Baseline will be summarized separately for severity scores and bothersome scores at 
each post-Baseline assessment, daily up to EOT (including self-completion by subject at home 
on Days 2, 4 and 6), PTE and at FFU. 
Total scores for severity and bothersomeness will be summarized by time point using descriptive 
statistics, for both the actual values and the change from baseline. 
Frequency of subjects with resolution of all clinical UTI symptoms, subjects with no worsening 
symptoms, and subjects with the absence of new UTI symptoms will be presented.   
7.5 
Efficacy Sensitivity Analysis 
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8 SAFETY ANALYSES 
8.1 
General  
The safety population will be used for all safety analyses and safety summaries will be presented 
by treatment group unless otherwise stated. All tables will have a corresponding listing including 
all patients randomized. 
8.2 
Duration of Exposure to Test Article and Compliance 
Exposure summary by treatment group will be presented for the safety, micro-ITT, and CE-PTE 
populations.  
Duration of exposure to test article (days) for the individual subject is the number of days subject 
received test article (last day of study test article – first day of test article + 1). Duration of 
treatment (days) will be summarized using descriptive statistics. The distribution of subjects by 
the total number of days on test article (1-3, 4-5, 6-7, and > 7 days) will be presented. 
The degree of test article compliance will be determined by presenting the number of tablets 
taken as a percentage of the number required by the protocol. 
 
 
The last dose date is the last day the subject is expected to receive test article based on the length 
of therapy determined by the investigator or the actual last date the subject took test article, if 
s/he prematurely discontinued test article. For subjects who complete the study, the last dose day 
used in the denominator calculation will be the last expected dosing day. For early termination 
subjects, the last day of study drug used in the denominator calculation will be the last expected 
dosing day before termination day. A subject is expected to receive a total of 38 tablets during 
the treatment phase for subjects enrolled at the time preceding protocol amendment 2, and 56 
tablets with amendment 2. For detail on dosing schedules refer to Table 2 of the study protocol.   
Descriptive statistics for treatment and fasting compliance will be presented by treatment group 
and by protocol version at which a subject entered the study.  
Number of subjects and percentage with a compliance ≥80% will be presented. A summary of 
compliance with the pre- and post-dose fasting requirements will also be provided.  The percent 
fasting compliance will be determined based on the total doses taken where fasting is required.  
The percentage of subjects who were < 50%, 50% to < 80%, and 80% to 100% compliance with 
the pre-dose and post-dose fasting requirements met will be summarized. 
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8.3 
Concomitant Medications 
Medications will be coded by WHODrug Anatomical Therapeutic Chemical Classification level 
3 and generic medication name. Treatments that have been administered within 7 days prior to 
the date of informed consent until the end of study are recorded in the eCRF.  
Medications are considered concomitant if taken on or after the first dose of test article, or if 
their stop date is unknown or marked as continuing. Thus, in cases where a medication starts 
prior to the first dose, and continues throughout the treatment period, the medication will be 
summarized as both prior and concomitant. 
All medications and significant non-drug therapies (including physical therapy and blood 
transfusions) administered after the subject starts treatment with test article will be listed. 
 Of note, summary of prior antiemetic and antibiotic medications will also be provided as 
described in Section 6.5 (Prior and Concomitant Medications).  
8.4 
Adverse Events 
Adverse events (AEs) will be recorded and reported from signing of the inform consent form to 
the end of study. AEs will be coded using the MedDRA to the system organ class (SOC) and 
preferred term (PT) levels.   
A treatment-emergent AE is defined as any AE that newly appeared or worsened in severity on 
or after the initiation of test article.  An AE is considered treatment emergent if the AE start date 
and time is on or after the start date and time of the first dose of test article. 
Summary tables will be provided for all treatment-emergent adverse events (TEAEs).   
An overall summary of AEs will include the number of subjects who experienced at least one AE 
of the following categories: any AE, any TEAE, any drug-related TEAE, any severe TEAE, any 
serious TEAE, any drug-related serious adverse event, any serious TEAE leading to death, any 
TEAE leading to premature discontinuation of test article, any TEAE leading to premature 
discontinuation of test article and premature discontinuation from study, and any serious TEAE 
leading to premature discontinuation of test article.   
The number and percentage of subjects reporting a TEAE in each treatment group will be 
tabulated by SOC and PT. The incidence of serious TEAEs, TEAEs judged to be related to test 
article, TEAE leading to premature discontinuation of test article and from study will be 
summarized by SOC and PT.  Additionally, a summary by SOC, PT, and severity (mild, 
moderate, and severe) will be provided. For all analyses of TEAEs, if the same AE (based on PT) 
is reported for the same subject more than once, the AE is counted only once for that PT and at 
the highest severity and strongest relationship to test article.   
In addition, all TEAEs, serious TEAEs, and TEAEs leading to discontinuation of test article will 
be provided in listings by treatment group, study site, subject, verbatim term, MedDRA SOC and 
PT, start and end date, seriousness flag, severity, relationship to test article, relationship to study 
protocol, action taken with test article, non-test article action taken and outcome.   
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For subjects with a TEAE of nausea or vomiting (based on the MedDRA PT), the total number 
of nausea and vomiting events, descriptive statistics of the study day of first onset of these 
events, descriptive statistics for the duration (in days) of events, and number of subjects who 
required anti-emetic medication will be presented by treatment group. 
Listings of all AEs for treated (by treatment group) and not treated subjects will be provided 
indicating day relative to the first intake of the test article intake to differentiate between TEAEs 
and pre-therapy AEs. 
8.5 
Clinical Laboratory Results 
Clinical laboratory safety assessments include hematology (including coagulation), serum 
chemistry, and urinalysis.   
Clinical laboratory parameters include those listed in the Appendix 1 Clinical Laboratory Tests 
(Central). 
Baseline is defined as the central lab value closest to and prior to the first dose of test article. If 
no central lab value is available prior to the first dose of study drug, the local lab value that is 
closest to and prior to the first dose of study drug will be used as baseline.  For by visit analyses, 
central lab values will be used unless no central lab value was obtained in the visit window.  In 
this case, local lab values will be used for the by visit analyses.  All lab values (central and local) 
are used for determination of the overall worst post-baseline value. 
Laboratory data will be summarized by timepoint and for the overall worst post-baseline value 
using descriptive statistics (based on International System [SI] units) for the actual results and 
change from baseline for hematology and serum chemistry assessments.  
Descriptive statistics (based on SI units) for chemistry, hematology and coagulation values and 
the change from baseline will be summarized by treatment group at each time point, and for the 
overall worst value post-baseline (which includes unscheduled visits).   
Appendix 2 Directionality of Worst Laboratory Parameters provides the directionality of the 
worst values for each laboratory parameter. 
Clinically notable laboratory values will be determined based on the modified Division of 
Microbiology and Infectious Diseases (DMID) criteria in Appendix 3 Modified Division of 
Microbiology and Infectious Diseases Adult Toxicity Table.  
Shift tables will be presented to show the number of subjects with a laboratory value with a 
grade of 0, 1, 2, 3 or 4 at baseline versus the value at each visit.  Number and percentage of 
subjects with at least a 2-grade increase from baseline (based on DMID criteria) will be 
summarized by treatment arm. Percentages for each laboratory test will be based on the number 
of subjects with a baseline and post-baseline evaluation of the specific laboratory test.  A listing 
will be provided for subjects who have at least a 2-grade increase from baseline in a given 
laboratory test.  
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The number and percentage (based on the number of subjects with a normal level at baseline) of 
subjects in each treatment group with an elevated transaminase level (> 3 × upper limit of normal 
[ULN], > 5×ULN, and > 10 × ULN), an elevated bilirubin level (> 1.5 × ULN and > 2 × ULN) 
will be presented by study visit.  A listing of subjects who meet the laboratory criteria for Hy’s 
law at the same visit will also be provided.  The laboratory criteria for Hy’s law is defined as 1) 
ALT or AST> 3 × ULN, ALP ≤ 2.0 × ULN, and total bilirubin > 1.5 ULN and 2) ALT or 
AST> 3 × ULN, ALP ≤ 2.0 × ULN, and total bilirubin > 2 × ULN. 
Tabulated results of urine dipstick tests for leukocyte esterase and nitrates will be summarized by 
treatment group across visits and will include descriptive statistics for the microscopic 
evaluations for WBCs. 
Subject listings of all laboratory data (local and central laboratory data) collected during the 
study will be provided, including calculated CrCl (using the Cockcroft-Gault equation).  
Laboratory values outside normal limits will be identified in the subject data listings with flags 
for low (L) and high (H) as will laboratory values that meet the clinically notable (CN) 
thresholds. 
8.6 
Vital Signs 
Vital signs will include blood pressure (diastolic and systolic), heart rate, and body temperature, 
and will be collected at Screening, Days 1, 3, 5, and EOT, as well as at the PTE. During the 
Follow-up call/visit vital signs are collected if the subject reports symptoms of potential 
recurrence and clinic visit is required. 
Additionally, height will be collected at the Screening visit, and body weight will be collected at 
the Screening and EOT visits.  
Blood pressure (systolic and diastolic) and heart rate will be summarized by time point and for 
the minimum and maximum post-baseline values using descriptive statistics, for both the actual 
values and the change from baseline.   
Figures (line graphs) of observed values for heart rate, systolic and diastolic blood pressure over 
time will also be provided by treatment group. 
Post-baseline vital signs will be defined as CN if they meet 1) the criterion value at the given 
visit, or 2) meet both the criterion value and the change from baseline criterion listed in Table 11.  
The incidence of CN vital signs will be summarized by time point and treatment group and will 
be listed and flagged in by-subject listings. An overall post-baseline incidence of CN values for 
each vital sign parameter, will also be summarized. A separate listing will be provided of 
subjects with values for a vital sign noted as CN. 
Table 11 
Criteria for Clinically Notable Vital Signs 
Vital Sign Parameter 
Flag 
Criterion Value 
Change from Baseline 
Systolic Blood Pressure 
(mmHg) 
High (CH) 
 180 
Increase of  20 mmHg 
Low (CL) 
 90 
Decrease of  20 mmHg 
Diastolic Blood Pressure 
High (CH) 
 105 
Increase of  15 mmHg 
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Table 11 
Criteria for Clinically Notable Vital Signs 
Vital Sign Parameter 
Flag 
Criterion Value 
Change from Baseline 
(mmHg) 
Low (CL) 
 50 
Decrease of  15 mmHg 
Heart Rate (bpm) 
High (CH) 
 120 
Increase of  15 bpm 
Low (CL) 
 50 
Decrease of  15 bpm 
 
8.7 
Pregnancies 
Results of local (urine or serum) and central (serum) pregnancy tests will be listed for all subjects 
enrolled in the study by treatment group. It is expected for pregnancy counts to be small and thus 
narratives will be provided in the CSR. 
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9 CHANGES FROM PROTOCOL 
Not applicable. 
10 REFERENCES 
1. Statistical Analysis Plan for Data Monitoring Committee Meetings: Bayesian Design for 
Phase II Trial for PTK0796-UUTI-17201 
2. Pathogen and CE Review Plan: PTK0796-uUTI-17201 
 
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APPENDIX 1 CLINICAL LABORATORY TESTS (CENTRAL) 
Table 12 
Clinical Laboratory Tests (Central) 
Hematology: 
 
Hematocrit (Hct) 
 
Hemoglobin (Hgb) 
 
Mean corpuscular hemoglobin (MCH) 
 
Mean corpuscular hemoglobin concentration 
(MCHC) 
 
Mean corpuscular volume (MCV) 
 
Platelet count 
 
Red blood cell (RBC) count  
 
White blood cell (WBC) count with differential 
 
Coagulation:  
 
Ratio of prothrombin time (PT) and 
international normalized ratio (INR) 
 
Pregnancy (all subjects): 
 
Serum β-human chorionic gonadotropin 
(β-HCG) 
 
Urinalysis:  
 
Bilirubin 
 
Glucose 
 
Ketones 
 
Leukocyte esterase 
 
Microscopic examination of sediment with 
WBC count  
 
Nitrites 
 
Occult blood 
 
potential of hydrogen (pH) 
 
Protein 
 
Specific gravity 
 
Urobilinogen 
Serum Chemistry: 
 
Albumin (ALB) 
 
Alkaline phosphatase (ALP) 
 
Alanine aminotransferase (ALT) 
 
Amylase 
 
Aspartate aminotransferase (AST) 
 
Blood urea nitrogen (BUN) 
 
Calcium (Ca) 
 
Carbon dioxide (CO2) 
 
Chloride (Cl) 
 
Creatinine 
 
Creatine phosphokinase (CK) 
 
Gamma-glutamyl transpeptidase (GGT) 
 
Glucose 
 
Lactate dehydrogenase (LDH) 
 
Lipase 
 
Magnesium 
 
Phosphorus (P) 
 
Potassium (K) 
 
Sodium (Na) 
 
Total bilirubin 
 
Total protein 
 
Uric acid 
 
 
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APPENDIX 2 DIRECTIONALITY OF WORST LABORATORY 
PARAMETERS 
Laboratory Test 
Parameter 
Worst Value 
Hematology 
Hematocrit 
Lowest value 
 
Hemoglobin 
Lowest value 
 
Red blood cell count 
Lowest value 
 
Mean cell hemoglobin 
Lowest value 
 
Mean cell hemoglobin concentration 
Lowest value 
 
Mean cell volume 
Lowest value 
 
White blood cell count 
Lowest value 
 
Platelets 
Lowest value 
 
Neutrophils  
Lowest value 
 
Lymphocytes  
Lowest value 
 
Monocytes  
Lowest value 
 
Eosinophils 
Highest value 
 
Basophils  
Lowest value 
Chemistry 
Albumin  
Lowest value 
 
Alkaline phosphatase 
Highest value 
 
Alanine aminotransferase ALT/SGPT) 
Highest value 
 
Amylase 
Highest value 
 
Aspartate aminotransferase (AST/SGOT) 
Highest value 
 
Urea 
Highest value 
 
Bicarbonate  
Lowest value 
 
Calcium 
Both highest value and lowest value 
 
Cholesterol  
Highest value 
 
Chloride  
Both highest value and lowest value 
 
Creatinine 
Highest value 
 
Creatine kinase (CK) 
Highest value 
 
Gamma-glutamyl transpeptidase (GGT) 
Highest value 
 
Blood glucose 
Both highest value and lowest value 
 
Lactate dehydrogenase (LDH) 
Highest value 
 
Lipase 
Highest value 
 
Magnesium  
Both highest value and lowest value 
 
Phosphate 
Both highest value and lowest value 
 
Potassium 
Both highest value and lowest value 
 
Sodium 
Both highest value and lowest value 
 
Total bilirubin 
Highest value 
 
Total protein 
Lowest value 
 
Uric acid 
Highest value 
Coagulation 
International normalized ratio (INR) 
Highest value 
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APPENDIX 3 MODIFIED DIVISION OF MICROBIOLOGY AND 
INFECTIOUS DISEASES ADULT TOXICITY TABLE 
The DMID Adult Toxicity Table (21-Nov-2007) was modified to exclude the clinical component 
of the toxicity grading because clinical signs and symptoms related to abnormal laboratory 
values are not collected in this study. In addition, Grade 0 was added to the table so that shifts 
from normal could be analyzed. The grades for several parameters including enzymes were 
modified to ensure that any possible numeric value can be categorized appropriately (eg, for 
creatinine, Grade 3 is defined as “>1.5-3.0×ULN” instead of “1.6-3.0×ULN”). 
For toxicity grades based on a multiple of the ULN, the normal range from the central laboratory 
will be applied.   
For toxicity grades based on fixed values, the grades will be assigned regardless of the normal 
actual range values from the central laboratory. For example, a hemoglobin value of 10.0 gm/dL 
will be assigned a grade 1 toxicity, even if the lower limit of normal from the laboratory was 9.8 
gm/dL.   
HEMATOLOGY 
 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin (gm/dL) 
> 10.5 
9.5-10.5 
8.0-9.4 
6.5-7.9 
< 6.5 
Absolute Neutrophil 
Count (count/mm3) 
> 1500 
1000-1500 
750-999 
500-749 
< 500 
Platelets (count/mm3) 
≥ 100,000 
75,000-99,999 
50,000-74,999 
20,000-49,999 
< 20,000 
WBCs (count/mm3) 
1000-10,999 
11,000-12,999 
13,000-14,999  
15,000-30,000 
> 30,000 or < 
1,000 
COAGULATION  
 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Prothrombin time 
(PT) (sec) 
≤1 x ULN 
1.01-1.25 x 
ULN 
1.26-1.5 x ULN 
1.51 - 3.0 x 
ULN 
> 3 x ULN 
International 
normalized ratio 
(INR) 
Increased 
≤ ULN 
> 1 - 1.5 x ULN 
> 1.5 - 2.5 x 
ULN 
> 2.5 x ULN 
 
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CHEMISTRY 
 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia (mEq/L) (Na) 
> 135 
130-135 
123-129 
116-122 
< 116  
Hypernatremia (mEq/L) (Na) 
< 146 
146-150 
151-157 
158-165 
> 165  
Hypokalemia (mEq/L) (K) 
> 3.4 
3.0-3.4 
2.5-2.9 
2.0-2.4 
< 2.0 
Hyperkalemia (mEq/L) (K) 
< 5.6 
5.6-6.0 
6.1-6.5 
6.6-7.0 
> 7.0 
Hypoglycemia (mg/dL) (glucose) 
 65 
55-64 
40-54 
30-39 
< 30  
Hyperglycemia (mg/dL) 
(nonfasting and regardless of 
prior history of diabetes)1 
(glucose) 
< 116 
116-160 
161-250 
251-500 
> 500  
Hypocalcemia (mg/dL) 
(corrected for albumin) 2 (Ca) 
> 8.4 
8.4-7.8 
7.7-7.0 
6.9-6.1 
< 6.1 
Hypercalcemia (mg/dL) (correct 
for albumin) 2 (Ca) 
 10.5 
10.6-11.5 
11.6-12.5 
12.6-13.5 
> 13.5 
Hypomagnesemia (mEq/L) 
(Magnesium) 
> 1.4 
1.4- 1.2 
1.1-0.9 
0.8-0.6 
< 0.6 
Hypophosphatemia (mg/dL) (P) 
 2.5 
2.0-2.4 
1.5-1.9 
1.0-1.4 
< 1.0 
Hyperbilirubinemia (total 
bilirubin) 
< 1.1×ULN 
1.1-1.5×ULN 
> 1.5-2.5×ULN 
> 2.5-5×ULN 
> 5×ULN 
Urea 
< 
1.25×ULN 
1.25-2.5×ULN 
> 2.5-5×ULN 
> 5-10×ULN 
>10×ULN 
Hyperuricemia (uric acid) 
(mg/dL) 
< 7.5 
7.5–10.0 
10.1–12.0 
12.1–15.0 
> 15.0 
Creatinine 
< 1.1×ULN 
1.1-1.5×ULN  
> 1.5-3.0×ULN 
> 3.0-6×ULN 
> 6×ULN  
1 The DMID toxicity table reports hyperglycemia detected in nonfasting specimens obtained from subjects with no 
prior diabetes. 
2 Calcium corrected for albumin = [0.8 x (normal albumin - subject's albumin)] + serum Ca level 
   Where normal albumin = 4 g/dl, albumin is in g/dL and calcium is in mg/dL 
 
ENZYMES 
 
Grade 0  
Grade 1  
Grade 2  
Grade 3  
Grade 4  
AST (SGOT) 
< 1.25×ULN 
1.25-2.5×ULN 
> 2.5-5×ULN 
> 5-10×ULN 
> 10×ULN 
ALT (SGPT) 
< 1.25×ULN 
1.25-2.5×ULN 
> 2.5-5×ULN 
> 5-10×ULN 
> 10×ULN 
GGT 
< 1.25×ULN 
1.25-2.5×ULN 
> 2.5-5×ULN 
> 5-10×ULN 
> 10×ULN 
Alkaline 
Phosphatase 
< 1.25×ULN 
1.25-2.5×ULN 
> 2.5-5×ULN 
> 5-10×ULN 
> 10×ULN 
Amylase 
< 1.1×ULN 
1.1-1.5×ULN 
> 1.5-2.0×ULN 
> 2.0-5.0×ULN 
> 5.0×ULN 
Lipase 
< 1.1×ULN 
1.1-1.5×ULN 
> 1.5-2.0×ULN 
> 2.0-5.0×ULN 
> 5.0×ULN 
 
 
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APPENDIX 4 CONCOMITANT MEDICATION START DATE 
IMPUTATION 
Prior and Concomitant Medication Start Date Imputation  
Parameter 
Type of 
Medication 
Imputation 
Start date for con 
meds  
Non-
Antibacterial  
If it cannot be determined whether or not the start date of a medication 
(non-antibacterial) is prior to the first dose of study drug, it will be assumed that the 
medication was received prior to the first dose of study drug. 
Antibacterial 
 
Missing start dates for antibacterials will be queried for a value.  If it cannot be 
determined whether or not the start date of an antibacterial is prior to the first dose of 
study drug, it will be assumed that the medication was received prior to the first dose 
of study drug unless the indication notes that the medication was received after the 
first dose of study drug. 
 
Stop date for con 
meds  
Non-
Antibacterial 
If it cannot be determined whether or not the stop date of a medication (nonantibacterial) is 
after the first dose of study drug, it will be assumed that the medication was received 
after the first dose of study drug 
 
Antibacterial 
 
Missing stop dates for antibacterials will be queried for a value.  If it cannot be 
determined whether or not the stop date of an antibacterial is after the first dose of 
study drug, it will be assumed that the medication was received after the first dose of 
study drug unless the indication notes that the medication was received prior to the 
first dose of study drug.  If it cannot be determined whether the antibacterial was 
received prior to the assessment of Early Clinical Response, the EOT and/or the PTE 
Visit, the antibacterial will be assumed to have been received through the PTE Visit. 
 
 
  
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Document Approvals
Approved Date: 
Approval Task
Verdict:  Approve
23-May-2019 15:34:12 GMT+0000
Approval Task
Verdict:  Approve
23-May-2019 16:00:39 GMT+0000
Approval Task
Verdict:  Approve
31-May-2019 15:29:40 GMT+0000
Approval Task
Verdict:  Approve
03-Jun-2019 13:05:16 GMT+0000
Final Approval Task
Verdict:  Approve
03-Jun-2019 13:06:05 GMT+0000
Number: GEN-STP-0292               Version: 1.0               Status: Approved    Approved Date:
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