Clinical trial NCT04169061
Conditions: Keratitis
Keywords: Severe or recalcitrant keratitis
Sponsor: Mallinckrodt
Start date: 2019-11-13; Completion date: 2020-12-07
Enrollment: 36 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
We will need about 36 participants for this study.

Volunteers might be able to participate if:

* they have bad noninfectious keratitis
* early treatments failed or were not well tolerated

Participants will be in the study for about 22 weeks:

* 4 weeks for tests to see if the study might be good for them
* 12 weeks of treatment with Acthar gel
* 4 weeks to wean off Acthar gel and follow-up with the doctor

Detailed description:

Arms: arm 1: Participants receive:

* a shot of Acthar (80 units) under the skin twice a week for 12 weeks
* a shot of Acthar (40 units) twice a week for 2 weeks
* a shot of Acthar (40 units) once a week for 2 more weeks

At each visit they will have medical tests and answer questions about their symptoms.
Interventions: intervention 1: Acthar
Intervention descriptions: intervention 1: Acthar gel for subcutaneous injection

Protocol documents:
Prot_SAP_001.pdf: 
CONFIDENTIAL AND PROPRIETARY 
CLINICAL STUDY PROTOCOL 
A Multicenter, Open-Label Study to Assess the Efficacy and 
Safety of Acthar® Gel in Subjects with Severe Keratitis 
Protocol Number: MNK14084113 
Date of Original Protocol: 08 August 2019 
Date of Protocol Amendment 1: 12 August 2019 
Date of Protocol Amendment 2: 11 September 2019 
Mallinckrodt ARD LLC 
1425 U.S. Route 206 
Bedminster, NJ 07921 
United States of America 
NCT04169061


 
 
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CONFIDENTIAL AND PROPRIETARY 
 
AMENDMENT HISTORY 
Protocol Amendment 2 Summary of Changes: 
 
Protocol Amendment 2 was created to: 
1. Remove asessments and language in the protocol related to 
 
 due to its proprietary nature 
2. Include a 4 week Acthar tapering period, which followed the 12 week treatment period of 
the study 
a. Because of the addition of an Acthar tapering period, Visit 7 was changed from a 
safety phone call to an in-person safety visit 
3. Stringency of Hepatitis C virus (HCV) assay reporting by the clinical testing laboratory is 
less detailed than was originally planned for the study, so details on the HCV assay were 
updated to highlight the more qualitative nature of the assay results 
 
 
 
Protocol Amendment 1 Summary of Changes: 
 
Protocol Amendment 1 was created to remove 
 from the screening 
assessment. 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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CONFIDENTIAL AND PROPRIETARY 
 
Disclosure Statement 
Restricted Distribution of Documents 
This document contains information that is confidential and proprietary to the sponsor. This 
information is being provided to the investigator solely for the purpose of evaluating and/or 
conducting a clinical study for the sponsor. The investigator may disclose the contents of this 
document only to study personnel under his/her supervision, institutional review boards 
(IRBs)/independent ethics committees (IECs), or duly authorized representatives of regulatory 
agencies for this purpose under the condition that they maintain confidentiality. The contents of 
this document may not be used in any other clinical study, disclosed to any other person or 
entity, or published without the prior written permission of the sponsor. The foregoing shall not 
apply to disclosure required by any regulations; however, the investigator will give prompt 
notice to the sponsor of any such disclosure. All other nonpublic information provided by the 
sponsor, as well as any information that may be added to this document, also is confidential and 
proprietary to the sponsor and must be kept in confidence in the same manner as the contents of 
this document. 
 
 


 
 
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CONFIDENTIAL AND PROPRIETARY 
 
SPONSOR SIGNATURE 
My signature, in conjunction with the signature of the investigator, confirms the agreement of 
both parties that the clinical study will be conducted in accordance with the protocol and 
applicable laws and other guidance documents and regulations including, but not limited to:  
* ICH E6(R2): Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice, 
which has its ethical foundation in the Declaration of Helsinki   
* the US Code of Federal Regulations (CFR) (as appropriate, including 42 CFR 11: Final Rule 
for Clinical Trials Registration and Results Information Submission)   
* NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information  
* all applicable national and local regulations (as appropriate, including the EU Clinical Trials 
Regulation)   
* protections for privacy (as appropriate, including the EU General Data Protection Regulation 
(GDPR)   
* provisions of all local ethics committees   
Nothing in this document is intended to limit the authority of a physician to provide emergency 
medical care. 
 
 
 
 
 
Sponsor Signature 
 
Date of Signature 
(DD Month YYYY) 
 
, PhD 
 
 
Sponsor Name (print) 
 
 
 
 
 
o=Mallinckrodt, ou=Clinical 
Development, 
email
@mnk.com, 
c=US 
Reason: I am approving this 
document 
Date: 2019.09.11 15:34:48 -04'00' 
Adobe Acrobat version: 11.0.19
11 September 2019


 
 
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CONFIDENTIAL AND PROPRIETARY 
 
INVESTIGATOR SIGNATURE 
I have read the MNK14084113 clinical study protocol and pledge that this study will be 
conducted in accordance with the protocol. In addition, by completing and signing the Statement 
of Investigator (FDA-Form 1572), I agree to abide, for the duration of this clinical trial, by all 
applicable guidance documents laws and regulations including, but not limited to:  
* ICH E6(R2): Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice, 
which has its ethical foundation in the Declaration of Helsinki   
* the US Code of Federal Regulations (CFR) (as appropriate, including 42 CFR 11: Final Rule 
for Clinical Trials Registration and Results Information Submission)   
* NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information  
* all applicable national and local regulations (as appropriate, including the EU Clinical Trials 
Regulation)   
* protections for privacy (as appropriate, including the EU General Data Protection Regulation 
(GDPR)   
* provisions of my local ethics committee   
Nothing in this document is intended to limit the authority of a physician to provide emergency 
medical care. 
 
 
 
 
 
Investigator’s Signature 
 
Date of Signature 
(DD Month YYYY) 
 
 
 
 
Investigator’s Name and Title (print) 
 
 
 
 


 
 
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CONFIDENTIAL AND PROPRIETARY 
 
TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ..................................................................................................1 
SPONSOR SIGNATURE ................................................................................................................2 
INVESTIGATOR SIGNATURE.....................................................................................................5 
TABLE OF CONTENTS .................................................................................................................6 
LIST OF TABLES ...........................................................................................................................9 
ABBREVIATIONS .......................................................................................................................10 
SYNOPSIS ....................................................................................................................................12 
SCHEDULE OF STUDY EVENTS ..............................................................................................14 
1. 
BACKGROUND INFORMATION AND RATIONALE..........................................18 
1.1. 
Disease/Condition Under Study .................................................................................18 
1.2. 
Study Rationale ...........................................................................................................18 
1.3. 
Assessment of Potential Benefits and Risks ...............................................................18 
2. 
OBJECTIVES .............................................................................................................20 
2.1. 
Assessments of Efficacy .............................................................................................20 
2.2. 
Assessment of Safety ..................................................................................................20 
2.3. 
Outcome Measures .....................................................................................................20 
3. 
STUDY DESIGN .......................................................................................................21 
3.1. 
Overall Design ............................................................................................................21 
3.2. 
Duration of Subject Participation ...............................................................................21 
3.3. 
Duration of Study .......................................................................................................21 
3.4. 
Number of Subjects ....................................................................................................21 
3.5. 
Treatment/Dose Rationale ..........................................................................................21 
3.6. 
End of Study Definition ..............................................................................................21 
4. 
STUDY POPULATION .............................................................................................23 
4.1. 
Inclusion Criteria ........................................................................................................23 
4.2. 
Exclusion Criteria .......................................................................................................24 
4.3. 
Screen Failures ............................................................................................................27 
5. 
STUDY TREATMENT ..............................................................................................29 


 
 
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5.1. 
Treatment Administration ...........................................................................................29 
5.2. 
Study Treatment Preparation/Handling/Accountability .............................................29 
5.3. 
Storage of Clinical Supplies .......................................................................................30 
5.4. 
Measures to Minimize Bias ........................................................................................30 
5.4.1. 
Interactive Phone/Web Response System ..................................................................30 
5.4.2. 
Emergency Identification of Study Treatment ...........................................................30 
5.5. 
Study Treatment Compliance .....................................................................................30 
5.6. 
Prior and Concomitant Therapy ..................................................................................31 
5.6.1. 
Permitted Concomitant Therapies ..............................................................................31 
5.6.2. 
Prohibited Concomitant Therapies .............................................................................31 
6. 
DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ..................................................................32 
6.1. 
Discontinuation of Study Treatment ...........................................................................32 
6.2. 
Subject Discontinuation/Withdrawal from the Study .................................................32 
7. 
STUDY ASSESMENTS AND PROCEDURES ........................................................34 
7.1. 
Efficacy Assessments .................................................................................................34 
7.1.1. 
Ophthalmic Examination ............................................................................................34 
7.1.2. 
Patient-reported Outcomes (PROs) ............................................................................34 
7.1.3. 
Corneal and Conjunctival Staining Score ...................................................................34 
7.1.4. 
T-Cell Assessments ....................................................................................................35 
7.2. 
Safety Assessments .....................................................................................................35 
7.2.1. 
Medical, Ophthalmic, and Surgical History ...............................................................35 
7.2.2. 
Physical Examination .................................................................................................35 
7.2.3. 
Height and Weight ......................................................................................................35 
7.2.4. 
Vital Signs ..................................................................................................................36 
7.2.5. 
Clinical Laboratory Tests ...........................................................................................36 
7.3. 
Adverse Events ...........................................................................................................37 
7.4. 
Treatment Overdose ....................................................................................................37 
7.5. 
Pharmacokinetic Assessments ....................................................................................37 
7.6. 
Genetics ......................................................................................................................37 


 
 
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7.7. 
Biomarkers ..................................................................................................................37 
7.8. 
Health Economics and Outcomes Research Assessments ..........................................37 
8. 
STATISTICAL CONSIDERATIONS .......................................................................38 
8.1. 
Sample Size Determination ........................................................................................38 
8.2. 
Populations for Analysis .............................................................................................38 
8.3. 
Statistical Analyses .....................................................................................................38 
8.3.1. 
Efficacy Analyses .......................................................................................................38 
8.3.2. 
Safety Analyses ..........................................................................................................38 
8.3.3. 
Interim Analyses .........................................................................................................39 
8.3.4. 
Handling Missing Data ...............................................................................................39 
9. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................40 
9.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................40 
9.1.1. 
Regulatory and Ethical Considerations ......................................................................40 
9.1.2. 
Financial Disclosure ...................................................................................................40 
9.1.3. 
Subject Information and Consent ...............................................................................40 
9.1.4. 
Data Protection ...........................................................................................................41 
9.1.5. 
Committees Structure .................................................................................................41 
9.1.6. 
Dissemination of Clinical Study Data ........................................................................41 
9.1.7. 
Data Quality Assurance ..............................................................................................41 
9.1.8. 
Source Documents ......................................................................................................42 
9.1.9. 
Study and Site Closure................................................................................................42 
9.1.10. 
Publication Policy .......................................................................................................43 
9.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................44 
9.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up and Reporting ........................................................................45 
9.3.1. 
Safety ..........................................................................................................................45 
9.3.2. 
Definitions ..................................................................................................................45 
9.3.3. 
Adverse Event and Serious Adverse Event Classifications ........................................46 
9.3.4. 
Adverse Event and Serious Adverse Event Recording and Reporting .......................47 


 
 
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9.3.5. 
Adverse Events of Special Interest .............................................................................48 
9.4. 
Appendix 4: Pregnancy Reporting ..............................................................................48 
9.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ..............49 
10. 
REFERENCES ...........................................................................................................50 
LIST OF TABLES 
Table 1: 
Schedule of Study Events ...........................................................................................14 
Table 2: 
Efficacy Assessments for Study MNK14084113 .......................................................20 
Table 3: 
Adverse Event Relationships ......................................................................................46 
Table  4: 
Adverse Event Severity Grades ..................................................................................47 
Table 5: Reporting Requirements for Adverse Events ..................................................................48 
 


 
 
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CONFIDENTIAL AND PROPRIETARY 
 
ABBREVIATIONS 
Abbreviation Term 
AE 
Adverse event 
ACTH 
adrenocorticotropic hormone 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase  
BCVA 
Best corrected visual acuity 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
eCRF 
Electronic case report form 
ET 
Early Termination 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
HbA1c 
glycosylated hemoglobin 
HBcAb 
Hepatitis B core antibody 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus antibody 
HIPAA 
Health Insurance Portability and Accountability Act 
IDEEL 
Impact of Dry Eye on Everyday Life  
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IGRA 
Interferon gamma release assay 
ID 
Identification 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 


 
 
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Abbreviation Term 
IXRS 
Interactive Phone/Web Response System 
LASIK 
Laser-assisted in situ keratomileusis  
logMAR 
Logarithm of the Minimum Angle of Resolution  
MCR 
Melanocortin receptors 
MM 
Medical monitor 
ODS 
Ocular Discomfort Score 
OTC 
Over-the-counter 
PRO 
Patient-reported outcomes 
QOL 
Quality of life 
QTcF 
QT interval corrected using Fridericia’s Formula  
SAE 
Serious adverse event 
SC 
Subcutaneously 
SD 
Standard deviation 
TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 
TNF-α 
Tumor necrosis factor- alpha  
U 
Units 
ULN 
Upper limit of normal 
US 
United States 
VAS 
Visual Analogue Scale 
 


 
 
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CONFIDENTIAL AND PROPRIETARY 
 
SYNOPSIS 
Study Title: A Multicenter, Open-label Study to Assess the Efficacy and Safety of Acthar® Gel in Subjects with 
Severe Keratitis 
Protocol Number: MNK14084113 
Type: Interventional/Phase 4 
Condition/Disease: Severe or Recalcitrant Keratitis 
Approximate Number of Subjects: Up to 36 
subjects enrolled 
Approximate Duration of Subject Participation: 22 weeks  
Approximate Number of Study Centers: 6 
Approximate Duration of Study: 1 year 
Rationale:  
Noninfectious keratitis can result from many different etiologies including systemic autoimmune 
disorder. Inflammatory cells express melanocortin receptors (MCRs) and anecdotal evidence suggests 
that adrenocorticotropic hormone (ACTH) gel, a MCR agonist, is beneficial in treating ocular 
inflammation and alleviating the associated symptoms (Perez, 2019). Acthar is believed to exert its 
effect through the activation of multiple MCRs present in immune cells, as well as in the eye, and the 
induction of cortisol in the adrenocortex. The introduction of Acthar to the treatment algorithm for 
keratitis may provide a treatment option when early treatments have failed or were not well tolerated.  
The study is being conducted to explore the efficacy and safety of Acthar in subjects with severe 
keratitis to better understand how different clinical parameters observed within the spectrum of this 
condition might be impacted by treatment with Acthar® Gel. 
Objectives and Endpoints:  
To evaluate the safety and efficacy of Acthar in subjects with severe keratitis when treated with Acthar 
gel. Efficacy endpoints include corneal staining, conjunctival staining, conjunctival redness, tear 
production, tear film stability, dryness, ocular discomfort, grittiness, burning, stinging, Quality of Life, 
and cytokine array levels. Safety endpoints include the incidence and severity of ocular adverse events 
(AEs), incidence and severity of other AEs, new or worsening cataracts, and the mean change in intra-
ocular pressure (IOP).  
Outcome Measures: 
Primary: The proportion of responders who improved on the IDEEL score. 
Secondary: Not applicable. 
Overall Design:  
This is a multicenter, multiple dose, open-label study to examine the efficacy of Acthar in adult 
subjects 18 years of age or older with a diagnosis of keratitis sicca. Up to 36 subjects with severe or 
recalcitrant keratitis who did not respond or tolerate treatment with topical cyclosporine or any 
immunosuppressant to treat keratitis will be enrolled. Subjects who meet entry criteria will be treated 
with Acthar 1 mL (80 units [U]) subcutaneously (SC) 2x (twice) per week for 12 weeks. After this 12 
weeks, Acthar will be tapered over 4 weeks. The 80 U dose will be reduced to 40 U 2x/week for 2 
weeks, followed by 40 U 1x/week for 2 additional weeks. Subjects will be reassessed at an in-clinic 


 
 
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CONFIDENTIAL AND PROPRIETARY 
 
Study Title: A Multicenter, Open-label Study to Assess the Efficacy and Safety of Acthar® Gel in Subjects with 
Severe Keratitis 
Protocol Number: MNK14084113 
Type: Interventional/Phase 4 
Condition/Disease: Severe or Recalcitrant Keratitis 
safety visit, 4 weeks after the last treatment dose for AE assessments and concomitant medication use. 
Endpoints will be measured at Baseline (Visit 2 [Day 1]), and Visit 3 through 6.  
Number of Subjects: 
Up to 36 subjects will be enrolled in this study at approximately 6 sites in the US. 
Treatment Groups and Duration: 
Subjects with severe or recalcitrant keratitis who did not respond or tolerate treatment with topical 
cyclosporine or any immunosuppressant to treat keratitis will be enrolled. Subjects will participate in 
the study for approximately 22 weeks, including a screening period of up to 28 days, an active 
treatment period of 12 weeks, an Acthar taper period of 4 weeks, and a follow up in-person safety visit 
4 weeks after the last dose of study drug. 


  
 
 
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CONFIDENTIAL AND PROPRIETARY 
 
SCHEDULE OF STUDY EVENTS 
Table 1: 
Schedule of Study Events 
Study procedures  
Visit 1 
Screening 
Day -28 to-1 
Visit 2 
Baseline 
Day 1 
Visit 3 
Phone 
Day 15 ±1 
Visit 4 
In Clinic 
Day 29 ±2  
Visit 5 
In Clinic 
Day 43 ±2  
Visit 6 
In Clinic 
Day 85 ±3 
Visit 7 
In Clinic / 
End of Acthar 
Taper 
Day 113 ±3 
Early 
Termination 
Informed consent 
X 
 
 
 
 
 
 
 
Urine pregnancy test 
X 
 
 
 
 
 
 
 
Demographic data, medical, 
surgical, ophthalmic history 
X 
 
 
 
 
 
 
 
Patient-Reported Outcomes 
 
 
ODS 
X 
X 
 
X 
X 
X 
 
X 
 
IDEEL and VAS 
 
X 
X 
X 
X 
X 
 
X 
Ophthalmic examination 
 
 
Visual Acuity 
X 
X 
 
X 
X 
X 
X 
X 
 
Slit Lamp Evaluation 
X 
X 
 
X 
X 
X 
X 
X 
 
Conjunctival redness 
X 
X 
 
X 
X 
X 
 
X 
 
Tear film breakup time 
X 
X 
 
X 
X 
X 
 
X 
 
Inferior corneal staining score 
X 
X 
 
X 
X 
X 
 
X 


 
 
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CONFIDENTIAL AND PROPRIETARY 
Study procedures  
Visit 1 
Screening 
Day -28 to-1 
Visit 2 
Baseline 
Day 1 
Visit 3 
Phone 
Day 15 ±1 
Visit 4 
In Clinic 
Day 29 ±2  
Visit 5 
In Clinic 
Day 43 ±2  
Visit 6 
In Clinic 
Day 85 ±3 
Visit 7 
In Clinic / 
End of Acthar 
Taper 
Day 113 ±3 
Early 
Termination 
 
Superior, central and total 
corneal staining score 
(fluorescein) 
X 
X 
 
X 
X 
X 
 
X 
 
Nasal, temporal and total 
conjunctival staining score 
(lissamine green) 
X 
X 
 
X 
X 
X 
 
X 
 
Schirmer’s Test 
X 
X 
 
X 
X 
X 
 
X 
 
IOP 
X 
 
 
 
 
X 
X 
X 
 
Undilated Fundoscopy 
X 
 
 
 
 
X 
X 
X 
Inclusion/Exclusion critera review 
X 
X 
 
 
 
 
 
 
Height a and weight  
X  
X 
 
 
 
X 
X 
X 
Vital signs b 
X 
X 
 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
 
 
X 
 
X 
Laboratory testing 
 
 
 
 
 
 
 
 
 
Chemistry and others c 
X 
X 
 
X 
X 
X 
 
X 
 
HbA1c 
X 
X 
 
X 
X 
X 
 
X 
 
Serum Pregnancy 
X 
X 
 
X 
X 
X 
 
X 


 
 
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CONFIDENTIAL AND PROPRIETARY 
Study procedures  
Visit 1 
Screening 
Day -28 to-1 
Visit 2 
Baseline 
Day 1 
Visit 3 
Phone 
Day 15 ±1 
Visit 4 
In Clinic 
Day 29 ±2  
Visit 5 
In Clinic 
Day 43 ±2  
Visit 6 
In Clinic 
Day 85 ±3 
Visit 7 
In Clinic / 
End of Acthar 
Taper 
Day 113 ±3 
Early 
Termination 
 
Hepatitis Serology d 
X 
 
 
 
 
 
 
 
 
IGRA for TB 
X 
 
 
 
 
 
 
 
 
Immunological protein assay e 
X 
X 
 
 
 
X 
 
X 
IXRS contact 
X 
X 
 
X 
X 
 
 
X 
Study Therapy 
 
 
 
 
 
 
 
 
 
Study drug and injection record 
training 
 
X 
 
 
 
 
 
 
 
Dispense study drug 
 
X 
 
X 
X 
 
 
 
 
Administer first dose in clinic f 
 
X 
 
 
 
 
 
 
 
Adverse event assessment 
X 
X 
X 
X 
X 
X 
X 
X 
 
Injection record review 
 
 
 
X 
X 
X 
X 
X 
 
Concomitant treatment review 
 
X 
X 
X 
X 
X 
X 
X 
 
Start Acthar Taper 
 
 
 
 
 
X 
 
 
 
End Acthar Taper 
 
 
 
 
 
 
X 
 
 
Study exit 
 
 
 
 
 
 
X 
X 
AE = adverse events; ET = early termination; HbA1c = glycosylated hemoglobin; IDEEL = Impact of Dry Eye on Everyday Life; IGRA = Interferon gamma 
release assay; IOP = Intraocular Pressure; ODS = Ocular Discomfort Score; TB = tuberculosis; VAS = Visual Analogue Scale. 


 
 
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CONFIDENTIAL AND PROPRIETARY 
 a Height at screening only. Weight at screening, Visits 2, 6, and ET.  
 b Blood pressure, respiratory rate, pulse rate and body temperature. For blood pressure, an average of 2 readings after the subject has been seated for ≥ 5 minutes 
at the Screening and Baseline Visits. Single readings after subject has been seated for ≥ 5 minutes at all other time points. 
c Refer to Section 9.2. 
d HBsAg, HBcAb, and HCV. 
e Refer to Table 2.  
f The first dose will be administered at the clinic and the subject should be observed for at least 1 hour after dosing. 


 
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CONFIDENTIAL AND PROPRIETARY 
1. 
BACKGROUND INFORMATION AND RATIONALE 
1.1. 
Disease/Condition Under Study 
Keratitis is a painful inflammation of the cornea which can result in partial or total loss of vision 
if left untreated and is a significant cause of ocular morbidity around the world (Sharma, 2001). 
It can result from infectious agents (eg, microbes including bacteria, fungi, amebae, and viruses) 
(Collier, 2010) or from noninfectious causes (eg, eye trauma, chemical exposure, and ultraviolet 
exposure). Conditions that affect the integrity of the ocular surface epithelium 
(exposure keratitis, neurotrophic keratitis, keratomalacia, recurrent corneal erosions) may also 
lead to development of sterile corneal ulcers. Non-infectious corneal ulcers may be associated 
with various collagen vascular or other autoimmune diseases, sometimes as the presenting sign 
of the disease (Donzis, 1987). 
As described in the Package Insert, Acthar® Gel (repository corticotropin injection, hereafter 
referred to as Acthar) is a naturally sourced complex mixture of adrenocorticotropic hormone 
(ACTH) analogues and other pituitary peptides (Mallinckrodt Package Insert, 2019) currently 
approved for the treatment of ocular inflammatory conditions including keratitis. ACTH is a 
member of the family of structurally related peptides known as melanocortin peptides. 
Melanocortin peptides, which include ACTH, as well as, α-, β-, and γ-melanocyte stimulating 
hormones, are derived from the natural protein pro-opiomelanocortin and exert their physiologic 
effects by binding to cell surface G-protein coupled receptors known as melanocortin receptors 
(MCRs) (Mountjoy, 1992). Five subtypes of MCRs have been identified to date (MC1R to 
MC5R), each with different tissue distributions, binding affinity characteristics, and 
physiological roles (Getting, 2006) (Montero-Melendez, 2015). ACTH binds to all 5 subtypes of 
MCR (Schioth, 1995). 
A detailed description of the chemistry, pharmacology, efficacy, and safety of Acthar is provided 
in the (Acthar® Gel Package Insert, 2019) 
1.2. 
Study Rationale 
Noninfectious keratitis can result from many different etiologies including systemic autoimmune 
disorder. Inflammatory cells express melanocortin receptors (MCRs) and anecdotal evidence 
suggests that Acthar Gel, a MCR agonist, is beneficial in treating ocular inflammation and 
alleviating the associated symptoms (Perez, 2019). Acthar is believed to exert its 
immunomodulatory effect through the activation of multiple MCRs present in immune cells, as 
well as in the eye, and the adrenocortex. The introduction of Acthar to the treatment algorithm 
for keratitis may provide a treatment option when early treatments have failed or were not well 
tolerated.  
The study is being conducted to explore the efficacy and safety of Acthar in subjects with severe 
keratitis to better understand how different clinical parameters observed within the spectrum of 
this condition might be impacted by treatment with Acthar® Gel.  
1.3. 
Assessment of Potential Benefits and Risks  
Common adverse reactions for Acthar include fluid retention, alteration in glucose tolerance, 
elevation in blood pressure, behavioral and mood changes, increased appetite, and weight gain. 


 
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Prolonged use of Acthar may produce posterior subscapular cataracts, glaucoma with possible 
damage to the optic nerves, and may enhance establishment of secondary ocular infections due to 
fungi and viruses. For a complete reference of known potential risks, refer to the Acthar® Gel 
Package Insert, 2019. More detailed information about the known and expected benefit, risks, 
and reasonably expected adverse events (AE) can be found in the Acthar® Gel Package Insert, 
2019.  


 
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2. 
OBJECTIVES 
To further evaluate the safety and efficacy of Acthar in subjects with severe keratitis when 
treated with Acthar gel. 
2.1. 
Assessments of Efficacy 
Table 2: 
Efficacy Assessments for Study MNK14084113 
Efficacy Assessments 
Corneal Staining  
Inferior, superior, central and total cornea regions as measured by 
the Ora Calibra™ Corneal Staining Scale (0 - 4)  
Conjunctival Staining  
Nasal, temporal and total conjunctiva regions as measured by the 
Ora Calibra™ Conjunctival Staining Scale (0-4) 
Conjunctival Redness 
As measured by the Ora Calibra™ Conjunctival Redness Scale 
(0 - 4) 
Tear Production 
Schirmer’s Test (mm) 
Tear Film Stability  
Tear Film Break-Up Time (seconds) 
Dryness 
As measured by the 0 - 100 mm Visual Analogue Scale (VAS) 
Ocular Discomfort  
As measured by the Ora Calibra™ Ocular Discomfort Scale (0 - 4) 
Ocular discomfort, dryness, 
grittiness, burning and 
stinging  
As measured by the Ora Calibra™ 4-symptom Questionnaire 
(0 - 5) 
Quality of Life  
As measured by IDEEL (Impact of Dry Eye on Everyday Life)  
Immunological protein assay 
Protein assay to detect levels of the cytokine array [interleukin 
1,6,17; interferon-ɤ]; ratio of T helper cells to T regulatory cells 
2.2. 
Assessment of Safety  
The frequency of adverse events (AEs), AEs of special interest (AESIs); clinical laboratory tests; 
metabolic panel; vital signs; physical examination; and ophthalmic findings (best corrected 
visual acuity, intraocular pressure, slit lamp examination, undilated eye examination) will be 
used to detect the presence of a safety signal(s). 
2.3. 
Outcome Measures 
The primary outcome measure is the proportion of responders who improved on the IDEEL 
score. There are no secondary outcome measures. 
 


 
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3. 
STUDY DESIGN 
3.1. 
Overall Design 
This is a multicenter, multiple dose, open-label study to examine the efficacy of Acthar in adult 
subjects 18 years of age or older with a diagnosis of keratitis sicca. Up to 36 subjects with severe 
or recalcitrant keratitis who did not respond or tolerate treatment with topical cyclosporine or any 
immunosuppressant to treat keratitis will be enrolled. Subjects who meet entry criteria will be 
treated with Acthar 1 mL (80 units [U]) subcutaneously (SC) 2x (twice) per week for 12 weeks, 
followed by a 4 week taper period of 40 U 2x/week for 2 weeks then 40 U 1x/week for 2 more 
weeks. Subjects will be reassessed at an in-clinic safety visit, 4 weeks after the last treatment 
dose for AE assessments, and concomitant medication use. Endpoints will be measured at 
Baseline and all other visits.  
3.2. 
Duration of Subject Participation 
Subjects will participate in the study for approximately 22 weeks, including a screening period of 
up to 28 days, an active treatment period of 12 weeks, an Acthar taper period of 4 weeks, and a 
follow up  in-person safety visit 4 weeks after the last treatment dose of study drug. 
3.3. 
Duration of Study 
The duration of the study from first subject first visit to last subject last visit will be dependent 
on the ability of the sites to identify and enroll eligible subjects. The entire study is expected to 
require approximately 1 year to complete. 
3.4. 
Number of Subjects 
Up to 36 subjects will be enrolled in this study at approximately 6 sites in the US. 
3.5. 
Treatment/Dose Rationale 
According to the Acthar Package Insert, the dosage should be individualized depending on the 
disease under treatment and the medical condition of the patient. The usual dose of Acthar is 
40 to 80 U (0.5 to 1 mL) given subcutaneously every 24 to 72 hours (Acthar® Gel Package 
Insert, 2019). In a survey of patients with ocular inflammatory disease that had been treated with 
Acthar and had registered with the sponsor’s patient support services, those with keratitis were 
most often treated with a subcutaneous injection of 80 U mL of Acthar 2x/week. To take into 
account the patient survey results, 80 U 2x/week was selected as the dose for this study. 
(Mallinckrodt Acthar Data Compendium, 2018). 
Following the 12 week period of treatment with 80 U, Acthar will be tapered over a 4 week 
period. The 80 U dose will be reduced to 40 U 2x/week for 2 weeks, followed by 40 U 1x/week 
for 2 additional weeks. 
3.6. 
End of Study Definition 
A subject is considered to have completed the study if the subject has completed the final 
assessments at Visit 7. 


 
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The end of the study is defined as the completion of the final assessment for the last subject 
enrolled in the trial. 


 
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4. 
STUDY POPULATION 
Prospective approval of protocol deviations in recruitment and enrollment criteria, also known as 
protocol waiver or exemption, is not permitted. 
4.1. 
Inclusion Criteria 
To be eligible to participate in the study, at the Screening Visit and the Baseline Visit (except as 
noted below) each subject must:  
1. Be adequately informed and understand the nature and risks of the study and must be able 
to provide a signature and date on the ICF; 
2. Be 18 years of age or older at the Screening Visit and may be male or female; 
3. Have normal lid anatomy; 
4. Have a reported history of severe keratitis in one or both eyes and a history of previous 
treatment for keratitis within the previous 6 months; 
5. Did not respond adequately or did not tolerate previous treatment with topical 
cyclosporine or LFA-1 antagonist; 
6. Have all the following in at least one eye (the same eye) at screening and baseline: 
a. Have an inferior corneal fluorescein staining score of at least 2 points in any field 
(Ora Calibra™ Scale) in at least one eye at the Screening and Baseline visits; 
b. Have a sum corneal fluorescein staining score  4, based on the sum of the 
central, superior, and inferior regions of the cornea (Ora Calibra™ Scale) in at 
least one eye at the Screening and Baseline Visits; 
c. Have a sum lissamine green conjunctival score of  2, based on the sum of the 
temporal and nasal regions of the conjunctiva (Ora Calibra™ Scale) in at least one 
eye at Screening and Baseline visits; 
d. Have a conjunctival redness score  1 (0-4 point Ora scale) in at least one eye  at 
the Screening and Baseline Visits; 
e. Have a Schirmer score  1 mm and  10 mm/5min in at least one eye at the 
Screening and Baseline Visits; 
f. Have an Ocular Discomfort Score (ODS) of  2 (0-4 point Ora scale) in at least 
one eye  at the Screening and Baseline Visits; 
7. If female, of nonchildbearing potential (history of hysterectomy, bilateral oophorectomy, 
bilateral tubal ligation; or postmenopausal with no history of menstrual flow in the 12 
months prior to the Screening Visit); or, if of childbearing potential, be nonpregnant, 
nonlactating, and agree to use 2 forms of effective contraception when with a male 
partner for the duration of the study (through Visit 6). Acceptable forms of contraception 
include hormonal measures (oral contraceptive pills, contraceptive patch, contraceptive 
ring, injections), intrauterine devices, double barrier method (condom plus diaphragm, 
condom or diaphragm plus spermicidal gel or foam, surgical sterilization of the male 
partner), and abstinence; 


 
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8. If male with reproductive potential, agree to use 2 forms of effective contraception 
(abstinence, surgical sterilization [vasectomy], or condom with spermicide) with a female 
partner for the duration of the study (through Visit 6); 
9. Subjects must have a mean systolic blood pressure ≤ 150 mm Hg and a diastolic blood 
pressure of ≤ 90 mm Hg determined by the average of 2 seated readings taken at least 
5 minutes apart at the Screening and Baseline Visits; 
10. Be able to communicate effectively with study personnel; 
11. Be able and willing to follow all protocol requirements and study restrictions; 
12. Be able and willing to return for all study visits 
4.2. 
Exclusion Criteria 
A subject is ineligible for study participation if the subject meets any of the following criteria at 
the Screening or Baseline Visit: 
1. Subject is from a vulnerable population, as defined by the US CFR Title 45, Part 46, 
Section 46.111(b) and other local and national regulations, including but not limited to, 
employees (temporary, part-time, full time, etc.) or a family member of the research staff 
conducting the study, or of the sponsor, or of the clinical research organization, or of the 
IRB/IEC; 
2. Have any ocular condition that, in the opinion of the investigator, could affect study 
parameters including, but not limited to, glaucoma, diabetic retinopathy, blepharitis, 
meibomian gland disease, lid margin inflammation, ocular allergies, follicular 
conjunctivitis, iritis, uveitis, neuropathic pain and/or active ocular inflammation not 
related to keratitis; 
3. Have a history of laser-assisted in situ keratomileusis (LASIK) or similar type of corneal 
refractive surgery within 12 months prior to the Baseline visit, and/or any other ocular 
surgical procedure (eg, cataract surgery, eyelid surgery) within 12 months prior to the 
Baseline Visit; or any scheduled ocular surgical procedure during the study phase; 
4. Have active or any history of ocular herpes; and other ocular infection within 30 days 
prior to the Baseline visit; 
5. Have current punctal plugs (within 30 days prior to Screening visit), punctal occlusion, or 
history of nasolacrimal duct obstruction; 
6. Be unwilling to avoid wearing contact lenses for 7 days prior to the Screening visit and 
for the duration of the study phase; 
7. Have best corrected visual acuity < 0.7 Logarithm of the Minimum Angle of Resolution 
(logMAR) in each eye at the Screening and Baseline Visits; 
8. Use prohibited prescription or over-the-counter (OTC) medications or devices and be 
unable to discontinue their use for the required period before entry into the study as 
follows: 


 
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a. Ophthalmic cyclosporine (Restasis®) or ophthalmic lymphocyte function-
associated antigen-1 (LFA-1) antagonist (Xiidra®): 12 weeks prior to the 
Screening visit; 
b. Corticosteroids (topical and systemic), ocular autologous serum, antibiotics 
(topical and systemic), mast cell stabilizers (topical and systemic), 
vasoconstrictors (topical and systemic): 30 days prior to the Screening visit; 
c. Systemic tetracycline compounds (tetracycline, doxycycline or minocycline), 
unless the dose has been stable for at least 30 days prior to the Screening visit and 
will remain stable during the study phase, in which case this is permitted; 
d. Any medication (topical and systemic) known to cause ocular drying, such as the 
use of systemic anticholinergic medications (eg, antihistamines and 
antidepressants), unless the dose has been stable for at least 30 days prior to the 
Screening visit and will remain stable during the study phase; 
e. Antihistamines (topical and systemic): 7 days prior to the Screening visit; 
f. Topical or nasal vasoconstrictors within 14 days prior to screening; 
g. Unable to refrain from using artificial tears 
h. Subject has received glucocorticosteroid implants such as Retisert®, Iluvien®, or 
Yutiq™ within 3 years prior to the Baseline Visit or has had complications related 
to the device and/or subject has had a glucocorticoid implant removed within 90 
days prior to the Baseline Visit or has had complications related to the removal of 
the device; 
i. Any FDA-approved medical devices other than punctal plugs (eg Lipiflow® and 
Truetear®) for dry eye 12 weeks prior to the Screening visit; 
9. Subject is unwilling to receive, or is intolerant of, SC injections; 
10. Subject has a history of sensitivity to ACTH preparations or sensitivity to porcine protein 
products; 
11. Subject has Type 1 or Type 2 diabetes mellitus or is taking antidiabetic medication (a 
history of gestational diabetes mellitus is not exclusionary); 
12. Subject has proliferative or severe nonproliferative diabetic retinopathy, clinically 
significant macular edema due to diabetic retinopaty, or neovascular/wet age-related 
macular degeneration; 
13. Subject has a history of chronic active hepatitis including active or chronic hepatitis B, or 
acute or chronic hepatitis C; 
14. Subject has a history of tuberculosis (TB) infection, any signs/symptoms of TB, or any 
close contact with an individual with an active TB infection; 
15. Subject has an active corneal infection, any other systemic infection; 
16. Subject has received a live or attenuated-live vaccine within 30 days prior to screening; 
17. Subject had ocular trauma, penetrating intraocular surgery, refractive surgery, corneal 
transplantation, or eyelid surgery within 12 weeks prior to screening; 


 
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18. Subject is unwilling to abstain from eyelash growth medications for the duration of the 
trial; 
19. Subject is under treatment with any corticosteroids, immunosuppressants, 
immunomodulators, or biologic agents for a concomitant condition (eg, rheumatoid 
arthritis under treatment with a tumor necrosis factor- alpha [TNF-α] drug).  Subjects are 
specifically excluded for any of the following; 
a. Subject has received intraocular or periocular corticosteroids within 30 days prior 
to Baseline Visit;  
b. Subject has received Ozurdex® (dexamethasone implant) within 6 months prior 
to the Baseline Visit;  
c. Subject has received intravitreal anti-VEGF therapy within 45 days of the 
Baseline Visit with Lucentis® (ranibizumab) or Avastin® (bevacizumab) or has 
received anti-VEGF Trap (aflibercept) within 60 days of the Baseline Visit; 
d. All others, subject has received treatment within 30 days prior to baseline; 
20. Subject has any known contraindication(s) to Acthar® Gel Package Insert, 2019 
including, but not limited to: 
a. Any known history of scleroderma, osteoporosis, or ocular herpes simplex. For 
the purposes of this study, osteoporosis is defined as evidence of current vertebral 
or long bone fracture, or lumbar T-score > 2.0 standard deviations (SD) below the 
mean of the reference population;  
b. Any primary adrenocortical insufficiency, or adrenal cortical hyperfunction,  
c. Any current congestive heart failure (defined as New York Heart Association 
Functional Class III to IV),  
d. Peptic ulcer (within 24 weeks prior to the Screening Visit);  
e. Recent major surgery (within 24 weeks prior to the Screening Visit);  
21. Subject has a clinically significant infection requiring administration of intravenous 
antibiotics or hospitalization in the 4 weeks prior to the Screening Visit or between the 
Screening Visit and the first dose of study drug; 
22. Subject has known immune-compromised status (not related to disease/condition under 
study), including but not limited to, individuals who have undergone organ 
transplantation or who are known to be positive for the human immunodeficiency virus; 
23. Subject has any solid tumor malignancy currently diagnosed or undergoing therapy, or 
has received therapy for any solid tumor malignancy in the 5 years prior to the Screening 
Visit; with the exception of treated and cured basal cell carcinoma, treated and cured 
squamous cell carcinoma of the skin, and treated and cured carcinoma in situ of the 
cervix; 
24. Subject has a diagnosis of, is undergoing therapy for, or has received therapy for a 
hematologic malignancy in the 5 years prior to the Screening Visit; 


 
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25. Subject has current or recent (within 24 weeks prior to the Screening Visit) drug or 
alcohol abuse as defined in Diagnostic and Statistical Manual of Mental Disorders , 2013, 
Fifth Edition, Diagnostic Criteria for Drug and Alcohol Abuse; 
26. Subject has any of the following laboratory abnormalities at the Screening Visit: 
a. Hemoglobin ≤ 8.0 g/dL; 
b. Platelet count ≤ 50,000 cells/μL; 
c. Absolute neutrophil count (ANC) ≤ 1000 cells/μL;  
d. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total 
bilirubin > 2 times upper limit of normal (ULN);  
e. Glycosylated hemoglobin (HbA1c) > 6.5; 
f. Positive Hepatitis B surface antigen (HBsAg) or Hepatitis B core antibody 
(HBcAb), or positive or indeterminant Hepatitis C virus antibody (HCV); 
g. Systolic blood pressure > 150 mm Hg and diastolic blood pressure > 90 mm Hg 
(average of 2 assessments) at the Screening or Baseline Visits does not qualify for 
the study; 
h. Positive or indeterminate interferon gamma release assay (IGRA) for TB; 
27. Subject has any other clinically significant disease, disorder or laboratory abnormality 
(including those listed on the Prescribing Information Section 5: Warnings and 
Precautions [Acthar® Gel Package Insert, 2019]) which, in the opinion of the investigator 
(by its nature or by being inadequately controlled), might put the patient at risk due to 
participation in the study, or may influence the results of the study or the subject’s ability 
to complete the study; 
28. Subject is participating in or plans to participate in any other interventional research 
study from the time of screening and throughout this study. 
4.3. 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently treated. 
Subjects will be allowed to repeat any single screening assessment/procedure once, if necessary, if 
it is within the screening window. However, laboratory results indicating a positive or 
indeterminant TB test, positive hepatitis B surface antigen, hepatitis B core antibody and positive or 
indeterminant hepatitis C antibody cannot be rescreened. The subject will not be considered a screen 
failure unless the repeat assessment/procedure result does not meet eligibility criteria. The period 
from the start of screening related procedures at the Screening Visit to the Baseline Visit must 
not exceed 28 days, inclusive of any repeat screening procedures.  
Subjects who do not meet all of the eligibility criteria at the Screening or Baseline Visits will be 
deemed a screen failure and the reason for screen failure will be documented.  
Rescreening 
A subject who is a screen failure at the Screening or Baseline Visit may be rescreened. The 
subject must repeat all screening procedures. The period from the start of rescreening related 


 
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procedures to the first dose of study drug must not exceed 28 days. Subjects may be rescreened 
only once. 
 


 
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5. 
STUDY TREATMENT 
Acthar is a naturally sourced complex mixture of adrenocorticotropic hormone (ACTH) 
analogues and other pituitary peptides used to provide a prolonged release after intramuscular or 
subcutaneous (SC) injection. Acthar contains 0.5% phenol, not more than 0.1% cysteine (added), 
sodium hydroxide and/or acetic acid to adjust pH, and water for injection.. Acthar is currently 
labeled for use in keratitis (Acthar® Gel Package Insert, 2019). Acthar is supplied as 5 mL 
multidose vials containing 80 U of ACTH per mL.   
5.1. 
Treatment Administration 
Following a screening period of up to 28 days, subjects who meet entry criteria will be treated 
with Acthar 1 mL (80 units [U]) subcutaneously (SC) 2x (twice) per week for 12 weeks. After 
this 12 week period of treatment with 80 U, Acthar will be tapered over a 4 week period. The 80 
U dose will be reduced to 40 U 2x/week for 2 weeks, followed by 40 U 1x/week for 2 additional 
weeks. An in-clinic safety visit will also take place 4 weeks after the last treatment dose. The 
subject or subject’s caregiver will receive training/instructions and will administer the first dose of 
study drug in the clinic under the supervision of study staff. The subject will remain in the clinic for at 
least 1 hour postdose to monitor for allergic, including anaphylactic, reactions. Thereafter, all doses 
will be administered by the subject or the subject’s caregiver at home. If a subject misses a dose, that 
dose will be skipped and the reason for the missed dose will be recorded. 
5.2. 
Study Treatment Preparation/Handling/Accountability 
Study treatment will be provided by the sponsor or sponsor’s representative and will be labeled 
as required by local and national regulations. 
Acthar is supplied as 5 mL multidose vials. Acthar vials contain 80 U of ACTH per mL. The 
vials should not be over pressurized prior to withdrawing the product. The vials should be 
warmed to room temperature before using.  
The investigator or designee will confirm that appropriate temperature control conditions have 
been maintained during transit for all study treatments received and any discrepancies are 
reported and resolved prior to study treatment administration. 
The study treatment will be maintained in a monitored, environmentally controlled (in 
accordance with treatment labeling), secure, locked area with restricted access at the study site.  
Only subjects enrolled in the study will receive study treatment and only authorized study staff 
will dispense study treatment. 
In accordance with the International Council for Harmonisation (ICH) requirements, at all times 
the investigator will be able to account for all study treatment furnished to the study site. An 
accountability record will be maintained for this purpose. The investigator must maintain 
accurate records indicating dates and quantity of study treatment received, to whom it was 
administered (subject-by-subject accounting) and accounts of any study treatment accidentally or 
deliberately destroyed. All unused study treatment not involved in immediate subject treatment 
will be maintained under locked, temperature-controlled storage at the study site.  


 
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5.3. 
Storage of Clinical Supplies 
Study drug will be supplied in kits containing the appropriate amount of vials. Study drug will be 
stored under refrigeration between 2° to 8°C (36° to 46°F). Please refer to the Pharmacy Manual 
for complete information regarding handling, storage, preparation, and accountability of study 
treatment. 
5.4. 
Measures to Minimize Bias 
This is an open label study, no randomization or stratification will be employed in treatment 
assignment. 
5.4.1. 
Interactive Phone/Web Response System  
The investigator or designee will contact interactive phone/web response system (IXRS) to 
register subjects at screening. The subject’s identification (ID) number will be determined by the 
IXRS and will be used to identify the subjects for the duration of the study within all systems and 
documentation. 
Each subject will be assigned a unique ID number. If the subject is not eligible to receive study 
treatment, or should discontinue from the study, the subject ID number will not be reassigned to 
another subject.  
In the event that a subject repeats any evaluation during the screening window, they will not 
receive a new ID number. In addition, subjects who fail screening and are rescreened will not 
receive a new subject ID number. At the Baseline Visit, qualified subjects who meet all of the 
eligibility criteria will be enrolled into the study.  
The investigator or designee must contact the IXRS to report a subject as a screen failure if the 
subject does not meet eligibility criteria prior to enrollment. 
The investigator must maintain a subject master log linking the subject ID to the subject’s name. 
The investigator must follow all applicable privacy laws in order to protect a subject’s privacy 
and confidentiality. Information that could identify a subject will be masked on material received 
by the sponsor. 
5.4.2. 
Emergency Identification of Study Treatment 
Not applicable. 
5.5. 
Study Treatment Compliance 
Prior to beginning the administration of study treatment, subjects and/or their caregiver will be 
trained on dosing and mode of administration and must exhibit proper technique. Subjects and/or 
their caregiver will be trained on the completion of the injection record, will complete study 
record entries to record all study drug administration and will bring it, along with all study drug 
kits including used vials, to each visit. Each time study treatment is dispensed compliance will be 
emphasized. Injection record training is an ongoing process, as the record will be reviewed with 
the subject at each visit to monitor compliance with study drug administration. 


 
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5.6. 
Prior and Concomitant Therapy 
The start and stop date, dose, unit, frequency, route of administration, and indication for all prior 
(taken within the 30 days prior to the Screening Visit) and concomitant (taken from the 
Screening Visit through Visit 7) medications and nondrug therapies (eg, blood transfusions, 
oxygen supplementation, physical therapy, etc) received will be recorded.  
In addition, all prior treatments for severe keratitis administered be recorded with start and stop 
date, dose, unit, frequency and route of administration. 
5.6.1. 
Permitted Concomitant Therapies 
Permitted concomitant medications include lid hygiene, warm compresses and artificial tears or 
any medication not mentioned in the exclusion criteria provided the subject has been on a stable 
dose for at least 4 weeks prior to the Screening Visit. Patients should be instructed not to use 
ophthalmic preparations 2 hours prior to each study visit. 
5.6.2. 
Prohibited Concomitant Therapies  
The following treatments will not be permitted during the study (from the Baseline Visit through 
Visit 7): 
 Administration of live or live-attenuated vaccines. 
 Use of eyelash growth medications. 
 Topical, inhaled, intra-articular, or intra-ocular corticosteroids. 
 Any systemic corticosteroids, immunosuppressants, immunomodulators, or 
biologic agents for a concomitant condition (eg, rheumatoid arthritis being treated 
with a TNF-α drug). 
 Any investigational drug, device, or procedure administered as part of a research 
study.  
If any prohibited medication is taken during the study, all pertinent information will be recorded 
in source documents and the electronic case report form (eCRF). The designated study medical 
monitor (MM) must be informed immediately and will determine whether to continue the subject 
in the study in collaboration with the sponsor. 


 
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6. 
DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL 
6.1. 
Discontinuation of Study Treatment 
Subjects who discontinue, or are withdrawn from study treatment for any reason, will be 
encouraged to complete the Early Termination (ET) Visit and provide any additional follow-up 
information as required by the study, unless the subject specifically indicates that they will not 
participate in any further evaluations. 
Permanent study treatment discontinuation is required for any of the following: 
 Elevated blood pressure (defined as systolic blood pressure not more than 180 and 
diastolic blood pressure not more than 100 mm Hg). 
 Hyperglycemia (HbA1c greater than 6.5%, or fasting plasma glucose greater than 
126 mg/dL, or classic symptoms of hyperglycemia with random plasma glucose 
greater than 200 mg/dL). 
 Infections that are considered SAEs or lead to treatment discontinuation. 
 The subject becomes pregnant during the active treatment phase of the study. 
 Discontinuation of study treatment for abnormal liver function should be 
considered by the investigator when a subject meets one of the conditions outlined 
in Section 9.5.  
 The reason for study treatment discontinuation will be recorded. 
6.2. 
Subject Discontinuation/Withdrawal from the Study 
Subjects may withdraw from the study at any time at their own request, or may be withdrawn at 
any time at the discretion of the investigator for safety, behavioral, compliance, or administrative 
reasons. 
If the subject withdraws consent for disclosure of future information, the sponsor may retain and 
continue to use any data collected before such withdrawal of consent. If a subject withdraws 
from the study, the subject may request destruction of any samples taken and not tested and the 
investigator must document this in the site study records. 
The reason for study discontinuation/withdrawal will be recorded. A subject may be 
discontinued from the study for the following medical or administrative reasons: 
Withdrawal by Subject 
Subjects will be free to discontinue from the study at any time. 
Adverse Event 
If a dosed subject suffers an adverse event (AE) that, in the judgment of the investigator, 
sponsor, or MM; presents an unacceptable consequence or risk to the subject, the subject will be 
discontinued from study drug.  
Death 
In the event that a subject dies during the study, death will be the reason for discontinuation. 


 
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Lost to Follow-up 
Every effort should be used to maintain contact with subjects during their participation in the 
study. A subject may be considered lost to follow-up if the there is no response to at least 
3 attempts to reach the subject by phone and no response to a certified letter (or equivalent) sent 
to the last known address of the subject, if possible. Efforts to contact the subject should be noted 
in the source documentation. 
Met Withdrawal Criteria 
Discontinuation for safety and/or tolerability issues is outlined in Section 6.1. 
Other 
If the above reasons are not applicable, please use the “Other” option in the eCRF and provide 
the appropriate reason for subject withdrawal. 


 
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7. 
STUDY ASSESMENTS AND PROCEDURES 
7.1. 
Efficacy Assessments 
Efficacy assessments will be evaluated at times specified in the Schedule of Study Events 
(Table 1). Below is a general instruction for the administration of these assessments. Specific 
instructions and equipment specifications (where appropriate) will be provided in a separate 
document. 
7.1.1. 
Ophthalmic Examination 
An ophthalmic examination will be completed at specified times during the study and will 
include the following: 
 Best corrected visual acuity (BCVA) measured using the using the Early Treatment 
Diabetic Retinopathy Study (ETDRS) chart (Hilton, 2009). 
 Intra-ocular pressure (IOP) will be measured using Goldmann Applanation Tonometry 
(Ramakrishnan, 2009). 
 
Complete Slit lamp examination (including evaluation of the cornea and lens and grading 
of superficial puncta.  
 Undilated funduscopic evaluation. 
7.1.2. 
Patient-reported Outcomes (PROs) 
The following 4 questionnaires were used to assess quality of life (QOL) measures (Sheppard, 
2014): 
Impact of Dry Eye on Everyday Life (IDEEL) Questionnaire: The IDEEL comprises 
57 questions and 3 modules: the impact on daily life module (activity/work limitations and 
emotional impact), the treatment satisfaction module, and the symptom bother module. Each 
module is scored from 0 to 100; higher scores on the impact on daily life and treatment 
satisfaction modules indicate a better quality of life (QOL) and higher treatment satisfaction. In 
contrast, higher scores on the symptom bother module indicate more bothersome dry eye 
symptoms. A 12-point difference in symptom bother module scores indicates a clinically 
important change in bothersome dry eye symptoms (Grubbs, 2014).  
Ocular Discomfort Score (ODS): The ODS is a scale in which subjects are asked to subjectively 
rate 5 areas of ocular discomfort: ocular discomfort, dryness, grittiness, burning, and stinging.  
Subjects are asked to grade their discomfort on a 5-point scale where 0 is no discomfort and 4 is 
constant discomfort (Stonecipher, 2016). 
Visual Analog Scale (VAS) of Eye Dryness: The VAS is a 7-item, patient-reported symptom 
index with items of eye dryness, burning/stinging, itching, foreign body sensation, eye 
discomfort, photophobia, and pain. Subjects are asked to subjectively rate each ocular symptom 
by placing a vertical mark on the horizontal line from 0 to 100 (0 = no discomfort, 100 = 
maximal discomfort) to indicated their level of discomfort (Holland, 2017).   
7.1.3. 
Corneal and Conjunctival Staining Score  
Corneal and conjunctival staining using fluorescein or lissamine green dye is an objective 
assessment of the inferior, superior, central, and total regions of the cornea as well as the nasal, 


 
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temporal and total regions of the conjunctiva. Both fluorescein and lissamine green scores are 
obtained using the Ora Calibra™ Scale for each region that is scored from 0 to 4 where 0 = none 
and 4 = confluent.  
7.1.4. 
T-Cell Assessments 
Blood samples for T-cell assessments (T-cell effector total number, T-cell regulatory, and 
regulatory/effector T-cell ratio) will be collected at specified times during the study and shipped 
to a central laboratory. Detailed instructions for the collection, handling, storage and shipment of 
the samples will be provided in a separate laboratory manual. 
7.2. 
Safety Assessments 
All safety assessments will be performed at times outlined in the Schedule of Study Events 
(Table 1). Safety assessments that will be evaluated include adverse events, ophthalmic 
examinations, physical examination, clinical laboratory test results, metabolic panel, pregnancy 
testing, and vital signs. 
Additional (unscheduled) safety assessments may be performed as needed. 
7.2.1. 
Medical, Ophthalmic, and Surgical History  
Medical, ophthalmic, and surgical history will be obtained at the Screening Visit. Medical 
history will include a review of the following systems: general, dermatological, respiratory, 
cardiovascular, gastrointestinal, genitourinary, gynecological, endocrine, musculoskeletal, 
hematological, neuropsychological, immune (allergies), and head, eyes, ears, nose, and throat. 
Historical and current medical conditions including date of last menstrual period for female 
subjects will be recorded.  
Ophthalmic history will include the date and approximate time of onset, suspected cause, 
symptoms, course, laterality, and any treatment (drug name, dose, how administered, tapering 
scheme) for the current keratitis episode; and the date of any previous episodes with treatment 
given and response to treatment; as well as any previous or antecedent ocular trauma or surgery 
and any previous or antecedent ocular conditions. 
7.2.2. 
Physical Examination 
The complete physical examination will include evaluation of the head, eyes, ears, nose, throat, 
neck (including thyroid), cardiovascular system (including assessment of heart, peripheral 
pulses, presence or absence of edema), lungs, abdomen (including liver and spleen, bowel 
sounds), lymph nodes, musculoskeletal system (including spine, joints, muscles) neurological 
system (including cranial nerves, reflexes, sensation, strength), skin, extremities, and other 
conditions of note. 
The findings of the physical examinations will be recorded. Any change from the Screening Visit 
physical examination that is considered clinically significant by the investigator will be recorded 
as an AE.  
7.2.3. 
Height and Weight 
Height and weight will be collected at baseline (Visit 2), Visit 6, and Early Termination.  


 
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7.2.4. 
Vital Signs 
Vital signs will be obtained after the subject has been seated for 5 minutes (minimum) and will 
include systolic and diastolic blood pressures, pulse rate, respiratory rate, and body temperature. 
The results, date, and time for all vital sign assessments will be recorded. Additionally, at the 
Screening and Baseline Visits, blood pressure will be measured with an average of 2 readings, 
with at least 5 minutes between assessments after the subject has been seated for a minimum of 5 
minutes prior to the initial blood pressure assessment. A subject with systolic blood pressure 
> 150 mm Hg and diastolic blood pressure > 90 mm Hg (average of 3 assessments) at the 
Screening or Baseline Visits does not qualify for the study (Section 4.2). 
If an on-study systolic blood pressure is > 150 mm Hg and diastolic blood pressure is 
> 90 mm Hg, an AE will be recorded if the investigator determines the change is clinically 
significant or requires a change in the subject’s clinical management.  
7.2.5. 
Clinical Laboratory Tests  
Required clinical laboratory tests are listed in Section 9.2. Specific instructions for collection, 
processing, storage, and shipment of clinical laboratory samples will be provided in separate 
laboratory manual(s). 
It is not required for laboratory samples to be collected under fasted conditions. The date and 
time of the sample collection must be documented on the laboratory report. Investigators must 
review and sign laboratory reports and document the clinical significance of each laboratory 
abnormality. New clinically significant laboratory abnormalities or clinically significant changes 
in laboratory values will be reported as AEs. 
Hematology with differential, serum chemistry, lipid profile, and urinalysis samples will be 
collected at the specific times starting at screening and throughout the study according to the 
schedule of events (Table 1). 
In addition: all female subjects of childbearing potential will have a serum pregnancy test at 
Screening, all other site visits except for Visit 3 which is by phone, and Visit 6/Early 
Termination Visits. Urine pregnancy tests will be done only at Screening. Any positive urine 
pregnancy test will be confirmed with a serum pregnancy test. Results must be available prior to 
protocol mandated study treatment. Subjects with positive results at the Screening or Baseline 
Visits will be ineligible for study entry. Any female subject that becomes pregnant during the 
study will be immediately withdrawn and will have the pregnancy reported as per Section 9.4. 
If applicable, the subject’s agreement to use contraception throughout their study participation, 
and for 28 days after ending study participation, will be documented. 
HBsAg and HBcAb will be performed at the Screening Visit. Results of these tests must be 
negative or nonreactive for subjects to qualify for the study.  
HCV antibody testing will be performed at the Screening Visit. Results of this test must be 
negative for subjects to qualify for the study. 
IGRA testing for tuberculosis will be performed at the Screening Visit. Results of this test must 
be negative for subjects to qualify for the study.  
Thyroid stimulating hormone (TSH) will be measured at the Screening Visit. Results of this test 
must be within the normal range for subjects to qualify for the study. 


 
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Hemoglobin A1c (HbA1c) testing will be performed at the Screening Visit. HbA1c must be 
≤ 6.5% for subjects to qualify for the study. Additional HbA1c tests will be done at specified 
times during the protocol. 
Out-of-Range Laboratory Values 
Laboratory values from samples collected at the Screening Visit will be evaluated by the 
investigator for eligibility of the subject in the study. Clinical laboratory tests may be repeated 
once to determine subject eligibility. 
Laboratory values that fall outside the reference range from samples collected at the Baseline 
Visit and throughout the study will be assessed by the investigator for clinical significance. If the 
out of range value is deemed clinically significant by the investigator, an AE will be recorded. 
7.3. 
Adverse Events 
Adverse events will be recorded from signing of the ICF and followed by the investigator until 
the AE is resolved, resolved with sequela, or stabilized.  All safety measures (which includes 
standard of care activities) should be provided by the study site to the subject. Any study site 
follow-up should be documented. 
Refer to Section 9.3.4 for additional details on the handling of AEs and SAEs. 
7.4. 
Treatment Overdose 
For this study, any dose of Acthar greater than 80 U within a 24 (± 1) hour time period will be 
considered an overdose. The sponsor does not recommend specific treatment for an overdose.  
In the event of an overdose, the investigator or designee should: 
 Contact the MM immediately. 
 Closely monitor the subject for any AE/SAE and laboratory abnormalities until 
the treatment can no longer be detected (at least 48 hours). 
 Document the quantity of the excess dose, as well as the duration of the overdose. 
7.5. 
Pharmacokinetic Assessments  
Not applicable for this study.  
7.6. 
Genetics 
Not applicable for this study. 
7.7. 
Biomarkers 
Not applicable for this study. 
7.8. 
Health Economics and Outcomes Research Assessments  
Not applicable for this study.  


 
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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Sample Size Determination 
Approximately 36 subjects will be screened in order to have 30 analysable subjects enrolled in 
this study. No formal sample size calculations will be performed. The sample size was 
determined empirically.    
8.2. 
Populations for Analysis 
For the purposes of analysis, the following populations are defined 
 The Modified Intent-to-Treat (mITT) population will include all subjects who receive 
at least 1 dose of study drug and who contribute any postbaseline efficacy data to the 
study. 
 The Per-Protocol (PP) population will include a subset of the mITT population with 
subjects who do not have any major protocol deviations.  
 The Safety Population will include all subjects who receive 1 or more doses of study 
drug. 
8.3. 
Statistical Analyses  
This section provides a general summary of the statistical methods to be used in analyzing study 
data. A more detailed statistical analysis plan will be provided in a separate document that will 
be finalized prior to database lock. 
8.3.1. 
Efficacy Analyses 
All efficacy analyses will be performed on the mITT population. Selected analyses may be 
performed on the Per-Protocol population.  
Baseline and change from baseline at each posttreatment visit will summarized for all  numerical 
variables with descriptive statistics. Frequency and percentage will be calculated for categorical 
variables. The nominal p-values along with the 95% confidence intervals (CI) will be provided 
as appropriate. For subjects who have both eyes affected, the change from baseline will be 
determined based on the eye with the worst severity at baseline.  If both eyes have the same 
severity at baseline, the right eye will be used to determine change from baseline.  
8.3.2. 
Safety Analyses  
All safety data will be summarized with descriptive statistics or frequency tables as appropriate. 
Safety analyses will be performed on the safety population. Safety endpoints include the 
incidence and severity of ocular AEs, incidence and severity of other AEs, new or worsening 
cataracts, and the mean change in IOP. 
AEs will be coded using MedDRA version 22.0 by preferred term within system organ class. 
The number of AEs and the number of subjects reporting AEs will be listed and summarized 
descriptively by system organ class, preferred term, severity, and causality for each treatment 
group. Only treatment-emergent adverse events (TEAE) (events that are new in onset or 
aggravated in severity following treatment) will be included in all summaries. Serious adverse 
events (SAE) (including death) will be summarized.  


 
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Other safety assessments include vital signs (heart rate, diastolic/systolic blood pressures, 
respiratory rate, and body temperature), clinical laboratory tests, ophthalmology examinations, 
physical examinations, HbA1c,  pregnancy test, hepatitis serology, IGRA for TB, etc. All of 
these assessments will be listed and summarized descriptively. 
8.3.3. 
Interim Analyses 
No formal interim analyses are planned for this study.  
8.3.4. 
Handling Missing Data 
A full description of the missing data imputation method for all endpoints will be described in 
the statistical analysis plan. 


 
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9. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
9.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
9.1.1. 
Regulatory and Ethical Considerations 
The study will be conducted in full compliance with applicable international, national and local 
regulatory requirements; US Food and Drug Administration (FDA) regulations including 
21 Code of Federal Regulations (CFR) 314.106 and 312.120, (where applicable), ICH guidelines 
for GCP, in accordance with the ethical principles that have their origins in the Declaration of 
Helsinki, and European regulation 536/2014/EU (where applicable). 
It is the responsibility of the investigator to obtain the approval of the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) before the start of the study. A copy of the approval 
letter along with a roster of IRB/IEC members and compliance letter and/or the US Department 
of Health and Human Services general assurance number (if applicable) will be provided to the 
sponsor and retained as part of the study records. During the course of the study, the investigator 
will provide timely and accurate reports to the IRB/IEC on the progress of the study at 
appropriate intervals (not to exceed 1 year) and at the completion of the study. The investigator 
will notify the IRB/IEC of SAEs or other significant safety findings per IRB/IEC guidelines. The 
study protocol, ICF, advertisements (if any), and amendments (if any) will be approved by the 
IRB/IEC in conformance with international, national and local regulatory requirements. 
Any change in the study plan requires a protocol amendment. An investigator must not make any 
changes to the study without IRB/IEC and sponsor approval except when necessary to eliminate 
apparent immediate hazards to the subjects. A protocol change intended to eliminate an apparent 
immediate hazard to subjects may be implemented immediately, but the change must then be 
documented in an amendment, reported to the IRB/IEC within 5 working days, and submitted to 
the appropriate regulatory agency in the required time frame, if appropriate.  
9.1.2. 
Financial Disclosure 
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to the sponsor to submit complete and accurate financial certification or 
disclosure statements to the appropriate regulatory authorities. Investigators are responsible for 
providing information on financial interests during the course of the study and for 1 year after the 
end of the study. 
9.1.3. 
Subject Information and Consent 
The ICF must be approved by the sponsor and the IRB/IEC before any subject provides consent. 
The investigator will provide Mallinckrodt with a copy of the IRB/IEC-approved ICF and a copy 
of the IRB/IEC’s written approval before the start of the study. 
At the Screening Visit (and at other time as may be required by the study or when changes are 
made to the consent form), subjects will read the consent form(s) and any privacy authorization 
as required by local and national regulations (such as the Health Insurance Portability and 
Accountability Act [HIPAA] authorization form), if applicable after being given an explanation 


 
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of the study. Before signing the consent form(s) and the privacy authorization form (if 
applicable), subjects will have an opportunity to discuss the contents of these forms with study 
site personnel.  
Subjects must assent understanding of and voluntarily sign these forms in compliance with ICH 
GCP and all applicable national and international regulations, before participating in any study-
related procedures. Subjects will be made aware that they may withdraw from the study at any 
time. Subjects unable to give written informed consent must orally assent to the procedures, and 
written informed consent must be obtained from a legally authorized representative in 
accordance with national and local laws, as applicable. 
The ICF must contain all applicable elements of informed consent and the mandatory statements 
as defined by national and local regulations including confidentiality. All versions of each 
subject's signed ICF must be kept on file by the site for possible inspection by regulatory 
authorities and/or authorized Mallinckrodt personnel. Signed copies of the consent form(s) and 
the HIPAA authorization form, if applicable, will be given to the subject.   
The subjects will be made aware of their right to see and copy their records related to the study 
for as long as the investigator has possession of this information. If the subject withdraws 
consent and/or HIPAA authorization, the investigator can no longer disclose health information, 
unless it is needed to preserve the scientific integrity of the study. 
9.1.4. 
Data Protection 
Study subjects will be assigned a unique identifier by the sponsor or designee. Any subject 
records or datasets that are transferred to the sponsor will contain the identifier only; subject 
names or any information which would make the subject identifiable will not be transferred.  
The subject must be informed that his/her personal study-related data will be used by the sponsor 
in accordance with local data protection law. The level of disclosure (in accordance with local 
and/or national law) must also be explained to the subject.  
The subject must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
9.1.5. 
Committees Structure 
No monitoring committees will be used for this study. 
9.1.6. 
Dissemination of Clinical Study Data 
Study results and de-identified individual subject data will be protected as required by local 
and/or national regulation.  
9.1.7. 
Data Quality Assurance 
The sponsor performs quality control and assurance checks on all clinical studies that it sponsors. 
Before enrolling any subjects in this study, sponsor personnel and the investigator review the 
protocol, the Prescribing Information (Mallinckrodt Package Insert, 2019), the electronic case 
report forms (eCRF) and instructions for their completion, the procedure for obtaining informed 
consent, and the procedure for reporting AEs and SAEs. A qualified representative of the 
sponsor will monitor the conduct of the study.  


 
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The investigator will permit study-related monitoring, audits, IRB review, and regulatory 
inspections by providing direct access to original source data and documents. 
Each subject’s eCRF should be fully completed and submitted to the Sponsor in a timely fashion.  
If an investigator retires, relocates, or otherwise withdraws from conducting the study, the 
investigator must notify the sponsor to agree upon an acceptable storage solution. Regulatory 
agencies will be notified with the appropriate documentation. 
Any significant changes in study personnel will require an updated Statement of Investigator (ie, 
FDA form 1572) to be filed with the sponsor. 
The investigator must notify their IRB of protocol deviations in accordance with local regulatory 
and IRB requirements. 
The eCRF data are stored in a database and processed electronically. The sponsor’s MM reviews 
the data for safety information. The data are reviewed for completeness, and logical consistency. 
Automated validation programs will identify missing data, out-of-range data, and other data 
inconsistencies. In addition, clinical laboratory data will be processed electronically. Requests 
for data clarification are forwarded to the study site for resolution. 
9.1.8. 
Source Documents 
All subject information recorded in the eCRF will be attributable to source data from the 
investigational site. 
The investigator shall retain and preserve 1 copy of all data collected or databases generated in 
the course of the study, specifically including but not limited to those defined by GCP as 
essential. Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational medicinal product. These documents should be 
retained for a longer period, however, if required by the applicable regulatory requirements or by 
an agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained. Prior to 
destruction of any study essential documents, the investigator must first obtain written approval 
from the sponsor.  
9.1.9. 
Study and Site Closure 
The sponsor may suspend or terminate the study or part of the study at any time for any reason. 
If the investigator suspends or terminates the study, the investigator will promptly inform the 
sponsor and the IRB/IEC and provide them with a detailed written explanation. Upon study 
completion, the investigator will provide the sponsor, IRB/IEC, and regulatory agency with final 
reports and summaries as required by regulations. Study termination and follow-up will be 
performed in compliance with the sponsor or designee standard operating procedures.  
The sponsor, investigator, or local and national regulatory authorities may discover conditions 
during the study that indicate that the study or study site should be terminated. This action may 
be taken after appropriate consultation between the sponsor and investigator. Conditions that 
may warrant termination of the study/study site include, but are not limited to: 


 
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 The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled 
in the study. 
 The decision on the part of the sponsor to suspend or discontinue testing or evaluation 
of the study drug. 
 Failure of the investigator to enroll subjects into the study at an acceptable rate. 
 Failure of the investigator to comply with pertinent regulations. 
 Submission of knowingly false information from the study site to the sponsor, study 
monitor, or local and national regulatory authorities. 
 Insufficient adherence to protocol requirements. 
9.1.10. 
Publication Policy 
The sponsor’s decision to publish or otherwise publicly communicate the results of this study 
will be made in accordance with all applicable laws, regulations, and sponsor policies regarding 
publication and communication of clinical study results. 
Terms and provisions of the investigator’s publication rights are governed by the Publication 
Section in the Clinical Trial Agreement per site. 
 
 


 
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9.2. 
Appendix 2: Clinical Laboratory Tests  
Serum Chemistry: 
Alanine aminotransferase (ALT) 
Chloride 
Albumin (total) 
Creatinine 
Alkaline phosphatase  
Glucose 
Aspartate aminotransferase (AST) 
Phosphorus 
Bilirubin (total) 
Potassium 
Blood urea nitrogen 
Protein, total 
Calcium 
Sodium 
Bicarbonate 
Uric acid 
Lipid Profile: 
 
High density lipoprotein 
Triglycerides 
Low density lipoprotein 
Total cholesterol 
Hematology Assays: 
White blood cell count, including differential 
Hematocrit 
Platelet count 
Hemoglobin 
Red blood cell count 
Urinalysis: 
Color 
Ketones 
Clarity 
Protein 
Albumin 
pH 
Bilirubin 
Specific gravity 
Blood 
Urea 
Creatinine 
Microscopy (WBC/ high power field (HPF), 
RBC/HPF and urinary casts) 
Glucose 
Diabetes Screen: 
HbA1c 
Hormones: 
Serum and urine beta-human chorionic 
gonadotropin (pregnancy test) 
Thyroid Stimulating Hormone 
Hepatitis and HIV Serology: 
 
Hepatitis B core antibody 
Hepatitis C virus antibody (HCV) 
Hepatitis B surface antigen 
Human immunodeficiency virus (HIV) 
TB Assay: 
Interferon gamma release assay (IGRA) 
Immunological protein assay: 
 
Protein assay to detect levels of the cytokine array 
[interleukin 1,6,17; interferon-ɤ]; ratio of T helper 
cells to T regulatory cells 
 


 
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9.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-Up and Reporting 
9.3.1. 
Safety 
For safety information about Acthar, refer to the most recent version of the Prescribing 
Information (Mallinckrodt Package Insert, 2019).  
9.3.2. 
Definitions 
Adverse Event  
An AE is any untoward or undesirable medical occurrence in a subject who is administered a 
study treatment, which does not necessarily have to have a causal relationship with this 
treatment. Examples of AEs include but are not limited to: 
 Clinically significant laboratory findings. 
 Clinically significant changes in physical examination findings. 
 An AE occurring due to study drug overdose whether accidental or intentional. 
 An AE occurring from study drug abuse. 
 An AE associated with study drug withdrawal. 
 Unexpected Adverse Event. 
An unexpected AE is defined as an AE, the nature and severity of which is not consistent with 
the applicable product information in the most recent version of the Prescribing Information 
(Mallinckrodt Package Insert, 2019). 
Serious Adverse Event  
An SAE is defined as any untoward medical occurrence that at any dose results in any of the 
following outcomes: 
 Death. 
 Life-threatening AE. 
 Inpatient hospitalization or prolongation of existing hospitalization. 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
 Results in a congenital anomaly/birth defect. 
Death  
Death is an outcome of an event. The cause of death should be recorded and reported on the SAE 
Form. All causes of death must be reported as SAEs. The investigator should make every effort 
to obtain and send death certificates and autopsy reports to the sponsor or designee, or state not 
available. 
Life-Threatening Event  


 
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An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the subject at immediate risk of death. It 
does not include an adverse event or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death. For example, hepatitis that resolved without evidence of 
hepatic failure would not be considered life threatening, even though hepatitis of a more severe 
nature can be fatal. Similarly, an allergic reaction resulting in angioedema of the face would not 
be life threatening, even though angioedema of the larynx, allergic bronchospasm, or 
anaphylaxis can be fatal. 
Hospitalization  
Hospitalization is defined as an official admission to a hospital. Hospitalization or prolongation 
of a hospitalization constitutes a criterion for an AE to be serious. The following situations 
should not be reported as SAEs: 
 A hospitalization or prolongation of hospitalization is needed for a procedure required 
by the protocol. 
 A hospitalization or prolongation of hospitalization is part of a routine procedure 
followed by the center (eg, stent removal after surgery). This should be recorded in 
the study file. 
 A hospitalization for a preexisting condition that has not worsened. 
Important Medical Events 
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, may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency department or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
AEs (serious or non-serious) that commonly occur in the study population or background 
regimen will be considered anticipated events. Such events include known consequences of the 
condition under investigation (eg, symptoms, disease progression) and other events that may be 
common in this study population. Anticipated events are to be recorded on the eCRF and 
reported as SAEs when serious. These SAEs will not be expedited to health authorities, but 
included in aggregate safety reports.  
9.3.3. 
Adverse Event and Serious Adverse Event Classifications 
Study Drug Relatedness 
The following classifications should be used when evaluating the relationship of AEs or SAEs to 
study treatment. 
Table 3: 
Adverse Event Relationships 
Relationship 
Definition 
Not Related 
No relationship between the AE and the administration of study treatment; the AE cannot 
be explained by other etiologies such as concomitant medications or subject’s clinical state. 


 
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Relationship 
Definition 
Unlikely Related 
The current state of knowledge indicates that a relationship to study treatment is unlikely. 
Possibly Related 
An AE that follows a plausible temporal sequence from administration of the study 
treatment to the start of the AE and follows a known response pattern to the suspected study 
treatment. The reaction might have been caused by the subject’s clinical state or 
concomitant medications. 
Related 
The AE that follows a plausible temporal sequence from administration of the study 
treatment to the start of the AE and follows a known response pattern to the study 
treatment. The suspected causality can be confirmed with a positive re-challenge test or 
supporting laboratory data. 
 
Severity Assessment 
For purposes of consistency, the investigator may use the intensity grades presented in the 
following table, if required: 
Table  4: 
Adverse Event Severity Grades 
Grade 
Definition 
Mild 
Does not interfere with subject's usual function and activities 
Moderate 
Interferes to some extent with subject's usual function and activities 
Severe 
Interferes significantly with subject's usual function and activities 
 
To ensure there is no confusion or misunderstanding of the difference between the terms 
“serious” and “severe,” which are not synonymous, the following note of clarification is 
provided: 
The term “severe” is used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical importance (such as a severe headache). This is not the same as “serious,” which is 
based on the subject/event outcome or action criteria usually associated with events that pose a 
threat to a subject's life or functioning. Seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations. 
If an AE increases in severity (eg, from moderate to severe); decreases in severity (eg, changes 
from moderate to mild); or if there is a change in seriousness, a new AE will be opened and the 
original AE will be closed. If an AE is still ongoing at the time of a subject’s completion of the 
follow-up visit, the resolution/stop date and time is left blank.  
9.3.4. 
Adverse Event and Serious Adverse Event Recording and Reporting 
AEs and SAEs will be recorded from signing of the ICF through completion of the Follow-up 
Visit. The investigator is required to record the AE or SAE regardless of the severity of the event 
or its relationship to study treatment. The investigator must follow up on all AEs and SAEs 
reported to have occurred through the Follow-up Visit until the event has resolved or stabilized 
or at such time the investigator refers the subject to a nonstudy physician. The investigator will 
document the further follow-up information in the subject’s source document.  


 
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During the period specified above, the investigator will: 
 Record all AEs and SAEs from the signing of the ICF through the completion of the 
Follow-up Visit. 
 Report all SAEs on an SAE Report Form to Mallinckrodt Global Pharmacovigilance or 
designee. 
 Report all pregnancies to Mallinckrodt Global Pharmacovigilance or designee on the 
appropriate form. 
 Submit any Expedited Safety Report or Suspected Unexpected Serious Adverse Reaction 
from Mallinckrodt Global Pharmacovigilance or designee to the IRB/IEC. 
The reporting requirements for AEs are summarized in the following table: 
Table 5: Reporting Requirements for Adverse Events 
Seriousness 
Reporting Time 
Type of Report 
All Serious 
Within 24 hours of first knowledge of 
event 
Initial report on the SAE Form, appropriate 
eCRF, and source document 
Within 24 hours of receipt of follow-up 
information 
Follow up report on the SAE Form, appropriate 
eCRF, and source document 
Nonserious 
Per case report form submission 
procedure 
Appropriate eCRF and source document 
9.3.5. 
Adverse Events of Special Interest 
An adverse event of special interest is an event of scientific and medical concern specific to the 
sponsor’s product or program, for which ongoing monitoring and rapid communication by the 
investigator to the sponsor can be appropriate. Such an event might warrant further investigation 
in order to characterize and understand it.  
AEs of special interest for this study are outlined below. Adverse events of special interest will 
be followed until resolution or return to baseline.  
 Increased IOP of 10 mm Hg or more from baseline confirmed upon repeat testing. 
 New or worsening cataracts. 
 New or worsening glaucoma. 
9.4. 
Appendix 4: Pregnancy Reporting 
Certain information regarding pregnancy, although not considered an SAE, must be recorded, 
reported, and followed up as indicated. This includes the following:  
Subjects should not become pregnant during the study. If a female subject, or the female partner 
of a male subject, becomes pregnant during any active treatment period, study treatment must be 
discontinued immediately and the investigator must report the pregnancy by submitting the 
appropriate form to Mallinckrodt Global Pharmacovigilance, or designee, within 24 hours of 
confirmation of a pregnancy (ie, positive serum pregnancy test result). The outcome of 
pregnancy (eg, spontaneous abortion, live birth, still birth, congenital anomalies, birth defects) 
must be reported by submitting the appropriate form to Mallinckrodt Global Pharmacovigilance, 


 
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or designee, within 24 hours of the pregnancy outcome being submitted to the study site. If the 
pregnancy results in a live birth, a postdelivery follow-up will be performed at least 28 days after 
the baby is born and must be reported to Mallinckrodt Global Pharmacovigilance, or designee, 
within 24 hours of the study site becoming aware of the follow-up information. 
9.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments 
All events of alanine aminotransferase (ALT)   3 × upper limit of normal (ULN) and with total 
bilirubin  2 × ULN (> 35% direct bilirubin) or ALT  3 × ULN and international normalized 
ratio (INR) >1.5 (if INR measured) which may indicate severe liver injury (possible Hy’s Law) 
must be reported as an SAE as outlined in Section 9.3.4. 
Subjects with confirmed Hy’s Law liver injury will be immediately withdrawn from study 
treatment and no rechallenge will be allowed.  
 
 


 
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10. 
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