Clinical trial NCT04750655
Conditions: Antibiotic Resistance Ocular Surface Microbiome Gut Resistome
Sponsor: University of California, San Francisco
Start date: 2021-03-01; Completion date: 2023-08-31
Enrollment: 108 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
In this study, the investigators seek to determine the effect of antibiotic use post-surgery on antimicrobial resistance. The investigators will be studying adults (aged 18 or older) who will undergo eye surgery at University of California, San Francisco (UCSF). We seek to gain a better understanding of how antibiotic use during the perioperative period influences local and systemic antibiotic resistance at the individual level.

Detailed description:
Antibiotic use has saved millions of lives globally. However, this comes at the cost of selecting for antibiotic-resistant organisms at the individual and the community level. It is estimated that every year, approximately 700,000 deaths are associated with drug resistance globally. This places a significant burden on the public health system and the judicious use of antibiotics is more important than ever before.

The proposed masked, randomized controlled trial evaluates the effects of topical antibiotic use on the selection of antibiotic resistance determinants at the local and systemic levels. The results will provide guidance for antibiotic usage in ophthalmology and may have the potential to inform public health policies.

Arms: arm 1: intraoperative/ intracameral antibiotic (moxifloxacin) only; no postoperative topical antibiotic drops arm 2: intraoperative/ intracameral antibiotic (moxifloxacin); postoperative topical antibiotic drops four times a day for 1 week arm 3: intraoperative/ intracameral antibiotic (moxifloxacin); postoperative topical antibiotic drops once a day for 1 week
Interventions: intervention 1: Moxifloxacin (Topical)
Intervention descriptions: intervention 1: We are using moxifloxacin as indicated and as intended for use as an antibiotic during surgery. Frequency of postoperative antibiotics dependent on group randomization.

Protocol documents:
Prot_001.pdf: 
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Antibiotic Resistance in Eye Surgeries 
(ARIES Trial) 
 
 
 
 
Manual of Operations and Procedures 
 
 
 
 
 
University of California, San Francisco 
Francis I. Proctor Foundation, University of California San Francisco  
 
NCT04750655 
January 12, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
Abbreviations .............................................................................................................. 4 
Chapter 1: Overview ................................................................................................. 5 
1.1. 
Executive Summary ................................................................................................. 5 
1.2. 
Objectives ............................................................................................................... 5 
1.3. 
Study Partners ......................................................................................................... 5 
1.4. 
Study Site ................................................................................................................ 5 
Chapter 2: Context .................................................................................................... 6 
Chapter 3: Study Design ........................................................................................... 7 
3.1. 
Randomization ........................................................................................................ 7 
Figure 1: Trial Profile ............................................................................................................ 8 
Chapter 4: Study Eligibility ..................................................................................... 9 
4.1. 
Eligible Participants ................................................................................................. 9 
4.2. 
Study Schedule ...................................................................................................... 10 
Chapter 5: Core Study Elements ............................................................................. 11 
Chapter 6: Registering Participants for Specimen Collection .............................. 12 
Chapter 7: Specimen Collection for Resistance and Microbiome Testing ............ 12 
7.1 
Participants ........................................................................................................... 12 
7.2 
Conjunctival, Nasopharyngeal, Buccal, and Rectal Swabs ...................................... 12 
7.2.1 
Conjunctival Swabs: ......................................................................................................... 12 
7.2.2 
Nasopharyngeal Swabs: ................................................................................................... 12 
7.2.3 
Buccal Swabs: .................................................................................................................... 13 
7.2.4 
Rectal Swabs: ..................................................................................................................... 13 
7.2.5 
Materials for Swab Collection for Molecular Testing ............................................... 14 
7.2.6 
Protocol for Tubing and Handling of Samples ........................................................... 14 
Chapter 8: Training ................................................................................................. 15 
8.1 
Standardization ..................................................................................................... 15 
Chapter 9: Sample Organization, Transport, and Storage ................................... 15 
9.1 
De-identification ................................................................................................... 15 
9.2 
Specimen Transport ........................................................................................... 15 
9.3 
Specimen Storage ............................................................................................... 16 
9.3.1 
Short-term Sample Storage ............................................................................................. 16 
9.3.2 
Long-term Sample Storage .............................................................................................. 16 
9.4 
Catalog Specimens ............................................................................................. 16 


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Chapter 10: Study Medication ................................................................................ 16 
10.1    Study Medication Description .................................................................................. 16 
10.2 
Dosage Information ............................................................................................... 16 
10.3 
Medication Procurement/Donation ...................................................................... 17 
10.4 
Medication Quality Control ................................................................................... 17 
10.5 
Adverse Reactions/Side Effects ............................................................................. 17 
10.6 
Adverse Events Systems ........................................................................................ 17 
10.6.1 
Passive Adverse Events Monitoring ......................................................................... 17 
10.6.2 
Active Adverse Events Monitoring ........................................................................... 17 
10.6.3 
Adverse Events Data .................................................................................................... 18 
Chapter 11: Protection of Human Subjects ............................................................ 19 
11.1 
Institutional Review Board Approval ..................................................................... 19 
11.2 
Written Consent .................................................................................................... 19 
11.3 
Risks and Benefits of Study Procedures ................................................................. 19 
11.3.1 
Swabbing Procedures .................................................................................................. 19 
11.3.2    Antibiotic Frequency ........................................................................................................ 19 
Chapter 12: Study Monitoring ................................................................................ 20 
Chapter 13: Data and Safety Monitoring Committee Charter ............................. 20 
13.1 
Primary Responsibilities of the DSMC .................................................................... 20 
13.2 
DSMC Membership ........................................................................................... 21 
13.3 
Conflicts of Interest ........................................................................................... 21 
13.4 
Timing and Purpose of the DSMC Meetings .................................................. 21 
13.5 
Procedures to Ensure Confidentiality and Proper Communication ......................... 22 
13.6 
Statistical Monitoring Guidelines ........................................................................... 23 
13.7 
DSMC Contact Information .................................................................................... 24 
Chapter 14: Data Collection, Management, and Security .................................... 25 
14.1 
Scope of Data ........................................................................................................ 25 
14.2 
Data Storage, Management, and Security .............................................................. 25 
14.3 
Data Monitoring and Cleaning .............................................................................. 25 
Appendix .................................................................................................................. 26 
Appendix 2. Instructions on Self-Collected Rectal Samples ................................................. 27 
Appendix 3. DEQ-5 Questionnaire ...................................................................................... 28 
Appendix 4. SPEED Questionnaire ...................................................................................... 29 
  


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Abbreviations 
DCC: Data Coordinating Center  
IRB: Institutional Review Board 
NP swabs: nasopharyngeal swabs 
PCR: polymerase chain reaction  
MR: Medical Record 
UCSF: University of California San Francisco  


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Chapter 1: Overview 
 
1.1. 
Executive Summary 
 
Antibiotic use has saved many lives, but also comes with the issue of selecting 
for antibiotic-resistant organisms.  
 
In this study, we hope to determine the effect of antibiotic use post-surgery on 
bacterial resistance and gain a better understanding of how antibiotic use during 
the perioperative period influences local and systemic antibiotic resistance in the 
individual.  
 
1.2. 
Objectives  
 
1: Determine if the use of topical ocular antibiotics for eye surgeries will 
lead to local (ocular surface) antibiotic resistance. We hypothesize that topical 
ocular antibiotics for eye surgeries leads to ocular surface antibiotic resistance. 
 
2: Determine if the use of topical ocular antibiotics for eye surgeries will 
lead to systemic antibiotic resistance. We hypothesize that topical ocular 
antibiotic use for eye surgeries leads to systemic antibiotic resistance. 
 
3: Determine if the frequency of topical ocular antibiotic usage for eye 
surgeries affects local antibiotic resistance. We hypothesize greater frequency 
of topical ocular antibiotic usage for eye surgeries will increase local antibiotic 
resistance.  
 
1.3. 
Study Partners 
This study was designed by investigators at UCSF.  Funding is supported by internal 
grants. 
1.4. 
Study Site 
The study visits will be conducted at Mount Zion and Mission Bay campus at 
UCSF.  
 
The study samples will be stored and processed at the Heintz Lab at 490 Illinois 
Street Floor 2, San Francisco, CA 94158. 
 


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Chapter 2: Context 
 
Antibiotic use has saved millions of lives globally. However, this comes at the cost 
of selecting for antibiotic-resistant organisms at the individual and community 
level. It is estimated that every year, approximately 700,000 deaths are associated with 
drug resistance globally. This places a significant burden on the public health system 
and the judicious use of antibiotics is more important than ever before. 
There exists little consensus on the use of antibiotics in ophthalmology, whether 
it’s frequency, type of antibiotics, or when to use antibiotics. In the US, when or how 
the patients are instructed to take antibiotics for eye procedures is generally dependent 
on the individual ophthalmologist, which leads to a wide range of practice patterns. 
Furthermore, there are almost no randomized controlled trials evaluating the effects 
of commonly used topical antibiotics on antibiotic resistance at the local or systemic 
level in the host. 
The proposed masked, randomized controlled trial evaluates the effects of topical 
antibiotic use on the selection for antibiotic resistance genes at the local and 
systemic levels. The results will provide guidance for antibiotic usage in 
ophthalmology and have the potential to inform public health policies.  


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Chapter 3: Study Design 
 
The research team will assess antibiotic resistance over four weeks, comparing 
frequency of antibiotic use among adult patients undergoing ocular surgeries. 
All eligible participants will be randomized. A random sample of 108 (36/arm) 
participants from UCSF will be selected to participate in the “ARIES” study, 
which will entail biospecimen collection via nasopharyngeal, conjunctival, 
buccal, and rectal swabs 1-week post-op. Baseline will entail conjunctival swab 
collection.  4-week post-op sample collection will include conjunctival, 
nasopharyngeal, and buccal swabs. All biologic specimens collected will be 
stored and made available to Dr. Thuy Doan for laboratory testing of antibiotic 
resistance. 
 
 
3.1. 
Randomization  
 
Randomization of Treatment Allocation. All eligible UCSF adult patients 
undergoing ocular surgery will be randomized in a 1:1:1 fashion to three groups: 
• Group 1: intraoperative/intracameral antibiotic (moxifloxacin) only; no 
postoperative antibiotic drops  
• Group 2: intraoperative/intracameral antibiotic (moxifloxacin); 
postoperative antibiotic drops four times a day for 1 week and then stop  
• Group 3: intraoperative/intracameral antibiotic (moxifloxacin); 
postoperative antibiotic drops once a day for 1 week and then stop  
Refer to SAP for randomization details.  
 
Study Participants: UCSF adult patients undergoing ocular surgeries will be 
recruited if they consent and the study doctor deems the participant meets all 
study criteria. 


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Figure 1: Trial Profile 
 
 
 
  
36 participants 
 
Group 1: intraoperative/ 
intracameral antibiotic 
(moxifloxacin) only; no 
postoperative antibiotic 
drops 
36 participants 
 
Group 3: intraoperative/ 
intracameral antibiotic 
(moxifloxacin); 
postoperative antibiotic 
drops once a day for 1 
week and then stop 
36 participants 
 
Group 2: intraoperative/ 
intracameral antibiotic 
(moxifloxacin); 
postoperative antibiotic 
drops four times a day 
for 1 week and then 
stop 
• 
Prior to Surgery: IOP measurement; Snellen best-corrected visual acuity; collect 
conjunctival swab  
• 
1 Day Post-Op: IOP measurement; complete surveys (DEQ-5 and SPEED 
Questionnaire)  
• 
1 Week Post-Op: IOP measurement; collect NP swab, conjunctival swab, buccal 
swab, rectal swab; complete surveys (DEQ-5 and SPEED Questionnaire) 
• 
1 Month Post-Op: IOP measurement; collect NP swab, conjunctival swab, 
buccal swab; complete surveys (DEQ-5 and SPEED Questionnaire) 
108 participants 


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Chapter 4: Study Eligibility   
 
4.1. 
Eligible Participants 
To be eligible for the trial, participants must meet the following criteria: 
1. Over 18 years of age 
2. Undergoing cataract surgeries that would benefit from intracameral antibiotics 
3. Able to provide swabs 
4. No systemic antibiotics within the past 3 months or within one month after 
 the cataract surgery 
5. No immunosuppression medications such as Prednisone, Methotrexate, Cellcept, or  
anti-TNF inhibitors within the past 3 months 
6. No patients needing tubes or trabs 
7. No allergy to fluoroquinolones  
8. Has ability to consent for the study 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


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4.2. 
Study Schedule 
The schedule for examination and treatment is shown below in Table 1:  
 
 
Pre-Op 
1-Day  
Post-Op 
1-Week 
Post-Op 
4-Week 
Post-Op 
Consent 
X 
 
 
 
Randomization 
X 
 
 
 
Specimen 
Collection 
X 
 
X 
X 
Survey 
 
X 
X 
X 
 
 
 
 
 


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Chapter 5: Core Study Elements 
An overview of core elements for the ARIES study is provided here but will be 
described in more detail in the following chapters.  
We will conduct the following study activities for the ARIES study: 
Recruitment 
UCSF adult patients undergoing cataract surgeries will be recruited if they meet 
the criteria as written above. 
 
Enrollment 
The study will be explained by the study doctors or study coordinators. The patient 
will be enrolled in the study after obtaining written consent from the patient (and 
witness if needed).   
The participant will be randomly assigned to one of three groups only after obtaining 
consent. 
 
Survey 
An ocular symptom/quality of life survey (DEQ-5 and SPEED questionnaires) will 
be given to the patient to be filled at 1-Day post-op, 1-Week post-op, and 4-Week 
post-op.  
 
Specimen Collection 
All participants will have NP swabs, conjunctival swabs, and buccal swabs collected 
by the study doctors or study coordinator. Rectal swabs will be collected by the 
patient themselves by following instruction guide (see Appendix).  
All specimens will immediately be placed in a Zymo preservative after collection 
and labeled with the participants study number. Samples will then be 
transported to the Heintz laboratory at 490 Illinois Street Floor 2, San Francisco, 
CA 94158 for long-term storage at -80C and processing.  
 
Conjunctival swabs will be collected prior to surgery. Conjunctival, NP, buccal, and 
rectal swabs will be collected 1-Week post-op. Conjunctival, NP, and buccal swabs 
will be collected 4-Week post-op.  
 
Specimen Processing 
Metagenomics deep sequencing (MDS) and or directed PCRs will be conducted on 
all collected samples. Trained laboratory technicians in the Ralph & Sophie Heintz 
laboratory will be responsible for processing all samples. 


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Chapter 6: Registering Participants for Specimen Collection 
Samples will be collected with reference to age, surgical history, and history of 
ocular disease, but participant names will not be included in laboratory records 
to ensure privacy.  Samples will thus not be associated with an individual’s 
name, but with a random identification number, masking laboratory personnel 
and preventing identification of individuals.   
 
At each time point, each participant selected for specimen collection will be 
assigned an identification number for database anonymity.  
Chapter 7: Specimen Collection for Resistance and Microbiome 
Testing  
 
7.1 
Participants 
We will collect nasopharyngeal, conjunctival, buccal, and rectal swab samples from 
all 108 participants. The swabbing will occur prior to surgery (conjunctival), 1-week 
post-op (conjunctival, NP, buccal, rectal), and 4-Week post-op (conjunctival, NP, 
buccal).  The enrolled participants will be given instructions on when and where to 
go for swabbing visits after surgery.  
 
7.2 
Conjunctival, Nasopharyngeal, Buccal, and Rectal Swabs 
All swabs will be stored in DNA/RNA shield media by Zymo and MDS and/or 
directed PCRs will be performed on all samples to evaluate for changes in 
antibiotic resistance and microbiome.  
 
7.2.1 
Conjunctival Swabs: 
The examiner will: 
1. Have the patient sit or lay on a chair with their head well supported. The 
chair will be adjusted to the appropriate height to ensure the patient’s 
safety.  
2. Each individual will use new bottle of proparacaine eyedrop for local 
anesthesia before taking conjunctival sample. Instruct the patient to look 
up and expose the conjunctiva by gently pulling down the lower lid of the 
surgical eye. Gently sweep the conjunctival swab along the lower fornix 
from inner to outer canthus without touching the eyelids.  
3. Place each swab in a separate tube containing 2.0 mL DNA/RNA shield 
media by Zymo, break it off at its natural break-off point, and close the 
cap of the tube with the swab immersed. 
4. Place study number label on the collection tube and then store at -80C 
until processing. 
7.2.2 Nasopharyngeal Swabs: 
The examiner will: 


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1. Place an adult flocked swab with a nylon tip through the right nostril 
and down the nasopharynx of each participant. Note that if the swab is 
not perpendicular to the frontal plane of the face, it is likely not in the 
inferior turbinate. 
2. Once you reach the nasopharynx, rotate the swab 180° as you remove 
the swab from the nose.  
3. Place the swab in a tube containing 1.0 mL DNA/RNA shield media 
by Zymo media, cut the handle off using sterile scissors, and close the 
cap of the tube with the swab immersed. 
4. Place study number label on the collection tube and then store at -80C 
until processing.  
 
Do not attempt to collect the NP swab if you are not successful after three attempts. 
7.2.3 Buccal Swabs: 
The examiner will: 
1. Have the patient rinse mouth with water prior to sample collection 
2. Instruct the patient to open their mouth and insert the buccal swab into 
one side of their mouth, between the cheek and upper gum. Press firmly 
and twirl swab against the inside of their inner cheek and over the gums 
for at least 30 seconds using an up/down and front/back motion on each 
side (1 minute total for both sides). Hold the swab as close to its head as is 
comfortable for the patient. While you rub the cotton swab, turn the 
plastic shaft. This will ensure the entire tip is covered with cells from the 
cheek. This sampling technique should collect buccal cells without 
drawing blood.  
3. Place the swab in a tube containing 2.0 mL DNA/RNA shield media by 
Zymo, break the swab at its break-off point, and close the cap of the tube 
with the swab immersed. 
4. Place study number label on the collection tube and then store at -80C 
until processing. 
 
7.2.4 Rectal Swabs: 
The test will require that the participant themselves to obtain a good sample.  It 
is important to describe the test to the participant thoroughly to ensure a good 
sample is taken. The rectal swabs include an instruction guide (see Appendix) 
with the following instructions: 
1. Put on a clean pair of gloves. 
2. Partially open the fecal swab package and remove the top section of the 
collection vial (this can be discarded). 
3. Remove the swab from the package. Take care that the cotton tip is not 
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4. Insert the tip of the swab into your anus only as far as needed to contact 
fecal material (1-3cm) and rotate 180 degrees.  The tip should be a 
brownish color when removed. 
5. Place swab into the preservative in the collection tube. Make sure the 
swab is fully submerged in the liquid preservative and then break the 
swab off using the pre-scored breaking point.  
6. Screw the cap back on the tube and make sure that it’s tightened. Wrap 
the area where the cap meets the tube with Parafilm to ensure that the 
sample will not leak, and then place the tube into the appropriate sample 
box.  
7. If the swab cannot be broken off while the tip is fully submerged in the 
liquid, try twirling the swab in the liquid first (to release the contents of 
the sample into the preservative) before breaking it off. Avoid rubbing the 
sample on the tip of the swab off on the side of the tube where there is no 
liquid. 
8. Hand the tube with the sample to the investigator/study coordinator. 
9. The investigator/study coordinator places the number label on the 
collection tube.  
10. Tube will be stored at -80C until sample processing.  
 
7.2.5 
Materials for Swab Collection for Molecular Testing 
 
Swabs 
Conjunctival, NP, and buccal specimens will be collected using sterile, 
individually wrapped adult flocked swabs with a plastic swab shaft 
(manufactured by Copan or similar manufacturer). Rectal swab specimen will be 
collected using sterile individually wrapped swab (Zymo Research). 
 
 
Sample Tubes 
Conjunctival, NP, and buccal samples for molecular testing will be collected into 
sterile 2.0ml microcentrifuge tubes, manufactured by Sarstedt®. (DNA-free tubes 
will be used for collection in DNA/RNA shield (Zymo).) Rectal swab specimens 
will be stored in 2 mL sterile tube with DNA/RNA Shield solution provided as 
part of the DNA/RNA Shield Collection Tube with Swab (Cat # R1108).  
 
-80°C Freezer 
A dedicated -80°C freezer located at the Heintz laboratory will be available for 
storage of study samples, including nasopharyngeal, conjunctival, buccal, and 
rectal swabs. 
 
7.2.6 
Protocol for Tubing and Handling of Samples 
The tubing and handling protocol must be carefully followed in order to prevent 
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laboratory and/or to other institutions for processing.  The person in charge of 
labeling, tubing, arranging, and handling the samples needs to perform this task 
in the most orderly and attentive manner. 
 
1. Both hands of the tuber should be gloved at all times. The tuber's gloves 
only need to be changed when any potential contamination of the gloves 
occurs. The tuber opens the capped, hinged lid of a microcentrifuge tube, 
which has been labeled with the participant’s random identification 
number. 
2. The investigator/study coordinator should screw the cap of the 
microcentrifuge tube tightly, flick the tube to mix the sample with the 
media (for tubes with DNA/RNA shield media), and place it in the 
sample collection box until transfer to a -80C for storage in the Heintz lab.  
 
All samples will be in sample boxes, labeled with the participant’s study number 
for easy future identification. 
Chapter 8: Training  
 
8.1   Standardization 
The research team will work together prior to the baseline visit to standardize all 
study procedures. We will review the format, general logistics, and procedures for all 
participants. Training and standardization of sample processing will be under the 
guidance of Dr. Thuy Doan. 
 
Chapter 9: Sample Organization, Transport, and Storage 
 
9.1    De-identification 
All specimens will be labeled in the outpatient clinic with a random 
identification number linked to their name, MR number, and surgical/ocular 
disease history, but to facilitate masking, only the designated Study Coordinator 
and the Biostatician will have access to the key linking the ID with patient 
information. Age, gender, and surgical/ocular disease history will be available 
for each specimen, but names will be kept confidential. Therefore, all specimens 
will be de-identified. Please note that the Study Coordinator who is unmasked to 
the study arms will not be collecting samples at 1-week post-op (primary end 
point) to prevent potential biases.  
 
9.2    Specimen Transport  
After sample collection, samples from the clinic will be transported to the Heintz 
laboratory for storage and processing. 
 


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9.3   Specimen Storage 
Sample storage will occur in two stages: short-term and long-term. 
 
9.3.1 Short-term Sample Storage 
Samples will be labeled with study ID only and are unidentifiable without access 
to the study database. All samples will be transported to the Heintz laboratory 
for storage and processing.  
 
9.3.2 Long-term Sample Storage 
All samples processed by the Heintz laboratory will be stored in the -80°C 
freezer for at least 5 years.  
 
9.4   Catalog Specimens 
We will create a list of study data and specimens, including the age, gender, 
surgical history, ocular disease history, group participant was in, and symptom 
questionnaire. We will also list the date of collection and transport, and the 
storage conditions while in the field and while banked at UCSF. This will 
facilitate identification of specimens for future analyses. 
 
Chapter 10: Study Medication 
All adult participants over 18 years of age will be given moxifloxacin 
intracamerally during surgery. Depending on which group the participant is 
assigned to, the participants may also be instructed to take topical moxifloxacin 
at home. 
 
We will monitor as described in the adverse events section. The treatment and 
monitoring schedule for all study arms is shown in Table 1. 
 
10.1    Study Medication Description  
 
Moxifloxacin  
Will be purchased by the subjects 
 
10.2     Dosage Information 
Moxifloxacin will be administered intracamerally during surgery for all 
participants. The study doctor will use a different moxifloxacin vial for each 
participant. 
 
All participants in Group 2 and Group 3 will also be taking topical moxifloxacin 
eyedrops at home.  
• Group 2: 4 times a day 


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• Group 3: once a day 
Individuals who are allergic to fluoroquinolones will not be in the study. 
 
10.3     Medication Procurement/Donation 
None. 
10.4     Medication Quality Control 
Intracameral moxifloxacin will be obtained through UCSF pharmacy in 
compliance with UCSF policy. Topical antibiotics will be dispensed as 
prescribed. All topical medications are FDA approved.  
 
10.5     Adverse Reactions/Side Effects 
Moxifloxacin is generally well-tolerated.  The most common side effects of 
moxifloxacin are diarrhea, nausea, dizziness, and headache, each of which may 
occur as likely as 4% when taking orally and 8% when taking intravenously.  
Rarer side effects include dysphagia and stomatitis.  Diarrhea due to Clostridium 
difficile has been reported in rare cases.  
 
During the consent process, the common adverse reactions that may occur will 
be explained to the participant and they will be advised to communicate adverse 
events to UCSF study staff immediately. If, for any reason, the participant needs 
further care, they will be referred to the nearest health center for examination 
and treatment. 
 
The trial sites will be masked to molecular outcomes. There will be no interim 
analysis given that this is a small study. Statistical monitoring is discussed in the 
Statistical Analysis Plan. The Data Safety and Monitoring Committee (DSMC) 
will be given authority to discontinue treatments at any time if there is evidence 
of unexpected harm.  
 
10.6     Adverse Events Systems 
Both active and passive monitoring systems for adverse events are in place for 
this study. We will monitor adverse events at 1-Day post-op, 1-Week post-op, 
and 4-Week post-op. 
 
10.6.1 Passive Adverse Events Monitoring  
We will implement a passive monitoring system during the study, by instructing 
patients to report any adverse events during the study period. Patients will be 
referred for follow up care on a case-by-case basis.  
 
10.6.2 Active Adverse Events Monitoring 
 
Ocular Symptoms/Quality Survey  


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To identify any adverse events during the study, the research team will 
administer the survey (DEQ-5 and SPEED questionnaires) to each participant at 
1-day, 1-week, and 4-weeks after surgery. This survey will be completed by the 
participants themselves before specimen collection.  
 
10.6.3 Adverse Events Data 
We will keep records and report all potential adverse events to the DSMC. 
Reporting of non-serious and serious adverse events will follow UCSF IRB 
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Chapter 11: Protection of Human Subjects 
Study staff will proceed only if participants consent to participate. To be able to 
collect specimens, we will obtain written informed consent from the participant. 
This written consent will contain information regarding all study activities with 
patient contact.  We will collect one written consent form each patient the first 
time we enroll them. The subsequent visits we will explain the study to the 
participant, but we will only obtain verbal consent. If, at any time, the participant 
elects to withdraw themself from the study, they will be free to do so. 
Individuals who withdraw will be offered the same medical treatment outside 
the study. 
 
11.1   Institutional Review Board Approval 
 
 
UCSF Committee on Human Research 
UCSF’s Committee on Human Research will annually review study protocol for 
ethical approval. 
 
11.2   Written Consent 
Each participant will be asked to sign the written consent form if they agree to be 
included in the study. 
 
11.3   Risks and Benefits of Study Procedures 
   
11.3.1 Swabbing Procedures 
There are minimal risks to the participant who receives nasopharyngeal, 
conjunctival, and buccal swabbing. Participants may experience some temporary 
discomfort, but the swabbing involves minimal risk. Any adverse effects, such as 
nosebleeds, will be treated immediately by the examiners. Other health care will 
be provided at no cost to the study participant if necessary to address a study-
related adverse health event. 
  
11.3.2    Antibiotic Frequency 
There are minimal risk of antibiotic resistance developing within the participant 
depending on how frequent they are instructed to take antibiotics. This will be 
rare, however, as all moxifloxacin regimens are commonly used in current 
practice. 


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Chapter 12: Study Monitoring  
The project will be continuously monitored by the study team. 
Chapter 13: Data and Safety Monitoring Committee Charter 
This Charter is for the Data Safety and Monitoring Committee (DSMC). The 
Charter will define the primary responsibilities of the DSMC, its relationship 
with other trial components, its membership, and the purpose and timing of its 
meetings. The Charter will also provide the procedures for ensuring 
confidentiality and communication, statistical monitoring guidelines to be 
implemented by the DSMC, and an outline of the content of the Open and 
Closed Reports that will be provided to the DSMC. 
 
13.1     Primary Responsibilities of the DSMC 
The DSMC will be responsible for safeguarding the interests of trial participants, 
assessing the safety and efficacy of the interventions during the trial, and 
monitoring the overall conduct of the trial. The DSMC will provide 
recommendations about stopping or continuing the trial. To contribute to the 
integrity of the trial, the DSMC may also formulate recommendations relating to 
the selection/recruitment/retention of participants, to protocol-specified 
regimens, and the procedures for data management and quality control.  
 
The DSMC will be advisory to the trial leadership group, hereafter referred to as 
the Steering Committee (SC). The SC will be responsible for promptly reviewing 
the DSMC recommendations and determining, whether to continue or terminate 
the trial, and to determine whether amendments to the protocol are required. If 
needed, the DSMC may seek the advice of a content expert outside of the 
committee.  
 
 


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13.2 
DSMC Membership 
The DSMC is an independent multidisciplinary group consisting of 
epidemiologists, biostatisticians, and clinicians that collectively has experience in 
the conduct and monitoring of randomized clinical trial. 
 
13.3 
Conflicts of Interest 
The DSMC membership has been restricted to individuals free of apparent 
conflicts of interest. The source of these conflicts may be financial, scientific, or 
regulatory. Thus, neither study investigators nor individuals employed by the 
sponsor, nor individuals who might have regulatory responsibilities for the trial 
products, are members of the DSMC. 
 
The DSMC members will disclose to fellow members any consulting agreements 
or financial interests they have with the sponsor of the trial, with the contract 
research organizations (CRO), or with other sponsors having products that are 
being evaluated or that are competitive with those in the trial. The DSMC will be 
responsible for deciding whether these consulting agreements or financial 
interests materially impact their objectivity.  
 
The DSMC members will be responsible for advising fellow members of any 
changes in any of the membership requirements that occur during the course of 
the trial. It may be appropriate for DSMC members who develop significant 
conflicts of interest resign from the DSMC.  
 
DSMC membership is to be for the full duration of the trial. If any members leave 
the DSMC, the SC, in consultation with the DSMC, will promptly appoint a 
replacement.   
 
13.4 
Timing and Purpose of the DSMC Meetings  
 
Organizational Meeting 
The initial meeting of the DSMC will be an Organizational Meeting. This is 
during the final stages of protocol development and the purpose is to provide 
advisory review of scientific and ethical issues relating to study design to discuss 
the standard operating procedures and to discuss the format and content of the 
Open and Closed Reports that will be used to present trial results. 
 
The Organizational Meeting will be attended by all DSMC members, lead trial 
investigators, and the trial biostatistician. The DSMC will be given the drafts of 
the trial protocol, the Statistical Analysis Plan, the DSMC Charter, and the 
current version of the case report forms. At subsequent meetings, committee 
members will receive Open and Closed Data Reports. 
 


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Formal Interim Analysis Meetings 
There will be no planned interim analysis given this is a small trial.  
 
13.5      Procedures to Ensure Confidentiality and Proper Communication 
To enhance the integrity and credibility of the trial, procedures will be 
implemented to ensure the DSMC has access to all emerging information from 
the trial regarding comparative results of efficacy and safety, aggregated by 
treatment arm.  
 
Closed Sessions 
Sessions involving only DSMC members and, where appropriate, those 
unmasked trial investigators (on the Data Coordinating Committee) who 
generate the Closed Reports (called Closed Sessions) will be held to allow 
discussion of confidential data from the trial, including information about the 
relative efficacy and safety of interventions.  
 
At a final Closed Session, the DSMC will develop a consensus on its list of 
recommendations, including that relating to whether the trial should continue. 
 
Open Session  
In order for the DSMC to have access to information provided, by study 
investigators, or members of regulatory authorities, a joint session between these 
individuals and DSMC members will be held between the Closed Sessions.  
 
Open and Closed Reports 
For each DSMC meeting, Open and Closed Reports will be provided. Open 
Reports will include data on recruitment and baseline characteristics, pooled 
data on eligibility violations, and completeness of follow-up and compliance. The 
study statistician (TCP) will prepare these Open Reports.  
 
Closed reports, available only to those attending the Closed Sessions of the 
meeting, will include analyses of primary and secondary efficacy endpoints, 
including subgroup and adjusted analyses, AEs and symptom severity, and 
Open Report analyses that are displayed by intervention group. These Closed 
Reports will be prepared by the study biostatistician.  
 
The Open and Closed Reports should provide information that is accurate, with 
follow-up that is complete to within two months of the date of the DSMC 
meeting. The Reports should be provided to DSMC members approximately 
three days prior to the date of the meeting. 
 
Minutes of the DSMC Meeting 


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The research team will prepare minutes for the open portion of the meeting, 
including the DSMC’s recommendations. 
 
Recommendations to the Steering Committee (SC) 
At each meeting of the DSMC during the trial, the committee will make a 
recommendation to the Steering Committee to continue or terminate. This 
recommendation will be based primarily on safety and efficacy considerations 
and will be guided by statistical monitoring guidelines defined in this Charter. 
 
Recommendations to amend the protocol or conduct of the study made by the 
DSMC will be considered and accepted or rejected by the SC. The SC will be 
responsible for deciding whether to continue or to stop the trial based on the 
DSMC recommendations.  
 
The DSMC will be notified of all changes to the protocol or to study conduct. The 
DSMC concurrence will be sought on all substantive recommendations or 
changes to the protocol or study conduct prior to implementation.  
 
The SC may communicate information in the Open Report to the sponsor and 
may inform them of the DSMC recommended alterations to study conduct or 
early trial termination in instances in which the SC has reached a final decision 
agreeing with the recommendation. The SC will maintain confidentiality of all 
information it receives other than that contained in the Open Reports until after 
the trial is completed or until a decision for early termination has been made. 
 
13.6     Statistical Monitoring Guidelines 
The SC will propose statistical rules for a futility stopping rule and an efficacy 
stopping rule at the first DSMC meeting.  
 
 


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13.7     DSMC Contact Information  
 
Table 2: DSMC Contact Information 
Julie Schallhorn  
Julie.Schallhorn@ucsf.edu 
Catherine Oldenburg 
Catherin.Oldenburg@ucsf.edu 
Gerami Seitzman 
Gerami.Seitzman@ucsf.edu 


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Chapter 14: Data Collection, Management, and Security 
 
14.1       Scope of Data 
Genetic data will be collected in this trial from specimen collection.  
14.2 
Data Storage, Management, and Security 
Data will be recorded electronically using an encrypted and secure Excel 
spreadsheet and REDCap, which can securely store confidential information. 
Only people on the study team will have access to the information. 
  
14.3 
Data Monitoring and Cleaning  
Data monitoring and cleaning will be overseen by the data coordinating center 
(DCC) at the coordinating site. Data collection will be monitored on a weekly 
basis by the study coordinator using the dashboard function on REDCap.  
 


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Appendix 
 
Appendix 1. SAP 
Appendix 2. Instructions for self-sample collection  
Appendix 3. DEQ-5 Questionnaire 
Appendix 4. SPEED Questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 2. Instructions on Self-Collected Rectal Samples 
 


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Appendix 3. DEQ-5 Questionnaire 
 


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Appendix 4. SPEED Questionnaire 
 
For the Standardized Patient Evaluation of Eye Dryness (SPEED) Questionnaire, please answer the following questions by 
checking the box that best represents your answer. Select only one answer per question.
1. Report the type of SYMPTOMS you experience and when they occur: 
2. Report the FREQUENCY of your symptoms using the rating list below: 
3. Report the SEVERITY of your symptoms using the rating list below: 
4. Do you use eye drops for lubrication?
YES
NO
If yes, how often?
Cornea. 2013 Sep;32(9):1204-10    
© 2011 TearScience, Inc. All rights reserved.
13-ADV-123 A
SPEED
TM QUESTIONNAIRE
Dryness, Grittiness or Scratchiness
Soreness or Irritation
Burning or Watering
Eye Fatigue
Symptoms
 
 Yes 
              No 
          Yes                    No                    Yes                    No
Within past 72 hours
At this visit
Within past 3 months
0 = Never          1 = Sometimes          2 = Often          3 = Constant
Dryness, Grittiness or Scratchiness
Soreness or Irritation
Burning or Watering
Eye Fatigue
Symptoms
            0                       1                        2                       3
0 = No Problems       
1 = Tolerable - not perfect, but not uncomfortable       
2 = Uncomfortable - irritating, but does not interfere with my day
3 = Bothersome - irritating and interferes with my day
4 = Intolerable - unable to perform my daily tasks
Dryness, Grittiness or Scratchiness
Soreness or Irritation
Burning or Watering
Eye Fatigue
Symptoms
            0                       1                        2                       3                        4
Name: _________________________________      Date: ____/____/____      Sex:    M    F  (Circle)      DOB: ____/____/____
For office use only
Total SPEED score (Frequency + Severity) = ____/28