Clinical trial NCT03287635
Conditions: Dry Eye Disease
Sponsor: Toyos Clinic
Start date: 2018-07-01; Completion date: 2020-03-04
Enrollment: 19 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Study Title: A Phase 4 Study to Assess the Clinical Efficacy of H.P. Acthar Gel 80 U/ml to Improve the Signs and Symptoms in Subjects with Dry Eye Disease

Detailed description:
Objectives: The primary objective of this study is to investigate the safety and efficacy of H.P. Acthar Gel 80 U/ml in subjects with a documented clinical diagnosis of dry eye disease.

Study Population: The study population will consist of subjects diagnosed with dry eye disease.

Number of Subjects: Approximately 12 subjects

Investigational Product: H.P. Acthar Gel 80 U/ml sufficient for the duration of the study will be supplied by Mallinkrodt to the enrolled subjects

Route and Duration of Administration: Product will be injected subcutaneously weekly by subjects for approximately 12 weeks.

Study Design: This is a Phase 4, single center single arm study designed to evaluate the safety and efficacy of H.P. Achthar Gel in subjects with dry eye disease.

Approximately 25 subjects will be screened and 12 subjects enrolled at one center in the United States.

Subjects will be given 80 international units of study medication subcutaneously depending on the severity of the disease as determined by the primary investigator.

The study will include 3 study visits over 12 weeks. At Visit 1 Screening (14 +/- 1 days prior to Day 1), subjects meeting inclusion/exclusion criteria will begin investigational drug use. Subjects will return for evaluations at Visit 2 (Day 42+/-3 days) and Visit 3 (Day 84 +/-5 days). Subjects will be released from the study at the end of Visit 3 (Day 84+/- 5 days.)

Arms: arm 1: Patients who continue to experience clinically significant symptoms of dry eye disease even after utilizing traditional methods of treatment for dry eye including but not limited to artificial tears, warm compresses, topical anti-inflammatories like cyclosporine and/or lifitegrast. Patients will receive repository corticotropin intramuscular injections 80 u/ml 2-3 times weekly for up to 3 months as judged by the investigator.
Interventions: intervention 1: Corticotropin 80Unit/Ml Repository Injection
Intervention descriptions: intervention 1: H.P. Acthar Gel (repository corticotropin injection) is an adrenocorticotropic hormone (ACTH) analogue used for: Treatment during an exacerbation or as maintenance therapy in selected cases of systemic lupus erythematosus.

Protocol documents:
Prot_004.pdf: 
 
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
 


A Phase 4 Study to Assess the Clinical Efficacy of H.P. 
Acthar Gel 80 u/ml to Improve the Signs and Symptoms 
in Subjects with Dry Eye Disease 
 
Protocol Number: MMT-4233 
National Clinical Trial (NCT) Identified Number:  NCT03287635 
Principal Investigator: Melissa Toyos, M 
 Sponsor: Toyos Clinic 
Funded by: unrestricted grant from Mallinkrodt Pharmaceuticals 
Version Number:  v.1 
10 May 2018 
 


  
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
 
Table of Contents 
Funded by: unrestricted grant from Mallinkrodt Pharmaceuticals .............................................................. ii 
Version Number:  v.1 ............................................................................................................................................... ii 
10 May 2018 ................................................................................................................................................................ ii 
Table of Contents .......................................................................................................................................................... ii 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
1.2 
Schema ................................................................................................................................................. 2 
Example #1 Flow diagram (e.g., randomized controlled trial) ...................................................................................... 2 
Prior to 3 
Visit 1 3 
Visit 2 3 
Visit 3 3 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 6 
2 
INTRODUCTION ............................................................................................................................................ 6 
2.1 
Study Rationale .................................................................................................................................... 6 
2.2 
Background........................................................................................................................................... 6 
2.3 
Risk/Benefit Assessment .................................................................................................................... 7 
2.3.1 
Known Potential Risks ..................................................................................................... 7 
2.3.2 
Known Potential Benefits ................................................................................................ 7 
2.3.3 
Assessment of Potential Risks and Benefits ................................................................ 7 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................ 8 
4 
STUDY DESIGN ............................................................................................................................................. 8 
4.1 
Overall Design ...................................................................................................................................... 8 
4.2 
Scientific Rationale for Study Design................................................................................................ 9 
4.3 
Justification for Dose ........................................................................................................................... 9 
4.4 
End of Study Definition ....................................................................................................................... 9 
5 
STUDY POPULATION .................................................................................................................................. 9 
5.1 
Inclusion Criteria .................................................................................................................................. 9 
5.2 
Exclusion Criteria ............................................................................................................................... 10 
5.3 
Screen Failures .................................................................................................................................. 10 
5.4 
Strategies for Recruitment and Retention ...................................................................................... 11 
6 
STUDY INTERVENTION ............................................................................................................................ 11 
6.1 
Study Intervention(s) Administration ............................................................................................... 11 
6.1.1 
Study Intervention Description ..................................................................................... 11 
6.1.2 
Dosing and Administration ............................................................................................ 11 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 11 
6.2.1 
Acquisition and accountability ...................................................................................... 11 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 12 
6.2.3 
Product Storage and Stability ....................................................................................... 12 
6.2.4 
Preparation ...................................................................................................................... 12 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 12 
6.4 
Study Intervention Compliance ........................................................................................................ 12 
6.5 
Concomitant Therapy ........................................................................................................................ 12 
6.5.1 
Rescue Medicine ............................................................................................................ 12 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 12 


  
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7.1 
Discontinuation of Study Intervention ............................................................................................. 12 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 13 
7.3 
Lost to Follow-Up ............................................................................................................................... 13 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 14 
8.1 
Efficacy Assessments ....................................................................................................................... 14 
8.2 
Safety and Other Assessments ....................................................................................................... 15 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 15 
8.3.1 
Definition of Adverse Events (AE) ............................................................................... 15 
8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 16 
8.3.3 
Classification of an Adverse Event .............................................................................. 16 
OR 
16 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 17 
8.3.5 
Adverse Event Reporting .............................................................................................. 18 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 18 
8.3.7 
Reporting Events to Participants ................................................................................. 18 
8.3.8 
Events of Special Interest ............................................................................................. 19 
8.3.9 
nReporting of Pregnancy .............................................................................................. 19 
8.4 
Unanticipated Problems .................................................................................................................... 19 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................. 19 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 19 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 20 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 20 
9.1 
Statistical Hypotheses ....................................................................................................................... 20 
9.2 
Sample Size Determination .............................................................................................................. 20 
9.3 
Populations for Analyses .................................................................................................................. 20 
9.4 
Statistical Analyses............................................................................................................................ 21 
9.4.1 
General Approach .......................................................................................................... 21 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 21 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 21 
9.4.4 
Safety Analyses .............................................................................................................. 21 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 21 
9.4.6 
Planned Interim Analyses ............................................................................................. 22 
9.4.7 
Sub-Group Analyses ..................................................................................................... 22 
9.4.8 
Tabulation of Individual participant Data .................................................................... 22 
9.4.9 
Exploratory Analyses ..................................................................................................... 22 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 22 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 22 
10.1.1 
Informed Consent Process ........................................................................................... 22 
10.1.2 
Study Discontinuation and Closure ............................................................................. 23 
10.1.3 
Confidentiality and Privacy ........................................................................................... 23 
All research activities will be conducted in as private a setting as possible. ................................................... 24 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 24 
10.1.5 
Key Roles and Study Governance .............................................................................. 24 
10.1.6 
Safety Oversight ............................................................................................................. 25 
10.1.7 
Clinical Monitoring .......................................................................................................... 25 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 25 
10.1.9 
Data Handling and Record Keeping ............................................................................ 26 


  
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10.1.10 
Protocol Deviations ........................................................................................................ 26 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 27 
10.1.12 
Conflict of Interest Policy .............................................................................................. 27 
10.2 
Additional Considerations ................................................................................................................. 27 
10.3 
Abbreviations ...................................................................................................................................... 28 
10.4 
Protocol Amendment History ........................................................................................................... 29 
11 
REFERENCES ............................................................................................................................................. 30 
 


A Phase 4 Study to Assess the Clinical Efficacy of H.P. Acthar Gel 80 u/ml to Improve the Signs and Symptoms in Subjects with 
Dry Eye Disease> 
Version 1 
Protocol MMT-4233 
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STATEMENT OF COMPLIANCE 
 
 
(1) [The trial will be conducted in accordance with International Conference on Harmonisation 
Good Clinical Practice (ICH GCP) and applicable United States (US) Code of Federal Regulations 
(CFR). The Principal Investigator will assure that no deviation from, or changes to the protocol 
will take place without prior agreement from the Investigational New Drug (IND) or 
Investigational Device Exemption (IDE) sponsor, funding agency and documented approval from 
the Institutional Review Board (IRB), except where necessary to eliminate an immediate 
hazard(s) to the trial participants. All personnel involved in the conduct of this study have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval.  Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled.  Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented to the study.  All 
changes to the consent form will be IRB approved; a determination will be made regarding 
whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form.] 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
A Phase 4 Study to Assess the Clinical Efficacy of H.P. Acthar Gel 80 U/ml 
to Improve the Signs and Symptoms in Subjects with Dry Eye Disease 
Study Description: 
This study will test the efficacy of a systemic intervention and 
adrenocorticotropin injection for severe dry eye unrelieved by traditional 
dry eye treatments.  
Objectives: 
 
The primary objective of the study is to investigate the safety and efficacy 
of H.P. Acthar gel injections in subjects who have a documental clinical 
diagnosis of dry eye disease. Secondary objective is to demonstrate safety 
for use of Acthar H.P. Gel in dry eye subjects.  
 
 
 
Endpoints: 
Primary Endpoint: Improvement of patient comfort over the length of the 
study using a validated dry eye comfort questionnaire, OSDI and 
improvement of spk in cornea over study treatment period 
Secondary Endpoints: conjunctival staining with lissamine green 
Study Population: 
12 study subjects 18-85 will be enrolled with male or female in the 
Nashville, TN area who are generally healthy but have persistent signs and 
symptoms of dry eye diseases after treatment with traditional dry eye 
treatments including but not limited to: IPL, cyclosporing, lifitegrast, 
loteprednol, artificial tears and warm compresses 
Phase: 
4 


A Phase 4 Study to Assess the Clinical Efficacy of H.P. Acthar Gel 80 u/ml to Improve the Signs and Symptoms in Subjects with 
Dry Eye Disease> 
Version 1 
Protocol MMT-4233 
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Description of 
Sites/Facilities Enrolling 
Participants: 
Single site study in  Nashville, TN and surrounding areas. 
Description of Study 
Intervention: 
Acthar is an adrenocorticotropic hormone given subcutaneously twice 
weekely. 
Study Duration: 
6 months 
Participant Duration: 
12 weeks 
 
 
1.2 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Example #1 Flow diagram (e.g., randomized controlled trial) 


A Phase 4 Study to Assess the Clinical Efficacy of H.P. Acthar Gel 80 u/ml to Improve the Signs and Symptoms in Subjects with 
Dry Eye Disease> 
Version 1 
Protocol MMT-4233 
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Prior to  
Enrollment 
 
 
 
 
 
 
 
 
 
 
Visit 1 
Time Point  
 
 
 
Visit 2 
Time Point  
 
 
Visit 3 
Time Point  
 
 
 
 
 
 
 
 
 
 
 
Total N:  Obtain informed consent. Screen potential participants by inclusion and 
exclusion criteria; obtain history, document. 
Perform baseline assessments.written and informed consent, ocular and systemic 
medical history 
Visual analog subject rated assessments,  Administer initial study intervention.  
Concomitant medications, adverse events, subject rated assessment of eye dryness, 
bcva, slit lamp biomicroscopy, corneal fluorescein staining, conjunctival lissamine 
staining, anesthetized Schirmer 
Final Assessments 
<Concomitnat medications, adverse 
events, subject rated assessment of 
ocular discomfort by visual analog 
scale, , bcva, slit lamp biomicroscopy, 
corneal fluorescein staining, 
conjunctival lissamine staining, 
anesthetized Schirmer testing, iop, 
dilated ophthalmoscopy, urine 
pregnancy test, release of subject 
form the study> 
Arm 1 
N 
Concomitant medications, adverse events, BCVA, iop, slit lamp biomicroscopy 


A Phase 4 Study to Assess the Clinical Efficacy of H.P. Acthar Gel 80 u/ml to Improve the Signs and Symptoms in Subjects with 
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A Phase 4 Study to Assess the Clinical Efficacy of H.P. Acthar Gel 80 u/ml to Improve the Signs and Symptoms in Subjects with 
Dry Eye Disease> 
Version 1 
Protocol MMT-4233 
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NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
 
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Example #3 provided as a guide, customize as needed: Timeline diagram (e.g., randomized controlled 
trial) 
 
 
 
 


A Phase 4 Study to Assess the Clinical Efficacy of H.P. Acthar Gel 80 u/ml to Improve the Signs and Symptoms in Subjects with 
Dry Eye Disease> 
Version 1 
Protocol MMT-4233 
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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
u 
Procedures 
Screening 
Day -7 to -1 
Enrollment/Baseline 
Visit 1, Day 1 
Study Visit 2  
Day 7  +/-1 day 
Study Visit 3 
Day 14 +/- 1 day 
Final Study Visit 13 
Day 84 +/-1 day  
Informed consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Randomization 
X 
 
 
 
 
Administer study intervention 
 
X 
 
 
 
Concomitant medication 
review 
X 
X----------------------------------------------
-----------------------------------------------
X 
Bcva 
X 
X 
x 
x 
X 
Slit lamp biomicroscopy 
X 
x 
x 
x 
x 
IOP 
X 
X 
x 
X 
X 
Corneal fluorescein stain 
X 
X 
 
X 
X 
Conjunctival liissamine stain 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
anesthetized schirmer 
X 
x 
 
x 
x 
Dilated ophthalmoscopy 
X 
 
 
 
x 
Training on study medications 
X 
Discpense study meds 
 
 
\ 
X 
 
 
 
 
 
 
 
2 
 
INTRODUCTION 
2.1 
STUDY RATIONALE  
Many people suffer from dry eye disease and are incompletely relieved of signs and symptoms with 
traditional treatments like artificial tears, warm compresses, prescription eye drops, and IPL. Those most 
severely affected may find relief using a systemic medication that increases the body’s endogenous 
production of corticosteroid to reduce surface inflammation. This study will attempt to demonstrate 
improvement in both signs and symptoms of dry eye and the safety of use of this medicine in patients 
suffering with moderate to severe dry eye.  
 
2.2 
BACKGROUND  
 
Acthar is approved by the FDA for the treatment of severe allergic and inflammatory eye conditions. Dry 
eye disease is a disease that affects millions of Americans and may be underdiagnosed. Dry eye disease 
is diagnosed by evaluating the signs and symptoms of dry eye including self-reported ocular comfort and 
staining of both the cornea and the conjunctiva by special stains. Moderate to severe dry eye disease is 
characterized by a self-perpetuating and progressive increase in inflammation of the ocular surface. For 
patients that continue to experience bothersome symptoms and/or loss of function due to dry eye 
despite compliance with current and traditional therapies, the use of corticotropin hormone may offer 
some relief.  


A Phase 4 Study to Assess the Clinical Efficacy of H.P. Acthar Gel 80 u/ml to Improve the Signs and Symptoms in Subjects with 
Dry Eye Disease> 
Version 1 
Protocol MMT-4233 
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2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
 
Known risks of Acthar use include 
Infections 
Cushing’s syndrome 
High blood pressure 
Bleeding stomach ulcers 
Irritability 
Depression 
Insomnia 
Mood swings 
Loss of diabetic control 
Cataracts 
Glaucoma 
Allergy to acthar 
Long term use can affect children’s growth and development 
Osteoporosis 
Birth defects 
 
The most common side effects are 
Increased blood sugar 
Increased blood pressure 
Fluid retention 
Changes in appetite 
Weight gain 
Cardiac hypertrophy 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
 
By activating the release of endogenous cortisol and impacting steroid independent immunomodulatory 
and anti-inflammatory pathways, Acthar reduces inflammation in the body without synthetic steroids. 
Immediate benefits in dry eye disease would be reduced symptomatology and improvement of function 
which would be expected to extend long term and help to prevent and reduce future damage from 
chronic inflammation.  
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
Moderate to severe dry eye can cause significant discomfort and interfere with even daily normal 
function. Patients can experience depression, reduced function at work, social anxiety if others 
incorrectly interpret red eyes as staying out too late, use of illegal drugs or episodes of crying. Patients 
who have exhausted all currently available therapies and still experience bothersome signs and 
symptoms especially if symptoms interfere with jobs and normal daily function may feel that the 
increased risk of systemic anti-inflammatory may be worth the benefits of reduced ocular surface 
inflammation. 


A Phase 4 Study to Assess the Clinical Efficacy of H.P. Acthar Gel 80 u/ml to Improve the Signs and Symptoms in Subjects with 
Dry Eye Disease> 
Version 1 
Protocol MMT-4233 
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3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
The primary objective is the efficacy 
of H.P. Acthar gel injections in 
subjected with documented 
moderate to severe dry eye disease 
who have failed traditional 
therapies. 
 
The primary endpoint(s) are 
improvement in comfort over the 
course of the trial with a validated 
dry eye comfort questionnaire, OSDI 
and improvement in the number of 
corneal spk using fluorescein stain 
over the course of the trial.  
Both endpoints have 
been validated in 
recent dry eye 
approvals (lifitegrast). 
Secondary 
 
 
The secondary objective is  
improvement in conjunctival 
staining with lissamine green and 
demonstration of safety of use of in 
dry eye subjects.  
Conjunctival staining with lissamine 
green is another method of 
measuring ocular surface 
inflammation and safety will be 
measured by collecting intraocular 
pressure, assessing AEs, slit lamp 
biomicroscopy, BCVA and dilated 
ophthalmoscopy 
Lissamine green 
staining has also been 
used in recent 
approvals (lifitegrast) 
and safety of 
adrenocorticotropic 
stimulators must 
measure common side 
effects of steroid like 
glaucoma, cataract 
and potential change in 
vision. 
 
 
 
. 
. 
 
 
 
 
 
 
 
 
 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
• 
The hypothesis is that use of H.P. Acthar gel subcutaneously has the ability to reduce ocular 
surface inflammation in moderate to severe dry eye and improve the signs and symptoms over 
the course of the trial. 
 
• 
Single site pilot study Pilot study  


A Phase 4 Study to Assess the Clinical Efficacy of H.P. Acthar Gel 80 u/ml to Improve the Signs and Symptoms in Subjects with 
Dry Eye Disease> 
Version 1 
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• 
H.P. Acthar gel will be dosed two or three times weekly to control signs and symptoms at the 
discretion of the primary investigator. 
 
• 
One study arm of active intervention for up to 89 days 
• 
Single site 
• 
Study intervention is use of H.P. Acthar Gel) 
• 
No interim analysis is planned  
There are no planned stratifications.  
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
This is a small single site study with no control designed to show efficacy in moderate to severe dry eye 
disease which may be used in the future as a basis for a larger, multi-site, randomized placebo 
controlled study. Potential pitfalls include the small number of participants, the variable nature of the 
disease and the often inverse relationship of signs to symptoms in dry eye disease.  
 
4.3 
JUSTIFICATION FOR DOSE 
H.P. Acthar gel will be injected subcutaneously two or three times weekly. Subjects will self-administer 
the dose recommended by the treating physician which may range from 80 international units two to 
three times per week. Nursing support from Mallinkrodt to train study coordinator and study personnel 
who will train subjects on proper administration techniques will be available at all times points in the 
study. Patients will self-inject the study medicine for the length of the study, 12 weeks. 
 
 
4.4 
END OF STUDY DEFINITION 
 A participant is considered to have completed the study if he or she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Activities (SoA), 
Section 1.3. 
 
 
5 
STUDY POPULATION 
 
 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Provision of signed and dated informed consent form and HIPPA authorization. 
2. Stated willingness to comply with all study procedures and availability for the duration of the 
study  
3. Male or female, aged 18 and older. 
4. Diagnosed with moderate to severe dry eye in one or both eyes.   
5. History of persistent symptoms despite use of artificial tears and one or more of the following 
ophthalmic drops: loteprednol, cyclosporine or lifitegrast. 
6. At least 40 mm on the ocular discomfort scale.  
7. At least 5 spk on one or both corneas. 


A Phase 4 Study to Assess the Clinical Efficacy of H.P. Acthar Gel 80 u/ml to Improve the Signs and Symptoms in Subjects with 
Dry Eye Disease> 
Version 1 
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8. A grade of 1 or greater in the nasal or temporal areas of one or both eyes. 
9. Have normal lid anatomy. 
10. Ability to take subcutaneous injected medication and be willing to adhere to the study regimen 
11. For females of reproductive potential: use of highly effective contraception for at least 1 month 
prior to screening and agreement to use such a method during study participation and for an 
additional 4 weeks after the end of Acthar administration  
12. For males of reproductive potential: use of condoms or other methods to ensure effective 
contraception with partner 
13. Are postmenopausal (no menstrual cycle for at least one year prior to Visit 1) or have undergone 
bilateral tubal ligation, hysterectomy, hysterectomy with uni or bilateral oophorectomy, or 
bilateral oophorectomy.  
 
5.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
 
1. Have a known hypersensitivity or contraindication to the investigational product or their 
components.  
2. Have used topical or nasal vasoconstrictors within 14 days prior to screening.  
3. Pregnancy or lactation 
4. Subjects can be on the following medications if they have been on a stable dose for 12 weeks: 
topical cyclosporing, topical liftigrast and/or topical loteprednol etabonate. Tetracycline 
compounds, omega 3s, anticholinergics, anticonvulsants, antidepressants, retinoids, systemic 
immunosuppressive agents including oral corticosteroids, non-steroidals, antihistamines, or 
mast cell stabilizers, punctal plugs, contact lens wear and glaucoma medications. 
5. Subjects must be unwilling to abstain from eyelash growth medications for the duration of the 
trial.  
6. Subjects must not have had penetrating intraocular surgery, refractive surgery or corneal 
transplantation, eyelid surgery within 12 weeks prior to Visit 1.  
7. Febrile illness within one week. 
8. Treatment with another investigational drug or other intervention within one month.  
9. Subjects with a history of herpetic keratitis. 
10. Have serious or severe disease or uncontrolled medical condition that in the judgement of the 
investigator could confound study assessments or limit compliance.  
 
 
 
5.3 
SCREEN FAILURES 
 Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants, to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (SAE). 
 


A Phase 4 Study to Assess the Clinical Efficacy of H.P. Acthar Gel 80 u/ml to Improve the Signs and Symptoms in Subjects with 
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Individuals who do not meet the criteria for participation in this trial (screen failure) because of OSDI 
score may be rescreened. Rescreened participants should be assigned the same participant number as 
for the initial screening. 
 
5.4 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Anticipate 25 screenings for 12 enrolled subjects.  
• 
One site in the US. 
• 
Source of participants will be outpatient clinics and general public 
• 
Potential participants will be identified and approached by chart review, during regular dry eye 
clinic visits and self-identified by general dry eye study signs within our clinics 
 
6 
STUDY INTERVENTION 
The study intervention is H.P. Acthar Gel (repository corticotropin injection) an adrenocorticotropic 
hormone (ACTH) analogue used on label as currently approved by the FDA for ocular inflammation. This 
study will be used to gather data specifically about the efficacy and safety of use of Acthar in moderate 
to severe dry eye.  
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
There is no control, only study intervention with H.P. Acthar gel used subcutaneously 80 IU 2-3 times 
weekly. The drug is currently approved for all ocular inflammation and will be studied in this 
investigation specifically for moderate to severe dry eye disease.  
 
 
6.1.2 DOSING AND ADMINISTRATION 
Each participant will be started at 80 IU subcutaneously 2-3 weekly and the dosing increased to up to 
three times weekly at the discretion of the primary investigator.  The dosing will remain consistent unless 
the investigator decides to reduce or escalate the dosing at the one month mark. The dosing may be 
stopped altogether and the subject followed only for safety in the event of uncontrolled hypertension, 
blood sugar, glaucoma or other serious adverse events in the opinion of the investigator The dosing of 
study drug will continue for 12 weeks. 
 
  Missed or delayed doses should be taken as soon as realized unless it would result in two doses being given at 
once, in which case the investigator should be contacted for a modified dosing schedule.  
 
 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
Study drug will be provided by Mallinkrodt and shipped to the investigative site from Mallinkrodt . It will 
be dispensed to the subject at the time of enrollment by the study coordinator. Unused or expired study 
drug will be returned to Mallinkrodt.  


A Phase 4 Study to Assess the Clinical Efficacy of H.P. Acthar Gel 80 u/ml to Improve the Signs and Symptoms in Subjects with 
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6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
Study drug formulation, appearance, packaging, and labeling  will be as normally supplied by the 
manufacturer, Mallinkrodt Pharmaceuticals. .   
 
6.2.3 PRODUCT STORAGE AND STABILITY 
H.P. Acthar gel is stored under refrigeration 2-8 degrees Celsius or 36-46 degrees Fahrenheit. Study drug 
temperature stability will be monitored with downloadable temperature monitors to ensure safety. 
 
 
6.2.4 PREPARATION 
Study drug should be warmed to room temperature before using. It is supplied in 5 ml multi-dose vials 
with 80 USP units per ml. Subjects will be instructed to withdraw 1ml.  
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 All subjects will receive active drug with no control.  
 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
Adherence to the protocol will be assessed by verbally discussing with the subject and return of 
participant drug log.   
 
6.5 
CONCOMITANT THERAPY 
 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications to be reported in the Case Report Form (CRF) are 
concomitant prescription medications, over-the-counter medications and supplements. 
 
 
6.5.1 RESCUE MEDICINE 
 The study site will not supply rescue medication.  
 
The use of rescue medications is allowable at any time during the study and the date and time of rescue 
medication administration as well as the name and dosage regimen of the rescue medication must be 
recorded. 
   
 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
Discontinuation during study does not mean discontinuation from the study, and remaining study 
procedures should be completed as indicated by the study protocol.  If a clinically significant finding is 


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identified (including, but not limited to changes from baseline) after enrollment, the investigator or 
qualified designee will determine if any change in participant management is needed. Any new clinically 
relevant finding will be reported as an adverse event (AE). 
 
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
Subject rated assessment of eye dryness, use of concomitant medications since last visit, 
occurrence of AEs since last visit, unused investigational product will be collected, BCVA, slit 
lamp biomicroscopy, iop, dilated fundus exam and pregnancy test for women of childbearing 
potential. 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
• 
Pregnancy 
• 
Significant study intervention non-compliance  
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
• 
Disease progression which requires discontinuation of the study intervention 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• 
Participant unable to receive study intervention for 14 days. 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (CRF). Subjects who sign the informed consent form and are randomized but do not receive 
the study intervention may be replaced.  Subjects who sign the informed consent form, and are 
randomized and receive the study intervention, and subsequently withdraw, or are withdrawn or 
discontinued from the study, will be replaced. 
 
7.3 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she fails to return for 2 scheduled visits and is 
unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within 72 hours 
and counsel the participant on the importance of maintaining the assigned visit schedule and 
ascertain if the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 


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8 
STUDY ASSESSMENTS AND PROCEDURES 
. 
 
8.1 
EFFICACY ASSESSMENTS  
List and describe all study procedures and evaluations to be done as part of the study to support the 
determination of efficacy, as per the primary and secondary objectives outlined in this protocol. Discuss 
the sequence of events that should occur during the screening process and any decision points regarding 
participant eligibility.  Include the time frame prior to enrollment within which screening procedures/ 
evaluations must be performed (e.g., within 28 days prior to enrollment).   
 
In addition, indicate where appropriate, that procedures/evaluations will be performed by qualified 
personnel.  
 
• 
Once enrolled, initial study visit will occur within one week and can occur on the same day. Study 
assessments on each study day will occur in this order: 
• 
Subject rated assessment of ocular discomfort by visual analog scale. Subjects will be asked to 
subjectively rate their eye dryness at Visit 1,2, and 3. Subjects will be instructed to rate eye 
dryness using the scale below. The total length of the line from “no dryness” to “maximal 
dryness” is 100 mm. The length of the line between the “no dryness” starting point and the 
first point at which the subject mark crosses the line will be measured in mm. This assessment 
is a general assessment of both eyes. 
Instantaneous Evaluation of Eye Dryness 
 
Please place a single line across the line below to indicate the severity of your eye dryness at 
the present time: 
 
No dryness_________________________________________Maximal dryness 
• 
Significant non-ocular and significant ocular medical history 
• 
Concomitant medication usage and significant medications taken 6 months prior to screening 
• 
Inclusion/Exclusion criteria 
• 
Urine pregnancy test if required 
• 
BCVA Subjects will be placed at the predetermined mark for ETDRS testing 
• 
. LogMAR will be assessed with ETDRS or modified ETDRS charts and with subjects own 
corrective lenses or BCVA measured in office whichever is better. Scores are recorded 
according to ETDRS protocol and right eyes tested first.  
• 
Slit lamp biomicroscopy – 8 mm x 2 mm slit lamp beam wil be used right to left and left to 
right to examine thoroughly the structures of the anterior segment: lids, lashes, conjunctiva, 
corea, iris, anterior chamber, and lens. Results will be recorded as normal or abnormal. 
Abnormal findings will be followed by explanation of pathology. 
• 
Corneal fluorescein staining. One drop of tetracaine or properacaine will be applied to the 
surface of the eye. One drop of Fluress will be applied to the eye, excess blotted and 60 
seconds elapsed before the examiner looks for spk. Alternatively, one drop of properacaine or 
tetracaine can be applied to a fluorescein strip, holding the strip to the inferior fornix for 10 


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seconds and allow 120 seconds elapsed prior to examination. Cobalt filter will be used to count 
discrete and macropunctate staining. 
• 
Conjunctival lissamine staining. One drop of lissamine green will be applied to each eye, 
excess blotted, and 60 seconds elapsed before staining is evaluated. 
• 
Anesthetized Schirmers. Fold the rounded ened of the test strip at the notched area. Instill 1-2 
drops of properacaine or tetracaine and wait 5 minutes. Ask the subject to look up and away 
from the strip. Place the rounded ened of the strip towards the temporal one-third of the 
lower lid. Repeat procedure on contralateral eye. Instruct the subject to relax and gently close 
their eyes. Remove strips after 5 minutes and mark with ink the leading and lowest edges of 
moisture. Measure halfway between the 2 lines and record and the amount of wetting.  
• 
IOP measurements will be performed using Goldman applanation tonometry according to the 
investigators standard protocol. All pressures will be recorded in mm Hg. IOP will be measured 
at each time point and at the investigator’s discretion. 
• 
Dilated ophthalmoscopy will occur at the first and last study visit and include assessment of 
the optic nerve head for pallor and cupping.  
• 
Training on study medication dosage will be done by specialists at Mallinkrodt directly with 
the subject until the subject is deemed by the specialist to be adequately trained and prepared 
for dosing.  
• 
Dispense study medications and temperature log. The study coordinator will dispense both the 
study medications and the temperature log with instructions on how to begin logging 
temperatures and when to return the thermometer for downloadable records.  
  
8.2 
SAFETY AND OTHER ASSESSMENTS 
• 
BCVA Subjects will be placed at the predetermined mark for ETDRS testing 
• 
 LogMAR will be assessed with ETDRS or modified ETDRS charts and with subjects own 
corrective lenses or BCVA measured in office whichever is better. Scores are recorded 
according to ETDRS protocol and right eyes tested first.  
• 
Slit lamp biomicroscopy – 8 mm x 2 mm slit lamp beam wil be used right to left and left to 
right to examine thoroughly the structures of the anterior segment: lids, lashes, conjunctiva, 
cornea, iris, anterior chamber, and lens. Results will be recorded as normal or abnormal. 
Abnormal findings will be followed by explanation of pathology. 
• 
IOP measurements will be performed using Goldman applanation tonometry according to the 
investigators standard protocol. All pressures will be recorded in mm Hg. IOP will be measured 
at each time point and at the investigator’s discretion. 
• 
Dilated ophthalmoscopy will occur at the first and last study visit and include assessment of 
the optic nerve head for pallor and cupping.  
Adverse events will be collected at each time point 
 
h   
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.3 
 
 


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8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
8.3.3.1 SEVERITY OF EVENT 
 For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s 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”. 
 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect.  
 
• 
Related – The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
 
OR 
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 


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result, occurs in a plausible time relationship to study intervention administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
study intervention (dechallenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory rechallenge 
procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within 
a reasonable time after administration of the study intervention, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of the 
study intervention) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 
 
 
8.3.3.3 EXPECTEDNESS  
: 
 
The primary investigator will be responsible for determining whether an adverse event (AE) is 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 previously described for the study intervention. 
 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
Describe how AEs and SAEs will be identified and followed until resolved or considered stable.  Specify  
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 


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Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The study coordinator will record all reportable events with start dates occurring any time after 
informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of 
study participation.  At each study visit, the study coordinator will inquire about the occurrence of 
AE/SAEs since the last visit.  Events will be followed for outcome information until resolution or 
stabilization. 
 
 
8.3.5 ADVERSE EVENT REPORTING  
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
 
The study clinician will immediately report to the sponsor any serious adverse event, whether or not 
considered study intervention related, including those listed in the protocol or investigator brochure and 
must include an assessment of whether there is a reasonable possibility that the study intervention 
caused the event. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be 
reported in accordance with the protocol unless there is evidence suggesting a causal relationship 
between the study intervention and the event (e.g., death from anaphylaxis). In that case, the 
investigator must immediately report the event to the sponsor. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. Other supporting documentation 
of the event may be requested by the Data Coordinating Center (DCC)/study sponsor and should be 
provided as soon as possible. 
 
The study sponsor will be responsible for notifying the Food and Drug Administration (FDA) of any 
unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case later 
than 7 calendar days after the sponsor's initial receipt of the information.  In addition, the sponsor must 
notify FDA and all participating investigators in an Investigational New Drug (IND) safety report of 
potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later 
than 15 calendar days after the sponsor determines that the information qualifies for reporting.] 
 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
Participants will be informed about AEs and SAEs, and study-related results on an individual or aggregate 
level. Incidental findings associated with study procedures will be monitored by the primary investigator 
and reported appropriately as required.  


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8.3.8 EVENTS OF SPECIAL INTEREST  
 
8.3.9 NREPORTING OF PREGNANCY  
Should a participant become pregnant during the study, the primary investigator will create a plan to 
stop or taper the study drug as quickly as possible. The primary investigator will communicate with the 
physician managing the pregnancy and the subject and pregnancy will be followed to term.  
 
 
8.4 
UNANTICIPATED PROBLEMS 
. 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the Data Coordinating Center (DCC)/lead principal investigator (PI). The UP report will 
include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 


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• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the DCC/study 
sponsor within 24 hours of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and to the DCC/study sponsor within <insert timeline in 
accordance with policy> of the investigator becoming aware of the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office for 
Human Research Protections (OHRP) within <insert timeline in accordance with policy> of the 
IRB’s receipt of the report of the problem from the investigator.] 
 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
Unanticipated problems affecting the study or study participants will be reported to subjects by the primary 
investigator as soon as they are known.  
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
State the formal and testable null and alternative hypotheses for primary and key secondary endpoints, 
specifying the type of comparison (e.g., superiority, equivalence or non-inferiority, dose response) and 
time period for which each endpoint will be analyzed. 
 
• 
Primary Efficacy Endpoint(s): the study will attempt to demonstrate the improvement in mean 
average from baseline to final visit of both corneal staining and subjective ocular discomfort as 
measured by the OSDI scale. Ed  
 
 
 
• 
Secondary Efficacy Endpoint(s):improvement in mean average from baseline to final visit of 
conjunctival lissamine green staining. The study will demonstrate no change in baseline to final 
intraocular pressure, no worsened BCVA, and stable slit lamp biomicroscopy and dilated fundus 
exams. 
 
 
 
9.2 
SAMPLE SIZE DETERMINATION 
 
This is a small pilot study of 12 participants completing the study assessments. There is no placebo and it 
is not powered to show statistical significance.  
 
9.3 
POPULATIONS FOR ANALYSES 
 
• 
Intention-to-Treat (ITT) Analysis Dataset (i.e., all randomized participants) 
• 
Safety Analysis Dataset: defines the subset of participants for whom safety analyses will be 
conducted (e.g., participants who took at least one dose of study intervention) 


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9.4 
STATISTICAL ANALYSES 
 
 
9.4.1 GENERAL APPROACH 
As a guide, the following should be addressed, as appropriate: 
 
• 
Categorical and continuous data will be presented as percentages, means with standard 
deviations, median, and range).  
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
For each primary endpoint: 
The improvement of patient comfort as measured by the dry eye comfort questionnaire OSDI 
defined as the mark listed in mm by the patient describing sensation of dryness. It will be 
measured at each study visit and reported as an ordinal endpoint. Descriptive statistics will be 
used for intent to treat patients and safety populations who receive at least one dose of the 
study drug.  
• 
The improvement of corneal staining after fluorescein instillation in which discrete superficial 
punctate stains are counted.. Descriptive statistics will be used for intent to treat patients and 
safety populations who receive at least one dose of the study drug.  
• 
MIissing data will be handled by imputation. Outliers will be evaluated by the primary 
investigator. Subjects who are nonadherent will be referred for re-training and those lost to 
follow up will be contacted by the study coordinator at least 3 times by phone and ultimately 
with certified letter if telephone contacts are unsuccessful.  
  
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
For each secondary endpoint: 
 
• 
The improvement of conjunctival  staining after lissamine green instillation in which discrete 
superficial punctate stains are counted.. Descriptive statistics will be used for intent to treat 
patients and safety populations who receive at least one dose of the study drug.  
• 
IOPs wlll be analyzed for mm Hg increase from baseline, also noting 10 mm Hg increase from 
baseline  It will be measured at each visit. Descriptive statistics will be used for intent to treat 
patients and safety populations who receive at least one dose of the study drug.  
9.4.4 SAFETY ANALYSES 
  
Safety endpoints will be analyzed as summary statistics during treatment, coded as per Medical 
Dictionary for Regulatory Activities and counted once only for a given participant. Start/stop dates, 
severity as determined by the investigator, relationship, expectedness, outcome and duration will be 
reported. Adverse events leading to premature discontinuation from the study and serious treatment-
emergent AEs will be presented separately in a listing.  
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
Include content in this section if applicable, otherwise note as not-applicable. 
 


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Because  all subjects will receive active intervention, Intervention groups will not be compared . 
 
9.4.6 PLANNED INTERIM ANALYSES  
No interim analysis is planned.  
 
9.4.7 SUB-GROUP ANALYSES 
No sub-group analyses are planned.  
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
Individual participant data will not be listed by measure and time point. 
1 
 
9.4.9 EXPLORATORY ANALYSES 
No exploratory analyses are planned. 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
. 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
 
 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.  The following consent materials are submitted with this 
protocol.: informed consent document. 
 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. The 
study coordinator and primary investigator will explain the research study to the participant and answer 
any questions that may arise. A verbal explanation will be provided in terms suited to the participant’s 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
research participants.  Participants will have the opportunity to carefully review the written consent 
form and ask questions prior to signing. The participants should have the opportunity to discuss the 
study with their family or surrogates or think about it prior to agreeing to participate. The participant 
will sign the informed consent document prior to any procedures being done specifically for the study. 
Participants must be informed that participation is voluntary and that they may withdraw from the 
study at any time, without prejudice. A copy of the informed consent document will be given to the 


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participants for their records if requested. The informed consent process will be conducted and 
documented in the source document (including the date), and the form signed, before the participant 
undergoes any study-specific procedures. The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they decline 
to participate in this study. 
 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
  
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, investigator, funding agency, the 
Investigational New Drug (IND) or Investigational Device Exemption (IDE) sponsor and regulatory 
authorities.  If the study is prematurely terminated or suspended, the Principal Investigator (PI) will 
promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will provide 
the reason(s) for the termination or suspension.  Study participants will be contacted, as applicable, and 
be informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA).] 
 
 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
• 
Initials will be attached to data/samples 
 
• 
Personally identifiable information will be released to third parties such as insurance carriers and 
primary physicians if warranted. 
• 
Study coordinator, primary and sub-investigators will have access to records, data, and samples.  
Monitors or auditors outside of study investigators will need access as well. 
 
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be held in 


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strict confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), regulatory agencies or pharmaceutical company supplying study product may 
inspect all documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at Toyos Clinic. This will not include the participant’s contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique study 
identification number. The study data entry and study management systems used by the clinic site and 
research staff will be secured and password protected. At the end of the study, all study databases will 
be de-identified and archived at Toyos Clinic. 
 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored at Toyos Clinic onsite at 2204 Crestmoor 
Nashville, TN or in appropriate storage facility where Toyos Clinic records are kept. After the study is 
completed, the de-identified, archived data will be transmitted to and stored at Toyos Clinic.  for use by 
other researchers including those outside of the study.  
 
 
When the study is completed, access to study data will be provided through Toyos Clinic.] 
 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
Provide the name and contact information of the Principal Investigator and the Medical Monitor. 
Principal Investigator 
Melissa Toyos, MD partner 
Toyos Clinic 
2204 Crestmoor Nashville, TN 
615.327.44 
mtoyos@toyosclinic.com 
 
 
 
 


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10.1.6 SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of an IRB and a Data and Safety Monitoring Board (DSMB) 
composed of individuals with the appropriate expertise, including studies and Acthar specifically.. 
Members of the DSMB should be independent from the study conduct and free of conflict of interest, or 
measures should be in place to minimize perceived conflict of interest.  The DSMB will meet at least 
semiannually to assess safety and efficacy data on each arm of the study. The DMSB will operate under 
the rules of an approved charter that will be written and reviewed at the organizational meeting of the 
DSMB. At this time, each data element that the DSMB needs to assess will be clearly defined. The DSMB 
will provide its input to Toyos Clinic. 
 
 
10.1.7 CLINICAL MONITORING 
 
 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s).  
 
• 
The primary investigator will conduct the monitoring on-site, once, for random review of 
certain data,, safety. Independent audits will not be conducted by <insert text> to ensure 
monitoring practices are performed consistently.] 
 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management plan will be 
developed to describe a site’s quality management.] 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is 
conducted and data are generated and biological specimens are collected, documented (recorded), and 
reported in compliance with the protocol, International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)).  
 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 


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10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.   
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study.   
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered onto the CRF provided by Toyos clinic. 
 
10.1.9.2 STUDY RECORDS RETENTION  
 
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an International Conference on Harminosation (ICH) region and until there are no pending 
or contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study intervention. These documents should be 
retained for a longer period, however, if required by local regulations. No records will be destroyed 
without the written consent of the sponsor, if applicable. It is the responsibility of the sponsor to inform 
the investigator when these documents no longer need to be retained. 
 
 
10.1.10 
PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 14 working days of identification of the protocol deviation, or within 14 working days 
of the scheduled protocol-required activity.  All deviations must be addressed in study source 
documents, reported to sponsor . .  Protocol deviations must be sent to the reviewing Institutional 


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Review Board (IRB) per their policies. The site investigator is responsible for knowing and adhering to 
the reviewing IRB requirements.  
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
 This study is not funded by the NIH. 
 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  The study 
leadership in conjunction with the NIH Institute has established policies and procedures for all study 
group members to disclose all conflicts of interest and will establish a mechanism for the management 
of all reported dualities of interest.] 
 
 
10.2 ADDITIONAL CONSIDERATIONS 
Not applicable. 
 
 


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10.3 ABBREVIATIONS 
The list below includes abbreviations utilized in this template.  However, this list should be customized for 
each protocol (i.e., abbreviations not used should be removed and new abbreviations used should be 
added to this list). 
 
AE 
Adverse Event 
ACTH 
Adrenocorticotropic hormone 
AR 
Adverse Reaction 
BCVA 
Best Corrected Visual Acuity 
CRF 
Case Report Form 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
IOP 
Intraocular Pressure 
IPL 
Intense Pulsed Light 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
KCS 
Keratoconjunctivitis Sicca 
ITT 
Intention-To-Treat 
MLT 
Micropulsed Laser Trabeculoplasty 
mm 
Millimeter 
Mm Hg 
Millimeter of mercury 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NSAID 
Non-steroidal 
OSDI 
Ocular surface disease index 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SLT 
Selective laser trabeculoplasty 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UPT 
Urine pregnancy test 
US 
United States 
 
 
 


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10.4 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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11 REFERENCES  
 
• 
 
Benko, A, McAloose C, Becker P, Wright D, Sunyer T, Kawasawa Y, Olsen J, Kovacs W,. Repository 
corticotrophin injection exerts direct acute effects on human B cell gene expression distinct from 
the actions of glucocorticoids. Clin Exp Immunol 2018 Apr:192(1):68-81 
• 
Philbin M, Niewoehner J, Wan G, Clinical and Economic Evaluation of Repository Corticotropin 
Injection: A Narrative Literature Review of Treatment Efficacy and Healthcare Resource 
Utilization for Seven Key Indications 
• 
Olsen N, Decker D, Higgins P, Becker P, McAloose C, Benko, Kovacs W, Direct Effects of HP Acthar 
Gel on human B lymphocyte activation in vitro, Arthritis Res Ther 2015 Oct 27:17:300. 
• 
Patel A, Seely G, Aggarwal R, Repository Corticotropin Injection for Treatment of Idiopathic 
Inflammatory Myopathies, Case Rep Rheumatol 2016;2016:9068061 epub 
• 
Lan N, Karin M, Nguyen T, Weisz A, Birnbaum M, Eberhardt N, Baxter J, Machanisms of 
glucocorticoid hormone action, J JSteroid Biochem. 1984 Jan;20(1):77-88. 
• 
Nelson W, Philbin M, Gallagher J, Heap K, Carroll S, Wan G, A Retrospective Medical Record 
Review of Utilization Patterns and Medical Resource Use Associated with Repository 
Corticotropin Injection among Patients with Rheumatologic Diseases in the United States. 
Rheumatol Ther 2017 Dec;4(2):465-474. 
• 
Baughman R, Sweiss N, Keijsers r, Birring S, Shipley R, Saketkoo L, Lower E, Repository 
Corticotropin for Chronic Pulmonary Sarcoidosis Lung, 2017 Jun;195(3):313-322. 
• 
Gold L, Schepman P, Wang W, Philbin M, Niewoehner J, Damal K, Hansen R, Healthcare Costs 
and Resource Utilization in Patients with Infantile Spasms Treated with H.P. Acthar Gel Adv Ther 
2016 Aug;33(8):1293-304. 
• 
Zhou Y, Lower E, Baughman R, Sarcoidosis patient with lupus pernio and infliximab-induced 
myosistis: Response to Acthar gel Respir Med Case Rep.2015 Nov 19;17:5-7. 
• 
Metersky M, Is There Any Reliable Clinical Evidence to Suggest That Acthar is More Effective 
Than Other Forms of Corticosteroids in Treating Sarcoidosis and Other Diseases It IS Being 
Marketed to Treat? Chest, 2016 Mar;149(3):886. 
• 
Brod S, Bauer V, Hood Z, Oral ACTH (H.P. Acthar Gel) inhibits IL-1 and IL-17 secretion in humans 
Biomed Pharmacother, 2012 Feb;66(1):36-39 
• 
Hagan S, Fyfe M, Ofori-Frimpong B, Oliver K, Foster M, Sirohi S, Solanke Y, Doughty M, Rowley A, 
Taylor M, Webber S, Walshe C, Narrow Spectrum Kinase Inhibitors Demonstrate Promise for the 
Treatment of Dry Eye Disease and Other Ocular Inflammatory Disorders, Invest Ophthalmol Vis 
Sci, 2018 Mar 1;59(3):1443-1453. 
• 
Deveney T, Asbell P, Patient and physician perspective on the use of cyclosporing ophthalmic 
emulsion 0.05% for the management of chronic dry eye, Clin Ophthalmol, 2018 Mar 23:12:569-
576. 
• 
Gilger B, Immune Relevant Models for Ocular Inflammatory Diseases, ILAR J, 2018 Feb 21. Epub 
ahead of print 
Ophthalmology Center http://acthar.com/healthcare-professional cited 2018 April 
.https://www.acthar.com/pdf/Acthar-PI.pdf accessed 2018 April 11.  
  

ICF_006.pdf: 
Study: Autologous Serum Tears for Dry Eye Disease Study Protocol 
Protocol: TOYOS-GENIUSPRP-19-01 
Date: October 16, 2019 
 
Version Date: 16 Oct 2019 
 
Cover Page 
NCT03287635 
Clinical Efficacy of H.P. Acthar Gel 80 Units/ml to Improve the Signs and Symptoms in Subjects 
with Dry Eye Disease 
 
Date May 10, 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study: Autologous Serum Tears for Dry Eye Disease Study Protocol 
Protocol: TOYOS-GENIUSPRP-19-01 
Date: October 16, 2019 
 
Version Date: 16 Oct 2019 
 
 
 
Participant Informed Consent Form and Authorization to Use and Disclose Medical Information 
 
TITLE: Evaluation of the Safety and Efficacy of Autologous Serum Tears Prepared with the 
Genius PRP for Dry Eye Disease 
 
PROTOCOL NO:      TOYOS-GENIUSPRP-19-01 
 
 
         
SPONSOR:  
Toyos Clinic 
 
INVESTIGATORS:  
Rolando Toyos, MD 
1365 South Germantown Road 
Germantown, TN 38138 
 
Melissa Toyos, MD 
 
 
 
2204 Crestmoor Road 
 
 
 
Nashville, TN 37215 
 
 
 
United States 
 
 
 
 
Wang Yan, MD 
 
 
 
Tianjin Eye Hospital 
 
 
 
4 Gansu Road 
 
 
 
Heping, Tianjin, China 
 
Zhang Lin 
 
 
 
Tianjin Eye Hospital 
 
 
 
4 Gansu Road 
 
 
 
Heping, Tianjin, China 
 
 
SITES:   
 
Toyos Clinic 
 
 
 
1365 South Germantown Road 
 
 
 
Germantown, TN 38138 
 
 
 
United States 
 
 
 
615.327.4015 
 
 
 
 
 
 
 
 
Tianjin Eye Hospital 
 
 
 
4 Gansu Road 
 
 
 
Heping, Tianjin, China 
 
 
 
+86 22 2731 3336 


Study: Autologous Serum Tears for Dry Eye Disease Study Protocol 
Protocol: TOYOS-GENIUSPRP-19-01 
Date: October 16, 2019 
 
Version Date: 16 Oct 2019 
 
 
 
STUDY-RELATED NUMBERS:   
Rolando and Melissa Toyos, MD 
 
 
 
 
 
888-315-3937 (24 hours) 
 
 
 
 
 
 
Madison Rupard 
 
 
 
 
 
615.327.4015 (24 hours) 
 
SUB-INVESTIGATORS:  
 
Rolando Toyos, MD 
 
 
 
 
 
Melissa Toyos, MD 
 
 
 
 
 
Wang Yan, MD 
 
 
 
 
 
Zhang Lin, MD 
 
 
 


Study: Autologous Serum Tears for Dry Eye Disease Study Protocol 
Protocol: TOYOS-GENIUSPRP-19-01 
Date: October 16, 2019 
 
Version Date: 16 Oct 2019 
 
 INTRODUCTION 
You are being asked to participate in a medical research study. Before agreeing to participate in 
this research study. It is important that you read the following explanation of this research 
study. No guarantees or assurances can be made as to the results of the study. 
 
The decision to participate in this study is up to you. Your participation is completely voluntary. 
Your decision will not affect your relationship with your regular doctor or your current or future 
medical care. 
 
Please read this form carefully. Feel free to discuss the study with your family, friends, and 
healthcare provider before you make your decision whether to participate. Ask about anything 
you don’t understand or would like explained better. Take time to decide whether or not you 
want to take part in this study and ask the study doctor or study staff as many questions about 
the study as you would like. You cannot take part in this research study until you sign this form. 
 
This form explains the following: 
• Purpose of the study 
• Procedures involved in the study 
• Possible benefits 
• Possible risks 
• How your medical information will be used and who may view it 
 
Background and Purpose 
Dry eye disease is a condition that can affect a patient’s quality of life. Symptoms of dry eye 
include but are not limited to irritation, redness, burning, foreign body sensation, dryness, pain 
and blurry vision. In many cases, dry eye disease is caused by chronic inflammation that can 
damage both the surface of the eye and the nerves in the ocular surface that help to maintain 
normal health.  
 
In dry eye disease due to neurotrophic keratitis, the nerves in the eye may be damaged enough 
to allow ongoing and worsening damage to the surface of the eye as well as a loss of feeling or 
pain due to the chronic nature of the disease. 
  
Dry eye disease may be caused by a variety of factors including hormonal changes, bacterial 
infections, systemic medications, allergies, use of eye drops that contain preservatives or 
inflammation, pollution or poor diet. Dry eye disease is especially prevalent in Asian 
populations.   
 
In recent years, a growing number of doctors have observed that application of the topical 
application of growth factors including nerve growth factor which is contained within platelet 
rich plasma (PRP) prepared from a patient’s own blood can help to improve the signs and 
symptoms of dry eye disease.   


Study: Autologous Serum Tears for Dry Eye Disease Study Protocol 
Protocol: TOYOS-GENIUSPRP-19-01 
Date: October 16, 2019 
 
Version Date: 16 Oct 2019 
 
PURPOSE OF STUDY 
You are being asked to take part in this study because you have been diagnosed with dry eye 
disease. 
 
The purpose of this research study is to study the effects, safety and efficacy of intense pulse 
light with the Lumenis M22 applied to the upper eyelids of subjects who have a diagnosis of dry 
eye disease caused by MGD> 
 
The Genius PRP has been approved for use the United States for the preparation of platelet rich 
plasma (PRP) for intraoperative use during orthopedic procedures. This system is a cleared 
(approved) device (by the United States Food and Drug Administration (FDA) for orthopedic 
use. The use of GENIUS PRP for reducing the symptoms of dry eye caused by dry eye disease in 
this study is investigational. An investigational use is one that is not approved by the United 
States Food and Drug Administration (FDA). Because this is a research study, IPL for dry eye 
disease caused by dry eye disease will be used only during this study and not after the study is 
over.  
 
Approximately 20 men and women between the ages of 18-85 will be enrolled in this study 
being conducted with enrollment, data collection and follow up visits at Tianjin Eye Hospital 
and data analysis and manuscript preparation primarily at Toyos Clinic’s Nashville location. 
 
DURATION OF THE STUDY 
 
Participation in the study will last 4 weeks. During this period, you will receive study treatment 
twice daily for four consecutive weeks.   Four (4) weeks after initiation of the study treatment, 
you will be asked to return to the clinic for a follow up visit. 
 
YOUR RESPONSIBILITIES 
 
If you agree to participate in the study, you will attend 2 visits at the clinic, enrollment and final 
follow up visit. 
 
Screening/baseline visit: At this first visit, the study doctor will determine if you are eligible to 
participate in the study. The study doctor or staff will give you a detailed explanation about the 
study and review this consent document. Before any study-related tests or procedures are 
performed, you will be asked to read and sign this document. You may sign it at this visit or if 
you wish to have some time to think more about, consult with others, you may elect to take it 
home for as long as you wish. If you decide that you wish to participate in the study, you must 
return with a signed informed consent form. 
 
 After the informed consent is signed, you will be asked questions about your medical history or 
demographic information including age, gender, race and skin type). This visit can occur on the 


Study: Autologous Serum Tears for Dry Eye Disease Study Protocol 
Protocol: TOYOS-GENIUSPRP-19-01 
Date: October 16, 2019 
 
Version Date: 16 Oct 2019 
 
same day as the screening visit or up to a week later. If you are eligible to participate in the 
study you will have a brief examination including: 
 
Visual acuity test: the doctor or study staff will use a chart and ask them to read them from top 
to bottom as the letters become smaller. 
 
Slit lamp exam: the doctor will examine the structures of the eye using a microscope and beam 
of light. 
 
Confocal imaging: the doctor will examine the nerves in the front of the eye with a special high 
resolution microscope. 
 
VAS Scales: you will be asked to rate your current ocular pain and dryness symptoms at each 
study visit. 
 
Tear film break up time: the study doctor will measure the time it takes from a blink of the eye 
to the time a dry spot is formed on the surface of the eye using a yellow dye and a topical 
anesthetic or a drop of liquid dye. The doctor will ask you to blink and start a stopwatch. Your 
doctor will repeat this three time and take the average of these measurements. 
 
First study visit: The first study will consist of a blood draw by an approved technician and 
preparation of the PRP by an investigator. The patient will have their visual acuity tested with a 
slit lamp examination of the front of the eye, a subjective visual analog pain scale will be 
completed by the patients, and a confocal image will be taken. 
 
Final study visit. The same procedures except the blood draw and PRP prepartion will be done 
at this study visit.  
  
Procedures 
 
Enrollment/Baseline 
Visit 1, Day 1 
Study Visit 
2 Day 
30+/-3 day 
Informed 
Consent 
 
x 
 
Demographics 
 
x 
 
Medical History 
 
x 
 
VAS Scale pain 
 
x 
x 
Administer 
Study 
Intervention 
 
X 
 
Concomitant 
medication 
review 
 
X 
X 


Study: Autologous Serum Tears for Dry Eye Disease Study Protocol 
Protocol: TOYOS-GENIUSPRP-19-01 
Date: October 16, 2019 
 
Version Date: 16 Oct 2019 
 
 
BCVA 
 
X 
X 
Slit Lamp 
Biomicroscopy 
 
X 
X 
Dilated 
ophthalmoscopy 
 
X 
X 
Confocal 
imaging 
 
X 
x 
Non-invasive 
tear break up 
time 
 
X 
x 
 
 
 
 
 
POTENTIAL SIDE EFFECTS AND RISKS 
The Genius PRP treatment used in this study may cause all, some or none of the listed risks/side 
effects. There may be potential risks to you by taking part in this study including risks that are 
currently unknown.  
 
Possible risks of this procedure include: 
*eye pain 
*eye irritation 
*autoimmune deposits in eye that disappear after stopping study drug 
*eye watering 
 
 
 
Risks of procedures and tests for this study 
You will have various eye examinations which may product temporary eye irritation. 
 
-Blood draw, which allows the investigator to create PRP with the patient’s own blood. 
This procedure involves a needle for venipuncture that will allow for 60 cc of blood to be 
removed. There may be some minor discomfort with the blood draw, local irritation or bruising 
or need to re-stick if blood flow is insufficient. The PRP will be prepared aseptically. 
 
-Slit lamp examination which allows an examination of the frontal eye structures of the 
eye, including the eyelid, sclera (the white of the eye), conjunctiva (a clear mucous membrane 
that covers the sclera just behind the iris), and the cornea. The instrument used for this test 
consists of a high-intensity light source that can be focused to shine a thin sheet of light into the 
eye. 
 
-Dilated ophthalmoscopy, which allows examination of the back of the eye. The test 
may involve placing drops in the eye in order to dilate (expand) the pupils, which may cause 
you to experience some light sensitivity for a few hours after this examination. The dilating 
drops may rarely cause increased pressure in the eye leading to nausea and pain. 
 
- Confocal imaging, which allows for high resolution of the nerves within the front of the 
eye may or may not require contact with the front of the eye. 


Study: Autologous Serum Tears for Dry Eye Disease Study Protocol 
Protocol: TOYOS-GENIUSPRP-19-01 
Date: October 16, 2019 
 
Version Date: 16 Oct 2019 
 
- Tear Break Up Time – depending on the type of testing, a drop of fluorescein stain may be 
instilled into the eye, the lids held open for several seconds until the tear film breaks up or the 
patient may sit in front of a technology with open eyes until the technician observes tear break 
up. 
 
 
 


Study: Autologous Serum Tears for Dry Eye Disease Study Protocol 
Protocol: TOYOS-GENIUSPRP-19-01 
Date: October 16, 2019 
 
Version Date: 16 Oct 2019 
 
Pregnant women are not eligible to take part in the trial. If you are a woman who may become 
pregnant, you must use an effective method of birth control while participating in the study and 
for four weeks after your last dose of study drug. If you become pregnant during the study, 
please let your study staff known immediately and cease use of the study product. If you 
become pregnant during the study, the study staff will ask to follow your pregnancy to its 
outcome. You should tell your study doctor about physical or emotional changes or side effects 
that may occur while taking part in this study. Promptly report any health problems or changes 
to a member of the study staff or your study doctor.  
 
New Findings 
We will tell you about any new information that may affect your health, welfare, or choice to 
stay in this research.  
 
Potential Benefits 
You may benefit as a result of your participation in this study. However, there is no assurance 
that you will benefit from your participation in this study. Results from this study may benefit 
other patients in the future. 
 
Your dry eye disease may worsen, improve or stay the same while receiving the study product. 
 
Alternative Treatment 
This clinical study is for research purposes only. You do not have to participate in the study to 
receive treatment for dry eye. There are other options available to you may include warm 
compresses, artificial tears, topical cyclosporine, topical lifitiegrast topical steroids, non-
steroidals, autologous serum tears or IPL. You may choose to take part in a different study, if 
one is available and for which you may be eligible. 
 
Costs 
There will be no charge to you for your participation in this study. Study-related procedures and 
study visits will be provided to you at no charge or to your insurance company. If you are 
injured or get sick because of being in this research, call the study doctor immediately. The 
study doctor will provide emergency medical treatment. Your insurance may be billed for this 
treatment. No other payment is available from the study doctor.  
 
You will not be paid for being in this study. 
 
Voluntary Participation/Withdrawal 
Your decision to participate in this clinical research study is voluntary. You may choose not to 
participate or you may withdraw from the study for any reason at any time without penalty or 
loss of any benefits you are otherwise entitled. You should tell the study doctor or study team if 
you decide to leave the study. 
 


Study: Autologous Serum Tears for Dry Eye Disease Study Protocol 
Protocol: TOYOS-GENIUSPRP-19-01 
Date: October 16, 2019 
 
Version Date: 16 Oct 2019 
 
The study doctor can stop the study or your participation in the study at any time without your 
consent if it appears to be medically harmful to you, if you fail to follow directions for 
participating in the study, if the study is canceled, or for administrative reasons. If you withdraw 
or are withdrawn from the study, you will no longer receive access to study product but may be 
asked to continue in the study for safety measures. 
 
Confidentiality 
Information from this study will be given to the sponsor. “Sponsor” includes any persons or 
companies that are contracted by the sponsor to have access to the research information 
during and after the study. 
 
It is possible that regulatory agencies such as the U.S. Food and Drug Administration (FDA) may 
inspect confidential study materials and absolute confidentiality cannot be assured. However, 
all medical records and research materials will be held confidential to the extent permitted by 
law. Medical records which identify you and the consent form signed by you may also be looked 
at and/or copied for research or regulatory purposes by: 
1. Department of Health and Human Services (DHHS) agencies 
2. The institution where the research is being done, and 
 
If the results of this study are published or presented at meetings, you will not be identified. 
This permission or authorization has no end date. You have a right to see your study records 
but will not be able to do so until the study has ended.  
 
You may withdraw your permission at any time by writing your study doctor a letter. If you 
withdraw permission after you have entered the study, you cannot continue participating in the 
study. If you refuse to give permission or withdraw permission, your medical care and 
relationship with your health care providers at the study center will not be affected.  
 
If you have questions, concerns, or complaints, or think this research has hurt you or made you 
sick, talk to the research team at the phone number listed above on the first page. 
 
This research is being overseen by an Institutional Review Board (“IRB”). An IRB is a group of 
people who perform independent review of research studies. You may talk to them at XXXX if: 
You have questions, concerns, or complaints that are not being answered by the 
research team 
You are not getting answers from the research team. 
You cannot reach the research team. 
You want to talk to someone else about the research. 
You have questions about your rights as a research subject. 
 
. 
 


Study: Autologous Serum Tears for Dry Eye Disease Study Protocol 
Protocol: TOYOS-GENIUSPRP-19-01 
Date: October 16, 2019 
 
Version Date: 16 Oct 2019 
 
Consent 
I have read the statements in this informed consent document. I have had an 
opportunity to ask questions and all of my questions have been answered to my 
satisfaction. I voluntarily agree to participate in this study, if and until I decide 
otherwise. I do not give up any of my legal rights by signed this consent document. I 
may request a copy of this signed consent document. 
 
 
 
Printed Name of Participant 
 
 
 
___________________________________________     ___________________________ 
Signature of Participant 
 
 
 
 
Date 
 
 
 
I have carefully explained to the participant the nature and purpose of the above study. 
There has been an opportunity for the participant to ask questions about this research 
study. I have been available to answer any questions that the participant has about the 
study. 
 
 
 
Printed Name of Person Conducting Consent Discussion 
 
 
 
 
_____________________________________________  _______________________ 
Signature of Person Conducting Consent Discussion  
  Date 
 
 
 


Study: Autologous Serum Tears for Dry Eye Disease Study Protocol 
Protocol: TOYOS-GENIUSPRP-19-01 
Date: October 16, 2019 
 
Version Date: 16 Oct 2019 
 
Authorization to Use and Disclose Protected Health Information 
 
During your participation in this research study, the study doctor and study staff will 
collect or create health information about you and record it on study documents. The 
study doctor will keep this protected health information.  
 
Under federal law, your protected health information (PHI) that is created or obtained 
during this research study cannot be used or disclosed without your permission. This 
permission is called an “Authorization.” You do not have to sign this Authorization, 
however, you may not participate in this study unless you give your permission to use 
and disclose your PHI by signing this authorization. By signing, you are agreeing to allow 
the study doctor and study staff to use your health information to conduct this study. 
 
This Authorization will never expire unless and until you revoke (cancel or withdraw) it. 
 
You have a right to revoke your Authorization at any time. If you revoke it, your health 
information will no longer be used for this study, except to the extent the parties have 
already taken action based upon your prior Authorization or need the information to 
complete analysis and reports for this research. To revoke your Authorization, you must 
write to the study doctor, state that you are revoking your Authorization to Use or 
Disclose Protected Health Information. The study doctor’s mailing address is Toyos 
Clinic, 2204 Crestmoor Road, Nashville, TN 37215. If you revoke this Authorization, you 
will not be allowed to continue in the study. 
 
You may receive a copy of this Authorization after you have signed it. 
 
 
 
Printed Name of Participant 
 
___________________________________________     ___________________________ 
Signature of Participant 
 
 
 
 
Date 
 
I have carefully explained to the participant the nature and purpose of this form. I have 
been available to answer any questions that the participant has about this form. 
 
 
Printed Name of Person Obtaining the Authorization 
 
 
__________________________________________________      ___________________ 
Signature of Person Obtaining the Authorization 
 
 
Date 


Study: Autologous Serum Tears for Dry Eye Disease Study Protocol 
Protocol: TOYOS-GENIUSPRP-19-01 
Date: October 16, 2019 
 
Version Date: 16 Oct 2019 
 
 
 
 

SAP_005.pdf: 
Cover Page 
NCT03287635 
Clinical Efficacy of H.P. Acthar Gel 80 Units/ml to Improve the Signs and Symptoms in Subjects 
with Dry Eye Disease 
 
Date May 10, 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan Acthar Pilot Study 
 
The statistical analysis plan for this study includes analysis of patients completing the trial and 
measuring the change from baseline to final visit including intervisit changes. For each of these 
time points, P-values will be collected, standard deviations, standard error means, 95% 
confidence intervals of the difference and 2-tailed t test applied. There is no placebo or control 
in this study and the number of participants was not powered to show statistical differences.