Clinical trial NCT03757234
Conditions: Acute Pyelonephritis
Sponsor: Paratek Pharmaceuticals Inc
Start date: 2018-11-19; Completion date: 2019-07-24
Enrollment: 201 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate the safety and efficacy of intravenous (iv) or iv/per oral (po) omadacycline as compared to iv or iv/po levofloxacin in the treatment of female adults with acute pyelonephritis.

Detailed description:
This was a randomized (1:1:1:1:1), double-blind, double-dummy, adaptive designed, Phase 2 study. Based on review of the efficacy and microbiology data, the DMC modified the randomization algorithm, and no further participants were enrolled in the following treatment arms after May 2019: the omadacycline 200 iv/100 iv, omadacycline 200 iv/300 po or 100 iv, and omadacycline 200 iv/450 po or 100 iv arms. After this change, participants were randomized in a 1:1 ratio to either the omadacycline 200 iv/200 iv or levofloxacin arms.

Arms: arm 1: On Day 1, participants received omadacycline 200 milligrams intravenously (iv). On Days 2 through 7, participants continued to receive omadacycline 200 milligrams iv. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. arm 2: On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. arm 3: On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv or omadacycline 300 milligrams per oral (po). All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state. arm 4: On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv or omadacycline 450 milligrams po. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state. arm 5: On Day 1, participants received levofloxacin 750 milligrams iv. On Days 2 through 7, participants received levofloxacin 750 milligrams iv or levofloxacin 750 milligrams po. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state.
Interventions: intervention 1: Omadacycline intervention 2: Levofloxacin intervention 3: Omadacycline
Intervention descriptions: intervention 1: po tablets intervention 2: iv solution/po tablets intervention 3: iv solution

Protocol documents:
Prot_000.pdf: 
Omadacycline  
 Paratek Pharma, LLC. 
PTK0796-AP-17202-Version 1.0; 26Mar2018 
IND # 75,928 IND # 73,431 
Confidential and Proprietary  
Page 1 of 88 
Clinical Trial Protocol:  PTK0796-AP-17202
Study Title: 
A Randomized, Double-Blinded, Adaptive Phase 2 Study to Evaluate the 
Safety and Efficacy of IV or IV/PO Omadacycline and IV/PO 
Levofloxacin in the Treatment of Adults with Acute Pyelonephritis 
Study Number: 
PTK0796-AP-17202 
Study Phase: 
2 
Product Name: 
Omadacycline (PTK 0796) 
IND Number: 
75,928 
73,431 
Indication: 
Acute Pyelonephritis 
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 
Global Medical 
Monitor: 
Regional Medical 
Monitor: 
 
 
Original Protocol Version 1: 
26 March 2018 
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 Council on Harmonisation Harmonised 
Tripartite Guidelines for Good Clinical Practice. 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
PTK0796-AP-17202 Protocol
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NCT Number: NCT03757234
This NCT number has been applied to the document for
purposes of posting on clinicaltrials.gov


Omadacycline  
 Paratek Pharma, LLC. 
PTK0796-AP-17202-Version 1.0; 26Mar2018 
IND # 75,928 IND # 73,431 
 
Confidential and Proprietary  
Page 2 of 88 
 
SYNOPSIS 
Sponsor: 
Paratek Pharma, LLC.  
 
Name of Finished Product: 
Omadacycline for injection, 100 mg lyophilized vial drug 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 
IV or IV/PO Omadacycline and IV/PO Levofloxacin in the Treatment of Adults with Acute 
Pyelonephritis 
 
Study Number: 
PTK0796-AP-17202 
 
Study Phase:  2 
 
Study Rationale: 
Omadacycline is the first member of the aminomethylcycline class of antibiotics, which are 
semi-synthetic derivatives of the tetracycline class.  Omadacycline has in vitro activity against 
the most common bacterial pathogens associated with acute pyelonephritis (AP).  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 not been evaluated in adults with AP. 
 
Primary Objective:  
To evaluate the efficacy of intravenous (iv) and iv to oral (iv/po) dosing regimens of 
omadacycline and levofloxacin in the treatment of adults with AP.   
 
 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
PTK0796-AP-17202 Protocol
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Omadacycline  
 Paratek Pharma, LLC. 
PTK0796-AP-17202-Version 1.0; 26Mar2018 
IND # 75,928 IND # 73,431 
 
Confidential and Proprietary  
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Secondary Objectives: 
• To evaluate the safety of omadacycline in the treatment of adults with AP.   
• To evaluate the PK of omadacycline in adults with AP.  
Study Design: 
This is a randomized, double-blinded, adaptive designed Phase 2 study evaluating 4 once-daily 
iv or iv/po dosing regimens of omadacycline compared to levofloxacin in the treatment of adults 
with AP.  The planned length of subject participation in the study is up to 30 days.   
Initially, eligible subjects will be randomly assigned to receive either a once-daily dosing 
regimen of omadacycline or a once-daily regimen of levofloxacin.  All subjects initially will 
receive at least 1 day of iv treatment, and will receive a total of 7 to 10 days of treatment (iv and 
oral combined).  Subjects with baseline bacteremia (ie, confirmed from local blood culture 
drawn at screening) can receive up to 14 days of treatment.  
Switch from active iv to active po study drug therapy is optional, and will occur based on 
treatment group assignment and the decision should be made by the investigator based on 
evaluation of the criteria below.  Criteria will be confirmed and documented in the source 
documents. Upon decision to switch, subjects randomized to iv only treatment groups will begin 
to receive placebo po in addition to their active iv test article. Those randomized to an iv/po 
treatment group will begin to receive active po test article and placebo iv infusions. 
• Afebrile for ≥ 24 hours (highest daily oral, tympanic, rectal, or core temperature 
< 37.8ºC [100.0ºF]) without the use of anti-pyretics,  
• Improvement or resolution of the signs and symptoms of the index AP.   
• Ability to tolerate and ingest oral therapy (eg, no nausea, vomiting), and 
• For subjects with bacteremia identified at screening, follow-up blood cultures must be 
negative. 
Subjects will be randomized to one of the following treatment groups, dosing in all treatment 
groups is once-per-day: 
Group 
Test Article 
Study Day 
Study Days 
Study Days 
1 
2 to 7 
8 to 10a 
1 
Omadacycline  
200 mg iv  
200 mg iv 
200 mg iv  
2 
Omadacycline 
200 mg iv 
100 mg iv 
100 mg iv 
3 
Omadacycline 
200 mg iv 
300 mg po or 
100 mg iv 
300 mg po or 
100 mg iv 
4 
Omadacycline 
200 mg iv 
450 mg po or 
100 mg iv 
450 mg po or 
100 mg iv 
5 
Levofloxacin 
750 mg iv 
750 mg po or 
750 mg iv 
750 mg po or 
750 mg iv 
iv = intravenous, po = per oral 
a 
The total duration of treatment for subjects is 7-10 days, up to 14 days of treatment for subjects with 
bacteremia.  
 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
PTK0796-AP-17202 Protocol
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 Paratek Pharma, LLC. 
PTK0796-AP-17202-Version 1.0; 26Mar2018 
IND # 75,928 IND # 73,431 
 
Confidential and Proprietary  
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Dosing blinded iv and oral double-blind, double-dummy: 
Dosing 
 
Group 1 
Group 2 
Group 3 
Group 4 
Group 5 
omadacycline 
omadacycline 
Omadacycline 
omadacycline 
Levofloxacin 
Day 1 
 
omadacycline 
200 mg iv in 
150 mL NS 
omadacycline 
200 mg iv in 
150 mL NS 
omadacycline 
200 mg iv in 
150 mL NS 
omadacycline 
200 mg iv in 
150 mL NS 
levofloxacin 
750 mg iv in 
150 mL saline 
Days2 to 
7-10a, b, c 
  continue iv 
omadacycline 
200 mg iv in  
150 mL NS 
omadacycline 
100 mg iv in 
150 mL NS 
omadacycline 
100 mg iv in 
150 mL NS 
omadacycline 
100 mg iv in 
150 mL NS  
levofloxacin 
750 mg iv in 
150 mL saline 
switch to pob 
omadacycline 
200 mg iv in  
150 mL NS 
and 
three placebo 
tablets 
resembling 
omadacycline 
and  
three over-
encapsulated 
placebo tablets 
resembling 
levofloxacin 
omadacycline 
100 mg iv in 
150 mL NS 
and 
three placebo 
tablets 
resembling 
omadacycline 
and  
three over-
encapsulated 
placebo tablets 
resembling 
levofloxacin 
150 mL NS 
and  
two 150 mg 
omadacycline 
tablets, one 
placebo tablet 
resembling 
omadacycline, 
and  
three over-
encapsulated 
placebo tablets 
resembling 
levofloxacin 
150 mL NS 
and 
three 150 mg 
omadacycline 
tablets  
and  
three over-
encapsulated 
placebo tablets 
resembling 
levofloxacin 
150 mL NS 
and 
three placebo 
tablets 
resembling 
omadacycline 
and 
 three over-
encapsulated 
250 mg 
levofloxacin 
tablets 
Dosing in all treatment groups is once-per-day. 
All iv doses will be administered as continuous infusions over 90 minutes.  
All oral doses will be taken in a fasted state (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 prior to dosing; 
after dosing, no food for 2 hours, no dairy products, antacids or multivitamins containing multivalent cations for 
4 hours). 
iv = intravenous, NS = normal saline, po = per oral. 
a 
The total duration of treatment is 7-10 days, Subjects with bacteremia can continue treatment for up to 14 days .  
b 
Starting on Day 2, per investigator’s discretion, subjects may be switched to oral dosing per oral switch criteria. 
c 
All therapy may be discontinued after the seventh day of treatment, when the infection is considered clinically 
cured (based on normalization of the clinical signs and symptoms of infection and the investigator’s clinical 
assessment that continued systemic antibacterial therapy is no longer needed). 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
PTK0796-AP-17202 Protocol
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PTK0796-AP-17202-Version 1.0;26Mar2018 
IND # 75,928 IND # 73,431 
 
Confidential and Proprietary  
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During the study period, blood and urine samples will be collected for safety analysis, 
microbiological analysis and for omadacycline PK analysis.  Safety assessments will include 
monitoring of adverse events (AEs), clinical laboratory test results, vital sign measurements, 
pregnancy testing (for women only) and physical examination findings. 
The iv treatment phase and oral treatment phase will be blinded and the oral treatment phase 
is double-dummy.  All subjects should remain in a hospital setting during treatment.  
However, subjects may receive iv treatment in certain outpatient centers in circumstances 
where the principal site investigator has identified that sufficient resources are available to 
complete all study procedures as defined in the protocol and the sponsor or sponsor’s 
designee has reviewed and approved the process for outpatient iv test article administration.   
Subject visits occur on Days 1 to 7.  If treatment extends beyond 7 days, subject visits may 
occur on Days 8 to 10.  If treatment extends beyond 10 days for cases of bacteremia, visits 
will occur on Days 11 to 13.  An end of treatment (EOT) visit will be conducted on the day of 
or within 2 days following the last dose.  Subjects will return to the study site for a Post 
Therapy Evaluation (PTE) on Day 21 (± 2 days).  A Final Follow-up visit (Final Follow-up) 
will be conducted on Day 28 (± 2 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 were considered to be clinical successes and had no AEs or 
clinically significant laboratory or electrocardiogram (ECG) 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. 
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: 
• In PTK0796-SDES-0501, the PK of omadacycline iv were linear over the entire dose 
range (25 mg to 600 mg) as assessed by area under the concentration time curve 
(AUC).  Therefore, the loading dose given on Day 1 in the pivotal Phase 3 trials, 
100 mg iv every 12 hours (q12h), is from an exposure perspective comparable to the 
200 mg iv loading dose on Day 1 to be utilized in this study. 
• In PTK0796-MDES-0601, 200 mg iv for seven days was safe and well tolerated.  
Alanine aminotransferase (ALT) was reported as increased in 26% of subjects 
however the post-baseline change was approximately 30 IU/L on the last day of 
infusion.  A heart rate model demonstrated that the post-baseline increase in heart rate 
for a 200 mg dose could be minimized to 15 beats per minute with infusion over 
60 minutes.  
• In PTK0796-UUTI-15103, omadacycline dosed as 200 mg iv on Day 1 followed by 
300 mg po daily for 5 days, 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 
demonstrated high urinary concentration on Day 1 and Day 5.  For the 200 mg iv load 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
PTK0796-AP-17202 Protocol
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PTK0796-AP-17202-Version 1.0; 26Mar2018 
IND # 75,928 IND # 73,431 
 
Confidential and Proprietary 
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followed by 300 mg daily dosing group, mean urinary concentrations ranged from 22 
to 65 µg/mL on Day 1 and 21 to 42 µg/mL on Day 5.  For the 300 mg dosing group, 
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, mean urinary concentrations ranged 
from 11 to 25 µg/mL on Day 1 and 30 to 48 µg/mL on Day 5. 
• The driver of efficacy for omadacycline in urinary tract infection (UTI) is not known, 
however the extensive tissue distribution of omadacycline suggests that plasma levels 
may not be the best predictor of efficacy for every indication.  Extensive tissue 
distribution is likely essential for the eradication of susceptible bacteria in the 
intracellular compartment of peripheral tissues.  In the BAL-15104 study examining 
lung tissue concentrations following iv administration of 100 mg omadacycline in 
healthy subjects, at steady-state, the concentration of omadacycline was 25.79-fold 
higher in alveolar cells (AC, 302.46 h·µg/mL) than in plasma, and 1.47-fold higher in 
epithelial lining fluid (ELF, 17.23 h·µg/mL) than in plasma. 
• A pragmatic assumption was made in the recently completed Phase 1 study of 
uncomplicated UTI (PTK0796-UUTI-15103) that maximizing the time of 
omadacycline concentration in urine above the pathogen minimum inhibitory 
concentration (MIC) (ideally, throughout the dosing interval) would be desirable.  In 
addition, the omadacycline concentrations in urine determined in the phase 1 study 
demonstrated that the urine concentrations were above the E. coli MIC90 of 2 µg/mL.  
It is appropriate to determine the optimal iv and oral dose for AP to achieve clinical 
success similar to a standard comparator.  Therefore, both the standard 100 mg iv dose 
as well as the higher 200 mg iv dose will be explored.  Oral doses of 300 mg and 450 
mg will be explored as was done in the PTK0796-UUTI-15103 and is being explored 
for the uncomplicated UTI (acute cystitis) in PTK0796-UUTI-17201. 
 
Study Population:  
Approximately 200 subjects will be enrolled at approximately 35 sites.  Initially, subjects will 
be randomized (1:1:1:1:1) to 1 of 5 treatment groups.  Enrollment of a total of approximately 
200 subjects is planned to achieve at least 150 evaluable subjects.  If required, to improve the 
precision of the interim or projected final analysis estimates of overall success, enrollment 
may be increased above the approximate 200 subjects.   
Adaptive Design:  
This is an adaptive dose-response finding study.  Initially, allocation to treatment arms will be 
equal between treatment arms.  During the course of the study, 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 (overall response comprised of clinical and 
microbiologic response).  When there is sufficient information available about the dose-
response, results from the Bayesian analysis will be reviewed by a Data Monitoring 
Committee (DMC) to determine if enrollment in any omadacycline treatment group(s) should 
be initiated, stopped, or modified.  Modifications to omadacycline treatment groups may also 
be based on safety and tolerability.  It is possible that not all treatment arms will be enrolling 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
PTK0796-AP-17202 Protocol
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IND # 75,928 IND # 73,431 
 
Confidential and Proprietary 
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subjects at the same time.  Arms may be dropped based on the Bayesian analysis or initiated 
based on the Bayesian analysis of the ongoing treatment arms.  There will always be at least 
one omadacycline arm and the levofloxacin arm open. 
Modifications to the total number of subjects enrolled may also be based on the evaluability 
rate for the microbiological intent-to-treat (micro-ITT) population. 
Bayesian analyses will be conducted after efficacy data (overall response at PTE) are 
available for approximately 40, 80 and 100 subjects in the micro-ITT population in order to: 
• Determine omadacycline treatment group(s) that can be initiated or dropped from the 
trial, or  
• Modify the randomization ratios among the treatment groups to improve the precision 
of the selected dose groups comparison of overall success to that of the levofloxacin 
group. 
Additional analyses may be carried out for the same purposes.  Response criteria are targeted 
towards estimating the probability that the overall success rate (proportion of subjects) for 
each omadacycline treatment group is within 10% of that of the levofloxacin group.  If at the 
interim analyses, that probability falls below 30% for a particular treatment group, recruitment 
for that treatment group may be stopped or curtailed.  If that probability exceeds 70% for a 
particular treatment group, recruitment for that treatment group may be stopped or increased 
to improve the precision of the estimate. Concurrent bacteremia are higher among adults >65 
years of age.  After approximately 100 subjects have been enrolled, the inclusion of females 
>65 years of age may be allowed based on review of interim analysis. 
 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
PTK0796-AP-17202 Protocol
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PTK0796-AP-17202-Version 1.0; 26Mar2018 
IND # 75,928 IND # 73,431 
 
Confidential and Proprietary 
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Main Criteria for Inclusion: 
 Written and signed informed consent must be obtained before any assessment is 
1.
performed.   
 a. Females age 18-65 years. 
2.
b. Females age 18 years or older.  
Inclusion 2a will be followed for first 100 subjects enrolled. Following an interim 
analysis, see adaptive design section for additional information, inclusion 2b may be 
allowed. An administrative memo will be issued to sites to formally notify them if/when 
Inclusion 2b will be followed. No subjects >65 years may be enrolled until an 
administrative memo is received and acknowledged by the investigator. 
 Clinical signs and symptoms of acute uncomplicated pyelonephritis with onset or 
3.
worsening within 96 hours prior to randomization.  Clinical signs and symptoms are 
defined as:  
 Flank pain or costovertebral angle tenderness on physical examination plus at least one 
•
of the following: 
o Chills or rigors or warmth associated with fever (oral, tympanic, rectal or core 
temperature > 38°C [> 100.4°F], which must be observed and documented by a 
health care provider), or 
o Nausea or Vomiting 
 A clean-catch midstream urine sample with dipstick analysis positive (at least ++) for 
4.
leukocyte esterase or pyuria (white blood cell [WBC] count > 10/μL in unspun urine or 
≥ 10 per high power field in spun urine sediment). 
 Female subjects must have a negative pregnancy test at Screening, and agree to comply 
5.
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.   
 Ability to communicate well with the investigator, to understand and comply with the 
6.
requirements of the study. 
Main Criteria for Exclusion: 
 Pregnant or nursing (breastfeeding) women. 
1.
 Receipt of any dose of a potentially therapeutic antibacterial agent (with potential activity 
2.
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 pyelonephritis 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.] 
 Anticipated need for systemic antibacterial therapy other than test article (for treatment or 
3.
prophylaxis) during the study period. 
 Infection at baseline that in the Investigator’s judgment would require more than 10 days 
4.
of antibacterial therapy (subjects determined to have bacteremia based on blood cultures 
collected at screening can be treated for up to 14 days). 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
PTK0796-AP-17202 Protocol
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 Symptoms of AP present longer than 7 days prior to randomization.  
5.
 Confirmed or suspected AP caused by a pathogen that is resistant to tetracyclines or 
6.
fluoroquinolones, including infection caused by fungi (eg, Candida spp.) or mycobacteria 
(eg, urogenital tuberculosis). 
 Known or suspected rapidly-progressing or life-threatening illness including septic shock. 
7.
Septic shock can be identified using the clinical criteria of hypotension requiring 
vasopressor therapy to maintain mean arterial blood pressure of 65mmHg or greater and 
having a serum lactate level greater than 2 mmol/L after adequate fluid resuscitation. 
 Use of an indwelling urinary catheter, nephrostomy tubes or other indwelling urinary tract 
8.
device within the 30 days prior to randomization.  
 Confirmed or suspected urinary retention (≥ 100 mL of residual urine after voiding) from 
9.
any cause, including neurogenic bladder or obstruction. 
 History of surgically modified or abnormal urinary tract anatomy (eg, bladder diverticula 
10.
or redundant urine collection system). 
 Confirmed or suspected complete or partial obstruction of the urinary tract, or obstructive 
11.
uropathy that is scheduled to be medically or surgically relieved during the study therapy 
period (eg, renal calculi, urethral or ureteral stricture). 
 Confirmed or suspected renal disease or condition that, in the opinion of the investigator, 
12.
may confound the assessment of efficacy, including but not limited to the following: 
• Perinephric or intrarenal abscess 
• Emphysematous pyelonephritis 
• Chronic pyelonephritis, including xanthogranulomatous pyelonephritis 
• Polycystic kidney disease 
• Renal carcinoma 
 History of renal transplant or a surgically created intestinal conduit for urinary diversion. 
13.
 Suspected or confirmed non-renal source of infection (eg, prostatitis, epididymitis, 
14.
orchitis, endocarditis, osteomyelitis, abscess, meningitis, pneumonia). 
 Confirmed or suspected vaginitis or sexually transmitted infection or lower UTI (ie, 
15.
cystitis) without symptoms/signs of AP. 
 Has any of the following at Screening: 
16.
• 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) 
 History of unstable cardiac disease (eg, unstable angina, myocardial infarction, acute 
17.
congestive heart failure, unstable cardiac arrhythmia, etc.) within the 3 months prior to 
randomization. 
 Significant immunological disease determined by any of the following: 
18.
• 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 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
PTK0796-AP-17202 Protocol
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Syndrome (AIDS)-defining illness as determined by the investigator. 
 Receipt of cancer chemotherapy, radiotherapy, or potent, non-corticosteroid 
19.
immunosuppressant drugs (eg, cyclosporine, azathioprine, tacrolimus, 
immune-modulating monoclonal antibody therapy, etc.) within the 3 months prior to 
randomization, or the receipt of systemic corticosteroids equivalent to or greater than 
40 mg of prednisone per day (see equivalent corticosteroid doses in Appendix 2) or 40 mg 
of prednisone per day for more than 14 days in the 30 days prior to randomization. 
 History of hypersensitivity or allergic reaction (eg, anaphylaxis, urticaria, other significant 
20.
reaction) to any tetracycline (eg, minocycline, doxycycline or tigecycline) or 
fluoroquinolone (eg, levofloxacin, ciprofloxacin, moxifloxacin) antibiotic. 
 Inability to swallow 6 tablets in succession. 
21.
 History of pseudotumor cerebri, or prior (within 2 weeks prior to randomization) or 
22.
planned concomitant use of isotretinoin. 
 History of systemic lupus erythematosus or lupus-like syndrome. 
23.
 Has current evidence of pancreatitis. 
24.
 History of myasthenia gravis. 
25.
 Screening calculated creatinine clearance (CrCl) < 50 mL/minute, using the 
26.
Cockcroft-Gault equation (see equation in Appendix 2), requires any form of dialysis (eg, 
hemodialysis, peritoneal dialysis, or continuous veno-venous hemofiltration), or other 
evidence of severe renal disease. 
 History of tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, or central 
27.
nervous system effects (eg, hallucinations, anxiety, depression, insomnia, severe 
headaches, and confusion). * 
 Has a QT interval > 500 msec, or known long QT syndrome. * 
28.
 Current use of antiarrhythmic agents of Class IA (eg, quinidine, procainamide) or Class III 
29.
(eg, amiodarone, sotalol). * 
 Use of other investigational drugs within 5 half-lives or 30 days prior to randomization, 
30.
whichever is longer. 
 Has previously been treated with omadacycline or previously enrolled in this study. 
31.
 Unable or unwilling, in the opinion of the investigator, to comply with the protocol 
32.
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. 
* Exclusions required due to fluoroquinolone comparator 
 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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Test Article; Dose; and Mode of Administration:  
Group 1:  Omadacycline 200 mg iv every 24 hours (q24h) 
Group 2:  Omadacycline 200 mg iv × 1 day followed by 100 mg iv q24h  
Group 3:  Omadacycline 200 mg iv × 1 day followed by mg iv q24h or 300 mg po q24h  
Group 4:  Omadacycline 200 mg iv × 1 day followed by 100 mg iv q24h or 450 mg po q24h  
Group 5:  Levofloxacin 750 mg iv q24h × 1 day followed by 750 mg iv or 750 mg po q24h 
Duration of Treatment:  
The total duration of therapy for subjects will be 7 to 10 days, with the exception of subjects 
with bacteremia confirmed from local blood culture drawn at screening can receive up to 14 
days of treatment. 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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Pharmacokinetic Assessments 
Blood collection (plasma): 
Blood samples will be collected and analyzed for omadacycline concentration at the following 
times: 
• Just prior to the dose on Day 3 and just prior to last dose of test article;  
• 2 to 3 hours after dose on Day 3 and 2 to 3 hours after last dose of test article. 
Urine Collection: 
Urine will be collected, the volume recorded, and analyzed for omadacycline concentration at 
the following times:  
• Day 3 to 4:  pooled total urine from 0 to 24 hours after the Day 3 dose;  
• Day 6 to 7:  pooled total urine from 0 to 24 hours after the Day 6 dose. 
Omadacycline urine concentration data will be used to determine the 24-hour average urinary 
concentration and amount of drug excreted in the urine in a dosing interval at steady-state.  
 
Safety Assessments: 
• Physical examinations; 
• Vital signs (body temperature, blood pressure, heart rate),  
• Height and body weight; 
• Laboratory tests (hematology, serum chemistry, urinalysis); 
• AEs and serious adverse events (SAEs); 
• AEs of interest (nausea and vomiting); 
• Concomitant medications; 
• Pregnancy assessments (for women only). 
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;  
• Modified Patient symptom assessment questionnaire (mPSAQ) 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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Statistical Methods:  
Enrollment of approximately 200 subjects is planned to achieve at least 150 subjects in the 
micro-ITT population.  The Bayesian posterior probability that the overall success rate at the 
PTE Visit is within 0.10 of that of the levofloxacin group will be estimated for each 
omadacycline treatment group.  The target probability is 0.70.  If the true underlying overall 
success rates for the levofloxacin and omadacycline treatment groups are 0.69, then the 
sample size of N = 30 per treatment group has approximately 65% power/probability to yield 
the target probability (N = 80 per treatment group for 80% power).  If the true underlying 
overall success rates for the levofloxacin and omadacycline treatment groups are 0.78, then 
the sample size of N = 30 per treatment group has approximately 68% power/probability to 
yield the target probability (N = 64 per treatment group for 80% power).  The sample size 
may be increased for a particular omadacycline treatment group by changing the 
randomization ratio and/or dropping a treatment group to have improved power/probability of 
achieving the target probability that overall success rates for an omadacycline treatment group 
is within 0.10 of that of the levofloxacin group.  If–required to improve the precision of the 
interim or projected final analyses estimates of overall response rates or posterior 
probabilities, the sample size may be increased to a maximum sample size provided in the 
Statistical Analysis Plan (SAP).  
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 micro-ITT population will consist of subjects in the ITT population who have an 
appropriately collected pretreatment baseline urine culture with at least 1 uropathogen 
at ≥ 105 colony forming units (CFU)/mL and not more than 2 bacterial isolates at any 
count.  If more than 2 bacterial isolates are identified, the culture will be considered 
contaminated regardless of colony count, unless 1 of the isolates that grows in the 
urine at ≥ 105 CFU/mL is also isolated from a blood culture at the same visit.  
• The clinically evaluable (CE) population will consist of all ITT subjects who received 
test article, have acute uncomplicated pyelonephritis, 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 and 
micro-ITT populations who have an appropriately collected post-baseline urine sample 
and an interpretable post-baseline urine sample.  An interpretable post-baseline urine 
culture is one that has a clearly identified pathogen or one where the baseline 
pathogen(s) can be excluded (ie, there is no growth of the baseline pathogen). 
All safety data will be summarized by treatment group and the incidence of AEs will be 
presented by system organ class (SOC) and preferred term (PT) according to the Medical 
Dictionary for Regulatory Activities (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 primary efficacy outcome is overall response at the PTE Visit in the micro-ITT 
population, which is a composite of per-subject microbiologic response and investigator 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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assessment of clinical response. 
The number and percentage of subjects within each category of overall response, investigator 
assessment of clinical response, and microbiological response will be presented at each time 
point measured by treatment group.  Exact 95% confidence intervals (CIs) will be determined 
for the point estimates of the overall, clinical and microbiologic success rates.  A comparison 
of overall success at PTE between each omadacycline treatment group and the levofloxacin 
group will be conducted using a beta distribution with an uninformative Bayesian prior 
distribution. 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
TABLE OF CONTENTS .........................................................................................................15 
LIST OF IN-TEXT TABLES ..................................................................................................19 
LIST OF APPENDICES ..........................................................................................................19 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................20 
1 
DISCLOSURE STATEMENT ........................................................................................23 
2 
CONTACTS ....................................................................................................................24 
 
Emergency Contacts ..............................................................................................24 
2.1
 
Additional Contacts ...............................................................................................24 
2.2
3 
INTRODUCTION ...........................................................................................................25 
 
Acute Pyelonephritis ..............................................................................................25 
3.1
 
Omadacycline ........................................................................................................25 
3.2
4 
STUDY OBJECTIVES ....................................................................................................27 
 
Primary Objective ..................................................................................................27 
4.1
 
Secondary Objectives.............................................................................................27 
4.2
5 
INVESTIGATIONAL PLAN ..........................................................................................28 
 
Overall Study Description......................................................................................28 
5.1
5.1.1 
Adaptive Design...........................................................................................28 
 
Rationale for Study Design ....................................................................................29 
5.2
 
Rationale for Control Group ..................................................................................29 
5.3
 
Approximate Duration of Subject Participation ....................................................30 
5.4
 
Approximate Duration of Study .............................................................................30 
5.5
 
Approximate Number of Subjects .........................................................................30 
5.6
6 
STUDY POPULATION SELECTION ...........................................................................31 
 
Study Population ....................................................................................................31 
6.1
 
Inclusion Criteria ...................................................................................................31 
6.2
 
Exclusion Criteria ..................................................................................................32 
6.3
 
Screen Failures .......................................................................................................34 
6.4
7 
STUDY TREATMENT(S) ..............................................................................................35 
 
Treatments Administered .......................................................................................35 
7.1
 
Identity of the Investigational Product:  Omadacycline ........................................35 
7.2
 
Comparator Test Article:  Levofloxacin ................................................................36 
7.3
 
Dose Selection Rationale .......................................................................................37 
7.4
 
Description of Treatments......................................................................................38 
7.5
 
Test Article Administration ...................................................................................38 
7.6
7.6.1 
Intravenous Treatment Phase .......................................................................38 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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7.6.2 
Selection and Timing of iv Dose for Each Subject ......................................39 
7.6.3 
Management While on iv Test Article .........................................................39 
7.6.4 
Investigator’s Decision to Continue or Discontinue Treatment ..................40 
7.6.5 
Investigator’s Decision to Switch from iv to po Treatment .........................40 
7.6.6 
Oral Treatment Phase ...................................................................................40 
 
Management While on Oral Test Article ...........................................41 
7.6.6.1
 
Dose Adjustments and Interruptions of Test Article .............................................42 
7.7
 
Method of Assigning Patients to Treatment Groups..............................................42 
7.8
7.8.1 
Subject Numbering ......................................................................................43 
 
Dispensing Test Article..........................................................................................43 
7.9
 
Blinding..................................................................................................................43 
7.10
 
Emergency Unblinding of Treatment Assignment ................................................44 
7.11
 
Prior & Concomitant Therapy ...............................................................................45 
7.12
 
Prohibited Therapy.................................................................................................45 
7.13
7.13.1 
Concomitant Medications That May Interact with Levofloxacin ................46 
 
Permitted Treatments .............................................................................................46 
7.14
 
Treatment Compliance ...........................................................................................46 
7.15
 
Packaging and Labeling .........................................................................................46 
7.16
 
Storage and Accountability ....................................................................................46 
7.17
 
Investigational Product Retention at Study Site ....................................................47 
7.18
8 
STUDY PROCEDURES .................................................................................................48 
 
Informed Consent...................................................................................................48 
8.1
 
Subject Demographics/Other Baseline Characteristics .........................................48 
8.2
 
Medical History .....................................................................................................48 
8.3
 
Physical Examination.............................................................................................48 
8.4
 
Vital Signs ..............................................................................................................49 
8.5
 
Height and Weight .................................................................................................49 
8.6
 
Clinical Laboratory Tests .......................................................................................49 
8.7
8.7.1 
Central Laboratory Parameters ....................................................................50 
8.7.2 
Local Laboratory Parameters .......................................................................50 
 
Pregnancy Assessments .....................................................................50 
8.7.2.1
 
Urine Culture and Dipstick Tests .......................................................50 
8.7.2.2
 
Blood Cultures ...................................................................................51 
8.7.2.3
 
Efficacy Assessments.............................................................................................52 
8.8
8.8.1 
Investigator’s Assessment of Clinical Response .........................................52 
 
Investigator’s Assessment of Clinical Response at EOT ...................52 
8.8.1.1
 
Investigator’s Assessment of Clinical Response at PTE ...................52 
8.8.1.2
 
Investigator’s Assessment of Clinical Response at Final Follow-
8.8.1.3
up........................................................................................................52 
 
Microbiologic Response ........................................................................................53 
8.9
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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Modified Patient Symptom Assessment Questionnaire .........................................53 
8.10
 
Pharmacokinetic Assessments ...............................................................................54 
8.11
8.11.1 
PK Blood Collection and Processing ...........................................................54 
8.11.2 
PK Urine Collection and Processing............................................................54 
8.11.3 
Storing and Shipping of PK Samples...........................................................54 
 
Adverse Events ......................................................................................................54 
8.12
 
Serious Adverse Events .........................................................................................55 
8.13
 
Other Reportable Information ................................................................................56 
8.14
 
Overdose ................................................................................................................56 
8.15
 
Medication Errors ..................................................................................................56 
8.16
 
Recording and Reporting .......................................................................................57 
8.17
8.17.1 
Serious Adverse Event Reporting ................................................................57 
8.17.2 
Assessment of Relatedness ..........................................................................57 
8.17.3 
Assessment of Severity ................................................................................58 
8.17.4 
Laboratory Findings .....................................................................................58 
8.17.5 
Worsening or Progression of Disease Under Study .....................................58 
8.17.6 
Pregnancies ..................................................................................................59 
 
Concomitant Medication Assessments ..................................................................59 
8.18
 
Subject Discontinuation or Withdrawal .................................................................59 
8.19
9 
STUDY ACTIVITIES .....................................................................................................61 
 
Screening Phase .....................................................................................................61 
9.1
 
Double-Blind Treatment Phase ..............................................................................61 
9.2
9.2.1 
Day 1 Visit Procedures ................................................................................61 
9.2.2 
Day 2 Visit Procedures ................................................................................62 
9.2.3 
Day 3 Visit Procedures ................................................................................62 
9.2.4 
Day 4 Visit Procedures ................................................................................63 
9.2.5 
Day 5 Visit Procedures ................................................................................63 
9.2.6 
Day 6 Visit Procedures ................................................................................64 
9.2.7 
Day 7 Visit Procedures ................................................................................64 
9.2.8 
Day 8, 9 Visit Procedures ............................................................................65 
9.2.9 
Day 10 Visit Procedures ..............................................................................65 
9.2.10 
Day 11, 12, 13 Visit Procedures ..................................................................66 
 
EOT Visit Procedures ............................................................................................66 
9.3
 
Follow-up Phase.....................................................................................................67 
9.4
9.4.1 
Post-Treatment Evaluation Visit (Day 21) Procedures ................................67 
9.4.2 
Final Follow-up ............................................................................................67 
10 STUDY SUSPENSION, TERMINATION, AND COMPLETION ................................69 
 
Study Completion and Post-Study Test Article .....................................................69 
10.1
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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Study Suspension or Termination ..........................................................................69 
10.2
11 QUALITY CONTROL AND ASSURANCE .................................................................70 
12 PLANNED STATISTICAL METHODS ........................................................................71 
 
General Considerations ..........................................................................................71 
12.1
 
Determination of Sample Size ...............................................................................71 
12.2
 
Analysis Populations ..............................................................................................72 
12.3
 
Demographics and Baseline Characteristics ..........................................................72 
12.4
 
Primary Endpoint(s) ...............................................................................................72 
12.5
12.5.1 
Efficacy Endpoint ........................................................................................72 
 
Secondary Endpoint(s) ...........................................................................................73 
12.6
12.6.1 
Safety Endpoint(s) .......................................................................................73 
12.6.2 
Efficacy Endpoint(s) ....................................................................................73 
 
Interim Analysis .....................................................................................................74 
12.7
 
Data Monitoring Committee ..................................................................................75 
12.8
13 ADMINISTRATIVE CONSIDERATIONS ....................................................................76 
 
Investigators and Study Administrative Structure .................................................76 
13.1
 
Institutional Review Board or Independent Ethics Committee Approval .............76 
13.2
 
Ethical Conduct of the Study .................................................................................76 
13.3
 
Patient Information and Consent ...........................................................................76 
13.4
 
Direct Access, Data Handling, and Record Keeping .............................................77 
13.5
13.5.1 
Investigator ..................................................................................................77 
13.5.2 
Sponsor ........................................................................................................77 
 
Protocol Adherence ................................................................................................77 
13.6
13.6.1 
Violations/Deviations ..................................................................................77 
13.6.2 
Protocol Amendments ..................................................................................77 
 
Subject Injury .........................................................................................................78 
13.7
 
Pre-Study Documentation ......................................................................................78 
13.8
 
Retention of Data ...................................................................................................79 
13.9
 Publication and Disclosure Policy .........................................................................79 
13.10
14 REFERENCE LIST .........................................................................................................80 
APPENDIX 1 
SCHEDULE OF EVENTS ..........................................................................81 
APPENDIX 2 
EQUATIONS AND CONVERSION FACTORS .......................................84 
APPENDIX 3 
MODIFIED PATIENT SYMPTOM ASSESSMENT 
QUESTIONNAIRE (MPSAQ) ........................................................................................85 
APPENDIX 4 
SPONSOR SIGNATURE ............................................................................87 
APPENDIX 5 
INVESTIGATOR’S SIGNATURE .............................................................88 
 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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LIST OF IN-TEXT TABLES 
Table 1. 
Description of Treatment Groups ..........................................................................38 
Table 2. 
Dosing Blinded iv and Oral Double-Blind, Double-Dummy Design ....................42 
Table 3. 
Clinical Laboratory Tests (Central) .......................................................................50 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events .................................................................................................81 
Appendix 2 
Equations and Conversion Factors .........................................................................84 
Appendix 3 
Modified Patient Symptom Assessment Questionnaire (mPSAQ) ........................85 
Appendix 4 
Sponsor Signature ..................................................................................................87 
Appendix 5 
Investigator’s Signature .........................................................................................88 
 
 
 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
ABSSSI 
acute bacterial skin and skin structure infections 
AC 
alveolar cells 
AE 
adverse Event 
AIDS 
Acquired Immune Deficiency Syndrome 
ALT 
alanine aminotransferase (SGPT) 
AP 
acute pyelonephritis 
AST 
aspartate aminotransferase (SGOT) 
AUC 
area under the concentration time curve 
β-hCG 
serum β-human chorionic gonadotropin 
BP 
Blood pressure 
CABP 
community-acquired bacterial pneumonia 
CD4 
cluster of differentiation 4 
CE 
clinically evaluable 
CFR 
Code of Federal Regulations 
CFU 
colony forming units 
CI 
confidence interval  
CrCl 
creatinine clearance 
CRF 
case report form 
CSA 
clinical study agreement 
CSR 
Clinical Study Report 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ELF 
epithelial lining fluid 
EOT 
end of treatment 
ESBL 
extended spectrum beta-lactamase 
GCP 
Good Clinical Practice 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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HIV 
Human Immunodeficiency Virus 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IUD 
intrauterine device 
iv 
intravenous 
IxRS 
interactive voice/web response system 
ME 
microbiologically evaluable 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
minimum inhibitory concentration 
micro-ITT 
microbiological intent-to-treat 
OTC 
over-the-counter 
PI 
Principal Investigator 
PK 
pharmacokinetics 
po 
Per Oral 
mPSAQ 
Modified Patient Symptom Assessment Questionnaire 
PT 
preferred term 
PTE 
Post Therapy Evaluation 
q24h 
every 24 hours 
q12h 
every 12 hours 
REB 
Research Ethics Board 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TFL 
tables, figures, and listings 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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ULN 
Upper Limit of Normal 
US 
United States 
UTI 
urinary tract infection  
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. 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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2 
CONTACTS 
 
Emergency Contacts 
2.1
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:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
2.2
SAE contact information: 
E-Mail: 
 
 
 
 
 
 
 
 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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3 
INTRODUCTION 
 
Acute Pyelonephritis 
3.1
Acute pyelonephritis (AP), or upper UTI, is a common infection featuring fever, chills, , 
flank pain, costovertebral angle tenderness, and nausea or vomiting.1  Nearly all cases of AP 
are caused by the ascension of uropathogens from the urinary bladder to the kidney; a 
minority of cases are caused by the hematogenous route.1  The incidence of AP is highest 
among young women, followed by infants and the elderly population.1  The annual rates of 
AP among ambulatory women and men are approximately 12–13 and 2–3 cases per 10,000, 
respectively.2  Although the mortality associated with AP is relatively low, UTIs including 
AP account for approximately 5% to 7% of all cases of severe sepsis.3,4 
Acute pyelonephritis is caused predominantly by members of the Enterobacteriaceae; for 
example, E. coli causes approximately 80% of cases of AP in women and 70% of cases in 
men.2  Although rates of antibacterial resistance against various antimicrobial classes is 
increasing among E. coli strains causing AP (eg, > 10%-20% resistance to trimethoprim 
sulfamethoxazole), the rate of fluoroquinolone resistance remains relatively low in the United 
States (US) (eg, ciprofloxacin resistance increased from 0.2% of E. coli isolates to 1.5% of 
isolates between 1997 and 2001).2  However, recent global data suggests that 
fluoroquinolone resistance in complicated UTI may be as high as 35% to 50% in some 
countries, underlying the urgent medical need for new antibacterial agents for these 
infections.5 
 
Omadacycline 
3.2
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), 
uncomplicated UTI and AP. 
Omadacycline has been evaluated in two global Phase 3 studies, one comparing the safety 
and efficacy of iv and/or po omadacycline to iv and/or po linezolid in the treatment of adult 
subjects with ABSSSI (PTK0796-ABSI-1108; PTK0796-ABSI-16301).  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).  In all three studies, omadacycline was well-tolerated and 
demonstrated non-inferiority to its respective comparator. 
The drug is active against strains expressing both mechanisms of tetracycline resistance, 
namely efflux and ribosomal protection.6  Omadacycline has in vitro activity against the most 
common AP uropathogens including E. coli.  Resistance to other antibiotics does not affect 
omadacycline activity.  Omadacycline is not affected by tetracycline-resistance, presence of 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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extended spectrum beta-lactamase (ESBL), or other common resistance mechanisms.  
Omadacycline is active against the Enterobacteriaceae with a significant proportion of 
isolates having a minimum inhibitory concentration (MIC) < 2.0 μg/ml.  The MICs for at 
least 90% of the isolates tested (MIC90) for omadacycline 2 µg/mL for E. coli, regardless of 
ESBL status.6 
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 UTI study population.  
This study is intended to evaluate the efficacy and safety of iv/po omadacycline as compared 
to iv/po levofloxacin in the treatment of adult subjects with AP.  This 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 AP pathogens 
(see dose selection discussion in Section 7.4). 
Please refer to the current version of the Investigator's Brochure for additional information on 
omadacycline.7 
 
 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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4 
STUDY OBJECTIVES 
 
Primary Objective  
4.1
The primary objective of this study is: 
To evaluate the efficacy of intravenous (iv) and iv to oral (iv/po) dosing regimens of 
omadacycline and levofloxacin in the treatment of adults with AP. 
 
Secondary Objectives  
4.2
The secondary objectives of this study are: 
• To evaluate the safety of omadacycline in the treatment of adults with AP.   
• To evaluate the PK of omadacycline in adults with AP. 
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5 
INVESTIGATIONAL PLAN 
 
Overall Study Description 
5.1
This is a randomized, double-blinded, adaptive designed Phase 2 study evaluating once-daily 
iv or iv/po dosing regimens of omadacycline compared to one once-daily dosing regimen of 
iv/po levofloxacin in the treatment of adults with AP.  The planned length of subject 
participation in the study is up to 30 days which includes a total duration of study therapy for 
7 to 10 days (iv only or iv and oral combined).  Subjects with bacteremia confirmed from 
local blood culture drawn at screening can receive up to 14 days of treatment.  
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 iv or iv/po omadacycline dosing regimens or a regimen of iv/po 
levofloxacin (see Table 1 and Table 2).  Subjects should receive their first dose of test article 
at the site within 4 hours after randomization.  Iv and oral treatment will be double-blinded 
and oral treatment will be 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.  Blood will also be drawn during each subject’s Screening 
evaluation for microbiologic culture; repeat samples will be taken during subsequent visits if 
bacteremia is identified during Screening.  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. 
Subject visits occur on Days 1 to 7.  If treatment extends beyond 7 days, subject visits may 
occur on Days 8 to 10.  If treatment extends beyond 10 days for subjects with bacteremia 
based on screening culture, visits will occur on Days 11 to 13.  An end of treatment (EOT) 
visit will be conducted on the day of or within 2 days following the last dose of test article.  
Subjects will return to the study site for a Post Therapy Evaluation (PTE) on Day 21 (± 2 
days).  A Final Follow-up visit (Final Follow-up) will be conducted on Day 28 (± 2 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 were considered to 
be clinical successes and had no AEs or clinically significant laboratory or electrocardiogram 
(ECG) 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, allocation to treatment arms will 
be equal between treatment arms.  During the course of the study, Bayesian analysis will be 
used to adaptively allocate new subjects to one of the treatment arms, conditional on the 
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availability of primary efficacy endpoint data (overall response comprised of clinical and 
microbiologic response).  When there is sufficient information available about the dose-
response, results from the Bayesian analysis will be reviewed by a Data Monitoring 
Committee (DMC) to determine if enrollment in any omadacycline treatment group(s) should 
be initiated, stopped, or modified.  Modifications to omadacycline treatment groups may also 
be based on safety and tolerability.  It is possible that not all treatment arms will be enrolling 
subjects at the same time.  Arms may be dropped based on the Bayesian analysis or initiated 
based on the Bayesian analysis of the ongoing treatment arms.  There will always be at least 
one omadacycline arm and one levofloxacin arm open.  Modifications to the total number of 
subjects enrolled may also be based on the evaluability rate for the microbiological intent-to-
treat (micro-ITT) population. 
Bayesian analyses will be conducted after efficacy data (overall response at PTE) are 
available for approximately 40, 80 and 100 subjects in the micro-ITT population in order to: 
• Determine omadacycline treatment group(s) that can be initiated or dropped from the 
trial, or  
• Modify the randomization ratios among the treatment groups to improve the precision 
of the selected dose groups comparison of overall success to that of the levofloxacin 
group. 
Additional analyses may be carried out for the same purposes.  Response criteria are targeted 
towards estimating the probability that the overall success rate (proportion of subjects) for 
each omadacycline treatment group is within 10% of that of the levofloxacin group.  If at the 
interim analyses, that probability falls below 30% for a particular treatment group, 
recruitment for that treatment group may be stopped or curtailed.  If that probability exceeds 
70% for a particular treatment group, recruitment for that treatment group may be stopped or 
increased to improve the precision of the estimate. Concurrent bacteremia are higher among 
adults >65 years of age. 11  After approximately 100 subjects have been enrolled, the 
inclusion of females >65 years of age may be allowed based on review of interim analysis. 
 
Rationale for Study Design  
5.2
Omadacycline is the first member of the aminomethylcycline class of antibiotics, which are 
semi-synthetic derivatives of the tetracycline class.  Omadacycline has in vitro activity 
against the most common bacterial pathogens associated with AP.  Omadacycline has been 
shown to have a sufficient 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 not been evaluated in adults with acute pyelonephritis. 
 
Rationale for Control Group 
5.3
According to contemporary guidelines for management of AP by the Infectious Diseases 
Society of America and European Society for Microbiology and Infectious Diseases, 
once-daily fluoroquinolone therapy―including levofloxacin 750 mg―is an appropriate 
empiric antibacterial regimen for AP where the prevalence of fluoroquinolones resistance of 
community uropathogens is not known to exceed 10%.8  In regions with low levels of 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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fluoroquinolone resistance among outpatient uncomplicated pyelonephritis isolates (eg, in 
most areas of the US), the fluoroquinolones are the preferred antimicrobial class for oral 
therapy for acute uncomplicated pyelonephritis.8  Recent studies support the use of relatively 
short courses of levofloxacin therapy (ie, 5-7 days) versus the traditional 14-day regimen for 
mild to moderate AP.9  This was further demonstrated in a contemporary complicated UTI 
trial in which ceftolozane-tazobactam was compared to levofloxacin 750 mg every 24 hours 
(q24h) for 7 days; approximately 82% of subjects enrolled in this trial were diagnosed with 
AP.10  Both treatment regimens were associated with high and similar overall outcomes 
(clinical cures and microbiological eradication rates) at the test-of-cure visit among subjects 
with AP (79.0% vs 73.2%, treatment difference 5.8% [95% confidence interval (CI):  -0.7, 
12.3%]), supporting the durable efficacy of fluoroquinolone therapy in AP. 
 
Approximate Duration of Subject Participation 
5.4
Subjects will participate in the study for up to 30 days.  Following Screening, eligible 
subjects will be randomly assigned to receive 7 to 10 days of iv/po treatment of either 
omadacycline or levofloxacin.  Subjects with bacteremia confirmed from local blood culture 
drawn at screening can receive up to 14 days of treatment.  Subjects will return to the site for 
an EOT visit on the day of or within 2 days following the last dose of test article.  Subjects 
will return to the study site for a PTE on Day 21 (± 2 days).  A final follow-up assessment 
will be conducted Day 28 (± 2 days) following the first dose of test article. 
 
Approximate Duration of Study 
5.5
The study is expected to be clinically complete in approximately 12 months. 
 
Approximate Number of Subjects 
5.6
Approximately 200 subjects will participate in this study at up to 35 sites. 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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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 
6.1
Approximately 200 subjects will be enrolled at approximately 35 sites.  Initially, subjects 
will be randomized (1:1:1:1:1) to 1 of 5 treatment groups.  Enrollment of a total of 
approximately 200 subjects is planned to achieve at least 150 evaluable subjects.  If required, 
to improve the precision of the interim or projected final analysis estimates of overall 
response, enrollment may be increased above the approximate 200 subjects.  
 
Inclusion Criteria 
6.2
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. a. Females age 18-65 years. 
b. Females age 18 years or older.  
Inclusion 2a will be followed for first 100 subjects enrolled. Following an interim 
analysis, see adaptive design section for additional information, inclusion 2b may be 
allowed. An administrative memo will be issued to sites to formally notify them if/when 
Inclusion 2b will be followed. No subjects >65 years may be enrolled until an 
administrative memo is received and acknowledged by the investigator. 
3.  Clinical signs and symptoms of acute uncomplicated pyelonephritis with onset or 
worsening within 96 hours prior to randomization.  Clinical signs and symptoms are 
defined as:  
• Flank pain or costovertebral angle tenderness on physical examination plus at least 
one of the following: 
o Chills or rigors or warmth associated with fever (oral, tympanic, rectal or core 
temperature > 38°C [> 100.4°F], which must be observed and documented by a 
health care provider), or 
o Nausea or Vomiting 
4. A clean-catch midstream urine sample with dipstick analysis positive (at least ++) for 
leukocyte esterase or pyuria (white blood cell [WBC] count > 10/μL in unspun urine or 
≥ 10 per high power field in spun urine sediment).   
5. Female subjects 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.   
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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6. Ability to communicate well with the investigator, to understand and comply with the 
requirements of the study. 
 
Exclusion Criteria 
6.3
Patients who meet any of the following exclusion criteria will be excluded from the study: 
Main Criteria for Exclusion: 
1. Pregnant or nursing (breastfeeding) women. 
2. 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 pyelonephritis 
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.] 
3. Anticipated need for systemic antibacterial therapy other than test article (for treatment or 
prophylaxis) during the study period. 
4. Infection at baseline that in the Investigator’s judgment would require more than 10 days 
of antibacterial therapy (subjects determined to have bacteremia based on blood cultures 
collected at screening can be treated for up to 14 days). 
5. Symptoms of AP present longer than 7 days prior to randomization.  
6. Confirmed or suspected AP caused by a pathogen that is resistant to tetracyclines or 
fluoroquinolones, including infection caused by fungi (eg, Candida spp.) or mycobacteria 
(eg, urogenital tuberculosis). 
7. Known or suspected rapidly-progressing or life-threatening illness including septic shock. 
Septic shock can be identified using the clinical criteria of hypotension requiring 
vasopressor therapy to maintain mean arterial blood pressure of 65mmHg or greater and 
having a serum lactate level greater than 2 mmol/L after adequate fluid resuscitation. 
8. Use of an indwelling urinary catheter, nephrostomy tubes or other indwelling urinary 
tract device within the 30 days prior to randomization.  
9. Confirmed or suspected urinary retention (≥ 100 mL of residual urine after voiding) from 
any cause, including neurogenic bladder or obstruction. 
10. History of surgically modified or abnormal urinary tract anatomy (eg, bladder diverticula 
or redundant urine collection system). 
11. Confirmed or suspected 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 (eg, renal calculi, urethral or ureteral stricture). 
12. Confirmed or suspected renal disease or condition that, in the opinion of the investigator, 
may confound the assessment of efficacy, including but not limited to the following: 
• Perinephric or intrarenal abscess 
• Emphysematous pyelonephritis 
• Chronic pyelonephritis, including xanthogranulomatous pyelonephritis 
• Polycystic kidney disease 
• Renal carcinoma 
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13. History of renal transplant or a surgically created intestinal conduit for urinary diversion. 
14. Suspected or confirmed non-renal source of infection (eg, prostatitis, epididymitis, 
orchitis, endocarditis, osteomyelitis, abscess, meningitis, pneumonia). 
15. Confirmed or suspected vaginitis or sexually transmitted infection or lower UTI (ie, 
cystitis) without symptoms/signs of acute pyelonephritis.  
16. 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) 
17. History of unstable cardiac disease (eg, unstable angina, myocardial infarction, acute 
congestive heart failure, unstable cardiac arrhythmia, etc.) within the 3 months prior to 
randomization. 
18. 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. 
19. Receipt of cancer chemotherapy, radiotherapy, or potent, non-corticosteroid 
immunosuppressant drugs (eg, cyclosporine, azathioprine, tacrolimus, 
immune-modulating monoclonal antibody therapy, etc.) within the 3 months prior to 
randomization, or the receipt of systemic corticosteroids equivalent to or greater than 
40 mg of prednisone per day (see equivalent corticosteroid doses in Appendix 2) or 40 
mg of prednisone per day for more than 14 days in the 30 days prior to randomization. 
20. History of hypersensitivity or allergic reaction (eg, anaphylaxis, urticaria, other 
significant reaction) to any tetracycline (eg, minocycline, doxycycline or tigecycline) or 
fluoroquinolone (eg, levofloxacin, ciprofloxacin, moxifloxacin) antibiotic. 
21. Inability to swallow 6 tablets in succession. 
22. History of pseudotumor cerebri, or prior (within 2 weeks prior to randomization) or 
planned concomitant use of isotretinoin. 
23. History of systemic lupus erythematosus or lupus-like syndrome. 
24. Has current evidence of pancreatitis. 
25. History of myasthenia gravis. 
26. Screening calculated creatinine clearance (CrCl) < 50 mL/minute, using the 
Cockcroft-Gault equation (see equation in Appendix 2), requires any form of dialysis (eg, 
hemodialysis, peritoneal dialysis, or continuous veno-venous hemofiltration), or other 
evidence of severe renal disease. 
27. History of tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, or 
central nervous system effects (eg, hallucinations, anxiety, depression, insomnia, severe 
headaches, and confusion). * 
28. Has a QT interval > 500 msec, or known long QT syndrome. * 
29. Current use of antiarrhythmic agents of Class IA (eg, quinidine, procainamide) or Class 
III (eg, amiodarone, sotalol). * 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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30. Use of other investigational drugs within 5 half-lives or 30 days prior to randomization, 
whichever is longer. 
31. Has previously been treated with omadacycline or previously enrolled in this study. 
32. 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. 
* Exclusions required due to fluoroquinolone comparator 
 
Screen Failures 
6.4
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. 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 
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7 STUDY TREATMENT(S) 
7.1 
Treatments Administered 
Test articles will be supplied by Paratek Pharma, Inc (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 iv or iv/po dosing regimens of omadacycline treatment or an iv/po regimen of 
levofloxacin.  Intravenous treatment will be double-blind and oral treatment will be 
double-blind and double-dummy.  
7.2 
Identity of the Investigational Product:  Omadacycline 
Intravenous Formulation (Omadacycline) 
Name 
Omadacycline  
Excipients 
Tosylate acid counter ion, sucrose, hydrochloric acid and sodium hydroxide to adjust the 
pH 
How supplied 
Sterile, lyophilized powder for reconstitution packaged in a clear, glass vial with a rubber 
stopper and aluminum overseal.  The labeled content of the vial is 100 mg of omadacycline 
base.  There is a 4% overfill to allow for the extraction of a 100 mg dose. 
Storage 
Store at 25˚C (77˚F).  Excursions permitted to 15°C to 30°C (59-86˚F) 
Preparation and 
handling 
To prepare the 100 mg dose, add 5 mL of the reconstituted solution (the content of one 100 
mg vial) to the infusion container 150 mL Normal Saline (NS). 
 
To prepare the 200 mg dose, add 10 mL of the reconstituted solution (the contents of two 
100 mg vials) to the infusion container of 150 mL NS. 
The prepared infusion solution should be used within 8 hours or stored at up to 24 hours at 
2°C to 8°C (36°F to 46°F). 
Please refer to the Pharmacy Manual for additional information. 
Administration 
Please reference Table 2 in Section 7.6.6.1  
 
 
 
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Oral Formulation (Omadacycline) 
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 
Store at 25˚C (77˚F).  Excursions permitted to 15°C-30°C (59-86˚F) (Per Pharmacy 
Manual) 
Preparation and 
handling 
No special requirements 
Administration 
Please reference Table 2 in Section 7.6.6.1  
7.3 
Comparator Test Article:  Levofloxacin 
Intravenous Formulation (Levofloxacin) 
Name 
Levofloxacin 
Excipients 
Sodium chloride, sodium hydroxide (for pH adjustment), hydrochloric acid (for pH 
adjustment), and water for injection 
How supplied 
Levofloxacin 5 mg/ml in saline.  Single-Use premixed solution in container for 
intravenous infusion.  
Storage 
Store at 25˚C (77 ˚F) or below.  Do not freeze or refrigerate 
Preparation and 
handling 
Transfer 150 mL of solution into an evacuated container.  
Please refer to Pharmacy Manual for additional information. 
Administration 
Please reference Table 2 in Section 7.6.6.1  
 
Oral Formulation (Levofloxacin) 
Name 
Levofloxacin Tablet, 250 mg 
Excipients 
Over encapsulated in DB0, Swedish Orange capsule shell with microcrystalline cellulose 
backfill. 
How supplied 
High-Density Polyethylene (HDPE) bottles with induction seal, child resistant closure and 
desiccant 
Storage 
Store at 25˚C (77 ˚F).  Excursions permitted to 15°C-30°C (59-86˚F) (In Pharmacy 
Manual) 
Preparation and 
handling 
No special requirements 
Administration 
Please reference Table 2 in Section 7.6.6.1  
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Omadacycline  
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PTK0796-AP-17202-Version 1.0; 26Mar2018 
IND # 75,928 IND # 73,431 
 
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Dose Selection Rationale 
7.4
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: 
• In PTK0796-SDES-0501, the PK of omadacycline iv were linear over the entire dose 
range (25 mg to 600 mg) as assessed by area under the concentration time curve (AUC).  
Therefore, the loading dose given on Day 1 in the pivotal Phase 3 trials, 100 mg iv every 
12 hours (q12h), is from an exposure perspective comparable to the 200 mg iv loading 
dose on Day 1 to be utilized in this study. 
• In PTK0796-MDES-0601, 200 mg iv for seven days was safe and well tolerated.  Alanine 
aminotransferase was reported as increased in 26% of subjects however the post-baseline 
change was approximately 30 IU/L on the last day of infusion.  A heart rate model 
demonstrated that the post-baseline increase in heart rate for a 200 mg dose could be 
minimized to 15 beats per minute with infusion over 60 minutes.  
• In PTK0796-UUTI-15103, omadacycline dosed as 200 mg iv on Day 1 followed by 300 
mg po daily for 5 days, 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 demonstrated 
high urinary concentration on Day 1 and Day 5.  For the 200 mg iv load followed by 
300 mg daily dosing group, mean urinary concentrations ranged from 22 to 65 µg/mL on 
Day 1 and 21 to 42 µg/mL on Day 5.  For the 300 mg dosing group, 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, mean urinary concentrations ranged from 11 to 25 µg/mL on 
Day 1 and 30 to 48 µg/mL on Day 5. 
• The driver of efficacy for omadacycline in urinary tract infection (UTI) is not known, 
however the extensive tissue distribution of omadacycline suggests that plasma levels 
may not be the best predictor of efficacy for every indication.  Extensive tissue 
distribution is likely essential for the eradication of susceptible bacteria in the 
intracellular compartment of peripheral tissues.  In the BAL-15104 study examining lung 
tissue concentrations following iv administration of 100 mg omadacycline in healthy 
subjects, at steady-state, the concentration of omadacycline was 25.79-fold higher in 
alveolar cells (AC, 302.46 h·µg/mL) than in plasma, and 1.47-fold higher in epithelial 
lining fluid (ELF, 17.23 h·µg/mL) than in plasma. 
• A pragmatic assumption was made in the recently completed Phase 1 study of 
uncomplicated UTI (PTK0796-UUTI-15103) that maximizing the time of omadacycline 
concentration in urine above the pathogen MIC (ideally, throughout the dosing interval) 
would be desirable.  In addition, the omadacycline concentrations in urine determined in 
the phase 1 study demonstrated that the urine concentrations were above the E. coli 
MIC90 of 2 µg/mL.  It is appropriate to determine the optimal iv and oral dose for AP to 
achieve clinical success similar to a standard comparator.  Therefore, both the standard 
100 mg iv dose as well as the higher 200 mg iv dose will be explored.  Oral doses of 300 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
PTK0796-AP-17202 Protocol
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PTK0796-AP-17202-Version 1.0; 26Mar2018 
IND # 75,928 IND # 73,431 
 
Confidential and Proprietary 
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mg and 450 mg will be explored as was done in PTK0796-UUTI-15103 and is being 
explored for the uncomplicated UTI (acute cystitis) in PTK0796-UUTI-17201. 
 
Description of Treatments 
7.5
Subjects will be randomized to 1 of the following 5 treatment groups: 
Table 1. 
Description of Treatment Groups 
Group 
Test Article 
Study Day 
1 
 
Study Days 
2 to 7 
Study Days 
8 to 10a 
1 
omadacycline  
200 mg iv  
 
200 mg iv 
200 mg iv  
2 
omadacycline 
200 mg iv 
 
100 mg iv 
100 mg iv 
3 
omadacycline 
200 mg iv 
 
300 mg po or 
100 mg iv 
300 mg po or 
100 mg iv 
4 
omadacycline 
200 mg iv 
 
450 mg po or 
100 mg iv 
450 mg po or 
100 mg iv 
5 
levofloxacin 
750 mg iv 
 
750 mg po or 
750 mg iv 
750 mg po or 
750 mg iv 
Dosing in all treatment groups is once-per-day. 
All iv doses will be administered as continuous infusions over 90 minutes.  
All oral doses will be taken in a fasted state (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 prior to 
dosing; after dosing, no food for 2 hours, no dairy products, antacids or multivitamins containing multivalent 
cations for 4 hours). 
iv = intravenous, po = per oral. 
a 
The total duration of treatment for subjects is 7-10 days, up to 14 days of treatment for subjects with 
bacteremia.  
 
It is possible that not all treatment arms will be enrolling subjects at the same time.  Arms 
may be dropped based on the Bayesian analysis or initiated based on the Bayesian analysis of 
the ongoing treatment arms.  There will always be at least one omadacycline arm and the 
levofloxacin arm open.   
 
Test Article Administration 
7.6
7.6.1 
Intravenous Treatment Phase 
The iv treatment phase (minimum 1 day, 1 dose) will follow a double-blind design for 
omadacycline and levofloxacin.  Infusions of both test articles will be administered 
continuously over approximately 90 minutes.  All infusion start and stop times are to be 
recorded in the source documents and on the eCRF.  Because the color of the test article and 
placebo infusions are different, all infusion bags and iv tubing will be covered with materials 
provided by the sponsor (as described in the Pharmacy Manual) so that subjects and blinded 
study personnel will not know the identity of the test article being administered.  Subjects in 
each study arm will receive the same infusion volumes with the same blinded administration 
instructions.  All iv infusions will be administered by qualified blinded personnel.  However, 
unblinded personnel may administer the iv infusions provided they will not be performing 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
PTK0796-AP-17202 Protocol
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Confidential and Proprietary 
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any efficacy assessments. If gravity administration is not the standard of care then an 
infusion pump may be used.  If an infusion pump is used then an unblinded administrator 
will be required.   
7.6.2 
Selection and Timing of iv Dose for Each Subject 
To facilitate study enrollment at all times of the day and permit subjects to be “shifted” to a 
more practical dosing schedule consistent with hospital schedules, provision is made for 
limited adjustment of the dosing interval.  Specifically, infusion times may be adjusted up to 
± 2 hours per infusion interval until the desired administration schedule is achieved.   
Once the desired start of infusion time is determined, subsequent infusions should be 
“anchored” to that time.  That is, thereafter, the start of infusion should be within ± 1 hour of 
the specified target infusion time. 
7.6.3 
Management While on iv Test Article  
While the subject is receiving iv therapy, the investigator will assess the subject daily and 
choose one of the following outcomes based on the overall clinical response of the subject: 
• Continue iv test article 
• Assess for po test article using the protocol defined criteria (after a minimum of 1 days [1 
doses] of iv therapy), see Section 7.6.5.  Note, the first po dose should be administered in 
the morning, 12 to 24 hours after the last dose of iv test article. 
• Discontinue test article – this decision will prompt the EOT evaluation (even if the 
subject does not complete the minimum of 7 days of dosing) 
Subjects who meet the criteria and are switched to po test article administration will continue 
to receive iv infusions throughout their treatment phase in order to maintain the blind.  
Subjects randomized to an IV only treatment group will continue to receive active IV 
treatment and placebo po treatment.  Subjects randomized to an IV/PO treatment group will 
receive placebo IV and active po treatment. At all times during the study the decision to 
continue iv, switch to po, or discontinue test article is made based on the clinical judgment of 
the investigator.  Each daily decision is to be recorded on source documents and the 
information transferred to eCRFs by blinded study site personnel. 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
PTK0796-AP-17202 Protocol
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7.6.4 
Investigator’s Decision to Continue or Discontinue Treatment 
At all times during the study the decision to continue iv, switch to po, or discontinue test 
article is made based on the clinical judgment of the investigator.  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).  If the AP is caused by a microorganism that is not susceptible to 
levofloxacin in vitro, the decision to continue or discontinue study treatment should be based 
on the subject's clinical course and the investigator’s clinical judgment.  These cases should 
be discussed with the Medical Monitor.  The rationale for this decision should be recorded in 
source documents.   
7.6.5 
Investigator’s Decision to Switch from iv to po Treatment 
Initially, all randomized subjects will receive at least 1 day of iv antibacterial therapy.  
Beginning on the day 2 visit, the subject may be eligible to switch from iv to po therapy. 
Switch from active iv to active po study drug therapy is optional, and will occur based on 
treatment group assigned. Upon decision to switch, subjects randomized to iv only groups 
will begin to receive placebo po in addition to their active iv test article. Those in an iv/po 
group will begin to receive active po test article and placebo iv infusions. The decision 
should be made by the investigator based on by the investigator based on evaluation of the 
criteria below. Criteria will be confirmed and documented in source documents: 
•  Afebrile for ≥ 24 hours (highest daily oral, tympanic, rectal, or core temperature 
< 37.8ºC [100.0ºF]) without the use of anti-pyretics,  
• Improvement or resolution of the signs and symptoms of the index AP, 
• Ability to tolerate and ingest oral therapy (eg, no nausea, vomiting), and 
• For subjects with baseline bacteremia, follow-up blood cultures must be negative. 
Subjects who are switched to po test article administration will continue to receive iv 
infusions in order to maintain the blind.  Switch to po will not be permitted until after the 
subject has completed at least the first day of iv treatment (after 1 dose).  The date and time 
the investigator confirmed the criteria for the subject’s eligibility for po treatment were met 
and made the decision to switch to po treatment will be recorded on source documents and 
the information transferred to eCRFs by study site personnel. 
7.6.6 
Oral Treatment Phase 
When switching from iv to po test article the recommended interval between doses will be 
maintained.  The first po dose, for both omadacycline and levofloxacin treatment arms, 
should be given in the morning 12 to 24 hours after the last dose of iv test article. 
The po treatment phase will employ a double-blind, double-dummy design using 
omadacycline placebo comparator tablets of matching size and shape to active omadacycline 
tablets and matching over-encapsulated placebo and active levofloxacin tablets. 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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To maintain investigator and subject blinding, subjects in both arms will receive both tablets 
and over-encapsulated tablets during each dose.  Subjects in groups 1 and 2 will receive 
placebo omadacycline tablets and placebo over encapsulated levofloxacin tablets.  Subjects 
in groups 3, 4 and 5 will also continue to receive iv placebo infusions to maintain the blind. 
The po treatment will be administered by study staff during visit assessments.   
All doses of oral test article should be taken with water.   
All oral doses 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. 
 
Management While on Oral Test Article 
7.6.6.1
While the subject is receiving po therapy, the investigator will assess the subject daily and 
choose one of the following outcomes based on the overall clinical response of the subject: 
• Continue po test article 
• Discontinue test article – this decision will prompt the EOT evaluation (even if the 
subject does not complete the minimum of 7 days of dosing) 
At all times during the study the decision to continue or discontinue test article is made based 
on the clinical judgment of the investigator.  Each daily decision is to be recorded on source 
documents and the information transferred to eCRFs by blinded study site personnel. 
 
 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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Table 2. 
Dosing Blinded iv and Oral Double-Blind, Double-Dummy Design 
 
Dosing 
 
Group 1 
Group 2 
Group 3 
Group 4 
Group 5 
omadacycline 
omadacycline 
omadacycline 
omadacycline 
Levofloxacin 
Day 1 
 
omadacycline 
200 mg iv in 
150 mL NS 
omadacycline 
200 mg iv in 
150 mL NS 
omadacycline 
200 mg iv in 
150 mL NS 
omadacycline 
200 mg iv in 
150 mL NS 
levofloxacin 
750 mg iv in 
150 mL saline 
Days2 to 
7-10a, b, c 
  continue iv 
omadacycline 
200 mg iv in  
150 mL NS 
omadacycline 
100 mg iv in 
150 mL NS 
omadacycline 
100 mg iv in 
150 mL NS 
omadacycline 
100 mg iv in 
150 mL NS  
levofloxacin 
750 mg iv in 
150 mL saline 
switch to pob 
omadacycline 
200 mg iv in  
150 mL NS 
and 
three placebo 
tablets 
resembling 
omadacycline 
and  
three over-
encapsulated 
placebo tablets 
resembling 
levofloxacin 
omadacycline 
100 mg iv in 
150 mL NS 
and 
three placebo 
tablets 
resembling 
omadacycline 
and  
three over-
encapsulated 
placebo tablets 
resembling 
levofloxacin 
150 mL NS 
and  
two 150 mg 
omadacycline 
tablets, one 
placebo tablet 
resembling 
omadacycline, 
and  
three over-
encapsulated 
placebo tablets 
resembling 
levofloxacin 
150 mL NS 
and 
three 150 mg 
omadacycline 
tablets  
and  
three over-
encapsulated 
placebo tablets 
resembling 
levofloxacin 
150 mL NS 
and 
three placebo 
tablets 
resembling 
omadacycline 
and 
 three over-
encapsulated 
250 mg 
levofloxacin 
tablets 
Dosing in all treatment groups is once-per-day. 
All iv doses will be administered as continuous infusions over 90 minutes.  
All oral doses will be taken in a fasted state (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 prior to 
dosing; after dosing, no food for 2 hours, no dairy products, antacids or multivitamins containing multivalent 
cations for 4 hours). 
iv = intravenous, NS = normal saline, po = per oral. 
a 
The total duration of treatment is 7-10 days, Subjects with bacteremia can continue treatment for up to 14 
days.  
b 
Starting on Day 2, per investigator’s discretion, subjects may be switched to oral dosing per oral switch 
criteria. 
c 
All therapy may be discontinued after the seventh day of treatment, when the infection is considered 
clinically cured (based on normalization of the clinical signs and symptoms of infection and the 
investigator’s clinical assessment that continued systemic antibacterial therapy is no longer needed). 
 
Dose Adjustments and Interruptions of Test Article 
7.7
No dose adjustments or planned interruptions of test article will be permitted during this 
study. 
 
Method of Assigning Patients to Treatment Groups 
7.8
All eligible subjects will be randomized via an IxRS that assigns them to the treatment arm.  
The site delegate will contact the IxRS after confirming that the subject fulfills all the 
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inclusion criteria and has 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).  It is possible that not all treatment arms will be enrolling subjects at 
the same time.  Arms may be dropped based on the Bayesian analysis or initiated based on 
the Bayesian analysis of the ongoing treatment arms.  There will always be at least one 
omadacycline arm and the levofloxacin arm open.  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.  
Subjects who have been pre-screened, 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.  Re-screening is at the discretion of the investigator and 
in consultation with the medical monitor.  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 
7.9
Each study site will be supplied by the sponsor with the investigational product and 
comparator.  The IxRS will instruct the pharmacist or designee as to the appropriate therapy, 
omadacycline or levofloxacin, to be administered.  The unblinded site pharmacist or designee 
will prepare the test article as instructed.  The unblinded pharmacist or designee will provide 
the blinded nurse administering the infusion with the appropriate solutions for each subject 
covered to conceal the identity of the test article using materials provided by the sponsor and 
labeled with blinded administration instructions.  The po test article will be supplied to the 
sites in kits that contain active omadacycline tablets or matched placebo tablets, and active 
levofloxacin over-encapsulated tablets or matched placebo over-encapsulated tablets 
resembling levofloxacin.  Oral test article supplies are completely blinded.  Therefore, oral 
test article supplies can be transferred from the unblinded study personnel to blinded study 
personnel for storage, dispensation, and reconciliation.  The study coordinator/staff will 
instruct the subject on the use of po test article.  The procedures are detailed in the Pharmacy 
Manual. 
 Blinding 
7.10
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, 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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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 this 
analysis, modifications may be made to the omadacycline treatment groups. 
The investigator and sponsor will be blinded to treatment arm assignments.  The iv and po 
phases of the study will be double-blind.   
Because the color of the iv test article infusions and placebo infusions differ, all infusion 
bags and iv tubing will be covered with materials provided by the sponsor so that subjects 
and blinded study personnel will not know the identity of the test article being administered.  
The infusion regimen will follow a blinded design with subjects in each study arm receiving 
the same infusion volumes with the same administration instructions.  Blinded study 
personnel will administer the infusions and collect, review and enter data regarding the iv 
infusions (eg, start and stop times) into an eCRF.  If gravity administration is not the standard 
of care then an infusion pump may be used.  If an infusion pump is used then an unblinded 
administrator will be required.  Personnel identified as unblinded administrators will not 
participate in any study procedures other than iv administration of test article and the 
collection, review and entry of iv related data (eg, start and stop times) into an eCRF. 
During the po phase, a double-blind, double-dummy design will be used to ensure the blind 
is maintained.  Subjects on the omadacycline arms may receive active omadacycline tablets 
and over-encapsulated levofloxacin placebo tablets.  Subjects on the levofloxacin arm will 
receive omadacycline placebo tablets and over-encapsulated active levofloxacin tablets.  
Infusions will be administered concomitantly along with the po treatment to maintain the 
overall study blind. 
The unblinded source documentation binder containing all descriptions of pharmacy 
preparations and infusions or distributions of test article and any unblinded subject 
randomization data should be stored separately, and under lock and key, separate from the 
documents containing blinded information. 
Data that could potentially lead to unblinding will not be accessible to anyone other than the 
following site personnel:  
• unblinded study pharmacist or designee 
• unblinded study monitor  
• unblinded administrator(s)  
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 
7.11
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 
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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. 
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 
7.12
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  
7.13
• 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 AP) are prohibited for 72 hours prior to randomization through EOT, with 
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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 oral doses  
7.13.1 
Concomitant Medications That May Interact with Levofloxacin 
Use of antiarrhythmic agents of Class IA (eg, quinidine, procainamide) or Class III (eg, 
amiodarone, Sotalol) is prohibited from the time that informed consent is obtained through 
EOT. 
  Permitted Treatments 
7.14
All other treatments not specified as prohibited are permitted during the study.  Subjects 
requiring additional or alternative antibacterial therapy for their AP will be judged as Clinical 
Failures and test article will be discontinued.  Further treatment for their infection is 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  
7.15
Intravenous and oral administration will be managed by study personnel.  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 charts.   
 Packaging and Labeling 
7.16
The investigational test article, omadacycline and comparator, levofloxacin, will be packaged 
by the sponsor and supplied to the investigator.  Please refer to the Pharmacy manual for 
additional information.  
 Storage and Accountability 
7.17
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 iv drug 
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accountability will be performed by unblinded personnel.  Oral drug accountability can be 
performed by blinded or unblinded personnel. 
 Investigational Product Retention at Study Site 
7.18
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.   
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
PTK0796-AP-17202 Protocol
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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 
8.1
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 
8.2
Subject demographic and Baseline characteristic data to be collected on all subjects include:  
date of birth, gender, and race/ethnicity.   
 
Medical History 
8.3
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 UTI and AP 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 
8.4
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 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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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 AE screen of the subject’s 
eCRF. 
 
Vital Signs 
8.5
Vital signs include blood pressure (BP), heart rate, and body temperature.  
• 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 BP and heart rate 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 calibrated device, with an 
appropriately sized cuff.  
Heart rate will be measured using an automated calibrated device, when available.  If not 
available, heart rate will be measured manually.  
Temperature will be obtained using an electronic (rapid reading) device whenever possible.   
 
Height and Weight 
8.6
Height and body weight will be collected. 
 
Clinical Laboratory Tests 
8.7
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 – 11 mL per 
visit, or approximately 44 mL (3 tablespoons) over the course of the study.  In addition, a 
blood culture will be collected at Screening and repeated if positive.  The preferred volume 
for each blood culture bottle is 10 mL.  However, since these are analyzed locally, site staff 
should refer to their individual laboratory or manufacturers’ recommendation. 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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8.7.1 
Central Laboratory Parameters 
Clinical laboratory tests will include the following:  
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 
 
 
Pregnancy (all female subjects): 
• 
Serum β-human chorionic gonadotropin 
(β-HCG) 
 
 
Serum Chemistry: 
• 
Alkaline phosphatase (ALP) 
• 
Alanine aminotransferase (ALT) 
• 
Aspartate aminotransferase (AST) 
• 
Blood urea nitrogen (BUN) 
• 
Calcium (Ca) 
• 
Carbon dioxide (CO2) 
• 
Chloride (Cl) 
• 
Creatinine 
• 
Creatine phosphokinase (CK) 
• 
Gamma-glutamyl transpeptidase (GGT) 
• 
Lipase 
• 
Magnesium 
• 
Phosphorus (P) 
• 
Potassium (K) 
• 
Sodium (Na) 
• 
Total bilirubin 
 
8.7.2 
Local Laboratory Parameters 
 
Pregnancy Assessments  
8.7.2.1
All subjects will have a local urine or serum pregnancy test at the site at the Screening.  
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 8.17.6). 
 
 
 
Urine Culture and Dipstick Tests 
8.7.2.2
A clean-catch midstream urine sample should be collected, analyzed by urine dipstick test for 
leukocyte esterase, and optionally sent to the local laboratory for microscopic examination.  
If sent for microscopic evaluation, the sample should be analyzed for pyuria (WBC count > 
10/μL in unspun urine or ≥ 10 per high power field in spun urine). Results will be recorded 
on the eCRF.   
The sample will also be used for quantitative urine culture by appropriate methods using a 
calibrated loop that would identify bacteria at a lower limit of 1.0 × 103 colony forming units 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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(CFU)/mL.  A 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 of the same species as 
the Baseline pathogen with a CFU count of ≥ 1 × 104 CFU/mL and should be considered a 
persisting pathogen and should be sent to the central laboratory.  At any visit after Screening, 
any culture with a CFU count of < 104 CFU/mL should be considered a microbiologic cure. 
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 AP 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, levofloxacin 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.  
 
Blood Cultures 
8.7.2.3
Two sets of blood cultures (1 set = 1 aerobic bottle + 1 anaerobic bottle) should be collected 
within the 24 hours prior to the first dose of test article.  Each set of blood cultures should be 
collected by direct venipuncture from independent body sites at least 15 minutes apart.  If 
bacteria are isolated from baseline blood cultures, repeat blood cultures should be collected 
on the day that the positive blood culture is detected.  If subsequent blood cultures are also 
positive, repeat the blood cultures as necessary until negative blood cultures are obtained.  
Blood culture isolates should be sent to the Central Laboratory. 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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Efficacy Assessments 
8.8
8.8.1 
Investigator’s Assessment of Clinical Response 
 
Investigator’s Assessment of Clinical Response at EOT 
8.8.1.1
The investigator will determine whether or not the subject meets the criteria of 1 of the 
following clinical outcomes:  
• Clinical Success:  The complete resolution or significant improvement of the baseline 
signs and symptoms of AP at the EOT visit such that no additional 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 alternative or additional systemic 
antimicrobial therapy for the current infection is required or death prior to the EOT visit. 
• Indeterminate:  EOT visit not completed. 
 
Investigator’s Assessment of Clinical Response at PTE 
8.8.1.2
For subjects who were determined to be a clinical success or indeterminate at the EOT visit, 
the investigator will determine whether or not the subject meets the criteria of 1 of the 
following clinical outcomes: 
• Clinical Success:  The complete resolution or significant improvement of the baseline 
signs and symptoms of AP symptoms at the PTE such that no additional 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 or 
death at or before the PTE visit. 
• Indeterminate:  PTE visit not completed. 
 
Investigator’s Assessment of Clinical Response at Final Follow-up 
8.8.1.3
For subjects that were determined to be a clinical success at the PTE visit, the investigator 
will determine whether or not the subject meets the criteria of 1 of the following clinical 
outcomes: 
• Clinical Cure: The complete resolution or significant improvement of the baseline signs 
and symptoms of AP at FFU visit such that no additional antimicrobial therapy is 
required for the current infection. 
• 
Relapse: The reappearance of signs and symptoms at or before the FFU Visit such that 
use of alternative or additional systemic antimicrobial therapy for the current infection. 
• Clinical Failure:  Death between the PTE and Final Follow-up.  
• Indeterminate:  Final Follow-up visit not completed. 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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Microbiologic Response 
8.9
Microbiologic outcome at EOT and PTE will be programmatically determined for each 
pathogen isolated at baseline.  Per-pathogen microbiologic response categories are 
eradication, persistence and indeterminate. 
Category 
Criteria 
Eradication 
The demonstration that the baseline bacterial pathogen is reduced to < 104 CFU/mL 
on urine culture and negative on repeat blood culture (if positive at baseline) 
Persistence 
The urine culture taken at the study visit grows ≥ 104 CFU/mL of the baseline 
pathogen identified at study entry and/or a positive blood culture at the study visit 
demonstrates the same baseline pathogen.  Pathogens that are a persistence at EOT 
will be considered a persistence at PTE. 
Indeterminate 
No follow-up urine culture is available, or the follow-up urine culture cannot be 
interpreted for any reason.  For a baseline blood pathogen, no follow-up blood culture 
is available. 
CFU = colony forming units, EOT = end of treatment, PTE = post therapy evaluation. 
An overall per-subject microbiologic response at EOT and PTE will be programmatically 
determined for each subject based on the individual outcomes for each baseline pathogen.  
For a subject to have a microbiologic response of success, the outcome for each baseline 
pathogen must be eradicated.  If the outcome for any pathogen is persistence, the subject will 
be considered to have a microbiologic response of failure.  Subjects with a persistence at 
EOT will be considered a persistence at PTE. 
Category 
Criteria 
Success 
The outcome of all baseline pathogens must be eradication at the specified visit (EOT or 
PTE) 
Failure 
The outcome of at least 1 baseline pathogen is persistence.  Subjects with a persistence at 
EOT will be considered a persistence at PTE. 
Indeterminate 
The outcome of at least 1 baseline pathogen is indeterminate and there is no outcome of 
persistence for any baseline pathogen 
EOT = end of treatment, PTE = post therapy evaluation. 
 Modified Patient Symptom Assessment Questionnaire 
8.10
The subject will report the severity of their pyelonephritis symptoms and how bothersome 
they are with the Modified Patient Symptom Assessment Questionnaire (mPSAQ).  The 
questionnaire will be completed during each study visit.  The subject will rate the severity 
and how bothersome each symptom on a 4-point scale (no symptom, mild, moderate, severe 
and not at all, a little, moderately, a lot) and the results will be recorded in the eCRF.   The 
investigator must review the subject’s responses and record any AEs as appropriate. See 
Appendix 3 for the mPSAQ. 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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 Pharmacokinetic Assessments 
8.11
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, date and time of last food intake, as well as actual sample 
collection date and time will be entered on the eCRF. 
8.11.1 
PK Blood Collection and Processing 
Blood samples will be collected and analyzed for omadacycline concentration at the 
following times:  
• Just prior to the dose on Day 3 and just prior to last dose of test article; 
• 2 to 3 hours after dose on Day 3 and 2 to 3 hours after last dose of test article.   
 
8.11.2 
PK Urine Collection and Processing 
Urine will be collected, the volume recorded, and analyzed for omadacycline concentration at 
the following times:  
• Day 3 to 4:  pooled total urine from 0 to 24 hours after the Day 3 dose;  
• Day 6 to 7:  pooled total urine from 0 to 24 hours after the Day 6 dose 
Omadacycline urine concentration data will be used to determine the 24-hr average urinary 
concentration and amount of drug excreted in the urine in a dosing interval at steady-state. 
8.11.3 
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  
8.12
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: 
• 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 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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 Serious Adverse Events 
8.13
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  
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. 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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 Other Reportable Information  
8.14
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.  Both maternal and paternal exposures are considered 
other reportable information.  For exposure involving the female partner of a male 
subject, the necessary information must be collected from the subject, while respecting 
the confidentiality of the partner. 
• 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 
8.15
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 750 mg of levofloxacin in a single administration 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 levofloxacin 
USPI). 
The physician managing the overdose may order any test he/she thinks is necessary to 
manage the subject properly. 
 Medication Errors 
8.16
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 
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 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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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 
8.17
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. 
Adverse events 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.  
8.17.1 
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: 
 
8.17.2 
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: 
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• 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. 
Adverse events and SAEs also will be assessed for their potential relationship to the protocol.  
A protocol-related AE 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. 
8.17.3 
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. 
8.17.4 
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. 
8.17.5 
Worsening or Progression of Disease Under Study 
Worsening or progression of the qualifying pyelonephritis 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 
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investigator considers to be distinct from the qualifying pyelonephritis should be reported as 
AEs in all cases, whether non-serious or serious. 
8.17.6 
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 
8.18
The investigator should instruct the subject to notify the study site about any new 
medications they take after the start of the test article.   
All prescription medications, over-the-counter (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 Concomitant Medications/Non-Drug Therapies 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 
8.19
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 
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.   
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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 
9.1
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: 
• mPSAQ 
• Demographics 
• Medical history 
• Physical examination 
• Vital signs:  body weight & height, body temperature, BP, heart rate 
• 12-lead ECG (to confirm eligibility) 
• Review of inclusion/exclusion criteria 
• Laboratory tests (blood):   
o Blood culture 
o Hematology (includes coagulation) 
o Serum Chemistry 
o Serum pregnancy test 
• Laboratory tests (urine): 
o Urinalysis via dipstick with optional microscopic exam 
o Urine culture 
o Urine pregnancy test 
• Concomitant medications (past 7 days) 
• AEs since the signing of the ICF 
 
Double-Blind Treatment Phase  
9.2
The double-blind treatment period is 7 to 10 days in duration.  Subjects with bacteremia 
confirmed from local blood culture drawn at screening can receive up to 14 days of 
treatment.  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: 
 
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• Review of inclusion/exclusion criteria 
• Randomization 
• Concomitant medications 
• Vital signs:  body temperature, BP, heart rate 
• AEs  
• Laboratory tests (blood) 
• Blood culture (as required if bacteremia was confirmed at Screening and has not 
resolved) 
• Dispensation and Administration of test article  
9.2.2 
Day 2 Visit Procedures 
The following assessments will be performed: 
• mPSAQ 
• Concomitant medications 
• Laboratory tests (urine): 
Urinalysis via dipstick with optional microscopic exam 
Urine culture 
• Laboratory tests (blood): 
Blood culture (as required if bacteremia was confirmed at Screening and has not 
resolved) 
• Vital signs:  body temperature 
• AEs  
• Administration and accountability of test article 
• Assessment for po switch 
 
9.2.3 
Day 3 Visit Procedures 
The following assessments will be performed: 
• mPSAQ 
• Concomitant medications 
• Laboratory tests (urine): 
Urinalysis via dipstick with optional microscopic exam  
Urine culture 
• Laboratory tests (blood): 
Hematology (includes coagulation) 
Chemistry 
Blood culture (as required if bacteremia was confirmed at Screening and has not 
resolved) 
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• Vital signs:  body temperature, BP, heart rate 
• AEs  
• PK blood collection 
• PK urine collection 
• Administration and accountability of test article 
• Assessment for po switch 
 
9.2.4 
Day 4 Visit Procedures 
The following assessments will be performed: 
• mPSAQ 
• Concomitant medications 
• Laboratory tests (urine): 
• Urinalysis via dipstick with optional microscopic exam  
• Urine culture 
• Laboratory tests (blood): 
• Blood culture (as required if bacteremia was confirmed at Screening and has not 
resolved) 
• Vital signs:  body temperature 
• AEs 
• Administration and accountability of test article 
• Assessment for po switch 
9.2.5 
Day 5 Visit Procedures 
The following assessments will be performed: 
• mPSAQ 
• Concomitant medications 
• Laboratory tests (urine): 
• Urinalysis via dipstick with optional microscopic exam  
• Urine culture 
• Laboratory tests (blood): 
• Blood culture (as required if bacteremia was confirmed at Screening and has not 
resolved) 
• Vital signs:  body temperature 
• AEs  
• Administration and accountability of test article 
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• Assessment for po switch 
9.2.6 
Day 6 Visit Procedures 
The following assessments will be performed: 
• mPSAQ 
• Concomitant medications 
• Laboratory tests (urine): 
• Urinalysis via dipstick with optional microscopic exam  
• Urine culture 
• Laboratory tests (blood): 
• Blood culture (if bacteremia is positively identified during Screening)  
• PK urine collection 
• Vital signs:  body temperature 
• AEs  
• Administration and accountability of test article 
• Assessment for po switch 
9.2.7 
Day 7 Visit Procedures 
Beginning on Day 7, subjects are eligible to have their test article discontinued at the 
discretion of the investigator (see Section 8.8.1.1).  If the investigator determines that the 
subject does not need further antibacterial therapy on Day 7, the EOT evaluation may be 
performed the day of or within 2 days of the last dose of test article.   
The following assessments will be performed: 
• mPSAQ 
• Concomitant medications 
• Laboratory tests (urine): 
• Urinalysis via dipstick with optional microscopic exam  
• Urine culture 
• Laboratory tests (blood): 
• Blood culture (if bacteremia is positively identified during Screening) 
• Vital signs:  body temperature, BP, heart rate 
• AEs 
• Assessment for po switch  
• Investigator’s decision to continue or discontinue test article 
• Administration and accountability of test article 
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9.2.8 
Day 8, 9 Visit Procedures 
Day 8 and 9 visits will only be performed if the EOT visit does not coincide with the day of 
the last dose.  The following assessments will be performed only if the subject is still 
receiving test article: 
• mPSAQ 
• Concomitant medications 
• Laboratory tests (urine): 
• Urinalysis via dipstick with optional microscopic exam  
• Urine culture 
• Laboratory tests (blood): 
• Blood culture (if bacteremia is positively identified during Screening) 
• Vital signs:  body temperature 
• AEs 
• Assessment for po switch  
• Investigator’s decision to continue or discontinue test article 
• Administration and accountability of test article 
9.2.9 
Day 10 Visit Procedures 
Day 10 visit will only be performed if the EOT visit does not coincide with the day of the last 
dose.  The following assessments will be performed only if the subject is still receiving test 
article: 
• mPSAQ 
• Concomitant medications 
• Laboratory tests (urine): 
• Urinalysis via dipstick with optional microscopic exam  
• Urine culture 
• Laboratory tests (blood): 
• Blood culture (if bacteremia is positively identified during Screening)  
• Vital signs:  body temperature, BP, heart rate 
• AEs 
• Assessment for po switch 
• Investigator’s decision to continue or discontinue test article 
• Administration and accountability of test article 
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9.2.10 
Day 11, 12, 13 Visit Procedures 
Day 11, 12, and 13 visits will only be performed for subjects with bacteremia whose 
treatment duration is extended beyond 10 days and if the EOT visit does not coincide with 
the day of the last dose. 
The following assessments will be performed only if the subject is still receiving test article: 
• mPSAQ 
• Concomitant medications 
• Laboratory tests (urine): 
• Urinalysis via dipstick with optional microscopic exam  
• Urine culture 
• Laboratory tests (blood): 
• Blood culture (if bacteremia is positively identified during Screening) 
• Vital signs:  body temperature 
• AEs 
• Assessment for po switch  
• Investigator’s decision to continue or discontinue test article 
• Administration and accountability of test article 
 
EOT Visit Procedures 
9.3
The EOT 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: 
• mPSAQ 
• Concomitant medications 
• Physical examination 
• Laboratory tests (urine): 
• Urinalysis via dipstick with optional microscopic exam 
• Urine culture 
• Laboratory tests (blood):   
• Hematology (includes coagulation) 
• Chemistry 
• PK Blood Collection 
• Serum pregnancy test 
• Blood culture (if bacteremia is positively identified during Screening) 
• Vital signs:  body weight, body temperature, BP, heart rate 
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• AEs  
• Investigator’s assessment of clinical response  
• Accountability of test article 
 
Follow-up Phase 
9.4
9.4.1 
Post-Treatment Evaluation Visit (Day 21) Procedures 
The PTE visit should be conducted on Day 21 (± 2 days).  This evaluation should also be 
conducted for any prematurely withdrawn subject.  The following assessments will be 
performed at the PTE visit: 
• mPSAQ 
• Concomitant medications 
• Physical examination 
• Laboratory tests (urine): 
• Urinalysis via dipstick with optional microscopic exam 
• Urine culture 
• Laboratory tests (blood):   
• Hematology (includes coagulation)  
• Chemistry  
• Serum pregnancy test 
• Vital signs:  body weight, body temperature, BP, heart rate 
• AEs 
• Investigator’s assessment of clinical response  
9.4.2 
Final Follow-up 
The Final Follow-up assessment should be conducted on Day 28 (± 2 days) after 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 or ECG 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: 
• mPSAQ 
• Concomitant medications 
• AEs 
• Investigator’s assessment of clinical response 
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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, BP, heart rate 
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10 STUDY SUSPENSION, TERMINATION, AND COMPLETION 
 Study Completion and Post-Study Test Article 
10.1
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 8.17.6, and SAEs described in Section 8.17.1. 
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 
10.2
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 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 
12.1
All analyses of data for this study will comply with International Council 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 SAP incorporating the sections below and with mock tables, figures, and listings (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, 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 source data verified; all safety and microbiology 
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 
12.2
Enrollment of approximately 200 subjects is planned to achieve at least 150 subjects in the 
micro-ITT population.  The Bayesian posterior probability that the overall success rate at the 
PTE Visit is within 0.10 of that of the levofloxacin group will be estimated for each 
omadacycline treatment group.  The target probability is 0.70.  If the true underlying overall 
success rates for the levofloxacin and omadacycline treatment groups are 0.69, then the 
sample size of N = 30 per treatment group has approximately 65% power/probability to yield 
the target probability (N = 80 per treatment group for 80% power).  If the true underlying 
overall success rates for the levofloxacin and omadacycline treatment groups are 0.78, then 
the sample size of N = 30 per treatment group has approximately 68% power/probability to 
yield the target probability (N = 64 per treatment group for 80% power).  The sample size 
may be increased for a particular omadacycline treatment group by changing the 
randomization ratio and/or dropping a treatment group to have improved power/probability 
of achieving the target probability that overall success rates for a treatment group is within 
0.10 of that of the levofloxacin group.  If required to improve the precision of the interim or 
projected final analyses estimates of overall success rates or posterior probabilities, the 
sample size may be increased to a maximum sample size provided in the SAP.  
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 Analysis Populations  
12.3
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 micro-ITT population will consist of subjects in the ITT population who have an 
appropriately collected pretreatment baseline urine culture with at least 1 uropathogen at 
≥ 105 CFU/mL and not more than 2 bacterial isolates at any count.  If more than 2 
bacterial isolates are identified, the culture will be considered contaminated regardless of 
colony count, unless 1 of the isolates that grows in the urine at ≥ 105 CFU/mL is also 
isolated from a blood culture at the same visit.  
• The clinically evaluable (CE) population will consist of all ITT subjects who received 
test article, have acute uncomplicated pyelonephritis, 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 and 
micro-ITT populations who have an appropriately collected post-baseline urine sample 
and an interpretable post-baseline urine sample.  An interpretable post-baseline urine 
culture is one that has a clearly identified pathogen or one where the baseline pathogen(s) 
can be excluded (ie, there is no growth of the baseline pathogen). 
 Demographics and Baseline Characteristics 
12.4
Demographics (including age, ethnicity and race) and baseline characteristics will be 
summarized in the ITT and micro-ITT  populations by treatment 
group.  Baseline microbiology will be summarized in the micro-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
12.5.1 
Efficacy Endpoint 
The primary efficacy outcome is overall response at the PTE Visit in the micro-ITT 
population, which is a composite of per-subject microbiologic response and investigator’s 
assessment of clinical response as follows: 
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Category 
Criteria 
Success: 
A subject who is deemed a clinical success AND a microbiologic success 
Failure: 
A subject who is deemed a clinical failure OR a microbiologic failure 
Indeterminate: 
Insufficient data are available to determine if the subject is an overall success or failure 
The number and percentage of subjects with overall success, overall failure and 
indeterminate response at the PTE Visit in the micro-ITT population will be determined by 
treatment group.  Exact 95% CIs will be determined for the point estimates of the overall 
success rates in each treatment group. 
A comparison of the overall success rate at the PTE Visit between each omadacycline 
treatment group and the levofloxacin treatment group will be conducted using a beta 
distribution with an uninformative Bayesian prior distribution. 
 Secondary Endpoint(s) 
12.6
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.  Adverse events 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 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 leading to discontinuation of 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 and overall worst 
post-baseline 
• Clinically notable laboratory parameters (meeting predefined criteria as specified in the 
SAP) by visit and overall worst post-baseline 
12.6.2 
Efficacy Endpoint(s) 
The number and percentage of subjects with an overall response of success, failure and 
indeterminate at the EOT (micro-ITT and ME populations) and PTE Visits (ME population, 
by definition subjects in the ME population cannot have an indeterminate response) will be 
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determined by treatment group.  Exact 95% CIs will be determined for the point estimates of 
the overall success rates in each treatment group. 
The number and percentage of subjects with an Investigator’s assessment of clinical success, 
clinical failure and indeterminate response at the EOT, PTE and Final Follow-up Visits (ITT, 
micro-ITT, CE and ME populations; by definition subjects in the CE and ME populations 
cannot have an indeterminate response) will be determined by treatment group.  Exact 95% 
CIs will be determined for the point estimates of the clinical success rates in each treatment 
group. 
The number and percentage of subjects with a per-subject microbiologic response of success, 
failure 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% CIs will be determined for the 
point estimates of the microbiologic success rates in each treatment group.  
Overall success, clinical success and per-pathogen microbiologic eradication at the PTE visit 
will be presented by pathogen and by pathogen and MIC for the micro-ITT and ME 
populations.   
 Interim Analysis 
12.7
This is an adaptive dose-response finding study.  Initially, allocation to treatment arms will 
be equal between treatment arms.  During the course of the study, 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 (overall response comprised of clinical and 
microbiologic response).  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 group(s) should be initiated, stopped, or modified.  
Modifications to omadacycline treatment groups may also be based on safety and tolerability.  
It is possible that not all treatment arms will be enrolling subjects at the same time.  Arms 
may be dropped based on the Bayesian analysis or initiated based on the Bayesian analysis of 
the ongoing treatment arms.  There will always be at least one omadacycline arm and the 
levofloxacin arm open. 
Modifications to the total number of subjects enrolled may also be based on the evaluability 
rate for the micro-ITT population. 
Bayesian analyses will be conducted after efficacy data (overall response at PTE) are 
available for approximately 40, 80 and 100 subjects in the micro-ITT population in order to: 
• Determine omadacycline treatment group(s) that can be initiated or dropped from the 
trial, or  
• Modify the randomization ratios among the treatment groups to improve the precision of 
the selected dose groups comparison of overall success to that of the levofloxacin group 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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Additional analyses may be carried out for the same purposes.  Response criteria are targeted 
towards estimating the probability that the overall success rate (proportion of subjects) for 
each omadacycline treatment group is within 10% of that of the levofloxacin group.  If at the 
interim analyses, that probability falls below 30% for a particular treatment group, 
recruitment for that treatment group may be stopped or curtailed.  If that probability exceeds 
70% for a particular treatment group, recruitment for that treatment group may be stopped or 
increased to improve the precision of the estimate.  
Concurrent bacteremia are higher among adults >65 years of age.11 After approximately 100 
subjects have been enrolled, the inclusion of females >65 years of age may be allowed based 
on review of interim analysis. 
 Data Monitoring Committee 
12.8
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. 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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13 ADMINISTRATIVE CONSIDERATIONS 
 Investigators and Study Administrative Structure 
13.1
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 or Independent Ethics Committee Approval 
13.2
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 
13.3
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 
13.4
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
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
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 
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prior to IRB/IEC/REB approval.  Notwithstanding the need for approval of formal protocol 
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 
13.7
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 
13.8
The investigator must provide the sponsor with the following documents before enrolling any 
subjects: 
• Completed and signed form 1572 or equivalent 
• 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.  
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• 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. 
 Retention of Data 
13.9
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 
13.10
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. 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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14 REFERENCE LIST
                                                 
1 Geerlings SE.  Clinical Presentations and Epidemiology of Urinary Tract Infections.  
Microbiology Spectrum.  2016 Oct;4(5). 
2 Czaja CA, Scholes D, Hooton TM, Stamm WE.  Population-Based Epidemiologic Analysis 
of Acute Pyelonephritis.  Clinical Infectious Diseases.  2007 Aug 1;45(3):273-80. 
3 Foxman B, Klemstine KL, Brown PD.  Acute Pyelonephritis in US Hospitals in 1997: 
Hospitalization and In-Hospital Mortality.  Annals of epidemiology.  2003 Feb 
28;13(2):144-50. 
4 Wagenlehner FM, Pilatz A, Weidner W.  Urosepsis-From the View of the Urologist. 
International Journal of Antimicrobial Agents.  2011 Dec 31;38:51-7. 
5 Cek M, Tandoğdu Z, Wagenlehner F, Tenke P, Naber K, Bjerklund-Johansen TE.  
Healthcare-Associated Urinary Tract Infections in Hospitalized Urological Patients-A Global 
Perspective: Results from the GPIU Studies 2003–2010.  World Journal of Urology.  2014 
Dec 1;32(6):1587-94. 
6 Doi Y, Park YS, Rivera JI, Adams-Haduch JM, Hingwe A, Sordillo EM, et al.  
Community-Associated Extended Spectrum Beta-Lactamase-Producing Escherichia coli 
Infection in the United States.  Clinical Infectious Diseases.  2012 Nov 12;56(5):641-8. 
7 Paratek Pharmaceuticals, Inc.  Omadacycline/PTK 0796 Investigator's Brochure, 
Edition 10.0.  2016. 
8 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. Clinical Infectious Diseases.  
2011 Mar 1;52(5):103-20. 
9 Peterson J, Kaul S, Khashab M, Fisher AC, Kahn JB.  A Double-Blind, Randomized 
Comparison of Levofloxacin 750 mg Once-Daily for Five Days with Ciprofloxacin 
400/500 mg Twice-Daily for 10 Days for the Treatment of Complicated Urinary Tract 
Infections and Acute Pyelonephritis.  Urology.  2008 Jan 31;71(1):17-22. 
10 Wagenlehner FM, Umeh O, Steenbergen J, Yuan G, Darouiche RO.  
Ceftolozane-Tazobactam Compared with Levofloxacin in the Treatment of Complicated 
Urinary-Tract Infections, Including Pyelonephritis: a Randomised, Double-Blind, Phase 3 
Trial (ASPECT-complicated UTI).  The Lancet.  2015 May 22;385(9981):1949-56. 
11 Johnson JR, Russo TA. Acute Pyelonephritis in Adults. New England Journal of Medicine. 
2018 Jan 4; 378(1):48-59 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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Appendix 1 
Schedule of Events 
Study Phase 
Screeninga 
Treatment Phase 
Follow-up Phase 
Evaluation 
 
Day 1b 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7c 
 
Day  
8, 9 
Day  
10c 
Day 
11, 12, 
13 
EOTd 
PTEt 
Day 
21 
Final 
Follow-
upu 
Day 
28 
 
Only performed if EOT visit does 
not coincide with day of last dose OR 
treatment extends beyond 7 days 
 
Signed Informed Consente 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Modified Patient symptom assessment 
questionnaire (mPSAQ) f  
X 
 
X-------------------------------------------------------------------------------------------X 
X 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior & Concomitant Medicationsg 
X 
X---------------------------------------------------------------------------------------------------------------------------------X 
Clean-catch, midstream urine sample for: 
 
 
Dipstick for leukocyte esterase and 
nitritesh with optional urinalysis for WBC 
counts 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xu 
 
Urine cultureh  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xu 
Physical examinationi 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Vital signs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight and heightv 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Body temperature 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xu 
 
Blood pressure 
X 
Xj 
 
X 
 
 
 
X 
 
X 
 
X 
X 
Xu 
 
Heart rate 
X 
Xj 
 
X 
 
 
 
X 
 
X 
 
X 
X 
Xu 
12-lead ECGk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology and coagulation 
X 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
Serum chemistry 
X 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
Local urine or serum pregnancy testl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central serum pregnancy testm 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Blood culturen 
X 
As Requiredn 
 
 
Adverse Eventso 
X 
X----------------------------------------------------------------------------------------------------------------------------------X 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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Study Phase 
Screeninga 
Treatment Phase 
Follow-up Phase 
Evaluation 
 
Day 1b 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7c 
 
Day  
8, 9 
Day  
10c 
Day 
11, 12, 
13 
EOTd 
PTEt 
Day 
21 
Final 
Follow-
upu 
Day 
28 
 
Only performed if EOT visit does 
not coincide with day of last dose OR 
treatment extends beyond 7 days 
 
Review of Inclusion and Exclusion 
criteria - Randomization (if Eligible) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Test Article Administration and 
accountabilityp 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
PK blood collectionr 
 
 
 
X 
 
 
 
Xr 
 
 
PK urine collection 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Assessment for po switchq 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Assessment of need to continue therapy 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
Investigator’s Assessment of Clinical 
Response 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
AE = adverse event, BP = blood pressure, CFU = colony forming unit, ECG = electrocardiogram, 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, WBC = white blood cell. 
a 
Following the signing of an ICF, all screening evaluations should be completed within the 24 hours prior to randomization. The blood culture sample collection should be 
completed within 24 hours prior to the first dose of test article. 
b 
Study Day 1 is the first day of test article administration. 
c 
A Day 7 and 10 visits should be conducted for subjects with treatment extending beyond 7 or 10 days, unless this visit coincides with the EOT visit.  
d 
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. 
e 
Written and signed ICF must be obtained before any study-related assessment is performed. 
f 
Subject assessment of symptoms severity will be collected daily through EOT, at PTE and at Final Follow-up. 
g 
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. 
h 
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.  WBC counts should be measured by 
microscopy from spun or unspun urine or dipstick analysis for leukocyte esterase and nitrites. 
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 (± 15 minutes) 1 hour after and 3 hours after the completion of the doses on Day 1.   
k 
A 12-lead ECG should be performed at Screening to confirm eligibility. 
l 
All women will have a local urine or serum pregnancy test at Screening which results will be used to confirm eligibility. 
m 
All women will have blood collected for a serum β-hCG pregnancy test at the Central Laboratory at the Screening, EOT and PTE visits.   
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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Study Phase 
Screeninga 
Treatment Phase 
Follow-up Phase 
Evaluation 
 
Day 1b 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7c 
 
Day  
8, 9 
Day  
10c 
Day 
11, 12, 
13 
EOTd 
PTEt 
Day 
21 
Final 
Follow-
upu 
Day 
28 
 
Only performed if EOT visit does 
not coincide with day of last dose OR 
treatment extends beyond 7 days 
 
n 
If bacteria are isolated from baseline blood cultures, repeat blood cultures should be collected. If subsequent blood cultures are also positive, repeat the blood cultures as 
necessary until negative blood cultures are obtained.  
o 
A subject’s AEs and SAEs will be recorded and reported from signing of the ICF to the Final Follow-up assessment. 
p 
Subjects should receive their first dose of test article within 4 hours after randomization.  The total duration of test article therapy (iv plus po) for all subjects will be 7-10 days.  
The pharmacist or designee will be unblinded to prepare appropriate iv doses of the IxRS identified test article.  An unblinded field monitor will perform drug accountability 
and review the pharmacist’s records. 
q 
Oral test article may be dispensed and reconciled by blinded or unblinded personnel.  All oral doses should be taken in a fasted state (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).  Following oral doses, no 
food should be consumed for 2 hours and no dairy products, antacids or multivitamins containing multivalent cations should be consumed for 4 hours.  For sites in which 
outpatient administration has been approved, subjects will be asked to return all unused po test article and packaging at each visit. and the EOT visit subjects will return any 
remaining unused po test article and site staff will perform accountability. 
r 
PK blood collection will occur just prior to and 2-3 hours after doses on Day 3 and last day of test article.  On days of PK collection, the date and time of last food intake prior to 
dosing will be collected. 
s 
Starting on Day 2, subjects may be switched to po medication based on clinical stability and investigator discretion.  
t 
A PTE will occur on Day 21 (± 2 days) for all subjects.   
u 
The Final Follow-up may be performed via phone call. The visit should be in person if potential recurrence is known, so the procedures to be completed.  If they are not 
known and the subject mentions it during the call, the subject must be asked to come to the clinic as soon as possible for an in person visit where the procedures will be 
conducted. 
v 
Height should be collected only at screening.  
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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Appendix 2 
Equations and Conversion Factors 
1. Cockcroft-Gault equation to calculate creatinine clearance (CrCl) (relevant to Exclusion 
criterion number 26): 
 
(140-age [yrs]) * weight (kg) * (Z) 
Z = 0.85, if Female 
Cr (mg/dL) * 72 
 
2.  Corticosteroid conversions (relevant to Exclusion criterion number 19): 
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. 
 
 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
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Appendix 3 
Modified Patient Symptom Assessment Questionnaire 
(mPSAQ) 
Pyelonephritis Symptoms 
Symptom Assessment 
Please indicate whether 
you have had the 
symptom in the past 24 
hours? 
Bothersome Assessment 
If you have experienced the 
symptom in the past 24 
hours, please indicate how 
bothersome they were? 
Lower back pain or flank pain 
No symptom 
Mild 
Moderate 
Severe 
Not at all 
A little 
Moderately 
A lot 
Chills, rigors or warmth 
No symptom 
Mild 
Moderate 
Severe 
Not at all 
A little 
Moderately 
A lot 
Pain or uncomfortable pressure in the lower 
abdomen/pelvic area 
No symptom 
Mild 
Moderate 
Severe 
Not at all 
A little 
Moderately 
A lot 
Pain or burning when passing urine 
No symptom 
Mild 
Moderate 
Severe 
Not at all 
A little 
Moderately 
A lot 
Frequency of urination or going to the toilet very 
often 
No symptom 
Mild 
Moderate 
Severe 
Not at all 
A little 
Moderately 
A lot 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
PTK0796-AP-17202 Protocol
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 Paratek Pharma, LLC. 
PTK0796-AP-17202-Version1.0; 26Mar2018 
IND # 75,928 IND # 73,431 
 
Confidential and Proprietary 
Page 86 of 88 
Urgency of urination or a strong and uncontrollable 
urge to pass urine 
No symptom 
Mild 
Moderate 
Severe 
Not at all 
A little 
Moderately 
A lot 
 
 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
PTK0796-AP-17202 Protocol
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Omadacycline 
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PTK0796-AP-17202-Version 1.0; 26Mar20 18 
IND # 75,928 IND # 73,431 
Appendix 4 
Sponsor Signature 
Study Title: 
A Randomized, Double-Blinded, Adaptive Phase 2 Study to 
Evaluate the Safety and Efficacy of IV or IV /PO Omadacycline and 
IV/PO Levofloxacin in the Treatment of Adults with Acute 
Pyelonephritis 
Study Number: 
PTK0796-AP-17202 
Final Date: 
26 March 2018 
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 =--
.--=----
Paratek Pharmaceuticals, Inc 
Confidential and Proprietary 
Page 87 of88 
Date: 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
PTK0796-AP-17202 Protocol
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PTK0796-AP-17202-Version1.0; 26Mar2018 
IND # 75,928 IND # 73,431 
 
Confidential and Proprietary 
Page 88 of 88 
Appendix 5 
Investigator’s Signature 
Study Title: 
A Randomized, Double-Blinded, Adaptive Phase 2 Study to 
Evaluate the Safety and Efficacy of IV or IV/PO Omadacycline and 
IV/PO Levofloxacin in the Treatment of Adults with Acute 
Pyelonephritis 
Study Number: 
PTK0796-AP-17202 
Final Date: 
26 March 2018 
 
 
I have read the protocol described above.  I agree to comply with all applicable regulations 
and to conduct the study as described in the protocol.  
 
 
Signed: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date:  
 
 
 
 
 
 
Investigator Name:___________________________________ 
Investigator Title:____________________________________  
Investigator Affiliation:_______________________________ 
Investigator Address:_________________________________ 
Investigator Phone Number:____________________________ 
 
Number: GEN-CDMED-1912               Version: 2.2               Status: Approved    Approved Date: 4/9/2018
PTK0796-AP-17202 Protocol
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SAP_001.pdf: 
Omadacycline (PTK 0796) 
Paratek Pharma, LLC 
PTK0796-AP-17202 Statistical Analysis Plan 
Page 1 of 49 
Statistical Analysis Plan 
Sponsor: 
Paratek Pharma, LLC 
Protocol No: 
PTK0796-AP-17202 
PRA Project Id: 
PTKCUT16-CUT162 
Title: 
A Randomized, Double-Blinded, Adaptive Phase 2 Study to Evaluate the 
Safety and Efficacy of IV or IV/PO Omadacycline and IV/PO 
Levofloxacin in the Treatment of Adults with Acute Pyelonephritis 
SAP Version 
No./Date: 
04 June 2019 
Approvals 
Representative/ Title: 
 
Signature /Date: 
Representative/ Title: 
 
Signature /Date: 
Biostatistician / 
Title (Owner): 
 
Number: GEN-STP-0293               Version: 1.0               Status: Approved    Approved Date:
PTK0796-AP-17202 Statistical Analysis Plan
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NCT Number: NCT03757234
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Table of Contents 
1 
INTRODUCTION ....................................................................................................................6 
2 
STUDY OBJECTIVES, ENDPOINTS, AND MEASURES ...................................................7 
3 
STUDY DESIGN .....................................................................................................................8 
3.1 
Sample Size Considerations .................................................................................................8 
3.2 
Data Monitoring Committee ................................................................................................9 
3.3 
Randomization and Blinding ...............................................................................................9 
3.4 
Interim Analyses ................................................................................................................11 
3.5 
Final Analyses and Reporting ............................................................................................11 
4 
ANALYSIS POPULATIONS ................................................................................................13 
4.1 
Intent-to-treat Population ...................................................................................................13 
4.2 
Safety Population ...............................................................................................................13 
4.3 
Microbiological ITT Population ........................................................................................13 
4.4 
Clinically Evaluable Population ........................................................................................13 
4.5 
Microbiologically Evaluable Populations ..........................................................................15 
5 
OVERALL STATISTICAL CONSIDERATIONS ................................................................17 
5.1 
General ...............................................................................................................................17 
5.2 
Definitions..........................................................................................................................17 
5.3 
Missing Data and Data Imputation Methods .....................................................................18 
5.4 
Visit Windows ...................................................................................................................19 
5.5 
Multiple comparison and multiplicity ................................................................................20 
6 
POPULATION SUMMARIES ..............................................................................................21 
6.1 
Subject Disposition ............................................................................................................21 
6.2 
Demographic and Baseline Characteristics .......................................................................21 
6.3 
Baseline Microbiology .......................................................................................................22 
6.3.1 
Urine ............................................................................................................................22 
6.3.2 
Blood ............................................................................................................................23 
6.4 
General Medical History, AP, and UTI History ................................................................23 
6.5 
Prior Medications ...............................................................................................................24 
6.6 
Protocol Deviations ............................................................................................................24 
6.7 
Other Baseline Summaries .................................................................................................24 
7 
EFFICACY ENDPOINTS AND ANALYSES ......................................................................26 
7.1 
Efficacy Endpoints .............................................................................................................26 
7.1.1 
Investigator’s assessment of clinical response .............................................................26 
7.1.1.1 
Investigator’s Assessment of Clinical Response at EOT .......................................26 
7.1.1.2 
Investigator’s Assessment of Clinical Response at PTE .......................................27 
7.1.1.3 
Investigator’s Assessment of Clinical Response at FFU .......................................28 
7.1.2 
Microbiologic Response ..............................................................................................29 
7.1.2.1 
Pathogen Determination.........................................................................................29 
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7.1.2.2 
Microbiologic Response ........................................................................................30 
7.1.2.3 
Other microbiological endpoints............................................................................30 
7.1.3 
Overall Response (Composite) ....................................................................................31 
7.1.4 
Modified Patient Symptom Assessment Questionnaire ...............................................32 
7.2 
Efficacy Endpoint Analysis ...............................................................................................34 
7.2.1 
Investigator’s Assessment of Clinical Success ............................................................34 
7.2.2 
Microbiological  Response Analysis ...........................................................................34 
7.2.2.1 
Per-Subject Microbiological Analysis ...................................................................34 
7.2.2.2 
Per-Pathogen Microbiological Favorable Outcome by Baseline Pathogen ...........35 
7.2.2.3 
Susceptibility, Super Infections, and New Infections ............................................35 
7.2.3 
Overall Response (Composite) ....................................................................................35 
7.2.4 
Sensitivity Analyses .....................................................................................................35 
7.2.4.1 
Analysis of Modified Response Cut off.................................................................35 
7.2.5 
Modified Patient Symptom Assessment Questionnaire ...............................................35 
8 
SAFETY ENDPOINTS AND ANALYSES ..........................................................................36 
8.1 
General ...............................................................................................................................36 
8.2 
Duration of Exposure to Test Article and Compliance ......................................................36 
8.3 
Concomitant Medications ..................................................................................................37 
8.4 
Adverse Events ..................................................................................................................37 
8.5 
Clinical Laboratory Results ...............................................................................................38 
8.6 
Vital Signs ..........................................................................................................................39 
8.7 
Pregnancies ........................................................................................................................40 
9 
CHANGES FROM PROTOCOL ...........................................................................................41 
10 REFERENCES .......................................................................................................................43 
APPENDIX 1 CLINICAL LABORATORY TESTS (CENTRAL) AND LOCAL 
URINALYSIS.........................................................................................................................44 
APPENDIX 2 DIRECTIONALITY OF WORST LABORATORY PARAMETERS .................44 
APPENDIX 3 MODIFIED DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES ADULT TOXICITY TABLE .............................................................................46 
APPENDIX 4 CONCOMITANT MEDICATION START DATE IMPUTATION .....................48 
APPENDIX 4 ADVERSE EVENT START/STOP DATE IMPUTATION .................................48 
 
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Glossary of Abbreviations  
Abbreviation 
Definition 
AE 
Adverse event 
AP 
acute pyelonephritis 
ATC 
Anatomical Therapeutic Chemical Classification 
BMI 
Body Mass Index 
CE 
clinically evaluable 
CFU 
colony forming unit 
CI 
confidence interval 
CN 
clinically notable 
CrCl 
creatinine clearance 
DMC 
Data Monitoring Committee 
DMID 
Division of Microbiology and Infectious Diseases 
eCRF 
electronic case report form 
EOT 
end of treatment 
FFU 
final follow-up 
ICF 
informed consent form 
ITT 
intent-to-treat 
iv 
Intravenous(ly) 
IxRS 
Interactive Response System 
LEV 
levofloxacin 
ME 
microbiologically evaluable 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
minimum inhibitory concentration 
micro-ITT 
microbiological intent to treat 
mPSAQ 
modified Patient Symptom Assessment Questionnaire  
N 
number of subjects 
OMC 
omadacycline 
PK 
pharmacokinetic 
po 
oral(ly) 
PT 
preferred term 
PTE 
Post Therapy Evaluation 
QTc 
QT, corrected 
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SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SI 
International System  
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
UTI 
urinary tract infection 
WBC 
white blood cell 
Number: GEN-STP-0293               Version: 1.0               Status: Approved    Approved Date:
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1 INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for Paratek 
Pharma Protocol PTK0796-AP-17202 (A Randomized, Double-Blinded, Adaptive Phase 2 Study 
to Evaluate the Safety and Efficacy of intravenous (iv) or iv/po omadacycline and iv/po 
levofloxacin in the Treatment of Adults with Acute Pyelonephritis). 
The reader of this SAP is encouraged to read the study protocol for details on the conduct of this 
study, the operational aspects of clinical assessments, and the timing for completing the 
participation of a patient in this study.  
The SAP is intended to be in agreement with the protocol, especially with regards to the primary 
and all secondary endpoints and their respective analyses. However, the SAP may contain more 
details regarding these particular points of interest, or other types of analyses (e.g. other 
endpoints). When differences exist in descriptions or explanations provided in the study protocol 
and this SAP, the SAP prevails; the differences will be explained in the Clinical Study Report. 
Methods of reporting of pharmacokinetic (PK) data are outside of scope of this SAP. 
Number: GEN-STP-0293               Version: 1.0               Status: Approved    Approved Date:
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2 STUDY OBJECTIVES, ENDPOINTS, AND MEASURES 
The primary objective of this study is to evaluate the efficacy of iv and iv to oral (iv/po) dosing 
regimens of omadacycline and levofloxacin in the treatment of adults with acute pyelonephritis 
(AP). 
The efficacy endpoints include clinical response, microbiological response, and the composite of 
clinical and microbiological (overall) response, as measured by the number and percentage of 
subjects achieving success.  
The efficacy outcomes are measured by the number and percentage of subjects with successes in 
the ITT, micro-ITT populations, and other populations of interest as appropriate.  
The secondary objectives of this study are: 
 To evaluate the safety of omadacycline in the treatment of adults with AP. 
 To evaluate the PK of omadacycline in adults with AP  
Methods of reporting of PK data are outside of scope of this SAP. 
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3 STUDY DESIGN 
This is a randomized, double-blinded, adaptive designed Phase 2 study evaluating once-daily iv 
or iv/po dosing regimens of omadacycline compared to one once-daily dosing regimen of iv/po 
levofloxacin in the treatment of adults with AP. The planned length of subject participation in the 
study is up to 30 days, which includes a total duration of study therapy for 7 to 10 days (iv only 
or iv and oral combined). Subjects with bacteremia confirmed from local blood culture drawn at 
screening can receive up to 14 days of treatment. 
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 iv or iv/po omadacycline dosing regimens or a regimen of iv/po 
levofloxacin (Table 1). Subjects should receive their first dose of test article at the site within 4 
hours after randomization. IV and oral treatment will be double-blinded and oral treatment will 
be double-dummy. 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. Blood will also be drawn during each subject’s Screening evaluation 
for microbiologic culture; repeat samples will be taken during subsequent visits if bacteremia is 
identified during Screening. 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. 
Subject visits occur on Days 1 to 7. If treatment extends beyond 7 days, subject visits may occur 
on Days 8 to 10. If treatment extends beyond 10 days for subjects with bacteremia based on 
screening culture, visits will occur on Days 11 to 13. An end of treatment (EOT) visit will be 
conducted on the day of or within 2 days following the last dose of test article. Subjects will 
return to the study site for a Post Therapy Evaluation (PTE) on Day 21 (± 2 days). A Final 
Follow-up visit (Final Follow-up) will be conducted on Day 28 (± 2 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 were considered to be clinical successes and 
had no AEs or clinically significant laboratory or electrocardiogram 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.  
A study schedule of events is provided in Table 1 of the protocol. 
For details regarding interim adaptive design refer to Section 3.4. 
3.1 
Sample Size Considerations 
Enrollment of approximately 200 subjects is planned to achieve at least 150 subjects in the 
micro-ITT population. The Bayesian posterior probability that the overall success rate of the 
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composite endpoint at the PTE Visit is within 0.10 of that of the levofloxacin group will be 
estimated for each omadacycline treatment group. The target probability is 0.70. If the true 
underlying overall success rates for the levofloxacin and omadacycline treatment groups are 
0.69, then the sample size of N = 30 per treatment group has approximately 65% 
power/probability to yield the target probability (N = 80 per treatment group for 80% power). If 
the true underlying overall success rates for the levofloxacin and omadacycline treatment groups 
are 0.78, then the sample size of N = 30 per treatment group has approximately 68% 
power/probability to yield the target probability (N = 64 per treatment group for 80% power). 
The sample size may be increased for a particular omadacycline treatment group by changing the 
randomization ratio and/or dropping a treatment group to have improved power/probability of 
achieving the target probability that overall success rates for a treatment group is within 0.10 of 
that of the levofloxacin group.  
The decisions affecting changes of randomization to treatment groups, hence affecting total 
sample size, will be based on the recommendation of the Data Monitoring Committee (DMC) at 
interim analyses in a blinded to study team manner based on safety, and tolerability of 
treatments. Details are documented in the Data Monitoring Committee Charter for Phase II Trial 
for PTK0796-AP-17202.  
3.2 
Data Monitoring Committee 
A DMC will provide ongoing monitoring of data. The charter for the DMC will outline 
membership, all roles, responsibilities, and decision-making criteria.1 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. 
3.3 
Randomization and Blinding 
Initially, subjects will be randomized 1:1:1:1:1 to one of the following 5 treatment groups: 
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Table 1 
Description of Treatment groups 
Group 
Test Article 
Study Day 
Study Days 
Study Days 
1 
2 to 7 
8 to 10a 
Group 1 
omadacycline  
200 mg iv 
200 mg iv 
200 mg iv 
Group 2 
omadacycline  
200 mg iv 
100 mg iv 
100 mg iv 
Group 3 
omadacycline  
200 mg iv 
300 mg po or 100 mg iv 
300 mg po or 100 mg iv 
Group 4 
omadacycline  
200 mg iv 
450 mg po or 100 mg iv 
450 mg po or 100 mg iv 
Group 5 
levofloxacin 
750 mg iv 
750 mg po or 750 mg iv 
750 mg po or 750 mg iv 
iv = intravenous, po = per oral;  
Note: dosing in all treatment groups is once-per-day:aThe total duration of treatment for subjects is 7-10 days, up to 
14 days of treatment for subjects with bacteremia. 
All eligible subjects will be randomized via an Interactive Response System (IxRS) that assigns 
them to the treatment arm. The site delegate will contact the IxRS after confirming that the 
subject fulfills all the inclusion criteria and has 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.  
It is possible that not all treatment arms will be enrolling subjects at the same time. Arms may be 
dropped based on DMC recommendations. There will always be at least one omadacycline arm 
and the levofloxacin arm open.  
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 on DMC recommendation and will be incorporated into the 
IxRS system.  
The investigator and sponsor will be blinded to treatment arm assignments. The iv and po phases 
of the study will be double-blind. 
Because the color of the iv test article infusions and placebo infusions differ, all infusion bags 
and iv tubing will be covered with materials provided by the sponsor so that subjects and blinded 
study personnel will not know the identity of the test article being administered. The infusion 
regimen will follow a blinded design with subjects in each study arm receiving the same infusion 
volumes with the same administration instructions. Blinded study personnel will administer the 
infusions and collect, review and enter data regarding the iv infusions (eg, start and stop times) 
into an electronic case report form (eCRF). If gravity administration is not the standard of care, 
then an infusion pump may be used. If an infusion pump is used, then an unblinded administrator 
will be required. Personnel identified as unblinded administrators will not participate in any 
study procedures other than iv administration of test article and the collection, review and entry 
of iv related data (eg, start and stop times) into an eCRF. 
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During the po phase, a double-blind, double-dummy design will be used to ensure the blind is 
maintained. Subjects on the omadacycline arms may receive active omadacycline tablets and 
over-encapsulated levofloxacin placebo tablets. Subjects on the levofloxacin arm will receive 
omadacycline placebo tablets and over-encapsulated active levofloxacin tablets. Infusions will be 
administered concomitantly along with the po treatment to maintain the overall study blind. 
Data that could potentially lead to unblinding will not be accessible to anyone other than the 
following site personnel: 
 unblinded study pharmacist or designee 
 unblinded study monitor 
 unblinded administrator(s) 
Unblinding is only to occur in the case of subject emergencies and at the conclusion of the study. 
3.4 
Interim Analyses 
This is an adaptive dose-response finding study.  
Interim analyses will be conducted when data are available for approximately 40, 80 and 100 
subjects in order for DMC to provide recommendation on the following: 
 Omadacycline treatment group(s) that can be initiated or dropped from the trial 
 Modification of the randomization ratios among the treatment groups  
 Need for extension of the trial beyond 200 enrolled subjects to provide more precise 
estimates of the efficacy outcome 
To protect the integrity of the clinical study, neither the actual randomization schedule nor the 
data from the data reviews will be made available to the Sponsor Study team or the Study 
Reporting team. Data for the unblinded data reviews by the DMC will only be released to the 
DMC, the independent reporting statistician, and the DMC Reporting team. For details refer to 
Data Monitoring Committee Charter for Phase II Trial for PTK0796-AP-17202. 
Decisions on randomization re-allocation and/or dropping dose groups will be based primarily on 
safety and tolerability. Efficacy will only be considered for dose-reallocation if the DMC deems 
the response rates as too low to proceed with enrollment. Efficacy is not pre-planned with 
statistical decision criteria due to high variability in small sample sizes. 
Based on the results of analyses during the interim reviews, the DMC may recommend 
continuation of enrollment above 200 subjects. The purpose of an increase in sample size, among 
other reasons, may be due to the need to provide more precise estimates of the efficacy outcome 
or for further exploration of safety and tolerability data. 
3.5 
Final Analyses and Reporting 
All analyses identified in this SAP will be performed according to the study protocol, ie, after the 
end of study as defined in the study protocol.  
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This SAP and any corresponding amendments will be approved before database lock. The 
randomization codes will not be unblinded until this SAP has been approved and issued. 
 
 
 
 
 
 
 
 
 
 
 
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4 ANALYSIS POPULATIONS 
The following subject analysis populations have been defined. 
4.1 
Intent-to-treat Population 
The intent-to-treat (ITT) population will consist of all randomized subjects regardless of whether 
or not the subject received test article.  
A subject is considered randomized when the IxRS provides the test article assignment by 
providing the kit number (i.e., completes a randomization transaction). Subjects in this 
population will be summarized according to randomized test article assignment. 
4.2 
Safety Population 
The Safety population will consist of all randomized subjects who receive any amount of test 
article. All safety analyses will be conducted in this population; subjects will be summarized 
according to actual test article received. 
4.3 
Microbiological ITT Population 
The micro-ITT population will consist of subjects in the ITT population who have an 
appropriately collected pretreatment baseline urine culture with at least 1 uropathogen at ≥ 105 
colony forming unit (CFU)/mL and not more than 2 bacterial isolates at any count. If more than 
2 bacterial isolates are identified, the culture will be considered contaminated regardless of 
colony count, unless 1 of the isolates that grows in the urine at ≥ 105 CFU/mL is also isolated 
from a blood culture at the same visit.  
Rules for Sponsor’s determination of qualifying pathogens is described in the Pathogen and CE. 
4.4 
Clinically Evaluable Population 
The clinically evaluable (CE) population will consist of all ITT subjects who received test 
article, have acute uncomplicated pyelonephritis (AP), an assessment of outcome, and meet all 
other evaluability criteria.  
Inclusion into the CE populations will be determined programmatically based on the data on the 
eCRF and a manual review by the Sponsor as necessary prior to unblinding. Details on allocation 
to each CE population are described in the Pathogen and CE.   
Since patient count may differ depending on timepoint, CE populations will be defined by 
milestone visit (CE-EOT, CE-PTE and CE-FFU). To be included in the populations, subjects 
must meet all criteria defined below:   
1. Qualifying infection: 
Inclusion Criterion #2: Females age 18 years or older  
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Inclusion Criterion #3: Clinical signs and symptoms of acute uncomplicated pyelonephritis 
with onset or worsening within 96 hours prior to randomization. 
Inclusion Criterion #4: A clean-catch midstream urine sample with dipstick analysis positive 
(at least ++) for leukocyte esterase or pyuria (white blood cell [WBC] count > 10/μL in unspun 
urine or ≥ 10 per high power field in spun urine sediment). 
2. Assessment of Outcome for CE population: 
Subjects must meet all of the following to be included in the CE populations: 
 Subject did not meet one of the exclusion criteria 6 through 15 of the protocol (Baseline 
event exclusion) 
 Received the randomized test article and was at least 80% compliant with the dosing regimen 
(Compliance to test article intake). 
 Study personnel involved in the assessment of efficacy remained blinded to study treatment, 
unless a treatment limiting AE occurred which required emergency unblinding.   
In addition, for each endpoint the following needs to be satisfied, as appropriate: 
a. For the CE-EOT population: 
i. Completed the investigator’s assessment of clinical response (i.e., was not 
deemed an indeterminate outcome) at the EOT visit, and  
ii. The EOT visit occurred on the day of, or within ± 2 days, following the 
last dose of test article (3 days window).    
b. For the CE-PTE population: 
i. The Overall Clinical Response (based on the investigator's assessment) at 
the PTE Visit is not Indeterminate (see Table 5).   
ii. The PTE Visit occurred Day 21 (± 2 days), unless the subject was 
considered to be a Clinical Failure based on the investigator’s assessment 
at the EOT visit.  
c. For the CE-FFU population: 
i. The overall Clinical Response (based on the investigator's assessment) at 
the Final Follow-up (FFU) Visit is not Indeterminate.   
ii. The FFU Visit occurred on Day 28 (± 2 days) from the first dose of test 
article), unless the subject was considered to be a Clinical Failure based on 
the investigator’s assessment at the PTE visit. 
3. Other Evaluability Criteria 
a. Prior Antibiotic Therapy 
Exclusion Criterion #2: 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 pyelonephritis while receiving prophylactic antibacterial 
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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.] 
Subjects who meet exclusion criteria #5 will be excluded from the CE populations. 
b. Concomitant Antibiotic Therapy 
Subjects who receive any systemic concomitant antibiotic therapy from the start of 
administration of the first dose of test article through the EOT visit (CE-EOT 
population), PTE visit (CE-PTE population) or FFU visit (CE-FFU population) that is 
potentially effective against the baseline pathogen, will be excluded from the CE 
population.  If no pathogen is isolated and the systemic concomitant antibiotic is 
effective against Gram-negative uropathogens, the subject will be excluded from the 
respective CE population. Subjects who are a clinical failure on the particular visit 
and received non-study antibiotics for insufficient therapeutic effect of the test article, 
will not be excluded from the CE populations. Subjects who receive a systemic 
concomitant antibiotic that is not potentially effective against the baseline pathogen 
will be included in the CE populations. 
c. Evaluable Success and Failure  
Evaluable success: The subject received at least 3 doses of active test article and the 
investigator classifies the subject as a clinical success at the EOT visit (CE EOT 
population) or the overall clinical response (based on the investigator's assessment) at 
the PTE visit (CE-PTE population) or the overall clinical response (based on the 
investigator's assessment) at the FFU visit (CE-FFU population) is clinical 
success/cure.  
 
Evaluable failure: The subject received at least 2 doses of active test article and the 
investigator classifies the subject as a clinical failure at the EOT visit (CE EOT 
population) or the overall clinical response (based on the investigator's assessment) at 
the PTE Visit (CE-PTE population) or the overall clinical response (based on the 
investigator's assessment) at the FFU visit (CE-FFU population) is clinical 
failure/relapse.   
 
4.5 
Microbiologically Evaluable Populations 
The microbiologically evaluable (ME) population will include subjects in the CE and micro-ITT 
populations who have both an appropriately collected post-baseline urine sample and an 
interpretable post-baseline urine sample. An interpretable post-baseline urine culture is one that 
has a clearly identified pathogen or one where the baseline pathogen(s) can be excluded (ie, there 
is no growth of the baseline pathogen).  
Since patient count may differ depending on timepoint, ME populations will be defined by 
milestone visit (ME-EOT and ME-PTE). 
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The ME populations consist of subjects in the micro-ITT population and the CE-EOT and CE-
PTE populations, respectively who also have:   
 A clean-catch urine specimen at the EOT and PTE visits, and  
 Interpretable urine culture results at the EOT and PTE visits. 
Subjects with an unfavorable microbiological outcome at EOT will be included in the ME-PTE 
population, regardless of whether they provide a urine culture at the PTE visit.   
An interpretable post-baseline urine culture is one that has a clearly identified pathogen or one 
where the baseline pathogen(s) can be excluded (i.e., there is no growth of the baseline 
pathogen).  A urine culture is considered uninterpretable if more than two bacterial isolates are 
identified, unless any of the following is observed:    
 There is <104 CFU/mL of the baseline pathogen(s), indicating eradication. 
 There is ≥104 CFU/mL of the baseline pathogen(s), indicating persistence 
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. 
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5 
OVERALL STATISTICAL CONSIDERATIONS  
5.1 
General 
All analyses will use SAS version 9.4 or higher. Results will be reported by treatment group, 
unless otherwise specified. 
Unless otherwise stated, listings corresponding to all summaries will be provided. Generally, 
listings will be provided for all randomized patients, however sometimes they may be limited to 
a smaller set depending on parameter (e.g. compliance to a test article will be limited to safety 
population). 
Unless otherwise noted, categorical variables will be summarized using counts and percentages. 
Percentages will be rounded to one decimal place, except 100% will be displayed without any 
decimal places and percentages will not be displayed for zero counts.  
Continuous variables will be summarized using the number of observations (n), mean, standard 
deviation (SD), median, minimum and maximum.  
5.2 
Definitions 
In Table 2 general definitions are provided used in the statistical analysis. 
Table 2 
General Definitions 
Variable 
Definition 
Baseline 
 
Unless otherwise stated, baseline is defined as the value closest to but prior to the 
initiation of test article administration.   
Change from baseline 
Change from baseline will be defined as the post-baseline value minus the baseline 
value (on a subject level). Change from baseline will only be calculated for subjects 
who have both baseline and at least one post-baseline value for any parameter.  
 
Duration Variables 
Duration variables will be calculated using the general formula: 
Duration (days) = End date - Start date + 1 
If applicable, where time is collected: 
 Duration (hh:mm) = End datetime - Start datetime 
 
Calculated Creatinine 
Clearance (mL /min), 
Cockcroft-Gault equation 
(140 – age [yrs]) * weight [kg] * Z 
Creatinine [mg/dL] * 72 
   Z = 0.85 for Female subjects 
Body Mass Index (BMI) 
BMI = Weight (kg) / Height (m)2 
 
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5.3 
Missing Data and Data Imputation Methods 
Missing data will be handled as outlined below  
1. Adverse Events and Safety Data: 
 All missing and partial dates for AEs will be queried for a value. If no value can be obtained, 
substitutions will be made as detailed in Section 8.4. These substitutions will be used in 
calculations; however, the actual value recorded on the eCRF will be used in all listings. 
 If the time of the first dose of test article is missing, it will be imputed with time of 
randomization + 1 minute. If time is missing for other doses it will be imputed with time of 
previous dose + 12 h. 
 An AE is considered treatment emergent if the AE start date and time is on or after the start 
date and time of the first dose of test article.   
 If time of the AE is missing and it occurred on the same date as the first dose of test article, 
the AE will be defined as treatment emergent. If the start date of the AE is partial or missing 
and it cannot be determined if the AE occurred prior to or after the first dose of test article, 
the AE should be defined as treatment emergent. Appendix 4 Adverse Event Start/Stop Date 
Imputation provides imputation for partial or missing date information. For AE listings, all 
dates and times will be displayed as reported on the Case Report Forms. 
 If no value can be obtained for all other times for events and assessments occurring after 
randomization, the time will not be imputed but will remain missing.   
 The severity and causality assessment for AEs cannot be missing.  Missing data will be 
queried for a value. The highest severity and most related causality should be used if query is 
missing. If query will return missing, then the highest severity and most related causality will 
be used for the purpose of summaries.   
 If the reported value of a clinical laboratory parameter cannot be used in a statistical 
summary table (e.g., a character string is reported for a parameter of the numerical type), a 
coded value must be appropriately determined and used in the statistical analyses. A value 
that is in the lower limit of the normal range will be calculated as 99.99% of the value if it is 
reported as “<” (e.g.  <5 will be converted to 5*0.99=4.9995). A value that is in the upper 
limit of the normal range will be converted to 100.01% if it is reported as “>” (e.g.>7 will be 
converted to 7*1.001=7.007). However, the actual values as reported in the database will be 
presented in data listings.  
 Prior and Concomitant Medication start date imputation will be imputed according to table in 
Appendix 4 Concomitant Medication Start Date Imputation. 
2. Efficacy Data 
 Analysis of efficacy data will be based on the available data, unless otherwise stated. 
 Missing data for clinical and microbiological outcomes is denoted “indeterminate”, unless 
any of the below rules apply.  
 Missing microbiological outcomes at EOT will be imputed by last day of test article intake. 
 The Overall Clinical Response at PTE and FFU visits are derived based on the “worst case 
scenario” to accommodate for missing visit assessments and intercurrent events (eg rescue 
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medication at EOT visit). Similar imputations were applied to microbiological response 
endpoints. Details are described in Section 7.   
 mPSAQ data for bothersome score will be imputed with score of 0 for each question for 
which severity is answered “Did not have”. 
 
5.4 
Visit Windows 
Subjects will participate in the study for up to 30 days. Following Screening, eligible subjects 
will be randomly assigned to receive 7 to 10 days of iv/po treatment of either omadacycline or 
levofloxacin. Subjects with bacteremia confirmed from local blood culture drawn at screening 
can receive up to 14 days of treatment. Subjects will return to the site for an EOT visit on the day 
of or within 2 days following the last dose of test article. Subjects will return to the study site for 
a PTE on Day 21 (± 2 days). A final follow-up assessment will be conducted Day 28 (± 2 days) 
following the first dose of test article. A tabular summary of the visit schedule is displayed in 
Table 3. 
Table 3 
Scheduled Study Visits 
Study Visit 
Study Day 
Notes 
Baseline 
Day -1 or Day 1 
Except where indicated, last measurement prior to the first 
dose of test article.  Screening assessments are to be taken 
within 24 hours prior to randomization if no test article is 
taken, the date and time of randomization is used in place of 
randomization date. 
On Treatment (note:  
analysis visit will be 
each Study Day) 
Day 1 to Day 7 
Day 8 to Day 14 (latest 
on treatment Day) 
As entered in the eCRF for these visits 
EOT 
Not later than Day 16 
Within 2 days following the last dose of test article 
PTE 
Day 21 
On Day 21 (± 2 days) after the subject's first day of test 
article 
Final Follow-up (FU) 
Day 28 
On Day 28 (± 2 days) after the subject's first day of test 
article 
Study Day is calculated relative to the first dose of test article (Day 1); there is no Day 0 – the day prior to the first 
dose of test article is Day -1.  If no test article is taken, study day is calculated relative to the date of 
randomization. 
For efficacy outcomes, the data collected at the EOT, PTE and FFU visits, regardless of when 
these occur will be utilized in the analysis in the ITT and micro-ITT population. The CE and ME 
populations exclusions due to windowing are outlined in Sections 4.4 and 4.5.  
For each safety outcome and UTISA data, analyses will utilize assessments occurring during the 
scheduled visit windows (provided in Table 3). Thus, if a subject has a visit outside the 
scheduled visit window, for example, a PTE Visit occurred 20 days after the subject's first 
investigational product dose, the assessment will not be summarized with the PTE Visit but will 
be considered an unscheduled assessment. If a subject does not have an assessment at a 
scheduled visit and an unscheduled assessment was taken within the window for the time point 
(for example, 21 days (± 2 days) after the subject's first day of therapy for PTE), these 
assessments will be summarized in the by time point analyses. If more than one measurement is 
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taken during the visit window, the value taken on the scheduled visit will be utilized or if no 
scheduled visit was done, the first (earliest) measurement in the visit window will be used. If 
more than one measurement is taken on the same day, the assessment closest to the start of the 
dose will be used for on treatment values and the last measurement on the day will be used for 
post-treatment values. For worst overall post-baseline analyses, all assessments including those 
obtained from unscheduled visits will be included. 
5.5 
Multiple comparison and multiplicity  
No adjustment for multiplicity will be applied to any endpoints, thus any inferential statistics will 
be nominal.  
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6 POPULATION SUMMARIES 
Unless otherwise stated, listings corresponding to all summaries in this section will be provided 
for all randomized subjects (ITT analysis population). 
6.1 
Subject Disposition 
The number of subjects included in each of the analysis populations defined in this SAP and the 
reasons for exclusion will be summarized by treatment group. A listing will be provided to 
indicate each subject’s inclusion/exclusion from the populations, and the reason for exclusion 
from a population will be presented.   
A list of randomized subjects who did not meet all inclusion/exclusion criteria, and which 
criteria were not met will be presented.   
The number and percentage of subjects completing the study (completing the EOT, PTE and 
FFU visits, as reported on CRF), as well as the completion status of EOT, PTE, and FFU visits 
will be presented. Reasons for not completing the study and for missing visits, as recorded on the 
eCRF, will be summarized (number and percentage) by treatment group for ITT, micro-ITT, CE 
and PTE populations.  
The number and percentage of subjects completing and prematurely discontinuing test article and 
the reasons for discontinuation will be presented by treatment group. A listing of all subjects who 
prematurely discontinued from test article or who did not complete the study will be presented, 
along with the primary reason for discontinuation of test article or not completing the study.  
The number of screen failures and reason for screen failure will be presented overall. For 
randomized subjects, a listing will be provided that indicates the date and time of randomization, 
randomization number, randomized treatment assignment, drug unit identifications, and 
corresponding drug codes. 
6.2 
Demographic and Baseline Characteristics 
Demographic characteristics will be summarized in ITT, micro-ITT, CE-PTE, and ME-PTE 
populations analysis sets defined in this SAP. The summary table will include age, race, and 
ethnicity, along with baseline characteristics for height, weight, body mass index (BMI), number 
of prior urinary tract infections (UTIs) (lifetime), and renal function. Age will be summarized as 
a continuous variable and as categorical, based on the following groups: 18 to 45 years, > 45 to 
65 years, > 65 years.  
Renal function will be categorized as normal (creatinine clearance [CrCl] > 89 mL/min), mild 
renal impairment (CrCl > 60 to 89 mL/min), moderate renal impairment (CrCl 30 to 60 mL/min) 
and severe renal impairment (CrCl < 30 mL/min). Creatinine clearance will be calculated from 
the local laboratory data and will be determined from the Cockcroft-Gault equation, for female 
subjects: 
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Gender will not be included in the summary, as all subjects enrolled in this study will be female, 
per inclusion criteria.  
General medical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) and summarized by system organ class (SOC) and preferred term (PT). 
Results of the Modified Patient Symptom Assessment Questionnaire (mPSAQ) will be 
summarized as the number and percentage of subjects responding to each item, including 
individual severity symptom scores, individual bothersome scores, and overall severity and 
bothersome score.  
6.3 
Baseline Microbiology 
6.3.1 
Urine 
The microbiological assessment of the urine culture by the local laboratory will be summarized 
by treatment group for the ITT and micro-ITT populations.  
The number of subjects with local urine culture performed, number of subjects with a clean catch 
sample, number of subjects with urine culture growth and number of isolates per subject where 
CFU count ≥105 CFU/mL.   
Each isolate identified will also be reported and will include the CFU counts as recorded on the 
CRF (<103 CFU/mL, 103≤ and <104 CFU/mL, 104≤ and <105 CFU/mL, and ≥ 105 CFU/mL). 
Test article received disk diffusion value (mm) to baseline pathogen will be provided for micro-
ITT population. 
All of the below reports will be provided for micro-ITT and ME populations. 
 The number and percentage of subjects with a positive urine culture by pathogenic organism 
will be provided for the micro-ITT and ME populations.   
 The number and percentage of subjects with a Gram-positive organism (aerobes and 
anaerobes) and with a Gram-negative organism (aerobes and anaerobes) will be presented by 
genus and species.  
 The number and percentage for minimum inhibitory concentration (MIC) data will be 
provided as:  
o The MIC distribution to omadacycline and levofloxacin, across treatment groups 
o The MIC distribution to the test article received, by treatment group  
o MIC summary statistics (ie, range, MIC50, and MIC90) to the test article received. The 
MIC range will be provided for all baseline pathogens. The MIC50 and MIC90 will be 
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provided only for those pathogens isolated at least 10 times in a treatment group. MIC50 
and MIC90 values are defined as the lowest concentration of the antibiotic at which 50% 
and 90% of the isolates were inhibited. 
o MIC summary statistics (ie, range, MIC50, and MIC90) to the test article received for each 
pathogen at baseline. 
A listing will be provided that includes for each subject all baseline and post-baseline isolates 
identified by Genus and species from the local and central urine culture including the CFU count 
and whether or not the isolate is a pathogen.   
6.3.2 
Blood 
Blood culture samples are taken at screening and as required during treatment. If bacteria are 
isolated from baseline blood cultures, repeated blood cultures will be collected. If subsequent 
blood cultures were also positive, repeated blood cultures as necessary were taken until negative 
blood cultures were obtained. 
The pathogenic organisms identified from the baseline blood culture will be presented by genus 
and species.     
The number and percentage of subjects with a positive blood culture by pathogenic organism 
will be provided for the micro-ITT and ME populations.  The number and percentage of subjects 
with a Gram-positive organism (aerobes and anaerobes) and with a Gram-negative organism 
(aerobes and anaerobes) will be presented by genus and species.   
A listing will be provided that includes all baseline and post-baseline isolates obtained from the 
blood.  
Similar tables providing the MIC data for the pathogens identified from the baseline blood 
cultures will be provided for the micro-ITT and ME populations as described for the urine 
cultures in Section 6.3.1 above. 
6.4 
General Medical History, AP, and UTI History 
Significant medical history (at any time) and any medical history within the past 6 months 
including ongoing medical conditions at the time of signing of the informed consent form (ICF) 
will be recorded.  
In addition, subject history of prior UTI infection and AP will be captured, where possible, 
diagnoses are to be recorded. Of note, any event or change in the subject’s condition or health 
status occurring after signing the ICF will be reported as an AE. All medical history will be 
coded using the MedDRA. 
The incidence of medical history abnormalities will be summarized using descriptive statistics by 
SOC and PT. Patients are counted only once in each PT and SOC category. Summaries will be 
presented by treatment group and for all patients. 
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6.5 
Prior Medications 
Treatments that have been administered within the 7 days prior to the date of informed consent, 
or during the Screening phase, will be recorded in the eCRF. The investigator is to instruct the 
subject to notify the study site about any new medications he/she takes after the start of the test 
article. All medications and significant non-drug therapies (including physical therapy and blood 
transfusions) administered after the subject starts treatment with test article must be listed in the 
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. 
If a medication is taken prior to the first dose of test article or if their start date is unknown, then 
it will be summarized as a prior medication. Medications are considered concomitant if taken on 
or after the first dose of test article, or if their stop date is unknown or marked as continuing. 
Thus, in cases where a medication starts prior to the first dose, and continues throughout the 
treatment period, the medication will be summarized as both prior and concomitant.  
Summary of prior antiemetic medication will also be provided for the ITT population.  
Summaries of prior antibiotic use will be summarized for ITT and micro-ITT populations. 
6.6 
Protocol Deviations 
Deviations will be reviewed in a blinded manner by the sponsor and categorized into general 
categories (eg. inclusion/exclusion criteria).  The sponsor will also categorize the protocol 
deviations as major and minor.  Review of deviations will be conducted and finalized prior to 
unblinding the database.   
A major deviation is defined as one that potentially affects the efficacy and/or safety analyses. 
The number and percentage of subjects with at least one major protocol deviation or with at least 
one minor protocol deviation will be summarized for the ITT and micro-ITT population. The 
summaries of major deviations will also be presented by category.  
A listing of all protocol deviations will be provided. 
6.7 
Other Baseline Summaries 
Abnormal laboratory results and abnormal vital signs at baseline will be reported. 
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. 
Significant and relevant findings that are present prior to the start of test article must be included 
in the subject’s eCRF. Relevant findings (except for signs and symptoms related to the index AP) 
that are present prior to the start of test article must be included in the relevant medical 
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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 AE screen of 
the subject’s eCRF. 
Subject listings of all physical examination results by body system will be provided. 
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7 EFFICACY ENDPOINTS AND ANALYSES 
7.1 
Efficacy Endpoints 
In this phase 2 study all efficacy endpoints are exploratory and are analyzed as per Table 4 
below. 
Table 4 
Efficacy Endpoints 
Endpoint 
Visit 
Population 
(Overall) Investigator’s assessment of clinical response 
PTE/EOT/FFU 
ITT 
micro-ITT 
CE, ME 
(Overall) Microbiologic response 
PTE/EOT 
micro-ITT 
ME 
Modified Patient Symptom Assessment Questionnaire (mPSAQ) 
By visit/day 
ITT, micro-ITT, 
CE-EOT, CE-
PTE 
 
7.1.1 
Investigator’s assessment of clinical response 
7.1.1.1 
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:  The complete resolution or significant improvement of the baseline signs 
and symptoms of AP at the EOT visit such that no additional 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 alternative or additional systemic antimicrobial 
therapy for the current infection is required or death prior to the EOT visit. 
 Indeterminate: EOT visit not completed.  
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7.1.1.2 
Investigator’s Assessment of Clinical Response at PTE 
For subjects who were determined to be a clinical success or indeterminate at the EOT visit, the 
investigator will determine whether or not the subject meets the criteria of 1 of the following 
clinical outcomes: 
 Clinical Success:  The complete resolution or significant improvement of the baseline signs 
and symptoms of AP symptoms at the PTE such that no additional 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, or death 
occurred at or before the PTE visit. 
 Indeterminate: PTE visit not completed.  
Overall Clinical Response at PTE (based on the investigator’s assessment) is determined as 
follows (Table 5) from the investigator's assessments at the EOT and PTE Visits: 
Table 5 
Investigator's Assessment of Clinical Response at PTE Visit 
EOT Visit 
PTE Visit 
Overall Clinical Response at PTE Visit  
Success 
Success 
Success 
Success 
Failure 
Failure 
Success 
Indeterminate 
Indeterminate 
Failure 
Success 
Failure 
Failure 
Failure 
Failure 
Failure 
Indeterminate 
Failure 
Indeterminate 
Success 
Indeterminate 
Indeterminate 
Failure 
Failure 
Indeterminate 
Indeterminate 
Indeterminate 
EOT = end of treatment; PTE = post-therapy evaluation. 
 
The derived Overall Investigator’s Clinical Response is based on the “worst case scenario” to 
accommodate for missing visit assessment and intercurrent events (eg rescue medication at EOT 
visit). For the ITT and micro-ITT populations, the proportion of subjects with a Clinical Success 
is defined using the following formula (missing information at the PTE visit will be counted as 
Indeterminate): 
# of subjects with Clinical Success 
_____________________________________________________________________________________________________________________________________________________________________________________________________________________________ 
(# of subjects with Clinical Success + # of subjects with Clinical Failure + # of subjects with 
Indeterminate response) 
 
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By definition, subjects in the CE-PTE population cannot have an Indeterminate response.  Thus, 
for the CE population, the proportion of subjects with a Clinical Success is defined using the 
following formula: 
# of subjects with Clinical Success 
_____________________________________________________________________________________________________________________________________________________________________________________________________________________________ 
(# of subjects with Clinical Success + # of subjects with Clinical Failure) 
 
7.1.1.3 
Investigator’s Assessment of Clinical Response at FFU 
For subjects that were determined to be a clinical success at the PTE visit, the investigator will 
determine whether or not the subject meets the criteria of 1 of the following clinical outcomes:   
 Clinical Cure: The complete resolution or significant improvement of the baseline signs and 
symptoms of AP at FFU visit such that no additional antimicrobial therapy is required for the 
current infection.  
 Relapse: The reappearance of signs and symptoms at or before the FFU Visit such that use 
of alternative or additional systemic antimicrobial therapy for the current infection.  
 Clinical Failure: Death between the PTE and Final Follow-up or failure at PTE visit.  
 Indeterminate: Final Follow-up visit not completed. If FFU visit assessment is not within 
the visit window the EOT response is defined as indeterminate. 
Overall   Response (based on the investigator’s assessment) is determined as defined in Table 6. 
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Table 6 
Investigator's Assessment of Clinical Response at FFU Visit 
Overall Clinical Response at  
PTE Visit 
Clinical Response at  
FFU Visit 
Overall Clinical Response at FFU 
Visit 
Success 
Clinical Cure 
Clinical Success 
Success 
Clinical Failure 
Clinical Failure 
Success 
Indeterminate 
Indeterminate 
Success 
Relapse 
Relapse 
Failure 
Clinical Cure 
Clinical Failure 
Failure 
Clinical Failure 
Clinical Failure 
Failure 
Indeterminate 
Clinical Failure 
Failure 
Relapse 
Clinical Failure 
Indeterminate 
Clinical Cure 
Indeterminate 
Indeterminate 
Clinical Failure 
Clinical Failure 
Indeterminate 
Indeterminate 
Indeterminate 
Indeterminate 
Relapse 
Relapse 
PTE = post-therapy evaluation; FFU = Final Follow-up 
 
7.1.2 
Microbiologic Response 
Per-pathogen and per-subject microbiologic response will be programmatically determined at the 
EOT and PTE Visits in the micro-ITT and ME populations (by definition subjects in the ME 
population cannot have an indeterminate response). 
Microbiological response will be derived using electronically transferred microbiology data from 
the central laboratory (or local laboratory if central data are not available).   
Overall per-pathogen microbiological response at PTE is determined as follows (Table 7) from 
the per-pathogen microbiological responses at the EOT and PTE Visits. 
7.1.2.1 
Pathogen Determination 
A pathogen is defined as bacteria implicated as causative in a subject’s AP.  Baseline pathogens 
and post-baseline pathogens will be identified for each patient programmatically with manual 
review and confirmation. Sponsor determination review will be performed in a blinded manner 
by Sponsor’s internal microbiology review committee. Details are documented in the Pathogen 
and CE2. 
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7.1.2.2 
Microbiologic Response 
Per-pathogen microbiological response will be programmatically determined at the EOT and 
PTE Visits in the micro-ITT and ME populations (subjects in the ME population cannot have an 
indeterminate response). 
Pathogen microbiological outcome categories are: eradication, persistence, and indeterminate 
and these are defined in the following table (Table 7).  
Table 7 
Per-Pathogen Microbiologic Response at EOT and PTE 
Category  
Criteria  
Eradication  
The demonstration that the baseline bacterial pathogen is reduced to < 104 CFU/mL on 
urine culture and negative on repeat blood culture (if positive at baseline)  
Persistence  
The urine culture taken at the study visit grows ≥ 104 CFU/mL of the baseline pathogen 
identified at study entry and/or a positive blood culture at the study visit demonstrates the 
same baseline pathogen. Pathogens that demonstrate persistence at EOT will be considered 
as persistence at PTE.  
Indeterminate  
No follow-up urine culture is available, or the follow-up urine culture cannot be 
interpreted for any reason. For a baseline blood pathogen, no follow-up blood culture is 
available.  
CFU = colony forming units, EOT = end of treatment, PTE = post therapy evaluation.  
 
Per-subject microbiological responses will be based on per-pathogen outcomes (see Table 8). An 
overall per-subject microbiologic response at EOT and PTE will be programmatically 
determined for each subject based on the individual outcomes for each baseline pathogen. For a 
subject to have a microbiologic response of success, the outcome for each baseline pathogen 
must be eradicated. If the outcome for any pathogen is persistence, the subject will be considered 
to have a microbiologic response of failure. A persistent baseline pathogen at EOT will be 
considered persistence at PTE. 
Table 8 
Per-Subject Microbiologic Response at EOT and PTE 
Category 
Criteria 
Success 
The outcome of all baseline pathogens must be eradication at the specified visit (EOT 
or PTE) 
Failure  
The outcome of at least 1 baseline pathogen is persistence. Subjects with a persistence 
determination at EOT will be considered to have persistence at PTE.  
Indeterminate  
The outcome of at least 1 baseline pathogen is indeterminate and there is no outcome of 
persistence for any baseline pathogen  
 
7.1.2.3 
Other microbiological endpoints 
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7.1.4 
Modified Patient Symptom Assessment Questionnaire 
The subject will report the severity of their pyelonephritis symptoms and how bothersome they 
are with the mPSAQ. The questionnaire will be completed during each study visit. The subject 
will rate the severity and how bothersome each symptom on a 4-point scale (no symptom, mild, 
moderate, severe and not at all, a little, moderately, a lot) and the results will be recorded in the 
eCRF. The investigator had to review the subject’s responses and record any AEs as appropriate.  
The mPSAQ is a self-administered, 6-item questionnaire that assesses the levels of ‘severity’ and 
‘bothersomeness’ for each of the seven most frequently reported symptoms and signs of 
pyelonephritis symptoms: 
Lower back pain or flank pain 
Chills, rigors or warmth  
Pain or uncomfortable pressure in the lower abdomen/pelvic area 
Pain or burning when passing urine 
Frequency of urination or going to the toilet very often 
Urgency of urination or a strong and uncontrollable urge to pass urine 
 
Each item has a Likert-type response scale, the ‘severity’ item response options being ‘did not 
have’, ‘mild’, ‘moderate’, ‘severe’, scored 0–3; and the bothersomeness item response options 
being ‘not at all’, ‘a little’, ‘moderately’, ‘a lot’, scored 0–3. 
Total scores of the 6 items for the symptom severity scores and total scores for the 6 items 
related to the bothersomeness will be calculated for each subject and visit. The total scores for 
severity and bothersomeness will be between 0 and 18. The total score 0 is indicating the least 
severity of symptoms and a total score of 18 is indicating the worst symptom severity. For 
bothersomeness, the total score 0 is indicating the least bothersome score and a total score of 18 
is indicating the most bothersome score. 
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For calculating the individual subject score by visit for both sub-scales the scores of non-missing 
item scores are summed up and divided by the number of non-missing items and then multiplied 
by 6. If less than 4 items are answered for each sub-scale, the total score is set to ‘missing’ for 
the sub-scale of the subject. 
Total scores of the 6 items (Item 1 to 6) for the severity of symptoms scores and total scores for 
the 6 items related to the bothersomeness (Item 7 to 12) will be calculated.  
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7.2 
 Efficacy Endpoint Analysis 
The efficacy endpoints include clinical response, microbiological response, and the composite of 
clinical and microbiological (overall) response, as measured by the number and percentage of 
subjects achieving success. The efficacy outcomes are measured by the number and percentage 
of subjects with successes in the ITT, micro-ITT populations, and other populations (CE and 
ME) as appropriate.  
7.2.1 
Investigator’s Assessment of Clinical Success 
The number and percentage of subjects with clinical success, failure, and indeterminate response 
as per investigator’s assessment at the PTE visit in the ITT population will be determined by 
treatment group. Difference in success rates between levofloxacin and each omadacycline group 
will be provided. Point estimates will be provided together with the corresponding 95% 
confidence interval.  
In addition, 95% credible intervals will be provided for the difference in success rates using the 
modeling as follows. Assuming the likelihood for number of responders to have binomial 
distribution [𝑌i~𝐵𝑖𝑛(𝑛i, 𝑝i)] and non-informative beta priors [pi ~ Beta(0.5, 0.5)]. The posterior 
probability of non-inferiority will be computed as P(pOMC – pL > -0.1 | data) for assessment. 
Reason for investigator assessment of clinical failure and indeterminant at EOT, and for overall 
assessment at PTE and FFU visits will be tabulated for ITT, micro-ITT, and CE populations. 
The analysis as described above will be repeated for EOT and FFU visits and provided also for 
CE and ME populations, as appropriate. 
Overall clinical success at the PTE and EOT visits will be presented by pathogen and by 
pathogen and MIC for the micro-ITT and ME populations. 
The analyses as described above will be repeated for pooled groups 2-4. 
7.2.2 
Microbiological  Response Analysis 
7.2.2.1 
Per-Subject Microbiological Analysis 
The per-subject microbiological (overall) response at the EOT and PTE Visits in the micro-ITT, 
ME-EOT and ME-PTE populations will be determined to support the clinical findings.  
The number and percentage of subjects classified with a favorable (eradication and presumed 
eradication) and unfavorable (persistence, presumed persistence, and indeterminate) 
microbiological response (by definition, indeterminates are excluded from the ME population) 
will be tabulated for both treatment groups. Exact 95% CIs will be determined for the point 
estimates of the favorable microbiologic outcome rates in each treatment group. 
Concordance of microbiological  outcome with  clinical outcome at EOT and PTE visits for  
micro-ITT and ME populations will be provided. 
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7.2.4 
Sensitivity Analyses 
7.2.5 
Modified Patient Symptom Assessment Questionnaire 
Results of the mPSAQ questionnaire will be summarized in all populations.  
Shifts from baseline will be summarized separately for symptom scores and bothersome scores at 
each post-Baseline assessment, daily up to EOT, PTE and at Final Follow-up. 
Scores for symptoms and bothersomeness will be summarized by time point using descriptive 
statistics, for both the actual values and the change from baseline.   
 
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8 SAFETY ENDPOINTS AND ANALYSES 
8.1 
General  
The safety population will be used for all safety analyses and safety summaries will be presented 
by treatment group.  
8.2 
Duration of Exposure to Test Article and Compliance 
Exposure summary by treatment group and separately by route of administration (iv, po) will be 
presented for the Safety and micro-ITT populations.  
The distribution of subjects by the total number of days on therapy (0, 1, 2-3, 4-6, 7-10, 11-14, 
and > 14 days), the number of days on iv infusion and the number of days of oral test article will 
be presented.   
A summary of the number of days of iv therapy prior to oral switch defined as 24-hour periods 
(ie, time to oral switch), the day of oral switch, and the criteria for iv to oral switch will be 
presented by treatment group.  For the Safety population, the summary of test article exposure 
will be based on the actual treatment received whereas for all other analysis sets, the summary 
will be based on the randomized treatment. 
Treatment compliance is defined as the number of iv doses (including partial doses, active and 
placebo) and oral  
 
 
The number of dosed expected to be received by the patient will be calculated over the time 
period defined by the first infusion date and the last dose date.   
All oral doses 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. 
Number of subjects and percentage with a compliance ≥80% will be presented.  A summary of 
compliance to oral test article intake with the pre and post-dose fasting requirements will also be 
provided for subjects switching to oral administration.  The percent fasting compliance will be 
determined based on the total doses taken for days the subjects were on po medication.  The 
percentage of subjects who were < 50%, 50% to < 80%, and 80% to 100% compliance with the 
pre-dose and post-dose fasting requirements met will be summarized. 
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8.3 
Concomitant Medications 
Medications will be coded by WHODRUG Anatomical Therapeutic Chemical Classification 
(ATC) level 3 and generic medication name. Treatments that have been administered within 7 
days prior to the date of informed consent until the end of study are recorded in the eCRF.  
Medications are considered concomitant if taken on or after the first dose of test article, or if 
their stop date is unknown or marked as continuing. Thus, in cases where a medication starts 
prior to the first dose, and continues throughout the treatment period, the medication will be 
summarized as both prior and concomitant. Subjects will be counted only once for an ATC class 
and generic medication name. 
All medications and significant non-drug therapies (including physical therapy and blood 
transfusions) administered after the subject starts treatment with test article will be listed. 
8.4 
Adverse Events 
Adverse events (AEs) will be recorded and reported from signing of the ICF to the end of study. 
AEs will be coded using the MedDRA to the SOC and PT levels.   
A treatment-emergent AE is defined as any AE that newly appeared or worsened in severity on 
or after the initiation of test article.  An AE is considered treatment emergent if the AE start date 
and time is on or after the start date and time of the first dose of test article. 
Summary tables will be provided for all treatment-emergent adverse events (TEAEs).   
An overall summary of AEs will include the number of subjects who experienced at least one AE 
of the following categories: any AE, any TEAE, any drug-related TEAE, any severe TEAE, any 
serious TEAE, any drug-related serious adverse event, any serious TEAE leading to death, any 
TEAE leading to premature discontinuation of test article and any TEAE leading to premature 
discontinuation from study, and any serious TEAE leading to premature discontinuation of test 
article.   
The number and percentage of subjects reporting a TEAE in each treatment group will be 
tabulated by SOC and PT. The incidence of serious TEAEs, TEAEs judged to be related to test 
article, TEAE leading to premature discontinuation of test article and from study will be 
summarized by SOC and PT.  Additionally, a summary by SOC, PT, and severity (mild, 
moderate, and severe) will be provided. For all analyses of TEAEs, if the same AE (based on PT) 
is reported for the same subject more than once, the AE is counted only once for that PT and at 
the highest severity and strongest relationship to test article.   
For the two omadacycline dose groups and the levofloxacin treatment group with the possibility 
to switch from iv to oral test article AEs will be summarized by incidence of subjects with events 
starting during iv treatment and events starting after the switch to oral treatment and combined 
for the total treatment group. This summary will be presented by SOC and PTs. 
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In addition, all AEs (including non-TEAEs), serious TEAEs, and TEAEs leading to 
discontinuation of test article will be provided in listings by treatment group, study site, subject, 
verbatim term, MedDRA SOC and PT, start and end date, seriousness flag, severity, relationship 
to test article, relationship to study protocol, action taken with test article, non-test article action 
taken and outcome.   
For subjects with a TEAE of nausea or vomiting (based on the MedDRA PT), the total number 
of nausea and vomiting events, descriptive statistics of the study day of first onset of these 
events, and descriptive statistics for the duration (in days) of events, will be presented by 
treatment group. 
Listings of hospitalizations will be provided.  
8.5 
Clinical Laboratory Results 
Clinical laboratory safety assessments include hematology (including coagulation), serum 
chemistry, and urinalysis.   
Clinical laboratory parameters include those listed in the Appendix 1 Clinical Laboratory Tests 
(Central) and Local Urinalysis. 
Baseline is defined as the central lab value closest to and prior to the first dose of test article. If 
no central lab value is available prior to the first dose of study drug, the local lab value that is 
closest to and prior to the first dose of study drug will be used as baseline.  For by visit analyses, 
central lab values will be used unless no central lab value was obtained in the visit window.  In 
this case, local lab values will be used for the by visit analyses.  All lab values (central and local) 
are used for determination of the overall worst post-baseline value. 
Laboratory data will be summarized by timepoint and for the overall worst post-baseline value 
using descriptive statistics (based on International System [SI] units) for the actual results and 
change from baseline for hematology and serum chemistry assessments.  
Descriptive statistics (based on SI units) for chemistry, hematology and coagulation values and 
the change from baseline will be summarized by treatment group at each time point, and for the 
overall worst value post-baseline (which includes unscheduled visits).   
Appendix 2 Directionality of Worst Laboratory Parameters provides the directionality of the 
worst values for each laboratory parameter. 
Clinically notable laboratory values will be determined based on the Appendix 3 Modified 
Division of Microbiology and Infectious Diseases Adult Toxicity Table(DMID) criteria.  
Shift tables will be presented to show the number of subjects with a laboratory value with a 
grade of 0, 1, 2, 3 or 4 at baseline versus the value at each visit.  Number and percentage of 
subjects with at least a 2-grade increase from baseline (based on DMID criteria) will be 
summarized by treatment arm. Percentages for each laboratory test will be based on the number 
of subjects with a baseline and post-baseline evaluation of the specific laboratory test.  A listing 
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will be provided for subjects who have at least a 2-grade increase from baseline in a given 
laboratory test.  
The number and percentage (based on the number of subjects with a normal level at baseline) of 
subjects in each treatment group with an elevated transaminase level (> 3 × upper limit of normal 
[ULN], > 5×ULN, and > 10 × ULN), an elevated bilirubin level (> 1.5 × ULN and > 2 × ULN) 
will be presented by study visit.  A listing of subjects who meet the laboratory criteria for Hy’s 
law at the same visit will also be provided.  The laboratory criteria for Hy’s law is defined as 1) 
ALT or AST> 3 × ULN, ALP ≤ 2.0 × ULN, and total bilirubin > 1.5 ULN and 2) ALT or AST> 
3 × ULN, ALP ≤ 2.0 × ULN, and total bilirubin > 2 × ULN. 
Tabulated results of urine dipstick tests for leukocyte esterase and nitrates will be summarized by 
treatment group across visits and will include descriptive statistics for the microscopic 
evaluations for white blood cells. 
Subject listings of all laboratory data (local and central laboratory data) collected during the 
study will be provided, including calculated CrCl (using the Cockcroft-Gault equation).  
Laboratory values outside normal limits will be identified in the subject data listings with flags 
for low (L) and high (H) as will laboratory values that meet the clinically notable (CN) 
thresholds. 
8.6 
Vital Signs 
Vital signs will include blood pressure (diastolic and systolic) and heart rate and will be collected 
at Screening, Days 1, Day 3, Day 7, Day 10 and at EOT, PTE and FFU visits. On Day 1, blood 
pressure and heart rate is recorded within 30 min before, and 1 hour (± 15 minutes) after and 3 
hours (± 15 minutes) after the completion of the first dose.  
Body temperature is recorded at all visits. 
Additionally, height will be collected at the Screening visit, and body weight will be collected at 
the Screening, EOT and FFU visits.  
Blood pressure (systolic and diastolic) and heart rate will be summarized by time point and 
treatment group and for the minimum and maximum post-baseline values using descriptive 
statistics, for both the actual values and the change from baseline. Temperature will be 
summarized by descriptive statistics including change from baseline) by time point 
Figures (line graphs) of observed values for heart rate, systolic and diastolic blood pressure over 
time will also be provided by treatment group. 
Post-baseline vital signs will be defined as CN if they meet 1) the criterion value at the given 
visit, or 2) meet both the criterion value and the change from baseline criterion listed in Table 11.  
The incidence of CN vital signs will be summarized by time point and treatment group and will 
be listed and flagged in by-subject listings. An overall post-baseline incidence of CN values for 
each vital sign parameter, will also be summarized. A separate listing will be provided of 
subjects with values for a vital sign noted as CN. 
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Table 11 
Criteria for Clinically Notable Vital Signs 
Vital Sign Parameter 
Flag 
Criterion Value 
Change from Baseline 
Systolic Blood Pressure 
(mmHg) 
High (CH) 
 180 
Increase of  20 mmHg 
Low (CL) 
 90 
Decrease of  20 mmHg 
Diastolic Blood Pressure 
(mmHg) 
High (CH) 
 105 
Increase of  15 mmHg 
Low (CL) 
 50 
Decrease of  15 mmHg 
Heart Rate (bpm) 
High (CH) 
 120 
Increase of  15 bpm 
Low (CL) 
 50 
Decrease of  15 bpm 
 
8.7 
Pregnancies 
Results of local (urine or serum) and central (serum) pregnancy tests will be listed for all subjects 
enrolled in the study by treatment group. As it’s expected for pregnancy counts to be small 
narratives will be provided in CSR.  
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9 CHANGES FROM PROTOCOL 
Table 12 outlines protocol deviations together with justification for change. 
Table 12 
Protocol Deviations and Justification for Change 
 
Protocol wording: 
SAP language 
Justification: 
Micro-ITT 
pop 
primary 
 
 
Bayesian analyses will be 
conducted after efficacy data 
(overall response at PTE) are 
available for approximately 40, 
80 and 100 subjects in the 
micro-ITT population 
Bayesian analyses will be 
conducted after efficacy data 
(overall response at PTE) are 
available for approximately 40, 
80 and 100 subjects in the ITT 
population 
Dose re-allocation criteria at 
the interims is not based on 
efficacy. Review is based on 
the safety and tolerability of 
the enrolled subjects (ITT). 
Interim 
analyses for 
efficacy 
Protocol sections: 5.1.1, 7.5, 
7.8, 7.10, 12.2, 12.5.1, and 12.7 
Protocol states that Bayesian 
analysis will be utilized in 
Interim Analysis decisions to 
alter sample size, 
randomization allocation, 
and/or stopping arm for 
efficacy or futility. 
 
Due to low probability of 
success of dose differentiation 
with 40, 80, and 100 subjects 
efficacy stopping rules were 
not defined, see Table X2 
DMC recommendations at 
Interim Analyses will be based 
on safety and tolerability. See  
Table 13 for details. 
Presentation 
of Efficacy 
Endpoints 
Protocol classifies efficacy 
endpoints as primary and 
secondary.  
All efficacy endpoints of the 
study will be considered 
exploratory and are presented 
in this as in order of clinical 
importance. 
In accordance with 
Administrative Memo dated 
5/20/2019 all efficacy 
endpoints of the study will be 
considered exploratory to 
understand the performance of 
omadacycline in the treatment 
of acute pyelonephritis and to 
inform dose selection for a 
potential Phase 3 program. 
 
Table 13 
Probability of Successful Non-Inferiority Differentiation of OMC Groups and 
LEV and Type 1 Error at Interim Analyses 
Null hypothesized rates for OMC and LEV are 75%, Alternative hypothesizes rates OMC=65% LEV=75% 
Non-inferiority margin is assumed 10% 
# of 
subjects/group 
Type I error when OMC rate is 62.5% and 
LEV=75% 
Probability of 
success 
Type I 
error 
10 
4.4% 
12.1% 
4.4% 
20 
3.0% 
12.1% 
3.0% 
30 
2.8% 
15.6% 
2.8% 
40 
2.8% 
18.9% 
2.8% 
OMC – omadacycline, LEV - levofloxacin 
 
Number: GEN-STP-0293               Version: 1.0               Status: Approved    Approved Date:
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PTK0796-AP-17202 Statistical Analysis Plan 
 
Page 42 of 49 
 
Table 14 illustrates probabilities of discontinuation at the analysis when data from 200 subjects is 
available for evaluation for various response rate scenarios.  
Power column indicates power of successful detecting non-inferiority at 10% of OMC versus 
LEV with additional enrollment of 50 subjects per arm beyond total of 200. 
Table 14 
Probabilities of Discontinuation 
Additional enrollment 50/arm subjects enrolled 
levofloxacin 
OMC High 
dose 
Pooled 
Groups 2-4 
Probability of 
any OMC 
group 
discontinuation 
at 200 subject 
analysis 
Pooled 
Groups 2-4 
OMC High 
dose 
Power* 
0.75 
0.75 
0.75 
0.0154 
0.88074 
0.10388 
0.5695 
0.75 
0.75 
0.625 
0.1003 
0.16462 
0.73509 
0.4377 
0.75 
0.625 
0.625 
0.7025 
0.16567 
0.13181 
0.0298 
The calculations were based on frequentist approach 
*Non-inferiority is based on lower limit of 95% confidence interval for difference in success rate to exceed -10% 
OMC – omadacycline LEV - levofloxacin 
 
Number: GEN-STP-0293               Version: 1.0               Status: Approved    Approved Date:
PTK0796-AP-17202 Statistical Analysis Plan
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PTK0796-AP-17202 Statistical Analysis Plan 
 
Page 43 of 49 
 
 
10 REFERENCES 
1. 
Data Monitoring Committee Charter for Phase II Trial for PTK0796-AP-17202 
2. 
Pathogen and CE Review Plan: PTK0796-AP-17202 
 
 
Number: GEN-STP-0293               Version: 1.0               Status: Approved    Approved Date:
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PTK0796-AP-17202 Statistical Analysis Plan 
 
Page 44 of 49 
 
APPENDIX 1 CLINICAL LABORATORY TESTS (CENTRAL) AND 
LOCAL URINALYSIS 
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 female subjects): 
 
Serum β-human chorionic gonadotropin 
(β-HCG) 
 
 
 
 
Urinalysis (Local Lab):  
 
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: 
 
Alkaline phosphatase (ALP) 
 
Alanine aminotransferase (ALT) 
 
Aspartate aminotransferase (AST) 
 
Blood urea nitrogen (BUN) 
 
Calcium (Ca) 
 
Carbon dioxide (CO2) 
 
Chloride (Cl) 
 
Creatinine 
 
Creatine phosphokinase (CK) 
 
Gamma-glutamyl transpeptidase (GGT) 
 
Lipase 
 
Magnesium 
 
Phosphorus (P) 
 
Potassium (K) 
 
Sodium (Na) 
 
Total bilirubin 
 
 
APPENDIX 2 DIRECTIONALITY OF WORST LABORATORY 
PARAMETERS  
Laboratory Test 
Parameter 
Worst Value 
Hematology 
Hematocrit 
Lowest value 
 
Hemoglobin 
Lowest value 
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PTK0796-AP-17202 Statistical Analysis Plan 
 
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Laboratory Test 
Parameter 
Worst Value 
 
Red blood cell count 
Lowest value 
 
Mean cell hemoglobin 
Lowest value 
 
Mean cell hemoglobin concentration 
Lowest value 
 
Mean cell volume 
Lowest value 
 
White blood cell count 
Lowest value 
 
Platelets 
Lowest value 
 
Neutrophils  
Lowest value 
 
Lymphocytes  
Lowest value 
 
Monocytes  
Lowest value 
 
Eosinophils 
Highest value 
 
Basophils  
Lowest value 
Chemistry 
Albumin  
Lowest value 
 
Alkaline phosphatase 
Highest value 
 
Alanine aminotransferase ALT/SGPT) 
Highest value 
 
Amylase 
Highest value 
 
Aspartate aminotransferase (AST/SGOT) 
Highest value 
 
Urea 
Highest value 
 
Bicarbonate  
Lowest value 
 
Calcium 
Both highest value and lowest value 
 
Cholesterol  
Highest value 
 
Chloride  
Both highest value and lowest value 
 
Creatinine 
Highest value 
 
Creatine kinase (CK) 
Highest value 
 
Gamma-glutamyl transpeptidase (GGT) 
Highest value 
 
Blood glucose 
Both highest value and lowest value 
 
Lactate dehydrogenase (LDH) 
Highest value 
 
Lipase 
Highest value 
 
Magnesium  
Both highest value and lowest value 
 
Phosphate 
Both highest value and lowest value 
 
Potassium 
Both highest value and lowest value 
 
Sodium 
Both highest value and lowest value 
 
Total bilirubin 
Highest value 
 
Total protein 
Lowest value 
 
Uric acid 
Highest value 
Coagulation 
International normalized ratio (INR) 
Highest value 
Number: GEN-STP-0293               Version: 1.0               Status: Approved    Approved Date:
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Page 46 of 49 
 
APPENDIX 3 MODIFIED DIVISION OF MICROBIOLOGY AND 
INFECTIOUS DISEASES ADULT TOXICITY TABLE 
The DMID Adult Toxicity Table (21-Nov-2007) was modified to exclude the clinical component of the 
toxicity grading because clinical signs and symptoms related to abnormal laboratory values are not 
collected in this study. In addition, Grade 0 was added to the table so that shifts from normal could be 
analyzed. The grades for several parameters including enzymes were modified to ensure that any possible 
numeric value can be categorized appropriately (e.g., for creatinine, Grade 3 is defined as “>1.5-
3.0×ULN” instead of “1.6-3.0×ULN”). 
For toxicity grades based on a multiple of the ULN, the normal range from the central laboratory will be 
applied.   
For toxicity grades based on fixed values, the grades will be assigned regardless of the normal actual 
range values from the central laboratory. For example, a hemoglobin value of 10.0 gm/dL will be 
assigned a grade of 1 toxicity, even if the lower limit of normal from the laboratory was 9.8 gm/dL.   
HEMATOLOGY 
 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin (gm/dL) 
> 10.5 
9.5-10.5 
8.0-9.4 
6.5-7.9 
< 6.5 
Absolute Neutrophil 
Count (count/mm3) 
> 1500 
1000-1500 
750-999 
500-749 
< 500 
Platelets (count/mm3) 
≥ 100,000 
75,000-99,999 
50,000-74,999 
20,000-49,999 
< 20,000 
WBCs (count/mm3) 
1000-10,999 
11,000-12,999 
13,000-14,999  
15,000-30,000 
> 30,000 or < 
1,000 
COAGULATION  
 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Prothrombin time 
(PT) (sec) 
≤1 x ULN 
1.01-1.25 x 
ULN 
1.26-1.5 x ULN 
1.51 - 3.0 x 
ULN 
> 3 x ULN 
International 
normalized ratio 
(INR) 
Increased 
≤ ULN 
> 1 - 1.5 x ULN 
> 1.5 - 2.5 x 
ULN 
> 2.5 x ULN 
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Page 47 of 49 
 
 
CHEMISTRY 
 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia (mEq/L) (Na) 
> 135 
130-135 
123-129 
116-122 
< 116  
Hypernatremia (mEq/L) (Na) 
< 146 
146-150 
151-157 
158-165 
> 165  
Hypokalemia (mEq/L) (K) 
> 3.4 
3.0-3.4 
2.5-2.9 
2.0-2.4 
< 2.0 
Hyperkalemia (mEq/L) (K) 
< 5.6 
5.6-6.0 
6.1-6.5 
6.6-7.0 
> 7.0 
Hypoglycemia (mg/dL) (glucose) 
 65 
55-64 
40-54 
30-39 
< 30  
Hyperglycemia (mg/dL) 
(nonfasting and regardless of 
prior history of diabetes)1 
(glucose) 
< 116 
116-160 
161-250 
251-500 
> 500  
Hypocalcemia (mg/dL) 
(corrected for albumin) 2 (Ca) 
> 8.4 
8.4-7.8 
7.7-7.0 
6.9-6.1 
< 6.1 
Hypercalcemia (mg/dL) (correct 
for albumin) 2 (Ca) 
 10.5 
10.6-11.5 
11.6-12.5 
12.6-13.5 
> 13.5 
Hypomagnesemia (mEq/L) 
(Magnesium) 
> 1.4 
1.4- 1.2 
1.1-0.9 
0.8-0.6 
< 0.6 
Hypophosphatemia (mg/dL) (P) 
 2.5 
2.0-2.4 
1.5-1.9 
1.0-1.4 
< 1.0 
Hyperbilirubinemia (total 
bilirubin) 
< 1.1×ULN 
1.1-1.5×ULN 
> 1.5-2.5×ULN 
> 2.5-5×ULN 
> 5×ULN 
Urea 
< 
1.25×ULN 
1.25-2.5×ULN 
> 2.5-5×ULN 
> 5-10×ULN 
>10×ULN 
Hyperuricemia (uric acid) 
(mg/dL) 
< 7.5 
7.5–10.0 
10.1–12.0 
12.1–15.0 
> 15.0 
Creatinine 
< 1.1×ULN 
1.1-1.5×ULN  
> 1.5-3.0×ULN 
> 3.0-6×ULN 
> 6×ULN  
1 The DMID toxicity table reports hyperglycemia detected in nonfasting specimens obtained from subjects with no 
prior diabetes. 
2 Calcium corrected for albumin = [0.8 x (normal albumin - subject's albumin)] + serum Ca level 
   Where normal albumin = 4 g/dl, albumin is in g/dL and calcium is in mg/dL 
 
ENZYMES 
 
Grade 0  
Grade 1  
Grade 2  
Grade 3  
Grade 4  
AST (SGOT) 
< 1.25×ULN 
1.25-2.5×ULN 
> 2.5-5×ULN 
> 5-10×ULN 
> 10×ULN 
ALT (SGPT) 
< 1.25×ULN 
1.25-2.5×ULN 
> 2.5-5×ULN 
> 5-10×ULN 
> 10×ULN 
GGT 
< 1.25×ULN 
1.25-2.5×ULN 
> 2.5-5×ULN 
> 5-10×ULN 
> 10×ULN 
Alkaline 
Phosphatase 
< 1.25×ULN 
1.25-2.5×ULN 
> 2.5-5×ULN 
> 5-10×ULN 
> 10×ULN 
Amylase 
< 1.1×ULN 
1.1-1.5×ULN 
> 1.5-2.0×ULN 
> 2.0-5.0×ULN 
> 5.0×ULN 
Lipase 
< 1.1×ULN 
1.1-1.5×ULN 
> 1.5-2.0×ULN 
> 2.0-5.0×ULN 
> 5.0×ULN 
 
Number: GEN-STP-0293               Version: 1.0               Status: Approved    Approved Date:
PTK0796-AP-17202 Statistical Analysis Plan
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PTK0796-AP-17202 Statistical Analysis Plan 
 
Page 48 of 49 
 
APPENDIX 4 CONCOMITANT MEDICATION START DATE 
IMPUTATION 
Parameter 
Type of 
Medication 
Imputation 
Start date for con 
meds  
Non-
Antibacterial  
If it cannot be determined whether or not the start date of a medication 
(non-antibacterial) is prior to the first dose of study drug, it will be assumed that the 
medication was received prior to the first dose of study drug. 
Antibacterial 
 
Missing start dates for antibacterials will be queried for a value.  If it cannot be 
determined whether or not the start date of an antibacterial is prior to the first dose of 
study drug, it will be assumed that the medication was received prior to the first dose 
of study drug unless the indication notes that the medication was received after the 
first dose of study drug. 
 
Stop date for con 
meds  
Non-
Antibacterial 
If it cannot be determined whether or not the stop date of a medication (nonantibacterial) is 
after the first dose of study drug, it will be assumed that the medication was received 
after the first dose of study drug 
 
Antibacterial 
 
Missing stop dates for antibacterials will be queried for a value.  If it cannot be 
determined whether or not the stop date of an antibacterial is after the first dose of 
study drug, it will be assumed that the medication was received after the first dose of 
study drug unless the indication notes that the medication was received prior to the 
first dose of study drug.  If it cannot be determined whether the antibacterial was 
received prior to the assessment of Early Clinical Response, the EOT and/or the PTE 
Visit, the antibacterial will be assumed to have been received through the PTE Visit. 
 
 
 
APPENDIX 4 ADVERSE EVENT START/STOP DATE IMPUTATION 
Parameter 
Missing 
Additional Conditions 
Imputation 
Start date 
for AEs 
 
D 
M and Y same as M and Y of first dose of test article 
Date of first dose of test article 
M and/or Y not same as date of first dose of test 
article 
First day of month 
D and M 
Y same as Y of first dose of test article 
Date of first dose of test article 
Y prior to Y of first dose of test article but same as Y 
of screening date 
Date of screening date 
D, M, Y 
None - date completely missing 
Date of first dose of test article 
Stop date 
for AEs 
 
D 
M and Y same as M and Y of last dose of test article 
Date of last dose of test article 
M and/or Y not same as date of last dose of test 
article 
Use last day of month 
D and M 
Y same as Y of last dose of test article 
Date of last dose of test article 
Y not same as Y of last dose of test article 
Use Dec 31 
D, M, Y 
None - date completely missing 
No imputation, but assume 
ongoing 
D=day, M=month, Y=year 
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PTK0796-AP-17202 Statistical Analysis Plan 
 
Page 49 of 49 
 
Note:  In all cases, if an estimated start date is after a complete stop date, use the first day of the stop date month. 
Similarly, if the estimated stop date is before a complete or imputed start date, use the last day of the start day 
month. 
In all cases, if it cannot be determined if the adverse event occurred prior to or after the first dose of test article, 
the adverse event should be defined as treatment emergent. 
 
 
Number: GEN-STP-0293               Version: 1.0               Status: Approved    Approved Date:
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Document Approvals
Approved Date: 
Approval Task
Verdict:  Approve
06-Jun-2019 17:17:43 GMT+0000
Approval Task
Verdict:  Approve
07-Jun-2019 14:58:07 GMT+0000
Approval Task
Verdict:  Approve
08-Jun-2019 01:54:53 GMT+0000
Final Approval Task
Verdict:  Approve
19-Jun-2019 18:23:49 GMT+0000
Number: GEN-STP-0293               Version: 1.0               Status: Approved    Approved Date:
PTK0796-AP-17202 Statistical Analysis Plan
This copy of the document was retrieved from the system by 
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