Clinical trial NCT02784704
Conditions: Complicated Intra-abdominal Infections Complicated Appendicitis
Sponsor: Tetraphase Pharmaceuticals, Inc
Start date: 2016-10-13; Completion date: 2017-05-19
Enrollment: 500 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 3, randomized, double-blind, double-dummy, multicenter, prospective study to assess the efficacy, safety, and pharmacokinetics (PK) of eravacycline compared with meropenem in the treatment of complicated intra-abdominal infections (cIAIs).

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Eravacycline intervention 2: Meropenem intervention 3: Placebo
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_000.pdf: 
 
 
 
CLINICAL TRIAL PROTOCOL 
A Phase 3, Randomized, Double-Blind, Double-Dummy, Multicenter, 
Prospective Study to Assess the Efficacy and Safety of Eravacycline 
Compared with Meropenem in Complicated Intra-abdominal Infections 
 
Protocol No.:     TP-434-025 
 
 
 
Sponsor: 
Tetraphase Pharmaceuticals, Inc.  
480 Arsenal Street, Suite 110 
Watertown, MA 02472 
 
 
USA 
 
 
 
Phone: +1-617-715-3600 
Fax: 
+1-617-926-3557 
 
 
EudraCT No.: 
2016-002208-21  
 
 
ClinicalTrials.gov No.: 
NCT02784704 
 
 
Version 2.0: 
20 March 2017 
This study will be conducted according to the protocol and in compliance with Good Clinical Practice (GCP), the 
Declaration of Helsinki, and applicable regulatory requirements. 
 
CONFIDENTIAL 
The information in this study protocol is strictly confidential and is available for review to Investigators, study site 
personnel, the Institutional Review Board (IRB)/Independent Ethics Committee (IEC), and the Regulatory 
Authorities. It will not be disclosed to third parties without written authorization from Tetraphase Pharmaceuticals, 
Inc. (the Sponsor), except to obtain informed consent from persons participating in the trial. Once the protocol is 
signed, its terms are binding for all parties. 


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1. 
SPONSOR SIGNATURE PAGE 
 
Sponsor: 
Tetraphase Pharmaceuticals, Inc. 
Protocol Number: 
TP-434-025 
Study Medication: 
Eravacycline 
Protocol Title: 
A Phase 3, Randomized, Double-Blind, Double-Dummy, 
Multicenter, Prospective Study to Assess the Efficacy and Safety 
of Eravacycline Compared with Meropenem in Complicated Intra-
abdominal Infections 
 
Date of Issue: 
20 March 2017 
 
Approved by:  
 
 
..........................................  
 ................................................................. 
Date 
 
 
 
Guy Macdonald 
 
 
 
 
Chief Executive Officer 
Tetraphase Pharmaceuticals, Inc.  
480 Arsenal Street, Suite 110 
Watertown, MA 02472 
 
        USA 
 
 
 
..........................................  
 ................................................................. 
Date 
  
Patrick T. Horn MD, PhD 
 
 
Chief Medical Officer 
Tetraphase Pharmaceuticals, Inc.  
480 Arsenal Street, Suite 110 
Watertown, MA 02472 
 
USA 
 
 


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INVESTIGATOR AGREEMENT 
I have read this protocol and agree that it contains all necessary details for carrying out this study.  I 
will conduct the study as outlined herein and will complete the study within the time designated.  
This trial will be conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality, and according to local legal and regulatory requirements and applicable 
United States federal regulations and International Conference on Harmonization (ICH) guidelines. 
 
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study.  I will discuss this material with them to ensure they are 
fully informed regarding the drug and the conduct of the study. 
 
I will use only the informed consent form approved by the Sponsor or its representative and will 
fulfill all responsibilities for submitting pertinent information to the Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) responsible for this study. 
 
I agree that the Sponsor or its representatives shall have access to any source documents from 
which case report form information may have been generated. I agree that regulatory authorities 
(FDA, EMA, and other local and country-related agencies) can audit and review source documents. 
 
I further agree not to originate or use the name of Tetraphase Pharmaceuticals, Inc.or any of its 
employees, in any publicity, news release, or other public announcement, written or oral, whether to 
the public, press, or otherwise, relating to his protocol, to any amendment hereto, or to the 
performance hereunder, without the prior written consent of Tetraphase Pharmaceuticals, Inc. 
 
 
__________________________________________ 
___________________ 
Investigator’s Signature 
 
 
 
 
Date 
 
 
___________________________________________________________________ 
Name of Investigator (Typed or Printed) 
 
 
___________________________________________________________________ 
Institution Name  
 
___________________________________________________________________ 
Institution Address 
 


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2. 
TABULATED PROTOCOL SUMMARY 
Name of Sponsor/Company: 
Tetraphase Pharmaceuticals, Inc.  
Name of Finished Products: 
Eravacycline for intravenous administration; and meropenem (comparator) 
Name of Active Ingredients: 
Eravacycline (TP-434) and meropenem (comparator) 
Title of Study: 
A Phase 3, Randomized, Double-Blind, Double-Dummy, Multicenter, Prospective 
Study to Assess the Efficacy and Safety of Eravacycline Compared with Meropenem 
in Complicated Intra-abdominal Infections 
Indication:  
Complicated Intra-abdominal Infections (cIAI) 
Anticipated Study Period: 
3Q 2016-4Q 2017 
Objectives: 
Primary Objective: 
▪ The primary objective is to compare the clinical response at the test-of-cure (TOC) visit in the microbiological 
intent-to-treat (micro-ITT) population for subjects in the 2 treatment arms 
NOTE: For the EMA, the primary analysis populations will be the all-treated (MITT) and the clinically evaluable 
(CE) populations 
Secondary Objectives: 
▪ To compare the clinical response for subjects in the 2 treatment arms at the end-of-treatment (EOT), TOC, and 
follow-up (FU) visits in the following populations: 
- 
Intent-to-treat (ITT) population 
- 
All-treated (MITT) 
- 
Clinically evaluable (CE) population  
- 
Micro-ITT population (for EOT and FU) 
- 
Microbiologically evaluable (ME) population 
▪ To compare the microbiologic response in the treatment arms at the EOT and TOC visits in the following 
populations: 
- 
Micro-ITT population 
- 
ME population 
▪ To assess the safety and tolerability of eravacycline administration in the safety population 
▪ To explore pharmacokinetic (PK) parameters of eravacycline 
Methodology: 
This is a phase 3, randomized, double-blind, double-dummy, multicenter, prospective study to assess the efficacy, safety 
and PK of eravacycline compared with meropenem in the treatment of cIAIs.  
Once an informed consent is obtained and study eligibility is established, subjects will be enrolled and randomized to 
either the eravacycline (1.0 mg/kg every 12 hours [q12h]) or the meropenem (1 g q8h) treatment arm in a 1:1 ratio.  
Randomization will be stratified based on primary site of infection (complicated appendicitis versus all other diagnoses).  
An enrollment cap of approximately 50% complicated appendicitis is planned. 
Specified study personnel will remain blinded to the identity of intravenous (IV) study drug until the database has been 
locked.  
Study drug will be administered in 24-h dosing cycles according to Table 1 below:  
Table 1: Study Drug Infusion Scheme of a 24-h Dosing Cycle 
Study Drug  
Treatment Arm 
1st Dose 
(of Dosing Cycle) 
2nd Dose  
(of Dosing Cycle) 
3rd Dose  
(of Dosing Cycle) 
4th Dose  
(of Dosing Cycle) 
5th Dose  
(of Dosing Cycle) 
60 min infusion 
30 min infusion 
30 min infusion 
60 min infusion 
30 min infusion 
Eravacycline, 1.0 mg/kg  q12h 
Eravacycline 
Placebo 
Placebo 
Eravacycline 
Placebo 
Meropenem, 1 g q8h 
Placebo 
Meropenem 
Meropenem 
Placebo 
Meropenem 
 


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Eravacycline concentration may be decreased (as long as the total infusion volume is ≤ 500 mL) and/or infusion time 
may be increased (to 120 minutes per IV bag) to manage infusion site reactions.  
Meropenem will be used in accordance with its most recent prescribing information.  
The interval between the 1st Doses of adjacent 24-h dosing cycles can be reduced by up to 4 h after each of the first two 
24-h dosing cycles. After the third 24-h dosing cycle, the allowable administration window for each infusion is ± 1 h. 
The investigator should collect appropriate specimens for culture at the time of the initial procedure and inoculate into 
appropriate media for aerobes and anaerobes immediately. These specimens will be cultured and quantified in the local 
laboratory or a reference regional laboratory.  The isolate(s) will be sent to a central microbiology laboratory for 
validation of identification and susceptibility testing.   
Aerobic and anaerobic blood cultures will be obtained at two separate sterile venipuncture sites prior to initiation of 
clinical trial drug therapy.  Upon knowledge of a positive culture for a pathogen, blood cultures should be repeated until 
sterile (ie, both sets of cultures from two separate venipuncture sites are negative for pathogens) through the FU visit.  If 
baseline cultures are negative, follow-up cultures should be obtained only if clinically indicated (eg, worsening of signs 
and symptoms, relapse, or new infection).  
Each subject will receive 4-14 complete dose cycles of study drug. A complete dose cycle is defined as all five doses for 
a dosing cycle. Clinical status will be assessed at EOT. A TOC visit will occur 25-31 days after the initial dose of study 
drug and a FU visit will take place 38-50 days after the initial dose of study drug. At any time, the investigator may 
discontinue the subject from study drug based on the best interest of the subject. Prior to starting non-study antibiotics 
the EOT assessments must be performed.  The subject will remain in the study and all applicable procedures should be 
followed though FU. 
Table 2: Timeline for Individual Study Subjects 
SCREENING 
ENROLLMENT 
STUDY DRUG 
TREATMENT 
END-OF-
THERAPY (EOT) 
TEST-OF-CURE 
(TOC) 
FOLLOW-UP 
(FU) 
Within 48-h of 
Initial Dose 
 
Dose Cycle 1 
through EOT 
Within 24-h of 
Last Dose 
25-31 Days after 
Initial Dose 
38-50 Days after 
Initial Dose 
Establish diagnosis  
of complicated 
intra- 
abdominal  
infections (cIAI) 
 
Verify eligibility  
for enrollment 
 
 
Use IWRS* to 
randomize to 
study drug 
Infuse study drug, 
either: 
 
• Eravacycline IV 
1.0 mg/kg q12h 
OR  
• Meropenem IV   
1 g q8h 
Expected 4 (min) to 
14 (max) study 
drug treatment 24-h 
dosing cycles. 
Review of subjects 
with Medical 
Monitor for 
therapies longer 
than seven 24-h 
dosing cycles.  
 
EOT assessments 
should be 
performed at 
premature 
withdrawal or 
treatment failure 
and within 24-h of 
last dose. 
Return to study 
center for 
assessment of 
clinical response 
and safety 
Return to study 
center for 
assessment of 
clinical response 
and safety 
 * IWRS = Interactive Web-based Response System 
Number of Subjects: 
Approximately 466 subjects will be randomized to receive study drug.  
Investigative sites will be recruited in approximately 75 centers worldwide.  
Criteria for Study Entry: 
Inclusion Criteria 
1. Male or female subject hospitalized for cIAI with one of the following diagnoses: 
a. 
Intra-abdominal abscess: one or more abscesses surrounding diseased or perforated viscera (including hepatic 
and splenic abscesses) 
b. Gastric or intestinal perforation associated with diffuse peritonitis 
c. 
Peritonitis: diffuse infection of the peritoneum (but not spontaneous bacterial peritonitis associated with 
cirrhosis and chronic ascites) 
d. Appendicitis with perforation, peritonitis or abscess 


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e. 
Cholecystitis with perforation or abscess 
f. 
Diverticulitis with perforation, peritonitis, or abscess 
Note:  Infections limited to the hollow viscus, such as simple cholecystitis and simple appendicitis, are not 
eligible.  Ischemic bowel disease without perforation is not eligible.  Acute suppurative cholangitis and acute 
necrotizing pancreatitis are not eligible. 
2. At least 18 years of age  
3. Evidence of a systemic inflammatory response with at least one of the following: 
a. 
Fever (oral, rectal, tympanic, or by temporal artery temperature > 100.4˚F / 38˚C) or hypothermia 
(temperature ≤ 95.9˚F / 35.5˚C) 
b. Elevated WBC (> Upper Limit of Normal (ULN) laboratory range); or proportion of band forms of the WBC 
differential beyond the ULN laboratory range 
c. 
Increased pulse (HR > 90 beats per minute) 
d. Increased respiratory rate (> 20 breaths per minute) 
4. Abdominal pain or flank pain (with or without rebound tenderness), or pain caused by cIAI that is referred to 
another anatomic area such as back or hip, or localized or diffuse abdominal wall rigidity, or mass, or ileus 
5. Able to provide informed consent 
6. Subjects must agree to use a highly reliable method of birth control 
a. 
Male subjects must agree to use an effective barrier method of contraception during the study and for 14 days 
following the last dose if sexually active with a female of childbearing potential 
b. Female subjects must not be pregnant or nursing. For females of childbearing potential, subjects must commit 
to either: 
i. Use at least two medically accepted, effective methods of birth control (eg, condom, spermicidal gel, oral 
contraceptive, indwelling intrauterine device, hormonal implant/patch, injections, approved cervical ring, 
etc.) during study drug dosing and for 14 days following last study drug dose, OR 
ii. Sexual abstinence 
And either  
7A. Meets All Inclusion Criteria for Pre-operative Enrollment: 
▪ 
Has a sonogram or radiographic imaging result congruent with the diagnosis of cIAI, AND  
▪ 
Acute surgical or percutaneous intervention (open laparotomy, laparoscopic surgery, or percutaneous 
drainage of an abscess) is foreseen within 24-h 
Or 
7B. Meets All Inclusion Criteria for Intra-operative/Post-operative Enrollment: 
▪ 
Visual confirmation of cIAI (presence of pus within the abdominal cavity), AND 
▪ 
Surgical intervention includes open laparotomy, laparoscopic surgery, or percutaneous draining of an abscess, 
AND 
▪ 
Intervention is adequate [ie, a procedure in which all communications between the gastrointestinal (GI) tract 
and the peritoneal cavity are closed, no necrotic intestine is left, and all infected collections are drained at the 
procedure], AND 
▪ 
Subjects who are enrolled in the trial post-operatively must receive no more than one dose of effective 
antibacterial drug therapy post-operatively before randomization 
 
Exclusion Criteria (Subjects must NOT meet any of the following exclusion criteria) 
1. Considered unlikely to survive the 6-8 week study period 
▪ 
Any rapidly-progressing disease or immediately life-threatening illness, including acute hepatic failure, 
respiratory failure and septic shock 
▪ 
Requirement for vasopressors (prior to enrollment) at therapeutic dosages (ie, dopamine > 5 µg/kg/min, any 
dose of norepinephrine, epinephrine, or phenylephrine) to maintain a systolic blood pressure  90 mm Hg or 
a mean arterial pressure  70 mm Hg following adequate fluid resuscitation 
2. Creatinine clearance of ≤ 50 mL/min as estimated by the Cockcroft-Gault equation 
𝑒𝐶𝐶𝑟[𝑚𝐿/𝑚𝑖𝑛] =
(140 −𝐴𝑔𝑒 [𝑦𝑟𝑠]) ×  𝐵𝑜𝑑𝑦 𝑊𝑒𝑖𝑔ℎ𝑡 [𝑘𝑔] × [0.85 𝑖𝑓 𝐹𝑒𝑚𝑎𝑙𝑒]
72 ×  𝑆𝑒𝑟𝑢𝑚 𝐶𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 [𝑚𝑔𝑑𝐿
⁄
]
 
3. Presence or possible signs of significant hepatic disease: 
a. 
Alanine aminotransferase or aspartate aminotransferase > 5 x ULN, OR  
b. Total bilirubin > 3 x ULN, unless isolated hyperbilirubinemia is directly related to the acute process 
4. Immunocompromised condition, including known HIV positivity (requiring anti-retroviral therapy or with CD4 
count < 300), AIDS, organ (bone marrow) transplant recipients, and hematological malignancy. 


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Immunosuppressive therapy, including use of high-dose corticosteroids (eg, > 20 mg prednisone or equivalent per 
day for greater than 2 weeks) 
5. History of moderate or severe hypersensitivity reactions to tetracyclines, carbapenems, β-lactam antibiotics, or to 
any of the excipients contained in the study drug formulations  
6. Participation in any investigational drug or device study within 30 days prior to study entry 
7. Known or suspected current central nervous system (CNS) disorder that may predispose to seizures or lower 
seizure threshold (eg, severe cerebral arteriosclerosis, epilepsy) 
8. Antibiotic-related exclusions:  
a. 
Receipt of effective antibacterial drug therapy for cIAI for a continuous duration of > 24-h during the 72-h 
preceding randomization [However, subjects with documented cIAI (ie, known baseline pathogen) who have 
received at least 72-h of antibiotic therapy and are considered treatment failures may be enrolled.  Treatment 
failure is defined as persistent fever and/or clinical symptoms; or the development of a new intra-abdominal 
abscess after ≥ 72-h of antibiotic therapy], OR 
b. Receipt of meropenem or any other carbapenem, or tigecycline for the current infection, OR 
c. 
Need for concomitant systemic antimicrobial agents effective in cIAI other than study drug  
9. Refusal of mechanical ventilation, dialysis or hemofiltration, cardioversion or any other resuscitative measures 
and drug/fluid therapy at time of consent 
10. Known or suspected inflammatory bowel disease or associated visceral abscess 
11. The anticipated need for systemic antibiotics for a duration of more than 14 days 
12. Systemic malignancy that required chemotherapy, immunotherapy, radiation therapy, or antineoplastic therapy 
within the previous 3 months or that is anticipated to begin prior to the TOC visit 
13. Known at study entry to have cIAI caused by a pathogen(s) resistant to one of the study drugs 
14. Any other unstable or clinically significant concurrent medical condition (ie, class IV heart or lung disease, end 
stage renal disease, or requiring hemodialysis, etc.) that would, in the opinion of the investigator, jeopardize the 
safety of a subject, impact their expected survival through the end of the study participation, and/or impact their 
ability to comply with the protocol 
Test Product, Dose and Route of Administration: 
Eravacycline was synthesized under current good manufacturing practices, and the drug product contains 50.0 mg 
(TP-434 free base equivalents) of lyophilized powder in a 10 mL vial.  Eravacycline will be reconstituted with 5 mL of 
sterile water and further diluted with sterile normal saline, to generate 0.3 mg/mL eravacycline solutions for 1.0 mg/kg 
q12h IV infusions. Please refer to applicable protocol section(s) and the Pharmacy Manual for additional information. 
Reference Therapy, Dose and Route of Administration: 
Meropenem 1 g administered by IV q8h. Meropenem infusion solutions will be prepared according to the full 
prescribing information of meropenem (comparator). 
Duration of Treatment: 
The expected minimum treatment duration is four 24-h dosing cycles unless Clinical Failure or Clinical Cure occurs 
earlier.  Maximum treatment duration is fourteen 24-h dosing cycles.  Subjects will remain on study drug treatment until 
symptoms of cIAI have resolved.  If study drug is needed for longer than seven 24-h dosing cycles, cases will be 
reviewed by the Medical Monitor.  The TOC visit will be 25-31 days after the initial dose of study drug.  The follow-up 
visit will be conducted 38-50 days after the initial dose of study drug. 
Pharmacokinetics: 
Cmax, Tmax, and AUC0-12 will be determined. 
 
Statistical Methods and Criteria for Evaluation: 
Sample Size Estimate: 
This study is designed to demonstrate non-inferiority of 1.0 mg/kg q12h eravacycline to meropenem, and a 12.5% non-
inferiority margin will be used to determine success.  A non-inferiority trial with a one-sided alpha of 0.025, 80% power, 
a non-inferiority margin (delta) of 12.5%, and projected response rates of 84% in the eravacycline group and 85% in the 
meropenem group would need 161 subjects per arm in the micro-ITT population. A sample size of approximately 466 
randomized subjects should provide sufficient numbers for this study, assuming 68.75% of enrolled subjects will meet 
the requirements for inclusion in the micro-ITT population. 


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Safety: 
Safety analyses will be conducted in the safety population. Subjects will be analyzed according to the treatment 
received. 
Adverse Events 
Verbatim descriptions of AEs will be mapped to Preferred Terms and System Organ Classes using Medical Dictionary 
of Regulatory Activities (MedDRA) and tabulated by treatment arm. The number and percentage of subjects who 
experience treatment-emergent AEs and serious AEs (SAEs) will be presented by reporting levels for System Organ 
Class and Preferred Term.  Each subject will be counted once for each level of reporting.  Tabulations by severity and by 
relationship to study drug, as reported by the investigators, will also be provided. Deaths and premature discontinuations 
from study drug due to an AE will be identified. 
Laboratory Data 
Hematology, chemistry, and coagulation will be summarized using: shift tables based on toxicity criteria; change from 
baseline; and the number and percentage of subjects with at least a two grade increase from baseline. Detailed listings of 
all laboratory data collected during the study will be provided.   
Other Safety Data 
Clinically relevant physical examinations will be performed and clinically significant findings collected as AEs. Vital 
signs and ECG findings will be summarized using descriptive statistics for change from baseline and percentage of 
subjects with an abnormal value as defined in the Statistical Analysis Plan. 
Efficacy Assessments: 
Clinical cure rates will be determined along with 95% CIs for each treatment arm overall and for the randomization 
stratification factor of primary site of infection. The clinical cure rate will be determined as the number of subjects with 
Clinical Cure (ie, complete or significant improvement of signs or symptoms such that no additional antibacterial 
therapy, surgical, or radiological intervention is required) at the respective visit divided by the number of subjects in the 
analysis population (ie, overall or by randomization strata).  A 95% CI around the difference in the eravacycline and 
meropenem clinical cure rates will be determined using the Miettinen and Nurminen method.  If the lower bound of the 
95% CI is above -12.5% for the difference in the overall clinical cure rate, noninferiority of eravacycline to meropenem 
will be concluded. 
Per pathogen and per subject microbiological response rates will be determined, along with 95% CIs, by treatment arm. 
The per pathogen microbiological response rate will be determined as the number of subjects with a favorable response 
(ie, eradication or presumptive eradication) at the respective visit divided by the number of subjects in the analysis 
population with that pathogen at baseline. The per subject microbiological response rate will be determined as the 
number of subjects with a favorable response (ie, eradication or presumptive eradication) at the respective visit divided 
by the number of subjects in the analysis population. 
Microbiology: 
Bacterial isolates cultured from aerobic and anaerobic cIAI specimens and blood will be evaluated for susceptibility and 
the emergence of resistance to study drugs and overgrowth of non-susceptible organisms. 


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3. 
SCHEDULE OF ASSESSMENTS  
The calendar day on which the first study drug infusion of the first 24-h dosing cycle is administered is Day 1. 
Study Procedure 
Screening1 
Within 48-h 
of Initial Dose 
 
Dose  
Cycle 11 
Dose  
Cycle 2 
Dose  
Cycle 3 
Dose  
Cycles 4-14 
EOT2 
TOC 
25-31 days after 
Initial Dose 
FU 
38-50 days after 
Initial Dose 
Informed Consent 
X 
ENROLLMENT 
 
 
 
 
 
 
 
Medical History/ Height and Weight 
X 
 
 
 
 
 
 
 
APACHE II score3 
X 
 
 
 
 
 
 
 
Physical Exam  
X 
 
 
 
 
X 
X 
X 
Temperature4 
X 
X 
X 
X 
X 
X 
X 
X 
Resting Vital Signs5 
X 
X 
X 
X 
X 
X 
X 
X 
Abdominal Exam6 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/Concomitant Medications7 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology/Chemistry8 
X 
X 
X 
X 
X 
X2 
X 
X 
Coagulation/ Urinalysis9 
X 
X 
 
 
 
X2 
X17 
X17 
Calculated Creatinine Clearance10 
X 
X 
X 
X 
X 
 
 
 
Serum Pregnancy Test11 
X 
 
 
 
 
X 
X 
X 
Blood Cultures12 
X 
X as indicated per protocol 
Intra-abdominal Cultures13   
X 
 
X 
X 
X 
X2 
X 
X 
Radiologic Examination14 
X 
X as clinically indicated 
12-Lead ECG 
X 
 
 
 
 
X 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
Clinical Response 
 
 
 
 
 
X 
X 
X 
Study Drug Administration15  
 
X 
X 
X 
X 
 
 
 
PK Assessments16 
 
X 
 
 
 
 
 
 
See footnotes on following page(s). 
 
 
 
 
 
 
 


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1. If Dose Cycle 1 and Screening occur on the same day the resting vital signs, abdominal exam, and safety labs do not need to be repeated. 
2. EOT assessments are to be performed at: (i) premature withdrawal, (ii) treatment failure, or (iii) within 24-h of last dose. 
If EOT occurs on the same day as a Dosing Cycle, then safety labs and any cultures do not need to be repeated provided samples are taken after the last 
dose of study drug. 
3. Serum bicarbonate may be used in place of arterial blood gases. Please referee to Appendix 1: APACHE II Score for instructions on how to calculate 
APACHE II Score. 
4. Record oral, rectal, tympanic, or by temporal artery prior to the initial dose of study drug and then q8h ± 1-h while hospitalized until EOT. 
5. RR, HR, B/P are performed prior to the initial dose of study drug; daily while hospitalized; and EOT, TOC, and FU. 
6. Performed at least once daily until resolution of all signs and symptoms of cIAI. 
7. < 24-h of continuous systemic antibacterial therapy for cIAI during the 72-h preceding enrollment is permitted. Documented cIAI treatment failures with a 
known baseline pathogen and ≥ 72-h of systemic antibiotic therapy may be enrolled. No concomitant systemic antibacterials are permitted after the initial 
dose of study drug through the FU visit.  All other medically necessary concomitant medications are permitted. 
8. Performed at Screening; Dose Cycles 1-4; every three 24-h dosing cycles thereafter while on study drug; and at EOT, TOC, and FU.   
9. Urine microscopy for RBC, WBC, crystals, and casts performed at Screening, Dose Cycle 1, and EOT. 
10. Creatinine clearance (Cockcroft-Gault equation) based upon local labs to be performed at: (i) Screening, (ii) Dose Cycles 1-4, and (iii) every three 24-h 
dosing cycles thereafter while on study drug. A creatinine clearance of ≤ 50 mL/min is exclusionary at Screening.  If at any time after Screening the 
locally calculated creatinine clearance is ≤ 50 mL/min then the subject’s meropenem and/or meropenem-matched placebo must be dose-adjusted in 
accordance with the meropenem package insert.  Thereafter, each time the creatinine clearance is calculated locally the meropenem and/or meropenem-
matched placebo must be dose-adjusted in accordance with the meropenem package insert.  For more information please refer to Section 10.3.2. 
11. If a serum pregnancy test is not available at the investigator site then a urine pregnancy test may be utilized locally. 
12. Obtain a set of aerobic and a set of anaerobic samples from two separate venipuncture locations at Screening. Upon knowledge of a positive culture for a 
pathogen, blood cultures should be repeated until sterile (ie, both sets of cultures from two separate venipuncture sites are negative for pathogens) through 
the FU visit. Await results before drawing additional sets of blood cultures. If baseline cultures are negative, follow-up cultures should be obtained only if 
clinically indicated (eg, worsening of signs and symptoms, relapse, or new infection).  
13. Cultures to be collected from the site of infection at the time of the initial surgical procedure, subsequent surgical re intervention(s) and if there are signs 
and symptoms of infection (if applicable). If it is not possible to obtain a tissue biopsy or aspirate then a swab may be obtained.  Samples collected from 
superficial swabs and abdominal drains are not allowed.  See Microbiologic Specimen Collection for additional information. 
 
For subjects that enter the study as a documented cIAI treatment failure (ie, with a known baseline pathogen), reasonable attempts should be made to 
provide the baseline isolates to the central laboratory.   
14. Required for pre-operative enrollment.  Only to be obtained at appropriate intervals thereafter if deemed necessary by the investigator. 
15. The expected minimum treatment duration is four 24-h dosing cycles unless Clinical Failure or Clinical Cure occurs earlier. Maximum treatment duration 
is fourteen 24-h dosing cycles. The 12-h interval between doses can be shortened (but not prolonged) by up to 4-h from the initial dose during Dosing 
Cycles 1-3 to adapt to a normal hospital schedule.  After the 3rd 24-h dosing cycle, the permitted administration window is q12h ± 1-h.  
 
Contact Medical Monitor for dosing beyond 7 dosing cycles. 
16. Please refer to Appendix 3:  Blood PK Sample Collection, Handling, Preparation and Shipping for schedule of PK assessments. 
17. Coagulation only.  Urinalysis does not need to be performed at the TOC and FU visits. 


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TABLE OF CONTENTS 
 
1. 
SPONSOR SIGNATURE PAGE ......................................................................................... 2 
2. 
TABULATED PROTOCOL SUMMARY ......................................................................... 4 
3. 
SCHEDULE OF ASSESSMENTS ...................................................................................... 9 
4. 
LIST OF ABBREVIATIONS ............................................................................................ 15 
5. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ...................... 17 
6. 
BACKGROUND AND RATIONALE .............................................................................. 18 
6.1 
INTRA-ABDOMINAL INFECTIONS .................................................................................... 18 
6.2 
PROPERTIES OF ERAVACYCLINE .................................................................................... 18 
6.3 
CLINICAL EXPERIENCE .................................................................................................. 19 
6.3.1 
Phase 2 Study in Subjects with cIAI (TP-434-P2-cIAI-1).................................... 20 
6.3.2 
Phase 3 Study in Subjects with cIAI (TP-434-008) .............................................. 20 
6.3.3 
Phase 3 Study in Subjects with cUTI (TP-434-010) ............................................. 20 
6.3.4 
Summary of Known and Potential Risks .............................................................. 21 
6.4 
DOSING RATIONALE ...................................................................................................... 21 
6.5 
POPULATION TO BE STUDIED ........................................................................................ 22 
6.6 
STATEMENT OF COMPLIANCE ........................................................................................ 22 
7. 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................... 22 
7.1 
PRIMARY OBJECTIVE ..................................................................................................... 22 
7.2 
PRIMARY ENDPOINT ...................................................................................................... 22 
7.3 
SECONDARY OBJECTIVES .............................................................................................. 22 
7.4 
SECONDARY ENDPOINTS ............................................................................................... 22 
7.5 
SAFETY PARAMETERS ................................................................................................... 23 
8. 
STUDY DESIGN ................................................................................................................. 23 
8.1 
NUMBER OF SUBJECTS ................................................................................................... 23 
8.2 
STUDY DESIGN .............................................................................................................. 23 
8.3 
MEASURES TAKEN TO MINIMIZE BIAS .......................................................................... 23 
8.4 
EXPECTED DURATION OF SUBJECT PARTICIPATION ....................................................... 24 
9. 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................... 24 
9.1 
INCLUSION CRITERIA FOR ENROLLMENT ....................................................................... 24 
9.2 
EXCLUSION CRITERIA .................................................................................................... 26 
9.3 
REQUALIFICATION FOR STUDY ENTRY .......................................................................... 27 
9.4 
SUBJECT WITHDRAWAL CRITERIA ................................................................................ 27 
9.4.1 
Early Discontinuation from Study Drug Administration ...................................... 27 
9.4.2 
Withdrawal from Study Protocol .......................................................................... 28 
9.5 
REPLACEMENT OF SUBJECTS ......................................................................................... 28 
9.6 
PRIOR AND CONCOMITANT MEDICATION ...................................................................... 28 
10. STUDY PROCEDURES .................................................................................................... 28 


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10.1 
GENERAL PROCEDURES ................................................................................................. 28 
10.1.1 
Temperature .......................................................................................................... 28 
10.1.2 
Abdominal Examination ....................................................................................... 29 
10.1.3 
Safety Laboratory Tests ........................................................................................ 29 
10.1.4 
ECGs ..................................................................................................................... 29 
10.1.5 
Microbiologic Specimen Collection ..................................................................... 29 
10.1.6 
Blood Cultures ...................................................................................................... 30 
10.1.7 
Radiologic Assessment ......................................................................................... 30 
10.1.8 
Clinical Response.................................................................................................. 30 
10.1.8.1 
Clinical Cure ................................................................................................. 30 
10.1.8.2 
Clinical Failure.............................................................................................. 30 
10.1.8.3 
Indeterminate/Missing .................................................................................. 31 
10.2 
TIME POINT SPECIFIC PROCEDURES .............................................................................. 31 
10.2.1 
Screening............................................................................................................... 31 
10.2.2 
Randomization and Enrollment of Subjects ......................................................... 32 
10.2.3 
Dose Cycle 1 ......................................................................................................... 32 
10.2.4 
Dosing Cycles 2 and 3 .......................................................................................... 33 
10.2.5 
Dosing Cycles 4 through 14 - while subject is on study drug .............................. 33 
10.2.6 
End-of-Therapy (EOT), Test of Cure (TOC) and Follow-Up (FU) ...................... 34 
10.3 
STUDY DRUG ADMINISTRATION .................................................................................... 34 
10.3.1 
Study Drug Infusions and Dosing Schedule ......................................................... 34 
10.3.2 
Meropenem and Meropenem-Matched Placebo Dose Adjustment ...................... 36 
10.3.3 
Treatment Compliance .......................................................................................... 36 
10.3.4 
Guidance to Investigators for Determining When to End Therapy ...................... 37 
10.4 
SPECIFIC RESTRICTIONS/REQUIREMENTS ...................................................................... 37 
10.4.1 
Avoidance of Pregnancy ....................................................................................... 37 
10.4.1.1 
Instructions for Male Subjects ...................................................................... 37 
10.4.1.2 
Instructions for Female Subjects ................................................................... 37 
10.4.2 
Pregnancy .............................................................................................................. 38 
10.4.2.1 
Follow-up in the Event of a Pregnancy......................................................... 38 
10.5 
STUDY DISCONTINUATION/TERMINATION CRITERIA ..................................................... 38 
11. QUALITY CONTROL AND QUALITY ASSURANCE ................................................ 39 
11.1 
QUALITY CONTROL ....................................................................................................... 39 
11.1.1 
Monitoring ............................................................................................................ 39 
11.2 
QUALITY ASSURANCE ................................................................................................... 39 
12. ASSESSMENT OF SAFETY ............................................................................................. 39 
12.1 
DEFINITIONS .................................................................................................................. 39 
12.1.1 
Adverse Event ....................................................................................................... 39 
12.1.2 
Adverse Drug Reaction (ADR) ............................................................................. 39 
12.1.3 
Serious Adverse Event (SAE) ............................................................................... 39 
12.1.4 
Unexpected Adverse Reactions ............................................................................ 40 
12.2 
AE COLLECTING AND REPORTING ................................................................................. 40 
12.3 
GRADING OF ADVERSE EVENTS .................................................................................... 42 
12.4 
RELATIONSHIP TO STUDY DRUG.................................................................................... 42 
12.5 
LABORATORY TEST ABNORMALITIES ............................................................................ 43 


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12.6 
FOLLOW-UP OF ADVERSE EVENTS ................................................................................. 43 
13. EVALUATION OF EFFICACY ....................................................................................... 44 
13.1 
ANALYSIS POPULATIONS ............................................................................................... 44 
13.2 
EFFICACY EVALUATIONS .............................................................................................. 44 
13.2.1 
Clinical Response.................................................................................................. 45 
13.2.2 
Per Pathogen Microbiological Outcomes ............................................................. 45 
13.2.3 
Per-Subject Microbiological Response ................................................................. 46 
14. STATISTICAL METHODS .............................................................................................. 46 
14.1 
DATA COLLECTION AND PROCESSING ........................................................................... 46 
14.2 
STATISTICAL METHODOLOGY ....................................................................................... 46 
14.2.1 
Efficacy Analyses ................................................................................................. 46 
14.2.2 
Safety Analyses ..................................................................................................... 47 
14.2.3 
Sample Size Considerations .................................................................................. 48 
14.2.4 
Handling of Missing Data ..................................................................................... 49 
14.2.5 
Surgical Adjudication Committee (SAC) ............................................................. 49 
14.3 
INTERIM ANALYSIS ....................................................................................................... 49 
15. STUDY DRUG MATERIALS ........................................................................................... 49 
15.1 
STUDY DRUG NOMENCLATURE ..................................................................................... 49 
15.2 
STUDY DRUG PREPARATION.......................................................................................... 50 
15.2.1 
Reconstitution ....................................................................................................... 50 
15.2.2 
Administration ...................................................................................................... 50 
15.3 
STUDY DRUG STORAGE ................................................................................................. 50 
15.4 
STUDY DRUG PACKAGING AND LABELING .................................................................... 50 
15.5 
STUDY DRUG COMPARATOR ......................................................................................... 51 
15.6 
STUDY DRUG ACCOUNTABILITY ................................................................................... 51 
15.7 
STUDY DRUG HANDLING AND DISPOSAL ...................................................................... 51 
15.8 
INVESTIGATOR’S BREAKING OF THE BLIND ................................................................... 51 
16. INVESTIGATOR REQUIREMENTS ............................................................................. 52 
16.1 
AE COLLECTION AND REPORTING ................................................................................. 52 
16.2 
PROTOCOL ADHERENCE ................................................................................................ 52 
16.3 
CASE REPORT FORMS .................................................................................................... 52 
16.4 
SOURCE DOCUMENT MAINTENANCE ............................................................................. 52 
16.5 
STUDY MONITORING REQUIREMENTS ........................................................................... 53 
16.6 
STUDY COMPLETION ..................................................................................................... 53 
17. PROTECTION OF HUMAN SUBJECTS AND GENERAL STUDY 
ADMINISTRATION .................................................................................................................. 53 
17.1 
INFORMED CONSENT ..................................................................................................... 53 
17.2 
IRB/IEC APPROVAL ...................................................................................................... 54 
17.3 
SUBJECT DATA PROTECTION ......................................................................................... 54 
18. DATA MANAGEMENT AND MONITORING .............................................................. 54 
18.1 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .......................................................... 54 


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18.2 
RETENTION OF RECORDS ............................................................................................... 55 
19. FINANCING AND INSURANCE ..................................................................................... 55 
20. PUBLICATION POLICY .................................................................................................. 55 
21. REFERENCES .................................................................................................................... 55 
Appendix 1: 
APACHE II Score ............................................................................................. 56 
Appendix 2:  Central Safety Laboratory Tests ....................................................................... 57 
Appendix 3:   Blood PK Sample Collection, Handling, Preparation and Shipping ................ 58 
 
LIST OF TABLES AND FIGURES 
Table 1: Study Drug Infusion Scheme of a 24-h Dosing Cycle ................................................... 23 
Table 2: Timeline for Individual Study Subjects .......................................................................... 24 
Table 3: Study Drug Infusion Scheme of a 24-h Dosing Cycle ................................................... 35 
Figure 1: Study Drug Infusion Scheme of a 24-h Dosing Cycle .................................................. 36 
 
 


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4. 
LIST OF ABBREVIATIONS 
ADR Adverse Drug Reaction 
  
CT Computed tomography 
AE Adverse event 
  
DG Dose group 
AIDS Acquired Immune Deficiency Syndrome 
  
dL Deciliter 
ALT Alanine aminotransferase 
  
ECG Electrocardiogram 
APACHE Acute Physiology and Chronic Health 
Evaluation 
  
eCRF Electronic case report form 
APS Acute Physiology Score 
  
eg For example 
AST Aspartate aminotransferase 
  
EMA European Medicines Agency 
AUC Area under the plasma concentration-time 
curve 
  
EOT End of Therapy 
AUC0-12 Area under the plasma concentration-time 
curve from time zero to time 12-h  
  
ESβL Extended-spectrum β-lactamase(s) 
AUC0-24 Area under the plasma concentration-time 
curve from time zero to time 24-h 
  
◦F Farenheight 
AUC0-inf Area under the plasma concentration-time 
curve from time zero to time infinity 
  
FDA Food and Drug Administration 
AUC0-tau(ss) Area under the plasma concentration-time 
curve from time zero to time tau over a 
dosing interval at steady state, where tau is 
the length of the dosing interval 
  
FU Follow-up 
B/P Blood pressure 
  
g Gram 
◦C Celsius 
  
GI Gastrointestinal tract 
CD4 Cluster of differentiation 4: a glycoprotein 
that is found primarily on the surface of 
helper T cells 
  
GCP Good clinical practice 
CE Clinically evaluable 
  
GGT Gamma-glutamyl transferase 
CI Confidence interval 
  
GMP Good manufacturing practices 
cIAI Complicated intra-abdominal infection 
  
GOT Glutamyl oxaloacetic transaminase 
CK Creatine kinase 
  
h Hour(s) 
CL Clearance 
  
HIV Human Immunodeficiency Virus 
Cmax Maximum observed plasma concentration 
  
HR Heart Rate 
CNS Central nervous system 
  
IAI Intra-abdominal Infection 
Conc Concentration 
  
IB Investigator’s Brochure 
CRA Clinical research associates 
  
ICH International Conference on Harmonization 
CRF Case report form 
  
IDSA The Infectious Diseases Society of 
America 
CRO Contract Research Organization 
  
ie In other words 
CV Coefficient of variation, Cardiovascular 
  
  
 
 
 
 
 
IEC Independent Ethics Committee 
  
MITT Modified intent-to-treat 


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IND Investigational New Drug 
  
mMITT Microbiologic modified-intent-to-treat  
IRB Institutional Review Board 
  
MRI Magnetic resonance imaging 
ITT Intent-to-treat 
  
N Number in a group 
IV Intravenous 
  
N/A Not applicable 
IWRS Interactive web-based response 
system 
  
ng Nanogram 
kg Kilogram 
  
PD Pharmacodynamic 
L Liter 
  
PHI Protected health information 
LAR Legally Authorized Representative 
  
PK Pharmacokinetics 
LDH Lactic dehydrogenase 
  
qXh Every X hours 
MAD Multiple ascending dose 
  
RBC Erythrocyte count 
Max Maximum 
  
RR Respiration Rate 
MCH Mean cell hemoglobin 
  
SAD Single ascending dose 
MCHC Mean cell hemoglobin concentration   
SAE Serious adverse event 
MCV Mean cell volume 
  
SOA Schedule of Assessments 
ME Microbiologically evaluable 
  
SUSAR Suspected unexpected serious adverse 
reaction 
MedDRA Medical Dictionary for Regulatory 
Activities 
  
T1/2 Elimination half-life 
µg Microgram 
  
TBD To be determined 
µmol Micromolar 
  
Tmax Time to Cmax 
mg Milligram 
  
TOC Test-of-cure 
MIC Minimum inhibitory concentration 
  
ULN Upper limit of normal 
MIC90 MIC of at least 90% of clinical 
isolates tested 
  
U.S. United States 
mL Milliliter 
  
λz Elimination rate constant 
mm Hg Millimeter of mercury 
  
WBC White blood cell (count) 
Min Minutes, Minimum 
  
WHODrug World Health Organization Drug 
Dictionary 
Micro-ITT Microbiological Intent-to-Treat 
Population 
  
0.9% NaCl Normal saline 
 
 
 
 
 


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5. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
 
SPONSOR: 
 
Tetraphase Pharmaceuticals, Inc. 
Sponsor’s Chief Medical Officer:  
480 Arsenal Street, Suite 110 
Patrick Horn, MD, PhD 
Watertown, MA 02472 | USA 
Phone: 
+1-617-715-3593 
Phone: +1-617-715-3600 
Mobile: 
+1-847-668-1044 
Fax: 
+1-617-926-3557 
E-mail: 
phorn@tphase.com 
 
 
CONTRACT RESEARCH ORGANIZATION: 
 
PSI CRO AG 
Baarerstrasse 113a 
6300 Zug | Switzerland  
 
 
 
CRO’s Medical Monitors: 
John Riefler, MD 
Julia Chebotareva, MD, PhD  
Mobile: +1 (267) 666 8511  
Phone: 
+38 (044) 492 8560 x 4231 
Email: John.Riefler@psi-cro.com 
Mobile: 
+38 (067) 509 1771 
 
 
Email: 
Julia.Chebotareva@psi-cro.com  


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6. 
BACKGROUND AND RATIONALE 
6.1 
Intra-abdominal Infections 
Complicated intra-abdominal infections (cIAIs) extend beyond the hollow viscus of origin into 
the peritoneal or retroperitoneal spaces and are associated with either abscess formation or 
peritonitis and systemic signs and symptoms of illness.  cIAIs are a common problem in clinical 
practice and consume substantial hospital resources and costs. Although a wide range of 
individual antimicrobial agents and combinations of agents are available for use in cIAI, no 
regimen to date has been consistently demonstrated to be superior or inferior. Antibiotics used 
for the empiric treatment of cIAIs should have activity against enteric Gram-negative aerobic 
and facultative bacilli and enteric Gram-positive streptococci, staphylococci, and enterococci. In 
addition, coverage for obligate anaerobic bacilli is recommended for distal small bowel, 
appendiceal, and colon-derived infections and for more proximal gastrointestinal (GI) 
perforations in the presence of obstruction or paralytic ileus. With the exception of carbapenem 
antibiotics, there are few broad-spectrum antibiotics to cover all the potential pathogens to which 
the peritoneum is exposed following a perforation of the intestinal tract [1]   
Infections due to multidrug-resistant organisms are even more difficult to treat and eradicate 
because they do not respond to many common antibiotics, and in some cases do not respond to 
even the most powerful ones, such as carbapenems. The carbapenems are becoming less 
effective because carbapenemases and porin changes that mediate resistance have become more 
common, even in enteric bacteria. Enterobacteriaceae, Pseudomonas, and Acinetobacter species 
are more likely than others to develop multidrug resistance. Thus, there is a need for broad-
spectrum antibiotics with appropriate pharmacokinetics (PK) to empirically cover the wide range 
of potential pathogens seen in cIAIs. Eravacycline (TP-434) is a candidate for the treatment of 
serious and life-threatening infections, including those caused by pathogens otherwise resistant 
to current treatment options. Eravacycline is very effective in animal models of infection [2]. 
6.2 
Properties of Eravacycline 
Eravacycline is a novel, synthetic, broad-spectrum fluorocycline antibiotic of the tetracycline 
class.  The mechanism of action behind the antibiotic property of eravacycline is related to its 
ability to bind to the bacterial 30S ribosomal subunit and inhibit protein synthesis [3]. 
Eravacycline is more potent than legacy tetracyclines and is highly active against clinically 
important MDR Gram-negative and Gram-positive aerobic and anaerobic pathogens, including 
Enterobacteriaceae that produce ESBLs and/or carbapenemases from all of the Ambler classes.  
Eravacycline is also unique among antimicrobials in late-stage development in that it possesses 
potent activity against CRAB, including those with blaOXA carbapenemases and against 
Enterobacteriaceae and A. baumannii containing MBLs, and isolates displaying MDR.  
Eravacycline exhibits potency profiles similar to those of the carbapenems but more broadly 
covers Gram-positive pathogens like MRSA and enterococci, and is active against carbapenem-
resistant Gram-negative bacteria. Eravacycline is being developed for the treatment of cIAIs and 
has been shown to have in vitro potency and spectrum to provide protection from infection by 
either monomicrobial or polymicrobial bacteria from the intestinal flora that commonly cause 
cIAIs [4]. 


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Eravacycline has low to no potential to inhibit or induce cytochrome P450 isoenzymes at the 
exposure expected in clinical studies. Major metabolites TP-6208 and TP-034 were not potent 
direct or metabolism-dependent inhibitors of microsomal P450 enzymes. TP-6208 did not induce 
major CYP enzymes (CYP1A2, CYP2B6, or CYP3A4), but TP-034 induced CYP2B6 and 
CYP3A4 [5]. In transport studies, eravacycline inhibited MDR1 (P-gp), OATP1B3, and OAT3 
activity at 20 µg/mL. Clinically relevant concentrations of TP-6208 or TP-034 did not inhibit any 
of 11 major transporters. Neither eravacycline (up to concentrations of 5 µg/mL) nor TP-6208 
(up to 2.5 µg/mL) were substrates for MDR1, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, 
OCT1, and OCT2, but TP-034 was identified as a potential substrate for the efflux transporters 
P-gp, BCRP, and BSEP [6].  
Eravacycline is highly active in vitro against emerging pathogens like Acinetobacter baumannii 
as well as clinically important species of Enterobacteriaceae (including those isolates that 
produce extended-spectrum beta-lactamases and/or are carbapenem-resistant) and anaerobes. 
Eravacycline may not exhibit high activity against Pseudomonas aerugonisa when it is the sole 
pathogen. The full description of the in vitro antibacterial activity of eravacycline can be found 
in the Investigator’s Brochure (IB).  
The high degree and reliability of in vitro antibacterial activity against multidrug-resistant Gram-
negative and Gram-positive aerobic, facultative, and obligate pathogens; efficacy observed with 
eravacycline in established animal models of infection; and the efficacy and tolerability 
established in a phase 2 and a phase 3 study of subjects with cIAIs warrant clinical development 
of eravacycline as a single therapy treatment option for cIAIs and other serious bacterial 
infections. 
6.3 
Clinical Experience 
Intravenously administered eravacycline has been studied in fifteen completed clinical trials in 
healthy subjects, in two studies with special populations (subjects with renal impairment and 
subjects with hepatic impairment), in phase 2 and phase 3 studies in subjects with cIAI, and in a 
phase 3 study in subjects with cUTI.   
The pharmacokinetics of eravacycline is linear and dose-proportional throughout the range of 
doses to be used clinically.  The phase 2 and phase 3 studies in subjects with cIAI confirmed the 
efficacy of IV eravacycline in the treatment of serious infections caused by Gram-negative, 
Gram-positive, and anaerobic pathogens, including multidrug resistant pathogens.  In the phase 3 
study in subjects with cUTI, the primary efficacy endpoint of non-inferiority to levofloxacin in 
combined clinical and microbiologic response at the Post-Treatment visit, 6-8 days after the 
completion of therapy, was not met. Outcomes at earlier timepoints and post-hoc analyses of 
subjects who only received IV eravacycline were favorable and the failure was attributed to 
inadequate exposures following transition to PO eravacycline.   
Throughout the clinical development program for eravacycline, gastrointestinal side effects of 
nausea and vomiting have been observed at the higher doses of eravacycline administered as 
both IV and PO formulations.   
Please refer to the current IB for details of the eravacycline clinical studies and adverse event 
(AE) profile. 


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6.3.1 
Phase 2 Study in Subjects with cIAI (TP-434-P2-cIAI-1) 
The proof of concept of eravacycline for the treatment of infections was demonstrated in a phase 
2 study of subjects with cIAI. The cure rates [% (95% confidence interval [CI])] in the 
microbiologically evaluable population (ME) population at the Test of Cure (TOC) visit were 
92.9 (80.5-98.5), 100 (91.4-100), and 92.3 (74.9–99.1) for the eravacycline 1.5 mg/kg q24h, the 
eravacycline 1.0 mg/kg q12h, and the ertapenem 1.0 g q24h groups, respectively.  There were no 
SAEs that were considered by the investigator to be related to study drug, and there were no new 
safety signals for eravacycline identified in this study.  Overall, treatment emergent AEs were 
reported as 35.8%, 28.6%, and 26.7% of subjects in the eravacycline 1.5 mg/kg q24h, the 
eravacycline 1.0 mg/kg q12h, and the ertapenem 1.0 g q24h groups, respectively.  Nausea was 
reported in 1.9%, 10.7%, and 6.7% of subjects; and vomiting in 5.7%, 1.8%, and 0% of subjects 
in the eravacycline 1.5 mg/kg q24h, the eravacycline 1.0 mg/kg q24h, and the ertapenem 1.0 g 
q24h groups, respectively.  The incidence of infusion site reactions was 1.9% and 3.6% in the 
eravacycline 1.5 mg/kg q24h and the eravacycline 1.0 mg/kg q12h groups, respectively, lower 
than the incidence observed in the phase 1 studies, probably resulting from the decreased dosing 
concentration used in the phase 2 study. 
6.3.2 
Phase 3 Study in Subjects with cIAI (TP-434-008) 
The efficacy of IV eravacycline for the treatment of cIAI was confirmed in a phase 3, randomized, 
double-blind, double-dummy, multicenter, prospective study comparing IV eravacycline (1.0 
mg/kg q12h [ERV]) with IV ertapenem (1 g q24h [ERT]) in subjects with cIAI. A total of 541 
subjects were enrolled in the study. The cure rates in the microbiological intent-to-treat population 
at the Test of Cure visit were 86.8 and 87.6% in the ERV and ERT groups, respectively. The 
between treatment group difference [% (95% CI)] was -0.80 (-7.1, 5.5), allowing non-inferiority 
to be declared and supporting the efficacy of eravacycline in the treatment of cIAI.  
Eravacycline was safe and generally well-tolerated in subjects with cIAI. The most commonly 
reported TEAEs were gastrointestinal disorders, including nausea (8.1% and 0.7% in the ERV 
and ERT groups, respectively) and vomiting (4.1% and 3.4% in the ERV and ERT groups, 
respectively). In the ERV group, 17 subjects (6.3%) experienced SAEs, compared with 16 
subjects (6.0) in the ERT group. None of the SAEs were considered related to treatment. Three 
subjects in the ERV group and 6 subjects in the ERT group died during the study. An equal 
percentage of subjects (1.9%) discontinued study drug due to a treatment-related TEAE. 
 
6.3.3 
Phase 3 Study in Subjects with cUTI (TP-434-010) 
The efficacy of an IV-to-PO transition regimen eravacycline for the treatment of cUTI was 
studied in a phase 3, randomized, double-blind, double-dummy, multicenter, prospective study 
comparing eravacycline (1.5 mg/kg q24h IV followed by 200 mg q12h PO [ERV]) with 
levofloxacin (750 mg q24h IV followed by 750 mg q24h PO [LEV]) in subjects with cUTI. A 
total of 908 subjects were enrolled in the study. The IV-to-PO transition regimen of eravacycline 
was not shown to be noninferior to levofloxacin in combined clinical and microbiological 
response at the Post-Treatment visit, 6-8 days after the completion of therapy. Additional post-
hoc analyses suggested that lower-then-expected eravacycline exposures during PO 
administration were responsible for the failure to meet the primary endpoint. Outcomes at earlier 
timepoints and among subjects who received only IV eravacycline (did not transition to PO) all 
favored eravacycline, supporting the efficacy of IV eravacycline in the treatment of cUTI.  


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Eravacycline was safe and generally well-tolerated in subjects with cUTI. As in cIAI, the most 
commonly reported TEAEs were gastrointestinal disorders, including nausea (18.0% and 3.1% in 
the ERV and LEV groups, respectively) and vomiting (7.3% and 1.3% in the ERV and LEV 
groups, respectively). These events rarely led to study drug discontinuation. In the ERV group, 
1.5% experienced SAEs, compared with 1.3% in the LEV group. None of the SAEs in the ERV 
group were considered related to treatment. 
6.3.4 
Summary of Known and Potential Risks 
Eravacycline is related to tetracyclines, a well-known class of antibiotics that has been utilized 
for over 50 years.  
The overall risk to the subjects of the present study is deemed to be acceptable, as indicated by 
the results of the nonclinical toxicology program, the initial phase 1 studies, the phase 2 cIAI 
study, and the phase 3 cIAI and cUTI studies.  As expected for this class of antibiotics, transient 
gastrointestinal adverse events of mild to moderate intensity were observed at the higher dose 
levels in the phase 1 studies.  Low levels of nausea and vomiting were observed in the cIAI 
phase 2 study and phase 3 studies. Higher levels of nausea and vomiting were seen in the phase 3 
cUTI study; however, few events led to discontinuation of study drug. 
Infusion site related adverse events (eg, pain, discomfort, and superficial phlebitis) were 
observed in the phase 1 MAD study.  The eravacycline concentration was reduced by 25-50% in 
the phase 2 cIAI study, and the reported incidence of infusion site related adverse events was 
greatly reduced. Low levels of infusion site related adverse events were observed in the phase 3 
cIAI and cUTI studies. 
In subjects with higher risk for poor outcomes from infections [ie, auto-immune syndrome or 
Drug Reaction with Eosinophila and Systemic Symptoms (DRESS) syndrome] the investigator 
should carefully review the inclusion and exclusion criteria to ensure the appropriate enrollment 
of subjects.  Clostridium difficile associated infections are seen with all antibiotics.  Care should 
be taken in subjects enrolled in this clinical study, any subject that has signs or symptoms of 
Clostridium difficile (eg, diarrhea or abdominal pain) should be evaluated for this infection. 
Please refer to the latest version of the eravacycline IB and the meropenem package insert for 
additional information on eravacycline and meropenem, respectively. 
6.4 
Dosing Rationale 
Two doses of eravacycline were evaluated in the phase 2 cIAI study based on tolerability and 
steady-state AUCs achieved in healthy volunteers in the phase 1 MAD study, and the clinical 
response rates for both doses were similar to the comparator, ertapenem.  The eravacycline 1.0 
mg/kg (up to a maximum of 150 mg) q12h dose was selected for the phase 3 cIAI study 
(TP-434-008), since this dose provided higher AUCs and acceptable tolerability. As the efficacy 
of IV eravacycline for the treatment of cIAI was confirmed in TP-434-008 study, the 
eravacycline 1.0 mg/kg q12h dose has been selected (with no maximum dose) for this study.  
 
The comparator, meropenem, was chosen because it is approved by the FDA and other 
regulatory authorities for the treatment of cIAI.  It will be given at the recommended dose of 1 g 
q8h for an expected minimum of four 24-h dosing cycles. 


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6.5 
Population To Be Studied 
Approximately 466 acutely hospitalized subjects with a diagnosis of cIAI requiring surgery will 
be recruited into this study.   
6.6 
Statement of Compliance 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and 
applicable regulatory and Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) requirements. 
7. 
STUDY OBJECTIVES AND ENDPOINTS 
7.1 
Primary Objective 
The primary objective of this study is to compare the clinical response at the test-of-cure (TOC) 
visit in the microbiological intent-to treat (micro-ITT) population for subjects in the 2 treatment 
arms.  
7.2 
Primary Endpoint 
The primary endpoint of this study will be the clinical response at the TOC visit in the micro-ITT 
population.   
NOTE: For the EMA, the primary analysis populations will be the all-treated (MITT) and the 
clinically evaluable (CE) populations.  
7.3 
Secondary Objectives  
The secondary objectives of the study are to: 
▪ Compare the clinical response for subjects in the 2 treatment arms at the end-of-treatment 
(EOT), TOC, and follow-up (FU) visits in the following populations: 
- Intent-to-treat (ITT) population 
- All-treated (MITT) population 
- Clinically evaluable (CE) population  
- Micro-ITT population  (for EOT, FU) 
- Microbiologically evaluable (ME) population  
▪ Compare the microbiologic response for subjects in the treatment arms at the EOT and TOC 
visits in the following populations: 
- Micro-ITT population 
- ME population 
▪ Assess the safety and tolerability of eravacycline administration in the safety population 
▪ Explore pharmacokinetic (PK) parameters of eravacycline 
7.4 
Secondary Endpoints 
The secondary endpoints of the study are: 
▪ Clinical response at the EOT, TOC, and FU visits  
▪ Microbiologic response for subjects in the 2 treatment arms at the EOT and TOC visits  


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7.5 
Safety Parameters 
The parameters that will be used to assess safety in this study include: 
▪ Vital signs 
▪ Adverse events 
▪ ECGs at specified time points 
▪ Safety labs at specified time points 
8. 
STUDY DESIGN 
8.1 
Number of Subjects 
The planned study enrollment is approximately 466 subjects. For this study, enrollment occurs at 
the time of randomization, and it is expected that more subjects will be screened than enrolled 
into the study.  This sample size was calculated as described in Section 14.2.3 based on the 
expectation that 68.75% of subjects will have a baseline pathogen identified and be included in 
the micro-ITT population.   
A pre-specified assessment of the actual number of subjects in the micro-ITT population was 
made following completion of the 250th subject. This assessment was performed using data 
blinded to treatment.  Since there was less than the expected proportion of subjects in the micro-
ITT population, the sample size was increased to a target of approximately 466 to provide a 
sufficient number of evaluable subjects. 
8.2 
Study Design 
This is a phase 3, randomized, double-blind, double-dummy, multicenter, prospective study to 
assess the efficacy, safety, and PK of eravacycline compared with meropenem.  Dosing in the 
study arms is described in the Table 1 below. 
Table 1: Study Drug Infusion Scheme of a 24-h Dosing Cycle 
Study Drug  
Treatment Arm 
1st Dose 
(of Dosing Cycle) 
2nd Dose  
(of Dosing Cycle) 
3rd Dose  
(of Dosing Cycle) 
4th Dose  
(of Dosing Cycle) 
5th Dose  
(of Dosing Cycle) 
60 min infusion 
30 min infusion 
30 min infusion 
60 min infusion 
30 min infusion 
Eravacycline, 1.0 mg/kg  q12h 
Eravacycline 
Placebo 
Placebo 
Eravacycline 
Placebo 
Meropenem, 1 g q8h 
Placebo 
Meropenem 
Meropenem 
Placebo 
Meropenem 
 
All subjects will remain hospitalized for the complete course of drug therapy.  
8.3 
Measures Taken to Minimize Bias 
Subjects will be assigned to study drug regimens using computerized randomization.  Except for 
the responsible study site pharmacist or designee, and separate unblinded clinical research 
associates (CRAs) to monitor drug supply and adherence to study drug blinding and 
randomization procedures, all study staff and participants will be blinded to the IV dosing 
regimens of subjects.   


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8.4 
Expected Duration of Subject Participation 
Individual subject participation in this study is expected to last approximately 6-8 weeks.  
Foreseen treatment duration at study entry is expected to be a minimum of four 24-h dosing 
cycles, (ie, in accordance with IDSA Guidelines and the Schedule of Assessments (SOA) for 
study drug administration).  However, study drug may be discontinued at the discretion of the 
investigator at any time.  Study drug treatment should be stopped when symptoms of cIAI have 
resolved or there is treatment failure.  A review of subjects requiring longer than 7 dosing cycles 
is required with the Medical Monitor. (Refer to Section 10.3.4 Guidance to Investigators for 
Determining When to End Therapy).  
The TOC evaluation will be conducted 25-31 calendar days after the first dose of study drug is 
administered and a follow-up visit will be performed 38-50 calendar days after the first dose of 
study drug is administered.  
The individual subject study timeline is shown in Table 2 below. 
Table 2: Timeline for Individual Study Subjects 
SCREENING 
ENROLLMENT 
STUDY DRUG 
TREATMENT 
END-OF-
THERAPY 
(EOT) 
TEST-OF-CURE 
(TOC) 
FOLLOW-UP 
(FU) 
Within 48-h of 
Initial Dose 
 
Dose Cycle 1 
through EOT 
Within 24-h of 
Last Dose 
25-31 Days after 
Initial Dose 
38-50 Days after 
Initial Dose 
Establish diagnosis  
of complicated 
intra- 
abdominal  
infections (cIAI) 
 
Verify eligibility  
for enrollment 
 
 
Use IWRS* to 
randomize to 
study drug 
Infuse study drug, 
either: 
 
• Eravacycline IV 
1.0 mg/kg q12h 
OR  
• Meropenem IV   
1 g q8h 
Expected 4 (min) to 
14 (max) study 
drug treatment 24-h 
dosing cycles. 
Review of subjects 
with Medical 
Monitor for 
therapies longer 
than seven 24-h 
dosing cycles.  
 
EOT assessments 
should be 
performed at 
premature 
withdrawal or 
treatment failure 
and within 24-h of 
last dose. 
Return to study 
center for 
assessment of 
clinical response 
and safety 
Return to study 
center for 
assessment of 
clinical response 
and safety 
*IWRS = Interactive Web-based Response System 
9. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
9.1 
Inclusion Criteria for Enrollment 
Subjects must meet all of the following criteria: 
1. Male or female subject hospitalized for cIAI with one of the following diagnoses: 
a. Intra-abdominal abscess: one or more abscesses surrounding diseased or perforated 
viscera (including hepatic and splenic abscesses) 
b. Gastric or intestinal perforation associated with diffuse peritonitis 
c. Peritonitis: diffuse infection of the peritoneum (but not spontaneous bacterial peritonitis 
associated with cirrhosis and chronic ascites) 
d. Appendicitis with perforation, peritonitis or abscess 
e. Cholecystitis with perforation or abscess 


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f. Diverticulitis with perforation, peritonitis, or abscess 
Note:  Infections limited to the hollow viscus, such as simple cholecystitis and simple 
appendicitis, are not eligible.  Ischemic bowel disease without perforation is not eligible.  
Acute suppurative cholangitis and acute necrotizing pancreatitis are not eligible 
2. At least 18 years of age 
3. Evidence of a systemic inflammatory response with at least one of the following: 
a. Fever (oral, rectal, tympanic, or by temporal artery temperature > 100.4˚F / 38˚C) or 
hypothermia (temperature ≤ 95.9˚F / 35.5˚C) 
b. Elevated WBC (> ULN laboratory range); or proportion of band forms of the WBC 
differential beyond the ULN laboratory range 
c. Increased pulse (HR > 90 beats per minute) 
d. Increased respiratory rate (> 20 breaths per minute) 
4. Abdominal pain or flank pain (with or without rebound tenderness), or pain caused by cIAI 
that is referred to another anatomic area such as back or hip, or localized or diffuse 
abdominal wall rigidity, or mass, or ileus 
5. Able to provide informed consent.  
6. Subjects must agree to use a highly reliable method of birth control 
a. Male subjects must agree to use an effective barrier method of contraception during the 
study and for 14 days following the last dose if sexually active with a female of 
childbearing potential 
b. Female subjects must not be pregnant or nursing. For females of childbearing potential, 
subjects must commit to either:   
i. Use at least two medically accepted, effective methods of birth control (eg, condom, 
oral contraceptive, indwelling intrauterine device, hormonal implant /patch, 
injections, approved cervical ring, etc.) during study drug dosing and for 14 days 
following last study drug dose, OR 
ii. Sexual abstinence 
And either  
7A. Meets All Inclusion Criteria for Pre-operative Enrollment: 
▪ Has a sonogram or radiographic imaging result congruent with the diagnosis of cIAI, AND 
▪ Acute surgical or percutaneous intervention (open laparotomy, laparoscopic surgery, or 
percutaneous drainage of an abscess) is foreseen within 24-h  
Or 
7B. Meets All Inclusion Criteria for Intra-operative/Post-operative Enrollment: 
▪ Visual confirmation of cIAI (presence of pus within the abdominal cavity), AND 
▪ Surgical intervention includes open laparotomy, laparoscopic surgery, or percutaneous 
draining of an abscess, AND 
▪ Intervention is adequate (ie, a procedure in which all communications between the GI tract 
and the peritoneal cavity are closed, no necrotic intestine is left, and all infected collections 
are drained at the procedure), AND 
▪ Subjects who are enrolled in the trial post-operatively must receive no more than one dose 
of effective antibacterial drug therapy post-operatively before randomization 
 


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9.2 
Exclusion Criteria 
Subjects must NOT meet any of the following exclusion criteria: 
1. Considered unlikely to survive the 6-8 week study period 
• Any rapidly-progressing disease or immediately life-threatening illness, including acute 
hepatic failure, respiratory failure and septic shock 
• Requirement for vasopressors (prior to enrollment) at therapeutic dosages (ie, dopamine 
> 5 µg/kg/min, any dose of norepinephrine, epinephrine or phenylephrine) to maintain a 
systolic blood pressure  90 mm Hg or a mean arterial pressure  70 mm Hg following 
adequate fluid resuscitation 
2. Creatinine clearance ≤ 50 mL/min as estimated by the Cockcroft-Gault equation 
𝑒𝐶𝐶𝑟[𝑚𝐿/𝑚𝑖𝑛] =
(140 −𝐴𝑔𝑒 [𝑦𝑟𝑠]) ×  𝐵𝑜𝑑𝑦 𝑊𝑒𝑖𝑔ℎ𝑡 [𝑘𝑔] × [0.85 𝑖𝑓 𝐹𝑒𝑚𝑎𝑙𝑒]
72 ×  𝑆𝑒𝑟𝑢𝑚 𝐶𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 [𝑚𝑔𝑑𝐿
⁄
]
 
3. Presence or possible signs of significant hepatic disease: 
a. Alanine aminotransferase or aspartate aminotransferase > 5 x ULN, OR 
b. Total bilirubin > 3 x ULN, unless isolated hyperbilirubinemia is directly related to the 
acute process 
4. Immunocompromised condition, including known HIV positivity (requiring anti-retroviral 
therapy or with CD4 count < 300), AIDS, organ (bone marrow) transplant recipients, and 
hematological malignancy. Immunosuppressive therapy, including use of high-dose 
corticosteroids (eg, > 20 mg prednisone or equivalent per day for greater than 2 weeks) 
5. History of moderate or severe hypersensitivity reactions to tetracyclines, carbapenems, β-
lactam antibiotics or to any of the excipients contained in the study drug formulations  
6. Participation in any investigational drug or device study within 30 days prior to study entry 
7. Known or suspected current central nervous system (CNS) disorder that may predispose to 
seizures or lower seizure threshold (eg, severe cerebral arteriosclerosis, epilepsy) 
8. Antibiotic-related exclusions:  
a. Receipt of effective antibacterial drug therapy for cIAI for a continuous duration of > 
24-h during the 72-h preceding randomization [However, subjects with documented cIAI 
(ie, known baseline pathogen) who have received at least 72-h of antibiotic therapy and 
are considered treatment failures may be enrolled.  Treatment failure is defined as 
persistent fever and/or clinical symptoms; or the development of a new intra-abdominal 
abscess after ≥ 72-h of antibiotic therapy], OR 
b. Receipt of meropenem or any other carbapenem, or tigecycline for the current infection, 
OR 
c. Need for concomitant systemic antimicrobial agents effective in cIAI other than study 
drug  
9. Refusal of mechanical ventilation, dialysis or hemofiltration, cardioversion or any other 
resuscitative measures and drug/fluid therapy at time of consent 
10. Known or suspected inflammatory bowel disease or associated visceral abscess 
11. The anticipated need for systemic antibiotics for a duration of more than 14 days 
12. Systemic malignancy that required chemotherapy, immunotherapy, radiation therapy or 
antineoplastic therapy within the previous 3 months or which is anticipated to begin prior to 
the TOC visit 
13. Known at study entry to have cIAI caused by a pathogen(s) resistant to one of the study 
drugs 


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14. Any other unstable or clinically significant concurrent medical condition (ie, class IV heart or 
lung disease, end stage renal disease, or requiring hemodialysis, etc.) that would, in the 
opinion of the investigator, jeopardize the safety of a subject, impact their expected survival 
through the end of the study participation, and/or impact their ability to comply with the 
protocol 
9.3 
Requalification for Study Entry 
Subjects not fulfilling the entry criteria may not be re-screened for participation even if their 
eligibility characteristics have changed, with the exception of creatinine clearance.  Creatinine 
clearance is the only screening parameter that can be retested in the establishment of eligibility.  
Volume depleted subjects should first receive volume replacement prior to having their 
creatinine clearance calculated. 
9.4 
Subject Withdrawal Criteria 
Subjects should be encouraged to complete all study evaluations.  However, subjects may 
withdraw consent to participate in this study at any time without penalty or loss of benefits to 
which the subject is otherwise entitled.   
Every reasonable effort should be made to determine the reason a subject discontinues study 
drug treatment and/or withdraws from the study prematurely and this information should be 
recorded on the appropriate page(s) of the electronic case report form (eCRF).   
9.4.1 
Early Discontinuation from Study Drug Administration 
If a subject prematurely discontinues study drug treatment (including withdrawal of consent for 
study drug treatment), every reasonable effort should be made to adhere to future protocol 
evaluations and examinations as specified in the Schedule of Assessments.   
The reason for early discontinuation of study drug treatment should be recorded on the 
appropriate page(s) of the eCRF.  Reasons for early discontinuation of study drug treatment may 
include, but are not limited to, the following: 
1. Occurrence of an AE, which, in the opinion of the investigator, warrants the subject’s 
permanent withdrawal from study treatment.  In the event of withdrawal due to the 
occurrence of an AE, the regional medical monitor must be notified within 24-h.  
Subjects withdrawn secondary to an ongoing non-serious AE (regardless of relationship 
to study drug) or SAE that is not related to study drug treatment must be followed 
clinically until the follow-up safety visit (Day 38-50).  Subjects withdrawn secondary to 
an ongoing study drug-related SAE must be followed clinically until resolution or 
stabilization 
2. Insufficient therapeutic effect requiring alternative systemic antibacterial treatment for 
the current IAI  
If a subject has been discharged from the hospital and refuses to return to the investigational site 
for scheduled evaluations, but is willing to undergo follow-up investigations, clinical response 
data, safety data, and concomitant medication information may be collected by telephone and/or 
through medical records.   


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9.4.2 
Withdrawal from Study Protocol 
Subjects who wish to discontinue study drug treatment should be encouraged to complete the 
TOC and FU visits after their last study drug administration.  If they choose to withdraw from 
the study completely, the reason for withdrawal should be recorded on the appropriate page(s) of 
the eCRF.  Reasons for withdrawal from the study may include, but are not limited to, the 
following: 
1. Significant subject noncompliance, defined as refusal or inability to adhere to the 
prescribed dosing and follow-up regimens 
2. Subject lost to follow-up 
3. At the request of the subject, investigator, or study sponsor 
9.5 
Replacement of Subjects 
Subjects who are randomized and withdraw prematurely from study will not be replaced.   
9.6 
Prior and Concomitant Medication 
Prior administration of systemic antibacterial agents effective in cIAI is allowed only in the 
following circumstances: 
≤ 24-h of continuous antibacterial drug therapy for cIAI during the 72-h preceding 
enrollment.  However, subjects with documented cIAI (ie, known baseline pathogen) who 
have received at least 72-h of systemic antibiotic therapy and are considered treatment 
failures may be enrolled. Treatment failure is defined as persistent fever and/or clinical 
symptoms; or the development of a new intra-abdominal abscess after ≥ 72-h of antibiotic 
therapy. 
The following concomitant medications are not permitted while on study therapy: 
• Valproic acid and divalproex sodium 
• Concomitant systemic antibacterials effective in cIAI are not permitted after the initial 
dose of study medication until the completion of the FU visit.   
 
All other concomitant medications necessary for the health and wellbeing of a subject will be 
permitted.  All concomitant medications will be recorded on the appropriate eCRF page. 
10. 
STUDY PROCEDURES 
Please also review the entire protocol, including the Schedule of Assessments and appendices, for 
additional details. 
10.1 
General Procedures 
10.1.1 
Temperature 
Temperatures should be recorded orally, rectally, aurally using a tympanic thermometer, or by 
temporal artery.  Axillary temperatures are not allowed. Temperature should be assessed prior to 
the initial dose of study drug and then q8h ± 1-h while hospitalized until EOT. 


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10.1.2 
Abdominal Examination 
A thorough clinical examination of the abdomen is to be performed at specified time points. 
Abdominal pain, tenderness to palpation, rebound tenderness, guarding, mass, and ascites will 
be assessed and severity graded as none, mild, moderate, or severe according to the following 
definitions: 
None: 
No signs or symptoms 
Mild: 
Awareness of signs and symptoms, but easily tolerated 
Moderate: Signs or symptoms of enough intensity to cause interference with usual activity 
Severe: 
Signs and symptoms of enough intensity that incapacitate and interfere with 
usual activity 
Other pertinent findings should be recorded, including inability to tolerate oral or enteral intake 
and presence or absence of ileus. 
 
The clinical abdominal examination will include an assessment of the surgical wound (if 
applicable).  The surgical wound examination will assess signs of infection such as: skin 
erythema, induration, tenderness, warmth to touch, fluctuance, swelling, and superficial wound 
pain.  If signs of infection are present, findings will be recorded and graded as mild, moderate, 
or severe according to the definitions above.  If present, the nature of any discharge (eg, 
purulent, serous, bloody, etc.) will be assessed and the drainage cultured if clinically indicated. 
10.1.3 
Safety Laboratory Tests 
Safety laboratory tests for this study (chemistry, hematology, coagulation, and urinalysis) are to 
be performed by a central laboratory, and only values from the central laboratory are to be 
entered into the laboratory section of the study database.  Values from local laboratories may be 
used to determine eligibility for study enrollment and as the basis for clinical decisions.  See 
Appendix 2: Central Safety Laboratory Tests for the complete list of safety laboratory tests. 
10.1.4 
ECGs 
Standard 12-lead ECGs are to be recorded with the subject in the supine position when indicated 
by the protocol. 
10.1.5 
Microbiologic Specimen Collection 
Appropriate aerobic and anaerobic specimens for culture at the time of the initial surgical 
procedure (or during re-intervention in the case of prior treatment failures) should be collected 
from the site of infection and directly inoculated into culture media during the surgical 
intervention; microbiologic specimens collected during routine operative care prior to subject 
consent may be used for study purposes.  For subjects that enter the study as a documented cIAI 
treatment failure (ie, with a known baseline pathogen), reasonable attempts should be made to 
provide the baseline isolates to the central laboratory.  The specimens should be representative of 
the material associated with the clinical infection.  Every effort should be made to collect 
specimens via a tissue biopsy or aspirate.  Samples collected by swabs are allowed only if it is 
not possible to collect tissue samples or aspirated fluid.  Samples collected from superficial 
swabs and abdominal drains are not allowed.  These specimens will be cultured and the species 
will be identified by the local or regional laboratory.  All purified isolate(s) will be sent to a 
central, reference laboratory at time points determined by the Sponsor for confirmation of 


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species identification and susceptibility analysis to eravacycline and meropenem.  Specific 
instructions for sample collection, processing, and shipment can be found in the laboratory 
manual(s) for this study. 
10.1.6 
Blood Cultures 
Aerobic and anaerobic blood cultures will be obtained at two separate sterile venipuncture sites 
prior to initiation of clinical trial drug therapy.  Upon knowledge of a positive culture for a 
pathogen, blood cultures should be repeated until sterile (ie, both sets of cultures from two 
separate venipuncture sites are negative for pathogens) through the FU visit.  If baseline cultures 
are negative, follow-up cultures should be obtained only if clinically indicated (eg, signs and 
symptoms of persistence, relapse, or new infection).      
These specimens will be cultured and the species will be identified by the local or regional 
laboratory.  All purified pathogen(s) will be sent to a central reference laboratory at time points 
determined by the Sponsor for confirmation of species identification and antimicrobial 
susceptibility analysis, including to study drugs. Specific instructions for sample collection, 
processing, and shipment can be found in the laboratory manual(s) for this study. 
10.1.7 
Radiologic Assessment 
Radiologic evaluation may be performed as part of the pre-operative diagnosis or if surgical 
re-intervention is clinically indicated.  Copies of all radiographic study reports will be collected 
and copies of the films or images may be requested as deemed necessary by the Sponsor. 
NOTE: If randomization is planned pre-operatively then radiographic evidence congruent with 
the diagnosis of cIAI is required. 
10.1.8 
Clinical Response 
Clinical outcome assessments will be made at the EOT, TOC, and FU visits.  Clinical responses 
will be classified as Clinical Cure, Clinical Failure, or Indeterminate/Missing based on clinical 
outcomes.  A favorable clinical response is “Clinical Cure.” 
Clinical response categories are defined below. 
10.1.8.1 Clinical Cure 
Clinical Cure is defined as complete resolution or significant improvement of signs or symptoms 
of the index infection such that no additional antibacterial therapy, surgical, or radiological 
intervention (eg, an ultrasound guided drainage) is required.  Routine imaging procedures (eg, an 
investigational ultrasound) are not considered radiological interventions. 
10.1.8.2 Clinical Failure 
Subjects are classified as a Clinical Failure based on: 
▪ Death related to cIAI  
▪ Persistence of clinical symptoms of cIAI 
▪ Unplanned surgical procedures or percutaneous drainage procedures for complication or 
recurrence of cIAI 


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▪ Post-surgical wound infections requiring systemic antibiotics 
▪ Initiation of rescue antibacterial drug therapy for treatment of cIAI 
 
Clinical Failures are to be documented by obtaining an appropriately performed wound or deep 
site culture, if feasible. 
10.1.8.3 Indeterminate/Missing 
If the subject’s outcome is neither Clinical Cure nor Clinical Failure then the outcome should be 
listed as “Indeterminate/Missing.”  The reason for an “Indeterminate/Missing” designation must 
be provided.  Study data are listed as “Indeterminate/Missing” if the Investigator did not 
complete an assessment or if the study visit was not conducted.  Deaths not related to cIAI will 
be considered “Indeterminate/Missing.” 
10.2 
Time Point Specific Procedures 
10.2.1 
Screening 
All potential study participants will undergo a screening evaluation.  Clinical assessments and 
local laboratory results performed during the subject’s hospitalization (within 48-h of screening) 
may be used to establish eligibility.  If any of the required screening assessments defined below 
were not performed, they must be performed prior to determining eligibility.  Screening may 
occur on the first day of dosing and will include the following activities: 
1. Obtain a signed informed consent:  Procedures performed as standard of care prior to signing 
the informed consent may be used to determine eligibility.  Informed consent must be 
obtained prior to performing any study specific procedures that are not standard of care; 
however, microbiologic specimens collected during routine operative care prior to subject 
consent may be used for study purposes. 
2. Clinical assessments: 
▪ Complete pertinent medical history including approximate time of onset and type of 
symptoms related to current condition (eg, abdominal pain, past surgeries, allergies, and 
known viral/bacterial diseases) 
▪ Complete physical examination, including: temperature, resting vital signs, height and 
weight. 
▪ Abdominal examination 
▪ 12-lead ECG 
▪ Prior and concomitant medication assessment: record both day and time for all 
antibiotics administered in the preceding 72-h  
3. Laboratory Assessments: 
▪ Safety Laboratory Tests (chemistry, hematology, coagulation, and urinalysis) 
▪ Calculate creatinine clearance (Cockcroft-Gault formula): 
𝑒𝐶𝐶𝑟[𝑚𝐿/𝑚𝑖𝑛] =
(140 −𝐴𝑔𝑒 [𝑦𝑟𝑠]) ×  𝐵𝑜𝑑𝑦 𝑊𝑒𝑖𝑔ℎ𝑡 [𝑘𝑔] × [0.85 𝑖𝑓 𝐹𝑒𝑚𝑎𝑙𝑒]
72 ×  𝑆𝑒𝑟𝑢𝑚 𝐶𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 [𝑚𝑔𝑑𝐿
⁄
]
 
4. Serum pregnancy test (women of childbearing potential only) 
NOTE: If a serum pregnancy test is not available at the investigator site then a urine 
pregnancy test may be utilized locally. 
5. APACHE II assessment 


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▪ Serum bicarbonate can be used in place of arterial blood gases for the completion of the 
APACHE II assessment.   
6. Microbiological assessments: 
▪ Obtain specimens for culture and in vitro susceptibility testing of all aerobic and 
anaerobic organisms considered to be pathogens from the following sites: 
- Site of infection during surgical intervention (should be taken with direct inoculation 
of sample into culture media) 
o Every effort should be made to collect specimens via a tissue biopsy or 
aspirate.  Samples collected by swabs are allowed only if it is not possible to 
collect tissue samples or aspirated fluid.  Samples collected from superficial 
swabs and abdominal drains are not allowed.  
- Blood cultures  
Specific instructions for sample collection, processing, and shipment can be found in the 
laboratory manual(s) for this study. 
7. Radiologic Assessment (at Investigator’s discretion): 
Perform a radiologic evaluation as part of the pre-operative diagnosis (computed 
tomography (CT) scan, ultrasound, and/or magnetic resonance imaging (MRI) scan), 
with or without contrast. Radiologic confirmation of cIAI is required in order for a 
subject to qualify for pre-operative enrollment.  Copies of all operative procedure notes,   
diagnostic study reports, as well as reports associated with percutaneous drainage 
procedure will be collected. 
8. Determine eligibility 
10.2.2 
Randomization and Enrollment of Subjects  
Once an informed consent is obtained and study eligibility is established, a blinded study site 
member will obtain a subject number and a study drug assignment for each subject from a 
computer-generated randomization scheme using an interactive web-based response system 
(IWRS).  Randomization to eravacycline (1.0 mg/kg q12h) or meropenem (1 g q8h) treatment 
arms will occur in a 1:1 ratio. For this study, enrollment is considered to occur at the time a 
subject is randomized.  Randomization will be stratified based on primary site of infection (ie, 
complicated appendicitis versus all other cIAI diagnoses).  No more than approximately 50% of 
subjects enrolled should have complicated appendicitis.   
The study will include approximately 75 sites.  No site should enroll more than 35 subjects.  
Each investigative site should enroll no more than 1 complicated appendicitis subject for every 2 
subjects enrolled into the study at their site.  A site specific change to the ratio of ‘complicated 
appendicitis: other cIAI diagnoses’ or to the total number of subjects that may be enrolled at any 
one site may be granted by the Sponsor. 
10.2.3 
Dose Cycle 1 
If Dose Cycle 1 and Screening occur on the same day the resting vital signs, abdominal 
examination, and safety laboratories do not need to be repeated. 
1. Assessments prior to the First Study Drug Administration: 
▪ Record temperature 
▪ Resting vital signs 
▪ Safety Laboratory tests (chemistry, hematology, coagulation, urinalysis) 


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▪ Calculate creatinine clearance (Cockcroft-Gault formula): 
𝑒𝐶𝐶𝑟[𝑚𝐿/𝑚𝑖𝑛] =
(140 −𝐴𝑔𝑒 [𝑦𝑟𝑠]) ×  𝐵𝑜𝑑𝑦 𝑊𝑒𝑖𝑔ℎ𝑡 [𝑘𝑔] × [0.85 𝑖𝑓 𝐹𝑒𝑚𝑎𝑙𝑒]
72 ×  𝑆𝑒𝑟𝑢𝑚 𝐶𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 [𝑚𝑔𝑑𝐿
⁄
]
 
▪ Abdominal examination 
▪ AE assessment 
▪ Concomitant medication assessment 
▪ PK sampling in accordance with Schedule of Assessments and Appendix 3:  Blood PK 
Sample Collection, Handling, Preparation and Shipping 
▪ Blood cultures (if indicated)  
2. IV Study Drug Infusions 
▪ Study drug administration per dosing schedule 
3. Assessments after the First Study Drug Administration: 
▪ PK sampling in accordance with Schedule of Assessments and Appendix 3:  Blood PK 
Sample Collection, Handling, Preparation and Shipping  
▪ Resting vital signs  
▪ Temperature every 8-h 
▪ AE assessment 
▪ Concomitant medication assessment 
4. Radiologic evaluation (if deemed necessary by the investigator) 
10.2.4 
Dosing Cycles 2 and 3 
1. Clinical Assessments:  
▪ Temperature every 8-h 
▪ Resting vital signs 
▪ Abdominal examination 
▪ AE assessment 
▪ Concomitant medication assessment 
2. Laboratory Assessments:  
▪ Safety Laboratory tests (chemistry, hematology) 
▪ Blood cultures (if indicated) 
▪ Intra -abdominal cultures (if indicated) 
▪ Calculate creatinine clearance (Cockcroft-Gault formula): 
𝑒𝐶𝐶𝑟[𝑚𝐿/𝑚𝑖𝑛] =
(140 −𝐴𝑔𝑒 [𝑦𝑟𝑠]) ×  𝐵𝑜𝑑𝑦 𝑊𝑒𝑖𝑔ℎ𝑡 [𝑘𝑔] × [0.85 𝑖𝑓 𝐹𝑒𝑚𝑎𝑙𝑒]
72 ×  𝑆𝑒𝑟𝑢𝑚 𝐶𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 [𝑚𝑔𝑑𝐿
⁄
]
 
3. IV Study Drug Infusions 
▪ Study drug administration per dosing schedule.  
4. Radiologic evaluation (if deemed necessary by the investigator) 
10.2.5 
Dosing Cycles 4 through 14 - while subject is on study drug 
1. Clinical Assessments:  
▪ Temperature every 8-h  
▪ Daily resting vital signs  
▪ Daily abdominal examination 
▪ AE assessment 
▪ Concomitant medication assessment 
▪ Evaluate subject’s requirement for continuation of study drug 
 


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2. Laboratory Assessments:  
▪ Safety laboratory tests (chemistry, heamatology) on Dosing Cycle 4 and repeated every 
3 dosing cycles while subject is on study drug 
▪ Calculate creatinine clearance (Cockcroft-Gault formula) on Dosing Cycle 4 and 
repeated every 3 dosing cycles while subject is on study drug: 
𝑒𝐶𝐶𝑟[𝑚𝐿/𝑚𝑖𝑛] =
(140 −𝐴𝑔𝑒 [𝑦𝑟𝑠]) ×  𝐵𝑜𝑑𝑦 𝑊𝑒𝑖𝑔ℎ𝑡 [𝑘𝑔] × [0.85 𝑖𝑓 𝐹𝑒𝑚𝑎𝑙𝑒]
72 ×  𝑆𝑒𝑟𝑢𝑚 𝐶𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 [𝑚𝑔𝑑𝐿
⁄
]
 
▪ Blood cultures (if indicated) 
▪ Intra -abdominal cultures (if indicated) 
3. IV Study Drug Infusions 
• Study drug administration per dosing schedule 
4. Radiologic evaluation (if deemed necessary by the investigator) 
 
10.2.6 
End-of-Therapy (EOT), Test of Cure (TOC) and Follow-Up (FU) 
The EOT, TOC, and FU procedures are to be performed at premature withdrawal or treatment 
failure and within 24-h of the last dose of study drug, 25-31 days after the initial dose of study 
drug, and 38-50 days after the initial dose of study drug, respectively. 
1. Clinical Assessments:  
▪ Complete physical examination, including temperature and resting vital signs 
▪ Abdominal examination 
▪ Clinical response assessment 
▪ AE assessment 
▪ 12-lead ECG at EOT visit only 
▪ Concomitant medication assessment 
▪ Radiologic evaluation (if deemed necessary by the investigator) 
2. Laboratory Assessments: 
▪ Safety laboratory tests 
- Chemistry, hematology, and coagulation (including fibrinogen)  
- Urinalysis at EOT visit only  
▪ Serum pregnancy test (women of childbearing potential only) 
NOTE: If a serum pregnancy test is not available at the investigator site then a urine 
pregnancy test may be utilized locally. 
▪ Blood culture (if indicated) 
▪ Intra -abdominal cultures if indicated 
10.3 
Study Drug Administration 
10.3.1 
Study Drug Infusions and Dosing Schedule 
Both eravacycline and meropenem, when prepared for infusion, are colored solutions.  The two 
drugs require different infusion volumes.  The dosing interval for meropenem is every 8-h.  For 
eravacycline, the dosing interval is every 12-h.  For these reasons, this study has been designed 
using double-dummy methodology.   
During each 24-h dosing cycle, the subject will receive five infusions according to Table 3 
below.   


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Table 3: Study Drug Infusion Scheme of a 24-h Dosing Cycle 
INFUSION 
TREATMENT ARM 
Eravacycline 
1.0 mg/kg q12h 
Meropenem 
1 g q8h 
1st Dose (of Dosing Cycle) 
final volume (mL)a 
wt(kg) ÷ 0.3 
wt(kg) ÷ 0.3 
drug 
amount (mg) 
Eravacycline 
wt(kg) x 1.0  
Placebo 
N/A 
conc (mg/mL)b 
0.3 
N/A 
infusion time (min)c 
60 ± 10 
60 ± 10 
2nd Dose (of Dosing Cycle) 
final volume (mL) 
50 
50 
drug 
amount (mg) 
Placebo 
N/A 
Meropenem 
1000 
conc (mg/mL) 
N/A 
16.7 
infusion time (min) 
30 ± 5 
30 ± 5 
3rd Dose (of Dosing Cycle) 
final volume (mL) 
50 
50 
drug 
amount (mg) 
Placebo 
N/A 
Meropenem 
1000 
conc (mg/mL) 
N/A 
16.7 
infusion time (min) 
30 ± 5 
30 ± 5 
4th Dose (of Dosing Cycle) 
final volume (mL)a 
wt(kg) ÷ 0.3 
wt(kg) ÷ 0.3 
drug 
amount (mg) 
Eravacycline 
wt(kg) x 1.0  
Placebo 
N/A 
conc (mg/mL)b 
0.3 
N/A 
infusion time (min)c 
60 ± 10 
60 ± 10 
5th Dose (of Dosing Cycle) 
final volume (mL) 
50 
50 
drug 
amount (mg) 
Placebo 
N/A 
Meropenem 
1000 
conc (mg/mL) 
N/A 
16.7 
infusion time (min) 
30 ± 5 
30 ± 5 
a Final infusion volume per bag must not exceed 500 mL  
b Concentration may be decreased as long as the total infusion volume does not exceed 500 mL  
c Infusion time may be increased to 120 minutes per IV bag 
All solutions for infusion will be prepared by an unblinded pharmacist or designee.  Specific 
instructions for preparation of study drugs are included in the Pharmacy Manual for this study.  
The eravacycline-matched placebo will consist of sterile normal saline (0.9% NaCl).  The 
meropenem-matched placebo will consist of sterile normal saline (0.9% NaCl).  


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Figure 1: Study Drug Infusion Scheme of a 24-h Dosing Cycle 
 
The 2nd Dose of a dosing cycle will be started immediately following the completion of the 1st 
Dose of the dosing cycle.  The 3rd Dose of the dosing cycle will be started 8-h following the start 
of the 2nd Dose of the dosing cycle. The 4th Dose of the dosing cycle will be started 12-h 
following the start of the 1st Dose of the dosing cycle. The 5th Dose of the dosing cycle will be 
started 8-h following the start of the 3rd Dose of the dosing cycle. (See Figure 1 above) 
The interval between the 1st Doses of adjacent 24-h dosing cycle can be reduced by up to 4 hours 
after each of the first two 24-h dosing cycles to allow for a more practical infusion schedule for 
the duration of therapy. After the third 24-h dosing cycle, the allowable administration window 
for each infusion is ± 1 h. 
In the event the Investigator considers the subject a Clinical Cure and it is not necessary to 
complete the entire dose cycle, study drug can be discontinued at any time after the 
administration of the 2nd Dose. This is to ensure that the study subject has received one infusion 
of study drug and its placebo-matched infusion. 
10.3.2 
Meropenem and Meropenem-Matched Placebo Dose Adjustment 
Meropenem dosing should be reduced in subjects with a creatinine clearance of 50 mL/min or 
less in accordance with the dosage and administration instructions found in the meropenem 
package insert. 
While a creatinine clearance of ≤ 50 mL/min is exclusionary at Screening; it is possible that a 
subject’s creatinine clearance may change while on study.  Investigators are instructed to locally 
calculate creatinine clearance at the Screening Visit, Dose Cycle 1 through Dose Cycle 4, and 
every three 24-h dosing cycles thereafter while on study drug (eg, Dose Cycle 7, Dose Cycle 10, 
and Dose Cycle 13). 
If at any time after Screening the locally calculated creatinine clearance is ≤ 50 mL/min then the 
subject’s meropenem and/or meropenem-matched placebo must be dose-adjusted in accordance 
with the meropenem package insert.  Thereafter, each time the creatinine clearance is calculated 
locally the meropenem and/or meropenem-matched placebo must be dose-adjusted in accordance 
with the meropenem package insert.  Specific instructions for the dose adjustments of 
meropenem and/or meropenem-matched placebo are included in the meropenem package insert 
and the Pharmacy Manual for this study. 
10.3.3 
Treatment Compliance 
The date, start and stop times, and volumes used in each infusion of study drug, will be recorded.  
These detailed records will be used to document compliance. 


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If an infusion administration is inadvertently delayed, the infusion must be started as soon as 
possible.  No infusion should be “missed” regardless of how long it may have been delayed. 
A complete dose cycle is defined as all five doses for a dosing cycle. 
Subjects will be considered compliant with study drug treatment if they do not miss more than 
20% of the expected study drug infusions, as defined by the interval between the first and last 
dose.   
10.3.4 
Guidance to Investigators for Determining When to End Therapy 
In accordance with guidelines, subjects are expected to remain on study drug treatment for a 
minimum of four 24-h dosing cycles (unless subject is a treatment failure or cure) and for a 
maximum of 14 dosing cycles.  Study drug treatment should be continued until resolution of 
infection signs and symptoms is documented, such as: 
▪ Maximum temperature (oral, rectal, tympanic, or by temporal artery) has been < 100.4˚F 
/ 38˚C for 24-h  
▪ Improvement of abdominal signs and symptoms presenting at study entry 
▪ A return of bowel function and restoration of oral/enteral intake 
Any subject requiring longer than seven 24-h dosing cycles of study drug therapy should be 
discussed with the Medical Monitor.     
10.4 
Specific Restrictions/Requirements 
Study drug must only be administered while subjects are hospitalized.  All subjects must have an 
EOT assessment, and return to investigational sites for TOC and FU assessments unless they 
have withdrawn consent.   
10.4.1 
Avoidance of Pregnancy 
10.4.1.1 
Instructions for Male Subjects 
There is no information on the effects of eravacycline on the development of the fetus in 
humans. Therefore, it is important that the partners of male subjects do not become pregnant 
during the study and for a total period of 14 days after the male subject has received the last dose 
of study drug. 
Subjects should avoid fathering a child by either being abstinent or only engaging in intercourse 
with an effective barrier method of contraception. 
Since there is a risk of drug being secreted in the ejaculate, subjects (including men who have 
had vasectomies) whose partners are currently pregnant should use barrier methods for the 
duration of the study and for two weeks afterwards. This is to ensure that the fetus is not exposed 
to the investigational product in the ejaculate. 
10.4.1.2 Instructions for Female Subjects 
Females of childbearing potential are eligible for enrollment in this study. There is no 
information on the effects of eravacycline on the development of the fetus in humans. Therefore, 


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it is important that female subjects enrolled into the study do not become pregnant during the 
study and for a total period of 14 days after the subject has received the last dose of study drug. 
Females of childbearing potential  must commit to either: (1) Using at least two medically 
accepted, effective methods of birth control (eg, condom, spermicidal gel, oral contraceptive, 
indwelling intrauterine device, hormonal implant /patch, injections, approved cervical ring) 
during study drug dosing and for 14 days following last study drug dose, or (2) sexual 
abstinence. 
10.4.2 Pregnancy 
Pregnancy is considered an immediately reportable event (but not an adverse event), and the 
investigator will record information concerning the pregnancy on the appropriate form and 
submit it to the Medical Monitor within 24-h of learning of a subject’s pregnancy.  Study drug 
administration will be stopped in any female subject who becomes pregnant while participating, 
and the subject will be followed to determine the outcome of the pregnancy. All pregnancies in 
the female partners of male subjects receiving at least one dose of eravacycline will be recorded 
from first dose to the last study visit. 
10.4.2.1 Follow-up in the Event of a Pregnancy 
The ethics committee and the Sponsor will be informed of all pregnancies in study subjects and 
in partners of male subjects. 
The subject will be asked to provide information on the outcome of the pregnancy, including 
premature termination should the case arise. Spontaneous miscarriages and congenital 
abnormalities will be reported as serious adverse events (SAEs). Information on the status of the 
mother and child will be forwarded to the Medical Monitor or designee. Generally, follow up 
will be in accordance with regulatory guidance and at least 6-8 weeks after the estimated 
delivery date. Any premature termination of the pregnancy will be reported. 
10.5 
Study Discontinuation/Termination Criteria 
The study Sponsor reserves the right to terminate this clinical study or participation of an 
investigative site at any time.  Reasons for study discontinuation/termination may include, but 
are not limited to, the following: 
1. Incidence and/or severity and composition of AEs in this or other studies indicate a potential 
health hazard to subjects 
2. Sponsor’s decision to discontinue investigation in a specific therapeutic area 
3. Subject enrollment is unsatisfactory 
4. An investigator requests to withdraw from participation 
5. Serious and/or persistent noncompliance by the investigator with the protocol, clinical 
research agreement, Form FDA 1572, or applicable regulatory guidelines in conducting the 
study 
6. IRB/IEC decision to terminate or suspend approval for the investigation or an investigator 
7. Untimely input of data into eCRFs 
8. Low pathogen recovery rate from microbiologic samples 


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11. 
QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 
Quality Control 
11.1.1 
Monitoring 
The Sponsor, or designee(s), will monitor the study for compliance to the protocol, applicable laws 
and regulations, and Good Clinical Practice.  The monitor(s) will verify data on the electronic case 
report form versus source data.  The monitor is also responsible for ensuring that the proper records 
are maintained.  Monitoring reports will be issued for each monitoring visit. 
11.2 
Quality Assurance 
Quality assurance personnel may audit the clinical trial sites and/or study-related materials at any 
time during the study. 
12. 
ASSESSMENT OF SAFETY 
Safety will be assessed through AEs, physical examinations, vital signs, ECGs, and the 
collection of central laboratory data (ie, chemistry, hematology, coagulation, and urinalysis). The 
Principal Investigator and designated study staff are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
12.1 
Definitions 
12.1.1 
Adverse Event 
An adverse event is any adverse experience in a subject administered a pharmaceutical product, 
whether or not it is considered drug-related, that occurs during a subject’s study participation 
(defined as after the time of initial informed consent).  This would include any side effect, injury, 
toxicity, sensitivity reaction, intercurrent illness, or sudden death.  A pre-existing condition is 
one that is present at study entry and is reported as part of the subject’s medical history.  It 
should be reported as an AE if the frequency, intensity, or character of the condition worsens 
during study drug treatment. Subjects should be instructed to report all AEs to the investigator or 
study staff.  Adverse events must be appropriately documented in the subject’s original source 
documents and entered into the eCRF.  Investigators should report syndromes rather than list 
symptoms.  Treatment failure (e.g. recurrent cIAI) is not considered an AE. 
12.1.2 
Adverse Drug Reaction (ADR) 
An adverse drug reaction (ADR) is any untoward and unintended response in a subject to an 
investigational medicinal product which is related to any dose administered to that subject. 
12.1.3 
Serious Adverse Event (SAE) 
An SAE is any AE, occurring at any dose and regardless of causality that: 
• Results in death. 
• Is life-threatening.  Life-threatening means that the subject was at immediate risk of death 
from the reaction as it occurred (ie, it does not include a reaction which hypothetically 
might have caused death had it occurred in a more severe form). 


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• Requires inpatient hospitalization or prolongation of existing hospitalization.  
Hospitalization admissions and/or surgical operations scheduled to occur during the study 
period, but planned prior to study entry, are not considered AEs if the illness or disease 
existed before the subject was enrolled in the trial, provided that it did not deteriorate in an 
unexpected manner during the study (eg, surgery performed earlier than planned). 
• Results in persistent or significant disability/incapacity.  Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
• Is a congenital anomaly/birth defect. 
• Is an important medical event.  An important medical event is an event that may not result 
in death, be life-threatening, or require hospitalization but may be considered an SAE 
when, based upon appropriate medical judgment, it may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in the 
definitions for SAEs.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
Clarification should be made between the terms “serious” and “severe” since the terms ARE 
NOT synonymous.  The term “severe” is often used to describe the intensity (severity) of a 
specific event (as in mild, moderate, or severe myocardial infarction); the event itself, however, 
may be of relatively minor medical significance (such as a severe headache).  This is NOT the 
same as “serious,” which is based on subject/event outcome or action criteria described above, 
and is usually associated with events that pose a threat to a subject’s life or functioning.  A 
severe AE does not necessarily need to be considered serious.  For example, persistent nausea of 
several hours duration may be considered severe nausea but not an SAE.  On the other hand, a 
stroke resulting in only a minor degree of disability may be considered mild, but would be 
defined as an SAE based on the above noted criteria.  Seriousness (not severity) serves as a guide 
for defining regulatory reporting obligations. 
Events that result from lack of efficacy of study drug (eg, treatment failure, ongoing cIAIs, 
wound infections requiring antibiotics, recurrence of abscesses) are not considered SAEs and as 
such prolonged hospitalizations, etc. for these events will not be considered SAEs. 
12.1.4 
Unexpected Adverse Reactions 
An adverse reaction is ‘unexpected’ if its nature and severity are not consistent with the 
information about the medicinal product in question set out in the most recent Investigator’s 
Brochure relating to the trial in question or the product information for meropenem. 
12.2 
AE Collecting and Reporting 
All AEs spontaneously reported by the subject and/or in response to an open question from study 
personnel or revealed by observation, physical examination or other diagnostic procedures will 
be recorded on the appropriate page of the eCRF starting from the time of initial informed 
consent.  Any clinically relevant deterioration in laboratory assessments or other clinical findings 
is considered an AE and must be recorded on the appropriate pages of the eCRF starting from the 
time of initial informed consent.  When possible, signs and symptoms indicating a common 
underlying pathology should be noted as one comprehensive event. 


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All SAEs that occur during the course of the study, as defined by the protocol, must be reported 
by the Investigator to the Sponsor or its pharmacovigilance designee/contract research 
organization (CRO) within 24-h from the point in time when the Investigator becomes aware of 
the SAE.  In addition all SAEs, including all deaths, which occur from the time of signing of the 
informed consent up to and including 30 days after administration of the last dose of study drug, 
must be reported to the Sponsor or its designated CRO within 24-h.  All SAEs and deaths must 
be reported whether or not considered causally related to the study drug.  The information 
collected will include a minimum of the following: Subject number, a narrative description of the 
event and an assessment by the Investigator as to the intensity of the event and relatedness to 
study drug.  Follow-up information on the SAE may be requested by Tetraphase or its 
representative CRO.  Detailed instructions for the collecting and reporting of SAEs will be 
provided in the Investigator Site File.  
If there are serious, unexpected ADRs associated with the use of the study drug, the Sponsor or 
its designated CRO will notify the appropriate regulatory agency(ies) and all participating 
Investigators on an expedited basis (7 days for fatal or life-threatening serious, unexpected 
ADRs; 15 days for all other serious, unexpected ADRs).  The Sponsor has delegated the 
responsibility to promptly notify the IRB/IEC of all unexpected serious ADRs involving risk to 
human subjects in accordance with the rules and regulations of the IRB/IEC to the Principal 
Investigator.  
An unexpected event is one that is not reported in the IB. 
Reporting of SAEs and SUSARs 
All SAEs must be reported to the designated CRO within 24-h of the investigational site’s 
knowledge of the occurrence.  Each investigational site will submit the SAE information to the 
CRO.   
The SAE information transmitted to the CRO will include the following (as available): 
▪ Subject ID, investigator name, and site number 
▪ SAE information: event term, onset date, severity, and casual relationship 
▪ Basic demographic information (eg, age, gender, weight, etc.) 
▪ The outcomes attributable to the event [eg, death, a life-threatening adverse drug 
experience, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant disability/incapacity, other important medical event(s)] 
▪ A summary of relevant test results, pertinent laboratory data, and any other relevant 
medical history 
▪ The first and last dates of study drug administration 
▪ A statement whether study drug was discontinued or study drug administration schedule 
was modified 
▪ A statement whether event recurred after reintroduction of study drug if administration had 
been discontinued or withheld 
▪ Supplemental information may include the following hospital records: laboratory results, 
radiology reports, progress notes, admission and emergency room notes, 
holding/observation notes, discharge summaries, autopsy reports, and death certificates 


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The SAE information should be transmitted within 24-h with as much of the above information 
as available at the time.  Supplemental information may be transmitted and should not delay the 
initial transmission.  The Sponsor or CRO may contact the investigational site to solicit 
additional information or follow-up on the event.  Investigational sites will be provided with 
detailed instructions on the procedures for transmitting SAEs to the CRO. 
For regulatory purposes, initial reports of serious ADRs should be transmitted within the 
prescribed time frame as long as the following minimum information is available: subject 
identification, suspect study drug, reporting source, and an event or outcome that can be 
identified as being both serious and unexpected for which, in the investigator’s opinion, there is a 
suspected causal relationship.  
A suspected unexpected serious adverse reaction (SUSAR) which is fatal or life-threatening must 
be reported to the competent authority and ethics committee immediately (within 7 days) after 
the Sponsor becomes aware of the event.  Any additional information must be reported within 
eight days of sending the first report.  
A SUSAR which is not fatal or life-threatening must be reported to the competent authority and 
ethics committee as soon as possible (within 15 days) after the Sponsor becomes aware of the 
event. 
All SUSARs occurring at the site will be entered into the European database established in 
accordance with Article 11 of the EU Clinical Trials Directive. 
12.3 
Grading of Adverse Events 
The severity of each AE will be categorized using the following criteria: 
Mild AE usually transient and requires no special treatment and does not interfere with 
the subject’s daily activities. 
Moderate AE produces a low level of inconvenience to the subject and may interfere with 
daily activities.  These events are usually ameliorated by simple therapeutic 
measures. 
Severe AE interrupts daily activity and requires systemic drug therapy or other medical 
treatment. 
Key: AE = adverse event 
 
12.4 
Relationship to Study Drug 
For each reported AE, the investigator must make an assessment of the relationship of the event 
to the study drug using the following scale: 
Not Related: An event that is definitely not associated with study drug administration and is 
judged clearly due to causes other than the study drug. 
Unlikely Related: An event that follows a temporal sequence from administration of the study 
drug, such that, a relationship is not likely and could be reasonably explained by the subject's 
clinical state, or other modes of therapy administered to the subject. 


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Possibly Related: An event that follows a reasonable temporal sequence from administration of 
the study drug, but that, may be due to another cause and could also be reasonably explained by 
the subject's clinical state, or other modes of therapy administered to the subject. 
Probably Related: An event that follows a reasonable temporal sequence from administration of 
the study drug, that is not easily explained by another cause (such as, known characteristics of 
the subject’s clinical state or other treatment) and is confirmed by improvement on stopping or 
slowing administration of the study agent (ie, de-challenge, if applicable). 
Definitely Related: An event that is clearly associated with study drug administration.   
In the event of death, the cause of death should be recorded as the AE.  “Death” is an outcome 
and is NOT the AE.  The only exception is “sudden death” when the cause is unknown. 
12.5 
Laboratory Test Abnormalities 
Clinically significant abnormal laboratory findings that are detected during the study or are 
present at baseline and significantly worsen will be reported as adverse events or SAEs. The 
Investigator will exercise his or her medical and scientific judgment in deciding whether an 
abnormal laboratory finding or other abnormal assessment is clinically significant.  
 
Clinical significance is at the discretion of the Investigator and may be defined as those findings 
which: 
• Are directly responsible for discontinuation from the study, 
• Require treatment or other therapeutic intervention, 
• Require further monitoring, or 
• Require further diagnostic evaluation (other than repeat of the same test to confirm the 
abnormality). 
 
All abnormal laboratory values considered to be clinically significant will be recorded on the 
adverse event page of the eCRF. Significant abnormal laboratory values occurring during the 
clinical study will be followed until repeat tests return to normal, stabilize, or are no longer 
clinically significant. 
 
All central laboratory data generated by the study will be included in the final study database. 
Throughout this study, subjects will have samples sent to local laboratories and to the central 
laboratory.  Only the values from the samples sent to the central laboratory will be captured in 
the study database and used for the safety analysis.  Investigators may report AEs based upon 
local laboratory values.  In this event, the actual value and the normal range for the local 
laboratory should be recorded on the AE form.  
12.6 
Follow-up of Adverse Events 
All AEs (regardless of relationship to study drug) and SAEs determined not to be study drug 
related (ie, not related and unlikely related) will be followed through the FU visit and be noted as 
“continuing” if not resolved at this visit.  Any SAE that is determined to be study drug related 
(possibly, probably, or definitely related) will be followed to resolution or stabilization. Subjects 
will be referred to their primary care doctor for further follow-up as needed post-study. 


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The outcome of AEs will be rated as: 
• Recovered/Resolved 
• Recovering/Resolving 
• Not Recovered/Not Resolved 
• Recovered/Resolved with Sequelae 
• Fatal 
• Unknown 
13. 
EVALUATION OF EFFICACY 
13.1 
Analysis Populations 
The following definitions will be used in assigning subjects into analysis populations: 
• Intent-to-treat (ITT) population – all subjects who are randomized 
• All Treated (MITT) Population - all randomized subjects who receive any amount of study 
drug. Analyses in this population are based on the treatment arm the subject was 
randomized to. 
• Safety Population - all randomized subjects who receive any amount of study drug. 
Analyses in this population are based on the treatment the subject actually received. 
• Microbiological intent-to-treat (micro-ITT) population – all randomized subjects who have 
at least one baseline bacterial pathogen that causes cIAI and against which the 
investigational drug has in vitro antibacterial activity 
• Clinically evaluable (CE) – all subjects in the ITT population who meet key 
inclusion/exclusion criteria and follow other important components of the trial 
• Microbiologically evaluable (ME) – all subjects in the micro-ITT population who meet key 
inclusion/exclusion criteria and follow other important components of the trial 
 
13.2 
Efficacy Evaluations 
The primary efficacy evaluation, clinical response at the TOC visit, will be conducted in the 
micro-ITT population. 
The following secondary evaluations will be performed: 
▪ Clinical response at EOT, TOC, and FU visits in the following populations: 
- ITT 
- MITT 
- CE 
- Micro-ITT (EOT and FU) 
- ME 
▪ Microbiologic responses at EOT and TOC visits in the following populations: 
- Micro-ITT  
- ME 
▪ PK parameters after eravacycline infusion, including 
- Cmax, Tmax, AUC0-12 


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13.2.1 
Clinical Response 
Clinical outcome assessments will be made at the EOT, TOC, and FU visits.  Clinical response 
will be classified by the investigator as Clinical Cure, Clinical Failure, or Indeterminate/Missing.  
Subjects who are assessed as a Clinical Failure at the EOT Visit will have the failure carried 
forward to the TOC Visit. Subjects who are assessed as a Clinical Failure at the TOC Visit will 
have the failure carried forward to the FU Visit.  For those subjects reviewed by the Surgical 
Adjudication Committee (SAC) (see Section 14.2.5), the committee assessment of clinical 
response will be used for analysis.  A favorable clinical response is “Clinical Cure”.   
13.2.2 
Per Pathogen Microbiological Outcomes 
Microbiological outcome assessments will be made at the EOT and TOC visits. 
Per-pathogen microbiologic response categories are eradication, presumptive eradication, 
persistence, persistence with decreased susceptibility, presumed persistence, and 
indeterminate/missing and are defined as follows: 
• Eradication – Absence of causative organism from an appropriately obtained specimen at 
the site of infection at each timepoint 
• Presumptive eradication – Absence of material to culture in a subject who has responded 
clinically to treatment (clinical cure) 
• Persistence – Continued presence of the original pathogen in cultures from the original 
site of infection or blood culture obtained during or upon completion of therapy  
• Persistence with decreased susceptibility – Continued presence of the original pathogen 
in cultures from the original site of infection obtained during or upon completion of 
therapy, and the MIC for the study drug received of the pathogen is > 2-fold (as least 2 
dilutions) higher than that of the original isolate 
• Presumed persistence – Absence of material to culture in a subject who is given 
additional antibiotics to treat the study entry cIAI (clinical failure) 
• Indeterminate/Missing – Culture not obtained and clinical response is indeterminate/ 
missing 
These categories will be further classified as follows: 
• Favorable 
o Eradicated 
o Presumed eradicated 
• Unfavorable 
o Persistence 
o Persistence with decreased susceptibility 
o Presumed persistence 
• Indeterminate/Missing 


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All bacterial isolates cultured from aerobic and anaerobic specimens will be evaluated for 
susceptibility to study drugs and the emergence of resistance and overgrowth of non-susceptible 
organisms.  
 
13.2.3 
Per-Subject Microbiological Response 
Per-subject microbiological response will be determined by the per pathogen microbiological 
outcomes. To have an overall per-subject favorable microbiologic response, the outcome for 
each baseline pathogen must be favorable (eradicated or presumed eradicated). If the outcome 
for any pathogen is unfavorable (persistence, persistence with decreased susceptibility or 
presumed persistence), the subject will be considered to have an unfavorable per-subject 
microbiologic response.  
14. 
STATISTICAL METHODS 
A detailed Statistical Analysis Plan (SAP) will be used to guide the analysis and reporting of data 
collected in this study.   
14.1 
Data Collection and Processing 
An IWRS will be used to allocate treatment assignments to subjects.  Creation and validation of 
the clinical database, data entry, data management, and transfer of central laboratory data will be 
conducted in accordance with 21 Code of Federal Regulations (CFR) Part 11 and the Guidance 
for Industry on Computerized Systems Used in Clinical Trials. 
eCRFs will be completed for all randomized subjects. Please refer to the CRF Completion 
Guidelines for instructions on which eCRFs will be completed for subjects who are randomized 
but not treated.  
14.2 
Statistical Methodology 
All data collected in this study will be presented in data listings and, where indicated, tabulated 
in summary tables.  Data will be presented and summarized using the SAS System (SAS Institute 
Inc, Cary, NC). 
Continuous variables will be summarized with the number of observations, mean, standard 
deviation, median, minimum, and maximum.   
Categorical variables will be summarized with frequencies and percentages.  Percentages will be 
based on non-missing data unless specified otherwise.   
Except where indicated in the SAP, Baseline is defined as the closest value prior to the start of 
treatment with study drug. 
14.2.1 
Efficacy Analyses 
The primary efficacy outcome measure is clinical response at the TOC Visit (incorporating the 
SAC assessment) in the micro-ITT population. The number and percentage of subjects in each 
treatment group defined as a clinical cure, clinical failure, and indeterminate/missing will be 


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tabulated. A 2-sided 95% CI for the observed difference in clinical cure rates (eravacycline 
treatment group minus meropenem treatment group) will be calculated using the method without 
stratification of Miettinen and Nurminen.  If the lower limit of the 95% CI for the difference in 
clinical cure rates in the micro-ITT population exceeds -12.5%, then non-inferiority of 
eravacycline to meropenem will be declared.  The primary efficacy outcome will also be 
assessed across the randomization stratification factor of primary site of infection.  For each site 
of infection stratum, a 2-sided 95% CI for the observed difference in clinical cure rates at the 
TOC Visit will be calculated for the micro-ITT population. The number and percentage of 
subjects in each treatment group with a secondary efficacy outcome (the SAC assessment of 
clinical response will be used, if available) of clinical cure, clinical failure, and 
indeterminate/missing will be presented for the following time points and analysis populations: 
• EOT Visit – ITT, MITT, CE, micro-ITT and ME populations 
• TOC Visit – ITT, MITT, CE and ME populations 
• FU Visit 
– ITT, MITT, CE, micro-ITT and ME populations 
Two-sided 95% unstratified CIs will be constructed for the observed difference in the clinical 
cure rates between the treatment groups for descriptive purposes; no conclusion of NI will be 
made. Analyses at the TOC Visit will also be presented by primary site of infection at baseline. 
Per-subject microbiological response will be summarized as favorable (eradicated, presumed 
eradicated), unfavorable (persistence, persistence with decreased susceptibility, presumed 
persistence), and indeterminate/missing at the EOT and TOC Visits in the Micro-ITT and ME 
Populations. Two-sided 95% unstratified CIs will be constructed for the observed difference in 
the rates of favorable response between the treatment groups for descriptive purposes; no 
conclusion of NI will be made. 
Microbiologic response by baseline pathogen will be determined as the proportion of subjects 
with a favorable microbiologic response (eradication or presumed eradication) at the TOC Visit 
for each pathogen isolated at baseline. The number and percentage of subjects in each treatment 
group with a microbiologic favorable outcome will be tabulated for the micro-ITT and ME 
populations. 
14.2.2 
Safety Analyses 
All safety analyses will be conducted in the Safety population.   
Verbatim descriptions of AEs will be coded using a current version of MedDRA.  Summary 
tables will be provided for all treatment-emergent adverse events (TEAEs).  A treatment-
emergent AE is defined as any AE that newly appeared, increased in frequency, or worsened in 
severity following initiation of study drug.  The number and percentage of subjects reporting a 
TEAE in each treatment group will be tabulated by system organ class and preferred term; by 
system organ class, preferred term, and severity; and by system organ class, preferred term, and 
relationship to study drug. The number and percentage of subjects reporting a SAE and reporting 
a TEAE leading to premature discontinuation of study drug in each treatment group will be 
summarized by system organ class and preferred term. For all analyses of TEAEs, if the same 
AE (based on preferred term) is reported for the same subject more than once, the AE is counted 
only once for that preferred term and at the highest severity and strongest relationship to study 


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drug.  Clinically relevant abnormal physical examination results are recorded as AEs and thus, 
physical exam data will not be summarized in a table. 
Descriptive statistics for hematology, chemistry, and coagulation data will be summarized by 
treatment group and time point, and for the overall worst value post-baseline.  Toxicity grades 
will be determined based on the modified DMID criteria and shift tables will be presented.  The 
number and percentage of subjects with at least a two grade increase from baseline (based on 
DMID criteria) will be summarized by treatment arm. 
Descriptive statistics of the change from baseline for vital signs will be summarized by treatment 
group and time point. Abnormal values, identified by threshold values defined in the SAP, will 
be summarized. 
Descriptive statistics for ECG parameters at baseline and the EOT Visit, and the change from 
baseline will be presented by treatment group.  QTcB at the EOT Visit and the increase from 
baseline for QTcB will be categorized and summarized by treatment group. 
14.2.3 
Sample Size Considerations 
This study is designed to demonstrate non-inferiority of 1.0 mg/kg q12h eravacycline to 
meropenem in the primary outcome measure of clinical response at the TOC Visit in the micro-
ITT Population.  An NI margin of 12.5% will be used, which is based on historical data 
regarding the treatment effect of antibiotics and the results of the previously completed 
eravacycline phase 3 cIAI study.  A 12.5% NI margin for the outcome measure of clinical 
response is robust and can sufficiently confirm a clinically meaningful treatment effect of 
eravacycline in the treatment of cIAI.   
The sample size calculation is based on ensuring sufficient power for the primary efficacy 
outcome for the FDA as well as the primary efficacy outcome for the EMA (which are secondary 
efficacy outcomes for the FDA).  Estimations of cure rates and numbers of subjects in the micro-
ITT population come from the recent phase 3 study with eravacycline in cIAI in which 
ertapenem was used as the comparator.  Clinical cure rates in the micro-ITT population at the 
TOC Visit were 86.8% and 87.6% in the eravacycline and ertapenem groups, respectively, with 
82.4% of randomized subjects included in the micro-ITT population.  Thus, it is reasonable to 
assume that the true rate of clinical cure at the TOC Visit will be at least 84% in the eravacycline 
group and 85% in the meropenem group. Based upon the results of the pre-specified blinded 
assessment of the actual number of subjects in the micro-ITT population following completion of 
the 250th subject, the evaluability rate is assumed to be 68.75%. 
Using a 12.5% non-inferiority margin, one-sided alpha of 0.025, 80% power, response rates of 
84% in the eravacycline group and 85% in the meropenem group, and the methodology of 
Farrington and Manning, a total of 161 subjects per arm in the micro-ITT population is required. 
A sample size of approximately 466 randomized subjects should provide sufficient numbers for 
this study, assuming 68.75% of enrolled subjects will meet the requirements for inclusion in the 
micro-ITT population. 
For the EMA, the rates of clinical cure in the phase 3 study were approximately 87% in the 
MITT population and 93% in the CE-TOC population.   Assuming clinical cure rates of 84% in 
the eravacycline group and 85% in the meropenem group in the MITT population and 89% in the 
eravacycline group and 90% in the meropenem group in the CE-TOC population, an NI margin 
of 12.5%, a one-sided alpha of 0.025, evaluability rates of 95% for the MITT population and 


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85% for the CE-TOC population, and the methodology of Farrington and Manning, there is more 
than 90% power in both the MITT population and the CE population to show non-inferiority 
with a sample size of 466 enrolled subjects.   
14.2.4 
Handling of Missing Data 
Details of the handling of missing data will be provided in the SAP. For the primary and secondary 
outcome measures of clinical response, subjects will be defined as an indeterminate/missing 
response if the investigator cannot determine whether the subject is a clinical cure or failure, 
including if the subject is lost to follow-up or misses the assessment.  By definition, subjects with 
an indeterminate/missing response are included in the denominator in the microITT and MITT 
populations and thus, are analyzed in the same manner as clinical failures.  Subjects with an 
indeterminate/missing response are excluded from the CE and ME populations.  For microbiologic 
response, if no post-baseline source specimen is obtained and the subject has an investigator's 
assessment of clinical response, the microbiologic response is based on the investigator's 
assessment of clinical response.  A microbiologic response will be considered 
indeterminate/missing only if the clinical response is indeterminate/missing. 
14.2.5 
Surgical Adjudication Committee (SAC) 
Adequate surgical source control is critical to the successful treatment of cIAIs.  An independent 
SAC will be established to review cases for all subjects classified as a clinical failure at any visit 
and all subjects classified as clinical cure at TOC or FU who undergo a second surgical 
procedure.   
The SAC will review these cases, assess the adequacy of surgical source control, evaluate the 
investigators’ clinical assessments, and either concur with the investigators’ assessment of 
clinical response or re-classify the clinical response in accordance with the rules specified in the 
SAC Charter. 
For additional information regarding the composition of the committee, roles and responsibilities 
of its members, working procedures, and decision rules refer to the SAC Charter.   
14.3 
Interim Analysis 
No interim analysis is planned for this study. 
15. 
STUDY DRUG MATERIALS 
15.1 
Study Drug Nomenclature 
TP-434 is the active ingredient in eravacycline drug product.  The chemical name of TP-434-046 
(bis HCl salt form) is: [(4S,4aS,5aR,12aS)-4-(dimethylamino)-7-fluoro-3,10,12,12a-
tetrahydroxy-1,11-dioxo-9-(2-(pyrrolidin-1-yl)ethanamido)-1,4,4a,5,5a,6,11,12a-
octahydrotetracene-2-carboxamide]bis-hydrochloride.  The molecular formula for the free base is 
C27H31FN4O8, and the molecular weight is 558.56.  Eravacycline is a yellow to orange solid that 
is soluble in water.   


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15.2 
Study Drug Preparation 
15.2.1 Reconstitution 
All study medications will be prepared for IV infusion by an unblinded pharmacist or his/her 
designee. Detailed instructions for the preparation of study drug are provided in the Pharmacy 
Manual for this study.   
The eravacycline drug product will be reconstituted using sterile WFI and will be diluted using 
0.9% NaCl.  Reconstituted eravacycline should be a “clear yellow solution” with no visible 
particulates in the vial.  Once WFI is added to eravacycline vials, swirl each vial gently until the 
drug dissolves completely (it should take approximately 1 to 2 minutes to achieve a clear yellow 
solution). 
The meropenem drug product will be prepared by the unblinded pharmacist according to the 
instructions in the meropenem package insert and will use 0.9% sodium chloride for 
reconstitution and normal saline for dilution. 
The unblinded pharmacist or his/her designee will provide the investigator with ready-to-use 
blinded infusion solutions for administration at scheduled study drug infusion times. It is the 
responsibility of the pharmacist/designee to maintain the blind of the infusion solutions.  
15.2.2 Administration 
In the event of discomfort and/or pain due to infusion, the following actions can be taken at the 
Investigators’ request: 
For the 1st Dose and 3rd Dose in any dosing cycle (in the following recommended order): 
• Decrease concentration (as long as total volume does not exceed 500 mL) 
• Increase length of infusion to 120 minutes per IV bag 
For the 2nd, 3rd, and 5th Dose in any dosing cycle: 
• Follow standard of care and meropenem package insert 
 
15.3 
Study Drug Storage 
Study drugs must be stored in a restricted access area under the storage conditions indicated on 
the product label and in the Pharmacy Manual.  For further details, please consult the Pharmacy 
Manual. 
 
15.4 
Study Drug Packaging and Labeling 
Packaging: 
▪ Eravacycline 
See Section 15.2. Eravacycline will be packaged according to current GMP and GCP 
guidelines. 
▪ Meropenem 
Meropenem for IV administration will be supplied in bulk in the original vials, which 
will be repackaged for the purposes of the study. Meropenem will be provided with study 


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specific labeling.  Purchased and repackaged meropenem will be packaged according to 
current GMP and GCP guidelines. 
Labeling: 
The study medication will be labeled according to the requirements of local law and legislation 
as well as current GMP and GCP guidelines.  Proof labels, detailing actual label text, will be 
available in the study files of all participating countries. 
15.5 
Study Drug Comparator 
Meropenem is a carbapenem antibiotic that has been approved for the treatment of cIAI.  The 
recommended dose is 1 g q8h for this indication.  Please consult the local prescribing product 
information for important information regarding warnings, precautions and AEs reported with 
the use of this product.   
15.6 
Study Drug Accountability 
It is the responsibility of the unblinded pharmacist to ensure that a current record of 
inventory/drug accountability is maintained.  Inventory records must be readily available for 
inspection by the unblinded study monitor and are open to inspection by the FDA or other 
regulatory authorities at any time.  For further details, please consult the Pharmacy Manual.   
15.7 
Study Drug Handling and Disposal 
Upon the completion or termination of the study, and upon written authorization from the 
Sponsor or its representative, all unused and/or partially used study drug must be destroyed at the 
investigative site or returned to a central drug depot, as instructed by the Sponsor or its 
representative.  It is the investigator’s responsibility to ensure that the Sponsor or its 
representative has provided written authorization for study drug destruction, that procedures for 
proper disposal of the study drug have been established, and that appropriate records of the 
disposal are documented and maintained. 
15.8 
Investigator’s Breaking of the Blind 
The study drug treatment assignment will be unblinded only in emergency situations when 
knowledge of the treatment received is absolutely necessary for management of the subject or 
when it is in the best interest of the subject. The investigator has unrestricted and immediate 
access to unblind the treatment code. The instructions for unblinding a subject can be found in 
the IWRS study manual. 
In the event unblinding is necessary, the investigator is encouraged but not required to contact 
the appropriate Medical Monitor to discuss the situation and the subject’s medical status.   
When a subject’s treatment assignment is unblinded, a comprehensive source note must be 
completed by the unblinding investigator that includes the date and time and the reason(s) the 
subject’s treatment code was unblinded. In the event the investigator chooses to discuss the 
unblinding with the Medical Monitor, the source note must also include a record of the 
discussion.  


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It is mandatory that all personnel who are involved in the unblinding and who have access to the 
unblinded treatment assignment information maintain the confidentiality of the information by 
not divulging the randomization code. 
16. 
INVESTIGATOR REQUIREMENTS 
16.1 
AE Collection and Reporting 
The Investigator’s responsibilities include the following: 
▪ Monitor and record all AEs, including SAEs, regardless of the severity or relationship to 
study treatment 
▪ Determine the seriousness, relationship and severity of each event 
▪ Determine the onset and resolution dates of each event 
▪ Monitor and record all pregnancies and follow up on the outcome of the pregnancy 
▪ Transmit SAE information to the designated CRO within 24-h of the study site staff 
becoming aware of new information 
▪ Ensure all AE and SAE information are supported by documentation in the subjects’ 
medical records 
▪ Report SAEs to local ethics committees, as required 
 
16.2 
Protocol Adherence 
Each investigator must adhere to the protocol as detailed in this document and agree that any 
changes to the protocol must be approved by the Sponsor prior to seeking approval from the 
IRB/IEC.  Each investigator will be responsible for enrolling only those subjects who have met 
the protocol inclusion and exclusion criteria. The Sponsor and/or its representative reserves the 
right to close sites when appropriate [eg, in instances where the protocol is not being followed; 
untimely input of data into eCRFs; under-enrollment (less than 1 subject per quarter); or low 
microbiological evaluability rate]. 
16.3 
Case Report Forms 
Electronic CRFs will be supplied by the Sponsor, or its representative, for the recording of all 
study data as specified by this protocol.  eCRFs should be handled in accordance with 
instructions from the Sponsor, or its representative.  eCRFs must be completed by the designated 
study personnel.  It is the responsibility of the principal investigator to ensure that accurate 
eCRFs are completed in a timely manner. 
16.4 
Source Document Maintenance 
Source documents are defined as the results of original observations and activities of a clinical 
investigation.  Source documents may include, but are not limited to, study progress notes, email 
correspondences, computer printouts, laboratory data, and recorded data from automated 
instruments.  All source documents produced in this study will be maintained by the 
investigator(s) and made available for inspection by Sponsor representatives and/or regulatory 
authorities.  The original signed informed consent form for each participating subject shall be 
filed with records kept by the investigator(s) and a copy given to the subject. 


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16.5 
Study Monitoring Requirements 
Site visits will be conducted by the Sponsor or authorized Sponsor representatives to inspect 
study data, subject’s medical records, and CRFs in accordance with ICH guidelines, GCPs, and 
the respective U.S. or foreign regulations and guidelines, as applicable. 
The investigator will permit representatives of the Sponsor and/or regulatory authorities the 
ability to inspect facilities and records relevant to this study. 
16.6 
Study Completion 
The Sponsor requires the following data and materials before a study can be considered complete 
or terminated: 
1. Laboratory findings, clinical data, and all special test results from screening through the end 
of the study follow-up period. 
2. eCRFs properly completed by appropriate study personnel and signed and dated by the 
investigator. 
3. Complete Drug Accountability records (drug inventory log and an inventory of returned or 
destroyed clinical material). 
4. Copies of protocol amendments and IRB/IEC approval/notification, if appropriate. 
17. 
PROTECTION OF HUMAN SUBJECTS AND GENERAL STUDY 
ADMINISTRATION 
This study will be conducted in compliance with the ICH E6 GCP (consolidated guidelines and 
the ethical principles of the Declaration of Helsinki), and any additional national or IRB/IEC-
required procedures. 
17.1 
Informed Consent 
This study will be conducted in compliance with ICH E6 GCP (consolidated guidelines 
pertaining to informed consent).  At the first visit, prior to initiation of any study-related 
procedures, subjects will give their written consent to participate in the study after having been 
informed about the nature and purpose of the study, participation/termination conditions, and 
risks and benefits. Clinical assessments and local laboratory results performed during the 
subject’s hospitalization (within 48-h of screening) may be used to establish eligibility, and 
microbiologic specimens collected during routine operative care prior to subject consent may be 
used for study purposes. 
For subjects with diminished decision-making capacity and where applicable law permits, a 
Legally Authorized Representative (LAR) may consent on behalf of a prospective subject to the 
subject’s participation in the procedure(s) involved in this research study.  Subjects should be re-
consented in cases where their capacity to make decisions has returned. 
In case of significant changes to safety, the subject will be re-consented.  A copy of the signed 
consent document or a second original must be given to the representative/ proxy consenter.  The 
original signed consent document will be retained by the investigator.  Local legal requirements 
must be observed and informed consent must be sought from the subject as soon as possible 


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afterwards, if feasible.  This procedure must have prior agreement from the IEC/IRB.  If 
applicable, the informed consent will be provided in a certified translation for non-English 
speaking subjects.  Signed consent forms must remain in the subject’s study file and be available 
for verification by Sponsor personnel or regulatory agency at any time. 
17.2 
IRB/IEC Approval 
This protocol, the informed consent document, and all relevant supporting data must be 
submitted to the IRB/IEC for approval.  IRB/IEC approval of the protocol, informed consent 
document, and any advertisement used to recruit study subjects must be obtained before the 
study may be initiated. 
17.3 
Subject Data Protection 
Prior to any testing under this protocol, including screening tests and assessments, candidates 
must also provide all authorizations required by local law (eg, Protected Health Information 
[PHI] authorization in North America). 
The subject will not be identified by name in the eCRF or in any study reports, and these reports 
will be used for research purposes only.  The Sponsor and designee(s) and various government 
health agencies may inspect the records of this study.  Every effort will be made to keep the 
subject’s personal medical data confidential. 
18. 
DATA MANAGEMENT AND MONITORING 
Training sessions, regular monitoring of investigators by sponsor-designated personnel, 
instruction manuals, data verification, cross-checking, and data audits will be performed to 
ensure quality of all study data.  Investigator meetings will be performed to prepare investigators 
and other study personnel for appropriate collection of study data. 
The Sponsor will perform internal and/or external audits of study data. 
It will be the responsibility of the investigator(s) to assure that essential laboratory and pharmacy 
manuals are available at the investigator/institutional site.  Any or all of these documents may be 
subject to, and should be available for, audit by the Sponsor’s auditor and/or inspection by 
regulatory authorities. 
18.1 
Direct Access to Source Data/Documents 
The investigator agrees by his/her participation that the results of this study may be used for 
submission to national and/or international registration and supervising authorities.  If required, 
these authorities will be provided with the names of investigators, their addresses, qualifications, 
and extent of involvement.  It is understood that the investigator is required to provide the 
Sponsor with all study data, complete reports, and access to all study records.   
Data generated by this study must be available for inspection by any regulatory authorities, by 
the Sponsor, and the IRB/IEC as appropriate.  At a subject’s request, medical information may 
be given to his or her personal physician or other appropriate medical personnel responsible for 
his or her welfare.  Subject medical information obtained during the course of this study is 
confidential and disclosure to third parties other than those noted above is prohibited. 


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18.2 
Retention of Records 
U.S. Investigational New Drug (IND) exemption regulations require that records and documents 
pertaining to the conduct of this study and the distribution of investigational drugs including 
CRFs, consent forms, laboratory test results, and medication inventory records must be kept on 
file by the principal investigator for a minimum of two years after notification by the Sponsor 
that a marketing application has been approved for eravacycline [Code of Federal Regulations, 
Title 21, Part 312, Section 62(c)].  If no application is filed or approved, these records must be 
kept for two years after the investigation has been discontinued and the U.S. FDA and applicable 
foreign authorities have been notified.  The Sponsor will notify the investigator of these events.  
No study records should be destroyed without prior authorization from the Sponsor.  This study 
will be conducted under a U.S. IND; for study sites outside the United States, the investigator 
must comply with U.S. FDA IND regulations and with those of the relevant national and local 
regulatory authorities. 
19. 
FINANCING AND INSURANCE 
The financing and insurance for this study are outlined in the Clinical Trial Agreement and must 
comply with all local and national rules and regulations. 
20. 
PUBLICATION POLICY 
The publication policy is outlined in the Clinical Trial Agreement.  The data generated in this 
clinical trial are the exclusive property of Tetraphase Pharmaceuticals Inc. and are confidential.  
Written approval from Tetraphase is required prior to disclosing any information related to this 
clinical trial. 
21. 
REFERENCES 
 
[1] Solomkin, J.S., et al., "Diagnosis and management of complicated intra-abdominal infection 
in adults and children: guidelines by the Surgical Infection Society and the Infectious 
Diseases Society of America," Clin Infect Dis, vol. 50, no. 2, pp. 133-164, 2010.  
[2] Grossman, T.H., Murphy, T., Slee, A., Lofland, D., Sutcliffe, J.A., Eravacycline (TP-434) is 
efficacious in animal models of infection, Antimicrob Agents Chemother, 2015.  
[3] Brown, R. and B. Bhyravbhatla, "Computational analysis of eravacycline binding to the 
ribosome A-site," Xtal Biostructures, Natick, MA, July 24, 2008. 
[4] Solomkin, J.S., Ramesh, M.K., Cesnauskas, G., Novikovs, N., Stefanova, P., Sutcliffe, J.A., 
Walpole, S.M., Horn, P.T., "Phase 2, randomized, double-blind study of the efficacy and 
safety of two," Antimicrob Agents Chemother, vol. 58, no. 4, pp. 1847-1854, 2014.  
[5] Sawi, J., "In vitro Evaluation of TP-034 as an Inducer of Cytochrome P450 Expression in 
Cultured Human Hepatocytes," XenoTech, LLC, Report No.: XT153026, November 2015. 
[6] Isringhausen, C., "In Vitro Evaluation of TP-034 as an inhibitor and a Substrate of Human 
P-gp, BCRP, BSEP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1 and 
MATE2-K Transporters," XenoTech, LLC, Report No.: XT158063, October 2015. 
 
 


Tetraphase Pharmaceuticals, Inc. 
Clinical Protocol TP-434-025 
20 March 2017 
 
Version 2.0 
Confidential 
Page 56 of 58 
APPENDIX 1: APACHE II SCORE 
Acute Physiology Score (APS) 
High Abnormal Range 
Normal 
Low Abnormal Range 
Points 
+4 
+3 
+2 
+1 
0 
+1 
+2 
+3 
+4 
1. 
Temperature rectal or tympanic (°C) 
Add 0.5°C if oral 
≥41 
39-40.9 
 
38.5-38.9 
36.0-38.4 
34-35.9 
32-33.9 
30-31.9 
≤29.9 
 
2. 
Mean arterial pressure (mmHg) 
≥160 
130-159 
110-129 
 
70-109 
 
50-69 
 
≤49 
 
3. 
Heart rate (ventricular response) 
≥180 
140-179 
110-139 
 
70-109 
 
55-69 
40-54 
≤39 
 
4. 
Respiratory rate (non-ventilated or 
ventilated) 
≥50 
35-49 
 
25-34 
12-24 
10-11 
6-9 
 
<5 
 
5. 
Oxygenation:AaDO2 or PaO2 (mmHg) 
i. if FiO2>0.5, record AaDO2 
≥500 
350-499 
200-349 
 
<200 
 
 
 
 
 
 
ii. if FiO2<0.5, record PaO2 
 
 
 
 
>70 
61-70 
 
55-60 
<55 
6. 
Arterial pH  
If no ABGs record Serum HCO3 below 
≥7.7 
7.6-7.69 
 
7.5-7.59 
7.33-7.49 
 
7.25-7.32 
7.15-7.24 
<7.15 
 
Not preferred, use ONLY if no ABGs  
Serum HCO3 (venous-mMol/L)  
<52 
41-51.9 
 
32-40.9 
22-31.9 
 
18-21.9 
15-17.9 
<15 
7. 
Serum Sodium (mMol/L) 
≥180 
160-179 
155-159 
150-154 
130-149 
 
120-129 
111-119 
≤110 
 
8. 
Serum Potassium (mMol/L) 
≥7 
6-6.9 
 
5.5-5.9 
3.5-5.4 
3-3.4 
2.5-2.9 
 
<2.5 
 
9. 
Serum Creatinine (mg/dL)  
Double points for acute renal failure 
≥3.5 
2-3.4 
1.5-1.9 
 
0.6-1.4 
 
<0.6 
 
 
 
10. 
Hematocrit (%) 
≥60 
 
50-59.9 
46-49.9 
30-45.9 
 
20-29.9 
 
<20 
 
11. 
White Blood Count (k/mm3) 
≥40 
 
20-39.9 
15-19.9 
3-14.9 
 
1-2.9 
 
<1 
 
12. 
Glasgow Coma Scale (see below) 
(Score = 15 minus actual GCS) 
15 – GCS = 
 
 
 
Total APS Points 
Sum of the 12 individual variable points 
A 
 
Age Points 
 
Age 
Points 
 
≤44 
0 
 
45-54 
2 
 
55-64 
3 
 
65-74 
5 
 
≥75 
6 
Total Age 
Points 
B 
APACHE II Score 
(A + B +C) 
APS Points 
A 
Age Points 
B 
CHE Points 
C 
Total APACHE 
II Score 
 
Chronic Health Evaluation (CHE) 
If “yes” give +5 for non-operative or emergency postoperative subjects 
and give +2 if elective postoperative subjects 
Liver 
    Cirrhosis with PHT or encephalopathy 
 
Cardiovascular 
    Class IV angina or at rest or with minimal self-care activities 
 
Pulmonary 
    Chronic hypoxemia or hypercapnia or polycytaemia of PHT > 40 mmHg 
 
Kidney 
    Chronic peritoneal or hemodialysis 
 
Immune System 
    Immune compromised host 
 
Total CHE Points C 
Glasgow Coma Scale 
(Circle Appropriate Responses) 
Eyes open 
Verbal - nonintubated 
4 - spontaneously 
5 - oriented 
3 - to speech 
4 - confused 
2 - to pain 
3 - inappropriate words 
1 - no response 
2 - incomprehensible sounds 
 
1 - no response 
 
Motor response 
Verbal - intubated 
6 - to verbal command 
5 - seems able to talk 
5 - localizes to pain 
3 - questionable ability to talk 
4 - withdraws to pain 
1 - generally unresponsive 
3 - flexion to pain 
2 - extension to pain 
1 - no response 


Tetraphase Pharmaceuticals, Inc. 
              Clinical Protocol TP-434-025                       
20 March 2017 
Version 2.0 
Confidential 
Page 57 of 58 
APPENDIX 2: CENTRAL SAFETY LABORATORY TESTS 
 
Hematology: 
Hemoglobin  
Neutrophils 
Hematocrit  
Lymphocytes 
Erythrocyte count (RBC)  
Monocytes 
Mean cell volume (MCV)  
Eosinophils 
Mean cell hemoglobin (MCH)  
Basophils 
Mean cell hemoglobin concentration (MCHC)  Platelets 
Leukocyte count (WBC) 
 
Coagulation: 
Prothrombin time  
Partial thromboplastin time 
Fibrinogen 
 
Urinalysis:  
pH  
Ketones 
Protein  
Bilirubin 
Glucose  
Urobilinogen 
Urine microscopy (RBC, WBC, crystals, and casts) 
 
Clinical Chemistry: 
Magnesium  
Lactic dehydrogenase (LDH) 
Bicarbonate  
Total and indirect bilirubin 
Sodium  
Total cholesterol 
Potassium  
Glucose, non-fasting 
Phosphorus  
Total protein 
Chloride  
Albumin 
Calcium  
Creatinine 
Alkaline phosphatase  
Urea nitrogen 
Gamma-glutamyl transferase (GGT)  
Uric acid 
Alanine aminotransferase (ALT/GPT)  
Amylase 
Aspartate aminotransferase (AST/GOT)  
Lipase 
Creatine kinase (CK) 
Serum pregnancy test (women of childbearing potential only) 
NOTE: If a serum pregnancy test is not available at the investigator site then a urine pregnancy test 
may be utilized locally. 
 
 
 


Tetraphase Pharmaceuticals, Inc. 
              Clinical Protocol TP-434-025                       
20 March 2017 
Version 2.0 
Confidential 
Page 58 of 58 
APPENDIX 3:  BLOOD PK SAMPLE COLLECTION, HANDLING, 
PREPARATION AND SHIPPING 
 
The timelines and procedures for PK sampling, handling, dispatch, and analysis are detailed in 
the Central Laboratory Manual.  
 
Dose Cycle 1 - PK Sampling Schedule 
Time 
PK 
Sample 
Number 
30 – 0 min prior to the start of the 1st Dose of Dose Cycle 1 
1 
 End of infusion of the 1st Dose of Dose Cycle 1 (± 2 min) 
2 
+3-h post the start of the 1st Dose of Dose Cycle 1a 
3 
+7-h post the start of the 1st Dose of Dose Cycle 1a 
4 
30 – 0 min prior to the start of the 4th Dose of Dose Cycle 1  
5 
a PK sample must be collected within ± 10 minutes of target time.   
 
 
 
 

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