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
Phase: PHASE2
Conditions: Uncomplicated Urinary Tract Infection, Cystitis
Sponsor: Paratek Pharmaceuticals Inc

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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

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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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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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 Paratek Pharmaceuticals, LLC 
PTK0796-UUTI-17201-Version 3.0 FINAL; 18-FEB-2019 
IND # 75,928 IND # 73,431 
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.  
 

Omadacycline  
 Paratek Pharmaceuticals, LLC 
PTK0796-UUTI-17201-Version 3.0 FINAL; 18-FEB-2019 
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  
 Paratek Pharmaceuticals, LLC 
PTK0796-UUTI-17201-Version 3.0 FINAL; 18-FEB-2019 
IND # 75,928 IND # 73,431 
 
Confidential and Proprietary 
Page 70 of 70 
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 
 Paratek Pharmaceuticals, LLC 
PTK0796-UUTI-17201-Version 2.0 FINAL; 29-OCT-2018 
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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