A Phase I/II Randomized, Double-Masked Placebo-Controlled Study For Determining The Safety Of Processed Amniotic Fluid (PAF) Drops After Photorefractive Keratectomy
Phase: PHASE1
Conditions: Photorefractive Keratectomy
Sponsor: University of Utah

Study Title 
A Phase I/II Randomized, Double-Masked 
Placebo-Controlled Study for Determining the 
Safety of Processed AmnioƟc Fluid (PAF) Drops 
aŌer PhotorefracƟve Keratectomy 
ClinicalTrials.gov ID (NCT Number) 
NCT04281004 
Principal InvesƟgator (PI) 
Mark Miﬄin, MD 
Document (ICF, Protocol, SAP) 
Protocol 
Update Date (Approval Date) 
December 1, 2021 

A Randomized, Double-Masked, Placebo-Controlled Study
For Determining The Safety Of Processed Amniotic Fluid
(pAF) Drops After Photorefractive Keratectomy.
(PRK)
Amniotic Fluid Trial Network
Cell Therapy & Regenerative Medicine
Protocol Version 1.05 
Version Date: December 01, 2021 
Printing Date: December 01, 2021

Copyright ⃝c 2016-2017. University of Utah School of Medicine on behalf of the Principal 
Investigator, Mark Miﬄin, M.D. and the Amniotic Fluid Trial Network (PRK). All rights re-
served.
This protocol is PRK Protocol Number 1.05, and has been authored by Mark Miﬄin, M.D., 
University of Utah, for implementation with the PRK investigators.

Protocol 1.05 (Dr. Miﬄin)
Page 3 of 36
PROTOCOL TITLE:
A Randomized, Double-Masked, Placebo-Controlled Study For Determining The Safety Of 
Processed Amniotic Fluid (pAF) Drops After Photorefractive Keratectomy.
Short Title: PRK
PRK Protocol Number: 1.05
Lead Investigator and Author:
Mark Miﬄin, M.D.
University of Utah
Protocol Version: 1.05
Version Date: December 01, 2021
I conﬁrm that I have read this protocol, I understand it, and I will conduct the study according 
to the protocol. I will also work consistently with the ethical principles that have their origin in 
the Declaration of Helsinki and will adhere to the Ethical and Regulatory Considerations as 
stated. I conﬁrm that if I or any of my staﬀ are members of the Institutional Review Board, we 
will abstain from voting on this protocol, its future renewals, and its future amendments.
Principal Investigator Name:
Principal Investigator Signature:
Date:
PRK Protocol Version 1.05
Protocol Version Date: December 01, 2021 
Amniotic Fluid Trial Network

Contents
Contents
4
List of Tables
6
1
Synopsis
7
2
Objectives
9
3
Rationale and Background
9
3.1
Photorefractive Keratectomy (PRK)
. . . . . . . . . . . . . . . . . . . . . . .
9
3.2
Amniotic ﬂuid (AF):
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10
3.3
Processed Amniotic Fluid (pAF): Preliminary Clinical Data . . . . . . . . . . .
12
4
Eligibility Criteria
12
5
Study Design and Procedures
13
5.1
Schedule of Events
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
5.2
Dosage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16
5.3
Drug Dispensation and Randomization . . . . . . . . . . . . . . . . . . . . . .
16
5.4
Assessment of Primary Endpoint(Safety) . . . . . . . . . . . . . . . . . . . . .
17
6
Safety Monitoring
17
6.1
Adverse Event Reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17
6.1.1
Deﬁnition of Adverse Event and Serious Adverse Event . . . . . . . . .
18
6.1.2
Classiﬁcation of an Adverse Event (Relatedness, Severity, and Expect-
edness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
18
6.1.3
Treatment or Action Taken: . . . . . . . . . . . . . . . . . . . . . . . .
20
6.1.4
Outcome of Event:
. . . . . . . . . . . . . . . . . . . . . . . . . . . .
20
6.1.5
Time Period for Adverse Events . . . . . . . . . . . . . . . . . . . . .
20
6.1.6
Data Collection Procedures for Adverse Events . . . . . . . . . . . . .
20
6.1.7
Unanticipated Problems (UP) . . . . . . . . . . . . . . . . . . . . . . .
21
6.1.8
Monitoring Serious Adverse Events
. . . . . . . . . . . . . . . . . . .
21
6.1.9
Follow-up of Serious, Unexpected and Related Adverse Events . . . . .
22
4

Protocol 1.05 (Dr. Miﬄin)
Page 5 of 36
7
Assessment of secondary endpoints
22
8
Other Medications
22
9
Patient Withdrawal From Study
23
10 Discontinuation of Study Drug
23
11 Discontinuation of Study
23
12 Statistical Considerations
24
12.1 General Statistical Methods:
. . . . . . . . . . . . . . . . . . . . . . . . . . .
24
12.2 Analyses for Other Outcomes:
. . . . . . . . . . . . . . . . . . . . . . . . . .
24
12.3 Statistical Power and Sample Size: Time to complete re-epithelization . . . . .
25
12.4 Sample Size calculations for pAF PRK study
. . . . . . . . . . . . . . . . . .
25
12.5 Sample size calculations: . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
25
12.6 Analysis of Safety Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26
13 Data Management
27
13.1 Clinical Site Data Management . . . . . . . . . . . . . . . . . . . . . . . . . .
27
13.2 Study Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
27
13.2.1 Site Monitoring Plan . . . . . . . . . . . . . . . . . . . . . . . . . . .
28
13.2.2 Clinical Site Monitoring
. . . . . . . . . . . . . . . . . . . . . . . . .
28
13.2.3 Remote Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28
14 Protection of Human Subjects
29
14.1 Institutional Review Board Approval . . . . . . . . . . . . . . . . . . . . . . .
29
14.2 Informed Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29
14.3 Potential Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29
14.4 Protection Against Potential Risks . . . . . . . . . . . . . . . . . . . . . . . .
29
14.5 Potential Beneﬁts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29
15 Regulatory Considerations
29
15.1 Food and Drug Administration . . . . . . . . . . . . . . . . . . . . . . . . . .
29
15.2 Health Insurance Portability and Accountability Act . . . . . . . . . . . . . . .
30
15.3 Inclusion of Women and Minorities . . . . . . . . . . . . . . . . . . . . . . . .
30
15.4 Protocol Amendments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
30
16 Data Coordinating Center
30
16.1 Security and Conﬁdentiality . . . . . . . . . . . . . . . . . . . . . . . . . . . .
32
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16.2 Record Access . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33
17 Bibliography
34
List of Tables
1
Schedule of Events
. . . . . . . . . . . . . . . . . . . . . . . . .
15
6

Protocol 1.05 (Dr. Miﬄin)
Page 7 of 36
1
Synopsis
Title
A Randomized, Double-Masked, Placebo-Controlled Study for deter-
mining the safety of processed Amniotic Fluid (pAF) Drops after Pho-
torefractive Keratectomy.
Short Title
pAF for the treatment of PRK
IRB Number
00099569
IND
19025
Phase
I/II
Design
This is a randomized, double-masked, placebo-controlled study to deter-
mine the safety of pAF in patients who undergo PRK.
Study Duration
Two years
Study Center(s)
Single Center-John A. Moran Eye Center
Objectives
Primary Objectives:
• To determine the safety of using processed Amniotic Fluid (pAF)
in patients following PRK.
Secondary Objectives:
• To determine if pAF hastens re-epithelialization following PRK
compared to placebo.
• To determine if pAF reduces post-operative pain following PRK
compared to placebo.
• To determine if pAF aﬀects visual outcome following PRK com-
pared to placebo.
• To determine if pAF aﬀects ocular surface staining and corneal
regularity following PRK compared to placebo.
Continued on next page
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Protocol 1.05 (Dr. Miﬄin)
Continued from previous page
Number of
Subjects
63 patients
Diagnosis and
Main Eligibility
Criteria
Inclusion:
1. Patients aged 21 years and older.
2. Patients undergoing PRK for visual correction in both eyes.
3. Willing and able to give consent for study participation and comply
with study procedures, including follow-up visits.
Exclusion:
1. Patients with any active eye disease, including keratoconus or any
other ectactic disorders.
2. Patients with documented uncontrolled diabetes.
3. Patients with severe dry eye as measured by corneal staining.
4. Patients with calculated PRK treatment resulting in residual stro-
mal bed <300 um.
5. Patients who have had previous eye surgery or refractive laser
procedures.
6. Patients with any active collagen vascular disease.
7. Patients who do not have potential of 20/20 or better best-corrected
vision in each eye.
Study Product,
Dose, Route,
Regimen
Individual patients will be randomized to one of two post-operative drop
regimens, control eyes that will receive placebo saline solution (NaCl
0.9%, Baxter Medical), and study eyes that will receive pAF four times
daily for seven days.
Both eyes of all patients will otherwise be treated with the standard post-
operative drop regimen for our center. This includes moxiﬂoxacin 0.3%,
prednisolone acetate 1%, and ketorolac 0.5% on a tapering schedule.
A bandage contact lens will also be placed as per standard post-PRK care.
All patients will be instructed to use supplemental preservative free
artiﬁcial tears from individual vials (any brand) no less than 3 but up to
8 times a day for both eyes for the ﬁrst 7 days.
Continued on next page
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Protocol 1.05 (Dr. Miﬄin)
Page 9 of 36
Continued from previous page
Statistical
Methodology
Standard statistics will be calculated and used to describe the two treat-
ment groups in terms of all study variables. Statistics will be compiled
for each variable at the study time points listed in the data collection
protocol.
2
Objectives
Primary Objectives:
a. To determine the safety of using pAF to improve ocular surface healing in PRK patients
compared to use of placebo drops.
Secondary Objectives:
a. To determine if pAF hastens re-epithelialization in patients following PRK compared to
placebo.
b. To determine if pAF reduces post-operative pain following PRK compared to placebo.
c. To determine if pAF aﬀects visual outcome following PRK compared to placebo.
d. To determine if pAF aﬀects ocular surface staining and corneal regularity following PRK
compared to placebo.
3
Rationale and Background
3.1
Photorefractive Keratectomy (PRK)
Photorefractive Keratectomy (PRK) is a common elective surgery used to correct refractive
errors (nearsightedness, farsightedness, and astigmatism). An excimer laser is used to remove
stromal corneal tissue to achieve the desired refractive outcome. The corneal epithelium is
removed prior to excimer laser treatment, creating a very well controlled and reproducible
surgical injury to the ocular surface. Post-operative healing is easily monitored and quite
predictable, but does cause potential discomfort and visual blurring for the patient, hence any
supportive measures or medication that hastens epithelial healing and recovery is desirable to
allow patients to regain visual function more quickly.1, 2 In rare circumstances, the creation of
these epithelial defects may also be associated with other side eﬀects or complications including
delayed epithelial healing, recurrent erosions, or dry eye. We propose that amniotic ﬂuid
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Protocol 1.05 (Dr. Miﬄin)
drops may be beneﬁcial in promoting ocular surface healing following PRK. Puriﬁed amniotic
ﬂuid (pAF) contains anti-inﬂammatory, anti-microbial and regenerative factors similar to solid
amniotic membrane.3 Amniotic membrane has growth factors and natural anti-inﬂammatory
factors and has demonstrated therapeutic eﬀect following a variety of ocular surface injuries or
surgery including: Stevens Johnson Syndrome and pterygium removal.4, 5 Anecdotal experience
has indicated that amniotic ﬂuid eye drops may be beneﬁcial in graft-versus-host disease, but
controlled studies are needed to determine if this has clear beneﬁcial eﬀects.
3.2
Amniotic ﬂuid (AF):
Early after conception and until the mothers water breaks for the delivery of their infant, the
fetus is bathed in amniotic ﬂuid. AF functions as a supportive cushion to the fetus and provides
a protective environment. AF is a rich source of nutrients, cytokines and growth factors that are
required for fetal development and maturation.6 AF also contains stem cells with the potential
to diﬀerentiate along multiple cell lineages.7, 8 The protective and regenerative properties
of AF are achieved via the exchange of water and solutes with surrounding tissues. This is
accomplished via the utilization of diﬀerent pathways during the course of a pregnancy that
likely contribute to changes in the composition of the AF with gestational age.6 A report
that concentrates of AF inhibited the development of peritonitis was among some of the ﬁrst
evidence that AF had protective biological properties.9 This was followed by a publication
by Shimberg and co-workers that AF accelerates defense-repair mechanisms within damaged
joints.9, 10 Since these early publications, more sophisticated evaluations have revealed the
presence of antimicrobial, immunomodulatory, and growth-promoting activities in AF.6 Reports
about antimicrobial activity in AF diﬀers11 among investigators. Some studies show that AF
is inhibitory, while others show no eﬀect against the same microorganisms. Yet, other reports
provide evidence that AF with low antimicrobial activity is associated with a high incidence
of an infectious syndrome in pregnant women.12 Components with antimicrobial, antiviral
and antifungal activity that are present in AF include lysozyme, peroxidase, transferrin, -lysin,
immunoglobulins and zinc-peptide complexes.11 Immunomodulatory properties of AF are
evident from studies showing that enteral feeding of AF suppresses the pro-inﬂammatory
responses in preterm pigs with necrotizing enterocolitis.13 While growth promoting activities of
AF are supported by animal studies as well as by in vitro studies showing that AF can enhance
neochondrogenesis,14 regenerate peripheral nerves15 and bone,16 accelerate re-epithelialization
in corneas,17 and promote healing of human skin wounds.18 Some of the factors that are found
in AF that may contribute to these activities include inﬂammatory mediators that include, but
are not limited to TNF-a, IL-6, IL8, and IL-10,19 trophic factors that include EGF, IGF-1, FGF,
HGF and TGF-a,20–24 and HA, an important factor in promoting re- epithelialization in human
skin wounds.18
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Based on the hypothesis that nutrients, cytokines and growth factors contained in the non-
cellular fraction of AF are useful for reparative and regenerative treatments in patients, Pierce et
al conducted a study at the University of Utah to address three issues. The ﬁrst was to determine
the feasibility of consenting and screening volunteer donors for the routine collection of AF from
full-term pregnant women scheduled for caesarean- section (C-sections) and then processing the
AF for clinical applications. The second aim was to develop a processing method that resulted
in a cell-free AF preparation suitable for clinical applications. The third goal was to gain a better
understanding about components of AF procured from full-term pregnancies.
With the above 3 goals in mind, human AF was collected by the staﬀof the Obstetrical and
Gynecological department at the University of Utah hospital and was processed by technical
staﬀof the Cell Therapy and Regenerative Medicine (CTRM) facility at the University of
Utah. Physician executed abdominal incisions were performed through the abdominal and
uterine muscles without cutting into the amnion membrane. Using a sterile soft suction catheter
connected to a sterile MediVac Suction Container (Cardinal Health, Waukegan, IL), a blunt
end insertion with a catheter was made into the amnion membrane and the AF was aseptically
suctioned into a MediVac Container. The container was labelled, wrapped in frozen Insul-ice
mats (Fisher Scientiﬁc, Hanover Park, IL) and placed in a temperature-monitored shipper that
was validated for transport between 2 and 8 ◦C. The AF was transported to the CTRM facility
at the University of Utah. Upon arrival at the CTRM facility, the product was immediately
placed into a refrigerator at 2-8 ◦C until processing occurred. At the time of processing, the
MediVac container with AF was aseptically placed in a biological safety cabinet and the AF
was transferred via aseptic techniques into sterile centrifuge tubes. The total volume and
gross appearance of the AF were recorded and samples were removed for sterility testing,
cell counts and other relevant testing. The AF was centrifuged at 1400Xg for 20 min at 4 ◦C.
Once centrifugation was complete, the supernatant was expressed into a new transfer pack and
the remaining cell pellet was characterized and cultured as described below. The supernatant
from the AF was processed using a proprietary ﬁltration technology to sterilize and eliminate
cellular debris from the ﬁnal product. AF collections and ﬁnal products were evaluated for
total volume, ﬂuid chemistries, total protein, and hyaluronic acid (HA) levels. Final products of
processed AF (pAF) were also assessed for their cellular content and for their protein proﬁles
using quantitative antibody arrays.
To validate the above described approach for collecting and processing AF, 36 pregnant
women consented and passed the donor screening criteria. AF was successfully collected from
17 individuals. Median AF volumes were 70 mL (range 10-815 mL; n = 17). Fluid chemistries
were similar, but some diﬀerences were noted in HA levels and cytokine proﬁles. Cytokine
arrays revealed that an average of 304 ± 20 (mean±SD; n=3) of 400 proteins tested were
present in AF with a majority of cytokines associated with host defense. Among the 300
proteins present in pAF were two proteins with functions known to be associated with ocular
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Protocol 1.05 (Dr. Miﬄin)
development and corneal stroma maintenance.
3.3
Processed Amniotic Fluid (pAF): Preliminary Clinical Data
The presence of peptides in processed amniotic ﬂuid (pAF) that have roles in ocular development
and corneal stroma maintenance, along with the understanding that one of the in utero beneﬁcial
functions of AF is to bathe the fetuses eyes, led us to hypothesize that pAF may be a valuable
treatment regimen to improve corneal re-epithelialization following PRK.
Our pAF has been clinically used in over 2000 applications for over 100 diﬀerent conditions.
A majority of treatments have been for wounds and burns with 3 patients receiving pAF for the
treatment of ocular GVHD. No adverse events have been directly associated with the injection
of pAF or when pAF has been topically applied for the treatment of ocular GVHD.
For the 3 patients treated for ocular GVHD at the University of Utah, each patient received a
dose of 0.5 ml per eye daily in 2 divided doses, and no toxicities were observed. One patient
with severe dry eye had a good partial response with a decrease in the need for artiﬁcial tears and
the use of PROSE lenses. A second patient had stabilization of the disease after discontinuation
of all immunosuppression. The third patient reported no change.
4
Eligibility Criteria
Inclusion Criteria:
1. Patients aged 21 years and older.
2. Patients undergoing PRK for visual correction in both eyes.
3. Willing and able to give consent for study participation and comply with study procedures,
including follow-up visits.
Exclusion Criteria:
1. Patients with any active eye disease, including keratoconus or any other ectactic disorders.
2. Patients with documented uncontrolled diabetes.
3. Patients with severe dry eye as measured by corneal staining.
4. Patients with calculated PRK treatment resulting in residual stromal bed <300 um.
5. Patients who have had previous eye surgery or refractive laser procedures.
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Page 13 of 36
6. Patients with any active collagen vascular disease.
7. Patients who do not have potential of 20/20 or better best-corrected vision in each eye.
5
Study Design and Procedures
This is a randomized, double-masked, placebo-controlled study to evaluate the safety of using
pAF in patients following PRK.
Pre-operatively each patient will be randomized to one of two post-operative drop regimens.
Neither the patient nor their doctors will know if they are receiving pAF or placebo. The vials
containing pAF and placebo (NaCl 0.9%, Baxter Medical) will be packaged the same by the
Cell Therapy and Regenerative Medicine (CTRM). The assigned drop will be administered in
both eyes throughout the study.
Regimen 1 will serve as the placebo control. For the ﬁrst week only, patients in this regimen
will receive placebo saline solution (NaCl 0.9%, Baxter Medical) for use four times daily.
Patients will otherwise be treated with our standard post-operative drop regimen, which includes
prednisolone acetate 1% suspension (4x/day for 7 days, then 2x/day for 2 additional weeks),
moxiﬂoxacin 0.3% (4x/day for 7 days), and ketorolac 0.5% (2x/day for 3 days only). The
prednisolone acetate will be tapered to ﬂuorometholone 0.1% suspension (3x/daily on days
22-60 then 2x/daily on days 61-90). A bandage contact lens will also be placed following
surgery as is standard care for PRK patients.
Regimen 2 will have a bandage contact lens placed post-PRK and have an identical drop
regimen with the exception of replacing the placebo saline with pAF four times daily for one
week.
All patients will be instructed to use supplemental preservative free artiﬁcial tears from
individual vials (any brand) no less than 3 but up to 8 times a day in both eyes the ﬁrst week.
After the ﬁrst week, they will continue to be allowed use of preservative free tears as needed per
the standard post PRK regimen in our center.
Patients are instructed to use oral medications as needed post-surgery. Ibuprofen or naproxen
may be helpful in preventing pain for the ﬁrst 3 days following the procedure. Patients will
also be prescribed hydrocodone-acetaminophen 5-325 mg every four hours as needed for
breakthrough pain. Patients will record how many pain pills are taken each day on a worksheet
provided by the research team after the surgery.
The patients will have a pain rating sheet and will be asked to grade their peak subjective
pain on a scale of 0 to 10 (with 10 being the most painful) for the ﬁrst 7 days. They will grade
each eye separately.
The day of surgery will be designated day 1, as surgery occurs in the early morning. The
size of the epithelial defect created by PRK will be measured at the time of surgery completion.
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Protocol 1.05 (Dr. Miﬄin)
Surgeons will administer the ﬁrst dose of masked study drug (placebo or pAF ﬂuid) directly
after surgery, the morning of day 1, and three more times that day. Patients will then administer
drops four times a day total for the next 6 days, for a total of 7 days of study drug administration.
The patients will begin ﬁlling out the pain survey the night of day 1.
At a designated time on day 1 (2nd visit post-surgery), 3, 4, 5, 6, 7, and 8 each patient will
be examined by one of the study investigators who will be masked to the drop regimen. The
investigator will grade the size of the epithelial defect on day 1(AM), 3, 4, 5, 6, 7, and 8 by
measuring the largest horizontal and vertical meridians using slit lamp biomicroscopy. If a
patient has re-epithelialized by an earlier exam day (i.e., day 3) they will be able to skip all
subsequent in person examinations except for day 8 (i.e., skip days 4, 5, 6, and 7). All patients
will still need to record their pain rating scale at the end of each day and return for the day 8
visit.
The study investigators will be masked to which drop is being used for each patient. Patients
will be required to store all drops in the freezer and will be masked as to which type of drop is
being used.
Patients will also be seen at post-operative months 1, 3, 6 and 12. At each of these visits
visual acuity and manifest refraction will be checked, along with a measure of ocular surface
staining and corneal regularity. These are all standard procedures performed for post-operative
PRK patients regardless of study participation.
5.1
Schedule of Events
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Baseline
Day of Surgery
(Friday)
Days after Surgery
Pre-Op
Screening1
Day 1
(AM)
Day 1
(2nd
visit
post-
surgery)
Day 3
Day 4*
Day 5*
Day 6*
Day 7*
Day 8 Friday AM
(in-person visit)*
Month
1 (Day
30±10)*
Month
3 (Day
90±14)*
Month
6 (Day
180±30)*
Month 12
(Day
365±30)*
Informed Consent
X
Eligibility
X
Medical History
X
Concomitant
medications2
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization3
X
PRK Surgery
X
Dispense Masked
Study Drug4
X
Study Drug
Compliance5
X
X
X
X
X
X
Pain Assessment6
X
X
X
X
X
X
Size of Epithelial
Defect7
X
X
X
X
X
X
X
Uncorrected VA8
X
X
X
X
X
X
Manifest Refraction
X
X
X
X
X
Target Post-OP
Refraction
X
BCVA8
X
X
X
X
X
Ocular Surface
Staining
X
X
X
X
X
Corneal Topography
X
X
X
X
X
Ocular Adverse
Events
X
X
X
X
X
X
X
X
X
X
X
1. The pre-op screening/baseline visit may be performed in 2 separate visits.
2. Record systemic medications at baseline and any subsequent changes; Record start and stop dates of ocular medications prescribed as standard care post-PRK surgery, note any deviations from prescribed
regimens.
3. Randomization to study drug assignment will occur when patient presents day of surgery.
4. First dose of study drug applied to each eye at completion of surgery. Three additional doses administered by patient on day of surgery, then 4x per day through Day 7.
5. Patient will document each use of study drug and oral pain medication in diary.
6. Patient will assess highest level of daily pain/discomfort at the end of each day.
7. Grade defect dimensions until healed.
8. Visual acuity will be measured on Snellen charts. Conversion to logMAR equivalents will be completed on the back end by the Biostatisticians.
* Study procedures may be performed via telehealth or by phone at the discretion of the treating provider.
Table 1: Schedule of Events

Page 16 of 36
Protocol 1.05 (Dr. Miﬄin)
5.2
Dosage
Based on randomization to receive the test article or the placebo, the patient will receive Comar
Eye Dropper Bottles that contain pAF or control saline solution (NaCl 0.9% Baxter Medical).
The patient will apply one drop 1-2 drops (one drop is approximately 50µL) in each eye four
times daily for a total of 7 days. The patient will apply 1-2 drops (0.25mL) in each eye four
times daily for a total of 7 days. Patients will be instructed to treat their eyes at regular intervals
during the day, approximately at breakfast, lunch, dinner, bedtime, or the equivalent. Surgeons
will administer the ﬁrst dose of pAF or placebo to patients the morning of surgery, Day 1.
The study treatment assignment for each patient will be randomly selected. Neither the
patient nor their doctors will know if they are receiving pAF or placebo. The eyedropper bottles
containing pAF and the placebo will be packaged identically.
Patients will be instructed to use preservative free artiﬁcial tears from individual vials (any
brand) no less than 3 but up to 8 times a day in both eyes during the ﬁrst 7 days of the study.
5.3
Drug Dispensation and Randomization
Upon acceptance into the study, and prior to surgery, the patient will be randomized as to
whether they will receive the pAF or the placebo. The study coordinator will notify CTRM
who will then select, package and release Comar Eye Dropper Bottles containing pAF or the
placebo saline solution (NaCl 0.9% Baxter Medical) to the clinical site. A small box of eight (8)
eyedropper bottles containing 3.0 mL of either pAF or placebo will be provided in a Thermosafe
box with dry ice to the patient for 7 days of treatment.
The small boxes will be packaged on dry ice and transported to the patient. The patient will
be provided with the instructions on how to store the eye drops at home, how to use the eye
drops and how to handle the dry ice. The patient will transport the eye drops to their home and
immediately transfer them to their kitchen refrigerator freezer. For each day of use the patient
will dispense the eye drops as follows:
1. The patient will remove the box containing the bottles from the freezer and remove a
single bottle from the small box. They will verify that the lot number on the bottles
match the labels on the small box. If the lot numbers on the bottle do not match the lot
numbers on the small box, the patient will be instructed to notify the study coordinator.
The study coordinator will notify CTRM, and CTRM will replace the bottle with the
correct lot number. The patient will have to come to the Moran to trade out the bottle(s).
On Day 1 of surgery, surgeons will administer the ﬁrst dose prior to patients leaving
the surgery center).
2. They will thaw the frozen ﬂuid in the bottle by placing the bottle in their hand or by
placing it at room temperature until the entire volume is completely thawed.
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3. For the 1st daily application (e.g. morning), they will remove the cap from the bottle.
They will invert the bottle over the right eye and squeeze to dispense 1-2 drops into the
right eye. They will then invert the bottle over the left eye and squeeze to dispense 1-2
drops into the left eye. They will then tightly cap the bottle.
4. They will then place the thawed bottle into refrigerate at a temperature between 1◦C and
10◦C (e.g. refrigerator). They will not re-freeze the thawed bottle.
5. For each subsequent application of the day, they will remove the same thawed bottle that
they used for the 1st application from the refrigerator and repeat steps 3 and 4.
6. After the ﬁnal application of the day, they will place the bottle into a box provided to
them for the placement of used bottles.
7. The patient will repeat these steps for each daily application.
8. After the 7th day of treatment, the patient will return all used and unused bottles to the
clinic. This will allow us to account for drug dispensed and monitor compliance.
9. The patients will also voluntarily record if they missed any doses of their medication.
5.4
Assessment of Primary Endpoint(Safety)
Safety and tolerability will be evaluated by the PI from the ﬁndings of scheduled eye exami-
nations at days 1 (day of surgery) through 8 (in-person follow-up visit) and at months 1, 3, 6
and 12 after initiation of pAF therapy. More frequent safety evaluations may be performed if
clinically indicated or at the discretion of the investigator. Information from the eye examination
at these additional safety evaluations will be collected and entered into the EDC as adverse
events as appropriate.
All ocular adverse events will be recorded from randomization through Month 12. Any
events that occur from time of consent to randomization will be recorded as medical history.
6
Safety Monitoring
6.1
Adverse Event Reporting
The site investigator is responsible for evaluating all adverse events at their Clinical Center
and ensuring that they are properly reported. Only ocular adverse events (as speciﬁed in 6.1.2)
that occur during this study will be recorded. The nature of each experience, date and time
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(where appropriate) of onset, outcome, course, and relationship to treatment will be documented.
6.1.1
Deﬁnition of Adverse Event and Serious Adverse Event
Adverse Event (AE) means any untoward medical occurrence associated with the use of an
intervention in humans, whether or not considered intervention-related (21 CFR 312.32 (a)). An
event constitutes a disease, a set of related signs or symptoms, or a single sign or symptom.
Serious Adverse Event (SAE): A serious adverse event (SAE) for this population is an
adverse event that:
1. results in death; or
2. is life-threatening (the patient was, in the view of the site investigator, in immediate
danger of death from the event as it occurred); or
3. requires inpatient hospitalization or prolongs an existing hospitalization; or
4. results in persistent or signiﬁcant disability or incapacity; or
5. results in congenital anomaly/birth defect; or
6. any other event that, based upon appropriate medical judgment, may jeopardize the
subject’s health and may require medical or surgical intervention to prevent one of the
other outcomes listed in this deﬁnition.
6.1.2
Classiﬁcation of an Adverse Event (Relatedness, Severity, and Expectedness
Relatedness: The suspected relationship between study interventions and any adverse event
will be determined by the site investigator using the criteria below. Relatedness must be assessed
by an investigator and may not be assessed by a research coordinator.
• Not Related: The event is clearly related to other factors, such as the subject’s clinical
state, therapeutic interventions, or concomitant drugs administered to the subject.
• Possibly Related: The event follows compatible temporal sequence from the time of
beginning the assigned study intervention, but could have been produced by other fac-
tors such as the subject’s clinical state, therapeutic interventions, or concomitant drugs
administered to the subject.
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• Probably Related: The event follows a reasonable temporal sequence from the time of
beginning the assigned study intervention, and cannot be reasonably explained by other
factors such as the subject’s clinical state, therapeutic interventions, or concomitant drugs
administered to the subject.
Severity:
The severity, which is a measure of intensity, of clinical adverse events and laboratory abnor-
malities will be recorded by the site investigator and categorized. The following guidelines will
be used to describe severity.
• Mild: The event requires minimal or no treatment and does not interfere with the partici-
pants daily activities.
• Moderate: The event results in a low level of inconvenience or concern with the therapeutic
measures. Moderate events may cause some interference with functioning.
• Severe: The event interrupts a participants usual daily activity and may require systemic
drug therapy or other treatment. Severe events are usually potentially life-threatening or
incapacitating. Of note, the term “severe” does not necessarily equate to “serious”.
Expectedness of the Event:
All adverse events, including serious adverse events, will be evaluated as to whether their
occurrence was expected or unexpected. An AE will be considered unexpected if the nature,
severity, or frequency of the event is not consistent with the risk information described for the
study intervention. The following events will be reported as AEs::
• Infection
• Delayed healing of the epithelial defect (after the 7-day post-surgery visit)
• Scarring or haze
• Severe irritation of conjunctiva or periocular skin in the ﬁrst week
• Poor refractive outcome (worse than 20/40 at 3 months or beyond)
• Pain or severe irritation at 3 months or beyond
• Corneal erosion
• Corneal haze
• Need for touch up surgery
There is a theoretical risk of infection with amniotic ﬂuid drops. A patient could have an
immune reaction to the study drops.
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6.1.3
Treatment or Action Taken:
For each adverse event, the site investigator will record whether an intervention was required:
• Medical or surgical procedure
• Concomitant medication: started, changed, or discontinued
• Other, specify
• No action taken
6.1.4
Outcome of Event:
Finally, the site investigator will record the clinical outcome of each adverse event as follows:
• Death
• Recovered and the patient returned to baseline status
• Recovered with permanent sequelae
• Symptoms persist
6.1.5
Time Period for Adverse Events
For purposes of this study, events that occur following randomization through the last study
visit will be reported as adverse events. Serious adverse events, unexpected medically attended
events, and new onset chronic illnesses will be recorded from randomization through twelve
months after the last study dose. Speciﬁcally, events that occur following consent to participate
in the study, but prior to actual randomization, are not adverse events. These should be recorded
as baseline conditions.
6.1.6
Data Collection Procedures for Adverse Events
After patient randomization all adverse events (including serious adverse events) will be recorded
according to relatedness, severity, and expectedness, as well as their duration and any treatment
prescribed. Any medical condition present at the time of randomization, recorded in the patient’s
baseline history at study entry, which remains unchanged or improves (unless the clinician feels
it is clinically relevant), will not be recorded as an adverse event at subsequent evaluations.
However, worsening of a medical condition that was present at the time of randomization will
be considered a new adverse event and reported.
Adverse events will be coded using the MedDRA coding vocabulary. Coding will be done
centrally at the Data Coordinating Center as this requires speciﬁc training.
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6.1.7
Unanticipated Problems (UP)
Unanticipated problems (UP) are deﬁned as incidents, experiences, or outcomes that are un-
expected, related or possibly to participation in the study, and suggest that the research places
subjects at a greater risk of harm than was previously known or recognized. The site investi-
gator will report unanticipated problems to the Data Coordinating Center within 24 hours of
becoming aware of the event. A detailed completed report will be required to be sent to the
Data Coordinating Center within 3 working days of the event. After receipt of the complete
report, the Data Coordinating Center will report these unanticipated problems to the CTRM in
an expedited manner (as close to 24 hours as possible).
In accordance with local IRB requirements, the site investigator may be required to report
such unanticipated problems to the IRB in addition to notifying the Data Coordinating Center. In
the event that the medical monitor believes that such an event warrants emergent suspension of
enrollment in the trial, and funding staﬀcannot be reached expeditiously, the Data Coordinating
Center will notify the study investigator and all site investigators to cease enrollment in the trial.
6.1.8
Monitoring Serious Adverse Events
A qualiﬁed physician will be designated to fulﬁll the function of the medical monitor for this
study. Site investigators and/or research coordinators will report serious adverse events to the
Data Coordinating Center within 24 hours of becoming aware of the event. A detailed completed
report will be required to be sent to the Data Coordinating Center within 3 working days of
the event, and the medical monitor will assess all serious adverse events reported from site
investigators.
For each of these serious adverse events, the site investigator will provide suﬃcient medical
history and clinical details for a safety assessment to be made with regard to continuation of the
trial. The medical monitor will sign oﬀon each SAE report after review. All SAE reports will
be retained at the Data Coordinating Center, and all SAE reports will be available for review by
funding staﬀ. The SAE reporting process may be incorporated into the Electronic Data Capture
(EDC) System in use for the study.
In the unlikely event that the medical monitor believes an unexpected and study-related
SAE warrants emergent cessation of enrollment in the trial, funding staﬀwill be immediately
consulted. If these individuals concur with the judgment of the medical monitor, or if the
funding staﬀcannot be reached expeditiously, the Data Coordinating Center will notify the study
investigator and all site investigators to cease enrollment in the trial. Resumption of enrollment
will not occur without consent of the funding staﬀ.
In accordance with local IRB requirements, the site investigator may be required to report
such events to the IRB in addition to notifying the Data Coordinating Center.
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6.1.9
Follow-up of Serious, Unexpected and Related Adverse Events
All serious, unexpected and related adverse events, that are unresolved at the time of the patient’s
termination from the study, will be followed by the site investigators until the events are resolved,
subject is lost to follow-up, the adverse event is otherwise explained or has stabilized, or 12
months have passed from the time of last study dose.
7
Assessment of secondary endpoints
1. Re-epithelialization will be graded by trained, masked examiners on days 1, 3, 4, 5, 6,
7, and 8 unless patient re-epithelializes sooner in which case they can skip visits until
day 8. Dimensions of the epithelial defects will be directly measured using slit lamp
bio-microscopy. The baseline epithelial defect will be measured by surgeons on Day 1
at the time of surgery. Examiners will be masked as to which patients are using pAF vs.
placebo. A vertical and horizontal measure of defect in mm will be performed, and defect
area calculated. A complete re-epithelization (absence of a defect) is deﬁned when the
measures equal zero.
2. Pain will be measured through a 0-10 scale on days 1, 2, 3, 4, 5, 6, and 7. Participants will
rate their peak pain at the end of each day and directly return the forms at their in-person
visit on day 8 to the examiners. They will complete a separate survey for each eye.
3. Uncorrected visual acuity will be measured at post-operative day 8, months 1, 3, 6, and
12 by trained physicians.
4. Manifest refraction and best-corrected visual acuity will be measured at months 1, 3, 6,
and 12 by trained physicians.
5. Ocular surface staining will be measured at post-operative months 1, 3, 6, and 12 using
an area density index.25 This is a published and validated index used to measure corneal
staining. Corneal regularity will also be measured at months 1, 3, 6, and 12 with the
Surface Regularity Index (SRI) obtained via Zeiss Atlas 9000 Corneal TopographyTM.
8
Other Medications
• Oral pain medications usage will be tracked for the ﬁrst 7 days.
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9
Patient Withdrawal From Study
• A subject may withdraw their consent at any time without aﬀect to their care.
10
Discontinuation of Study Drug
The study drug will be discontinued if any of the following occur:
• Development of severe ocular infection.
• Any other condition that in the opinion of the treating physician and ophthalmologist are
not compatible with participation in this study.
11
Discontinuation of Study
• Any ocular serious, related and unexpected adverse eﬀect that occurs in 1/3 of the patients
(e.g. 1 out of 3, 2 out 6, 3 out of 9, etc.)
• The determination of the number of patients having serious, related and unexpected ocular
adverse events in the study group will be reviewed by the DSMB, who may be unblinded
to the study drug. Thus, the blind will not be broken throughout the study.
• The purpose of the DSMB is to advise the study investigators regarding the continuing
safety of study subjects and the continuing validity and scientiﬁc merit of the study.
• The DSMB Chairperson will prepare a summary of each DSMB meeting that conveys the
public conclusions of the DSMB, with respect to protocol alterations and recommenda-
tions concerning continuation of the study.
• In the unlikely event that the medical monitor believes an unexpected and study-related
SAE warrants emergent cessation of enrollment in the trial, staﬀand the DSMB chair-
person will be immediately consulted. If these individuals concur with the judgment
of the medical monitor, or if the staﬀand the DSMB chairperson cannot be reached
expeditiously, the DCC will notify the study investigator and all site investigators to cease
enrollment in the trial. Resumption of enrollment will not occur without consent of the
staﬀafter discussion with the DSMB.
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12
Statistical Considerations
12.1
General Statistical Methods:
Simple descriptive statistics of patient characteristics, operation parameters, and vision/ocular
measurements will be calculated (overall and by pAF eye drop group vs. controls) at baseline,
post-op and each follow-up visit. Outcomes will be described using appropriate summary
measures and graphical approaches.
Between-group comparisons will be performed on:
• Time to complete re-epithelization (primary eﬃcacy outcome).
• Visual Acuity (best-corrected and uncorrected) (this measure at 30 days is the key sec-
ondary eﬃcacy outcome).
• Dimensions of the epithelial defects directly measured using slit lamp biomicroscopy
(exploratory eﬃcacy outcome).
• Pain in each eye using a 0-10 point VAS scale on days 1, 2, 3, 4, 5, 6, and 7. (exploratory
eﬃcacy outcome).
• Timing and frequency of use of rescue pain medication.
• Corneal staining and surface irregularity.
• Adverse event rate and complication rate.
For the primary eﬃcacy outcome, a mixed eﬀects model with time to healing as outcome
and assigned treatment arm as a predictor, including a random eﬀect for each patient to model
correlation between eyes in the same participant, will be ﬁt to carry out the primary analysis. A
two-sided probability value with an alpha level of 0.05 will be used to test the null hypothesis
that time to complete re-epithelialization is not diﬀerent between the two treatment arms. The
primary analysis will be performed on an intention to treat basis.
12.2
Analyses for Other Outcomes:
The key secondary eﬃcacy outcome at 30 days will be analyzed (on a logarithmic scale) using a
mixed eﬀects ANOVA model as for the primary aim. Exploratory outcomes will be analyzed in
appropriate fashion; for example, each patients pain level (worst in either eye) will be examined
on each evaluation day and compared between treatment groups for each day, while each patients
peak pain level at any time, and number of days until the patient is pain-free, will be compared
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between treatment arms. A Statistical Analysis Plan will fully delineate all analyses to be
performed, including additional analyses to assess robustness of the primary and secondary
eﬃcacy analyses.
12.3
Statistical Power and Sample Size: Time to complete re-epithelization
Time to complete re-epithelization will be measured from the end of surgery until the date of the
exam where complete re-epithelization is observed. While evaluation times will be collected,
since the time of surgery and the time of the follow-up exam are dependent upon scheduling,
time to complete re-epithelialization will be analyzed as an integer, being simply the number
of calendar days from the day of surgery to the date of the ﬁrst examination demonstrating
complete re-epithelization.
12.4
Sample Size calculations for pAF PRK study
A mixed eﬀects ANOVA model for diﬀerence in time to complete re-epithelization was used to
determine sample size. A within-subject correlation in healing times of r = 0.5 was assumed.
Calculations were performed to achieve a power of 80% and 90% and a level of signiﬁcance of
5% (two sided).
12.5
Sample size calculations:
Eliacik et al.,26 found a mean time to re-epithelization of 3.1 ± 0.6 days for the Comﬁlcon
Group and 3.6 ± 0.5 days for the Lotraﬁlcon Group. We used this 0.5-day diﬀerence as an
estimate of treatment eﬀect, and considered within-group standard deviations in the range of
0.5 to 0.7 days. Another key parameter in the estimation of statistical power is the intraclass
correlation between eyes in the same patient. This correlation was estimated to be in the range
of 0.5 to 0.75, as within-patient healing times have been reported to be nonuniform to a modest
extent in the study PIs experience. The table below shows true treatment diﬀerences detectable
with 80% and 90% power under diﬀerent estimates of the variability of re-epithelization time
and intraclass correlation, assuming that 56 participants (28 participants and therefore 56
eyes in each treatment arm) complete the trial. These values were calculated using PASS
[PASS 15 Power Analysis and Sample Size Software (2017). NCSS, LLC. Kaysville, Utah,
USA, ncss.com/software/pass.], treating the study as a cluster-randomized trial with clusters
(each participants eyes) of size two.
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Assumed
Within-
Group
Standard
Deviation of Primary
Outcome
Assumed ICC between
a Participants Eyes
Treatment Diﬀerence
Detectable with 80%
Power
Treatment Diﬀerence
Detectable with 90%
Power
0.5 days
0.5
0.33 days
0.38 days
0.5 days
0.6
0.34 days
0.39 days
0.5 days
0.75
0.35 days
0.41 days
0.6 days
0.5
0.39 days
0.45 days
0.6 days
0.6
0.41 days
0.47 days
0.6 days
0.75
0.42 days
0.49 days
0.7 days
0.5
0.46 days
0.53 days
0.7 days
0.6
0.47 days
0.55 days
0.7 days
0.75
0.49 days
0.57 days
Based on numerous power estimates (the above and others), a sample size of 56 patients 
completing the trial, yields acceptable power to ﬁnd a signiﬁcant treatment diﬀerence, if the true 
treatment diﬀerence is at least 0.5 days for the time to complete re-epithelialization outcome. 
In order to collect additional safety data and allow for a small number of patients being lost to 
follow-up, the study will enroll a total of 63 participants.
12.6 Analysis of Safety Data
The primary safety analyses will be based on the as-treated population, deﬁned as subjects who 
are randomized and receive at least one dose of study agent. Safety endpoints will include 
ocular adverse events, ophthalmic exam ﬁndings, and use of rescue treatments. The occurrence 
of ocular adverse events will be recorded from the time of randomization through the last study 
visit. AEs will be categorized by System Organ Class (SOC) Preferred Term (PT) using the 
Medical Dictionary for Regulatory Activities (MedDRA) and by severity using the Common 
Terminology Criteria for Adverse Events (CTCAE) dictionary.
In general, all AE tables will be presented by treatment group, causality and severity. Events 
in the right and left eyes will be considered as separate events. The following will be summarized 
and presented overall and by treatment group:
• The number and percentage of subjects experiencing an SAE.
• The number and percentage of subjects experiencing an SAE by preferred term and by
severity of event.
• The number and percentage of subjects experiencing an SAE by preferred term and by
relationship to study drug.
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• The number and percentage of subjects experiencing an AE.
• The number and percentage of subjects experiencing an AE by preferred term and by
severity of event.
• The number and percentage of subjects experiencing an AE by preferred term and by
relationship to study drug.
• The number and percentage of AEs that cause a subject to discontinue study drug.
• The number and percentage of AEs leading to death.
13
Data Management
13.1
Clinical Site Data Management
The Data Coordinating Center (DCC) will develop an electronic data capture system for this
trial. Currently the DCC uses multiple applications, such as OpenClinica or REDCap, and will
elect to use the most appropriate application at the time of implementation of the study.
The DCC will use an electronic discrepancy management system to notify sites of in-
consistent or erroneous data entry, which will be corrected by the clinical site. The discrep-
ancy/management system maintains an audit trail of all discrepancy resolution.
13.2
Study Monitoring
The investigators recognize the importance of ensuring data of excellent quality. Study moni-
toring is critical to this process. Monitoring has been a very eﬀective tool for maintaining data
quality in previous network studies, and we will utilize this process to ensure excellent quality
data in the proposed study. The DCC utilizes risk-based methodology to identify and correct
problems that may arise at sites. The risk-based approach to monitoring focuses on oversight
activities and preventing or mitigating key risks to data quality, as well as to processes critical to
human subject protection and integrity of the trial or study.
Study monitors must be provided with appropriate access to study materials and the medical
records for study subjects. If the medical records are in electronic form, the clinical investigator
or an authorized individual must provide any assistance necessary to facilitate the study monitor’s
review of data in the electronic medical record.
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13.2.1
Site Monitoring Plan
A supplemental study-speciﬁc risk-based monitoring plan, separate from the protocol will be
completed which outlines speciﬁc criteria for monitoring. This plan may include the number of
planned site visits, criteria for focused visits, additional visits or remote monitoring, a plan for
chart review and a follow up plan for non-compliance. The monitoring plan also describes the
type of monitoring that will take place (e.g., sample of all subjects within a site; key data or all
data), the schedule of visits, how they are reported and a time frame to resolve any issues found.
13.2.2
Clinical Site Monitoring
Site monitoring visits will be performed by a trained site monitor during the study period
to ensure regulatory compliance, patient safety, and to monitor the quality of data collected.
Essential document binders, regulatory documents and data collection forms may be reviewed.
Interim visits will take place depending on grant budget, site enrollment, and compliance issues
identiﬁed. The site monitor will provide each site with a written report, and sites will be required
to follow up on any deﬁciencies. It is anticipated that the study monitoring visits for this protocol
will consist of a site initiation visit (prior to patient enrollment), interim visits, and a close out
visit. The site initiation may take place as group training made up of site investigators and
research assistants.
13.2.3
Remote Monitoring
The Data Coordinating Center may supplement on-site monitoring with remote monitoring
activities. Remote monitoring involves detailed review of the data entered by the site and
consultations with the site investigator and/or research coordinator to review safety and data
quality. This may require uploading copies of medical records, patient study ﬁles, regulatory
documentation, or other source documents for the monitor to review. Alternatively, other
methods, such as remotely viewing source documentation, may be utilized. This helps assure
protocol compliance and accurate data collection. The Data Coordinating Center may conduct
more remote monitoring activities early in the trial to assure protocol compliance and identify
any training issues that may exist. Remote monitoring documents will be retained in accordance
with federal requirements.
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14
Protection of Human Subjects
14.1
Institutional Review Board Approval
The Data Coordinating Center and clinical center PI must obtain approval from the IRB prior to
participating in the study. The Data Coordinating Center will track IRB approval status and will
not permit subject enrollment without documentation of initial IRB approval and maintenance
of that approval throughout subsequent years of the project.
14.2
Informed Consent
If a subject is greater than 18 years of age or attains the age of 18 years during the study period,
informed consent is required. Subjects who are capable of giving consent and who are alert
and competent, will be asked, following an appropriate discussion of risks and beneﬁts, to give
consent to the study.
14.3
Potential Risks
Loss of conﬁdentiality of the subject is a potential risk of the study; however, safeguards are in
place to protect against this. There are no known or anticipated additional medical risks from
participating in the trial.
14.4
Protection Against Potential Risks
Regarding loss/breach of privacy and conﬁdentiality, all applicable parties (e.g. clinical sites,
DCC) will be responsible for ensuring that appropriate data security procedures are in place.
14.5
Potential Beneﬁts
There may be a potential beneﬁt in helping decrease pain and healing time with pAF treatment.
15
Regulatory Considerations
15.1
Food and Drug Administration
This trial is being conducted under an Investigational New Drug application. The clinical inves-
tigator at each participating site will complete a Form FDA 1572, “Statement of Investigator.”
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An annual progress report will be submitted to the FDA within 60 days of the anniversary of
the date that the IND went into eﬀect (21 CFR 312.33).
15.2
Health Insurance Portability and Accountability Act
Data elements collected include the date of birth and date of admission. Prior to statistical
analyses, dates will be used to calculate patient age at the time of the study events. The ﬁnal
data sets (used for study analyses and archived at the end of the study) will be de-identiﬁed, and
will exclude these speciﬁc dates. Data elements for race, ethnicity, and gender are also being
collected. These demographic data are required for Federal reporting purposes to delineate
subject accrual by race, ethnicity, and gender.
15.3
Inclusion of Women and Minorities
There will be no exclusion of patients based on gender, race, or ethnicity.
15.4
Protocol Amendments
Any amendments or administrative changes to an IRB approved protocol will not be initiated
without submission of an amendment for IRB review and approval. Any amendments to the
protocol that signiﬁcantly aﬀect the safety of subjects, the scope of the investigation, or the
scientiﬁc quality of the study are required to submit the amendment for FDA review.
16
Data Coordinating Center
The Data Coordinating Center (DCC) in the Department of Pediatrics at the University of
Utah School of Medicine provides data coordination and management services for a variety of
national research networks. Anchoring these services is a new state-of-the art, energy eﬃcient
data center completed in 2013. The data center facility supports more than 1400 users around the
world and provides a secure, reliable, enterprise-wide infrastructure for delivering critical DCC
systems and services. The new data center was built using high industry standards and energy
eﬃcient cooling solutions. The data center is cooled by Rittals LCP inline cooling technology,
providing eﬃciency, redundancy and modularity. Cooling is based upon a hot/cold aisle design
that allows for even air distribution with minimal hot spots. The data center electrical power
system contains a redundant Mitsubishi uninterruptible power system (UPS) with a diesel
backup generator. The data center is protected with a FM200 ﬁre suppression system, early
warning smoke detectors and a heat detection warning system to act as a secondary system to
the smoke detectors. Security guards are on-site conducting access control and rounds. Entry
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into the data center is restricted by card access and layered security measures and controls. The
data center and external building access points are monitored with video surveillance.
• In 2011 the data center began a large scale VMware server virtualization deployment.
Currently, the data center has virtualized about 99% of its environment. The virtual
environment consists of more than 200 virtual servers. The data centers virtualization
solution provides key advantages: high availability in the event of hardware failure,
virtual servers automatically go back online in a seamless process.
• Flexible infrastructure disk storage, memory and processor capacity can be increased or
reallocated at any time.
• Rapid deployment servers can be provisioned on-demand with minimal waiting on
hardware of software.
The data center also enhanced its storage resources by implementing a networked storage
system to support its virtualized environment. The data center currently manages over 50
terabytes of data. The storage solution consists of Dells EqualLogic PS Series Storage system
for providing a virtualized storage area network (SAN). Some of the beneﬁts that are realized
through this technology are:
• Storage architecture is no longer be a bottleneck for IT services;
• Performance is better than with the previous architecture;
• Tiered storage is now possible;
• Provisioning and reclamation of SAN disk will be much easier; and most important;
• The new architecture includes a redesign of the SAN fabric to include complete redun-
dancy.
Production servers running critical applications are clustered and conﬁgured for failover
events. Servers are backed up with encryption through a dedicated backup server that connects
across an internal 10 gigabit network to a tape drive. DCC storage area networking (SAN)
applications, clusters, and switch-to-switch links are also on a 10 gigabit network. Incremental
backups occur hourly Monday through Friday from 6 am to 6 pm. Incremental backups also are
performed each night with full system backups occurring every Friday. Tapes are stored in a
ﬁreproof safe inside the data center facility, and full backups are taken oﬀsite on a weekly basis
to an oﬀ-site commercial storage facility. In the event of catastrophic failure, such as a ﬁre in
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the server facility, daily backups would probably survive because of the ﬁre suppression system
and ﬁreproof safe, but there would be obvious delay in re-establishing data center function
because the servers will not survive such a disaster. Total destruction of the data center facility
could cause the loss of up to one weeks data. In future investments, the data center is making
co-location, disaster recovery and business continuity solutions a top priority. DCC information
systems are available 24 hours a day, 7 days a week to all users unless a scheduled maintenance
interruption is required. If this occurs, we notify all users of the relevant systems, and data entry
can be deferred until after the interruption is over. Critical systems availability has exceeded
99.9% for the past two years, and there has been no unscheduled downtime in over ﬁve years.
16.1
Security and Conﬁdentiality
The data center coordinates the network infrastructure and security with the Health Sciences
Campus (HSC) information systems at the University of Utah. This provides us with eﬀective
ﬁrewall hardware, automatic network intrusion detection, and the expertise of dedicated security
experts working at the University. Network equipment includes four high-speed switches. User
authentication is centralized with two Windows 2012 domain servers. Communication over
public networks is encrypted with virtual point-to-point sessions using transport layer security
(TLS) or virtual private network (VPN) technologies, both of which provide at least 128 bit
encryption. All of our Web-based systems use the TLS protocol to transmit data securely over
the Internet. Direct access to data center machines is only available while physically located
inside our oﬃces, or via a VPN client.
All network traﬃc is monitored for intrusion attempts, security scans are regularly run
against our servers, and our IT staﬀis notiﬁed of intrusion alerts. Security is maintained with
Windows 2012 user/group domain-level security. Users are required to change their passwords
every 90 days, and workstations time out after 5 minutes of inactivity. All ﬁles are protected at
group and user levels; database security is handled in a similar manner with group-level access
to databases, tables, and views in Microsoft SQL Server. Finally, all laptop computers in use in
the DCC or in the Department of Pediatrics are whole-disk encrypted.
The data center uses control center tools to continuously monitor systems and failure alerts.
Environmental and network systems are also monitored to ensure up time. Highly trained system
administrators on staﬀare available to respond in high risk emergency events. All personnel
involved with the DCC have signed conﬁdentiality agreements concerning data encountered
in the course of their daily work. All personnel (including administrative staﬀ) have received
Human Subjects Protection and Health Information Portability and Accountability Act (HIPAA)
education. We require all users to sign speciﬁc agreements concerning security, conﬁdentiality,
and use of our information systems, before access is provided.
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16.2
Record Access
The medical record and study ﬁles (including informed consent) must be made available to
authorized representatives of the Data Coordinating Center, upon request, for source veriﬁcation
of study documentation. In addition, medical information and data generated by this study must
be available for inspection upon request by representatives (when applicable) of the Food and
Drug Administration (FDA), NIH, other Federal funders, and the Institutional Review Board
(IRB) for each study site.
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17
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