A Prospective, Randomized, and Controlled Clinical Study to Evaluate PROKERA® in the Management of Signs and Symptoms Associated With Dry Eye Disease
Phase: NA
Conditions: Dry Eye Syndromes
Sponsor: BioTissue Holdings, Inc

 
 
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TissueTech, Inc. 
7300 Corporate Center Drive, Suite 700  
Miami, Florida 33126 
P: 305.412.4430 F: 305.412.4429                                                                                                                                              
 
Study Title: 
 A prospective, randomized, and controlled clinical study to evaluate 
PROKERA® in the management of signs and symptoms associated 
with dry eye disease.  
Protocol Number:           PROKERA-CS001 
Product Name: 
PROKERA® Slim 
Product Classification: 
Class II Medical Device  
Product Status: 
Cleared by the FDA under 510(k) #K032104 
Cleared Intended Use 
In eyes in which the ocular surface cells have been damaged, or 
underlying stroma is inflamed and scarred. 
Indication: 
To reduce signs and symptoms associated with dry eye disease.  
Short Title: 
PROKERA for DED 
Sponsor: 
TissueTech, Inc. and Its Subsidiaries 
7300 Corporate Center Drive, Suite 700, Miami, FL 33126 
 
 
 
Version:  
2 
Original Protocol: 
[05.30.2018] 
Revised: 
April 2, 2019 
 
 
                                                            Confidentiality Statement 
The confidential information in this document is provided to you as an Investigator, potential Investigator or 
consultant for review by you, your staff and applicable Institutional Review Board (IRB). It is understood that 
the information shall not be disclosed to others without written authorization from TissueTech, Inc., except to 
the extent necessary to obtain informed consent from those persons to whom the test article may be 
administered. 
IRB Approved at the 
Protocol Level 
Apr 05, 2019
20181506

 
 
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P: 305.412.4430 F: 305.412.4429                                                                                                                                              
 
BACKGROUND AND RATIONALE: 
Dry eye disease (DED) is one of the most common ocular surface disorders in the United States 
and worldwide. It affects nearly 30% of the population and its symptoms, such as ocular 
discomfort and visual fluctuations, represent the most frequent complaints in ophthalmic 
practice.1-4 Although DED starts from tear film insufficiency, it leads to inflammation and 
damage of ocular surface epithelial cells and stromal cells.1,5 Despite different underlying 
pathogenic processes, inflammation is a common denominator in DED, which in turn induces 
further damage to the corneal epithelium and its underlying structures.6 Different treatment 
modalities, such as steroids and cyclosporine, have been tried to suppress inflammation, however 
results are variable and refractory in some cases. Consequently, DED not only negatively 
impacts the quality of life2 but also increases the burden on health economics.7 
 
Cryopreserved amniotic membrane (AM) is designated as human cell and tissue-based product 
(HCT/P) by the U.S. Food and Drug Administration (FDA) when used in ocular surface 
reconstruction through Request for Designation in 2001. It is minimally manipulated and 
considered homologous when used to repair ocular surface damage.8 The effectiveness of AM 
has been credited to its anti-inflammatory, anti-scarring, and anti-angiogenic effects. 
PROKERA® is a Class II medical device comprised of AM fastened in between a ring system 
and has been cleared by the FDA to cover the corneal surface without sutures via 510(k) 
#K032104 and is intended for use in eyes, in which the ocular surface cells have been damaged 
or underlying stroma is inflamed and scarred.9 Clinical uses of both AM and PROKERA® in 
ophthalmology have been regarded as a standard of care in the United States and is supported by 
three Level I CPT Codes (65778 and 65779 for AM and 65780 for PROKERA®) issued by the 
American Medical Association and reimbursed by the Centers of Medicare and Medicaid 
Services (CMS). The clinical effectiveness of both AM and PROKERA® in managing a variety 
of ocular surface disorders have been supported by several hundred peer-reviewed scientific 
publications.10 
 
Among the ocular surface disorders managed by the device, PROKERA® has been used to 
manage ocular signs and symptoms of DED. In a retrospective study by Cheng et al,10 
PROKERA® was placed for 5 days (Range: 2-8 days) in 15 eyes of 10 patients with moderate to 
severe DED. The dry eye severity ranged  from Grade 1 to 4 according to the Report of the 
International Dry Eye Work Shop (DEWS) 2007.1 All patients experienced symptomatic relief 
for a mean period of 4.2 months (Range: 0.3-6.8). Such improvement was accompanied by 
reduction of Ocular Surface Disease Index (OSDI) symptom scores, the use of topical 
medications, conjunctival hyperemia, and corneal staining as well as improvement in the quality 
of vision.11  In a single site prospective, randomized, and controlled study conducted by John et 
al12, PROKERA® together with standard of care was placed in 10 patients for 3.4 ± 0.7 day 
(Range: 3-5 days) while standard of care was instituted in another 10 patients as the control. All 
20 patients presented with moderate to severe DED with DEWS Grade 2-4. Compared to the 
control arm of 10 patients receiving standard of care, the treatment arm of 10 patients receiving 
PROKERA® together with standard of care resulted in reduction of symptoms based on SPEED 

 
 
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P: 305.412.4430 F: 305.412.4429                                                                                                                                              
 
score and signs such as superficial punctate keratitis (SPK) measured by fluorescein staining, 
leading to an overall reduction of the mean DEWS severity score from 2.9 ± 0.3 at baseline to 
1.1 ± 0.3 at 1 month and 1.0 ± 0.0 at 3 months, respectively (both p ≤ 0 001).These palliative 
benefits are correlated with an increase of corneal nerve density measured by in vivo confocal 
microscopy from 12,241 ± 5,083 µm/mm2 at baseline to 16,364 ±3,734 µm/mm2 at 1 month, and 
18,827 ±5,453 µm/mm2 at 3 months(both p=0.015). The increase of corneal nerve density is also 
correlated with an increase of corneal sensitivity measured by a monofilament in the Bonnet-
Crochet esthesiometer. A lasting benefit for more than 3 months after one placement of 
PROKERA® was also demonstrated in a retrospective study by McDonald et al13 in 97 eyes of 
84 of patients with moderate to severe DED (DEWS 2-4), of which the majority presented with 
symptoms of ocular discomfort, blurry vision, ocular pain, redness, and light sensitivity. Most of 
the cases manifested the ocular sign of SPK due to exposure keratitis, filamentary keratitis, 
epithelial defect, and neurotrophic keratitis. A single placement of PROKERA® for 5.4 ± 2.8 
days leads to notable improvement of DED symptoms and reduction of ocular signs in 74 
subjects (88%) as evidenced by notable reduction of the mean DEWS severity score from 3.25to 
1.44 at 1 week, 1.45 at 1 month, and 1.47 at 3 months. Collectively, these data suggest that a 
single placement of PROKERA® is effective in reducing signs and symptoms of DED for a 
period lasting at least three months, presumably through a number of mechanisms known for 
AM including anti-inflammation as well as the resultant benefit to promote the return of corneal 
nerve density and corneal sensitivity, which has been reported to decline as DED increases its 
severity.12 
 
The present study is designed to further substantiate the effectiveness of PROKERA® in 
reducing signs and symptoms of DED.  
 
STUDY OBJECTIVES 
The primary objective is to evaluate the safety and effectiveness of PROKERA® in reducing 
signs and symptoms of dry eye disease (DED). 
 
STUDY DESIGN:  
We propose to conduct a prospective randomized, and controlled study to compare the 
effectiveness of PROKERA® plus standard of care (SOC) in the PROKERA® Arm to SOC 
alone in the Control Arm. Subjects presenting with moderate DED defined as corneal fluorescein 
staining score of ≥ 3 points out of 9,14 will be recruited and screened at the two to three 
participating clinical site(s) in the United States.  
 
Following a run-in period of 2 weeks during which enrolled subjects will use standard dry eye 
therapies consistent with what is described in the 2007 Report of the International Dry Eye 
WorkShop (DEWS)1,15 [e.g. preservative-free artificial tears, Restasis® (0.05% Cyclosporine A, 
Allergan, Inc. Irvine, CA),  Xiidra® (5% lifitegrast ophthalmic solution, Shire, Lexington, MA),  
punctal occlusion, etc.], enrolled subjects who still present with signs and symptoms of moderate 

 
 
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TissueTech, Inc. 
7300 Corporate Center Drive, Suite 700  
Miami, Florida 33126 
P: 305.412.4430 F: 305.412.4429                                                                                                                                              
 
DED at the screening visit, will continue in the study. Those subjects whose signs and symptoms 
abate during the run-in period will be discontinued from the study.  Subjects who continue in the 
study will be assigned an appropriate study identification code, and randomized to receive either 
PROKERA plus SOC or SOC alone.  
 
Subjects assigned to PROKERA plus SOC will have PROKERA inserted into one eye (study 
eye) and will then restart the SOC treatment for both eyes after randomization. After the 
PROKERA application for 5 ±1 days together with SOC, all subjects in the PROKERA® Arm 
will return to the clinic to have the PROKERA removed and will continue with the SOC 
treatment for both eyes. Subjects assigned to the Control Arm will start the SOC treatment for 
both eyes after randomization and will not return to the clinic at 5-day visit. Clinical symptoms 
will be evaluated by OSDI scale16 and the Eye Dryness Score (EDS).17,18 Signs of corneal 
epithelial damage will be evaluated by corneal fluorescein staining at the baseline, one month, 
two months and three months. To assess the potential for a contralateral effect, the above 
evaluation will also be conducted, for the subject’s fellow eye (i.e. non-study eye). In order to 
eliminate bias, all evaluators will be masked as to the treatment assignment.   
 
STUDY SUBJECTS AND RANDOMIZATION: 
Subjects will first be randomized in a 1:1 ratio to either PROKERA® Arm (i.e., PROKERA plus 
SOC) or Control Arm (i.e., SOC only) by a computer-generated randomization code. For the 
PROKERA® Arm, one eye of each subject will be randomly assigned as the primary study eye.   

 
 
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TissueTech, Inc. 
7300 Corporate Center Drive, Suite 700  
Miami, Florida 33126 
P: 305.412.4430 F: 305.412.4429                                                                                                                                              
 
 
STUDY FLOWCHART: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
STUDY PRODUCT AND MODE OF ADMINISTRATION: 
PROKERA® is manufactured by TissueTech, Inc. (Miami, FL), and is distributed by BioTissue, 
Inc., which is a solely owned subsidiary of TissueTech, Inc. PROKERA® is a corneal-epithelial 
insert, consisting of an ophthalmic conformer that incorporates cryopreserved amniotic 
membrane. PROKERA® is a Class II medical device that was cleared by the FDA under 510(k) 
#K032104 with the intended use in eyes in which the ocular surface cells have been damaged, or 
underlying stroma is inflamed and scarred. 
Following the evaluations performed at the baseline visit, PROKERA®(Slim) will be inserted in 
the subject’s primary study eye between the ocular surface and the eyelid as follows: 
1. Apply topical anesthesia 
2. Hold the upper eyelid 
Treatment Arm (N=25 
primary study eyes)  
PROKERA+ SOC
Subjects with DED 
Screening Evaluation 
(Visit 1; -14 Day) 
Baseline: Enrollment (N=50 Subjects) 
(Visit 2; Day 0) 
Control Arm (N=25 
primary study eyes) 
SOC
Day 5 ±1 PROKERA® Removal (Visit 3) 
1 Month follow up (Visit 4) 
3 Months follow up (Visit 6) 
Run-in Period (2 weeks) 
 
2 Months follow up (Visit 5) 

 
 
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P: 305.412.4430 F: 305.412.4429                                                                                                                                              
 
3. Ask the subject to look down 
4. Insert the PROKERA® into the superior fornix 
5. Pull lower eyelid down and slide PROKERA® under the lower eyelid 
6. Check centration under the slit lamp 
7. Apply a tape-tarsorrhaphy over the lid crease (standardized/specified in the full study 
protocol).  
 
STUDY POPULATION/ DURATION: 
A minimum of 50 subjects with moderate DED will be enrolled and randomized in this study. 
Following the baseline visit at which the subject will be randomized to either PROKERA® Arm 
or the Control Arm, one of the two eyes will be designated as the primary study eye. Each 
subject will be evaluated for a period of three months.  
 
PARTICIPANTS’ ELIGIBILITY:  
Inclusion Criteria 
• Subjects with moderate dry eye defined as corneal fluorescein staining score of ≥ 3  
• Age ≥ 18 years 
• Distance best corrected visual acuity better than 20/60 Snellen equivalent in each eye 
• Willing to sign a written informed consent to participate 
• Able to follow study instructions, with the intention of completing all required visits 
Exclusion Criteria 
• Presence of persistent corneal epithelial defect or ulcer in either eye 
• Presence of active ocular infection in either eye 
• Presence of ocular inflammation that is not related to keratoconjunctivitis sicca, e.g., 
allergy, severe blepharitis 
• Presence of other corneal disorder(s) that give rise to reduced corneal sensitivity, such as 
recurrent herpes keratitis 
• Presence of corneal diseases other than dry eye that can disturb the pre-corneal tear film 
such as epithelial basement membrane dystrophy (EBMD) 
• Contact lens wear  
• History of recent ocular surgery/trauma, which could affect corneal sensitivity, e.g., corneal 
transplantation, LASIK 
• Presence of cicatricial ocular surface diseases  
• A medical or ocular condition, or a personal situation, which in the principal investigator's 
opinion, is not appropriate for participation in the trial  

 
 
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P: 305.412.4430 F: 305.412.4429                                                                                                                                              
 
• Any scheduled or planned ocular or systemic surgery or procedure during the study 
• Pregnancy and women who are expecting to be pregnant. 
• Current enrolment in another interventional drug or device study or participation in such a 
study within 30 days of anticipated entry into this study 
 
ENDPOINTS/ OUTCOME MEASURES: 
 
1) EFFECTIVENESS ASSESSMENTS: 
Primary Effectiveness Endpoint:  
The primary effectiveness endpoint will be defined as the difference in mean change of the 
total corneal fluorescein staining score of the primary study eye from baseline to 1 month. 
 
Secondary Effectiveness Endpoints 
The secondary effectiveness endpoint will be defined as: 
• 
The difference in mean change of the EDS score from baseline to 1 month. 
• 
The difference in mean change of the OSDI score from baseline to 1 month. 
Exploratory Outcomes: 
 
• The mean changes of the corneal fluorescein staining score of the primary study eye from 
baseline at 2 months and 3 months. 
• The mean change of the EDS score from baseline at 1 week, 2 months and 3 months. 
• The mean change of the OSDI score from baseline at 1 week 2 months and 3 months. 
• The same analyses at each time point for the study eye will also be conducted for the 
subject’s fellow eye (i.e. non-study eye) 
 
The Dry eye sign of each eye will be evaluated by the degree of corneal fluorescein staining 
score. The corneal fluorescein staining score is the sum of three scores by subdividing the 
entire cornea into upper 1/3, middle 1/3, and lower 1/3, of which each will be graded from 0 
(no staining) to 3 (diffuse staining).  Thus, corneal fluorescein staining score ranges from 0 to 
9, with higher scores representing more severity. 
 
Dry eye symptoms will be evaluated using the EDS visual analog scale (VAS) to provide a 
direct assessment of the subject’s perception of their current eye dryness symptoms. The 
VAS has frequently been used for the collection of patient-reported outcomes and has been 

 
 
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7300 Corporate Center Drive, Suite 700  
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P: 305.412.4430 F: 305.412.4429                                                                                                                                              
 
commonly used to assess dry eye symptoms in clinical studies. As such, the 2007 report of 
the International Dry Eye Workshop (DEWS) listed the VAS as a well-defined symptom 
assessment methodology suitable for use in dry eye clinical trials. Specifically, 
patient-reported outcomes assessed using the EDS (via VAS) have been used in other dry eye 
studies and were recently used as the primary symptom endpoint for FDA approval of 
lifitegrast (Xiidra) for the treatment of the signs and symptoms of dry eye disease. 
 
The Dry eye symptoms will also be evaluated using the validated, 12-item Ocular Surface 
Disease Index (OSDI) (Allergan, Inc., Irvine, CA), which assesses symptoms of ocular 
discomfort, effects on visual function, and the impact of environmental triggers.  The 12 
items are graded on a scale of 0 to 4, where 0 indicates none of the time; 1, some of the time; 
2, half of the time; 3, most of the time; and 4, all of the time. The total OSDI score is then 
calculated on the basis of the following formula: OSDI= [(sum of scores for all questions 
answered) × 100]/ [(total number of questions answered) × 4]. Thus, the OSDI is scored on a 
scale of 0 to 100, with higher scores representing greater disability. 
 
2) SAFETY ASSESSMENTS: 
Adverse events (AEs) during this study are expected to have the same probability of 
occurrence and of the same magnitude as would be found with subjects with DED and not 
participating in the study. These could include worsening of the signs and symptoms of dry 
eye. Some adverse events might be related to PROKERA® placement (adverse device effects 
-ADEs) which include PROKERA® intolerance, eye irritation, lid swelling and mucus 
discharge. However, these device related risks are no different in type or frequency when the 
device is used for dry eye as compared to use of the device for other ocular surface disorders 
which are already on-label under the FDA 510(k) clearance.   
Safety will be assessed by documenting ADEs, in which the severity, cause and the 
resolution will be evaluated and reported. The Investigators will determine the severity, 
assign attribution, and report the event according to the Protocol guidelines. Serious ADEs 
such as vision threatening conditions may indicate patient withdrawal or termination of the 
study. 
 
STATISTICAL METHODS: 
The primary effectiveness analysis will be conducted on the primary effectiveness measure, the 
corneal fluorescein staining score change from baseline of the primary study eye, using a mixed-
effects model of repeated measures (MMRM) for all randomized eyes within the intent-to-treat 
(ITT) population, with 1 month being defined as the primary effectiveness endpoint.  The 
MMRM model will utilize Statistical Analysis System’s (SAS) PROC MIXED program to 
perform this analysis and define treatment (PROKERA plus SOC vs. SOC) at 1 month and 

 
 
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7300 Corporate Center Drive, Suite 700  
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P: 305.412.4430 F: 305.412.4429                                                                                                                                              
 
treatment-by-month as fixed effects and subject as random effect as well as the baseline corneal 
fluorescein staining score of the primary study eye as the covariate.  The effect of month 
includes 3 assessments at 1 month, 2 months, and 3 months. The comparison between 
PROKERA plus SOC and SOC at each month will be conducted, using a model-based t-test 
procedure, at the significance level of 0.05 (2-sided).  The comparison between PROKERA plus 
SOC and SOC at 1 month will be defined as the primary effectiveness endpoint, whereas the 
comparisons at 2 months and 3 months will be exploratory analyses.     
 
The OSDI total score change of the primary study eye from baseline over 3 months of the 
treatment assessment will be analyzed using the same MMRM model described above for the 
primary effectiveness measure. The comparison between PROKERA plus SOC and SOC at 1 
month will be defined as the secondary effectiveness endpoint whereas the comparisons at 1 
week, 2 months and 3 months will be exploratory analyses. 
 
To assess the potential for a contralateral eye effect, the above analyses will also be conducted, 
the subject’s fellow eye (i.e. non-study eye) as another exploratory outcome. 
 
 
SAMPLE SIZE CALCULATION 
The sample size is estimated according to the outcomes reported by John et al.11The mean 
corneal fluorescein staining score does not change in the control group (2.8 at baseline and 2.9 at 
3 months) while PROKERA® group reduces the corneal staining from the mean grading score of 
2.8 at baseline to 0.8 (SD=0.4) at 1 month and 0.6 (SD=0.5) at 3 months in patients with 
moderate to severe DED. This result yields a reduction of more than 70% or an effect size of 
more than 2.0 over 3 months from baseline.   
Assuming a large effect size of at least 0.85 for the PROKERA® Arm (i.e., PROKERA® plus 
SOC) against the Control Arm (i.e., SOC only) at 1 month from baseline for the corneal 
fluorescein staining score, 23 subjects per group or 46 subjects in total are needed to be 
randomized to yield an 90% power at a 2-tailed significance level of 0.05, using two-sample t-
test, to detect such a difference between the two treatments. The effect size of 1.00 is equivalent 
to a reduction of approximately 35% in corneal fluorescein staining score from baseline for the 
PROKERA® Arm compared to the Control Arm. To further account for an around 10% dropout, 
the study plans to enroll and randomize 50 subjects in total. 
 

 
 
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P: 305.412.4430 F: 305.412.4429                                                                                                                                              
 
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