Conditions: Sarcoidosis, Pulmonary
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 55
Healthy volunteers: no

Brief summary:
The purpose of this study is to find out if Acthar Gel is safe and effective to treat pulmonary sarcoidosis.

Participants will be randomly assigned (like flipping a coin) to receive a shot under their skin of Acthar Gel or a matching placebo gel that has no drug in it. They will receive their assigned shot twice a week for 24 weeks.

All participants who complete the 24-week treatment period will be eligible to receive Acthar Gel for 24 more weeks, even if they were originally in the placebo group.

Detailed description:

Arms:
arm 1: Participants received Acthar Gel as a 1 milliliter (mL) injection under the skin, twice weekly, for 24 weeks in the double-blind treatment (DBT) phase. Participants, who chose to continue into the optional OLE phase, then received Acthar Gel as a 1 mL injection under the skin, twice weekly, for another 24 weeks in the optional open-label extension (OLE) phase. arm 2: Participants received Acthar Gel matching placebo as a 1 mL injection under the skin, twice weekly, for 24 weeks in the DBT phase. Participants, who chose to continue into the optional OLE phase, then received Acthar Gel as a 1 mL injection under the skin, twice weekly, for another 24 weeks in the optional OLE phase.

Interventions: intervention 1: Acthar Gel intervention 2: Placebo
Intervention descriptions: intervention 1: Acthar Gel for subcutaneous (SC) injection (80 units per 1 mL) intervention 2: Placebo gel for SC injection

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
ACTHAR® GEL 
 
 
 
A MULTICENTER, RANDOMIZED, DOUBLE BLIND, 
PLACEBO CONTROLLED EXPLORATORY STUDY 
TO ASSESS THE EFFICACY AND SAFETY OF 
ACTHAR® GEL IN SUBJECTS WITH PULMONARY 
SARCOIDOSIS 
 
SPONSOR: MALLINCKRODT ARD LLC 
1425 US-206 
Bedminster, NJ 07921 
United States of America 
 
Protocol Number: MNK14344100 
Clintrials.gov Registry Number: NCT03320070 
Date of Protocol Version 2 Amendment 1: 15 May 2020 
 
 
This document is a confidential communication of Mallinckrodt Pharmaceuticals. Acceptance 
of this document constitutes the agreement by the recipient that no unpublished information 
contained herein will be published or disclosed without the prior written approval of 
Mallinckrodt, except that this document may be disclosed to appropriate institutional review 
boards/ethical committees so long as they are requested to maintain its confidentiality. 


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SPONSOR SIGNATURE PAGE 
 
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 guidance documents and regulations including, but not limited to: 
• International Council for Harmonisation (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 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. 
 
Refer to e-signature page 
Sponsor Signature 
 
, BSN, MD 
 
 
ACKNOWLEDGEMENT OF RECEIPT AND 
UNDERSTANDING OF SPONSOR STUDY MATERIALS 
 


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My signature confirms that the clinical study will be conducted in accordance with the 
protocol and applicable laws and other regulations including, but not limited to, the 
International Council for Harmonisation (ICH) Guideline for Good Clinical Practice (GCP), 
the US Code of Federal Regulations (CFR), protections for privacy, and generally accepted 
ethical principles such as the Declaration of Helsinki. 
Nothing in this document is intended to limit the authority of a physician to provide 
emergency medical care. 
 
I confirm that I have received, read, and understood the following document(s) for: 
PRODUCT:  
Acthar® Gel (Repository Corticotropin Injection)  
 
STUDY: 
Protocol MNK14344100 
Protocol Version 2 Amendment 1 
 
PRINCIPAL/COORDINATING INVESTIGATOR(S) 
 
Name: 
Title: 
 
 
 
SIGNATURE_________________________________________DATE: _______________ 


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2. 
SYNOPSIS 
Study Title: A Multicenter, Randomized, Double Blind, Placebo Controlled Exploratory Study to Assess the 
Efficacy and Safety of Acthar® Gel in Subjects With Pulmonary Sarcoidosis 
Protocol Number: MNK14344100 
Type: Phase 4 (US) / Phase 2 (all other countries) 
Condition/Disease:  
Pulmonary Sarcoidosis 
Approximate Number of 
Subjects: 100 
Approximate Duration of Subject Participation: Up to 14 months.  
Approximate Number of Study 
Centers: Approximately 75 sites 
globally 
Approximate Duration of Study: The estimated study period is 
approximately 4 years from first subject enrolled to last subject last 
visit (completed open-label extension and follow up visit). Expected 
enrollment period is approximately 3 years (first subject enrolled to last 
subject enrolled). 
Objective: The objective of the study is to evaluate the efficacy and safety of Acthar® Gel in the treatment of 
pulmonary sarcoidosis.  
Design:  
This is a multicenter, randomized, double-blind, placebo-controlled exploratory study evaluating the efficacy 
and safety of Acthar Gel in the treatment of pulmonary sarcoidosis. The study will have 3 phases: Screening 
(up to 28 days); double-blind treatment (24 weeks); and an optional open-label, 24 weeks extension. A follow-
up visit will be conducted 4 weeks (± 2 days) after the last dose of IMP is administered. Following signature of 
the ICF and a screening period of up to 28 days, subjects who meet all eligibility criteria will be randomly 
assigned to receive:  
• 
Double-blind treatment: Acthar Gel, 1 mL (80 U) or matching placebo (1 mL) administered twice 
weekly SC for up to 24 weeks. 
• 
Optional open-label treatment: Acthar Gel, 1 mL (80 U) administered twice weekly SC for up to 
24 weeks. 
Subjects will be assigned to treatment in a 1:1 ratio with up to 50 subjects per arm for a total of approximately 
100 subjects. 
Dose reduction of 50% may be implemented once during the study if a subject meets one of the following 
pre-specified safety criteria based on clinical judgment: 
• 
Uncontrolled hypertension (newly developed or worsening of existing hypertension) before/or in 
conjunction with addition/adjustment of antihypertensive therapy. 
• 
Uncontrolled diabetic signs/symptoms (newly developed of worsening of existing diabetes) before/or 
in conjunction with addition/adjustment of antihyperglycemic therapy. 
• 
Unacceptable toxicity defined as any adverse event (AE) of at least moderate intensity not adequately 
controlled by concomitant medication use or other nonstudy drug-related measure. 
The justification for dose reduction will be captured in the eCRF. Subjects will remain on the 40 U or 
matching placebo 2×/week for the remainder of the study. Subjects, who despite dose reduction continue to 
experience from any of the above mentioned AEs, they will be withdrawn from the study due to AE.  
Subjects will be followed every 4 weeks (± 5 days) for 24 weeks (Visit 2 to Visit 8). During each visit 
following randomization, steroid tapering evaluation will occur based on the following algorithm.  
 


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Incremental doses of prednisone for the study are 40, 30, 20, 10, 7.5, 5, 2.5, and 0 mg.
A justification for any deviation will be captured in the eCRF. In addition, subjects and physicians will 
complete patient reported outcomes, and safety will be evaluated based on targeted physical examination per 
organ involved, vital signs, imaging, and laboratory test results. Any additional visits, hospitalization, or 
additional tests or imaging performed beyond those dictated by the protocol, at the discretion of the 
investigator (or other disciplines for extra-pulmonary manifestations) will also be captured in the eCRF. 
Following the completion of the double blind phase, subjects will be invited to continue participation in an 
optional Open-label Extension Phase (Visit 9 to Visit 11). Subjects who decline participation in the Open-label 
Extension Phase, or those ineligible, will have their End-of-Treatment visit during Visit 8. 
All subjects will have a follow-up visit 4 weeks (± 2 days) after the last dose of IMP, regardless of treatment 
group, and/or participation in the optional Open-label Extension Phase.
During the optional Open-label Extension Phase, subjects will be treated with Acthar Gel 80 U 2×/week for up 
to 24 weeks. Subjects who had their dose reduced once by half will be treated with Acthar Gel 40 U 2×/week. 
There will be 3 scheduled visits during this phase: Visit 9, 4 weeks (± 5 days) into the extension phase 
(Week 28), Visit 10 (Week 36) and Visit 11 (Week 48). During these visits corticosteroid taper will follow the 
same procedures and algorithm as in the double blind phase. Subjects and physicians will complete patient 
reported outcomes, and safety will be evaluated based on targeted physical examination per organ involved, 
vital signs, imaging, and laboratory test results. Any additional visits, hospitalization, or additional tests or 
imaging performed beyond those dictated by the protocol, at the discretion of the investigator (or other 
disciplines for extra-pulmonary manifestations) will also be captured in the eCRF.
During Visit 11, End-of-Treatment procedures will be completed. 
Responder rate analysis (efficacy endpoints) will be determined by the investigator and an independent 
adjudication. Adjudication will serve to address inter-rater variability. In case of discrepancies, the 
adjudication determination will be utilized for purposes of efficacy endpoint analyses. Likewise, central HRCT 
and CXR readings will be used for the purpose of the imaging efficacy analyses.


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Entry Criteria:  
Inclusion Criteria 
The subjects must meet all of the following criteria for inclusion in the study: 
1. Subjects must 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. Subjects must be ≥ 18 and ≤ 90 years of age at Screening (Visit 1) and can be male or female. 
3. Female subjects must be of non-childbearing potential (history of hysterectomy, bilateral 
oophorectomy, or bilateral tubal ligation; or postmenopausal with no history of menstrual flow in the 
12 months prior to Screening (Visit 1); or if of childbearing potential must be non-pregnant, non-
lactating and agree to use effective contraception when with a male partner throughout study 
participation (through the Follow-up Visit). 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), and abstinence.  
4. Subjects must be able to communicate effectively with study personnel. 
5. Subjects must be able and willing to follow all protocol requirements and study restrictions including 
able and willing to inject SC Acthar Gel on their own or by caregiver. 
6. Subjects must be able and willing to return for all study visits. 
7. Subject with biopsy confirmed sarcoidosis meeting ATS criteria with onset of sarcoidosis ≥ 1 year 
prior to Screening. 
8. Symptomatic pulmonary disease defined as any one of the following criteria for PFT; imaging; 
steroid dose; or symptoms: 
• 
Decrease ≥ 5% absolute change of % predicted in the best available FVC within the past 2 years.  
• 
Decrease ≥ 5% absolute change of % predicted in the best available diffusing capacity of the 
DLCO within the past 2 years.  
• 
Radiographic progression in chest imaging on side by side comparison within the past 2 years. 
• 
Progression of pulmonary sarcoidosis necessitating increase in antisarcoidosis therapy in the past 
2 years. 
• 
Dyspnea with Medical Research Council Scale of ≥ 1 at Screening (Visit 1). 
9. Subject receiving ≥ 5 mg and ≤ 40 mg daily prednisone (or equivalent) for pulmonary sarcoidosis. 
10. Stable prednisone dose ≥ 4 weeks prior to Screening (Visit 1). 
11. Subjects treated with any disease modifying antisarcoidosis drugs (eg, methotrexate) must be on 
stable dose for ≥ 3 months prior to Screening (Visit 1). 
12. FVC ≥ 45% predicted. If FVC at Screening is more than 95% predicted, a documented decrease ≥ 5% 
absolute change of % predicted in the best available FVC is required after diagnosis of Sarcoidosis.  
13. DLCO ≥ 30%.  
Exclusion Criteria 
Subjects are ineligible for the study if they meet any of the following criteria: 
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. 


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2. Subject is unwilling to receive, or is intolerant of, SC injections. 
3. Subject has a history of sensitivity to ACTH preparations or sensitivity to porcine protein products. 
4. Any difference >10% in FVC on spirometry between the determination at Screening (Visit 1) and the 
determination at Visit 2. 
5. Pulmonary arterial hypertension requiring or receiving treatment. 
6. Extra pulmonary involvement that per the Investigator’s evaluation requires treatment that would 
impede corticosteroid tapering for pulmonary involvement.  
7. Treatment with antitumor necrosis factor-α antibody (eg, infliximab, adalimumab) in prior 3 months. 
8. Subject has any known contraindication(s) to Acthar Gel including, but not limited to: 
• 
Any known history of: 
o 
Scleroderma  
o 
Osteoporosis (evidence of vertebral or long bone fracture, or a lumbar T-score of more 
than -2.5 SD below the mean of the reference population). Subjects previously 
diagnosed as having osteoporosis and successfully treated will not be excluded solely on 
the basis of a historical diagnosis of osteoporosis as long as the lumbar T-score obtained 
per routine follow up within the 12 months prior to Screening (Visit1) is ≥ -2.5 SD. 
o 
Ocular herpes simplex  
• 
Any primary adrenocortical insufficiency or adrenal cortical hyperfunction. 
• 
Any current congestive heart failure (defined as New York Heart Association Functional Class 
III to IV). 
• 
Peptic ulcer requiring treatment or history of upper gastrointestinal bleeding within 24 weeks 
prior to Screening (Visit 1). 
• 
Recent major surgery (ie, major fluid or blood shift) within 24 weeks prior to Screening (Visit 1). 
9. Subject has uncontrolled diabetes, hypertension, or other contra-indication to increased dosage of 
glucocorticoids. 
10. Subject has chronic active hepatitis including active or chronic hepatitis B, or acute or chronic 
hepatitis C.  
11. Subject has a history of TB infection, any signs/symptoms of TB, or any close contact with an 
individual with an active TB infection.  
12. Subject has a clinically significant infection requiring administration of intravenous antibiotics or 
hospitalization in the 4 weeks prior to Screening (Visit 1) or between Screening and the first dose of 
IMP. 
13. 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. 
14. 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 Screening (Visit 1); 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. 
15. Subject has a diagnosis of, is undergoing therapy for, or has received therapy for a hematologic 
malignancy in the 5 years prior to Screening (Visit 1). 


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16. Subject has current or recent (within 24 weeks prior to Screening (Visit 1) drug or alcohol abuse as 
defined in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Diagnostic Criteria 
for Drug and Alcohol Abuse. 
17. Subject has any of the following laboratory abnormalities at Screening (Visit 1): 
• 
Hemoglobin ≤ 8.0 g/dL. 
• 
Platelet count ≤ 50,000 cells/μL. 
• 
Absolute neutrophil count ≤ 1,000 cells/μL. 
• 
Aspartate aminotransferase, alanine aminotransferase, or total bilirubin  2 times upper limit of 
normal. 
• 
Positive hepatitis B surface antigen or hepatitis B core antibody, or positive hepatitis C virus 
(HCV) antibody. (If HCV antibody is positive at Screening, HCV polymerase chain reaction will 
be automatically analyzed. Subjects with a positive HCV must have HCV polymerase chain 
reaction < 25 IU/mL at the Screening Visit to be eligible). 
• 
Positive or indeterminate IGRA for TB. 
18. Subject has any other clinically significant disease, disorder or laboratory abnormality (including 
those listed on the Prescribing Information Section 5: Warnings and Precautions) 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. 
19. Subject is: 1) currently participating in another interventional clinical study or 2) has participated in 
another interventional clinical study within 30 days or five half-lives, whichever is longer, prior to 
Screening (Visit 1) or 3) plans to participate in another interventional clinical study prior to 90 days 
following the completion of current study. 
20. Subject has any history of use of ACTH preparations for treatment of sarcoidosis. 
 
Concomitant Medications and Treatments:  
Subjects enrolled into the study must have been on stable prednisone dose for at least 4 weeks prior to 
Screening (Visit 1). Subjects who are treated with any disease modifying antisarcoidosis drug (eg, 
methotrexate) must have been on a stable dose for at least 3 months prior to Screening (Visit 1). Corticosteroid 
tapering will be initiated as of Week 4 (Visit 3) according to the tapering algorithm. All other antisarcoidosis 
medications should remain stable for the duration of the study. The dose may be reduced or discontinued only 
for toxicity but must not be increased. Treatment with antitumor necrosis factor-α antibody (eg, infliximab, 
adalimumab) in the 3 months prior to Screening (Visit 1) and any new antisarcoidosis medications are not 
permitted.  
Subjects are not permitted to receive live or live-attenuated vaccines during the study. 
All medications and nondrug therapies (eg, blood transfusions, oxygen supplementation, herbal remedies, 
vitamin supplements) taken from 30 days prior to Screening (Visit 1) and throughout the study will be 
recorded. 


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Investigational medicinal product and Treatment Administration:  
Acthar Gel, 1 mL (80 U) or matching placebo (1 mL) administered twice weekly SC for up to 24 weeks.  
Optional open-label extension: Acthar Gel, 1 mL (80 U) administered twice weekly SC for up to 24 weeks. 
Efficacy Evaluation: 
The following efficacy assessments will be evaluated: 
 
1. STS, a newly developed composite endpoint.  
Sarcoidosis Treatment Score (STS) is a composite combining the results of PFT, chest imaging, quality of life, 
and changes in corticosteroid dosing.  
 
 
Parameter 
Improved 
Unchanged 
Deteriorate 
Category of Assessment 
 
+1 
0 
-1 
PFTa 
FVC 
≥ 5% 
> -5% to < 5% 
≤ -5% 
DLCO 
≥ 5% 
> -5% to < 5% 
≤ -5% 
Imaging 
HRCT 
Improved 
Unchanged 
Worse 
Quality of Life 
King’s Sarcoidosis 
Questionnaire 
(General Health) 
≥ 4 
> -4 to < 4 
≤ -4 
Fatigue Assessment 
Score 
≤ -4 
> -4 to < 4 
≥ 4 
 
Corticosteroid taper 
(dosage) 
≥ 50% 
reduction  
< 50% reduction or 
≥ 5 mg increase for 
less than 2 weeks  
≥ 5 mg increase for 
more than 2 weeks 
aAbsolute change of predicted percentage.  
 
Subject tolerating Acthar Gel (or placebo) will be categorized according the following scoring:  
• 
Response is defined as scores of ≥ 3/6 points.  
• 
Partial Response is defined as scores of 2/6 points or stable with a reduction in corticosteroid dose (ie, 
a total score of +1 due to ≥ 50% reduction in corticosteroid dose).  
• 
Nonresponse is defined as scores of ≤ 1/6 points without significant corticosteroid taper (stable or 
deterioration in corticosteroid response). 
 
2. PFT. 
3. Imaging: HRCT; CXR (including Scadding Score). 
4. Corticosteroid tapering. 


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5. Physician Global Assessment.  
6. Patient reported outcomes (King’s Sarcoidosis Questionnaire, Fatigue Assessment Scale, and Patient's 
Global Assessment).  
7. Symptom Assessment (Medical Research Council Dyspnea Scale, Leicester Cough Questionnaire, 
and steroid toxicity questionnaire). 
8. Functional testing: 6MWT (including Borg Scale) 
9. Extra pulmonary response (ePOST score). 
10. Biomarkers, (eg, for genetic testing; optional). 
11. WPAI.  


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Endpoints: 
The endpoints for this study are: 
• 
STS response rate at 24 weeks (Visit 8). 
• 
STS response rate at 48 weeks (Visit 11). 
• 
Physician and subject independent responses to the question “Would you choose to continue current 
treatment?” at 24 and 48 weeks. 
• 
Time to response as evaluated at earlier time points (Weeks 4 to 20), as determined by the 
investigator based on clinical judgment and the following parameters: 
o 
Patient reported outcomes. 
o 
Corticosteroid tapering. 
o 
Patient Global Assessment. 
o 
Physician Global Assessment.  
o 
PFT (at applicable time points). 
o 
Extrapulmonary response (ePOST). 
o 
Supportive efficacy endpoints per applicable time points. 
▪ Six-minute walk test. 
▪ Symptom relief (Leicester Cough Questionnaire, Medical Research Council Dyspnea Scale, 
steroid toxicity questionnaire). 
▪ CXR (including Scadding score). 
• 
Percentage change in overall DLCO. 
• 
Percentage of subjects with improvement in DLCO of ≥ 5%; ≥10%; and ≥ 15%. 
• 
Percentage change in overall FVC. 
• 
Percentage of subjects with improvement in FVC of ≥ 5%; ≥10%; and ≥ 15%. 
• 
Percentage of improved/stable/deteriorate - side by side comparison of HRCT based on a 5-point 
Likert score: much worse; worse; unchanged; better; much better (central reader). 
• 
Percentage of improved/stable/deteriorated side by side comparison of CXRs based on a 5-point 
Likert score: much worse; worse; unchanged; better; much better (central reader). 
• 
Percentage change in Scadding Score (side by side comparison of CXRs by a central reader). 
• 
Percentage change in patient-reported outcomes and symptom questionnaires. 
• 
Percentage failed corticosteroid taper. 
• 
Time to failed corticosteroid taper (for subjects failing taper). 
• 
Change from baseline in WPAI over time. 
Biomarkers:  
• 
Biomarker levels will be compared between Screening, and every 12 weeks (up to 48 weeks for those 
subjects participating in the optional Open-label Extension Phase). Serum aliquots will be kept for 
each of these time point. Possible biomarkers include angiotensinogen, sIL-2R and vitamin D 1,25. 
The final selection of biomarkers will be made based on the scientific knowledge and emerging 
guidance closer to the completion of the study.  
• 
Genomic profile (optional) will be assessed based on the understanding of genetic factors at the time 
of study completion. 


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Outcome Measures 
Outcome measures are identified to facilitate trial registration and patient access to basic results disclosed on 
public registries. The primary outcome measures are: 
• 
Number of participants in each category of assessment based on FVC, Weeks 24 and 48 
• 
Number of participants in each category of assessment based on the DLCO, Weeks 24 and 48 
• 
Number of participants in each category of assessment based on HRCT, Weeks 24 and 48  
• 
Number of participants in each category of assessment based on the King's Sarcoidosis Questionnaire 
(General Health), Weeks 24 and 48 
• 
Number of participants in each category of assessment based on the FAS, Weeks 24 and 48 
• 
Number of participants receiving each dose of prednisone, Weeks 24 and 48 
Safety Evaluation:  
Overall safety will be determined by the incidence, severity and relationship of AEs, physical examinations, 
vital signs, clinical laboratory abnormalities, and imaging. 
Statistical Methods: 
Summary statistics will be provided for all study variables with descriptive statistics (number of observations, 
mean, SD, median, minimum, and maximum) for numerical (or continuous) variables. Frequency and 
percentages will be calculated for categorical variables. All data will be summarized by treatment groups as 
appropriate. 
Pearson’s chi-squared test will be used to evaluate the treatment difference between treatment groups for the 
categorical response endpoints. The continuous response endpoints will be analyzed using the 2-sample t-test. 
The time-to-event endpoints will be analyzed using the log-rank test. Kaplan-Meier curves will also be 
presented. 
Additional exploratory analyses will be performed as appropriate. Such analyses may include logistic 
regression model, analysis of variance model, and/or mixed-effects model. Subgroup analyses based on 
demographics, baseline characteristics, study compliance, etc, will also be performed. 
Sample Size Justification: 
Formal sample size calculations were not performed. The sample size is based on recent literature of 
comparative studies in sarcoidosis.  
Date of Issue: 13 May 2020 


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SUMMARY OF CHANGES 
The summary of changes presented below reflects the changes made in Version 2 
Amendment 1. Formatting, consistency, and minor editorial changes are not included.  
The primary reason for Version 2 Amendment 1 is to extend this product’s and this study’s 
treatment to countries other than the US, as currently Acthar Gel is only approved in the US. 
Additionally, updates or revisions are established for: study design that is revised to 
exploratory, changing enrollment and study duration timelines, adding WPAI questionnaire 
for collection of data for health economics and outcomes research, adding provisions for 
remote collection of data for those extenuating occasions when visits cannot be made in 
person, adding diary training and reviews, adding monitoring for possible allergic reactions to 
the first dose of Acthar Gel in the Open-label Extension Phase, removing an additional 
definition for SAEs that are not part of the standard definitions, and adding corticosteroid 
tapering for subjects entering the open label study period. Further detail is presented in 
Appendix 1. 
 
 


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TABLE OF CONTENTS 
1. 
TITLE PAGE ............................................................................................. 1 
SPONSOR SIGNATURE PAGE .................................................................................. 2 
ACKNOWLEDGEMENT OF RECEIPT AND UNDERSTANDING OF SPONSOR 
STUDY MATERIALS .............................................................................. 2 
2. 
SYNOPSIS ................................................................................................. 4 
SUMMARY OF CHANGES ...................................................................................... 13 
3. 
ABBREVIATIONS ................................................................................. 20 
4. 
STUDY SCHEMATIC AND SCHEDULE OF EVENTS ...................... 22 
4.1. 
Study Schematic ....................................................................................... 22 
4.2. 
Schedule of Study Events ........................................................................ 22 
5. 
ETHICAL CONSIDERATIONS ............................................................. 27 
5.1. 
Institutional Review Board/Independent Ethics Committee .................... 27 
5.2. 
Ethical Conduct of the Study ................................................................... 27 
5.3. 
Subject Information and Consent ............................................................. 27 
6. 
BACKGROUND INFORMATION AND RATIONALE ....................... 29 
6.1. 
Sarcoidosis Overview............................................................................... 29 
6.2. 
Acthar Gel Overview ............................................................................... 31 
6.3. 
Rationale .................................................................................................. 33 
6.4. 
Risk and Benefits ..................................................................................... 33 
7. 
OBJECTIVE AND EFFICACY .............................................................. 34 
7.1. 
Objective .................................................................................................. 34 
7.2. 
Assessments of Efficacy .......................................................................... 34 
7.2.1. 
Sarcoidosis Treatment Score .................................................................... 34 
7.2.2. 
Pulmonary Function Tests ....................................................................... 35 
7.2.3. 
Imaging (HRCT; CXR) ............................................................................ 36 
7.2.4. 
Corticosteroid Tapering ........................................................................... 37 
7.2.5. 
Steroid Toxicity Questionnaire ................................................................ 37 
7.2.6. 
King’s Sarcoidosis Questionnaire ............................................................ 37 


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7.2.7. 
Fatigue Assessment Scale (FAS) ............................................................. 37 
7.2.8. 
Patient’s Global Assessment .................................................................... 37 
7.2.9. 
Physician Global Assessment .................................................................. 38 
7.2.10. 
Medical Research Council Dyspnea Scale (MRC) .................................. 38 
7.2.11. 
Leicester Cough Questionnaire (LCQ) .................................................... 38 
7.2.12. 
Six Minute Walk Test (6MWT) ............................................................... 38 
7.2.13. 
Extrapulmonary Physician Organ Severity Tool (ePOST) ...................... 38 
7.2.14. 
Biomarkers/genomics ............................................................................... 38 
7.2.15. 
Work Productivity and Activity Impairment ........................................... 39 
7.3. 
Efficacy Endpoints ................................................................................... 39 
7.4. 
Primary Outcome Measures ..................................................................... 40 
8. 
STUDY DESIGN ..................................................................................... 42 
8.1. 
Description ............................................................................................... 42 
8.2. 
Approximate Duration of Subject Participation ....................................... 43 
8.3. 
Approximate Duration of Study ............................................................... 43 
8.4. 
Approximate Number of Subjects ............................................................ 43 
9. 
SELECTION OF SUBJECTS .................................................................. 44 
9.1. 
Inclusion Criteria ...................................................................................... 44 
9.2. 
Exclusion Criteria..................................................................................... 45 
9.3. 
Screen Failure........................................................................................... 47 
10. 
PRIOR AND CONCOMITANT MEDICATION ................................... 48 
10.1. 
Permitted Concomitant Medications ........................................................ 48 
10.2. 
Prohibited Concomitant Medications/Treatments.................................... 48 
11. 
PROCEDURES ........................................................................................ 49 
11.1. 
Study Days -28 to -1 (Screening Visit 1) ................................................. 49 
11.2. 
Visit 2 Procedures .................................................................................... 51 
11.3. 
Visits 3, 4, 6, and 7, Procedures ............................................................... 52 
11.4. 
Visit 5 Procedures .................................................................................... 53 


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11.5. 
Visit 8 Procedures .................................................................................... 53 
11.6. 
Visit 9 Procedures, Open-Label Extension Period ................................... 55 
11.7. 
Visit 10 Procedures, Open-Label Extension Period ................................. 56 
11.8. 
Visit 11 Procedures, Open-Label Extension Period ................................. 57 
11.9. 
Visit 12 Procedures, Follow-up Visit ....................................................... 58 
11.10. 
Early Termination Procedures ................................................................. 59 
12. 
INVESTIGATIONAL MEDICINAL PRODUCT .................................. 60 
12.1. 
Methods of Assigning Subjects to Treatment Groups ............................. 60 
12.1.1. 
Randomization ......................................................................................... 60 
12.1.2. 
Interactive Telephone/Web Response System ......................................... 60 
12.2. 
Identification of Investigational medicinal product ................................. 61 
12.3. 
Dosing Procedures ................................................................................... 61 
12.3.1. 
Treatment Discontinuation ....................................................................... 62 
12.4. 
Storage of Clinical Supplies ..................................................................... 62 
12.5. 
Drug Accountability ................................................................................. 62 
12.6. 
Compliance Monitoring ........................................................................... 62 
13. 
EFFICACY ASSESSMENTS .................................................................. 64 
14. 
SAFETY ASSESSMENTS AND PROCEDURES ................................. 65 
14.1. 
Adverse Events......................................................................................... 65 
14.2. 
Medical and Surgical History................................................................... 65 
14.3. 
Physical Examination ............................................................................... 65 
14.4. 
Vital Signs ................................................................................................ 65 
14.5. 
Clinical Laboratory Tests ......................................................................... 66 
14.6. 
12-Lead Electrocardiogram ...................................................................... 66 
15. 
STATISTICAL METHODS AND PLANNED ANALYSIS .................. 68 
15.1. 
General Considerations ............................................................................ 68 
15.2. 
Analysis Populations ................................................................................ 68 
15.3. 
Subject Characteristics ............................................................................. 68 


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15.3.1. 
Demographics .......................................................................................... 68 
15.3.2. 
Medical and Surgical History................................................................... 68 
15.3.3. 
Prior and Concomitant Medications......................................................... 68 
15.3.4. 
Subject Disposition and Exposure to Investigational Medicinal Product 68 
15.4. 
Safety Analysis ........................................................................................ 69 
15.4.1. 
Adverse Events......................................................................................... 69 
15.4.2. 
Clinical Laboratory Tests ......................................................................... 69 
15.4.3. 
Physical Examination Findings ................................................................ 69 
15.4.4. 
Electrocardiogram Findings ..................................................................... 69 
15.4.5. 
Vital Signs ................................................................................................ 69 
15.5. 
Efficacy Analysis ..................................................................................... 69 
15.6. 
Interim Analysis ....................................................................................... 69 
15.7. 
Statistical Power and Sample Size Considerations .................................. 70 
15.8. 
Deviations from Statistical Analysis Plan ................................................ 70 
16. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ................ 71 
16.1. 
Safety........................................................................................................ 71 
16.2. 
Definitions ................................................................................................ 71 
16.3. 
Adverse Event and Serious Adverse Event Classifications ..................... 73 
16.4. 
Adverse Event and Serious Adverse Event Recording and Reporting .... 74 
16.5. 
Pregnancy Reporting ................................................................................ 76 
17. 
SUBJECT DISCONTINUATION OR WITHDRAWAL ....................... 77 
17.1. 
Subject Withdrawal .................................................................................. 77 
18. 
STUDY SUSPENSION, TERMINATION, AND COMPLETION ........ 78 
19. 
PROTOCOL AMENDMENTS ............................................................... 79 
20. 
QUALITY CONTROL AND ASSURANCE .......................................... 80 
21. 
DIRECT ACCESS, DATA HANDLING, AND RECORD-KEEPING .. 81 
21.1. 
Investigator ............................................................................................... 81 
21.2. 
Sponsor ..................................................................................................... 81 


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22. 
SUBJECT INJURY .................................................................................. 82 
23. 
RECORDS RETENTION ........................................................................ 83 
24. 
BIOLOGICAL SAMPLES ...................................................................... 84 
25. 
PUBLICATION POLICY ........................................................................ 85 
25.1. 
Sponsor’s Publication Policy ................................................................... 85 
25.2. 
Investigator’s Ability to Publish .............................................................. 85 
26. 
REFERENCES ......................................................................................... 86 
ATTACHMENT 2: STERIOD TOXICITY QUESTIONNAIRE ............................ 114 
ATTACHMENT 3: EXTRAPULMONARY PHYSICIAN ORGAN SEVERITY 
TOOL - EPOST ..................................................................................... 115 
ATTACHMENT 4: KING’S SARCOIDOSIS QUESTIONNAIRE ........................ 116 
ATTACHMENT 5: FATIGUE ASSESSMENT SCALE ......................................... 120 
ATTACHMENT 6: PATIENT'S GLOBAL ASSESSMENT ................................... 121 
ATTACHMENT 7: PHYSICIAN GLOBAL ASSESSMENT ................................. 122 
ATTACHMENT 8: MEDICAL RESEARCH COUNCIL DYSPNEA SCALE ...... 123 
ATTACHMENT 9: LEICESTER COUGH QUESTIONNAIRE ............................. 124 
ATTACHMENT 10: WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT
 ................................................................................................................ 125 
ATTACHMENT 11: SCADDING CXR SCORE .................................................... 127 
ATTACHMENT 12: SIX-MINUTE WALK TEST ................................................. 129 
 


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LIST OF TABLES 
Table 1: 
Schedule of Study Events ........................................................................ 23 
Table 2:  
Determining the Sarcoidosis Treatment Score ......................................... 35 
Table 3:  
AE Relationships ...................................................................................... 73 
Table 4:  
AE Severity Grades .................................................................................. 73 
Table 5: 
Reporting Requirements for Adverse Events ........................................... 74 
 
 
LIST OF FIGURES 
Figure 1: 
Study Overview ........................................................................................ 22 
 
 


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3. 
ABBREVIATIONS 
Abbreviation 
Term 
6MWT 
Six-Minute Walk Test 
AE 
adverse event 
ACTH 
adrenocorticotropic hormone 
ATS 
American Thoracic Society 
CFR 
Code of Federal Regulations 
CXR 
chest x-ray 
DLCO 
Diffusing capacity of the lungs for carbon monoxide 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ePOST 
extrapulmonary Physician Organ Severity Tool  
FAS 
Fatigue Assessment Scale 
FDA 
Food and Drug Administration 
FEF 
Forced expiratory flow 
FEV1 
Forced expiratory volume in 1 second 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
Hb 
hemoglobin 
HbA1C 
hemoglobin (glycosylated) 
HCV 
hepatitis C virus 
HEOR 
Health Economics and Outcomes Research 
HIPAA 
Health Insurance Portability and Accountability Act 
HRCT 
high-resolution computed tomography 
ICF 
informed consent form 
ICH 
International Council For Harmonisation 
ID 
identification number 
IEC 
Independent Ethics Committee 
IGRA 
interferon gamma release assay 
IMP 
investigational medicinal product 


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Abbreviation 
Term 
IRB 
Institutional Review Board 
IXRS 
Interactive Telephone/Web Response System 
LCQ 
Leicester Cough Questionnaire 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intention to treat 
MM 
medical monitor 
MRC 
medical research chronic 
NHANES 
National Health and Nutrition Examination Survey 
PCR 
polymerase chain reaction 
PD 
pharmacodynamics 
PEFR 
peak expiratory flow rate  
PFT 
pulmonary function test(ing) 
RCI 
repository corticotropin injection 
RV 
residual volume 
SAE 
serious adverse event 
SC 
subcutaneous 
STS 
Sarcoidosis Treatment Score 
TB 
tuberculosis 
TEAE 
treatment emergent adverse event 
TLC 
total lung capacity 
WASOG 
World Association of Sarcoidosis and Other Granulomatous 
WPAI 
Work Productivity and Activity Impairment 
 


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4.
STUDY SCHEMATIC AND SCHEDULE OF EVENTS
4.1.
Study Schematic
An overview of the study is presented in Figure 1.
Figure 1:
Study Overview
Note: Visit 8 is the primary efficacy evaluation time point. Additional analyses of long term efficacy and safety 
of subjects participating in the Open-label Extension Phase will be conducted at the completion of Visit 12. PFT
and sample collection for assessment of biomarkers will be performed every 12 weeks. HRCT will be performed 
at Screening (Visit 1) and every 24 weeks thereafter (Visits 8 and 11).
4.2.
Schedule of Study Events
The schedule of study events is presented in Table 1.


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Table 1: 
Schedule of Study Events 
Assessments and Procedures 
Screening 
Randomization 
Double-Blind Treatment Perioda 
Open-label Extension  
(Optional)a 
Follow-up 
Visit 
1 
Visit 
2 
Visit  
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
Visit  
11 
Visit  
12 
Days/Week  
Days -28 to -1 
Day 0 
4  
(± 5 
days) 
8  
(± 5 
days) 
12 
(± 5 
days) 
16 
(± 5 
days) 
20 
(± 5 
days) 
24  
(± 5 
days) 
28  
(± 5 
days) 
36  
(± 5 
days) 
48  
(± 5 
days) 
4 weeks 
after final 
dose of IMP 
(± 2 days) 
Informed consentb 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Medical/surgical/medication 
historyc 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Height  
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signs including weightd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examinatione  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient reported outcomes and 
assessmentsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ePOSTg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physician Global Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study Drug Accountability and 
Diary Review 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Complete blood count 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical chemistry/liver function 
testsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HbA1C 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Lipid profilei 
X 
 
 
 
 
 
 
X 
 
 
X 
 
25-Hydroxy vitamin D, 1, 25-
dihydroxy vitamin D, parathyroid 
hormone 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
C-Reactive protein 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
Biomarkersj 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 


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Table 1: 
Schedule of Study Events (Continued) 
Assessments and Procedures 
Screening 
Randomization 
Double-Blind Treatment Perioda 
Open-label Extension  
(Optional)a 
Follow-up 
Visit 
1 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
Visit 
11 
Visit 
12 
Days/Week 
Days -28 to -1 
Day 0 
4  
(± 5 
days) 
8  
(± 5 
days) 
12 
(± 5 
days) 
16 
(± 5 
days) 
20 
(± 5 
days) 
24  
(± 5 
days) 
28  
(± 5 
days) 
36  
(± 5 
days) 
48  
(± 5 
days) 
4 weeks  
after final 
dose of IMP 
(± 2 days) 
Thyroid stimulating hormone; 
thyroxine T3 and T4 
X 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis serologyk 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinary analysis  
X 
 
 
 
X 
 
 
X 
 
X 
X 
X 
Pregnancy testing (serum) 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testing (urinary) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TB testingl 
X 
 
 
 
 
 
 
 
 
 
 
 
12 lead ECGm 
X 
 
 
 
 
 
 
X 
 
 
X 
 
PFTn 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
Spirometry 
 
X 
 
 
 
 
 
 
 
 
 
 
CXR and HRCTo 
X 
 
 
 
 
 
 
X 
 
 
X 
 
6MWTp 
X 
 
 
 
 
 
 
X 
 
 
X 
 
Injection and diary trainingq 
X 
X 
 
 
 
 
 
 
 
 
 
 
Randomization  
 
X 
 
 
 
 
 
 
 
 
 
 
IXRS contact, dispense IMP and 
equipmentr 
X 
X 
X 
X 
X 
X 
X 
Xr 
X 
X 
 
 
Dosing 2×/weeks 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study drug accountability and 
diary review 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Table 1: 
Schedule of Study Events (Continued) 
Assessments and Procedures 
Screening Randomization Double-Blind Treatment Perioda 
Open-label Extension  
(Optional)a 
Follow-up 
Visit 
1 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
Visit 
11  
Visit 
12 
Days/Week  
Days -28 
to -1 
Day 0 
4  
(± 5 
days) 
8  
(± 5 
days) 
12 
(± 5 
days) 
16 
(± 5 
days) 
20 
(± 5 
days) 
24  
(± 5 
days) 
28  
(± 5 
days) 
36  
(± 5 
days) 
48  
(± 5 
days) 
4 weeks 
after final 
dose of IMP 
(± 2 days) 
Corticosteroid taperingt 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant medications  
 
X 
X 
Safety (AEs)u 
X 
IMP = Investigational Medicinal Product; IXRS = Interactive Telephone/Web Response System 
a Visits 2 through 11 should occur within ± 5 days of the indicated weeks and should not be scheduled for the day of injection so as not to influence patient reported 
outcomes. Any additional visits, hospitalization, or additional tests or imaging performed beyond those dictated by the protocol, at the discretion of the investigator 
(or other disciplines for extrapulmonary manifestations) will also be captured in the eCRF. 
b Neutral language should be used in describing the study to neutralized placebo effect. 
c Medical history will include smoking history (classified into one the following categories: current smoker; ever smoked [more than 1cigarette/day for more 
than1year]; never smoked), length of sarcoidosis diagnosis, organ involvement, and prior and current medication. Occupational history should also be collected. 
d Every effort should be made for weight to be measured by the same calibrated scale at every visit.  
e Physical examination will also include targeted examination per organ(s) involved. All efforts must be undertaken for the same physician to perform the physical 
examination for each subject (per subject, per organ involved) at each visit.  
f Patient-reported outcomes include: Steroid toxicity questionnaire (Attachment 2); King’s Sarcoidosis Questionnaire (Attachment 4); Fatigue Assessment Scale 
(Attachment 5); Patient's Global Assessment (Attachment 6); Medical Research Council Dyspnea Scale (Attachment 8); Leicester Cough Questionnaire 
(Attachment 9), Work Productivity and Activity Impairment (WPAI) (Attachment 10). Prior to filling out any patient-reported outcomes at Visit 1, training will be 
provided as to the nature, purpose, and best way of filling these out. For example, reading the last question of the Fatigue Assessment Scale carefully. PRO 
assessments should be completed at each visit before undertaking any activities or tests that can influence the reporting. At Visit 8 and Visit 11 both the investigator 
and the subjects will asked independently if they would choose to continue treatment.  
g All efforts must be undertaken for the same physician to perform the Extrapulmonary Physician’s Organ Severity Tool (ePOST), per subject, (Attachment 3) side-
by-side with prior evaluations.  
h Chemistry panel including liver function tests will include: alanine aminotransferase; albumin (total); alkaline phosphatase; aspartate aminotransferase; 
bicarbonate; bilirubin (total); blood urea nitrogen; calcium; chloride; creatinine; creatine phosphokinase; glucose; phosphorus; potassium; protein (total); sodium; 
uric acid. Samples will be collected from subjects who have been fasted for at least 12 hours (drinking water is permitted). 


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i Lipid profile will include: high density lipoprotein; low density lipoprotein; triglycerides; total cholesterol. Samples will be collected from subjects who have been 
fasted for at least 12 hours. 
j Biomarkers sampling must include RNA and DNA samples (screening only), if genetic Informed Consent Form (ICF) is signed. 
k Hepatitis B surface antigen, hepatitis B core antibody, hepatitis C virus (HCV) antibody, HCV polymerase chain reaction (for subjects positive for HCV antibody 
only).  
l Tuberculosis (TB) will be tested by interferon gamma release assay (IGRA). Central laboratory test results must be negative for subjects to qualify for the study.  
m ECG will include assessment of sinus rhythm, heart rate, PR Interval, RR Interval, QRS Duration, Q-T Interval and QTcB. 
n Full pulmonary function test (PFT) results will include forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FVC % predicted (NHANES III 
reference values), FEV1/FVC ratio, peak expiratory flow rate (PEFR) or forced exploratory flow at maximum effort (FEFmax), total lung capacity, residual volume, 
diffusing capacity of the lungs for carbon monoxide (DLCO; uncorrected for Hb), DLCO: % predicted and DLCO/alveolar volume.  
o High-resolution computed tomography (HRCT) should be performed within 28 days of Day -1. Both CXR and HRCT should be evaluated side by side by 
investigator/radiologist/central reader for determining if the condition is improving, stable, or deteriorating based on a 5-point Likert score: much worse; worse; 
unchanged; better; much better. The CXR will also include Scadding scoring (Attachment 11).  
p The Six Minute Walk Test (6MWT) would be performed according to the ATS protocol (Attachment 12). Reasons for not performing the 6MWT will be captured 
in eCRF.  
q Subjects (and/or caregivers) will be trained on SC injections using the training tools provided separately. Additional training may be provided during Visit 2 before 
randomization occurs. SC injections training may be forgone if either the subject or caregiver is a medically trained professional.  
r The importance of adhering to treatment will be encouraged at every visit. At Visit 8, IMP will only be dispensed for subjects participating in the optional Open-
label Extension Phase.  
s Dosing will begin after Visit 2 procedures are completed and subject is randomized. The first dose of study drug for all subjects will be administered in the clinic 
and the subject will be observed for at least 1 hour after dosing. For subjects entering the Open Label Extension, the first dose given at Week 24 will be 
administered in the clinic and the subject will be observed for at least 1 hour after dosing.  All other doses will be administered by the subject or the subject’s 
caregiver at home 2×/week, but no dose should be administered on study visit days (see Section 12.3).  
t Corticosteroid taper will follow the specified algorithm. Corticosteroid tapering at Visit 8 is done for patients entering open label extension only. Reasons for 
determining worsening will be captured in the eCRF (FVC, DLCO, imaging, symptoms, other). Justification for any deviations will also be captured in the eCRF. 
u At each visit following signature of the ICF, AE will be reported based on questioning subjects as to new medical conditions since last visit and as to experiencing 
worsening of existing medical conditions since last visit, physical exam, laboratory and imaging findings. 
 


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5. 
ETHICAL CONSIDERATIONS 
This clinical study is designed to comply with International Council for Harmonisation (ICH) 
Guidance on General Considerations for Clinical Trials (62 FR 66113, 17 Dec 1997), 
Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authority 
for Pharmaceuticals (75 FR 3471, 21 Jan 2010), and Good Clinical Practice: Consolidated 
Guidance (62 FR 25692, 09 May 1997). 
5.1. 
Institutional Review Board/Independent Ethics Committee 
It is the responsibility of the investigator to obtain the approval of the IRB/IEC before the start 
of the study. The IRB must be registered and active with the Office for Human Research 
Protections of the US Department of Health and Human Services. A copy of the approval 
letter along with a roster of IRB members and/or the US Department of Health and Human 
Services general assurance number will be 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; and the 21 CFR §56.101-114 (where applicable). 
5.2. 
Ethical Conduct of the Study 
The study will be conducted in full compliance with applicable international, national and 
local regulatory requirements; US FDA regulations including 21 CFR §314.106 and 
§312.120, and ICH guidelines for GCP and in accordance with the ethical principles that have 
their origins in the Declaration of Helsinki. 
5.3. 
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, subjects will read the ICF and a HIPAA authorization form (if 
applicable) after being given an explanation of the study. Before signing the ICF and the 
HIPAA 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 guidelines and 21 CFR, Parts 50 and 312 (where applicable), before participating in 
any study-related procedures. Subjects will be made aware that they may withdraw from the 
study at any time.  
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 


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regulatory authorities and/or authorized Mallinckrodt personnel. Signed copies of the ICF 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. 


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6. 
BACKGROUND INFORMATION AND RATIONALE 
6.1. 
Sarcoidosis Overview  
Sarcoidosis is a chronic multisystem granulomatous disease, with a heterogeneous clinical 
presentation and disease course, characterized by the presence of noncaseating granulomas. 
Although sarcoidosis has been identified as a specific disease entity for more than a century, 
the specific cause of sarcoidosis is unknown. Current understanding is that the pathogenesis 
likely includes exposure to one or more, possibly airborne-transmitted antigens (bacterial, 
organic, anorganic), which then trigger an abnormal immune response in a genetically 
predisposed host (Ahmadzai et al., 2014; Chopra et al., 2016; Iannuzzi et al., 2007; 
Judson, 2012; Korsten et al., 2016). The disease may affect any organ system. Pulmonary is 
the most prevalent and is present in over 90% of patients. Ocular, lymph-node, and cutaneous 
manifestations are next in frequency (Al-Kofahi et al., 2016).  
To date, there is no gold standard for diagnosis. Presently, the diagnosis is a clinical one as no 
reliable diagnostic test exists ATS criteria described in Hunninghake et al., 1999). Several 
biomarkers have been explored, including amyloid A, lysozyme, calcium, angiotensin 
converting enzyme, vitamin D, tumor necrosis factor-α, and various interleukins (eg, sIL-2R), 
to name a few. Despite many potential biomarkers being identified for monitoring and 
diagnosis, there is still a lack of adequately specific and sensitive disease markers for clinical 
usage, necessitating further research on these fronts. Accordingly, the diagnosis is based on 
the combination of clinical, radiological and histological (noncaseating epithelioid cell 
granuloma) parameters. In lieu of diagnostic test(s), diagnostic criteria have been developed, 
and while vetted by experts, these are arbitrary and inexact (Chopra et al., 2016; Judson, 2014; 
Ahmadzai et al., 2014).  
Sarcoidosis does not mandate treatment because the disease may never cause symptoms, or 
organ dysfunction may remit spontaneously, in about 2/3 of patients (Iannuzzi et al., 2007), 
and therapy (particularly corticosteroids) is associated with a myriad of significant side 
effects. While the indications for treatment and the optimal treatment approach have not been 
standardized, the general consensus is that treatment should only be administered to avoid 
danger (eg, cardiac or neurologic manifestations) or to improve quality of life. (Judson, 2014; 
Baughman et al., 2012)  
Various expert driven treatment recommendations exist for pulmonary and extra-pulmonary 
manifestations of sarcoidosis, however, the available evidence to guide treatment is limited. 
Corticosteroids are typically the first-line when treatment is required. Several off label 
alternative agents may be used, usually as corticosteroid sparing agents, because of the 
development or concerns of significant corticosteroid toxicity. Although often a small amount 
of corticosteroid may be continued for adequate efficacy. Second-line disease-modifying anti-
sarcoid drugs may include antimetabolites (eg, methotrexate; azathioprine; leflunomide). 
Third-line typically includes anti-tumor necrosis factor-α biological agents (eg, infliximab; 
rituximab; adalimumab). Use of these agents should be individualized based on the patient’s 
potential for toxicity and the organ that is being treated. In the future, there are goals to 
develop “personalized” or “precision” medical care where therapy will be individualized 
based on the patient’s specific clinical features or genetics (Korsten et al., 2016; Judson, 2014; 
Judson, 2012; Baughman et al., 2012; Jamilloux et al., 2017). 


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Acthar® Gel has been included as third- or fourth-line therapy in several treatment algorithms 
(Korsten et al., 2016; Baughman et al, 2015). Three studies describing safety and efficacy of 
Acthar Gel in pulmonary sarcoidosis were recently published and described as follows.  
The first study was a retrospective chart review of 47 patients with advanced sarcoidosis seen 
at 2 clinical centers who received at least 1 dose of Acthar Gel with at least 6 months of 
posttreatment follow-up. All patients initially received Acthar Gel 80 U intramuscular or SC 
administration twice a week (2×/week). Eighteen patients (37%) discontinued drug within 6 
months due to study participation cost (4 patients), death (2 patients), or drug toxicity 
(11 patients), or noncompliance (1 patient). Of the remaining 29 patients, 11 experienced 
objective improvement in 1 or more affected organs. All but 2 patients noted disease 
improvement or oral glucocorticoid reduction. Twenty-one patients were treated for more than 
6 months (median 274 days). Nineteen patients were taking prednisone at time of starting 
Acthar Gel: 17 had their prednisone dosage reduced by more than 50%, and 1 patient 
discontinued cyclophosphamide therapy. Acthar Gel treatment for at least 3 months was 
associated with objective improvement in a third of the patients. A third of the patients were 
unable to take treatment for at least 3 months (Baughman et al., 2016). 
The second study was a prospective study of 16 patients with chronic pulmonary sarcoidosis 
receiving prednisone therapy with deterioration by at least 5% in FVC in the previous year. 
Acthar Gel was administered at a loading dose of 80 U SC for 10 days. Patients were 
randomized at Day 14 to receive either 40 U or 80 U Acthar Gel 2×/week for 24 weeks. The 
dose of prednisone was modified by the clinician who was blinded to the patient’s dosage of 
Acthar Gel. At Week 24, there was a decrease in the dose of prednisone and improvements in 
DLCO, the King’s Sarcoidosis Questionnaire (general health status), and the Fatigue Scale. 
There was no significant change in FVC % predicted. For the positron emission tomography 
scan, there was a significant fall in the standard uptake value of the lung lesions. Only 
3/8 patients remained on 80 U repository corticotropin for full 24 weeks. There was no 
significant difference in the response to therapy for those treated with 40 U vs 80 U Acthar 
Gel. The authors concluded that Acthar Gel treatment was prednisone-sparing and associated 
with significant improvement in DLCO, positron emission tomography scan, and patient-
reported outcome measures. A dose of 40 U repository corticotropin 2×/week was as effective 
as 80 U Acthar Gel and was better tolerated (Baughman et al., 2017).  
 
 
 
. 
The third study was large case series of patients with advanced symptomatic sarcoidosis 
treated with repository corticotropin injection (RCI). This large case series study describes 
patient characteristics, RCI utilization patterns, concomitant therapies, and physicians’ 
assessments of treatment response. The study included 302 patients (mean age = 51 years; 
52% women) with a mean of 4.8 years since initial diagnosis of sarcoidosis. Most patients 
(76%) had extrapulmonary involvement, primarily in the skin (28%), joints (25%), heart 
(22%), and eyes (22%); 34% had multiple (≥2) organ involvement. The mean duration of RCI 
treatment was 32.5 weeks, with 61.6% of patients continuing RCI therapy for ≥6 months. The 
RCI utilization pattern indicated an individualized approach to therapy, with a higher starting 
dose associated with a shorter duration of therapy compared with a lower starting dose. The 


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percentage of patients who used corticosteroids decreased from 61.3% during the 3 months 
before initiation of RCI to 12.9% at 3 months after RCI therapy; the mean daily dose of 
corticosteroid decreased from 18.2 mg to 9.9 mg. The proportion of patients given 
<10 mg/day of prednisone increased from 21% before RCI use to 47% at 3 months after RCI 
use. According to physicians’ assessments of change in patients’ health status after RCI 
therapy, overall status improved in 95% of patients, overall symptoms in 73%, lung function 
in 38%, and inflammation in 33%. The findings suggest that RCI is a viable treatment option 
for patients with advanced symptomatic sarcoidosis and provide insights on patient 
characteristics and practice patterns to help clinicians determine appropriate use 
(Chopra et al., 2019). 
Several studies of various agents (eg, infliximab, ustekinumab, golimumab; 
Baughman et al., 2006; Judson, 2014b; Gibson et al., 1996) have highlighted important issues 
that may confound trial results, including selecting patients with active disease, identifying 
IMP effects in patients receiving concomitant corticosteroids, and establishing proper study 
endpoints. Establishment of an appropriate endpoint is probably the single most challenging 
issue in the design of a clinical sarcoidosis trial (Judson, 2014). The appropriate endpoint in 
sarcoidosis is dependent upon whether one wishes to measure the degree of granulomatous 
inflammation, the physiologic impact of that inflammation, or the effect of physiologic 
impairment on the patient’s quality of life. This is a particularly important distinction in 
sarcoidosis, where active granulomatous inflammation may not significantly impair 
physiology or cause significant symptoms. Ideally, a clinically useful intervention in 
sarcoidosis should demonstrate a reduction in granulomatous inflammation that results in 
improved physiology and quality of life. Thus, multiple endpoints are likely needed to 
demonstrate clinical benefit (Baughman et al., 2012; Baughman et al, 2015).  
The WASOG Diseases Task Force suggested that clinical endpoints for pulmonary 
sarcoidosis should be based on 4 broad categories: PFT, chest imaging, quality of life, and 
steroid-sparing. A composite score that include 2 or more of these categories was proposed as 
more effective than individual scores; however, these have not been rigorously tested 
(Baughman et al, 2015).  
Clinical endpoints to measure disease activity in other systems affected by sarcoidosis such as 
skin, cardiac, ocular, and neurological endpoints are also planned for much needed attention 
by WASOG Disorders Task Force (Baughman et al, 2015).  
6.2. 
Acthar Gel Overview 
Acthar Gel is a naturally sourced complex mixture of ACTH analogs and other pituitary 
peptides. It is approved by the FDA for the treatment of symptomatic sarcoidosis 
(Mallinckrodt ARD LLC, 2019). ACTH is a member of the family of structurally related 
peptides known as melanocortin peptides. Melanocortin peptides, which in addition to ACTH 
include 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 (MCR) (Mountjoy et al, 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). MCRs 
play a key role in regulating inflammation and other cellular function (Catania, 2010). Acthar 
engages MCRs expressed on immune cells and other tissues throughout the body and is 


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thought to produce both an indirect anti-inflammatory effect and a direct cell effect 
(Catania, 2010; Wright et al., 2019; Olsen et al., 2015; Healy, 2017a; Wright et al., 2019b). 
Production of cortisol is mediated by activation of MC2Rs primarily expressed on the adrenal 
cortex. In in vitro studies in cultured cells lines expressing MCR1-MCR5, the relative 
functional potency of MCRs was measured. It was shown that 6% of Acthar’s relative 
functional potency occurred at MC2R. The remaining 94% occurred at the other MCRs 
(Wright et al., 2019). These data suggest that Acthar acts directly on cells involved in the 
pathogenesis of disease in addition to its indirect action via corticosteroid stimulation. 
The effects of Acthar on human B-lymphocyte function in vitro were evaluated using highly 
purified B-cell populations cultured in the absence of glucocorticoids and stimulated by 
recombinant interleukin-4 and cluster of differentiation 40 ligand as specific B-cell activating 
signals. Immunoglobulin G was measured in supernatants from healthy human peripheral B 
cells that had been cultured for 6 days. The percentage of cells that divided and 
immunoglobulin G production were assessed under basal conditions (unstimulated) or 
stimulated with interleukin-4/cluster of differentiation 40 ligand plus vehicle. Acthar reduced 
B cell proliferation and immunoglobulin G production independent of cortisol release 
(p<0.05, compared to vehicle-treated group) (Olsen et al., 2015; Healy, 2017aHealy_2017, 
Healy, 2017b). In further experiments to explore the direct effects of Acthar on human 
macrophages and focusing on induction of pro-inflammatory mediators following 
lipopolysaccharide stimulation, Acthar inhibited the production of the pro-inflammatory 
cytokines interleukin-6 and tumor necrosis factor (p<0.0001, compared to vehicle-treated 
group; (Healy, 2017aHealy_2017, Healy, 2017b). These data further demonstrate a direct 
effect of Acthar on immune cell modulation independent of cortisol release. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
While the exact mechanism of action of Acthar Gel is still unknown, further investigation is 
being conducted. This information is based on nonclinical data and pharmacodynamic data 
and the relationship to clinical benefit is unknown. 


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6.3. 
Rationale 
This study will provide additional data to support the efficacy and safety of Acthar Gel in 
pulmonary sarcoidosis.  
The Acthar Gel dose and dosing regimen for this study, namely 80 U 2×/week, are informed 
by patterns of clinical use in sarcoidosis, 2 recently published studies (Baughman et al., 2016; 
Baughman et al., 2017) and the package insert.  
The prescribing information for Acthar Gel recommends the use of 40 U to 80 U administered 
intramuscularly or SC every 24- to 72 hours in adults and children over 2 years of age; the 
specific dose is individualized according to the medical condition 
(Mallinckrodt ARD LLC, 2019).  
6.4. 
Risk and Benefits 
The most common adverse reactions for Acthar Gel are similar to those of corticosteroids and 
include fluid retention, alteration in glucose tolerance, elevation of blood pressure, behavioral 
and mood changes, increased appetite, and weight gain. Acthar Gel may also be associated 
with increased susceptibility to new infection and increased risk of exacerbation, 
dissemination, or reactivation of latent infections. For a complete reference of known 
potential risks please refer to the Acthar Gel product labeling (Mallinckrodt ARD LLC, 2019). 


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7. 
OBJECTIVE AND EFFICACY 
7.1. 
Objective 
The objective of this study is to evaluate the efficacy and safety of Acthar Gel in the treatment 
for pulmonary sarcoidosis. 
7.2. 
Assessments of Efficacy  
The following assessments will be performed during this study: 
• STS, a newly developed composite endpoint.  
• PFT. 
• Imaging: HRCT; CXR (including Scadding Score). 
• Corticosteroid tapering. 
• Physician Global Assessment. 
• Patient-reported outcomes: King’s Sarcoidosis Questionnaire; Fatigue Assessment 
Scale; Patient's Global Assessment.  
• Symptom Assessments: Medical Research Council Dyspnea Scale; Leicester 
Cough Questionnaire; steroid toxicity questionnaire. 
• Functional testing: 6MWT (including the Borg Scale). 
• ePOST. 
• Biomarkers (including RNA and DNA samples (screening only), if genetic ICF is 
signed). 
• WPAI. 
7.2.1. 
Sarcoidosis Treatment Score 
This is a newly developed composite score that combines the results of PFT, chest imaging, 
quality of life, and changes in corticosteroid dosing as recommended by the WASOG task 
force (Baughman et al., 2015) and based on the results of the Acthar Gel prospective study; 
(Baughman et al., 2017). Individuals may score from -6 to +6. Higher scores indicate 
improvement.  
Assessments and treatment scores categories are presented in Table 2. 


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Table 2:  
Determining the Sarcoidosis Treatment Score 
 
Parameter 
Improved 
Unchanged 
Deteriorate 
Category of 
Assessment 
 
+1 
0 
-1 
PFTa 
FVC 
≥ 5% 
> -5% to < 5% 
≤ -5% 
DLCO 
≥ 5% 
> -5% to < 5% 
≤ -5% 
Imaging 
HRCT 
Improved 
Unchanged 
Worse 
Quality of Life 
King’s Sarcoidosis 
Questionnaire 
(General Health) 
≥ 4 
> -4 to < 4 
≤ -4 
Fatigue Assessment 
Score 
≤ -4 
> -4 to < 4 
≥ 4 
 
Corticosteroid taper 
(dosage) 
≥ 50% 
reduction  
< 50% reduction 
or ≥ 5 mg 
increase for less 
than 2 weeks  
≥ 5 mg increase 
for more than 2 
weeks 
a Absolute change of % predicted. 
 
Subject tolerating Acthar Gel (or placebo) will be categorized according the following 
scoring:  
• Response is defined as scores of ≥ 3/6 points.  
• Partial Response is defined as scores of 2/6 points or stable with corticosteroid 
reduction (ie, a total score of +1 due to ≥ 50% reduction in corticosteroid dosage).  
• Non Response is defined as scores of ≤ 1/6 points without significant 
corticosteroid taper (stable or deterioration). 
 
7.2.2. 
Pulmonary Function Tests 
PFTs are routinely used in the evaluation of pulmonary sarcoidosis patients. However, there is 
no diagnostic pattern in PFTs. The most prevalent pattern of PFTs is restrictive lung disease, 
although obstruction can nevertheless also be present, either in isolation or concomitantly. 
FVC is most commonly used to measure response to therapy. Nonetheless, the volume of 
FVC does not correlate clinically with symptoms of dyspnea, and there is no definite 
consensus on how to follow changes in FVC in response to treatment. Based on 
intrapulmonary fibrosis, in the absence of better data, a decline of ≥ 5% (absolute change of 
predicted) FVC is consistent with refractoriness in sarcoidosis patients (Korsten et al., 2016; 
Baughman et al., 2015).  


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Diffuse lung capacity of carbon monoxide has also been used. However, there is a higher 
intra-subject variability than FVC. Significant reduction in DLCO may indicate refractory 
pulmonary disease in the absence of pulmonary arterial hypertension as a cause of drop in 
DLCO (Korsten et al., 2016; Baughman et al., 2015). 
PFT will follow ATS/European Respiratory Society task force for standardization of lung 
function testing (Miller et al., 2005) and the revisions provided for DLCO 
(Graham et al., 2017).  
PFT results will include FEV1, FVC, FVC % predicted (NHANES III reference values), 
FEV1/FVC ratio, PEFR or FEFmax, TLC, RV, DLCO (uncorrected for Hb), DLCO % 
predicted and DLCO/VA at screening visit, Visits 5, 8, 10, and 11 (every 12 weeks).  
At the randomization visit, spirometry results will include FEV1, FVC, FVC % predicted 
(NHANES III reference values), FEV1/FVC ratio and PEFR or FEFmax. 
Patients should be instructed to avoid smoking within at least 1 hour of testing, consuming 
alcohol within 4 hours of testing, performing vigorous exercise within 30 minutes of testing, 
wearing clothing that substantially restricts full chest and abdominal expansion, and eating a 
large meal within 2 hours of testing. Ideally, when patients return for repeat testing, the 
equipment and the operator should be the same, and the time of day should be within 2 hours 
of previous test times. The order of the tests should be kept constant for each subject on each 
subsequent PFT.  
7.2.3. 
Imaging (HRCT; CXR) 
Although granulomas are microscopic structures, sarcoidosis granulomas have a proclivity to 
coalesce into macroscopic nodular conglomerations that are capable of being detected with 
plain radiographic or HRCT radiographic techniques. HRCT reveals more sarcoidosis lung 
involvement than the CXR including, identifying more parenchymal and mediastinal/hilar 
disease as well as parenchymal details to reliably differentiate from other diffuse lung 
diseases. HRCT findings have been correlated with lung pathology and have been proposed as 
a biomarker of disease activity.  
The intriguing observations of chest radiographs in sarcoidosis published by Scadding in 1961 
(Scadding, 1961; Attachment 11) are still considered the gold standard because of the limited 
use of radiation and its association with resolution or progression of the disease although these 
stages do not necessarily progress or regress from one to another. However, interobserver 
variability and lack of association with functional clinical parameters (eg, PFT, 6MWT) are 
limiting factors (Korsten et al., 2016; Chopra et al., 2016). 
Imaging will be evaluated by the investigator/ radiologist and the central reader to determine 
if the condition is improving, stable, or deteriorating based on a 5-point Likert score: much 
worse; worse; unchanged; better; much better. 


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7.2.4.
Corticosteroid Tapering
Corticosteroids are typically the first- line when treatment of sarcoidosis is required. Concerns 
of significant corticosteroid toxicity results in efforts to taper as early as possible. There is 
little consensus regarding the optimal algorithm for tapering corticosteroids (Judson, 2014). 
Subjects will be evaluated at each visit (following randomization) and the following algorithm 
will be used to taper the corticosteroid dosage: 
Incremental doses of prednisone for the study are 40, 30, 20, 10, 7.5, 5, 2.5, and 0 mg 
(Baughman et al., 2002).
7.2.5.
Steroid Toxicity Questionnaire
This directed questionnaire (Attachment 2) provides a Likert scale for the subject to score 
several specific potential symptoms which could be attributed to steroid toxicity
(Baughman et al., 2002).
7.2.6.
King’s Sarcoidosis Questionnaire
The King’s Sarcoidosis Questionnaire (Attachment 4) is a 28 item questionnaire for subjects 
to indicate the status of their sarcoidosis and treatment (Patel et al., 2013). Higher scores 
indicate improvement. A change of 4 points is considered clinically meaningful. 
7.2.7.
Fatigue Assessment Scale (FAS)
The Fatigue Assessment Scale (Attachment 5) is a 10 item checklist for subjects to indicate 
their level of fatigue (De Vries et al., 2004). Lower scores indicate improvement (less 
fatigue). A change of 4 points is considered clinically meaningful. 
7.2.8.
Patient’s Global Assessment
The Patient’s Global Assessment (Attachment 6) is a numerical rating scale typically used for 
patient reported outcomes. Patients report on improvement/worsening of their overall disease 
compared to the condition at baseline and at every visit (Nikiphorou et al., 2016). 


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7.2.9. 
Physician Global Assessment 
The Physician Global Assessment (Attachment 7) is a physician's assessment of 
improvement/worsening of the patient's overall disease compared to the condition at baseline 
and at every visit as ranked on a numerical rating scale.  
7.2.10. 
 Medical Research Council Dyspnea Scale (MRC) 
The Medical Research Council Dyspnea scale (Attachment 8) is a 5 score for subjects to 
indicate their degree of breathlessness related to activity (Fletcher, 1952). 
7.2.11. 
 Leicester Cough Questionnaire (LCQ) 
The Leicester Cough Questionnaire (Attachment 9) is a 19 item questionnaire for subjects to 
indicate the impact of cough on various aspects of their life (Birring et al, 2003). 
7.2.12. 
 Six Minute Walk Test (6MWT) 
The 6MWT (Attachment 12) is objective evaluation of functional exercise capacity. It is a 
practical test that requires a 100-ft hallway but no exercise equipment or advanced training. It 
measures the distance walked on a flat, hard surface during the period of 6 minutes (treadmill 
are not recommended). The 6MWT evaluates the global and integrated responses of all the 
systems involved during exercise, including the pulmonary and cardiovascular systems, 
systemic circulation, peripheral circulation, blood, neuromuscular units, and muscle 
metabolism. It does not provide specific information on the function of each of the different 
organs and systems involved in exercise or the mechanism of exercise limitation, as is 
possible with maximal cardiopulmonary exercise testing. Changes in 6MWT after therapeutic 
interventions correlate with subjective improvement in dyspnea.  
The 6MWT will be performed according to ATS guidelines with an improvement of 
≥ 30 meters being considered as meaningful. Repeat testing should be performed about the 
same time of day to minimize intraday variability. The Borg Scale is used to compare 
shortness of breath and fatigue between baseline prior to the 6MWT test and upon completion 
of the 6MWT test (ATS, 2002).  
7.2.13. 
Extrapulmonary Physician Organ Severity Tool (ePOST) 
The ePOST examines 18 extrapulmonary organs and assigns a score to each one (0 = not 
affected to 6 = very severely affected). The state of sarcoidosis is evaluated at each visit, by 
the investigator. Investigators use all clinical information available to them, including 
laboratory analyses, and assessments by subspecialists to assess each organ system. Scores are 
calculated by the ePOST score divided by the number of extrapulmonary organs involved at 
any time during the study (Judson et al., 2008).  
7.2.14. 
 Biomarkers/genomics  
As stated in Section 6.1, despite many potential biomarkers being identified for monitoring 
and diagnosis, there is still a lack of adequately specific and sensitive disease markers for 
clinical usage, necessitating further research on these fronts. Accordingly, biomarkers levels 
will be collected as an exploratory assessment and compared between Screening, and every 
12 weeks (up to 48 weeks for those subjects participating in the optional Open-label 


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Extension Phase). These may include angiotensin-converting enzyme, sIL-2R and 
vitamin D 1,25. The final determination as to the selection of biomarkers will be made based 
on the evolution of the science and emerging guidance closer to the completion of the study.  
Genomic profile (optional) will be assessed based on the evolution of science at the time of 
study completion. 
7.2.15. 
Work Productivity and Activity Impairment 
The WPAI is a validated assessment of work and activity impairment associated with health 
problems (Zhang et al., 2010). This questionnaire is to be completed by subjects. When this 
assessment is required, it should be the first assessment done at any visit (with the subject 
completed efficacy questionnaires) and must be completed prior to any study drug dosing.  
Subjects will be provided a quiet, private place to complete the assessment. Subjects will be 
instructed to answer all questions to the best of their ability and without help from others 
(including study staff, relatives, or friends). Subjects may refrain from answering any 
question. 
The study staff should review the questionnaire after it is completed and encourage the 
subjects to complete any missing information. Study staff will record the refusal of subjects to 
answer any questions in the source documents. 
7.3. 
Efficacy Endpoints 
The endpoints for the efficacy objective are: 
• STS response rate at 24 weeks (Visit 8). 
• STS response rate at 48 weeks (Visit 11). 
• Physician and subject independent responses to the question “Would you choose to 
continue current treatment?” at 24 and 48 weeks. 
• Time to response as evaluated at earlier time points (Weeks 4 to 20) as determined 
by the investigator based on clinical judgment and the following parameters: 
o Patient reported outcomes. 
o Corticosteroid tapering. 
o Patient Global Assessment. 
o Physician Global Assessment  
o PFT (at applicable time points). 
o ePOST.  
o Supportive efficacy endpoints per applicable time points. 
− 6MWT. 
− Symptom relief (Leicester Cough Questionnaire, Medical Research 
Council Dyspnea Scale, steroid toxicity questionnaire). 
− CXR - change in Scadding score.  


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• Percentage change in overall DLCO. 
• Percentage of subjects with improvement in DLCO of ≥ 5%; ≥10%; and ≥ 15%. 
• Percentage change in overall forced vital capacity (FVC). 
• Percentage of subjects with improvement in FVC of ≥ 5%, ≥10%, and ≥ 15%. 
• Percentage of improved/stable/deteriorate side-by-side comparison of HRCT on a 
5-point Likert score: much worse; worse; unchanged; better; much better (central 
reader). 
• Percentage of improved/stable/deteriorated side-by-side comparison of CXRs on a 
5-point Likert score: much worse; worse; unchanged; better; much better (central 
reader). 
• Percentage change in Scadding Score (side-by-side comparison of CXRs by a 
central reader, (Scadding, 1961). 
• Percentage change in patient-reported outcomes and symptom questionnaires. 
• Percentage failed corticosteroid taper. 
• Time to failed corticosteroid taper (for subjects failing taper). 
• Change from baseline in WPAI over time. 
Biomarkers 
Biomarker levels will be compared between Screening, and every 12 weeks (up to 48 weeks 
for those subjects participating in the optional Open-label Extension Phase). Serum aliquots 
will be kept for each of these time points. Possible biomarkers include angiotensinogen, 
sIL-2R and vitamin D 1,25. The final selection of biomarkers will be made based on the 
scientific knowledge and emerging guidance closer to the completion of the study.  
The genomic profile (optional) will be assessed based on the understanding of genetic factors 
at the time of study completion. 
7.4. 
Primary Outcome Measures 
Outcome measures are identified to facilitate trial registration and patient access to basic 
results disclosed on public registries. 
The primary outcome measures are: 
• 
Number of participants in each category of assessment based on forced vital capacity, 
Weeks 24 and 48 
• 
Number of participants in each category of assessment based on the diffusing capacity 
of the lungs for carbon monoxide (DLCO), Weeks 24 and 48 
• 
Number of participants in each category of assessment based on high resolution 
computer tomography, Weeks 24 and 48  
• 
Number of participants in each category of assessment based on the King's Sarcoidosis 
Questionnaire (General Health), Weeks 24 and 48 


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• 
Number of participants in each category of assessment based on the Fatigue 
Assessment Score, Weeks 24 and 48 
• 
Number of participants receiving each dose of prednisone, Weeks 24 and 48 


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8. 
STUDY DESIGN 
8.1. 
Description 
This is a multicenter, randomized, double-blind, placebo-controlled exploratory study 
evaluating the efficacy and safety of Acthar Gel in the treatment of pulmonary sarcoidosis. 
The study will have 3 phases: Screening (up to 28 days); double blind treatment (24 weeks); 
and an optional open-label, 24 weeks extension. A follow-up visit will be conducted 4 weeks 
(± 2 days) after the last dose of IMP is administered. 
Following signature of the ICF and a screening period of up to 28 days, subjects who meet all 
eligibility criteria will be randomly assigned to receive either 1 mL (80 U) of Acthar Gel or 
1 mL of a matching placebo SC 2×/week. Subjects will be assigned to treatment in a 1:1 ratio 
with up to 50 subjects per arm for a total of approximately 100 subjects. 
Dose reduction of 50% may be implemented once during the study, if a subject meets one of 
the following prespecified safety criteria based on clinical judgment: 
• Uncontrolled hypertension (newly developed or worsening of existing 
hypertension) before/or in conjunction with addition/adjustment of 
antihypertensive therapy. 
• Uncontrolled diabetic signs/symptoms (newly developed of worsening of existing 
diabetes) before/or in conjunction with addition/adjustment of antihyperglycemic 
therapy. 
• Unacceptable toxicity defined as any AE of at least moderate intensity not 
adequately controlled by concomitant medication use or other non IMP-related 
measure 
The justification for dose reduction will be captured in the eCRF. Subjects will remain on the 
40 U or matching placebo 2×/week for the remainder of the study. Subjects who, despite dose 
reduction, continue to experience any of the above mentioned AEs, (meet a criteria as above) 
or experience another event will be withdrawn from the study due to AE (Section 12.3).  
Subjects will be followed every 4 weeks (± 5 days) for 24 weeks (Visit 2 to Visit 8). During 
each visit following Visit 2, steroid tapering evaluation will occur based on the corticosteroid 
tapering algorithm (Section 7.2.4). A justification for any deviation will be captured in the 
eCRF. 
In addition, subjects and physicians will complete patient reported outcomes, and safety will 
be evaluated based on targeted physical examination per organ involved, vital signs, imaging, 
and laboratory test results. Any additional visits, hospitalization, or additional tests or imaging 
performed beyond those dictated by the protocol, at the discretion of the investigator (or other 
disciplines for extra-pulmonary manifestations) will also be captured in the eCRF. Following 
the completion of the double blind phase, subjects will be invited to continue participation in 
an optional Open-label Extension Phase (Visit 9 to Visit 11). 
Subjects who decline participation in the Open-label Extension Phase, or those ineligible, will 
have their End-of-Treatment visit during Visit 8. 


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All subjects will have a follow-up visit 4 weeks (± 2 days) after the last dose of IMP, 
regardless of treatment group and/or participation in the optional Open-Label Extension 
Phase. 
During the optional Open-label Extension Phase, subjects will be treated with Acthar Gel 
80 U 2×/week for an additional 24 weeks. Subjects who had their dose reduced once by half 
will be treated with Acthar Gel 40 U 2×/week. There will be 3 scheduled visits during this 
phase. Visit 9, 4 weeks into the extension phase (Week 28), Visit 10 (Week 36) and Visit 11 
(Week 48). During these visits corticosteroid tapering will follow the same procedures and 
algorithm as in the double blind phase. Subjects and physicians will complete patient reported 
outcomes, and safety will be evaluated based on targeted physical examination per organ 
involved, vital signs, imaging, and laboratory test results. Any additional visits, 
hospitalization, or additional tests or imaging performed beyond those dictated by the 
protocol, at the discretion of the investigator (or other disciplines for extrapulmonary 
manifestations) will also be captured in the eCRF. 
During Visit 11 End-of-Treatment procedures will be completed. Responder rate analysis 
(efficacy endpoints) will be determined by the investigator and an independent adjudication. 
Adjudication will serve to address inter-rater variability. In case of discrepancies, the 
adjudication determination will be utilized for purposes of efficacy endpoint analyses. 
Likewise, central HRCT readings and CXR will be used for the purpose of the imaging 
efficacy analyses. 
8.2. 
Approximate Duration of Subject Participation 
Subjects will participate in the study for a total of approximately 14 months, including a 
screening period of up to 28 days, a double blind treatment period of 24 weeks, and an 
optional open-label extension period of an additional 24 weeks, and a follow up visit 4 weeks 
(± 2 days) after final dose of IMP. 
 
8.3. 
Approximate 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 site(s) to identify and enroll eligible subjects. The entire study is expected 
to require approximately 4 years to complete. 
8.4. 
Approximate Number of Subjects 
Approximately 100 subjects will be globally enrolled at approximately 75 sites.  


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9. 
SELECTION OF SUBJECTS 
9.1. 
Inclusion Criteria 
The subjects must meet all of the following criteria for inclusion in the study: 
1. Subjects must 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. Subjects must be ≥ 18 and ≤ 90 years of age at Screening (Visit 1) and can be male or 
female. 
3. Female subjects must be of nonchildbearing potential (history of hysterectomy, 
bilateral oophorectomy, or bilateral tubal ligation; or postmenopausal with no history 
of menstrual flow in the 12 months prior to Screening (Visit 1); or if of childbearing 
potential must be nonpregnant, nonlactating and agree to use effective contraception 
when with a male partner throughout study participation (through the follow-up visit). 
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), and abstinence.  
4. Subjects must be able to communicate effectively with study personnel. 
5. Subjects must be able and willing to follow all protocol requirements and study 
restrictions including able and willing to inject SC Acthar Gel on their own or by 
caregiver. 
6. Subjects must be able and willing to return for all study visits. 
7. Subject with biopsy confirmed sarcoidosis meeting ATS criteria with onset of 
sarcoidosis ≥ 1 year prior to Screening (Hunninghake et al., 1999). 
8. Symptomatic pulmonary disease defined as any one of the following criteria for PFT; 
imaging; steroid dose; or symptoms:  
• Decrease ≥ 5% absolute change of % predicted in the best available FVC 
within the past 2 years.  
• Decrease ≥ 5% absolute change of % predicted in the best available DLCO 
within the past 2 years.  
• Radiographic progression in chest imaging on side by side comparison within 
the past 2 years. 
• Progression of pulmonary sarcoidosis necessitating increase in antisarcoidosis 
therapy in the past 2 years. 
• Dyspnea with Medical Research Council Scale of ≥ 1 at Screening (Visit 1). 
9. Subject receiving ≥ 5 mg and ≤ 40 mg daily prednisone (or equivalent) for pulmonary 
sarcoidosis. 
10. Stable prednisone dose ≥ 4 weeks prior to Screening (Visit 1). 


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11. Subjects treated with any disease modifying antisarcoidosis drugs (eg, methotrexate) 
must be on stable dose for ≥ 3 months prior to Screening (Visit 1). 
12. Forced vital capacity (FVC) ≥ 45% predicted. If FVC at Screening is more than 
95% predicted, a documented decrease ≥ 5% absolute change of % predicted in the 
best available FVC is required after diagnosis of Sarcoidosis. 
13. Diffusing capacity of the lung for carbon monoxide (DLCO) ≥ 30%. 
9.2. 
Exclusion Criteria 
Subjects are ineligible for the study if they meet any of the following criteria: 
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. Subject is unwilling to receive, or is intolerant of, SC injections. 
3. Subject has a history of sensitivity to ACTH preparations or sensitivity to porcine 
protein products. 
4. Any difference >10% in FVC on spirometry between the determination at Screening 
(Visit 1) and the determination at Visit 2. 
5. Pulmonary arterial hypertension requiring or receiving treatment.  
6. Extra pulmonary involvement that per the Investigator’s evaluation requires treatment 
that would impede corticosteroid tapering for pulmonary involvement.  
7. Treatment with antitumor necrosis factor-α antibody (eg, infliximab, adalimumab) in 
prior 3 months. 
8. Subject has any known contraindication(s) to Acthar Gel 
(Mallinckrodt ARD LLC, 2019) including, but not limited to:  
• Any known history of: 
o Scleroderma  
o Osteoporosis (evidence of vertebral or long bone fracture, or a lumbar 
T-score of more than -2.5 SD below the mean of the reference population). 
Subjects previously diagnosed as having osteoporosis and successfully 
treated will not be excluded solely on the basis of a historical diagnosis of 
osteoporosis as long as the lumbar T-score obtained per routine follow up 
within the 12 months prior to Screening (Visit 1) is ≥ -2.5 SD. 
o Ocular herpes simplex.  
• Any primary adrenocortical insufficiency, or adrenal cortical hyperfunction. 
• Any current congestive heart failure (defined as New York Heart Association 
Functional Class III to IV). 


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• Peptic ulcer requiring treatment or history of upper gastrointestinal bleeding 
within 24 weeks prior to Screening (Visit 1). 
• Recent major surgery (ie, major fluid or blood shift) within 24 weeks prior to 
Screening (Visit 1). 
9. Subject has uncontrolled diabetes, hypertension, or other contra-indication to increased 
dosage of glucocorticoids. 
10. Subject has chronic active hepatitis including active or chronic hepatitis B, or acute or 
chronic hepatitis C.  
11. Subject has a history of TB infection, any signs/symptoms of TB, or any close contact 
with an individual with an active TB infection.  
12. Subject has a clinically significant infection requiring administration of intravenous 
antibiotics or hospitalization in the 4 weeks prior to Screening (Visit 1) or between 
Screening and the first dose of IMP. 
13. 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. 
14. 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 Screening 
(Visit 1); 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. 
15. Subject has a diagnosis of, is undergoing therapy for, or has received therapy for a 
hematologic malignancy in the 5 years prior to Screening (Visit 1). 
16. Subject has current or recent (within 24 weeks prior to Screening (Visit 1) drug or 
alcohol abuse as defined in Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition, Diagnostic Criteria for Drug and Alcohol Abuse (American Psychiatric 
Association, 2013). 
17. Subject has any of the following laboratory abnormalities at Screening (Visit 1): 
• Hemoglobin ≤ 8.0 g/dL. 
• Platelet count ≤ 50,000 cells/μL. 
• Absolute neutrophil count ≤ 1,000 cells/μL. 
• Aspartate aminotransferase, alanine aminotransferase, or total bilirubin  2 
times upper limit of normal. 
• Positive hepatitis B surface antigen or hepatitis B core antibody, or positive 
HCV antibody. Note: If HCV antibody is positive at Screening, HCV 
polymerase chain reaction will be automatically analyzed. Subjects with a 
positive HCV must have HCV polymerase chain reaction < 25 IU/mL at the 
screening visit to be eligible. 


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• Positive or indeterminate IGRA for TB. 
18. Subject has any other clinically significant disease, disorder or laboratory abnormality 
(including those listed on the Prescribing Information, Section 5: Warnings and 
Precautions [Mallinckrodt ARD LLC, 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. 
19. Subject is: 1) currently participating in another interventional clinical study or 2) has 
participated in another interventional clinical study within 30 days or five half-lives, 
whichever is longer, prior to Screening (Visit 1) or 3) plans to participate in another 
interventional clinical study prior to 90 days following the completion of current 
study. 
20. Subject has any history of use of ACTH preparations for treatment of Sarcoidosis. 
 
9.3. 
Screen Failure 
Subjects will be allowed to repeat any single screening assessment/procedure once, if 
necessary, if it is within the screening window. The subject will not be considered a screen 
failure unless the repeat assessment/procedure results do not meet eligibility criteria. The 
period from the beginning of screening-related procedures at Screening (Visit 1) to the 
Randomization (Visit 2) must not exceed 28 days, inclusive of any repeat screening 
procedures.  
Subjects who do not meet all of the eligibility criteria at screening or randomization visits 
(Visits 1 and 2) will be deemed a screen failure and the reason for the screen failure will be 
documented. A subject who is a screen failure at the screening or randomization visits may be 
rescreened. The subject must repeat all screening procedures (except HRCT as long as it is 
performed within 28 days of Day -1). The period from the start of rescreening-related 
procedures to the first dose of IMP must not exceed 28 days. Subjects may be rescreened only 
once. 


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10. 
PRIOR AND CONCOMITANT MEDICATION 
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 the Follow-up Visit) medications and nondrug therapies (eg, blood 
transfusions, oxygen supplementation) received will be recorded.  
In addition, all prior treatments for sarcoidosis administered since diagnosis will be recorded 
with start and stop date, dose, unit, frequency and route of administration to the extent of data 
availability. 
10.1. 
Permitted Concomitant Medications 
Subjects enrolled into the study must have been on stable prednisone dose for at least 4 weeks 
prior to Screening (Visit 1). Subjects who are treated with any disease modifying 
antisarcoidosis drugs (eg, methotrexate) must have been on a stable dose for at least 3 months 
prior to Screening (Visit 1). Corticosteroid tapering will be initiated as of Week 4 (Visit 3) 
according to the tapering algorithm described in Section 7.2.4. The dose of all other 
antisarcoidosis medications should remain stable for the duration of the study. The dose may 
be reduced or discontinued only for toxicity but must not be increased.  
10.2. 
Prohibited Concomitant Medications/Treatments 
The following treatments will not be permitted during the study: 
• No new antisarcoidosis medication is permitted. 
• Treatment with antitumor necrosis factor-α (eg, infliximab, adalimumab) in the 
3 months prior to Screening (Visit 1) and throughout the study.  
• Administration of live or live-attenuated vaccines. 
• Long acting corticotropins. 
• 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 eCRF. The designated study MM must be informed 
immediately so the sponsor may determine whether to continue the subject in the study. 


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11. 
PROCEDURES 
The schedule of study procedures is summarized in the Schedule of Events (Table 1).  
If the subject is unable to come to the study site for any visit after the Baseline visit, all 
procedures that can be completed remotely (eg, by telephone) will be conducted as scheduled. 
Collect as much information as possible, including but not limited to, AE information, new 
concomitant medications and changes in existing therapy, corticosteroid use, compliance with 
investigational therapy. Complete applicable physician assessments, PFT tests, 
subject-reported outcomes and assessments, 6MWT, ECG, imaging and laboratory tests at the 
next planned study visit as unscheduled procedures, if not already scheduled for that particular 
study visit. 
Changes in study visit schedule, missed visits, and procedures will be captured in the eCRF. 
11.1. 
Study Days -28 to -1 (Screening Visit 1) 
Screening assessments must be performed within 28 days prior to Visit 2.  
The following procedures will be performed at the screening visit: 
• Informed consent. Neutral language should be used in describing the study to 
neutralized placebo effect. 
• Injection and diary training. Subjects (or caregivers) will be trained on SC 
injections and diary completion using the training tools provided separately. The 
injection training may be foregone if either the subject or caregiver is a medically 
trained professional. 
• Inclusion/exclusion criteria. 
• Medical, surgical, and medication history. Medical history will include smoking 
history (classified into 1 the following categories: current smoker; ever smoked 
[more than 1 cigarette/day for more than 1 year]; never smoked), length of 
sarcoidosis diagnosis, organ involvement, and prior and current medication. 
Occupational history should also be collected. 
• Demographics.  
• Concomitant medications. 
• Height. 
• 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, and respiratory rate.  
• Weight measured. Every effort should be made for weight to be measured by the 
same calibrated scale at every visit. 
• Physical examination (see Section 14.3). The full physical examination will 
include a targeted examination of the organ(s) involved. All efforts must be 
undertaken for the same physician to perform the physical examination per subject, 
per organ involved, at each visit.  


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• Physician Global Assessment (Attachment 7) 
• ePOST. 
• 12-Lead ECG (see Section 14.6 ). 
• Patient-reported outcomes and assessments. Patient-reported outcomes include: 
Steroid toxicity questionnaire; King’s Sarcoidosis Questionnaire (Attachment 4); 
Fatigue Assessment Scale (Attachment 5); Patient's Global Assessment 
(Attachment 6); Medical Research Council Dyspnea Scale (Attachment 8); 
Leicester Cough Questionnaire (Attachment 9), WPAI (Attachment 10) Prior to 
filling out any patient-reported outcomes at Visit 1, training will be provided as to 
the nature, purpose, and best way of filling these out. For example, reading the last 
question of the Fatigue Assessment Scale carefully.  
• 6MWT: The 6MWT would be performed according to the ATS protocol 
(Attachment 12). Reasons for not performing the 6MWT will be captured in the 
eCRF. 
• Clinical laboratory tests. Samples will be collected from subjects who have been 
fasted for at least 12 hours (drinking water is allowed). The following tests will be 
conducted: 
o Complete blood count. 
o Clinical chemistry (including liver function tests). 
o HbA1C. 
o Lipid profile. 
o 25-Hydroxy vitamin D and 1, 25-dihydroxy vitamin D, and parathyroid 
hormone.  
o C-reactive protein.  
o Thyroid stimulating hormone, thyroxine T3 and T4. 
o Hepatitis serology- Hepatitis B surface antigen, Hepatitis B core antibody, 
hepatitis C virus antibody, hepatitis C polymerase chain reaction for subjects 
positive for hepatitis C antibody only. 
o Biomarkers (including RNA and DNA, if genetic ICF signed). 
o Serum human chorionic gonadotropin hormone (females of child bearing 
potential only). 
o Urine analysis (local laboratory).  
• Tuberculosis testing (tested by IGRA). 
• PFT. 
• CXR and HRCT should be performed within 28 days of Day -1. The CXR reading 
will also include Scadding scoring (Attachment 11). 
• AEs (collected from the time of signature of the ICF). 


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• Contact IXRS to register subject. 
• Schedule next visit and remind subjects to arrive in fasting condition for Visit 2 
(drinking water is permitted).  
11.2. 
Visit 2 Procedures 
The investigator or designee will complete the following procedures at Visit 2:  
• Inclusion/exclusion criteria review. 
• Spirometry (ascertain any difference in FVC < 10% compared with FVC 
performed at Visit 1 before continuing). 
• Vital sign determinations 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, and respiratory rate (see Section 14.4). 
• Weight measured. Every effort should be made for weight to be measured by the 
same calibrated scale at every visit. 
• Physical examination (see Section 14.3). The full physical examination will 
include a targeted examination of the organ involved. All efforts must be 
undertaken for the same physician to perform the physical examination (per organ 
involved) at each visit. 
• ePOST: All efforts must be undertaken for the same physician to perform the 
ePOST (Attachment 3) side-by-side with prior evaluations. 
• Physician Global Assessment (Attachment 7). 
• Patient reported outcomes and assessments. Patient-reported outcomes include: 
Steroid toxicity questionnaire; King’s Sarcoidosis Questionnaire (Attachment 4); 
Fatigue Assessment Scale (Attachment 5); Patient's Global Assessment 
(Attachment 6); Medical Research Council Dyspnea Scale (Attachment 8); 
Leicester Cough Questionnaire (Attachment 9), WPAI (Attachment 10).  
• Clinical laboratory tests:  
o Complete blood count. 
o Clinical chemistry including liver function tests (samples will be collected 
from subjects who have been fasted for at least 12 hours. Drinking water is 
allowed). 
o HbA1C.  
o Human chorionic hormone (urine pregnancy testing, females of child bearing 
potential only [performed at a local laboratory]). 
• Injection and diary training (if additional training is required). 
• Contact IXRS to randomize subject and dispense study drug kits. 
• Dosing will begin after Visit 2 procedures are completed and subject is 
randomized. Subjects (and/or caregivers) will be trained on SC injections and diary 


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completion using the training tools provided separately. Additional training may be 
provided during Visit 2 before randomization occurs. The injection training may 
be foregone if either the subject or caregiver is a medically trained professional. 
The subject or subject’s caregiver will administer the first dose of IMP in the clinic 
under the supervision of study staff. The subject will remain in the clinic for at 
least 1 hour postinjection to monitor for allergic or anaphylactic reactions. Instruct 
the subject as to appropriate scheduling of weekly injections and the importance of 
compliance. 
• AEs and concomitant medications. 
• Remind the subject to return in fasting condition (drinking water is allowed) for 
the next visit and to bring all used and unused vials in a cooler. Subsequent visits 
should not be scheduled for the day of injection so as not to influence patient 
reported outcomes.  
11.3. 
Visits 3, 4, 6, and 7, Procedures 
The investigator or designee will complete the following procedures at Visit 3, 4, 6, and 7: 
• Patient reported outcomes. Patient-reported outcomes include: Steroid toxicity 
questionnaire; King’s Sarcoidosis Questionnaire (Attachment 4); Fatigue 
Assessment Scale (Attachment 5); Patient's Global Assessment (Attachment 6); 
Medical Research Council Dyspnea Scale (Attachment 8); Leicester Cough 
Questionnaire (Attachment 9), WPAI (Attachment 10). 
• Vital sign determinations. 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, and respiratory rate (see Section 14.4).  
• Weight determination. Every effort should be made for weight to be measured by 
the same calibrated scale at every visit. 
• Physical examination (see Section 14.3). Full physical examination will include 
targeted examination per organ involved. All efforts must be undertaken for the 
same physician to perform the physical examination per subject, per organ 
involved at each visit.  
• ePOST: All efforts must be undertaken for the same physician to perform the 
ePOST (Attachment 3) side-by-side with prior evaluations. 
• Physician Global Assessment (Attachment 7). 
• Clinical laboratory tests:  
o Complete blood count. 
o Clinical chemistry, including liver function tests. Samples will be collected 
from subjects who have been fasted for at least 12 hours. 
o HbA1C. 
o Human chorionic hormone (urine pregnancy testing, females of child bearing 
potential only – local laboratory). 


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• Subject diary review. 
• Study drug accountability. 
• Corticosteroid tapering. (At Visit 3, if the subject improved or was stable at both 
Visit 2 and Visit 3, tapering can be applied). 
• AEs and concomitant medications. 
• Contact IXRS and dispense IMP kits and encourage compliance.  
• Remind the subjects to arrive in fasting condition (drinking water is permitted) for 
Visits 4, 5, 6, and 7 and to bring all IMP kits including used and unused vials to 
each visit in a cooler.  
11.4. 
Visit 5 Procedures 
In addition to all procedures described in Section 11.3 the following will also be performed at 
Visit 5 by the investigator or designee:  
• C-reactive protein. 
• 25-Hydroxy vitamin D, 1, 25-dihydroxy vitamin D, parathyroid hormone (Visit 5 
only).  
• Urinary analysis (local laboratory). 
• Subject diary review. 
• Study drug accountability. 
• Biomarkers sample collection (including RNA, if genetic ICF signed). 
• PFT. 
11.5. 
Visit 8 Procedures 
The investigator or designee will complete the following procedures at Visit 8: 
• Patient reported outcomes. Patient-reported outcomes include: Steroid toxicity 
questionnaire; King’s Sarcoidosis Questionnaire (Attachment 4); Fatigue 
Assessment Scale (Attachment 5); Patient's Global Assessment (Attachment 6); 
Medical Research Council Dyspnea Scale (Attachment 8); Leicester Cough 
Questionnaire (Attachment 9), WPAI (Attachment 10).  
• Vital sign determinations 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, and respiratory rate (see Section 14.4). 
• Weight measured. Every effort should be made for weight to be measured by the 
same calibrated scale at every visit. 
• Physical examination (see Section 14.3). The full physical examination will 
include a targeted examination of the organ involved. All efforts must be 
undertaken for the same physician to perform the physical examination, per 
subject, per organ involved, at each visit. 


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• Physician Global Assessment (Attachment 7). 
• ePOST: All efforts must be undertaken for the same physician to perform the 
ePOST (Attachment 3) side-by-side with prior evaluations. 
• 12-Lead ECG (see Section 14.6 ). 
• PFT (Section 7.2.2). 
• CXR and HRCT. Both CXR and HRCT should be evaluated side by side by 
investigator/radiologist for determining if the condition is improving, stable, or 
deteriorating based on a 5-point Likert score (Section 7.2.3). 
• 6MWT: The 6MWT (Section 7.2.12) would be performed according to the ATS 
protocol (Attachment 12). Reasons for not performing the 6MWT will be captured 
in eCRF. 
• Clinical laboratory tests:  
o Complete blood count. 
o Clinical chemistry (including liver function tests, samples will be collected 
from subjects who have been fasted for at least 12 hours, drinking water is 
permitted). 
o HbA1C. 
o Lipid profile. 
o C-reactive protein. 
o 25-Hydroxy vitamin D and 1, 25-dihydroxy vitamin D, and parathyroid 
hormone. 
o Biomarkers (including RNA, if genetic ICF signed). 
o Human chorionic hormone (urine pregnancy testing, females of child bearing 
potential only- local laboratory). 
o Urine analysis (local laboratory). 
• Subject diary review. 
• Study drug accountability. 
• AEs and concomitant medications. 
• Both the investigator and the subjects will independently be asked if they would 
choose to continue treatment. The investigator must respond before seeing the 
subject’s response. Subjects may continue to the optional Open-label Extension 
Phase irrespective of their response (eg, placebo treated) at the discretion of the 
principal investigator.  
• Subjects declining participation or ineligible (at the discretion of the principal 
investigator) for the Open-label Extension Phase will have end-of-treatment 
procedures completed (eg, return or study drug and equipment). 
• Contact IXRS. 


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• For subjects entering the Open-Label Extension Period: 
− Remind the subjects to arrive in fasting condition for Visit 9 (drinking water is 
permitted) and to bring all IMP kits including used and unused vials to each 
visit in a cooler.  
− Dispense IMP kits and equipment. 
− Administer Acthar Gel under supervision of study staff and observation for at 
least 1 hour thereafter. 
− Instruct the subject to inject Acthar Gel 80 U (1 mL) 2×/week unless the 
subject had a single reduction of dose, in which case only 40 U (0.5 mL) 
2×/week will be injected for the remainder of the study. 
− Corticosteroid tapering. 
11.6. 
Visit 9 Procedures, Open-Label Extension Period  
The investigator or designee will complete the following procedures at Visit 9: 
• Patient reported outcomes. Patient-reported outcomes include: Steroid toxicity 
questionnaire; King’s Sarcoidosis Questionnaire (Attachment 4); Fatigue 
Assessment Scale (Attachment 5); Patient's Global Assessment (Attachment 6); 
Medical Research Council Dyspnea Scale (Attachment 8); Leicester Cough 
Questionnaire (Attachment 9), WPAI (Attachment 10).  
• Vital sign determinations 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, and respiratory rate (see Section 14.4).  
• Weight determination. Every effort should be made for weight to be measured by 
the same calibrated scale at every visit. 
• Physical examination (see Section 14.3). Full physical examination will include 
targeted examination per organ involved. All efforts must be undertaken for the 
same physician to perform the physical examination per subject, per organ 
involved at each visit.  
• Physician Global Assessment (Attachment 7). 
• ePOST: All efforts must be undertaken for the same physician to perform the 
ePOST (Attachment 3) side-by-side with prior evaluations. 
• Clinical laboratory tests:  
o Complete blood count. 
o Clinical chemistry, including liver function tests. Samples will be collected 
from subjects who have been fasted for at least 12 hours. 
o HbA1C. 
o Human chorionic hormone (urine pregnancy testing, females of child bearing 
potential only- Local laboratory). 


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• Subject diary review. 
• Study drug accountability. 
• Corticosteroid tapering. 
• AEs and concomitant medications. 
• Contact IXRS, dispense IMP kits, and encourage compliance.  
• Remind the subjects to arrive in fasting condition for Visit 10 (drinking water is 
permitted) and to bring all IMP kits including used and unused vials to each visit in 
a cooler.  
11.7. 
Visit 10 Procedures, Open-Label Extension Period  
The investigator or designee will complete the following procedures at Visit 10: 
• Patient reported outcomes and assessments. Patient-reported outcomes include: 
Steroid toxicity questionnaire; King’s Sarcoidosis Questionnaire (Attachment 4); 
Fatigue Assessment Scale (Attachment 5); Patient's Global Assessment 
(Attachment 6); Medical Research Council Dyspnea Scale (Attachment 8); 
Leicester Cough Questionnaire (Attachment 9), WPAI (Attachment 10).  
• Vital sign determinations (see Section 14.4). 
• Weight measured. Every effort should be made for weight to be measured by the 
same calibrated scale at every visit. 
• Physical examination (see Section 14.3). The physical examination will include a 
targeted examination of the organ involved. All efforts must be undertaken for the 
same physician to perform the physical examination (per organ involved) at each 
visit.  
• Physician Global Assessment (Attachment 7). 
• ePost: All efforts must be undertaken for the same physician to perform the ePOST 
(Attachment 3) side-by-side with prior evaluations. 
• Clinical laboratory tests:  
o Complete blood count. 
o Clinical chemistry (including liver function tests, samples will be collected 
from subjects who have been fasted for at least 12 hours, drinking water is 
permitted). 
o HbA1C. 
o 25-Hydroxy vitamin D and 1, 25-dihydroxy vitamin D, and parathyroid 
hormone. 
o C-reactive protein. 
o Biomarkers (including RNA, if genetic ICF signed). 


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o Human chorionic hormone (urine pregnancy testing, females of child bearing 
potential only- Local laboratory). 
o Urine analysis (local laboratory). 
• Subject diary review. 
• Study drug accountability. 
• PFT (Section 7.2.2). 
• Corticosteroid tapering. 
• AEs and concomitant medications.  
• Contact IXRS, dispense IMP kits, and encourage compliance.  
• Remind the subjects to arrive in fasting condition (drinking water is permitted) for 
Visit 11 and to bring all IMP kits including used and unused vials to each visit in a 
cooler.  
11.8. 
Visit 11 Procedures, Open-Label Extension Period 
The investigator or designee will complete the following procedures at Visit 11: 
• Patient reported outcomes and assessments. Patient-reported outcomes include: 
Steroid toxicity questionnaire; King’s Sarcoidosis Questionnaire (Attachment 4); 
Fatigue Assessment Scale (Attachment 5); Patient's Global Assessment 
(Attachment 6); Medical Research Council Dyspnea Scale (Attachment 8); 
Leicester Cough Questionnaire (Attachment 9), WPAI (Attachment 10).  
• Vital sign determinations (see Section 14.4). 
• Weight measured. Every effort should be made for weight to be measured by the 
same calibrated scale at every visit. 
• Physical examination (see Section 14.3). The physical examination will include a 
targeted examination of the organ involved. All efforts must be undertaken for the 
same physician to perform the physical examination (per organ involved) at each 
visit.  
• Physician Global Assessment (Attachment 7). 
• ePOST: All efforts must be undertaken for the same physician to perform the 
ePOST (Attachment 3) side-by-side with prior evaluations. 
• 12-Lead ECG (see Section 14.6). 
• PFT (Section 7.2.2). 
• CXR and HRCT. Both CXR and HRCT should be evaluated side by side by 
investigator/radiologist for determining if the condition is improving, stable, or 
deteriorating based on a 5-point Likert score (Section 7.2.3). 
• 6MWT. The 6MWT (Section 7.2.12) would be performed according to the ATS 
protocol (Attachment 12). Reasons for not performing the 6MWT will be captured 
in eCRF. 


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• Clinical laboratory tests:  
o Complete blood count. 
o Clinical chemistry (including liver function tests, samples will be collected 
from subjects who have been fasted for at least 12 hours). 
o HbA1C. 
o Lipid profile. 
o C-reactive protein. 
o 25-Hydroxy vitamin D and 1, 25-dihydroxy vitamin D, and parathyroid 
hormone. 
o Biomarkers (including RNA, if genetic ICF signed). 
o Human chorionic hormone (urine pregnancy testing, females of child bearing 
potential only, local laboratory). 
o Urine analysis (local laboratory). 
• Subject diary review. 
• Study drug accountability. 
• AEs and concomitant medications.  
• Both the investigator and the subjects will be independently asked if they would 
choose to continue treatment.  
Used and unused medication and study supplies will be collected from the subjects and all 
other end-of-treatment procedures will be performed.  
11.9. 
Visit 12 Procedures, Follow-up Visit  
The following procedures will be completed at the follow-up visit 4 weeks (± 2) days after the 
final dose of IMP has been administered, regardless of treatment group, and/or participation in 
the optional open label extension: 
• Physical examination (see Section 14.3). The physical examination will include a 
targeted examination of the organ involved. All efforts must be undertaken for the 
same physician to perform the physical examination (per organ involved) at each 
visit.  
• Vital sign determinations (see Section 14.4). 
• Weight measured. Every effort should be made for weight to be measured by the 
same calibrated scale at every visit. 
• Clinical laboratory tests:  
o Complete blood count. 
o Clinical chemistry (including liver function tests, samples will be collected 
from subjects who have been fasted for at least 12 hours). 


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o Human chorionic hormone (urine pregnancy testing, females of child bearing 
potential only, local laboratory). 
o Urine analysis (local laboratory). 
• AEs and concomitant medications. 
11.10. 
Early Termination Procedures 
Subjects who discontinue participation for any reason prior to Visit 8 or Visit 11 will have the 
procedures listed for Visit 8 completed as soon as possible. The reason for discontinuation 
should be documented in eCRF. Unused medication and study supplies will be collected from 
the subjects. Subjects should also return to complete the follow-up procedures during Visit 12.  


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12. 
INVESTIGATIONAL MEDICINAL PRODUCT 
Acthar Gel is a naturally sourced complex mixture of ACTH analogs and other pituitary 
peptides in 16% gelatin for intramuscular or SC injection. Acthar Gel 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 Gel is obtained from processing porcine pituitary using an FDA 
approved process. Sarcoidosis is an approved indication for Acthar Gel 
(Mallinckrodt ARD LLC, 2019). 
Placebo is a sterile preparation of 16% gelatin for intramuscular or SC injection. Placebo 
contains 0.5% phenol, not more than 0.1% cysteine, sodium hydroxide and/or acetic acid to 
adjust pH, and water for injection. The placebo formulation is identical to Acthar Gel except 
that it contains no active medication. 
12.1. 
Methods of Assigning Subjects to Treatment Groups 
12.1.1. 
Randomization  
Subjects will be randomized according to computer-generated allocation scheme to receive 
either Acthar Gel 1 mL (80 U) or placebo 1 mL administered 2×/week. Both investigators and 
the subjects will be blinded to the treatment assignment. A block randomization will be 
performed. The biostatistician will decide on the details at the time of the creation of the 
randomization scheme. 
12.1.2. 
Interactive Telephone/Web Response System 
The investigator or designee will contact IXRS to register subjects at Screening (Visit 1). The 
subject’s identification number (ID) 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. 
Subject identification numbers will consist of 7 digits: the first 4 digits reflect the site number 
assigned to the Investigator and the last 3 digits are the subject number. 
A subject ID number will not be assigned to more than 1 subject. If a subject is not eligible to 
receive treatment, or should a subject discontinue from the study, the subject ID number 
cannot be reassigned to another subject. 
In the event that a subject is rescreened within the screening window, they do not need a new 
subject ID number. At the Randomization Visit, qualified subjects who meet all of the 
eligibility criteria will be randomized 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 randomization. 
The investigator or designee must contact IXRS to record each subject visit, to receive the 
IMP assignments, and to report any subject status changes. 
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. 


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12.2. 
Identification of Investigational medicinal product  
When knowledge of the IMP assignment is required for the medical management of an 
individual subject, the investigator may obtain the treatment assignment of the subject 
experiencing the AE or SAE. The treatment blind for that subject may be broken by accessing 
the IXRS using instructions provided in the Study Operations Manual. The investigator must 
notify the sponsor’s MM or physician designee before unblinding, if at all possible, or 
immediately after unblinding the treatment assignment. The investigator and sponsor should 
make every effort to document and limit the subjects who are unblinded to the treatment 
assignment. The investigator must also indicate in source documents that the blind was broken 
and provide the date and reason for breaking the blind.  
12.3. 
Dosing Procedures 
Both Acthar Gel and placebo are supplied as 5 mL multidose vials. Acthar Gel vials contain 
80 U of ACTH per mL. Vials will be labeled according to all applicable national and local 
regulations.  
The vials should be warmed to room temperature before using. The vials should not be over 
pressurized; assure that no excess air (beyond the volume of product to be withdrawn) is 
inserted into the vial prior to withdrawing the product. After use the vial should be returned to 
refrigeration.  
Subjects or their caregivers will administer SC injections of Acthar Gel or placebo after 
randomly assigned to treatment at Visit 2. The subject or subject’s caregiver will administer 
the first dose of study drug and the first dose of Acthar Gel in the Open-Label at Week 24 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 or anaphylactic reactions. All other doses will be 
administered by the subject or the subject’s caregiver at home, but no dose should be 
administered on study visit days. 
IMP cannot be taken on 2 consecutive days and cannot be taken more than 3 days apart. 
Therefore the following dosing schedule should be recommended to subjects at Visit 2, dose 
administration on either Monday and Thursday, Tuesday and Friday, or Wednesday and 
Saturday, and would be determined by the day of the week Visit 2 occurred.  
In the double-blind treatment period Acthar Gel, 1 mL (80 U) or matching placebo (1 mL) 
will be administered twice weekly SC for up to 24 weeks. In the optional open-label 
extension, Acthar Gel 1 mL (80 U) will be administered SC twice weekly for up to 24 weeks. 
If a dose reduction of IMP is deemed necessary, a reduction of 50% (40 U) may be 
implemented once during the study based on safety criteria previously defined (see 
Section 8.1). The justification for dose reduction will be captured in the eCRF.  
Subjects who, despite dose reduction, continue to experience any of the AE defined in 
Section 8.1, will be withdrawn from the study due to AE.  
Subject who required dose reduction (50%) will inject 40 U (0.5mL) throughout the study, 
including during the optional Open-label Extension Phase, if applicable.  


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12.3.1. 
Treatment Discontinuation 
Should any of the following occur, treatment with IMP may be reduced once by 50% 
(Section 8) or should be discontinued:  
• Development of accelerated hypertension (defined as systolic blood pressure 
≥ 180 mm Hg and/or diastolic blood pressure ≥ 100 mm Hg) that cannot be 
managed by the adjustment of concomitant medications such as antihypertensive 
medications. 
• Development of congestive heart failure (Class III or IV) that cannot be managed 
by the adjustment of concomitant medications such as diuretics and 
antihypertensive medications. 
• Development of uncontrolled diabetic signs/symptoms that cannot be managed by 
the adjustment of concomitant medications such as insulin and oral hypoglycemic 
agents.  
• Development of any other AE of at least moderate intensity and possibly, probably 
or definitely related to IMP that cannot be managed by the adjustment of 
concomitant medications. 
If the subject is withdrawn due to an AE, all efforts should be made to complete end-of-
treatment procedures (Visit 8, Section 11.5) as soon as deemed possible and follow-up 
procedures (Visit 12, Section 11.9). If applicable, the suitability of subject continuing into the 
optional Open-label Extension Phase will be determined by the investigator.  
12.4. 
Storage of Clinical Supplies 
Acthar Gel and placebo will be maintained in a temperature controlled, secure locked area 
with restricted access at the study site.  
Both Acthar Gel and Placebo will be supplied in kits containing the appropriate amount of 
vials. Both Acthar Gel and placebo will be stored under refrigeration between 2°to 8°C 
(36°to 46°F). Please refer to the Pharmacy Manual for complete information regarding storage 
and accountability of IMP.  
12.5. 
Drug Accountability 
In accordance with US FDA and ICH requirements, the investigator will, at all times, be able 
to account for all IMP furnished to the study site. A drug accountability record will be 
maintained for this purpose. The investigator must maintain accurate records indicating dates 
and quantity of IMP received, to whom it was dispensed (subject-by-subject accounting) and 
accounts of any IMP accidentally or deliberately destroyed. All unused IMP not involved in 
immediate subject dosing will be maintained under locked, temperature-controlled storage at 
the study site.  
12.6. 
Compliance Monitoring 
Prior to beginning the administration of IMP, subjects and/or their caregiver will be trained on 
dosing and SC injection, and must exhibit proper technique of SC administration during initial 
IMP administration at Visit 2. Subjects and/or their caregiver will be trained on the 


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completion of the study diary and will complete study diary entries to record all study drug 
administration and will bring it, along with all study drug kits including used vials to each 
visit. Used and unused vials will be inspected. Number of expected, administered doses and 
reason for discrepancies will be documented. Each time study drug is dispensed compliance 
will be encouraged. Subject diary training is an ongoing process as the diary will be reviewed 
with the subject at each visit to monitor compliance with study drug administration. 


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13. 
EFFICACY ASSESSMENTS 
Efficacy will be evaluated using a combination of measures including: patient reported 
outcomes, imaging, PFT, and corticosteroid tapering. Detailed description of efficacy 
assessments is provided in Section 7.2. 


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14. 
SAFETY ASSESSMENTS AND PROCEDURES 
Overall safety will be determined by the incidence, severity and relationship of AEs, physical 
examinations, vital signs, clinical laboratory abnormalities, and imaging. All safety 
assessments will be performed at times outlined in the Schedule of Study Events (Table 1). 
Additional (unscheduled) safety assessments may be performed as needed. 
14.1. 
Adverse Events 
AEs will be recorded from signing of the ICF and followed by the investigator until the AE is 
resolved or stabilized or at such time as the investigator refers the subject to a nonstudy 
physician for follow-up treatment. Any and 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 16 for additional details on the handling of AEs and SAEs. 
14.2. 
Medical and Surgical History  
Medical and surgical history will be obtained at Screening (Visit 1). Medical history will 
include a review of the following systems: general, dermatological, respiratory, 
cardiovascular, gastrointestinal, genitourinary, gynecological (when applicable), endocrine, 
musculoskeletal, hematological, neuropsychological, immune (allergies), and head, eyes, ears, 
nose, and throat. Historical and current medical conditions including and date of last 
menstrual period for female subjects will be recorded. Occupational history will also be 
collected.  
14.3. 
Physical Examination 
A complete physical examination will be performed at all visits and 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. Special emphasis will be made to 
sarcoidosis manifestations per organ involvement.  
The findings of the physical examinations will be recorded. Any changes in medical 
conditions, specifically new medical conditions and worsening of existing medical conditions 
will be recorded as AE, as appropriate. 
14.4. 
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, and respiratory rate. 
The investigator may perform additional unscheduled vital sign measurements to evaluate or 
manage a suspected AE. These unscheduled vital sign measurements should be obtained after 
the subject has been seated for at least 5 minutes, if possible. Unscheduled vital signs will be 
recorded. 
The date and time for all vital sign assessments will be recorded. 


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14.5. 
Clinical Laboratory Tests 
The clinical laboratory tests are listed in Attachment 1. Tests should be conducted as 
described in the Schedule of Study Events (Table 1). All clinical laboratory tests will be done 
at a central laboratory facility except for urine analysis, and urine pregnancy test which will 
be performed at the local laboratory. Specific instructions for collection, processing, storage, 
and shipment of clinical laboratory samples will be provided in a separate laboratory manual, 
where appropriate. 
Samples for serum chemistry testing for all visits will be collected under fasting conditions (at 
least 12 hours, drinking water is permitted). The date and time of the sample collection must 
be documented on the laboratory report. Investigators must review and sign laboratory 
reports. The clinical significance of each laboratory abnormality will be documented. New 
clinically significant laboratory abnormalities or clinically significant changes in laboratory 
values will be reported as AEs, as appropriate. 
In addition: 
All female subjects of child bearing potential will have a serum pregnancy test at Screening 
(Visit 1). Urine pregnancy tests will be done at all other visits throughout the study. Results 
must be available prior to dosing with IMP. Subjects with positive results will be ineligible for 
study entry (Visit 1 or Visit 2) or immediately withdrawn from the study (Visit 3 through 
Visit 11) and the pregnancy reported as per Section 16.5. 
HBsAg and HBcAb will be performed at Screening (Visit 1). Results of these tests must be 
negative or nonreactive for subjects to qualify for the study.  
HCV will be performed at Screening (Visit 1). A positive HCV will automatically trigger a 
HCV PCR analysis. HCV PCR must be < 25 IU/mL to qualify for the study. 
IGRA for TB will be performed at Screening (Visit 1). Results of this test must be negative 
for subjects to qualify for the study. 
Out-of-Range Laboratory Values 
Laboratory values from samples collected at Screening (Visit 1) 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 from scheduled or unscheduled laboratory assessments that fall outside the 
reference range from samples collected during the study or at study exit or early 
discontinuation will be assessed by the investigator for clinical significance. If the out of 
range value for samples is deemed clinically significant by the investigator, an AE will be 
recorded.  
14.6. 
12-Lead Electrocardiogram 
Electrocardiogram will include assessment of sinus rhythm, heart rate, PR Interval, RR 
Interval, QRS Duration, Q-T Interval and QTcB. 
A 12-lead ECG will be obtained for all subjects at Screening (Visit 1) and Visits 8 and 11. 
The date of the ECG must be documented on the ECG tracing. An appropriately trained and 
experienced physician must interpret this ECG. Date, time, and clinical parameters from the 


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all ECGs will be entered in the eCRF. At the discretion of the investigator a repeat ECG may 
be collected at the screening visit to confirm findings.  
Additional ECGs may be performed any time throughout the study if deemed clinically 
necessary and entered into eCRF.  


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15. 
STATISTICAL METHODS AND PLANNED ANALYSIS 
15.1. 
General Considerations 
This section provides a general description of the statistical methods to be used in analyzing 
both safety and efficacy data. The key statistical issues or considerations will be addressed in 
more detail in a statistical analysis plan to be provided as a separate document that will be 
finalized prior to database lock. The analyses for the double-blind phase data will be 
performed after the database lock for the double-blind phase.  
Unless otherwise specified, all statistical tests, when applicable, will be 2-sided with a 
significance level of 0.05. Summary statistics will be provided for all study variables with 
descriptive statistics (number of observations, mean, SD, median, minimum, and maximum) 
for numerical (or continuous) variables. Frequency and percentages will be calculated for 
categorical variables. All data will be summarized by treatment groups as appropriate. Data 
summary and analyses will be performed with SAS 9.4 or higher. 
15.2. 
Analysis Populations 
The following populations will be identified and analyzed in this study: 
A Modified Intent-to -Treat (mITT) Population that includes all randomized subjects who 
receive at least 1 dose of IMP and who contribute any efficacy data to the study will be used 
for the efficacy analyses. A Safety Population that includes all randomized subjects who 
receive at least 1 dose of IMP will be used for all the safety analyses. 
15.3. 
Subject Characteristics 
15.3.1. 
Demographics 
The demographic information will be summarized for each analysis population by treatment 
group. 
15.3.2. 
Medical and Surgical History 
Prior medical conditions or procedures will be summarized by body system and treatment 
group. 
15.3.3. 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded according to the WHO Drug Dictionary. The 
incidence (number and percent) of prior and concomitant medication use will be summarized 
by treatment group.  
15.3.4. 
Subject Disposition and Exposure to Investigational Medicinal Product 
Subject disposition and treatment exposure will be summarized. The number of subjects who 
complete the study and who do not complete the study along with the reasons for 
discontinuation from the study will be summarized.  


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15.4. 
Safety Analysis  
All subjects who receive at least 1 dose of IMP will be included in the safety analyses.  
15.4.1. 
Adverse Events 
The MedDRA coding terms will be used for coding AEs. The number of AEs and the number 
of subjects reporting AEs will be listed and summarized descriptively by body system, 
preferred term, severity, and causality for each treatment group. Only TEAEs (events that are 
new in onset or aggravated in severity following treatment), will be included in all summaries. 
SAEs and deaths will be summarized.  
15.4.2. 
Clinical Laboratory Tests 
Clinical laboratory test results will be summarized descriptively and presented in data listings.  
15.4.3. 
Physical Examination Findings 
All physical examination results will be summarized descriptively and presented in a data 
listing. 
15.4.4. 
Electrocardiogram Findings 
Electrocardiogram measured changes from baseline for sinus rhythm, heart rate, PR interval, 
RR interval, QRS duration, Q-T Interval, and QTcB will be summarized.  
15.4.5. 
Vital Signs 
Vital sign results (heart rate, diastolic/systolic blood pressures, respiratory rate and weight) 
and corresponding changes from baseline values will be summarized at each visit with 
descriptive statistics by treatment group.  
15.5. 
Efficacy Analysis  
Efficacy analyses will be performed on the mITT Population. All efficacy endpoints will be 
summarized and analyzed. Pearson’s chi-squared test will be used to evaluate the treatment 
difference between treatment groups for the categorical response endpoints. The continuous 
response endpoints will be analyzed using 2-sample t-test. The time-to-event endpoints will be 
analyzed using log-rank test. Kaplan-Meier curves will also be presented. 
Additional exploratory analyses will be performed as appropriate. Such analyses may include 
logistic regression model, analysis of variance model, and/or mixed-effects model. Subgroup 
analyses based on demographics, baseline characteristics, study compliance, etc, will also be 
performed. 
Missing data imputations will be performed as appropriate. In general, the last-observation-
carried-forward method will be used to impute missing data. Additional missing data 
imputation may be performed as needed. 
15.6. 
Interim Analysis 
No interim analysis of the data is planned. 


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15.7. 
Statistical Power and Sample Size Considerations 
Formal sample size calculations were not performed. The sample size is based on recent 
literature of comparative studies (Gibson et al., 1996; Baughman et al., 2006; Judson, 2014) in 
sarcoidosis. 
15.8. 
Deviations from Statistical Analysis Plan 
Any deviations from the planned statistical analysis will be described and justified in the final 
clinical study report as appropriate. 


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16. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
16.1. 
Safety 
For safety information about Acthar Gel, refer to the most recent version of the Package Insert 
(Mallinckrodt ARD LLC, 2019).  
16.2. 
Definitions 
AE  
An AE is any untoward or undesirable medical occurrence in a subject who is administered an 
IMP, 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 IMP overdose whether accidental or intentional. 
• An AE occurring from investigational medicinal abuse. 
• An AE associated with investigational medicinal withdrawal. 
• Unexpected AE. 
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 package insert 
(Mallinckrodt ARD LLC, 2019). 
Adverse experiences (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 underlying disease (disease-related) or condition under investigation (eg, 
symptoms, disease progression) and events unlikely to be related to the underlying disease or 
condition under investigation but common in the study population independent of drug 
therapy. Anticipated events, when reported, to be associated with the use of the investigational 
product, are a subset of unexpected AEs (events not listed in the package insert 
[Mallinckrodt ARD LLC, 2019]). However, these events do not warrant expedited reporting 
as individual cases when serious criteria have been met because it is not possible to determine 
that there is a reasonable possibility that the drug caused the event. As a result, they do not 
meet the definition of a suspected adverse reaction. 
SAE  
An SAE is defined as any untoward medical occurrence that at any dose results in any of the 
following outcomes: 
• Death. 
• A 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. 


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• Results in a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
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.  
Death  
Death is an outcome of an event. The event that resulted in 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 (if 
applicable) to Mallinckrodt. 
Life-Threatening Event  
A life-threatening event refers to immediate risk of death as the event occurred per the 
reporter. A life-threatening event does not include an event that, had it occurred in a more 
severe form, might have caused death but, as it actually occurred, did not create an immediate 
risk of 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; however, it is 
not in itself considered an SAE. In absence of an AE, a hospitalization or prolongation of a 
hospitalization should not be reported by the investigator as an SAE. Such situations include, 
but are not limited to, the following: 
• 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. 
• Note that the following hospitalizations are not considered SAEs in Mallinckrodt 
clinical studies:  
o A visit to the emergency department or other hospital department of less than 
24 hours that does not result in admission (unless considered "important 
medical event" or life-threatening event). 


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16.3. 
Adverse Event and Serious Adverse Event Classifications 
Investigational Medicinal Product Relatedness 
The following classifications should be used when evaluating the relationship of AEs or SAEs 
to study treatment (Table 3). 
Table 3:  
AE Relationships 
Relationship 
Definition 
Not Related 
No relationship between the experience and the administration of study 
treatment; related to other etiologies such as concomitant medications or 
subject’s clinical state. 
Unlikely Related 
The current state of knowledge indicates that a relationship is unlikely. 
Possibly Related 
A reaction that follows a plausible temporal sequence from administration of 
the study treatment and follows a known response pattern to the suspected 
study treatment. The reaction might have been produced by the subject’s 
clinical state or other modes of therapy administered to the subject. 
Related 
A reaction that follows a plausible temporal sequence from administration of 
the study treatment and follows a known response pattern to the suspected 
study treatment and can be confirmed with a positive re-challenge test or 
supporting laboratory data. 
 
Severity Assessment 
For purposes of consistency, if required, the investigator may use the intensity grades 
presented in Table 4.  
Table 4:  
AE 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 
 
If an AE increases in severity (eg, from moderate to severe); decreases in severity (eg, 
changes from moderate to mild); or 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 final visit, the resolution/stop date and time is left blank.  
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,” 


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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. 
16.4. 
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, which will take place 4 weeks (± 2 days) after the subject has received the last 
administration of IMP. 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 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.  
During the period specified above, the investigator will: 
Record all AEs and SAEs in the source documents from the signing of the ICF through the 
completion of the follow-up telephone call.  
Record all AEs and SAEs in the eCRF from the initial IMP dose through the completion of 
the follow-up telephone call.  
Report all SAEs on an SAE Report Form to Mallinckrodt Pharmacovigilance. 
Report all pregnancies to Mallinckrodt Pharmacovigilance on the Pregnancy Surveillance 
Form. 
Submit the Safety Alert from Mallinckrodt to the IRB/IEC. (Submit any Expedited Safety 
Report or Suspected Unexpected Serious Adverse Reaction from Global Pharmacovigilance 
to the IRB/IEC.) 
The reporting requirements for AEs are summarized in Table 5. 
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 
 
AEs 
AEs can be reported spontaneously or elicited during open-ended questioning (ie, "How have 
you been feeling since your last visit?"), examination, or evaluation of a subject. Signs and 
symptoms must be recorded using standard medical terminology.  


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All fields on the AE CRF page should be completed for each event with a full description of 
the event and date and time of onset/start and resolution/stop. A medical diagnosis if known, 
should be recorded in lieu of each individual sign and symptom associated with the diagnosis 
and experienced by the subject. If no medical diagnosis is known, the term used by the subject 
to describe the event or signs noted by the site personnel should be recorded.  
SAEs 
Initial Reporting 
SAEs (based on US FDA/ICH definition of an SAE) require immediate reporting to 
Mallinckrodt Global Pharmacovigilance or designated representative.  
• For all fatal or life-threatening events, the investigator, or designee, must report 
information to the MM. 
• For all SAEs, the investigator, or designee, must complete the SAE Report Form 
with the minimum information required by US FDA and ICH and fax it to 
Mallinckrodt Global Pharmacovigilance or designee within 24 hours of first 
knowledge of the event even if the experience does not appear to be related to the 
IMP. 
• The investigator, or designee, will receive acknowledgement of receipt of the SAE 
Report Form from Mallinckrodt. 
• If there is any doubt about whether the information constitutes an SAE, the 
information is to be treated as an SAE. 
The investigator(s) or designee is required to submit the Safety Alert to the responsible 
IRB/IEC. 
The sponsor will submit safety reports to the US FDA and other regulatory agencies, as 
appropriate. 
Follow Up Reporting  
The investigator or designee must complete an SAE Report Form for all follow-up 
information received and fax or e-mail it to Mallinckrodt Global Pharmacovigilance or 
designee within 24 hours of receipt (eg, detailed written descriptions that include copies of 
relevant subject records, autopsy reports and other supporting documents). The investigator(s) 
or designee will receive acknowledgement of receipt for each SAE Report Form from 
Mallinckrodt. 
• The investigator or designee is required to provide all related 
information/supporting documentation of an SAE until the SAE is resolved or 
stabilized or the subject has been referred to a nonstudy physician for follow-up 
treatment.  
• The investigator(s) or designee is required to submit the Safety Alert to the 
responsible IRB/IEC.  
• The sponsor will submit safety reports to the US FDA. (The sponsor will ensure 
that any Expedited Safety Report or Suspected Unexpected Serious Adverse 
Reaction are submitted to the FDA and other regulatory agencies as appropriate). 


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16.5. 
Pregnancy Reporting 
Certain information, although not considered an SAE, must be recorded, reported, and 
followed up as indicated. This includes the following:  
Pregnancy exposure to an IMP, except for exposure to prenatal vitamins. Subjects should not 
become pregnant during the study. If the subject becomes pregnant, study treatment must be 
discontinued immediately. The investigator must report the pregnancy by submitting the 
appropriate form to Mallinckrodt Global Pharmacovigilance within 24 hours of confirmation 
of a pregnancy (ie, positive serum or urine 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 within 
24 hours of the pregnancy outcome being submitted to the study site. If the pregnancy results 
in a live birth, a post-delivery follow-up will be performed at least 28 days after the baby is 
born and must be reported to Mallinckrodt Pharmacovigilance within 24 hours of the study 
site becoming aware of the follow-up information. Both maternal and paternal IMP exposures 
are collected.  
If the female partner of a male subject becomes pregnant during the study, the site will 
forward the appropriate forms to Mallinckrodt Global Pharmacovigilance or designee, within 
24 hours of being notified. 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 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. 


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17. 
SUBJECT DISCONTINUATION OR WITHDRAWAL 
17.1. 
Subject Withdrawal 
Subjects who discontinue, or are withdrawn from the study for any reason, will be required to 
have the early termination safety and efficacy assessment procedures (Visit 8, see 
Section 11.5) as well as follow up procedures (Visit 12, see Section 11.9).  
The reason for discontinuation 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. Subjects who have received at 
least 1 dose of IMP but do not complete the study will not be replaced. 
AE 
If a dosed subject experiences an 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 IMP. In addition, subjects who experience any of the AEs described in Section 12.3.1 
may have their dose reduced by 50% once or discontinued (Section 17). 
Death 
In the event that a subject dies during the study, death will be the reason for discontinuation. 
Lost to Follow-up 
Every effort should be made to maintain contact with subjects during their participation in the 
study. A subject may be considered lost to follow-up if there is no response to 3 attempts to 
reach the subject by telephone or electronically and no response to a certified letter sent to the 
last known address of the subject. Efforts to contact the subject should be noted in source 
documentation. 
Met Withdrawal Criteria 
Discontinuation from IMP is mandated if the subject becomes pregnant or receives live or 
live-attenuated vaccines. 
Worsening of Disease Activity 
Subjects may be withdrawn if, in the opinion of the investigator, there is a lack of efficacy 
during the study.  
Other 
If the above reasons are not applicable, please use the “Other” option and provide the 
appropriate reason for subject withdrawal. 


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18. 
STUDY SUSPENSION, TERMINATION, AND COMPLETION 
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 Mallinckrodt standard operating procedures.  


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19. 
PROTOCOL AMENDMENTS 
Any change in the study plan requires a protocol amendment or an administrative letter. 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.  


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20. 
QUALITY CONTROL AND 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 eCRFs 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.  
Study and Study Site Discontinuation Criteria 
The sponsor, investigator, MM 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: 
• 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, 
evaluation or development of the IMP. 
• 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 
• Study/study site termination and follow-up will be performed in compliance with 
Mallinckrodt standard operating procedures. 


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21. 
DIRECT ACCESS, DATA HANDLING, AND RECORD-
KEEPING 
21.1. 
Investigator 
The investigator will permit study-related monitoring, audits, IRB/IEC review, and regulatory 
inspections by providing direct access to original source data and documents. 
All subject information recorded in the eCRF will be attributable to source data from the 
investigational site. 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, US FDA form 1572) to be filed with the sponsor. 
The investigator must notify their IRB/IEC of protocol violations in accordance with local 
regulatory and IRB/IEC requirements. 
21.2. 
Sponsor 
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. Clinical laboratory data will be processed electronically. Requests 
for data clarification are forwarded to the study site for resolution. 


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22. 
SUBJECT INJURY 
In general, subject to specific provisions in the clinical trial agreement, if a subject is injured 
as a direct result of an IMP, the sponsor will pay for reasonable and necessary medical 
treatment for the injury, to the extent that such expenses are not covered by the subject’s 
medical insurance, a government program, or other responsible third party. If laws or 
regulations of the locality in which the study is taking place require additional payment of 
expenses, the sponsor shall comply with such laws or regulations. Where applicable, the 
sponsor has taken specific national insurance. 


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23. 
RECORDS RETENTION 
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 IMP. 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.  


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24. 
BIOLOGICAL SAMPLES 
Blood samples will be used only for scientific research. Each sample will be labeled with a 
code so that the laboratory personnel testing the samples will not know the subject’s identity. 
After the study ends, the clinical laboratory samples will be destroyed, with the exception of 
samples for biomarker and genomic analysis. Samples for biomarker analysis and optional 
genetic testing will be retained at a biologic storage facility for future testing for no more than 
5 years following the completion of the study. The subject may request that his or her 
samples, if still identifiable, be destroyed at any time; however, any data already collected 
from that sample will still be used for this research.  


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25. 
PUBLICATION POLICY 
25.1. 
Sponsor’s Publication Policy 
The sponsor’s policy is to publish or otherwise communicate the results of its hypothesis-
testing clinical studies, regardless of outcome, for marketed products, compound(s) or 
product(s) being investigated that are later approved for marketing. Hypothesis-testing clinical 
studies are those studies intended to provide meaningful results by examining prestated 
questions using predefined statistically valid plans for data analysis, thereby providing firm 
evidence of safety and/or efficacy to support product claims. 
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. 
25.2. 
Investigator’s Ability to Publish 
Terms and provisions of publication rights are governed by the publication section in the 
clinical trial agreement. 
 


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26. 
REFERENCES 
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review. Current Biomarker Findings 2014: 4: 93-104. 
Al-Kofahi K, Korsten P, Ascoli C, Virupannavar S, Mirsaeidi M. Management of 
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American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (5th 
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ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS 
Statement: Guidelines for the Six-Minute Walk Test. Am J Respir Crit Care Med. 2002;166: 
111–117.  
Baughman RP, Barney JB, O'Hare L, Lower EE. A retrospective pilot study examining the 
use of Acthar gel in sarcoidosis patients. Respiratory Medicine 2016; 110: 66-72. 
Baughman RP, Drent M, Culver DA, Grutters JC, Handa T. Endpoints for clinical trials of 
sarcoidosis. Sarcoidosis Vasculitis and Diffuse Lung Diseases 2012; 29: 90-98. 
Baughman RP, Grutters JC. New treatment strategies for pulmonary sarcoidosis: 
antimetabolites, biological drugs, and other treatment approaches. Lancet Respir Med 2015; 3: 
813-822. 
Baughman RP, Iannuzzi MC, Lower EE, Moller DR, Balkissoon RC. Use of Fluticasone in 
Acute Symptomatic Pulmonary Sarcoidosis. Sarcoidosis Vasculitis Diffuse Lung Diseases 
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Baughman RP, Lowera EE, Saketkoo LA. Clinical trials in pulmonary sarcoidosis. Curr Opin 
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Baughman RP, Kavuru M, Judson MA, Costabel U, du Bois R. Infliximab therapy in patients 
with chronic sarcoidosis and pulmonary involvement. Am J Respir Crit Care Med 2006; 174: 
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Baughman RP, Nunes H. Therapy for sarcoidosis: evidence-based recommendations. Expert 
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Baughman RP, Sweiss N, Keijsers R, Birring SS, Shipley R et al. Repository corticotropin for 
Chronic Pulmonary Sarcoidosis. Lung 2017; 195(3): 313-322. 
Birring SS, Prudon B, Carr AJ, Singh SJ, Morgan MDL, et al. Development of a symptom 
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Catania A, Lonati C, Sordi A, Carlin A, Leonardi P, Gatti S. The melanocortin system in 
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De Vries MH, Van Heck GL, Drent M. Measuring fatigue in sarcoidosis: the Fatigue 
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anti-inflammatory effect of repository corticotropin injection on human monocyte-derived 
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Healy LM, Lin YH, Jang JH,Rao V, Antel JP, Wright D. Melanocortin receptor mediated 
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2017b; Paris, France. Poster EP1481. 
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Judson MA, Baughman RP, Costabel U, Flavin S, Lo KH et al. Sarcoidosis Investigators. 
Efficacy of infliximab in extrapulmonary sarcoidosis: results from a randomised trial. Eur 
Respir J. 2008; 31: 1189-1196.  
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Mallinckrodt ARD LLC; Acthar® Gel; Package Insert: Mallinckrodt Pharmaceuticals, 
Bedminster, NJ, 2019. Accessed April 2020. 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi, R. et al. Standardisation of 
spirometry. Eur Respir J 2005; 26: 319–338. 
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encode the melanocortin receptors. Science. 1992;257(5074): 1248-1251. 
Nikiphorou E, Radner H, Chatzidionysiou K, Desthieux C, Zabalan C et al. Patient global 
assessment in measuring disease activity in rheumatoid arthritis: a review of the literature. 
Arthritis Res Ther 2016; 18(1): 251.  
Olsen NJ, Decker DA, Higgins P et al. Direct effects of HP Acthar Gel on human B 
lymphocyte activation in vitro. Arthritis Res Ther. 2015; 17:300. 
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57-65. 
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Unpublished Sponsor data: REF-MNK14314065. Mallinckrodt ARD LLC. 
Unpublished Sponsor data: REF-MNK03003. Mallinckrodt ARD LLC. 
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remyelination after cuprizone-induced demyelination [CMSC abstract NDM04]. Int J MS 
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APPENDIX 1. PROTOCOL AMENDMENT CHANGES 
The Summary of Changes presented below reflects the major changes made in Protocol 
Version 2 Amendment 1. Formatting, consistency, and minor editorial changes are not 
included. Refer to the Section Summary of Changes for a high level summary of the reasons 
for this amendment. 
 


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Rationale 
Location 
Original  
Revisions/Additions in Bold 
H.P. (highly purified) 
should be removed 
Globally 
H.P. Acthar® Gel  
Acthar® Gel 
To update Acthar 
package insert 
reference to the most 
current one. 
Globally 
(Mallinckrodt, 2015) 
(Mallinckrodt ARD LLC, 2019) 
Clarification 
Title Page and 
Synopsis 
 
 
 
Section 9.1 
Description 
A Phase 4 Multicenter, 
Randomized, Double Blind, 
Placebo Controlled Pilot Study 
to Assess the Efficacy and 
Safety of H.P. Acthar® Gel in 
Subjects with Pulmonary 
Sarcoidosis 
This is a Phase 4, multicenter, 
randomized, double-blind, 
placebo-controlled pilot study 
evaluating the efficacy and 
safety of Acthar in the treatment 
of pulmonary sarcoidosis. 
A Multicenter, Randomized, Double Blind, 
Placebo Controlled Exploratory Study to 
Assess the Efficacy and Safety of Acthar® 
Gel in Subjects with Pulmonary Sarcoidosis 
 
 
This is a multicenter, randomized, double-
blind, placebo-controlled exploratory study 
evaluating the efficacy and safety of Acthar 
in the treatment of pulmonary sarcoidosis. 
Company name & 
address change 
Title page 
Mallinckrodt ARD, Inc. 
675 McDonnell Boulevard 
Hazelwood, MO 63042 
United States of America 
Mallinckrodt ARD LLC 
1425 US Route 206  
Bedminster, New Jersey 07921 
United States of America 


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Rationale 
Location 
Original  
Revisions/Additions in Bold 
Addition of 
Clintrials.gov Registry 
Number 
Title page 
NA 
Clintrials.gov Registry Number: 
NCT03320070 
Updated header to 
remove H.P. 
All page headers 
H.P. Acthar® Gel (Repository 
Corticotrophin Injection)  
Protocol MNK14344100 Acthar® Gel 
(Repository Corticotropin Injection) 
Update of sponsor’s 
signature page for more 
detail about applicable 
laws and other 
regulations related to 
study conduct. 
Sponsor’s Signature 
Page 
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 regulations including, 
but not limited to, the 
International Council for 
Harmonisation (ICH) Guideline 
for Good Clinical Practice 
(GCP), the US Code of Federal 
Regulations (CFR), protections 
for privacy, and generally 
accepted ethical principles for 
human research such as the 
Declaration of Helsinki. 
• 
International Council for 
Harmonisation (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 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 


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Rationale 
Location 
Original  
Revisions/Additions in Bold 
Expand site regions 
Section 2 Synopsis, 
Type: 
Type: Phase 4 (US)/Phase 2 
(Canada) 
Type: Phase 4 (US)/Phase 2 (all other 
countries) 
Adjust the number of 
sites and their potential 
location 
Section 2 Synopsis, 
Approximate Number 
of Study Centers: 
Up to 45 in the US and/or 
Canada 
Approximately 75 sites globally 
Section 9.4 
Approximate Number 
of Subjects 
Up to 100 subjects will be 
enrolled at up to 45 sites in the 
US and/or Canada. 
Approximately 100 subjects will be 
globally enrolled at approximately 75 sites. 
Revise study duration. 
Section 2 Synopsis  
Approximate Duration of Study: 
The estimated study period is 
approximately 3 years from first 
subject enrolled to last subject 
last visit (completed open-label 
extension and follow up visit). 
Expected enrollment period is 
approximately 2 years (first 
subject enrolled to last subject 
enrolled). 
Approximate Duration of Study: The 
estimated study period is approximately 4 
years from first subject enrolled to last 
subject last visit (completed open-label 
extension and follow up visit). Expected 
enrollment period is approximately 3 years 
(first subject enrolled to last subject 
enrolled). 
 
Section 9.3 
The entire study is expected to 
require approximately 3 years to 
complete. 
The entire study is expected to require 
approximately 4 years to complete. 


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Clarification of dosing 
Section 2 Synopsis, 
Design 
1 mL (80 U) of Acthar or 1 mL 
of a matching placebo 
subcutaneously (SC) 2 x/week 
Double-blind treatment: Acthar, 1 mL 
(80 U) or matching placebo (1 mL) 
administered SC twice weekly for up to 24 
weeks.  
Optional open-label extension: Acthar 
Gel, 1 mL (80 U) administered twice 
weekly SC for up to 24 weeks. 
Subjects will be assigned to treatment in a 
1:1 ratio with up to 50 subjects per arm 
for a total of approximately 100 subjects. 
Section 2 Synopsis, 
Investigational 
medicinal product and 
Treatment 
Administration 
Acthar, 1 mL (80 U) or matching 
placebo (1 mL) administered 
twice weekly SC for up to 12 
months. 
Acthar Gel, 1 mL (80 U) or matching 
placebo (1 mL) administered twice weekly 
SC for up to 24 weeks.  
Optional open-label extension: Acthar 
Gel, 1 mL (80 U) administered twice 
weekly SC for up to 24 weeks. 
Section 13.3 Dosing 
Procedures 
Subjects or their caregivers will 
administer SC injections of 
Acthar or placebo after randomly 
assigned to treatment at Visit 2. 
The subject or subject’s 
caregiver will administer the first 
dose of IMP in the clinic under 
the supervision of study staff. 
The subject will remain in the 
clinic for at least 1 hour post 
Subjects or their caregivers will administer 
SC injections of Acthar Gel or placebo after 
randomly assigned to treatment at Visit 2. 
The subject or subject’s caregiver will 
administer the first dose of study drug and 
the first dose of Acthar in the Open-Label 
at Week 24 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 or 
anaphylactic reactions. All other doses 


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injection to monitor for allergic 
or anaphylactic reactions. 
will be administered by the subject or the 
subject’s caregiver at home, except for 
doses administered on the days of the 
study visits 
Section 13.3 Dosing 
Procedures 
Injections of 1 mL Acthar (80 U) 
or matching placebo will be 
administered SC 2x/week 
throughout the study. 
In the double-blind treatment period 
Acthar Gel, 1 mL (80 U) or matching 
placebo (1 mL) will be administered twice 
weekly SC for up to 24 weeks. In the 
optional open-label extension Acthar Gel, 
1 mL (80 U) will administered SC twice 
weekly for up to 24 weeks. 
Combining optional 
genomics assessment 
with biomarkers 
assessment 
Section 2 Synopsis, 
Efficacy Evaluation 
12. 
Genomics (optional). 
Removed  
Added high level 
Summary of Changes 
Summary of Changes 
Not applicable. 
See Section Summary of Changes. 
Combining optional 
genomics assessment 
with biomarkers 
assessment 
Table 1: Schedule of 
Study Events 
Genetic Sampling (Optional) 
Removed assessment. 
Table 1: Schedule of 
Study Events original 
footnote k 
k Genetic profile (optional) will 
be assessed based on the 
understanding of genetic factors 
at the time of study completion. 
Removed. 


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Clarification for 
biomarkers 
assessments 
Synopsis, Biomarkers 
• Genetic profile (optional) will 
be assessed based on the 
understanding of genetic factors 
at the time of study completion. 
• Genomic profile (optional) will be assessed 
based on the understanding of genetic factors 
at the time of study completion. 
Table 1: Schedule of 
Study Events footnote 
j 
 
j Biomarkers levels will be 
compared between baseline, and 
every 12 weeks (up to 48 weeks 
for those subjects participating in 
the optional Open-label 
Extension 
Phase). Aliquots will be kept for 
each of these time points. The 
final determination as to the 
selection of biomarkers will be 
made based on the scientific 
knowledge 
and emerging guidance closer to 
the completion of the study. 
j Biomarkers sampling must include RNA 
and DNA samples (screening only), if 
genetic Informed Consent Form (ICF) is 
signed 


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Sections 12.1 Study 
Days -28 to -1 
(Screening Visit 1), 
Section 12.4 Visit 5 
Procedures, 12.5 Visit 
8 Procedures,  
12.7 Visit 10 
Procedures, Open-
Label Extension 
Period, 12.8 Visit 11 
Procedures, Open-
Label Extension 
Period 
Biomarkers 
For Screening Visit 1:  
Biomarkers (including RNA and DNA, if 
genetic ICF signed).  
 
For all other visits listed:  
Screening Visit:1 
Biomarkers (including RNA, if genetic ICF 
signed).  
Clarification of ECG 
assessment 
Table 1: Schedule of 
Study Events, 
footnote m 
12 lead ECGm 
mECG will include assessment of  sinus 
rhythm, heart rate, PR Interval, RR 
Interval, QRS Duration, Q-T Interval and 
QTcB  
Heading of Section 
15.6 Screening 12-
Lead 
Electrocardiogram 
Screening 12-Lead 
Electrocardiogram 
12-Lead Electrocardiogram 
Section 15.6 12-Lead 
Electrocardiogram 
N/A 
Electrocardiogram will include assessment 
of  sinus rhythm, heart rate, PR Interval, 
RR Interval, QRS Duration, Q-T Interval 
and QTcB 


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Addition of a 
requirement to monitor 
1st dose for allergic or 
anaphylactic reactions 
in open label treatment 
so that subjects in 
Placebo group who 
enter the Open Label 
treatment period and 
receive their first 
Acthar dose receive the 
same level of safety 
monitoring as those 
who receive Acthar 
treatment in the Double 
Blind period. 
Table 1: Schedule of 
Study Events, footnote 
s 
s Dosing will begin after Visit 2 
procedures are completed and 
subject is randomized. Dosing 
will be performed 2×/week but 
not on visit days (see Section 
15.3). 
s Dosing will begin after Visit 2 procedures 
are completed and subject is randomized. 
The first dose of study drug for all 
subjects will be administered in the clinic 
and the subject will be observed for at 
least 1 hour after dosing. For subjects 
entering the Open Label Extension, the 
first dose given at Week 24 will be 
administered in the clinic and the subject 
will be observed for at least 1 hour after 
dosing. All other doses will be 
administered by the subject or the 
subject’s caregiver at home 2×/week but 
not on visit days. (see Section 13.3). 
Clarification for SC 
injections training 
Table 1: Schedule of 
Study Events, footnote 
q 
q Subjects (and/or caregivers) 
will be trained on SC injections 
using the training tools provided 
separately. Additional training 
may be provided during Visit 2 
before randomization occurs. 
The training may be forgone if 
either the subject or caregiver is 
a medically trained professional. 
The subject or subject’s 
caregiver will administer the first 
dose of IMP in the clinic under 
the supervision of study staff. 
q Subjects (and/or caregivers) will be trained 
on SC injections using the training tools 
provided separately. Additional training may 
be provided during Visit 2 before 
randomization occurs. SC injections training 
may be forgone if either the subject or 
caregiver is a medically trained professional. 


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The subject will remain in the 
clinic for at least 1 hour 
postinjection to monitor for 
allergic or anaphylactic 
reactions. 
Typo and added 
description of study of 
subjects with advanced 
symptomatic 
sarcoidosis treated with 
repository corticotropin 
injection (Chopra et al., 
2019). 
Section 7.1 
Sarcoidosis Overview 
 
 
 
 
 
 
.  
 
 
 
 
 
. 
The third study was large case series of 
patients with advanced symptomatic 
sarcoidosis treated with repository 
corticotropin injection (RCI). This large 
case series study describes patient 
characteristics, RCI utilization patterns, 
concomitant therapies, and physicians’ 
assessments of treatment response. The 
study included 302 patients 
(mean age = 51 years; 52% women) with a 
mean of 4.8 years since initial diagnosis of 
sarcoidosis. Most patients (76%) had 
extrapulmonary involvement, primarily in 
the skin (28%), joints (25%), heart (22%), 
and eyes (22%); 34% had multiple (≥2) 
organ involvement. The mean duration of 
RCI treatment was 32.5 weeks, with 
61.6% of patients continuing RCI therapy 


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for ≥6 months. The RCI utilization 
pattern indicated an individualized 
approach to therapy, with a higher 
starting dose associated with a shorter 
duration of therapy compared with a 
lower starting dose. The percentage of 
patients who used corticosteroids 
decreased from 61.3% during the 3 
months before initiation of RCI to 12.9% 
at 3 months after RCI therapy; the mean 
daily dose of corticosteroid decreased 
from 18.2 mg to 9.9 mg. The proportion of 
patients given <10 mg/day of prednisone 
increased from 21% before RCI use to 
47% at 3 months after RCI use. 
According to physicians’ assessments of 
change in patients’ health status after RCI 
therapy, overall status improved in 95% 
of patients, overall symptoms in 73%, 
lung function in 38%, and inflammation 
in 33%. The findings suggest that RCI is a 
viable treatment option for patients with 
advanced symptomatic sarcoidosis and 
provide insights on patient characteristics 
and practice patterns to help clinicians 
determine appropriate use (Chopra et al., 
2019). 
Update description and 
addition of supporting 
Section 7.2, Acthar 
Gel Overview 
NA 
Acthar Gel is a naturally sourced complex 
mixture of ACTH analogs and other 


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publications related to 
MCRs  
pituitary peptides. Further down in the 
same paragraph: 
MCRs play a key role in regulating 
inflammation and other cellular function 
(Catania, 2010). Acthar engages MCRs 
expressed on immune cells and other 
tissues throughout the body and is thought 
to produce both an indirect anti-
inflammatory effect and a direct cell effect 
(Catania, 2010; Wright et al., 2019; Olsen 
et al., 2015; Healy, 2017a; Wright et al., 
2019b). Production of cortisol is mediated 
by activation of MC2Rs primarily 
expressed on the adrenal cortex. In in 
vitro studies in cultured cells lines 
expressing MCR1-MCR5, the relative 
functional potency of MCRs was 
measured. It was shown that 6% of 
Acthar’s relative functional potency 
occurred at MC2R. The remaining 94% 
occurred at the other MCRs (Wright et 
al., 2019). These data suggest that Acthar 
acts directly on cells involved in the 
pathogenesis of disease in addition to its 
indirect action via corticosteroid 
stimulation. 
The effects of Acthar on human B-
lymphocyte function in vitro were 
evaluated using highly purified B-cell 
populations cultured in the absence of 


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glucocorticoids and stimulated by 
recombinant interleukin-4 and cluster of 
differentiation 40 ligand as specific B-cell 
activating signals. Immunoglobulin G was 
measured in supernatants from healthy 
human peripheral B cells that had been 
cultured for 6 days. The percentage of 
cells that divided and immunoglobulin G 
production were assessed under basal 
conditions (unstimulated) or stimulated 
with interleukin-4/cluster of 
differentiation 40 ligand plus vehicle. 
Acthar reduced B cell proliferation and 
immunoglobulin G production 
independent of cortisol release (p<0.05, 
compared to vehicle-treated group) 
(Olsen et al., 2015; Healy, 2017a, Healy, 
2017b). In further experiments to explore 
the direct effects of Acthar on human 
macrophages and focusing on induction of 
pro-inflammatory mediators following 
lipopolysaccharide stimulation, Acthar 
inhibited the production of the pro-
inflammatory cytokines interleukin-6 and 
tumor necrosis factor (p<0.0001, 
compared to vehicle-treated group; 
(Healy, 2017a, Healy, 2017b). These data 
further demonstrate a direct effect of 
Acthar on immune cell modulation 
independent of cortisol release. 


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s 


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. 
While the exact mechanism of action of 
Acthar Gel is still unknown, further 
investigation is being conducted. This 
information is based on nonclinical data 
and pharmacodynamic data and the 
relationship to clinical benefit is unknown. 
Update description 
Section 13, 
Investigational 
Medicinal Product 
Acthar contains a highly purified 
sterile preparation of prolonged-
release porcine ACTH analogue 
in 16% gelatin for intramuscular 
or SC injection. 
Acthar Gel is a naturally sourced complex 
mixture of ACTH analogs and other 
pituitary peptides in 16% gelatin for 
intramuscular or SC injection. 
Defining outcome 
measures for 
clinicaltrials.gov 
reporting 
Synopsis, Outcome 
Measures and Section 
8.4 Primary Outcome 
Measures 
Not available 
Outcome measures are identified to 
facilitate trial registration and patient 
access to basic results disclosed on public 
registries. 
The primary outcome measures are: 
• 
Number of participants in each 
category of assessment based on forced 
vital capacity, Weeks 24 and 48 
• 
Number of participants in each 
category of assessment based on the 


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diffusing capacity of the lungs for carbon 
monoxide (DLCO), Weeks 24 and 48 
• 
Number of participants in each 
category of assessment based on high 
resolution computer tomography, Weeks 
24 and 48  
• 
Number of participants in each 
category of assessment based on the 
King's Sarcoidosis Questionnaire (General 
Health), Weeks 24 and 48 
• 
Number of participants in each 
category of assessment based on the 
Fatigue Assessment Score, Weeks 24 and 
48 
• 
Number of participants receiving 
each dose of prednisone, Weeks 24 and 48 
Allowing subjects who 
had biopsy performed 
less than 1 year ago, 
but whose disease 
started for more than 1 
year ago.  
Section 10.1 Inclusion 
Criteria #7 
7. Subject with biopsy confirmed 
sarcoidosis meeting ATS criteria 
≥ 1 year at screening 
(Visit 1) (Hunninghake et al., 
1999). 
7. Subject with biopsy confirmed sarcoidosis 
meeting ATS criteria with onset of 
sarcoidosis ≥ 1 year prior to screening 
(Hunninghake et al., 1999). 
Clarification for 
“daily” prednisone  
Section 10.1 Inclusion 
Criteria #9 
9. Subject receiving ≥ 5 mg and 
≤ 40 mg prednisone (or 
equivalent) for pulmonary 
sarcoidosis. 
9. Subject receiving ≥ 5 mg and ≤ 40 mg 
daily prednisone (or equivalent) for 
pulmonary sarcoidosis. 


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Allowing subjects 
whose FVC is higher 
than 95% predicted at 
screening and can 
potentially show 
improvement in FVC. 
Section 10.1 Inclusion 
Criteria #12 
12. Forced vital capacity (FVC) 
≥ 45% ≤ 95% predicted. 
12. Forced vital capacity (FVC) ≥ 45% 
predicted. If FVC at Screening is more 
than 95% predicted, a documented 
decrease ≥ 5% absolute change of % 
predicted in the best available FVC is 
required after diagnosis of Sarcoidosis. 
Excluding subjects 
with prior history of 
Sarcoidosis treatment 
with Acthar 
Section 10.2 
Exclusion Criteria #8 
Not available 
Subject has any history of use of ACTH 
preparations for treatment of Sarcoidosis. 
Address missed 
procedures and visits 
Section 12 
PROCEDURES 
The schedule of study 
procedures is summarized in the 
Schedule of Events (Table 1). 
The schedule of study procedures is 
summarized in the Schedule of Events 
(Table 1). If the subject is unable to come 
to the study site for any visit after the 
Baseline visit, all procedures that can be 
completed remotely (eg, by telephone) will 
be conducted as scheduled. 
Collect as much information as possible, 
including but not limited to, AE 
information, new concomitant 
medications and changes in existing 
therapy, corticosteroid use, compliance 
with investigational therapy. Complete 
applicable physician assessments, PFT 
tests, subject reported outcomes and 
assessments, 6MWT, ECG, imaging and 
laboratory tests at the next planned study 
visit as unscheduled procedures, if not 


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already scheduled for that particular 
study visit. 
Changes in study visit schedule, missed 
visits, and procedures will be captured in 
the eCRF. 
Addition of WPAI, a 
questionnaire to assess 
HEOR outcomes 
Synopsis, Efficacy 
Evaluation 
Not Available 
11. 
WPAI. 
Table 1: Schedule of 
Study Events Footnote 
f 
f Patient-reported outcomes 
include: Steroid toxicity 
questionnaire (Attachment 2); 
King’s Sarcoidosis 
Questionnaire (Attachment 4); 
Fatigue Assessment Scale 
(Attachment 5); Patient's Global 
Assessment (Attachment 6); 
Medical Research Council 
Dyspnea Scale (Attachment 8); 
Leicester Cough Questionnaire 
(Attachment 9). 
f Patient-reported outcomes include: Steroid 
toxicity questionnaire (Attachment 2); 
King’s Sarcoidosis Questionnaire 
(Attachment 4); Fatigue Assessment Scale 
(Attachment 5); Patient's Global Assessment 
(Attachment 6); Medical Research Council 
Dyspnea Scale (Attachment 8); Leicester 
Cough Questionnaire (Attachment 9), Work 
Productivity and Activity Impairment 
(WPAI) (Attachment 10). 
Section 8.2 
Assessments of 
Efficacy 
Not available  
The following assessments will be performed 
during this study: 
- 
WPAI 
Section 8.2.15, Work 
Productivity and 
Activity Impairment 
Not available 
8.2.15 Work Productivity and Activity 
Impairment 


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The WPAI is a validated assessment of 
work and activity impairment associated 
with health problems (Zhang et al, 2010). 
This questionnaire is to be completed by 
subjects. When this assessment is 
required, it should be the first assessment 
done at any visit (with the subject 
completed efficacy questionnaires) and 
must be completed prior to any study 
drug dosing.  
Subjects will be provided a quiet, private 
place to complete the assessment. Subjects 
will be instructed to answer all questions 
to the best of their ability and without 
help from others (including study staff, 
relatives, or friends). Subjects may refrain 
from answering any question.  
The study staff should review the 
questionnaire after it is completed and 
encourage the subjects to complete any 
missing information. Study staff will 
record the refusal of subjects to answer 
any questions in the source documents. 
Synopsis, Endpoints 
and Section 8.3 
Efficacy Endpoints 
Not available 
• Change from baseline in WPAI over 
time. 


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Section 12 
PROCEDURES Visits 
1 through 11 
 
Patient reported outcomes. 
Patient-reported outcomes 
include: Steroid toxicity 
questionnaire; King’s 
Sarcoidosis Questionnaire 
(Attachment 4); Fatigue 
Assessment 
Scale (Attachment 5); Patient's 
Global Assessment (Attachment 
6); Medical Research 
Council Dyspnea Scale 
(Attachment 8); Leicester Cough 
Questionnaire (Attachment 
9). 
Patient reported outcomes. Patient-reported 
outcomes include: Steroid toxicity 
questionnaire; King’s Sarcoidosis 
Questionnaire (Attachment 4); Fatigue 
Assessment 
Scale (Attachment 5); Patient's Global 
Assessment (Attachment 6); Medical 
Research 
Council Dyspnea Scale (Attachment 8); 
Leicester Cough Questionnaire (Attachment 
9); WPAI (Attachment 10). 
Section 27 
Attachments 
Not available 
ATTACHMENT 10: WPAI 
 
Section 12.5 Visit 8 
Procedures 
For subjects interested in 
participating in the Open-Label 
Extension Period: Contact IXRS, 
dispense IMP kits and 
equipment, and instruct the 
subject to inject Acthar 80 U (1 
mL) 2x/week unless the subject 
had a single reduction of dose, in 
which case only 
• Contact IXRS. 
• For subjects entering the Open-Label 
Extension Period: 
o Remind the subjects to arrive in 
fasting condition for Visit 9 
(drinking water is permitted) and 
to bring all IMP kits including 
used and unused vials to each 
visit in a cooler.  


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40 U (0.5 mL) 2x/week will be 
injected for the remainder of the 
study. 
o Dispense IMP kits and 
equipment. 
o Administer Acthar Gel under 
supervision of study staff and 
observation for at least 1 hour 
thereafter. 
o Instruct the subject to inject 
Acthar Gel 80 U (1 mL) 
2×/week unless the subject had 
a single reduction of dose, in 
which case only 40 U (0.5 mL) 
2×/week will be injected for the 
remainder of the study. 
o Corticosteroid tapering. 
Addition of 
corticosteroid tapering 
for subjects entering 
open label extension 
Table 1: Schedule of 
Study Events 
Visit 8 procedures 
Not available 
Corticosteroid tapering for patients entering 
open label extension  
Section 12.5 Visit 8 
Procedures 
Not available 
- 
Corticosteroid tapering. 
Clarification for PFT 
assessment 
Table 1: Schedule of 
Study Events Footnote 
n 
n Full PFT (including DLCO) 
will be performed at Visits 1, 5, 
8, 10, and 11 (every 12 weeks).  
 
n Full PFT results will include will include 
forced expiratory volume in 1 second 
(FEV1), forced vital capacity (FVC), FVC 
% predicted (NHANES III reference 
values), FEV1/FVC ratio, peak expiratory 
flow rate (PEFR) or forced exploratory 


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flow at maximum effort (FEFmax), total 
lung capacity, residual volume, diffusing 
capacity of the lungs for carbon monoxide 
(DLCO; uncorrected for Hb), DLCO: % 
predicted and DLCO/alveolar volume. 
Section 8.2.2 
Pulmonary Function 
Tests (PFT)  
Not available 
PFT results will include FEV1, FVC, FVC 
% predicted (NHANES III reference 
values), FEV1/FVC ratio, PEFR or 
FEFmax, TLC, RV, DLCO (uncorrected 
for Hb), DLCO % predicted and 
DLCO/VA at screening visit, Visits 5, 8, 
10, and 11 (every 12 weeks).  
At the randomization visit, spirometry 
results will include FEV1, FVC, FVC % 
predicted (NHANES III reference values), 
FEV1/FVC ratio and PEFR or FEFmax. 
Enforcement of IMP 
compliance  
Table 1: Schedule of 
Study Events 
 
Not available in Assessments 
and Procedure column 
Study Drug Accountability and Diary 
Review 
Injection training 
Injection and Diary Training 
Section 12, 
PROCEDURES Visits 
3 through 11 
Not available 
Study Drug Accountability and Diary 
Review 
Sections 12.1 and 12.2 
Study Days -28 to -1 
• Injection training. Subjects (or 
caregivers) will be trained on SC 
injections using the training tools 
provided separately. The training 
• Injection and diary training. Subjects (or 
caregivers) will be trained on SC injections 
and diary completion using the training 
tools provided separately. The injection 


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(Screening Visit 1) 
and Visit 2 Procedures 
may be forgone if either the 
subject or caregiver is a 
medically trained professional. 
training may be foregone if either the subject 
or caregiver is a medically trained 
professional. 
Section 13.6 
Compliance 
Monitoring 
At each applicable visit, all IMP 
kits including used and unused 
vials will be inspected and 
compliance will be encouraged 
when IMP is dispensed. 
Subjects and/or their caregiver will be 
trained on the completion of the study 
diary and will complete study diary 
entries to record all study drug 
administration and will bring it, along 
with all study drug kits including used 
vials to each visit. Used and unused vials 
will be inspected. Number of expected, 
administered doses and reason for 
discrepancies will be documented. Each 
time study drug is dispensed compliance 
will be encouraged. Subject diary training 
is an ongoing process as the diary will be 
reviewed with the subject at each visit to 
monitor compliance with study drug 
administration. 
Typo to replace QTcF 
with QTcB 
Section 16.4.4 
Electrocardiogram 
Findings 
Electrocardiogram measured 
changes from baseline for heart 
rate, PR interval, QRS interval, 
QTcF, and RR interval will be 
summarized. 
Electrocardiogram measured changes from 
baseline for sinus rhythm, heart rate, PR 
interval, RR interval, QRS duration, Q-T 
Interval, and QTcB will be summarized. 
Over reporting of SAEs  Section 17.2 
Definitions 
Additionally, any AE that does 
not meet at least one of the 
above criteria, but that codes to a 
Additional AE definition was removed. 


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preferred term of the European 
Medicines Agency Important 
Medical Event list will also be 
considered as a SAE. 
Clarification 
Section 25 
After the study ends, the clinical 
laboratory samples will be 
destroyed, with the exception of 
samples for biomarker and 
genetic analysis. 
After the study ends, the clinical laboratory 
samples will be destroyed, with the 
exception of samples for biomarker and 
genomic analysis. 
Clarification 
ATTACHMENT 1: 
CLINICAL 
LABORATORY 
TESTS 
Hormones 
beta-Human chorionic 
gonadotropin (urinary pregnancy 
test) 
Urine and serum beta-human chorionic 
gonadotropin (pregnancy test) 
Clarification 
ATTACHMENT 1: 
CLINICAL 
LABORATORY 
TESTS 
Urinalysis 
In the event that any of the 
above assays are abnormal, a 
microscopic examination will be 
performed. 
In the event that any of the above assays are 
abnormal and evaluated by an investigator 
as clinically significant, a microscopic 
examination will be performed at a central 
laboratory. 
 


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ATTACHMENT 1: CLINICAL LABORATORY TESTS  
Serum chemistry 
Alanine aminotransferase  
Creatine phosphokinase 
Albumin (total) 
Gamma-glutamyl transferase 
Alkaline phosphatase  
Glucose 
Aspartate aminotransferase 
HbA1C 
Bilirubin (total) 
Phosphorus 
Blood urea nitrogen 
Potassium 
Calcium 
Protein (total) 
Chloride 
Sodium 
Creatinine level 
Urate 
 
 
Lipid Panel 
Cholesterol (total) 
Low density lipoprotein 
High density lipoprotein 
Triglyceride 
 
Hormones 
Urine and serum beta-human chorionic gonadotropin 
(pregnancy test) 
25-Hydroxy vitamin D 
Parathyroid hormone 
1, 25-Dihydroxy vitamin D 
Thyroid stimulating hormone 
Thyroxine T3 and T4 
 
Hematology Assays 
Hematocrit 
Platelet count 
Hemoglobin 
Red blood cell count  
White blood cell count, including differential  
 
Urinalysis 
Blood 
Nitrite 
Clarity 
Protein 
Color 
pH 
Glucose 
Specific gravity 
Leukocyte esterase 
 
In the event that any of the above assays are abnormal and evaluated by an investigator as clinically significant, 
a microscopic examination will be performed at a central laboratory. 
 
 
Hepatitis Serology 
Hepatitis B core antibody  
HCV antibody  
Hepatitis B surface antigen  
HCV PCR (only if positive for HCV antibody) 
 


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ATTACHMENT 2: STERIOD TOXICITY QUESTIONNAIRE  
 
Steroid Toxicity Questionnaire 
Please describe your experiences over the past four weeks regarding your experience using these rating 
numbers: 
(0) - None of the Time 
(1) A Little 
(2) Some of the Time 
(3) Most of the Time 
(4) All of the Time 
Experience 
None of the 
Time 
A Little 
Some of the 
Time 
Most of the 
Time 
All of the 
Time 
Increased appetite 
 
 
 
 
 
Mood swings 
 
 
 
 
 
Depression 
 
 
 
 
 
Difficulty sleeping 
 
 
 
 
 
Easy bruising 
 
 
 
 
 
Sore throat 
 
 
 
 
 
Coating of the tongue 
 
 
 
 
 
Hoarseness 
 
 
 
 
 
Wheezing 
 
 
 
 
 
Going to the bathroom at night 
 
 
 
 
 
Headaches 
 
 
 
 
 
Source: Baughman, 2002 
 


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ATTACHMENT 3: EXTRAPULMONARY PHYSICIAN ORGAN 
SEVERITY TOOL - ePOST  
 
ePOST Score 
Organ System 
0 
Not 
affected 
1 
Slight 
2 
Mild 
3 
Moderat
e 
4 
Mod to 
severe 
5 
Severe 
6 
Very 
Severe 
Lung 
 
 
 
 
 
 
 
Skin 
 
 
 
 
 
 
 
Peripheral Lymph Node 
 
 
 
 
 
 
 
Eyes 
 
 
 
 
 
 
 
Liver 
 
 
 
 
 
 
 
Spleen 
 
 
 
 
 
 
 
Central Nervous System 
 
 
 
 
 
 
 
Peripheral Nervous System 
 
 
 
 
 
 
 
Parotid/Salivary Glands 
 
 
 
 
 
 
 
Bone marrow 
 
 
 
 
 
 
 
Ear 
 
 
 
 
 
 
 
Nose 
 
 
 
 
 
 
 
Throat 
 
 
 
 
 
 
 
Cardiac 
 
 
 
 
 
 
 
Renal 
 
 
 
 
 
 
 
Bone/Joint 
 
 
 
 
 
 
 
Muscle 
 
 
 
 
 
 
 
Gastrointestinal  
 
 
 
 
 
 
 
Source: Judson et al. 2008


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ATTACHMENT 4: KING’S SARCOIDOSIS QUESTIONNAIRE  
General Health status 
 
In the last 2 weeks 
All of the 
time 
Most of the 
time 
A good bit 
of the time 
Some of the 
time 
A little of 
the time 
Hardly any 
of the time 
None of the 
time 
1 
I have felt frustrated 
1 
2 
3 
4 
5 
6 
7 
2 
I have had trouble concentrating 
1 
2 
3 
4 
5 
6 
7 
3 
I have lacked motivation 
1 
2 
3 
4 
5 
6 
7 
4 
I have felt tired 
1 
2 
3 
4 
5 
6 
7 
5 
I have felt anxious 
1 
2 
3 
4 
5 
6 
7 
6 
I have felt aches and pains in my muscles/ 
joints 
1 
2 
3 
4 
5 
6 
7 
7 
I have felt embarrassed 
1 
2 
3 
4 
5 
6 
7 
8 
I have worried about my weight 
1 
2 
3 
4 
5 
6 
7 
9 
I have worried about my sarcoidosis  
1 
2 
3 
4 
5 
6 
7 


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In the last 2 weeks 
A huge 
amount 
Considerable 
amount 
A moderate 
amount  
A modest 
amount 
A small 
amount  
A tiny 
amount 
None at all 
10 
Tiredness has interfered with my normal 
social activities such as going out with 
friends/family 
1 
2 
3 
4 
5 
6 
7 
Lung 
 
In the last 2 weeks 
All of the 
time 
Most of the 
time 
A good bit 
of the time 
Some of the 
time 
A little of 
the time 
Hardly any 
of the time 
None of the 
time 
11 
My cough has caused pain/discomfort 
1 
2 
3 
4 
5 
6 
7 
12 
I have been breathless climbing stairs or 
walking up slight inclines 
1 
2 
3 
4 
5 
6 
7 
13 
I have had to take deep breaths, also known 
as ‘air hunger’ 
1 
2 
3 
4 
5 
6 
7 
14 
My chest has felt tight 
1 
2 
3 
4 
5 
6 
7 
15 
I have had episodes of breathlessness 
1 
2 
3 
4 
5 
6 
7 
16 
I have experienced chest pains 
1 
2 
3 
4 
5 
6 
7 


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Medication 
 
In the last 2 weeks 
A huge 
amount 
Considerable 
amount 
A moderate 
amount  
A modest 
amount 
A small 
amount  
A tiny 
amount 
None at all 
17 
I have worried about side effects of my 
medication  
1 
2 
3 
4 
5 
6 
7 
18 
I have felt worse because of my medication  
1 
2 
3 
4 
5 
6 
7 
19 
I have gained weight because of my 
medication for sarcoidosis 
1 
2 
3 
4 
5 
6 
7 
Skin 
 
In the last 2 weeks 
A huge 
amount 
Considerable 
amount 
A moderate 
amount  
A modest 
amount 
A small 
amount  
A tiny 
amount 
None at all 
20 
I have been bothered by my skin problems 
1 
2 
3 
4 
5 
6 
7 
21 
I have been concerned about changes in 
colour of my skin lesions 
1 
2 
3 
4 
5 
6 
7 
 
In the last 2 weeks 
All of the 
time 
Most of the 
time 
A good bit 
of the time 
Some of the 
time 
A little of 
the time 
Hardly any 
of the time 
None of the 
time 
22 
I have been embarrassed about my skin 
1 
2 
3 
4 
5 
6 
7 
Eyes 
 
In the last 2 weeks 
All of the 
time 
Most of the 
time 
A good bit 
of the time 
Some of the 
time 
A little of 
the time 
Hardly any 
of the time 
None of the 
time 


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23 
I have had dry eyes 
1 
2 
3 
4 
5 
6 
7 
24 
I have had difficulty with bright lights 
1 
2 
3 
4 
5 
6 
7 
25 
My eyes have been red 
1 
2 
3 
4 
5 
6 
7 
26 
I have had pain in/or around the eyes 
1 
2 
3 
4 
5 
6 
7 
27 
I have had difficulty reading 
1 
2 
3 
4 
5 
6 
7 
 
In the last 2 weeks 
A huge 
amount 
Considerable 
amount 
A moderate 
amount  
A modest 
amount 
A small 
amount  
A tiny 
amount 
None at all 
28 
I have had blurred vision 
1 
2 
3 
4 
5 
6 
7 
29 
I have been worried about my eyesight 
1 
2 
3 
4 
5 
6 
7 
Source: Patel et al. 2013


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ATTACHMENT 5: FATIGUE ASSESSMENT SCALE 
The following ten statements refer to how you usually feel. Per statement you can choose one 
out of five answer categories, varying from Never to Always. Please circle the answer to each 
question that is applicable to you. Please give an answer to each question, even if you do not 
have any complaints at the moment. 
 
1 = Never, 2 = Sometimes; 3 = Regularly; 4 = Often and 5 = Always. 
 
 
 
Never 
Sometimes Regularly 
Often 
Always 
1. 
I am bothered by fatigue 
1 
2 
3 
4 
5 
2. 
I get tired very quickly 
1 
2 
3 
4 
5 
3. 
I don’t do much during the day 
1 
2 
3 
4 
5 
4. 
I have enough energy for 
everyday life 
1 
2 
3 
4 
5 
5. 
Physically, I feel exhausted 
1 
2 
3 
4 
5 
6. 
I have problems to start things 
1 
2 
3 
4 
5 
7. 
I have problems to think 
clearly 
1 
2 
3 
4 
5 
8. 
I feel no desire to do anything 
1 
2 
3 
4 
5 
9. 
Mentally, I feel exhausted 
1 
2 
3 
4 
5 
10. 
When I am doing something, I 
can concentrate quite well 
1 
2 
3 
4 
5 
 


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ATTACHMENT 6: PATIENT'S GLOBAL ASSESSMENT 
Date ___ ___ / ___ ___ / ___ ___ 
 
Subject Study Number: ________________ 
 
 
 
Sarcoidosis Activity Scale: PATIENT COMPLETES 
Considering all the ways your sarcoidosis affects you, rate how well you were doing in the past week  
 
 
______l_______I________l________l_______l________l_______l________l_______l________l______ 
0           1              2                3                 4               5                6               7                8              9               10 
Doing very poorly  
Doing very well 
 
 
 
 


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ATTACHMENT 7: PHYSICIAN GLOBAL ASSESSMENT 
Date ___ ___ / ___ ___ / ___ ___ 
 
Subject Study Number: ________________ 
 
 
 
Sarcoidosis Activity Scale: PHYSICIAN COMPLETES 
Indicate your assessment of the subject's sarcoidosis disease condition on the following scale. 
 
 
______l_______I________l________l_______l________l_______l________l_______l________l______ 
0           1              2                3                 4               5                6               7                8              9               10 
Poor  
Excellent  
 
 
 


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ATTACHMENT 8: MEDICAL RESEARCH COUNCIL DYSPNEA SCALE 
Rate your degree of breathlessness related to activity. 
 
 
 


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ATTACHMENT 9: LEICESTER COUGH QUESTIONNAIRE 
 
Source: Birring, et al, 2003 


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ATTACHMENT 10: WORK PRODUCTIVITY AND ACTIVITY 
IMPAIRMENT 
 
Work Productivity and Activity Impairment Questionnaire: 
Sarcoidosis V1.0 (WPAI: Sarcoidosis) 
 
 
 
The following questions ask about the effect of your sarcoidosis on your ability to work 
and perform regular activities.  Please fill in the blanks or circle a number, as indicated. 
 
1.  Are you currently employed (working for pay)?  
_____ NO ___ YES 
  If NO, check “NO” and skip to question 6. 
 
 
The next questions are about the past seven days, not including today. 
 
2. During the past seven days, how many hours did you miss from work because of 
problems associated with your sarcoidosis? Include hours you missed on sick 
days, times you went in late, left early, etc., because of your sarcoidosis. Do not 
include time you missed to participate in this study. 
 
_____HOURS 
 
 
3. During the past seven days, how many hours did you miss from work because of 
any other reason, such as vacation, holidays, time off to participate in this study? 
 
_____HOURS 
 
 
4. During the past seven days, how many hours did you actually work? 
 
_____HOURS  (If “0”, skip to question 6.) 
 
 


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5. During the past seven days, how much did your sarcoidosis affect your productivity 
while you were working? 
 
Think about days you were limited in the amount or kind of work you could do, days 
you accomplished less than you would like, or days you could not do your work as 
carefully as usual. If sarcoidosis affected your work only a little, choose a low 
number. Choose a high number if sarcoidosis affected your work a great deal. 
Consider only how much sarcoidosis affected 
productivity while you were working. 
Sarcoidosis 
had no effect 
on my work 
 
 
 
 
 
 
 
 
 
 
 
Sarcoidosis 
completely 
prevented me 
from working 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
CIRCLE A NUMBER 
 
6. During the past seven days, how much did your sarcoidosis affect your ability to do 
your regular daily activities, other than work at a job? 
 
By regular activities, we mean the usual activities you do, such as work around the 
house, shopping, childcare, exercising, studying, etc. Think about times you were 
limited in the amount or kind of activities you could do and times you accomplished 
less than you would like. If sarcoidosis affected your activities only a little, choose a 
low number. Choose a high number if sarcoidosis affected your activities a great deal.   
 
Consider only how much sarcoidosis affected your ability 
to do your regular daily activities, other than work at a job. 
Sarcoidosis 
had no effect 
on my daily 
activities 
 
 
 
 
 
 
 
 
 
 
 
Sarcoidosis 
completely 
prevented me 
from doing my 
daily activities 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
                           
CIRCLE A NUMBER 
 
WPAI: Sarcoidosis V1.0 (US English)      
 


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ATTACHMENT 11: SCADDING CXR SCORE 
 
 


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Source: Scadding, 1961 


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ATTACHMENT 12: SIX-MINUTE WALK TEST 
Visit 1, 8, 11 
Borg Scale  
  
 0  
Nothing at all 
 0.5  Very, Very Slight (just noticeable) 
 1  
Very Slight 
 2  
Slight 
 3  
Moderate 
 4  
Somewhat Severe 
 5  
Severe (heavy) 
 6 
 7  
Very Severe 
 8 
 9 
 10  
Very, Very Severe 
Maximal 
 
At the beginning of the 6-minute walk test, show the scale to the patient and ask the patient 
this: “Please grade your level of shortness of breath using this scale”. Then ask this: “Please 
grade your level of fatigue using this scale.”  
After the posttest recovery period, remind the patient of the breathing number that they chose 
before the exercise and ask the patient to grade their breathing level again. Then ask the patient 
to grade their level of fatigue, after reminding them their grade before the walk test. 
Vital Signs 
Baseline  
Six minutes 
1 Minute after 
walk 
Heart Rate 
 
 
 
Oxygen Sat 
 
 
 
Lpm
SA O2 
 
 
 
Borg Score (Shortness of Breath) 
 
 
 
Borg Score (Level of Fatigue) 
 
 
 
 
Laps 
 
# of Rests 
 
 
Limiting factors to test: 
 ⃝ SOB 
 ⃝ LOW Sp02 
 ⃝Heart Disease 
 ⃝Desaturation <80% 
 ⃝ Other:_____________ 
 
Total distance walked __________Feet ___________ Meters  


Signature Page for VV-CLIN-023158 v2.0
Signature Page for VV-CLIN-023158 v2.0
Approval
Clinical
18-May-2020 16:35:27 GMT+0000

SAP_001.pdf: 
Official Title: 
A Multicenter, Randomized, Double Blind, Placebo Controlled 
Exploratory Study to Assess the Efficacy and Safety of Acthar® Gel in 
Subjects with Pulmonary Sarcoidosis 
NCT Number: 
NCT03320070 
Document Date: 
SAP Version 3.0: 02 February 2022 


 
 
 
 
 
 
 
 
 
 
 
Mallinckrodt ARD, Inc. 
 
MNK14344100 
 
A Multicenter, Randomized, Double Blind, Placebo Controlled 
Exploratory Study to Assess the Efficacy and Safety of Acthar® Gel in 
Subjects with Pulmonary Sarcoidosis 
 
08JUL2021 
 
Draft Statistical Analysis Plan 
 
Version 3.0 
 
Prepared by: 
 
PPD 
3575 Quakerbridge Road, Suite 201 
Hamilton, NJ 08619 
 
 
 


Mallinckrodt ARD, Inc. 
Page 2 of 56 
 
MNK14344100 SAP Version 3.0 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ....................................................................................................... 4 
1. 
INTRODUCTION ............................................................................................................. 6 
2. 
STUDY OBJECTIVES ..................................................................................................... 6 
3. 
INVESTIGATIONAL PLAN ........................................................................................... 6 
3.1. OVERALL STUDY DESIGN AND PLAN ........................................................................ 6 
3.2. STUDY ENDPOINTS .................................................................................................... 7 
3.2.1. 
Efficacy Endpoints ............................................................................................ 7 
3.2.2. 
Biomarker and Genetic Endpoints .................................................................... 9 
3.2.3. 
Safety Endpoints ............................................................................................... 9 
4. 
GENERAL STATISTICAL CONSIDERATIONS ........................................................ 9 
4.1. SAMPLE SIZE ............................................................................................................. 9 
4.2. RANDOMIZATION, STRATIFICATION, AND BLINDING ................................................. 9 
4.3. REPORTING CONVENTIONS ....................................................................................... 9 
4.4. ANALYSIS POPULATIONS ........................................................................................ 11 
4.4.1. 
Modified Intent-to-Treat Population ............................................................... 11 
4.4.2. 
Safety Population ............................................................................................ 11 
4.4.3. 
Open-label Safety Population .......................................................................... 11 
5. 
SUBJECT DISPOSITION .............................................................................................. 12 
6. 
PROTOCOL DEVIATIONS .......................................................................................... 13 
7. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ................................... 13 
7.1. DEMOGRAPHICS ...................................................................................................... 13 
7.2. BASELINE DISEASE CHARACTERISTICS ................................................................... 14 
7.3. MEDICAL AND SURGICAL HISTORY ......................................................................... 14 
8. 
TREATMENTS AND MEDICATIONS ....................................................................... 15 
8.1. PRIOR AND CONCOMITANT MEDICATIONS .............................................................. 15 
8.2. PRIOR AND CONCOMITANT SARCOIDOSIS MEDICATIONS ........................................ 16 
8.3. STUDY TREATMENTS .............................................................................................. 16 
8.3.1. 
Extent of Exposure .......................................................................................... 16 
8.3.2. 
Treatment Compliance .................................................................................... 16 
9. 
EFFICACY ANALYSIS ................................................................................................. 17 
9.1. SARCOIDOSIS TREATMENT SCORE (STS) ................................................................ 17 
9.2. PHYSICIAN AND SUBJECT INDEPENDENT RESPONSE TO CONTINUE TO CURRENT 
TREATMENT ...................................................................................................................... 20 
9.3. PULMONARY FUNCTION TESTS ............................................................................... 20 
9.4. IMAGING ................................................................................................................. 22 
9.4.1. 
HRCT and CXR .............................................................................................. 22 


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MNK14344100 SAP Version 3.0 
9.4.2. 
Scadding Score ................................................................................................ 23 
9.5. PATIENT-REPORTED OUTCOMES AND SYMPTOM QUESTIONNAIRES ........................ 23 
9.6. SIX-MINUTE WALK TEST (6MWT) ........................................................................ 25 
9.7. EXTRAPULMONARY PHYSICIAN ORGAN SEVERITY TOOL (EPOST) ........................ 25 
9.8. CORTICOSTEROID TAPERING ................................................................................... 26 
10. 
SAFETY ANALYSIS ...................................................................................................... 27 
10.1. 
ADVERSE EVENTS ................................................................................................ 27 
10.2. 
CLINICAL LABORATORY EVALUATIONS .............................................................. 28 
10.2.1. 
Hematology .................................................................................................. 28 
10.2.2. 
Serum Chemistry ......................................................................................... 29 
10.2.3. 
Hormone ...................................................................................................... 29 
10.2.4. 
Lipid Panel ................................................................................................... 29 
10.2.5. 
Urinalysis, Hepatitis serology, Tuberculosis Testing and Pregnancy Testing
 
29 
10.3. 
VITAL SIGN MEASUREMENTS .............................................................................. 30 
10.4. 
PHYSICAL EXAMINATION .................................................................................... 30 
10.5. 
ELECTROCARDIOGRAM ........................................................................................ 30 
11. 
BIOMARKER ANALYSIS ............................................................................................ 30 
11.1. 
BIOMARKERS ....................................................................................................... 30 
11.2. 
GENETIC PROFILE ................................................................................................ 31 
12. 
INTERIM ANALYSIS .................................................................................................... 31 
13. 
CHANGES IN THE PLANNED ANALYSIS ............................................................... 31 
14. 
REFERENCES ................................................................................................................ 31 
15. 
APPENDICES ................................................................................................................. 33 
15.1. 
DATE IMPUTATION GUIDELINE ............................................................................ 33 
15.1.1. Adverse Events ................................................................................................. 33 
15.1.2. Prior/Concomitant Medications ........................................................................ 33 
15.2. 
CALCULATION OF PATIENT-REPORTED OUTCOMES AND SYMPTOM 
QUESTIONNAIRES .............................................................................................................. 35 
15.2.1. Steroid Toxicity Questionnaire ......................................................................... 35 
15.2.2. King’s Sarcoidosis Questionnaire .................................................................... 35 
15.2.3. Fatigue Assessment Scale (FAS) ...................................................................... 50 
15.2.4. Patient Global Assessment Score ..................................................................... 50 
15.2.5. Physician Global Assessment Score ................................................................. 50 
15.2.6 Medical Research Council Dyspnea Scale ........................................................ 50 
15.2.7 Leicester Cough Questionnaire ......................................................................... 50 
15.3. 
SCHEDULE OF STUDY EVENTS ............................................................................. 52 
15.4. 
SAS PROCEDURES ............................................................................................... 55 


Mallinckrodt ARD, Inc. 
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MNK14344100 SAP Version 3.0 
List of Abbreviations 
 
6MWT 
Six-Minute Walk Test 
AE 
 
adverse event 
ANOVA 
analysis of variance 
AR1 
first-order autoregressive 
ATC 
Anatomical Therapeutic Chemical  
BMI 
body mass index 
CXR 
chest x-ray 
CS 
Compound Symmetry 
DLCO 
Diffusing capacity of the lungs for carbon monoxide 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ePOST 
extrapulmonary Physician Organ Severity Tool  
FAS 
Fatigue Assessment Scale 
FEF 
forced expiratory flow 
FEV1 
forced expiratory volume in 1 second 
FVC 
forced vital capacity 
Hb 
hemoglobin 
HbA1c 
hemoglobin (glycosylated) 
HRCT 
high-resolution computed tomography 
IMP 
investigational medicinal product 
KSQ 
King’s Sarcoidosis Questionnaire 
LCQ 
Leicester Cough Questionnaire 
LLoQ 
lower limit of quantitation 
LOCF 
last observation carried forward  
LS 
least square 
MMRM 
mixed model with repeated measures 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
PEFR 
peak expiratory flow rate 
PFT 
pulmonary function test 


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MNK14344100 SAP Version 3.0 
PT 
preferred term 
RV 
residual volume 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SD 
standard deviation 
SE 
standard error 
SI 
International System of Units 
SOC 
system organ class 
STS 
sarcoidosis treatment score 
TEAE 
treatment-emergent adverse events 
TLC 
total lung capacity 
TTR 
time to response 
ULoQ 
upper limit of quantitation 
UN 
unstructured 
VA 
alveolar volume 
WHO 
World Health Organization 
WPAI 
Work Productivity and Activity Impairment 


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MNK14344100 SAP Version 3.0 
 
1. Introduction 
The purpose of the Statistical Analysis Plan (SAP) is to describe the analyses and data 
presentations for the Sponsor’s protocol MNK14344100. This SAP outlines the types of 
analyses that will address the study objectives and explains in detail how the data will be 
handled and analyzed. It contains the definitions of analysis populations and statistical 
methods for the analysis of safety and efficacy. 
2. Study Objectives 
The objective of the study is to evaluate the efficacy and safety of Acthar® Gel (Acthar) in 
the treatment of pulmonary sarcoidosis. 
3. Investigational Plan 
3.1. Overall Study Design and Plan 
This is a Phase 4, multicenter, randomized, double-blind, placebo-controlled exploratory 
study evaluating the efficacy and safety of Acthar in the treatment of pulmonary 
sarcoidosis. The study will have 3 phases: screening (up to 28 days); double-blind 
treatment (Visit 2 to Visit 8, 24 weeks); and an optional open-label extension (Visit 9 to 
Visit 11, 24 weeks). A follow-up visit will be conducted at 4 weeks (± 2 days) after the last 
dose of investigational medicinal product (IMP) is administered.  
An overview of the study is presented in Figure 1. 
Subjects who meet all eligibility criteria will be randomly assigned to receive either 1 mL 
(80 U) of Acthar or 1 mL of a matching placebo subcutaneously (SC) twice weekly. 
Following the completion of the double-blind phase, subjects will be invited to continue 
participation in an optional Open-label Extension Phase (Visit 9 to Visit 11, 24 weeks). 
Subjects who decline participation in the open-label extension phase, or those ineligible, 
will have their End-of-Treatment visit during Visit 8. 
Dose reduction of 50% may be implemented once during the study if a subject meets one 
of the prespecified safety criteria (refer to protocol Section 9.1). Once dose reduction is 
implemented, subjects will remain on the 40 U or matching placebo twice weekly for the 
remainder of the study.  
The schedule of study events is presented in Appendix 15.3. 


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Figure 1: Study Overview 
 
3.2. Study Endpoints 
3.2.1. Efficacy Endpoints 
The endpoints for the efficacy objective are: 
• Sarcoidosis treatment score (STS) response rate at 24 weeks (Visit 8). 
• STS response rate at 48 weeks (Visit 11). 
• Physician and subject independent responses to the question “Would you choose to 
continue current treatment?” at 24 and 48 weeks. 
• Time to response (TTR) as evaluated at earlier time points (Weeks 4 to 20) as 
determined by the investigator based on clinical judgment and the following 
parameters: 
o 
Patient reported outcomes. 
o 
Corticosteroid tapering. 
o 
Patient Global Assessment. 
o 
Physician Global Assessment  


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o 
Pulmonary function test (PFT) at applicable time points. 
o 
Extrapulmonary response by extrapulmonary Physician Organ Severity Tool 
(ePOST).  
o 
Supportive efficacy endpoints per applicable time points. 
▪ Six-minute walk test (6MWT). 
▪ Symptom relief (Leicester Cough Questionnaire, Medical Research Council 
Dyspnea Scale, steroid toxicity questionnaire). 
▪ Chest x-ray (CXR) (including Scadding score).  
• Percentage change in overall diffusion capacity of the lung for carbon monoxide 
(DLCO). 
• Percentage of subjects with improvement in DLCO of ≥ 5%; ≥10%; and ≥ 15%. 
• Percentage change in overall forced vital capacity (FVC). 
• Percentage of subjects with improvement in FVC of ≥ 5%, ≥10%, and ≥ 15%. 
• Percentage of subjects with improved/stable/deteriorate side-by-side comparison of 
high-resolution computed tomography (HRCT) on a 5-point Likert score: much 
worse; worse; unchanged; better; much better (central reader). 
• Percentage of subjects with improved/stable/deteriorated side-by-side comparison 
of CXRs on a 5-point Likert score: much worse; worse; unchanged; better; much 
better (central reader). 
• Percentage change in Scadding score (side-by-side comparison of CXRs by a 
central reader). 
• Percentage change in patient-reported outcomes and symptom questionnaires. 
• Percentage failed corticosteroid taper. 
• Time to failed corticosteroid taper (for subjects failing taper). 
• Change from baseline in Work Productivity and Activity Impairment (WPAI) over 
time 


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3.2.2. Biomarker and Genetic Endpoints  
Biomarkers levels will be compared between baseline, and every 12 weeks (up to 48 weeks 
for those subjects participating in the optional open-label extension phase). Serum aliquots 
will be kept for each of these time points. Possible biomarkers include angiotensinogen, 
sIL-2R and vitamin D 1, 25. The final selection of biomarkers will be made based on the 
scientific knowledge and emerging guidance closer to the completion of the study. 
Genomic profile (optional) will be assessed based on the understanding of genetic factors 
at the time of study completion. 
3.2.3. Safety Endpoints  
Overall safety will be determined by the incidence, severity and relationship of AEs, 
physical examinations, vital signs, clinical laboratory abnormalities, and imaging. 
4. General Statistical Considerations 
4.1. Sample Size 
Formal sample size calculations were not performed. The sample size is based on recent 
literature of comparative studies (Gibson et al., 1996; Baughman et al., 2006; Judson, 
2014) in sarcoidosis. There are 55 subjects randomized to this study. 
4.2. Randomization, Stratification, and Blinding 
An interactive telephone/web response system will be used to allocate eligible subjects to 
each treatment group. Subjects will be randomized according to computer-generated 
allocation scheme to receive either Acthar Gel 1 mL (80 U) or placebo 1 mL administered 
twice a week in a 1:1 ratio. Both investigators and the subjects will be blinded to the 
treatment assignment. A block randomization will be performed. 
4.3. Reporting Conventions 
The following reporting conventions apply generally to tables, listings, and figures: 
• All by-visit summaries and analyses will be provided separately for the double-
blind treatment phase and the open-label extension phase, unless otherwise 
specified. Only subjects who continued to the open-label extension phase will be 
included in the summaries of open-label extension phase based on the open-label 
safety populations.  


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• For subjects who continued into the open-label extension phase, the first dose of 
IMP at the open-label extension phase will be used as the cutoff date. Since the first 
dose administration date at the open-label extension phase is not collected 
electronically, and the dosing schedule is twice/week, either the first IMP kits and 
equipment dispense date or the next date after completion date of double-blind 
phase, whichever is the later date, has been used as the best estimate of the first 
dose of IMP in the open label extension phase. The assessments collected before 
the cutoff date will be summarized in the double-blind treatment phase and the 
assessments collected on or after the cutoff date will be summarized in the open-
label extension phase, unless specified otherwise. Subjects who did not continue 
into the open-label extension phase will be summarized in the double-blind 
treatment phase only. 
• Summaries for the double-blind treatment phase will be based on the treatments 
that the subjects actually received at the double-blind treatment phase. Summaries 
for the open-label extension phase will also be based on the treatment sequences 
that the subjects actually received during overall study phase, e.g. Acthar/Acthar 
and Placebo/Acthar. 
• Study Day 1 is defined as the date of the first dose of IMP at the double-blind 
treatment phase. Study days are calculated as the difference between the date of 
interest and Study Day 1 plus 1 day. For events before Study Day 1, study days will 
be calculated as the difference in days between Study Day 1 and the date of 
interest. The day before the date of the first dose at the double-blind treatment 
phase will be defined as Day -1. This means there will be no study Day 0. 
• Two baselines, baseline of overall study and baseline of active treatment, have been 
defined. Baseline of overall study is defined as the last assessment prior to the first 
dose of IMP at the double-blind treatment phase. Baseline of active treatment is 
defined as the last assessment prior to the first dose of active treatment in either the 
double-blind treatment phase or the open-label extension phase. All the analysis in 
the open-label extension phase that involves presenting change and/or percent 
change from baseline will present change/percent change from both baselines. 
• Summary statistics will be provided for all study variables with descriptive 
statistics (number of subjects, mean, standard deviation (SD), median, minimum, 


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and maximum) for numerical (or continuous) variables. Frequency and percentages 
will be calculated for categorical variables. 
• Unless specified otherwise for a given analysis, all statistical tests, when 
applicable, will be 2-sided with a significance level of 0.05. 
• All data collected will be presented in listings, sorted by treatment group, subject 
identifier and date/time of procedure or event, if applicable. 
All analyses will be conducted using SAS® Version 9.4 or higher. The Medical Dictionary 
for Regulatory Activities (MedDRA) version 23.0 will be used for coding adverse events 
(AEs), and medical and surgical histories. Prior or concomitant medication data will be 
coded according to the Anatomical Therapeutic Chemical (ATC) coding scheme of the 
World Health Organization (WHO) Drug Dictionary (Enhanced B2 dated March 2018 
version, or higher) level 2 term. 
4.4. Analysis Populations 
4.4.1. Modified Intent-to-Treat Population 
The modified Intent-to-Treat (mITT) Population includes all randomized subjects who 
receive at least 1 dose of IMP and who contribute any efficacy data to the study. The mITT 
Population will be used for the efficacy analyses based on the treatment they actually 
received during double-blind treatment phase. 
4.4.2. Safety Population 
The Safety Population includes all randomized subjects who receive at least 1 dose of IMP 
and will be used for all the safety analyses which will be based on the actual treatment 
received at the double-blind treatment phase.  
4.4.3. Open-label Safety Population 
The Open-label Safety Population includes subjects who continue into open-label 
extension phase and receive at least one dose of IMP during the open-label extension 
phase. The Open-label Safety Population will be used for all the safety and efficacy 
analyses for open-label extension phase and will be based on the actual treatment 
sequences received during the overall study phase (Acthar/Acthar or Placebo/Acthar) and 
total.  


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5. Subject Disposition 
A summary of analysis populations will be presented by treatment group and total for all 
randomized subjects, the mITT population, the safety population, and open-label safety 
population. Summary of subject disposition will be presented for double-blind treatment 
phase and open-label extension phase separately. 
Disposition of all randomized subjects in double-blind treatment phase will be summarized 
by treatment group and total descriptively, including summaries of the number and 
percentage of subjects who completed the double-blind treatment phase, subjects who 
continued into the open-label extension phase, subjects who early terminated from the 
double-blind treatment phase and the reasons for early termination from the double-blind 
treatment.  
In addition, disposition of subjects participating in the optional open-label extension phase 
will be summarized by actual treatment sequences and total descriptively, including 
summaries of the number and percentage of subjects who completed the double-blind 
treatment phase, subjects who continued into the open-label extension phase, subjects who 
completed the open-label extension phase, and subjects who early terminated from the 
open-label extension phase. The reasons for early termination from the open-label 
extension will also be summarized.  
The reasons for early termination from the double-blind treatment and the reasons for early 
termination from the open label extension will be summarized based on the following 
categories: 
• Adverse event 
• Death 
• Lack of efficacy 
• Lost to follow-up 
• Met withdrawal criteria 
• Non-compliance with study drug 
• Physician decision 
• Protocol violation 
• Study terminated by sponsor 


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• Withdrawal by subject 
• Other 
Subject disposition for all randomized subjects and subject disposition for open-label 
safety population will be provided in by-subject listing, respectively.  
6. Protocol Deviations 
The significant protocol deviations will be summarized by category using frequency 
tabulations based on the safety population in the double-blind treatment phase and on 
open-label safety population in the open-label extension phase separately. The cut off of 
two study phases has been defined in reporting conventions section 4.3. Listings of 
significant protocol deviations will be provided to support the summary tables. 
7. Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized by treatment group and 
total using the mITT population and safety population in the double-blind treatment phase 
and open-label safety population in the open-label extension phase. Individual subject 
listings will be provided to support the summary tables for all randomized subjects in the 
double-blind phase. 
7.1. Demographics 
Descriptive statistics will be provided for the following continuous variables collected at 
baseline: 
• Age (year) 
• Weight (kg) 
• Height (cm) 
• Body Mass Index (BMI) (kg/m2) as recorded on the electronic case report form 
(eCRF) 
The number and percentage of subjects will be provided for the following categorical 
variables: 
• Sex (Male, Female) 


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• Race (American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or Other Pacific Islander, White, Multiple, Other) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown, Unreported) 
• Female Fertility Status (Surgically Sterile, Post-Menopausal, Childbearing 
potential) 
A female fertility status listing will be provided for all randomized subjects.  
7.2. Baseline Disease Characteristics 
The following baseline disease characteristics and disease history will be summarized: 
• Smoking history (Current Smoker; Ever Smoked, and Never Smoked) 
• Current Employment Status (Full Time, Part Time, Retired, Home Maker, and Not 
Employed) 
• Ever Employed/Worked (Yes, No) 
• Organs involved in sarcoidosis (A subject may have more than one organ involved 
in sarcoidosis. The subject will be counted for each organ.) 
• Occupational History (Exposure to Mold, Bacteria or Other Microbial 
Contaminants, Fumes, Asbestos, Wood Burning Smoke, Insecticide, Silicates, 
Metal Dust or Inorganic Dust, Aerosols, Inorganic Particulate, and Other) and 
duration of exposure to each type in years 
• Time from sarcoidosis diagnosis (months) 
Time from sarcoidosis diagnosis in months will be calculated as: 
(date of screening - date of sarcoidosis diagnosis + 1)/30.4375. 
Sarcoidosis history, smoking history and occupational history data for all randomized 
subjects will be provided in listings. 
Disease characteristics for the subjects who enrolled in the open-label extension phase may 
be summarized using open-label safety population. 
7.3. Medical and Surgical History 
Medical and surgical history will be summarized by system organ class (SOC) and 
preferred term (PT) for the safety population. A subject will be counted only once within 


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each level of SOC and PT. Percentages are based on the number of subjects within each 
treatment group. SOC will be presented alphabetically and PTs within each SOC will be 
presented in decreasing order of frequency calculated based on the Acthar treatment group. 
Medical and surgical history data for all randomized subjects will be presented in a listing. 
8. Treatments and Medications 
Study treatments, medications and sarcoidosis specific medications will be summarized by 
treatment group and total based on the safety population in double-blind treatment phase 
and then open-label safety population in the open-label extension phase, respectively. 
Descriptive statistics will be provided for continuous variables and frequency counts and 
percentages will be applied to categorical variables. Missing or partially missing start/stop 
dates for prior/concomitant medications will be imputed in order to justify 
prior/concomitant status, refer to Appendix 15.1.2 for imputation details. 
8.1. Prior and Concomitant Medications 
All prior and concomitant medications will be coded using the WHO Drug dictionary. 
Prior medications are defined as all non-study medications that were started before the start 
of the study treatment and either ended before the start of the study treatment or continued 
into the study treatment period.  
Concomitant medications in the double-blind treatment phase are non-study medications 
that are ongoing during the double-blind treatment phase or with a start date occurring 
before the first dose of IMP in the open label extension phase. 
Concomitant medications in the open-label extension phase are non-study medications that 
are ongoing during the open-label extension phase or with a start date occurring on or after 
the first dose of IMP at the open label extension phase. 
Medications initiated prior to the first dose of IMP at the open-label extension phase and 
were continued into the open-label phase will be counted into both phases.  
Prior and concomitant medications will be summarized separately. Concomitant 
medications will be summarized by the double-blind and the open-label phase separately. 
The tables will present the number and percentage of subjects by WHO ATC level 2 and 
preferred drug name for each treatment group and total. ATC level 2 will be presented 
alphabetically, while preferred drug name within each ATC level 2 will be presented in 
decreasing order of frequency calculated based on the Acthar treatment group. In addition, 


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the number and percentage of subjects receiving at least one prior or concomitant 
medication will be presented. A subject with multiple occurrences of a drug class or drug 
is counted only once in the ATC 2 level or preferred drug name, respectively. 
All prior and concomitant medications for safety population will be presented in listings by 
study phases. 
8.2. Prior and Concomitant Sarcoidosis Medications 
The prior and concomitant sarcoidosis meditations will be summarized by preferred drug 
name for each treatment group and total. Concomitant sarcoidosis medications will be 
summarized by the double-blind and the open-label phase, respectively.  
8.3. Study Treatments 
Study treatments and extent of exposure summaries will be provided based on the safety 
population in the double-blind treatment phase and the open-label extension phase, 
respectively. Descriptive statistics will be provided for treatment duration, number of 
injections, dose reduction and justifications for dose reduction by study phases. 
A listing for each study phase will be provided for drug accountability and treatment 
compliance, respectively. 
8.3.1. Extent of Exposure 
Treatment duration of double-blind treatment phase (weeks) is defined as:  
[(date of last dose at double-blind treatment phase) – (date of first dose at double-blind 
treatment phase) + 1]/7. 
Treatment duration of open-label extension phase (weeks) is defined as:  
[(date of last dose at open-label extension phase) – (date of first dose at open-label 
extension phase) + 1]/7,  
Descriptive statistics will be provided for treatment durations by treatment group and total. 
8.3.2. Treatment Compliance 
During each visit, the number of injections that a subject was expected to take and the 
number of injections that a subject actually took since previous visit until prior to the 
current visit will be recorded on the eCRF.  
Treatment compliance (%) of double-blind treatment phase is defined as: 


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phase
 
 treatment
blind
-
double
 
during
 taken 
be
 
 to
expected
 
injections
 
of
Number 
100
phase)
 
 treatment
blind
-
double
 
during
 taken 
injections
 
of
(Number 

 
Treatment compliance (%) of open-label extension phase is defined as: 
phase
extension 
 
label
-
open
 
during
 taken 
be
 
 to
expected
 
injections
 
of
Number 
100
) 
phase
extension 
 
label
-
open
duration 
 
 the
during
 taken 
injections
 
of
(Number 

 
The study drug compliance rate in the double-blind treatment phase, and compliance rate 
in the open-label extension phase will be summarized by treatment group using the 
descriptive statistics. The compliance rates will also be summarized by categories (<80, 80 
to <=120, and >120).  
9. Efficacy Analysis 
All efficacy evaluations will be conducted using the mITT population unless otherwise 
specified and will be provided by treatment group for the double-blind treatment phase. 
Efficacy evaluations will only be summarized descriptively using the open-label safety 
population by treatment group and total for the open-label extension phase. All summaries 
and analyses will be conducted on the observed values unless otherwise specified. All 
efficacy data will be presented in listings based on the mITT population in the double-
blind treatment phase and based on the open-label safety population in the open-label 
extension phase. The derived efficacy variables will be displayed in data listings as well. 
Additional subgroup analyses by sex, race and ethnicity will be performed on missing 
imputed data as specified. Other exploratory analyses may be performed as appropriate. 
9.1. Sarcoidosis Treatment Score (STS) 
STS is a newly developed composite score that combines the results of PFT, chest 
imaging, quality of life, and changes in corticosteroid dosing. Individuals may score from -
6 to + 6. Higher scores indicate improvement. Subjects tolerating Acthar Gel (or placebo) 
will be categorized as Response, Partial Response, and Non Response. STS can be 
determined by using the assessments categories as presented in table below. 


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Table 1: Determining the Sarcoidosis Treatment Score 
 
Parameter 
Improved 
Unchanged 
Deteriorate 
Category of 
Assessment 
 
+1 
0 
-1 
PFTa 
FVC  
≥ 5% 
> -5% to < 5% 
≤ -5% 
DLCO  
≥ 5% 
> -5% to < 5% 
≤ -5% 
Imaging 
HRCT 
Improved 
Unchanged 
Worse 
Quality of Life 
King’s Sarcoidosis 
Questionnaire 
(General Health) 
≥ 4 
> -4 to < 4 
≤ -4 
Fatigue 
Assessment Score 
≤ -4 
> -4 to < 4 
≥ 4 
 
Corticosteroid 
taper (dosage) 
≥ 50% 
reduction  
< 50% 
reduction or ≥ 
5 mg increase 
for less than 2 
weeks  
≥ 5 mg increase 
for more than 2 
weeks 
aAbsolute change of % predicted.  
Subject tolerating Acthar (or placebo) will be categorized according the following scoring:  
• Response is defined as scores of ≥ 3/6 points.  
• Partial Response is defined as scores of 2/6 points or stable with corticosteroid 
reduction (ie, a total score of +1 due to ≥ 50% reduction in corticosteroid dosage).  
• Non Response is defined as scores of ≤ 1/6 points without significant corticosteroid 
taper (stable or deterioration). 
An STS responder is defined as a subject who has an assessed STS category of Response 
or Partial Response at 24 weeks (Visit 8) during double-blind treatment phase and at 48 
weeks (Visit 11) during open-label phase. 
The descriptive statistics for developed STS scores, number and percentage of subjects in 
each STS response category (response, partial response and non response) will be provided 
at both 24 weeks (Visit 8) and 48 weeks (Visit 11). At 24 weeks (Visit 8) during double-
blind treatment phase, the proportions of STS responder (defined as response or partial 
response) and non-responder, and corresponding odds ratio will be calculated. The 95% 
confidence interval (CI) of the odds ratio will be calculated as well based on asymptotic 
method. Pearson’s chi-square test (or Fisher’s exact test if any expected count is less than 
5) will be used to assess the comparability between treatment groups for the STS responder 


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vs. non-responder rate.  At 48 weeks (Visit 11) during open-label phase, the proportions of 
STS responder and non-responder along with 95% CI will be provided. The 95% CI will 
be calculated by using the exact (Clopper-Pearson) method. 
Missing STS scores will be imputed at 24 weeks (Visit 8) during double-blind treatment 
phase. Last observation carried forward (LOCF) method will be employed to impute 
missing component(s) if any component of STS is missing at the post-baseline visit during 
double-blind treatment phase. If there is still missing component(s) after applying LOCF 
imputation method, STS score will remain as missing. Subjects who do not provide data 
(after component level LOCF imputation) to allow classification as responders will be 
considered non-responders, that is, missing data will be imputed as non-responder. The 
same missing data imputation method will be applied to other similar efficacy endpoints in 
double-blind treatment phase. No imputation will be applied to the open-label extension 
phase. A bar plot of STS category will be provided at 24 weeks (Visit 8) during double-
blind treatment phase and at 48 weeks (Visit 11) during open-label phase, respectively. 
Sensitivity analyses with using only the observed data will be performed for the above 
analysis at 24 Weeks (visit 8) only. 
Subgroup analyses by sex, race and ethnicity will be performed in similar manner as 
specified above on the imputed data only. 
STS component scores including FVC % Predicted Score, DLCO % predicted Score, 
HRCT Score, King’s Sarcoidosis Questionnaire (KSQ) General Health Score, Fatigue 
Assessment Score and Corticosteroid Taper Score will be summarized. Number and 
percentage of subjects in each category (Improved, Unchanged and Deteriorate) of each 
STS component score presented in Table 1 will be provided at 24 weeks (Visit 8) and at 48 
weeks (Visit 11). Pearson’s chi-square test (or Fisher’s exact test if any expected count is 
less than 5) will be used to assess the comparability between treatment groups for each 
STS component at 24 Weeks (visit 8) only.   
Listings of STS components and STS scores will be provided by study phases. Subjects 
with any missing component of STS will be indicated. 
In addition, correlation analysis between STS score and each of its components and/or 
other assessments (e.g. Six-Minute Walk Test, Physician Global Assessment, ect.) may be 
performed based on the data from both study phases. Pearson or Spearman correlation 
coefficients and the corresponding p-values will be generated depending on the distribution 


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of the data. The data may also be presented in scatter plots with regression line, correlation 
coefficient and p-value annotated.  
9.2. Physician and Subject Independent Response to Continue to Current Treatment 
The number and percentage of physician and subject independent response (Yes, No) to 
the question “Would you choose to continue current treatment?” at week 24 (Visit 8) and 
at week 48 (Visit 11) will be summarized by treatment group. The response rate of “Yes” 
between treatment groups will be tested using Pearson’s chi-square test (or Fisher’s exact 
test if any expected count is less than 5), for both physician and subject at week 24 (Visit 
8) only. In the double-blind phase only, missing response will be imputed as “No”. 
Physician and subject independent response to continue current treatment will be provided 
in a listing by study phase. 
9.3. Pulmonary Function Tests 
Descriptive statistics of observed and change from baseline will be presented for PFT 
results including DLCO % predicted and FVC % predicted at each scheduled visit during 
double-blind treatment phase and open-label extension phase, respectively. In addition, 
change from baseline of active treatment will be presented for open-label extension phase. 
The treatment difference between Acthar and placebo for change from baseline to each 
visit in the double-blind treatment phase in DLCO % predicted and FVC % predicted will 
be evaluated using a two-sample T-test. Change in DLCO % predicted and FVC % 
predicted will be plotted in line graph over time showing the means and SEs by visit across 
both study phases. 
Also, the treatment effect for the change from baseline to each scheduled visit in the 
double-blind treatment phase in DLCO % predicted and FVC % predicted will be 
estimated using a mixed effect model with repeated measures (MMRM) model. The 
MMRM model will use change from baseline as the response variable, and include visit, 
treatment group, and visit-by-treatment group interaction as covariates. Additionally, visit 
(categorical) will be specified as a repeated effect and unstructured (UN) correlation matrix 
will be used to model intra-subject correlation. In case a convergence issue will arise using 
the UN correlation matrix, (1) first-order autoregressive (AR1) or (2) Compound 
Symmetry (CS) will be used to enable model convergence (in this order). The least square 
(LS) mean difference with 95% CI and p-value will be presented. 


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In addition, improvement in DLCO % predicted and FVC % predicted will be explored by 
using criteria (≥ 5%, ≥ 10% and ≥ 15%, respectively). Number and percentage of subjects 
with improvement will be provided at each scheduled visit by double-blind treatment 
phase and open-label extension phase. Pearson’s chi-square test (or Fisher’s exact test if 
any expected count is less than 5) will be used to compare the treatment difference 
between treatment groups in the double-blind treatment phase. The following endpoints 
will be included: 
• Percentage of subjects with improvement in DLCO % predicted of ≥ 5% 
• Percentage of subjects with improvement in DLCO % predicted of ≥10% 
• Percentage of subjects with improvement in DLCO % predicted of ≥ 15% 
• Percentage of subjects with improvement in FVC % predicted of ≥ 5% 
• Percentage of subjects with improvement in FVC % predicted of ≥10% 
• Percentage of subjects with improvement in FVC % predicted of ≥ 15% 
Percentage of subjects in each treatment group meeting each improvement criterion will be 
analyzed using both imputation and data as observed methods in double-blind treatment 
phase, and using data as observed method only in the open-label extension phase. For the 
analysis using imputation, mITT subjects without an evaluable assessment for the criterion 
will be considered as no improvement for that criterion. For the analysis of data as 
observed, mITT subjects without an evaluable assessment for the criterion will be excluded 
from the analysis for that criterion.  
Other PFT assessments including FEV1, FVC, FEV1/FVC ratio, PEFR or FEFmax, TLC, 
RV, DLCO (uncorrected for Hb) and DLCO/VA if available will be summarized by using 
descriptive statistics for observed and change from baseline at the scheduled visits during 
double-blind treatment phase and open-label extension phase.  The treatment difference 
between Acthar and placebo for change from baseline to each visit in the double-blind 
treatment phase will be evaluated using a two-sample T-test. 
A listing will be provided for the PFT data by subject and visit. 


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9.4. Imaging  
9.4.1. HRCT and CXR 
Imaging (HRCT and CXR) will be evaluated by the investigator/radiologist and the central 
reader to determine if the condition is improving, stable, or deteriorating based on a 5-
point Likert score: much worse; worse; unchanged; better; much better at week 24 (Visit 8) 
and week 48 (Visit 11). Data from central reader will be analyzed and listed. Data from 
investigator/radiologist will only be listed. 
Response (improved, stable, and deteriorate) based on the side-by-side comparison of 
HRCT and CXR is defined as: 
Response 
Likert Score 
Improved 
Better; Much Better 
Stable 
Unchanged 
Deteriorate 
Much Worse; Worse 
The number and percentage of subjects for each Likert score will be summarized for each 
treatment group by visits, along with number and percentage of subjects with each 
response of improved, stable, and deteriorate for HRCT and CXR, respectively. The 
percentage will be calculated based on number of subjects in each treatment group. A bar 
plot of responses will also be provided. 
Pearson’s chi-square test (or Fisher’s exact test if any expected count is less than 5) will be 
used to compare the treatment difference between treatment groups for the proportion of 
subjects with response of improved vs. not improved, and the proportion of subjects with 
response of not deteriorate vs. deteriorate at week 24 (Visit 8) for HRCT and CXR 
separately. Subjects who have missing assessments at the visit will be imputed as opposite 
outcome for the given categorization, i.e. missing response will be imputed as not 
improved or deteriorate, as applicable. 
A secondary analysis will then be performed by only including subjects with assessments 
evaluated. The percentage of subjects in each category will be calculated based on number 
of subjects with assessments in each treatment group at each scheduled visit (Visit 8 and 
Visit 11).  


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9.4.2. Scadding Score 
The number and percentage of subjects for each Scadding score (Stage 0, Stage I; Stage II; 
Stage III; and Stage IV) will be summarized at week 24 (Visit 8) and week 48 (Visit 11) by 
treatment group. Pearson’s chi-square test (or Fisher’s exact test if any expected count is 
less than 5) will be used to compare the treatment difference between treatment groups. 
The Scadding score will be converted to numeric score in the following manner: 
0 - Stage 0 
1 - Stage I 
2 - Stage II 
3 - Stage III 
4 - Stage IV 
Descriptive statistics of observed, change from baseline and percentage change from 
baseline values will be presented by treatment group at week 24 (Visit 8) and week 48 
(Visit 11) for the Scadding score. Baseline of active treatment, change from baseline and 
percentage change from baseline values will be presented as well for week 48 (Visit 11).  
Note that the percentage change will not be calculated for subjects with Scadding score 
stage 0 at baseline. 
The treatment difference between Acthar and placebo for both change from baseline and 
percentage change from baseline to week 24 (Visit 8) in Scadding score will be evaluated 
using a Wilcoxon rank sum test. 
A listing will be provided for the imaging data and Scadding score by subject and visit. 
9.5. Patient-Reported Outcomes and Symptom Questionnaires 
Descriptive statistics of observed, change from baseline and percentage change from 
baseline values will be provided at scheduled visits during double-blind treatment phase 
and open-label extension phase, respectively. Descriptive statistics of baseline of active 
treatment, change and percentage change from baseline of active treatment values at visits 
in open-label extension phase will be provided additionally. The change from baseline and 
percentage change from baseline values to each visit will be analyzed using similar 
statistical methodology for all patient-reported outcomes and symptom questionnaires 
unless specified otherwise at visits during double-blind treatment phase.  


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The patient-reported outcomes and symptom questionnaires will include the following: 
• Total score of Steroid Toxicity Questionnaire where lower scores indicate better 
status. 
• Scores of each of the 5 King’s Sarcoidosis Questionnaire Modules (General Health 
Status, Lung, Medication, Skin, and Eyes) where higher scores indicate 
improvement. 
• Total scores of each of the 4 King’s Sarcoidosis Questionnaire overall scales (Lung 
Health Status [General Health Status module and Lung module], Skin Health Status 
[General Health Status module and Skin module], Eye Health Status [General 
Health Status module and Eye module], Lung-Skin Health Status [General Health 
Status module, Lung module and Skin module]) where higher scores indicate 
improvement and a change of 4 points is considered clinically meaningful. 
• Total score of Fatigue Assessment Scale where lower scores indicate improvement 
and a change of 4 points is considered clinically meaningful. 
• Patient’s Global Assessment where higher scores indicate better status. 
• Physician Global Assessment where higher scores indicate better status. 
• Medical Research Council Dyspnea Scale where lower scores indicate better status. 
• Total score and each score of the 3 domains (Physical, Psychological and Social) of 
Leicester Cough Questionnaire where higher scores indicate better health status. 
• Work Productivity and Activity Impairment (WPAI) 
Calculation for above scores are provided in Appendix 15.2. 
The treatment difference between Acthar and placebo for both change from baseline and 
percentage change from baseline to visits in the double-blind treatment phase in each 
outcome or questionnaire score will be evaluated using a two-sample T-test. Wilcoxon 
rank sum test may be used if the data are not normally distributed. Percentage change in 
King’s Sarcoidosis Questionnaire and Fatigue Assessment Scale will plotted in line graph 
over time showing the means and SEs. For WPAI data, only a listing will be provided.  
If result is missing at a post-baseline visit, the missing result will be imputed using the 
LOCF method. No imputation will be applied to the open-label extension phase. All 


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summaries and analyses will be conducted on both the observed values and the LOCF 
values. 
Listings will be provided for each patient-reported outcome and symptom questionnaire by 
subject and visit. 
9.6. Six-Minute Walk Test (6MWT) 
Descriptive statistics of observed and change from baseline values at week 24 (Visit 8) and 
descriptive statistics of observed, change from baseline values, change from baseline of 
active treatment at week 48 (Visit 11) will be summarized by treatment group for the 
following measurements: 
• Total Distance Walked 
• Number of Laps 
• Number of Rests 
The number and percentage of subjects will be provided at scheduled visits by treatment 
group for the following categorical measurements: 
• Supplemental Oxygen Used (Yes, No) prior to the 6MWT, upon completion of the 
6MWT and 1 Minute after walk 
• Limiting Factors to Walk (SOB, LOW Sp02, Heart Disease, Desaturation <80%, 
Other) 
The treatment difference between Acthar and placebo for change from baseline in each 
assessment will be evaluated using a two-sample t-test for week 24 (Visit 8) only. A listing 
will be provided for the 6MWT data by subject and visit. 
9.7. Extrapulmonary Physician Organ Severity Tool (ePOST) 
The ePOST examines 17 extrapulmonary organs (Lung excluded) and assigns a score to 
each one (0 = not affected to 6 = very severely affected). The adjusted overall score will be 
derived as the sum of the ePOST score for each extrapulmonary organ divided by the 
number of extrapulmonary organs involved at any time by visit during the study. 
The ePOST score assigned for each individual extrapulmonary organ will be summarized 
categorically using number of subjects and percentage with score from 0 (not affected) to 6 
(very severe) for each treatment group by visits. 


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The adjusted overall score, changes from baseline and percent change from baseline, and 
changes and percent change from baseline of active treatment (open-label extension phase 
only) to each scheduled visit will be summarized by treatment group using descriptive 
statistics. 
A listing will be provided for the ePOST data by subject and visit. 
9.8. Corticosteroid Tapering 
The number and percentage of subjects who have dose adjustment and justifications for 
dose change will be summarized at each scheduled visit by treatment group and study 
phase. Descriptive statistics will be provided for doses and doses change from baseline at 
each scheduled visit. All corticosteroid dose will be converted to prednisone equivalent 
dose. Additionally, weekly average prednisone or equivalent daily dose (mg/day) will be 
calculated from prior and concomitant medication data for prednisone collected prior to 
week 4 (Visit 3) and post week 48 (Visit 11) and corticosteroid use data collected between 
week 4 (Visit 3) and week 48 (Visit 11). The average weekly daily dose change and 
percent change from baseline, and change and percent change from baseline of active 
treatment to week (from week 25 to week 48 in open-label phase only) will be summarized 
descriptively by weeks from week 1 to week 24 in double-blind phase and from 25 to week 
48 in open-label phase. The line plots of mean (+/- standard error) percent change of 
average weekly daily dose from baseline by weeks will be provided for double-blind 
treatment phase and overall study phase. 
Subjects whose corticosteroid dosage increased for more than 2 weeks will be considered 
as failing to corticosteroid taper. Pearson’s chi-square test (or Fisher’s exact test if any 
expected count is less than 5) will be used to compare the treatment difference between 
treatment groups for the percentage of subjects who fail corticosteroid taper in double-
blind treatment phase only. 
Time to failing corticosteroid taper is defined as: 
Time to failing corticosteroid taper (day) = date of failing corticosteroid taper - date of first 
dose + 1.  
Time to failing corticosteroid taper will be summarized by descriptive statistics by 
treatment group for subjects who fail corticosteroid taper. 
A listing will be provided for the corticosteroid use by subject and visit. 


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10. Safety Analysis 
All safety analyses will be conducted using safety population for the double-blind 
treatment phase and open-label safety population for the open-label extension phase 
separately. No imputation will be applied for missing data on any safety results. Missing or 
partially missing adverse event start dates will be imputed for treatment-emergent AE 
(TEAE) justification, refer to Appendix 15.1.1 for imputation details. All safety data will 
be presented in listings based on the safety population in the double-blind treatment phase 
and in the open-label extension phase, respectively. 
10.1. Adverse Events 
An AE is any untoward or undesirable medical occurrence in a subject who is administered 
an IMP, which does not necessarily have to have a causal relationship with this treatment.  
A TEAE is defined as an event that begin or worsen on or after the start of study drug 
through 30 days after the date of the last dose. The first dose of IMP at the open-label 
extension phase will be used as cutoff date, the TEAEs started before the cutoff date will 
be summarized in the double-blind treatment phase and the TEAES started on or after the 
cutoff date will be summarized in the open-label extension phase; Subjects who did not 
continue into the open-label extension phase will be summarized in the double-blind 
treatment phase only. 
If a subject experience the same AE more than once with different severity, then the event 
with the highest severity level will be tabulated in “by severity” tables. If a subject 
experience the same AE more than once with different relationship to study drug, then the 
event with the most related level will be tabulated in “by relationship” tables. Note that 
AEs with a missing severity will be considered as severe, and AEs with missing 
relationship will be considered as related to study drug. Adverse events are considered 
treatment-related if the relationship to study drug is possibly related, related or missing.  
The incidence of AEs will be summarized in tables with the number and percentage of 
subjects with AEs by SOC and PT. At each level of SOC or PT, a subject with multiple 
events will only be counted once per SOC or PT. Percentages of subjects with AEs will be 
calculated out of the number of subjects in the safety population. SOC will be presented 
alphabetically and PTs within each SOC will be presented in decreasing order of frequency 
based on the total number of subjects with each AE in the Acthar group. The following 
categories of TEAE will be summarized by SOC and PT by treatment group and total for 
the double-blind treatment phase and the open-label extension phase separately: 


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• TEAEs  
• TEAEs by severity (Mild, Moderate, and Severe) 
• TEAEs by relationship (Not Related, Unlikely Related, Possibly Related, and 
Related) 
• Treatment related TEAEs 
• Serious TEAEs 
• Serious TEAEs by relationship (Not Related, Unlikely Related, Possibly Related, 
and Related) 
• TEAEs leading to study drug discontinuation 
• TEAEs leading to death 
Overview tables of the above categories will also be provided. 
All AEs will be presented in a data listing by study phase and TEAEs will be flagged in the 
listing. 
10.2. Clinical Laboratory Evaluations 
Clinical laboratory tests (including serum chemistry, hematology, urinalysis, lipid panel, 
hormones, and hepatitis serology) will be collected per the timing presented according to 
the protocol. All summaries will be based on the International System of Units (SI) and the 
central lab results. Laboratory values that are below the limit of quantitation (LLoQ) or 
above the upper limit of quantitation (ULoQ) will be assigned the numerical part of the 
results. 
10.2.1. Hematology 
Descriptive statistics of observed and change from baseline values will be presented by 
treatment group and total at the scheduled visits for white blood cell count including 
differential, red blood cell count, hemoglobin, hematocrit, and platelet count. A shift table 
representing the change from baseline to the worst post-baseline values in normal, low, or 
high will also be provided by treatment group and total. A subject could be counted in both 
low and high categories if the subject experiences both low and high in the post-baseline 
visits. 


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A listing will be provided for all hematology tests by study phase and local lab data will be 
flagged in the listing. In addition, a listing of hematology tests will be provided for subjects 
with any clinically significant abnormality. 
10.2.2. Serum Chemistry 
Descriptive statistics of observed and change from baseline values will be presented by 
treatment group and total at the scheduled visits for alanine aminotransferase, albumin 
(total), alkaline phosphatase, aspartate aminotransferase, bilirubin (total), blood urea 
nitrogen, calcium, chloride, creatinine level, creatine phosphokinase, c-reactive protein, 
gamma-glutamyl transferase, glucose, HbA1C, phosphorus, potassium, protein (total), 
sodium and urate. A shift table representing the change from baseline the worst post-
baseline values in normal, low, or high will also be provided by treatment group and total. 
A subject could be counted in both low and high categories if the subject experiences both 
low and high in the post-baseline visits. 
A listing will be provided for all chemistry tests and local lab data will be flagged in the 
listing. In addition, a listing of chemistry tests will be provided for subjects with any 
clinically significant abnormality. 
10.2.3. Hormone 
Descriptive statistics of observed and change from baseline values will be presented by 
treatment group and total at the scheduled visits for parathyroid hormone, 25-Hydroxy 
vitamin D, and 1, 25-Dihydroxy vitamin D. 
A listing will be provided for all hormone tests by subject and visit. 
10.2.4. Lipid Panel 
Descriptive statistics of observed and change from baseline values will be presented by 
treatment group and total at the scheduled visits for cholesterol (total), high density 
lipoprotein, low density lipoprotein and triglyceride.  
A listing will be provided for all lipid panel tests by subject and visit. 
10.2.5. Urinalysis, Hepatitis serology, Tuberculosis Testing and Pregnancy Testing 
Listings will be provided for urinalysis, hepatitis serology tests, tuberculosis testing, and 
pregnancy testing by subject and visit. 


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10.3. Vital Sign Measurements 
Vital sign measurements include pulse rate (beats per minute), systolic blood pressure 
(mmHg), diastolic blood pressure (mmHg), respiratory rate (breaths per minute), weight 
(kg), and BMI (kg/m2) as collected on the eCRF. Descriptive statistics will be provided for 
observed and change from baseline values by treatment group and total at the scheduled 
visits.  
All vital signs will be presented in a listing by study phase. 
10.4. Physical Examination 
The number and percentage of subjects with different response (Normal, Abnormal Not 
Clinically Significant, and Abnormal Clinically Significant) will be summarized for each 
physical assessment by treatment group and total at scheduled visits. 
All physical examination results will be presented in a listing by study phase. 
10.5. Electrocardiogram 
The 12-lead electrocardiogram (ECG) assessments include heart rate (beats per minute), 
PR interval (milliseconds), RR interval (milliseconds), QRS duration (milliseconds), QT 
interval (milliseconds), and QTcB (milliseconds). Descriptive statistics will be provided 
for observed and change from baseline values by treatment group and total at the scheduled 
visits. 
The number and percentage of subjects with each ECG overall interpretation (Normal, 
Abnormal Not Clinically Significant, and Abnormal Clinically Significant) and the number 
and percentage of subjects with normal sinus rhythm (Yes, No) will be summarized by 
treatment group and total at scheduled visits.  
All ECG assessments will be presented in a by-subject listing by study phase. 
11. Biomarker Analysis 
11.1. Biomarkers 
Descriptive summary will be provided to describe the selected biomarker endpoints using 
the safety population by treatment group, if data is available. The selected biomarker 
endpoints may include angiotensin-converting enzyme, sIL-2R and vitamin D 1,25. The 
final determination as to the selection of biomarkers will be made based on the evolution 
of the science and emerging guidance closer to the completion of the study.  Descriptive 


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statistics will be provided for observed and change from baseline values for each selected 
biomarker at scheduled visits. 
All biomarker data will be presented in a listing by subject and visit. 
11.2. Genetic Profile 
Genetic sample obtained for subjects who has signed the genetic inform consent form at 
study entry may be explored and presented in tables. Descriptive statistics will be provided 
if data is available. 
All genetic data will be presented in a listing. 
12. Interim Analysis 
No formal interim analysis is planned. 
13. Changes in the Planned Analysis 
 The summary of changes presented below reflects the changes in the planned analysis 
described in protocol: 
• The protocol planned endpoint analysis for “Change from baseline in WPAI over 
time” will not be performed given very few subjects have taken WPAI 
questionnaire. WPAI data will be only presented in listings. 
• The protocol planned endpoint analysis for “Time to response (TTR) as evaluated 
at earlier time points (Weeks 4 to 20) as determined by the investigator based on 
clinical judgment” will not be performed.  
• The protocol planned analysis for biomarker and genetic endpoints may not be 
performed depending on the availability of the data.  
14. References 
Baughman RP, Kavuru M, Judson MA, Costabel U, du Bois R. Infliximab therapy in 
patients with chronic sarcoidosis and pulmonary involvement. Am J Respir Crit Care Med 
2006; 174:795–802. 
Birring, S.S.; Prudon, B.; Carr, A.J.; Singh, S.J.; Morgan, M.D.L., et al. Development of a 
symptom specific health status measure for patients with chronic cough: Leicester Cough 
Questionnaire (LCQ). Thorax 2003, 58, 339–343. 


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De Vries, M.H.; Van Heck, G.L.; Drent, M. Measuring fatigue in sarcoidosis: the Fatigue 
Assessment Scale (FAS). Br J Health Psychol 2004, 9, 279-291. 
Gibson GJ, Prescott RJ, Muers MF, Middleton WG, Mitchell DN et al. British Thoracic 
Society Sarcoidosis study: effects of long term corticosteroid treatment. Thorax 1996; 51: 
238-247. 
Judson MA. Advances in the diagnosis and treatment of sarcoidosis. F1000Prime Reports 
2014; 6: 89. 
Mallinckrodt ARD, Inc. A Phase 4 Multicenter, Randomized, Double Blind, Placebo 
Controlled Pilot Study to Assess the Efficacy and Safety of H.P. Acthar® Gel in Subjects 
with Pulmonary Sarcoidosis. Original, 06 October 2017. 
Patel, A.S.; Siegert, R.J.; Creamer, D.; Larkin, G.; Maher, T.M.; et al. The development 
and validation of the King’s Sarcoidosis Questionnaire for the assessment of health status. 
Thorax 2013, 68, 57-65. 


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15. Appendices 
15.1. Date Imputation Guideline 
15.1.1. Adverse Events 
Missing start dates for AE data will be handled as follows:  
• Missing day only: 
o If the month and year are the same as the first dose month and year, then it 
will be imputed as the date of the first dose. 
o If either the year is the same as the first dose year, but the month is prior to 
the first dose month or the year is prior to the first dose year, then it will be 
imputed as the last day of the collected month. 
o If either the year is the same as the first dose year, but the month is after the 
first dose month or the year is after the first dose year, then it will be 
imputed as the first day of the collected month. 
• Missing day and month: 
o If the year is the same as the first dose year, then it will be imputed as the 
date of the first dose. 
o If the year is prior to the first dose year, then it will be imputed as 
December 31st of the collected year. 
o If the year is after the first dose year, then it will be imputed as January 1st 
of the collected year. 
• Missing day, month and year: 
o It will be imputed as the date of the first dose. 
No imputation will be applied to the missing or partial stop dates for AEs. If the AE end 
date is complete and the partial AE start date imputed by the rules above is after the AE 
end date, then the start date will be imputed by the AE end date. 
15.1.2. Prior/Concomitant Medications 
Missing start dates for concomitant medications data will be handled as follows: 
• Missing day only: 


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o If the month and year are the same as the first dose month and year, then it 
will be imputed as the date of first dose. 
o If either the year is the same as the first dose year but the month is prior to 
the first dose month or the year is prior to the first dose year, then it will be 
imputed as the last day of the collected month. 
o If either the year is the same as the first dose year but the month is after the 
first dose month or the year is after the first dose year, then it will be 
imputed as the first day of the collected month. 
• Missing month: 
o If the year is the same as the first dose year, then it will be imputed as the 
date of first dose. 
o If the year is prior to the first dose year, then it will be imputed as 
December. 
o If the year is after the first dose year, then it will be imputed as January. 
• Missing day and month: 
o If the year is the same as the first dose year, then it will be imputed as the 
date of first dose. 
o If the year is prior to the first dose year, then it will be imputed as 
December 31st of the collected year. 
o If the year is after the first dose year, then it will be imputed as January 1st 
of the collected year. 
• Missing day, month and year: 
o It will be imputed as the date of first dose. 
Missing stop dates for concomitant medications data will be handled as follows: 
• Missing day only: 
o It will be imputed as the last day of the collected month or the death date, 
whichever is earlier. 
• Missing day and month: 


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o It will be imputed as December 31st of the collected year or the death date, 
whichever is earlier. 
• Missing day, month and year: 
o No imputation is needed. 
If the imputed start date is after the stop date, then the start date will be imputed as the stop 
date. 
15.2. Calculation of Patient-Reported Outcomes and Symptom Questionnaires 
15.2.1. Steroid Toxicity Questionnaire 
• Total score of Steroid Toxicity Questionnaire which is defined as the sum of 11 
item scores. Each item is graded in the following manner: 
0 - None of the Time 
1 - A Little 
2 - Some of the Time 
3 - Most of the Time 
4 - All of the Time 
15.2.2. King’s Sarcoidosis Questionnaire 
• KSQ – General Health Score 
This score is determined using the total score of answers recorded from the KSQ 
questionnaire general health module. The General Health module of the KSQ 
questionnaire includes questions 1-10 which can be completed using a scale of 1-7. 
The table below shows the rescore values that are added to calculate the total score: 
Item 
Max Score Rescored 
1 
2 
3 
4 
5 
6 
7 
I0001 
4 
Y 
0 
1 
2 
3 
3 
4 
4 
I0002 
6 
0 
1 
2 
3 
4 
5 
6 
I0003 
3 
Y 
0 
1 
1 
2 
2 
3 
3 
I0004 
6 
 
0 
1 
2 
3 
4 
5 
6 
I0005 
3 
Y 
0 
1 
2 
2 
3 
3 
3 
I0006 
2 
Y 
0 
0 
1 
1 
1 
2 
2 
I0007 
3 
Y 
0 
0 
0 
1 
2 
2 
3 
I0008 
2 
Y 
0 
0 
1 
1 
1 
2 
2 


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I0009 
2 
Y 
0 
0 
1 
1 
1 
2 
2 
I0010 
2 
Y 
0 
0 
1 
1 
1 
2 
2 
 
The total score can range from 0-33; this number is used to identify the KSQ 
General Health Score using the table below. For example, if the total score from the 
KSQ questionnaire is 22, the KSQ General Health score will be 59.9. 
 
Total Score 
KSQ General Health Score  
0 
0.0 
1 
9.3 
2 
15.7 
3 
20.2 
4 
23.8 
5 
26.7 
6 
29.4 
7 
31.7 
8 
33.9 
9 
36.0 
10 
38.0 
11 
39.9 
12 
41.7 
13 
43.5 
14 
45.3 
15 
47.1 
16 
48.9 
17 
50.7 
18 
52.5 
19 
54.3 
20 
56.2 
21 
58.0 
22 
59.9 
23 
61.9 
24 
63.9 
25 
66.1 
26 
68.4 
27 
70.9 
28 
73.6 
29 
76.7 
30 
80.3 
31 
84.7 


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32 
91.0 
33 
100.0 
 
• KSQ – Lung Score 
This score is determined using the total score of the answers recorded from the 
KSQ questionnaire lung module. The lung module of the KSQ questionnaire 
includes questions 11-16 which can be completed using a scale of 1-7. The table 
below shows the rescore values that are added to calculate the total score: 
 
Item 
Max Score 
Rescored 
1 
2 
3 
4 
5 
6 
7 
I0011 
5 
Y 
0 
1 
2 
3 
4 
4 
5 
I0012 
6 
Y 
0 
1 
2 
3 
4 
5 
6 
I0013 
6 
Y 
0 
1 
2 
3 
4 
5 
6 
I0014 
6 
Y 
0 
1 
2 
3 
4 
5 
6 
I0015 
6 
Y 
0 
1 
2 
3 
4 
5 
6 
I0016 
5 
Y 
0 
1 
2 
3 
4 
4 
5 
 
The total score can range from 0-34; this number is used to identify the Lung score 
using the table below. For example, if the total score from the KSQ questionnaire is 
19, the lung score will be 50.2. 
 
Total Score 
Lung Score  
0 
0.0 
1 
10.4 
2 
17.5 
3 
22.3 
4 
26.0 
5 
29.0 
6 
31.4 
7 
33.6 
8 
35.5 
9 
37.2 
10 
38.8 
11 
40.2 
12 
41.6 
13 
42.9 
14 
44.2 
15 
45.5 
16 
46.7 
17 
47.9 


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18 
49.1 
19 
50.2 
20 
51.4 
21 
52.6 
22 
53.8 
23 
55.1 
24 
56.4 
25 
57.8 
26 
59.3 
27 
61.0 
28 
62.9 
29 
65.2 
30 
68.0 
31 
71.7 
32 
77.1 
33 
85.8 
34 
100.0 
 
• KSQ – Medication Score 
This score is determined using the answers recorded from the KSQ questionnaire 
medication module. The medication module of the KSQ questionnaire includes 
questions 17-19 which can be completed using a scale of 1-7. The table below 
shows the rescore values that are added to calculate the total score: 
 
Item 
Max Score 
Rescored 
1 
2 
3 
4 
5 
6 
7 
I0017 
3 
Y 
0 
1 
2 
2 
2 
3 
3 
I0018 
3 
Y 
0 
1 
2 
2 
2 
3 
3 
I0019 
2 
Y 
0 
0 
1 
1 
1 
1 
2 
 
The total score can range from 0-8; this number is used to identify the Medication 
Score using the table below. For example, if the total score from the KSQ 
questionnaire is 7, the Medication score will be 80.9. 
 
Total Score 
Medication Score 
0 
0.0 
1 
14.5 
2 
26.8 
3 
37.2 
4 
47.0 
5 
56.5 


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6 
66.9 
7 
80.9 
8 
100.0 
 
• KSQ – Skin Score 
This score is determined using the answers recorded from the KSQ questionnaire 
skin module. The skin module of the KSQ questionnaire includes questions 20-22 
which can be completed using a scale of 1-7. The table below shows the rescore 
values that are added to calculate the total score: 
 
Item 
Max Score 
Rescored 
1 
2 
3 
4 
5 
6 
7 
I0020 
4 
Y 
0 
1 
2 
2 
2 
3 
4 
I0021 
3 
Y 
0 
1 
1 
2 
2 
2 
3 
I0022 
2 
Y 
0 
0 
1 
1 
1 
2 
2 
 
The total score can range from 0-9; this number is used to identify the Skin Score 
using the table below. For example, if the total score from the KSQ questionnaire is 
4, the Skin score will be 35.4. 
 
Total Score 
Skin Score 
0 
0.0 
1 
13.7 
2 
25.4 
3 
35.4 
4 
44.7 
5 
53.8 
6 
63.3 
7 
73.7 
8 
86.1 
9 
100.0 
 
• KSQ – Eye Score 
This score is determined using the answers recorded from the KSQ questionnaire 
eyes module. The eyes module of the KSQ questionnaire includes questions 23-29 
which can be completed using a scale of 1-7. The table below shows the rescore 
values that are added to calculate the total score: 
 
Item 
Max Score 
Rescored 
1 
2 
3 
4 
5 
6 
7 
I0023 
2 
Y 
0 
0 
1 
1 
1 
2 
2 


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I0024 
3 
Y 
0 
1 
2 
2 
2 
2 
3 
I0025 
3 
Y 
0 
1 
2 
2 
2 
3 
3 
I0026 
2 
Y 
0 
0 
1 
1 
1 
2 
2 
I0027 
2 
Y 
0 
0 
1 
1 
1 
2 
2 
I0028 
3 
Y 
0 
0 
0 
1 
1 
2 
3 
I0029 
2 
Y 
0 
0 
1 
1 
1 
1 
2 
 
The total score can range from 0-17; this number is used to identify the Eye Score 
using the table below. For example, if the total score from the KSQ questionnaire is 
12, the Eyes score will be 61.1. 
 
Total Score 
Eye Score 
0 
0.0 
1 
11.3 
2 
19.6 
3 
25.8 
4 
31.0 
5 
35.5 
6 
39.7 
7 
43.5 
8 
47.2 
9 
50.6 
10 
54.0 
11 
57.5 
12 
61.1 
13 
65.2 
14 
70.1 
15 
76.4 
16 
85.8 
17 
100.0 
 
• KSQ – General Health & Lung Score 
This score is determined using the answers recorded from the KSQ questionnaire 
general health module and lung module combined. The General Health module of 
the KSQ questionnaire includes questions 1-10 and the lung module of the KSQ 
questionnaire includes questions 11-16 which can be completed using a scale of 1-7 
The table below shows the rescore values that are added to calculate the total score: 
 
Item 
Max Score 
Rescored 
1 
2 
3 
4 
5 
6 
7 
I0001 
4 
Y 
0 
1 
2 
3 
3 
4 
4 


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I0002 
6 
0 
1 
2 
3 
4 
5 
6 
I0003 
3 
Y 
0 
1 
1 
2 
2 
3 
3 
I0004 
6 
0 
1 
2 
3 
4 
5 
6 
I0005 
3 
Y 
0 
1 
2 
2 
3 
3 
3 
I0006 
2 
Y 
0 
0 
1 
1 
1 
2 
2 
I0007 
3 
Y 
0 
0 
0 
1 
2 
2 
3 
I0008 
2 
Y 
0 
0 
1 
1 
1 
2 
2 
I0009 
2 
Y 
0 
0 
1 
1 
1 
2 
2 
I0010 
2 
Y 
0 
0 
1 
1 
1 
2 
2 
I0011 
5 
Y 
0 
1 
2 
3 
4 
4 
5 
I0012 
6 
Y 
0 
1 
2 
3 
4 
5 
6 
I0013 
6 
Y 
0 
1 
2 
3 
4 
5 
6 
I0014 
6 
Y 
0 
1 
2 
3 
4 
5 
6 
I0015 
6 
Y 
0 
1 
2 
3 
4 
5 
6 
I0016 
5 
Y 
0 
1 
2 
3 
4 
4 
5 
 
The total score can range from 0-67; this number is used to identify the General 
Health & Lung Score using the table below. For example, if the total score from the 
KSQ questionnaire is 40, the General Health & Lung score will be 58.1. 
 
Total Score 
General Health & Lung Score 
0 
0.0 
1 
11.6 
2 
19.0 
3 
23.8 
4 
27.2 
5 
29.9 
6 
32.0 
7 
33.8 
8 
35.4 
9 
36.7 
10 
38.0 
11 
39.1 
12 
40.1 
13 
41.0 
14 
41.9 
15 
42.8 
16 
43.5 
17 
44.3 
18 
45.0 


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19 
45.7 
20 
46.4 
21 
47.0 
22 
47.7 
23 
48.3 
24 
48.9 
25 
49.5 
26 
50.1 
27 
50.7 
28 
51.2 
29 
51.8 
30 
52.4 
31 
52.9 
32 
53.5 
33 
54.1 
34 
54.6 
35 
55.2 
36 
55.8 
37 
56.4 
38 
56.9 
39 
57.5 
40 
58.1 
41 
58.7 
42 
59.3 
43 
59.9 
44 
60.5 
45 
61.2 
46 
61.8 
47 
62.5 
48 
63.2 
49 
63.9 
50 
64.7 
51 
65.4 
52 
66.2 
53 
67.1 
54 
68.0 
55 
68.9 
56 
69.9 
57 
71.0 
58 
72.1 


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MNK14344100 SAP Version 3.0 
59 
73.3 
60 
74.7 
61 
76.2 
62 
77.9 
63 
80.0 
64 
82.6 
65 
86.1 
66 
91.5 
67 
100.0 
 
• KSQ – General Health & Skin Score 
This score is determined the answers recorded from the KSQ questionnaire general 
health module and skin module combined. The General Health module of the KSQ 
questionnaire includes questions 1-10 and the skin module of the KSQ 
questionnaire includes questions 20-22, which can be completed using a scale of 1-
7 The table below shows the rescore values that are added to calculate the total 
score: 
 
Item 
Max Score 
Rescored 
1 
2 
3 
4 
5 
6 
7 
I0001 
4 
Y 
0 
1 
2 
3 
3 
4 
4 
I0002 
6 
 
0 
1 
2 
3 
4 
5 
6 
I0003 
3 
Y 
0 
1 
1 
2 
2 
3 
3 
I0004 
6 
 
0 
1 
2 
3 
4 
5 
6 
I0005 
3 
Y 
0 
1 
2 
2 
3 
3 
3 
I0006 
2 
Y 
0 
0 
1 
1 
1 
2 
2 
I0007 
3 
Y 
0 
0 
0 
1 
2 
2 
3 
I0008 
2 
Y 
0 
0 
1 
1 
1 
2 
2 
I0009 
2 
Y 
0 
0 
1 
1 
1 
2 
2 
I0010 
2 
Y 
0 
0 
1 
1 
1 
2 
2 
I0020 
4 
Y 
0 
1 
2 
2 
2 
3 
4 
I0021 
3 
Y 
0 
1 
1 
2 
2 
2 
3 
I0022 
2 
Y 
0 
0 
1 
1 
1 
2 
2 
 
The total score can range from 0-42; this number is used to identify the General 
Health & Skin Score using the table below. For example, if the total score from the 
KSQ questionnaire is 25, the General Health & Skin score will be 51.2. 
 
0 
0.0 
1 
9.0 
2 
15.0 


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MNK14344100 SAP Version 3.0 
3 
19.2 
4 
22.3 
5 
25.0 
6 
27.3 
7 
29.3 
8 
31.1 
9 
32.8 
10 
34.3 
11 
35.8 
12 
37.1 
13 
38.4 
14 
39.6 
15 
40.8 
16 
41.9 
17 
43.0 
18 
44.1 
19 
45.1 
20 
46.1 
21 
47.2 
22 
48.2 
23 
49.2 
24 
50.2 
25 
51.2 
26 
52.2 
27 
53.2 
28 
54.3 
29 
55.4 
30 
56.5 
31 
57.7 
32 
59.0 
33 
60.4 
34 
62.0 
35 
63.7 
36 
65.6 
37 
67.9 
38 
70.6 
39 
74.2 
40 
79.1 
41 
87.1 
42 
100.0 


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MNK14344100 SAP Version 3.0 
 
• KSQ – General Health & Eye Score 
This score is determined by the answers recorded from the KSQ questionnaire 
general health module and eyes module combined. The General Health module of 
the KSQ questionnaire includes questions 1-10 and the eyes module of the KSQ 
questionnaire includes questions 23-29, which can be completed using a scale of 1-
7 The table below shows the rescore values that are added to calculate the total 
score: 
 
Item 
Max Score 
Rescored 
1 
2 
3 
4 
5 
6 
7 
I0001 
4 
Y 
0 
1 
2 
3 
3 
4 
4 
I0002 
6 
 
0 
1 
2 
3 
4 
5 
6 
I0003 
3 
Y 
0 
1 
1 
2 
2 
3 
3 
I0004 
6 
 
0 
1 
2 
3 
4 
5 
6 
I0005 
3 
Y 
0 
1 
2 
2 
3 
3 
3 
I0006 
2 
Y 
0 
0 
1 
1 
1 
2 
2 
I0007 
3 
Y 
0 
0 
0 
1 
2 
2 
3 
I0008 
2 
Y 
0 
0 
1 
1 
1 
2 
2 
I0009 
2 
Y 
0 
0 
1 
1 
1 
2 
2 
I0010 
2 
Y 
0 
0 
1 
1 
1 
2 
2 
I0023 
2 
Y 
0 
0 
1 
1 
1 
2 
2 
I0024 
3 
Y 
0 
1 
2 
2 
2 
2 
3 
I0025 
3 
Y 
0 
1 
2 
2 
2 
3 
3 
I0026 
2 
Y 
0 
0 
1 
1 
1 
2 
2 
I0027 
2 
Y 
0 
0 
1 
1 
1 
2 
2 
I0028 
3 
Y 
0 
0 
0 
1 
1 
2 
3 
I0029 
2 
Y 
0 
0 
1 
1 
1 
1 
2 
 
The total score can range from 0-50; this number is used to identify the General 
Health & Eyes Score using the table below. For example, if the total score from the 
KSQ questionnaire is 30, the General Health & Eyes score will be 55.7. 
 
Total Score 
General Health & Eye Score 
0 
0.0 
1 
9.1 
2 
15.3 
3 
19.5 
4 
22.8 
5 
25.5 
6 
27.8 


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Total Score 
General Health & Eye Score 
7 
29.8 
8 
31.7 
9 
33.4 
10 
34.9 
11 
36.4 
12 
37.7 
13 
39.0 
14 
40.2 
15 
41.4 
16 
42.5 
17 
43.5 
18 
44.5 
19 
45.5 
20 
46.5 
21 
47.5 
22 
48.4 
23 
49.3 
24 
50.2 
25 
51.1 
26 
52.0 
27 
52.9 
28 
53.8 
29 
54.8 
30 
55.7 
31 
56.6 
32 
57.6 
33 
58.6 
34 
59.6 
35 
60.7 
36 
61.8 
37 
62.9 
38 
64.1 
39 
65.3 
40 
66.7 
41 
68.1 
42 
69.6 
43 
71.2 
44 
73.0 
45 
75.1 


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MNK14344100 SAP Version 3.0 
Total Score 
General Health & Eye Score 
46 
77.6 
47 
80.6 
48 
84.6 
49 
90.7 
50 
100.0 
 
• KSQ – General Health & Lung & Skin Score 
This score is calculated with the following calculation below using the answers 
recorded from the KSQ questionnaire general health module, lung module and skin 
module combined. The General Health module of the KSQ questionnaire includes 
questions 1-10, the lung module of the KSQ questionnaire includes questions 11-16 
and the skin module of the KSQ questionnaire includes questions 20-22, which can 
be completed using a scale of 1-7 The table below shows the rescore values that are 
added to calculate the total score: 
 
Item 
Max Score 
Rescored 
1 
2 
3 
4 
5 
6 
7 
I0001 
4 
Y 
0 
1 
2 
3 
3 
4 
4 
I0002 
6 
0 
1 
2 
3 
4 
5 
6 
I0003 
3 
Y 
0 
1 
1 
2 
2 
3 
3 
I0004 
6 
0 
1 
2 
3 
4 
5 
6 
I0005 
3 
Y 
0 
1 
2 
2 
3 
3 
3 
I0006 
2 
Y 
0 
0 
1 
1 
1 
2 
2 
I0007 
3 
Y 
0 
0 
0 
1 
2 
2 
3 
I0008 
2 
Y 
0 
0 
1 
1 
1 
2 
2 
I0009 
2 
Y 
0 
0 
1 
1 
1 
2 
2 
I0010 
2 
Y 
0 
0 
1 
1 
1 
2 
2 
I0011 
5 
Y 
0 
1 
2 
3 
4 
4 
5 
I0012 
6 
Y 
0 
1 
2 
3 
4 
5 
6 
I0013 
6 
Y 
0 
1 
2 
3 
4 
5 
6 
I0014 
6 
Y 
0 
1 
2 
3 
4 
5 
6 
I0015 
6 
Y 
0 
1 
2 
3 
4 
5 
6 
I0016 
5 
Y 
0 
1 
2 
3 
4 
4 
5 
I0020 
4 
Y 
0 
1 
2 
2 
2 
3 
4 
I0021 
3 
Y 
0 
1 
1 
2 
2 
2 
3 
I0022 
2 
Y 
0 
0 
1 
1 
1 
2 
2 
 
The total score can range from 0-76; this number is used to identify the General 
Health & Lung & Skin Score using the table below. For example, if the total score 


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MNK14344100 SAP Version 3.0 
from the KSQ questionnaire is 50, the General Health & Lung & Skin Score will be 
49.5. 
 
Total Score 
General Health & Lung &Skin Score 
0 
0.0 
1 
8.5 
2 
14.1 
3 
17.9 
4 
20.6 
5 
22.8 
6 
24.6 
7 
26.2 
8 
27.5 
9 
28.7 
10 
29.8 
11 
30.7 
12 
31.6 
13 
32.4 
14 
33.1 
15 
33.8 
16 
34.5 
17 
35.1 
18 
35.6 
19 
36.2 
20 
36.7 
21 
37.2 
22 
37.7 
23 
38.2 
24 
38.7 
25 
39.1 
26 
39.5 
27 
40.0 
28 
40.4 
29 
40.8 
30 
41.2 
31 
41.6 
32 
42.0 
33 
42.4 
34 
42.8 
35 
43.2 


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Total Score 
General Health & Lung &Skin Score 
36 
43.6 
37 
44.0 
38 
44.4 
39 
44.8 
40 
45.2 
41 
45.6 
42 
46.0 
43 
46.4 
44 
46.8 
45 
47.2 
46 
47.7 
47 
48.1 
48 
48.6 
49 
49.0 
50 
49.5 
51 
50.0 
52 
50.5 
53 
51.0 
54 
51.5 
55 
52.1 
56 
52.6 
57 
53.2 
58 
53.9 
59 
54.5 
60 
55.2 
61 
56.0 
62 
56.8 
63 
57.6 
64 
58.6 
65 
59.6 
66 
60.7 
67 
61.9 
68 
63.3 
69 
64.8 
70 
66.6 
71 
68.8 
72 
71.4 
73 
74.8 
74 
79.6 


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MNK14344100 SAP Version 3.0 
Total Score 
General Health & Lung &Skin Score 
75 
87.3 
76 
100.0 
15.2.3. Fatigue Assessment Scale (FAS) 
• FAS Total Score is calculated by the total sum of all the answers recorded in the 
FAS questionnaire. The scores for questions 4 and 10 will be equal to the following 
when recorded. 
If the answer 1 is recorded this will equal 5. 
If the answer 2 is recorded this will equal 4. 
If the answer 3 is recorded this will equal 3. 
If the answer 4 is recorded this will equal 2. 
If the answer 5 is recorded this will equal 1. 
15.2.4. Patient Global Assessment Score 
• This score is the answer recorded by answering the patient global assessment 
question. 
15.2.5. Physician Global Assessment Score 
• This score is the answer recorded by answering the physician global assessment 
question. 
15.2.6 Medical Research Council Dyspnea Scale 
• This score is the answer recorded by answering the medical research council 
dyspnea scale. 
15.2.7 Leicester Cough Questionnaire 
• LCQ Total Score 
This score is calculated with the following calculation below. 
(LCQ Physical Score + LCQ Social Score +LCQ Psychological Score); 
• LCQ Physical Score 
This score is calculated with the following calculation below using the answers 
recorded from the LCQ questionnaire physical module. The physical module of the 
LCQ questionnaire includes questions 1,2,3,9,10,11,14 and 15. 


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MNK14344100 SAP Version 3.0 
(Total score from questions in module / Number of questions in module). 
• LCQ Social Score 
This score is calculated with the following calculation below using the answers 
recorded from the LCQ questionnaire social module. The social module of the LCQ 
questionnaire includes questions 7,8,18 and 19. 
(Total score from questions in module / Number of questions in module). 
• LCQ Psychological Score 
This score is calculated with the following calculation below using the answers 
recorded from the LCQ questionnaire social module. The psychological module of 
the LCQ questionnaire includes questions 4,5,6,12,13,16 and 17. 
(Total score from questions in module / Number of questions in module).


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MNK14344100 SAP Version 3.0 
 
15.3. Schedule of Study Events  
 
 


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MNK14344100 SAP Version 3.0 
 
 
 
 
 
 


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MNK14344100 SAP Version 3.0 
 
 
15.4. SAS Procedures 
• T test 
ods output ttests=ttest; 
proc ttest data=xxx sides=2 alpha=0.05 h0=0; 
  class TRT;  
  var AnalVar; 
run; 
• Pearson’s chi-square test 


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MNK14344100 SAP Version 3.0 
proc freq data=xxx;   
  tables TRT*AnalVar /chisq; 
  output out=chisq pchi; 
run; 
• Fisher’s exact test 
proc freq data=xxx;   
  tables TRT*AnalVar / fisher; 
  output out= fisher exact; 
run; 
 
• MMRM 
ods output lsmeans=lsm diffs=diff; 
proc mixed data=xxx; 
  class TRT AVISITN USUBJID; 
  model AnalVar = BASVAR TRT AVISITN TRT*AVISITN; 
  repeated AVISITN / type=UN subject=USUBJID; 
  lsmeans TRT*AVISITN / diff cl; 
run; 
 
 


Statistical Analysis Plan (SAP) Client Approval Form
Document Number: FORM-02894 v8.0
Page 1 of 1
Effective Date: 22 Nov 2021
Printed on: 2 February 2022
Client:
Mallinckrodt ARD, LLC
Protocol Number:
MNK14344100
Document Description:
Final Statistical Analysis Plan
SAP Title:
A Multicenter, Randomized, Double Blind, Placebo 
Controlled Exploratory Study to Assess the Efficacy 
and Safety of Acthar® Gel in Subjects with Pulmonary 
Sarcoidosis 
SAP Version Number:
3.0
Effective Date:
02FEB2022
Author(s):
For PPD: 
, 
Approved by:
Mallinckrodt ARD, LLC
Date (DD-MMM-YYYY)
Mallinckrodt ARD, LLC
Date (DD-MMM-YYYY)
Docu
cument 
02-Feb-2022