Effects of IV Omadacycline on Gut Microbiome
Phase: PHASE4
Conditions: Microbial Colonization
Sponsor: Wake Forest University Health Sciences

Omada microbiome
IRB00081259
NCT05515562
IRB Approval Date:  24APR2023

Omadacycline IV Microbiome Study 
Version: 2.0 
Version date: 24APR2023 
1 
Protocol Synopsis 
Title: Effects of IV Omadacycline on Gut Microbiome  
Version: 2.0 
Protocol Number: 001 
Version Date: 24APR2023 
Principal investigator: John C. Williamson, PharmD 
Accrual Target: 8 participants 
Population: Healthy participants between ages 18 and 40 years. 
Regimen: Participants will receive a 10-day course of omadacycline with 5 days of 
intravenous therapy followed by 5 days of oral therapy.  
Study Duration: 
Length of study: Approximately 12 months from First Participant First Visit to 
Last Participant Last Visit. 
Length of participation of study participants: Up to 36 days. 
Locations:  
University of Houston College of 
Pharmacy  
Laboratory and Data Analysis Center 
Jinhee Jo, Chenlin Hu, Anne J 
Gonzales-Luna, Khurshida Begum, 
M Jahangir Alam, and Kevin W. 
Garey 
High Point University Fred Wilson 
School of Pharmacy 
Recruitment Center 
Travis Carlson, PharmD 
Wake Forest University Health Sciences 
at Atrium Health Wake Forest Baptist 
Data and Sample Collection Center; IRB of 
record 
John Williamson, PharmD 

Omadacycline IV Microbiome Study 
Version: 2.0 
Version date: 24APR2023 
2 
 
1.0 STUDY OBJECTIVES  
 
 Primary Objective: 
To characterize the impact of 5 days of IV omadacycline followed by 5 days of 
oral omadacycline on the gut microbiome of healthy volunteers.  
 
2.0 BACKGROUND AND SCIENTIFIC RATIONALE 
 
Clostridioides difficile infection is a major health threat in the United States that is most 
often an outcome of perturbation of gut microbiota following antibiotic use [1]. Even the 
limited number of antibiotic regimens effective in the treatment of C. difficile infection 
have the ability to impact gut microbiome in a negative way and may increase the risk of 
relapse due to such perturbations [2,3,4]. Thus, there is an increasing need to identify 
candidate therapies for C. difficile that target this pathogen but have minimal effect on the 
native gut microbiome.  
 
Omadacycline is an aminomethylcycline tetracycline antibiotic that is approved by the 
US Food and Drug Administration (FDA) for the treatment of community-acquired 
bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections 
(ABSSSI) [5]. A recent study demonstrated in vitro activity of omadacycline against C. 
difficile [6].  
 
Given the clinical need to improve upon current antibiotic regimens for the treatment of 
C. difficile infection with a particular focus on the impact of therapies on gut microbiome, 
we propose this study to characterize the impact of IV omadacycline on gut microbiome 
of healthy volunteers. We plan to enroll healthy volunteers between the ages of 18 and 40 
years old and without history of cardiovascular, gastrointestinal, hepatic, or renal disease 
to receive 5 days of intravenous omadacycline followed by 5 days of oral omadacycline.  
 
2.1 Reproductive and Developmental Toxicity 
Based on animal data, there is reasonable suspicion that omadacycline has the potential to 
cause fetal harm [5,7]. We will only enroll females of childbearing potential who are not 
pregnant at baseline and who agree to use a reliable method of birth control or remain 
abstinent. Additionally, females of childbearing potential who use hormone-based oral 
contraceptives (OCs) will be required to use a second form of birth control (e.g. condom) 
because of a possible drug interaction with omadacycline which may lower the 
effectiveness of OCs. 
 
 

Omadacycline IV Microbiome Study 
Version: 2.0 
Version date: 24APR2023 
3 
3.0 PATIENT SELECTION  
 
3.1 Selection Criteria 
 
*Potential study volunteers who are excluded due to probiotic or antibiotic consumption may be 
re-screened at a later date when outside the exclusionary window(s). 
 
 
Investigator 
Signature 
 
Date of Signature 
(DDMMMYYYY) 
 
 
 
# 
Yes 
No Inclusion Criteria 
1 
 
 Is aged 18-40 years. 
2 
 
 Is willing and able to comply with all study procedures including providing 
informed consent, and visiting the ID Clinical Trials Center at Wake Forest 
Baptist Medical Center at the specified times to receive study medication and/or 
to deliver samples (must have reliable transportation). 
3 
 
 Is considered healthy, without history of cardiovascular, gastrointestinal, 
hepatic, or renal disease. 
4 
 
 Meets one of the three categories below:  
 1. Is female and of child 
bearing potential and agrees to 
use highly effective 
contraception during the study 
and for at least 7 days after the 
last dose of study product  
2. Is female and not of child 
bearing potential due to (One 
must be checked): 
surgical sterility OR 
congenital sterility OR  
post-menopausal state OR 
    
pre-menarchal state 
 3. Is male  
 
# 
Yes 
No Exclusion Criteria 
1 
 
 
Has consumed probiotics within 30 days prior to enrollment.* 
2 
 
 
Has consumed antibiotics within 90 days prior to enrollment.* 
3 
 
 
Has a known hypersensitivity to omadacycline or tetracycline-class 
antibacterial drugs.  
4 
 
 
Is pregnant or breastfeeding. 
5 
 
 
In the opinion of the investigator, is experiencing signs or symptoms of acute 
illness that increase the risk of adverse effects from participating in the study.  
6 
 
 
Has previously participated in the study.  

Omadacycline IV Microbiome Study 
Version: 2.0 
Version date: 24APR2023 
4 
3.2 Sample Size 
The study will enroll 8 participants.  
 
4.0 INVESTIGATIONAL PLAN 
 
4.1  Screening 
 
After signing informed consent, participants will undergo a brief interview about 
medications taken within the last 90 days with a particular focus on probiotic and 
antibiotic use. Volunteers who have received probiotics in the past 30 days and 
volunteers who have received antibiotics within the past 90 days will not be considered 
for participation. Participants will also undergo a limited review of their medical history 
to capture cardiovascular, gastrointestinal, renal, and hepatic diagnoses or conditions. 
Once the investigator confirms that the participant meets all patient selection criteria, the 
investigator and study team will schedule the patient’s first dose to occur on study Day 1. 
If dosing is to occur immediately, the participant will provide a stool sample directly 
following informed consent but before omadacycline dosing. If dosing is to occur on a 
subsequent day, the participant will bring a stool sample (obtained the morning of Day 1) 
to the clinic prior to dosing or will provide the sample in clinic just prior to Day 1 dosing.  
The screening period will begin no more than 5 days before study drug administration on 
study Day 1. 
 
4.2 Omadacycline dosing:  
 
Study Day 
Dose 
Route of administration and 
schedule 
Day 1 
200 mg 
Intravenous, infused over 60 minutes 
Days 2 – 5  
100 mg 
Intravenous, infused over 30 minutes 
Days 6 – 10  
300 mg  
Oral, two tablets once daily (dispensed 
as ten 150 mg tablets) 
 
Omadacycline powder will be provided by the sponsor, reconstituted with Sterile Water, 
and then further diluted for Injection under aseptic conditions as follows: 2 vials (200 
mg) to 2 mg/mL, and 1 vial (100 mg) to 1 mg/mL.  Each subject will receive 2 vials on 
day 1 followed by 1 vial on days 2-5 (4 additional vials). Subjects will then receive 2 oral 
tablets (300 mg) daily on study days 6 through 10 (5 days).   
 
4.3 Monitoring subjects during omadacycline infusions 
 
During the first infusion of omadacycline, subjects will be monitored by either a research 
nurse or investigator. At a minimum, the monitor will be present with the subject during 
the first 10 minutes of the infusion and will return every 5-10 minutes or sooner 
thereafter for the remainder of the 60-minute infusion. The monitoring study team 
member will, 
 
Observe the general appearance of the subject 
 
Examine skin color for possible infusion reaction 

Omadacycline IV Microbiome Study 
Version: 2.0 
Version date: 24APR2023 
5 
 
Examine the site of the infusion for possible redness or swelling 
 
Ask the subject if they are experiencing discomfort at the infusion site 
 
Ask the subject if they are experiencing any of the following symptoms: nausea, 
headache, dizziness, lightheadedness, fever, chills, shortness of breath, flushing, itching, 
or chest discomfort 
 
Report any symptoms to the investigator immediately, if investigator is not already 
present 
 
Along with investigator, assess the severity of any reported symptoms 
 
The research nurse will perform and record vital signs for any clinically significant 
symptoms. Depending on the severity of any symptoms reported, the investigator will 
determine whether the infusion should be held or discontinued. If needed, the research 
nurse or investigator will activate the institution’s code response system for “sudden 
illness” or “cardiac-pulmonary arrest”. 
 
If the subject tolerates the first infusion, subsequent infusions will be administered with 
less frequent monitoring. For these infusions, the monitoring research team member will 
be present with the subject for the first 5 minutes of the infusion and return every 10 
minutes or sooner for the remainder of the 30-minute infusion. The same approach to 
monitoring with be undertaken (see methods above). 
 
4.4 Laboratory Samples 
Female participants of childbearing potential must produce a negative urine pregnancy 
test on Day 1 prior to dosing. Results from pregnancy tests performed within 3 days prior 
to Day 1 will be accepted for eligibility. Due to the teratogenic potential of omadacycline, 
a urine pregnancy test must be repeated and confirmed negative on Day 5 prior to 
infusion. Omadacycline dosing will be discontinued if the Day 5 pregnancy test is 
positive. 
 
Participants will provide a total of 13 stool samples and 12 saliva samples during study 
participation. Two stool samples (one before and one after dosing) and one saliva sample 
will be provided on Day 1. On Days 2-10, Day 13 (+1), and Day 31 (±1) participants will 
provide the first stool sample of the day and one saliva sample per study day. Participants 
should deliver any home-collected stool samples to the clinic by 4:30pm on the day of 
collection and should store the sample in the refrigerator if not immediately bringing to 
the clinic. If the first stool sample of the day is collected after 4:30pm, it may be stored in 
the refrigerator overnight and delivered to the clinic the next morning. 

Omadacycline IV Microbiome Study 
Version: 2.0 
Version date: 24APR2023 
6 
 
4.5 Schedule of Events
Screening  
(-5 or 1)I 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 9 
Day 10 
Day 13 
(+1) 
Day 31 
(±1) 
Informed Consent 
X 
Eligibility 
X 
Enrollment 
X 
Limited Medical HistoryA 
X 
Limited Medication HistoryB 
X 
Investigational Product 
  
  
  
  
  
  
  
  
  
  
  
  
  
Omadacycline IV 200 mgC 
X 
Omadacycline IV 100 mgD 
X 
X 
X 
X 
Omadacycline Oral 300 mg 
X 
X 
X 
X 
X 
Laboratory Assessments 
  
  
  
  
  
  
  
  
  
  
  
  
  
Stool SampleE,F 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Saliva Sample  
XG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy test 
XJ 
XJ 
Safety Assessments 
  
  
  
  
  
  
  
  
  
  
  
  
  
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant MedicationsH 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
A 
History of cardiovascular, gastrointestinal, hepatic, or renal disease is exclusionary 
B 
No probiotic consumption within 30 days of enrollment. No antibiotic consumption within 90 days prior to enrollment.  
C 
Infused over 60 minutes 
D 
Infused over 30 minutes 
E 
 
All stool samples should be delivered to the clinic less than 24 hours after collection. Delivery will typically occur the same day as collection, but could be the following morning if the sample is collected after 
4:30pm 
F 
On all study days after Day 1, the first stool of every day should be the one collected 
G 
The saliva sample on Day 1 should be provided before omadacycline dosing 
H 
Assessment of antibiotic and probiotic use to occur at each study visit 
I 
Re-screening is allowable 
J 
Results from a recent pregnancy test (within 3 days prior to Day 1) will be accepted for eligibility determination. Pregnancy tests should be performed and confirmed negative prior to dosing on Days 1 and 5. 

Omadacycline IV Microbiome Study 
Version: 2.0 
Version date: 24APR2023 
7 
4.6 Setting  
4.6.1 Recruitment and advertising  
Advertisements will be posted on the campus of High Point University (HPU) in 
High Point, NC and Atrium Health Wake Forest Baptist (AHWFB) in Winston-
Salem, NC. Study team members at HPU and AHWFB will manage recruitment. 
 
4.6.2 Study procedures  
Study procedures including informed consent, eligibility confirmation, medical 
and medication history review, investigational product dispensing and 
administration, data collection, safety monitoring, and sample collection, 
temporary storage, and shipment will take place in the Wake Forest University 
Health Sciences Infectious Diseases Clinical Trials Center (IDCTC) at the 
Winston-Salem, NC campus of Atrium Health Wake Forest Baptist.  
 
4.6.3 Laboratory and Data Analysis 
The Garey Lab at University of Houston College of Pharmacy in Houston, TX 
will perform laboratory and data analysis.  
 
5.0 SUBJECT RECRUITMENT METHODS 
Study team members at HPU and AHWFB will post advertisements, receive initial 
contact from interested study candidates, and perform pre-screening. The contact 
information of candidates who appear eligible based on pre-screening will be transferred 
to the staff of the IDCTC team for management of consent and consent process 
documentation, final sign-off on eligibility, and study enrollment.  
  
6.0 ANALYTICAL PLAN 
 
6.1 University of Houston Microbiome analysis:  
DNA extraction:  
Prior to DNA extraction, the OMNIgene tubes will be vortexed vigorously for at least 10 
seconds.  DNA will be extracted from the tube by aliquoting 300 μL of the tube sample 
using the AnaPrep system DNA extractor (AnaPrep 2, BioChain Instruments, Newark 
CA) and the following protocol.  Approximately 400 uL of lysed bacteria will be mixed 
and loaded into the AnaPrep system and gDNA will be extracted using 400 microliter 
input volume and 100 uL elution volume.  DNA will be eluted in 100μL of buffer and 
concentration measured using a Nanodrop 2000 (Fisher Scientific, Waltham, MA).  If the 
DNA concentration is less than 10 μg/mL, the extraction will be repeated. A 50 μL 
portion of the extracted DNA will be used for qPCR analysis and the remainder used for 
16S rDNA amplicon generation. 
 
High-throughput metagenomics sequencing:   
Microbiome characterization will be performed by sequencing the V3-4 region of the 16S 
rRNA gene followed by extensive bioinformatics analysis related to microbial 
composition, diversity, and community structure. Microbial DNA extraction, 16S rRNA 
gene-based next-generation sequencing (using the Illumina MiSeq), quality filtering, and 
microbiome-based analysis will be performed [8].  Each sample will be amplified using a 

Omadacycline IV Microbiome Study 
Version: 2.0 
Version date: 24APR2023 
8 
barcoded primer, which yields a unique sequence identifier tagged onto each individual 
sample library. Illumina-based sequencing will yield > 15,000 reads per sample.  
Operational taxonomic units (OTUs) will be defined as >99% identity. To analyze 
differences across timepoints, the OTU table will be normalized to the lowest number of 
sequences per sample, then consolidated by summing to species level and to each 
successively higher taxonomic level. The alpha diversity parameters Chao and Shannon 
(based on number of OTUs) and Phylogentic Diversity (PD) (based on phylogenetic 
relationships), will be generated in QIIME or R; alpha diversity is widely regarded as an 
indication of microbiota health. For beta diversity, which describes the relationships 
between samples, weighted Unifrac distance matrices will be generated in QIIME.  
 
6.2 Statistical analyses 
In general, the healthy volunteer analyses will assess changes in total and species-specific 
microbiota over time as well as changes in microbial diversity.  Significance differences 
over time will be calculated using Mann-Whitney U test.  Analyses will be performed 
using SAS (SAS Institute, Cary NC) or R on log-transformed data. The LEfSe (Linear 
Effect Size) algorithm [9] will be used to identify significant differences in microbiota 
composition between baseline and each study time point, followed by Wilcoxon Signed 
Rank tests on identified taxa. The Benjamini-Hochberg procedure will be used to control 
the false discovery rate at 0.10 [10]. The MaAsLin algorithm will be used to find 
associations of taxa with treatment. For beta diversity, principal co-ordinates analyses on 
weighted Unifrac distance matrices generated in QIIME will be performed in the vegan 
package in the statistical program R. Finally, using the methods described by Burdet at al, 
Shannon diversity (a measure of alpha diversity) will be compared at each time point for 
subjects that receive moxifloxacin or comparators[11].   
 
6.3 Omadacycline pharmacokinetics 
All subject’s stool samples will be aliquoted for omadacycline concentrations. 
 
7.0 CONFIDENTIALITY AND PRIVACY 
Confidentiality will be protected by collecting only information needed to assess study 
eligibility and outcomes, minimizing to the fullest extent possible the collection of any 
information that could directly identify subjects, and maintaining all study information in 
a secure manner. To help ensure subject privacy and confidentiality, only a unique study 
identifier will appear on the data collection form. With the exception of full names and 
signatures on the informed consent document and consent process documentation form, 
any patient information corresponding to the unique study identifier will be maintained 
and stored separately from the patient’s study chart in WFUHS’s Clinical Trials 
Management Software, OnCore or “Wake Integrated Solution for Enterprise Research 
(WISER)”.  WISER access is limited to designated study personnel.  Following data 
collection, subject identifying information will be destroyed 6 years after study closure, 
consistent with data validation and study design, producing an anonymous analytical data 
set.  Data access will be limited to study staff.  Data and records will be kept locked and 
secured, with any computer data password protected.  No reference to any individual 
participant will appear in reports, presentations, or publications that may arise from the 
study. 

Omadacycline IV Microbiome Study 
Version: 2.0 
Version date: 24APR2023 
9 
 
8.0 DATA AND SAFETY MONITORING 
 
8.1 Stopping Criteria for the Study 
The study will be stopped if any of the following events occur or, if in the judgment of 
the investigator, participant safety is compromised: 
 Unexpected death of a participant.  
 Occurrence of a life-threatening hypersensitivity reaction.  
 A trend of unexpected SAEs related to the study product.  
 A pattern of clinical or laboratory events considered to be associated with 
the study product that may be considered minor in terms of individual 
events but collectively represent a serious potential concern.   
 Any other event(s) that is/are considered to be SAE(s) in the clinical 
judgment of the responsible investigator.  
 
8.2 Safety 
The principal investigator will be responsible for the overall monitoring of the data and 
safety of study participants. The principal investigator and appropriately trained 
appointees will be responsible for reporting unanticipated problems (UAP), adverse 
events (AE), serious adverse events (SAE), and protocol deviations (PD) in compliance 
with Wake Forest University Health Sciences Institutional Review Board (WFUHS IRB) 
policies. All events will be logged on either a PD log or AE log as appropriate, and the 
log will be retained in the regulatory binder. A current version of the staff signature log 
and delegation of duties will be retained in the regulatory binder.  
 
In addition to ongoing reporting as UAPs, PDs, AEs, and SAEs arise, self-monitoring 
will take place at the time of IRB Continuing Review to ensure protection of rights and 
well-being of study participants and data integrity. Self-monitoring will be performed by 
the principal investigator or an appropriately trained investigator appointee with protocol 
familiarity, such as a study coordinator or project manager of the Infectious Diseases 
Clinical Trials Unit (IDCTU). Self-monitoring will include the following: 
 
 Review study file to ensure compliance with local policies. 
 Verify written informed consent is on file for each participant. 
 Review the data collection forms for completion.  
 Note any safety issues including AEs, SAEs, UAPs, and PDs and verify 
appropriate reporting took place in accordance with local requirements.  
 
9.0 REPORTING OF UNANTICIPATED PROBLEMS, ADVERSE EVENTS, OR DEVIATIONS 
 
9.1 Definitions 
 
 Adverse Event Definition:  
An AE is any untoward medical occurrence in humans, whether or not considered 
drug-related, which occurs during the conduct of a clinical trial. An AE can 
therefore be any change in clinical status, routine labs, x-rays, physical 

Omadacycline IV Microbiome Study 
Version: 2.0 
Version date: 24APR2023 
10 
examinations, etc., that is considered clinically significant by the study 
investigator. 
 
 SAE Definition:  
An SAE or serious suspected adverse reaction or serious adverse reaction as 
determined by the investigator, or the sponsor is an AE that results in any of the 
following serious outcomes: 
 Death  
 Life Threatening  
 Requiring hospitalization  
 Permanently disabling  
 Causing cancer  
 Congenital anomaly/ birth defect  
 Important medical event that may not result in one of the above outcomes, but 
may jeopardize the health of the study participant or require medical or 
surgical intervention to prevent one of the outcomes listed in the above 
definition of serious event 
 
 UAP Definition:  
An unanticipated problem is any event, incident, experience, or outcome 
(including, but not limited to, adverse events and serious adverse events) which 
occurs in a research study and meets ALL of the following criteria: 
 Unexpected in nature, frequency, or severity (not articulated in the study 
protocol, informed consent or Investigator’s Brochure or not expected as a  
consequence of the natural history of a disease under study) 
 Related or possibly related to participation in the research (there is a reasonable 
possibility the that the event, incident, experience, or outcome may have been 
caused by the drug/device, procedures or interventions involved in the 
research) 
 Places subjects or others at a greater risk of harm than was previously known 
or recognized (causes physical, psychological, economic, or social harm to a 
human subject; increases the risk of harm of any kind; or otherwise 
compromises subject's safety, rights, welfare, or privacy). 
 
9.2 Assessing Severity and Causality of AEs, SAEs, UAPs 
 
 Criteria for Assessing Severity  
The Investigator will evaluate comments of the subject and any signs or 
symptoms associated with the event occurring in response to the antibiotic in 
order to judge the nature and severity of the adverse event. Severity refers to the 
intensity of discomfort/impairment of health and will be assessed according to the 
following criteria:  
 
Mild: Awareness of sign, symptom, or event, but easily tolerated  

Omadacycline IV Microbiome Study 
Version: 2.0 
Version date: 24APR2023 
11 
 
Moderate: Discomfort enough to interfere with usual activity and may warrant  
intervention  
 
Severe: Incapacitating with inability to do usual activities or significantly affects  
clinical status and warrants intervention  
 
To clarify the difference between the terms "serious" and "severe", which are not  
synonymous, the following note is provided:  
 
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 severe headache). This is not the same as "serious", which is 
based on patient/event outcome or action criteria usually associated with 
events that pose a threat to a patient's life or functioning. Seriousness (not 
severity) serves as a guide for defining regulatory reporting obligations.  
 
 Criteria for Assessing Causality  
The question of the relationship of an adverse event to study drug will be 
determined by the Investigator after thorough consideration of all facts that are 
available. Assessment of causality is based on considering associative connections 
(time or place), pharmacological explanations, previous knowledge of the drug, 
presence of characteristic clinical or pathological phenomena, exclusion of other 
causes, and/or absence of alternative explanations. The causal relationship of an 
adverse event to study drug will be assessed according to the following criteria:  
The Investigator will be responsible for determining the relationship between the 
administration of study drug and the occurrence of an AE as not suspected or 
suspected.  
 
Not suspected: The temporal relationship of the adverse event to study drug 
administration makes a causal relationship unlikely, or other drugs, therapeutic 
interventions, or underlying conditions provides a sufficient explanation for the 
observed event.  
 
Not related: Temporal relationship to study drug administration is missing or 
implausible, or there is evidence of another cause.  
 
Unlikely related: Temporal relationship to study drug administration makes a 
causal relationship improbable; and other drugs, chemicals, or underlying disease 
provide plausible explanations.  
 
Suspected: The temporal relationship of the adverse event to study drug 
administration makes a causal relationship possible, and other drugs, therapeutic 
interventions, or underlying conditions do not provide a sufficient explanation for 
the observed event.  

Omadacycline IV Microbiome Study 
Version: 2.0 
Version date: 24APR2023 
12 
 
Possibly related: Reasonable time sequence to administration of study drug, but 
the event could also be explained by concurrent disease of other drugs or 
chemicals. Information on drug withdrawal may be lacking or unclear.  
 
Definitely related: Plausible time relationship to study drug administration; event 
cannot be explained by concurrent disease or other drugs or chemicals. The 
response to withdrawal of the drug (dechallenge) should be clinically plausible.  
 
9.3 Reporting and Monitoring of AEs or SAEs 
 Reporting of Adverse Events  
All adverse events from the time of enrollment will be recorded in the Adverse 
Events section of the case report form. All adverse events will be described in 
terms of duration, severity, possible relation to study medications and treatment.  
  
All adverse events will be followed until resolution. 
 
Pregnancies that occur while on-study will not be considered an AE, but will be 
documented. Pregnancies will be followed to outcome if outcome occurs beyond 
the participant’s Final Study Visit. Any pregnancy-associated SAE will be 
reported to the extent that information can be collected. 
 
If the adverse event meets any of the criteria for Serious Adverse Events (see 
Section 9.1), the event will also be documented on a separate SAE Form.  
 
 
Reporting of Serious Adverse Events  
In the event of a Serious Adverse Event, information will be collected and 
recorded on the Serious Adverse Event section of the case report form. Serious 
Adverse Events will be reported from the time informed consent is obtained 
through the last protocol-specified study visit; whichever occurs later.  
 
 
Serious Adverse Event (SAE) Reporting to IRB and Study Sponsor:  
The Principal Investigator will be responsible for reporting any SAE thought to be 
directly attributable to the study medication to the IRB and Study Sponsor.  
 
9.4 Deviations 
Protocol deviations not meeting the WFUHS IRB Major Protocol Deviation definition 
will be tabulated and submitted to the IRB at the time of continuing review. Deviations 
meeting the criteria of a Major Protocol Deviation as defined by the WFUHS IRB will be 
reported per WFUHS IRB Policy.  
 
 
 
 
 
 

Omadacycline IV Microbiome Study 
Version: 2.0 
Version date: 24APR2023 
13 
 
 
 
10.0 
REFERENCES 
 
1. Duan J, Meng X, Liu S, Zhou P, Zeng C, Fu C, et al. Gut microbiota composition associated with 
Clostridium difficile-positive diarrhea and C. difficile type in ICU patients. Front Cell Infect 
Microbiol, 11 May 2020. doi.org/10.3389/fcimb.2020.00190. 
 
2. Jacques Pépin, Marie-Eve Alary, Louis Valiquette, Evelyne Raiche, Joannie Ruel, Fulop, K., 
Dominique Godin, & Claude Bourassa. (2005). Increasing Risk of Relapse after Treatment of 
Clostridium difficile Colitis in Quebec, Canada. Clinical Infectious Diseases, 40(11), 1591–1597. 
http://www.jstor.org/stable/4484249 
 
3. Petrella LA, Sambol SP, Cheknis A, Nagaro K, Kean Y, Sears PS, Babakhani F, Johnson S, Gerding 
DN. Decreased cure and increased recurrence rates for Clostridium difficile infection caused by 
the epidemic C. difficile BI strain. Clin Infect Dis. 2012 Aug;55(3):351-7. doi: 10.1093/cid/cis430. 
Epub 2012 Apr 20. PMID: 22523271; PMCID: PMC3491778. 
 
4. Singh T, Bedi P, Bumrah K, Singh J, Rai M, Seelam S. Updates in Treatment of Recurrent 
Clostridium difficile Infection. J Clin Med Res. 2019 Jul;11(7):465-471. doi: 10.14740/jocmr3854. 
Epub 2019 Jun 11. PMID: 31236163; PMCID: PMC6575119. 
 
5. Omadacycline [package insert]. Boston, MA: Paratek Pharmaceuticals, Inc.; 2018. 
 
6. Begum, Khurshida & Bassères, Eugénie & Miranda, Julie & Lancaster, Chris & Gonzales-Luna, 
Anne & Carlson, Travis & Rashid, Tasnuva & Eyre, David & Wilcox, Mark & Alam, PhD, M. 
Jahangir & Garey, Kevin. (2020). In vitro Activity of Omadacycline, a New Tetracycline Analog, 
and Comparators Against Clostridioides difficile. Antimicrobial Agents and Chemotherapy. 64. 
10.1128/AAC.00522-20. 
 
7. Tetracycline [package insert]. Sellersville, PA: Teva Pharmaceuticals USA; 2013. 
 
8.  Fadrosh DW, Ma B, Gajer P, et al. An improved dual-indexing approach for multiplexed 16S rRNA 
gene sequencing on the Illumina MiSeq platform. Microbiome 2014; 2(1): 6. 
 
9. Segata N, Izard J, Waldron L, et al. Metagenomic biomarker discovery and explanation. Genome 
Biol 2011; 12(6): R60. 
 
10. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach 
to multiple testing. Journal of the Royal Statistical Society Series B (Methodological) 1995; 
57(1):289±300. 
 
11. Burdet C, Nguyen TT, Duval X, et al. Impact of Antibiotic Gut Exposure on the Temporal Changes 
in Microbiome Diversity. Antimicrob Agents Chemother 2019; 63(10).