Conditions: Multiple Sclerosis, Relapsing-Remitting
Keywords: Relapsing, Remitting Multiple Sclerosis RRMS
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 35
Healthy volunteers: no

Brief summary:
This study will enroll about 66 participants who experienced a relapse of RRMS that steroids did not help. The doctor will put participants into a treatment group. Each person has an equal chance of being in either one of two groups (like flipping a coin). One group will receive a shot of study medicine (called Acthar Gel) under their skin every day for 14 days. The other group will receive a shot every day for 14 days, too, but there is no medicine in it (called placebo).

Detailed description:

Arms:
arm 1: Participants receive Acthar Gel under the skin once a day for 14 consecutive days arm 2: Participants receive Placebo under the skin once a day for 14 consecutive days

Interventions: intervention 1: Acthar Gel intervention 2: Placebo
Intervention descriptions: intervention 1: Acthar Gel 1 mL (80U) for subcutaneous injection intervention 2: Placebo for subcutaneous injection

Protocol document:
Prot_SAP_001.pdf: 
TITLE PAGE 
CLINICAL STUDY PROTOCOL 
A Multicenter, Randomized, Double Blind, Placebo Controlled Parallel 
Group, Pilot Study to Assess the Efficacy and Safety of Acthar® in Subjects 
With Relapsing-remitting Multiple Sclerosis 
Protocol Number: MNK14274069 
Date of Original Protocol: 
27 July 2016 
Date of Protocol Revision: 
21 September 2016 
Date of Protocol Amendment 1: 
30 January 2017 
Date of Protocol Amendment 2: 
07 November 2017 
Date of Protocol Amendment 3: 
15 August 2019 
Mallinckrodt ARD, LLC 
1425 US Route 206 
Bedminster, NJ 07921 
United States of America 
NCT03126760


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SUMMARY OF AMENDMENTS 
PROTOCOL AMENDMENT 3 
SUMMARY OF CHANGES 
Protocol Amendment 3 was created to enhance enrollment.  
The major changes are to: 
1. Expand the screening period from 14 days to 28 days 
2. Allow for Acthar use up to 6 months prior to study entry 
3. Provide an exception to allow a 2 day window after the initiation of high dose 
corticosteroids to obtain certain screening assessments (FSS and EDSS, MSIS-29). 
4. Allow prior and concomitant use of ocrelizumab 
5. Add a primary efficacy outcome measure 
A summary of changes provides the rationale and actual text. 
PROTOCOL AMENDMENT 2 
SUMMARY OF CHANGES 
Protocol Amendment 2 was developed to update the Mallinckrodt ARD, Inc. address; remove 
outdated contact information; increase the screening period; increase the window from onset 
of relapse symptoms to first dose of intravenous methylprednisolone (IVMP), oral prednisone, 
or oral methylprednisolone; expand the Expanded Disability Index Scale (EDSS) range at 
entry; correct Interactive Phone/Web Response System (IXRS) contact requirements; and 
allow concomitant treatment with alemtuzumab and natalizumab. 
Additional minor changes that do not impact study conduct or subject safety were also made.  
The major protocol changes are summarized below:  
The address of the sponsor, Mallinckrodt ARD, Inc. has been updated on the title page. 
Contact information for the Medical Monitor, Clinical Technical Lead, and Clinical Trial 
Manager have been removed and will now be made available in a separate document. 
The screening period has been increased from 24 days to 29 days and the approximate 
duration of subject participation has been increased from 10 to 11 weeks. 
The allowable window between the onset of relapse symptoms and the first dose of IVMP, 
oral prednisone, or oral methylprednisolone has been increased from 10 to 14 days. 
The EDSS range acceptable at entry (Inclusion Criterion 9) has been increased to 2.0 to 6.5 
(formerly 3.5 to 6.5). 
The Schedule of Study Events and Section 14 has been corrected to require IXRS contact at 
the Screening, and Baseline Visits only 


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Subjects treated with alemtuzumab are no longer excluded from the study (Exclusion 
Criterion 8) and alemtuzumab has been removed from the list of prohibited concomitant 
medications. 
Subjects treated with natalizumab are no longer excluded from the study as long as those 
subjects are currently negative for the John Cunningham (JC) virus based on a negative test 
result within the 6 months prior to the first dose of study drug.  
 
PROTOCOL AMENDMENT 1 
SUMMARY OF CHANGES 
Protocol Amendment 1 was developed to remove the requirement for male contraception, add 
ocrelizumab and daclizumab to the medications prohibited during the study, add microscopic 
examination to the urinalysis, and clarify the measurement of improvement prior to 
randomization. 
Additional minor changes that do not impact study conduct or subject safety were also made.  
The major protocol changes are summarized below:  
 Inclusion criterion 4 that required male subjects to use contraception during the 
study was removed. The numbering of the list of inclusion criteria was not 
changed and inclusion criterion 4 is now left intentionally blank. 
 Use of ocrelizumab or daclizumab for 6 months prior to the study was added to the 
exclusion criteria and ocrelizumab or daclizumab were added to the list of 
medication prohibited during the study. 
 Microscopic examination (including specific tests) was added to the list of 
analyses required for urinalysis. 
 The improvement in Functional Systems Score (FSS) required for randomization 
was clarified to allow subjects who failed to improve by at least 1 point in 1 or 
more functions (pyramidal, cerebellar, brainstem, sensory, bowel and bladder, 
visual, cerebral) to be randomized. 
 The address of the sponsor has been updated on the title page. 
 
 


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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 1 
SUMMARY OF AMENDMENTS ............................................................................... 2 
TABLE OF CONTENTS .............................................................................................. 4 
1. 
DISCLOSURE STATEMENT .................................................................. 9 
1.1. 
Restricted Distribution of Documents ........................................................ 9 
2. 
CONTACTS ............................................................................................. 10 
3. 
SPONSOR SIGNATURE ........................................................................ 11 
4. 
INVESTIGATOR SIGNATURE ............................................................. 12 
5. 
ABBREVIATIONS ................................................................................. 13 
6. 
SYNOPSIS ............................................................................................... 15 
7. 
STUDY SCHEMATIC AND SCHEDULE OF EVENTS ...................... 19 
7.1. 
Study Schematic ....................................................................................... 19 
7.2. 
Schedule of Study Events ........................................................................ 20 
8. 
ETHICAL CONSIDERATIONS ............................................................. 22 
8.1. 
Institutional Review Board/Independent Ethics Committee .................... 22 
8.2. 
Ethical Conduct of the Study ................................................................... 22 
8.3. 
Subject Information and Consent ............................................................. 22 
9. 
BACKGROUND INFORMATION AND RATIONALE ....................... 24 
9.1. 
Overview .................................................................................................. 24 
9.2. 
Product Description .................................................................................. 25 
9.3. 
Dosage and Administration ...................................................................... 26 
9.4. 
Dose Rationale ......................................................................................... 26 
9.5. 
Adverse Events......................................................................................... 26 
10. 
OBJECTIVES .......................................................................................... 27 
10.1. 
Primary Objectives ................................................................................... 27 
10.2. 
Secondary Objective ................................................................................ 27 
10.3. 
Exploratory Objective .............................................................................. 27 
10.4. 
Outcome Measures ................................................................................... 27 


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11. 
STUDY DESIGN ..................................................................................... 28 
11.1. 
Description ............................................................................................... 28 
11.2. 
Approximate Duration of Subject Participation ....................................... 28 
11.3. 
Approximate Duration of Study ............................................................... 28 
11.4. 
Approximate Number of Subjects ............................................................ 28 
12. 
SELECTION OF SUBJECTS .................................................................. 29 
12.1. 
Inclusion Criteria ...................................................................................... 29 
12.2. 
Exclusion Criteria..................................................................................... 30 
12.3. 
Screen Failure........................................................................................... 32 
13. 
PRIOR AND CONCOMITANT MEDICATION/NONDRUG 
THERAPIES ............................................................................................ 33 
13.1. 
Prohibited Concomitant Medications/Nondrug Therapies....................... 33 
13.2. 
Required and Allowed Concomitant Medications/Nondrug Therapies ... 33 
14. 
PROCEDURES/ASSESSMENTS ........................................................... 34 
14.1. 
Screening Visit (Study Days −42 to −14) Procedures/Assessments ........ 34 
14.2. 
Baseline Visit (Day 1) and First Dose Procedures/Assessments ............. 34 
14.3. 
Day 7 (± 1 Day) Procedures/Assessments ............................................... 35 
14.4. 
Day 14 (± 2 Days) Procedures/Assessments ............................................ 35 
14.5. 
Day 21 (± 2 Days)/Follow-up Visit 1 ...................................................... 36 
14.6. 
Day 42 (± 2 Days) Follow-up Visit 2/Early Termination 
Procedures/Assessments .......................................................................... 36 
15. 
INVESTIGATIONAL MEDICINAL PRODUCT (STUDY DRUG) ..... 37 
15.1. 
Methods of Assigning Subjects to Treatment Groups ............................. 37 
15.1.1. 
Randomization ......................................................................................... 37 
15.1.2. 
IXRS ......................................................................................................... 37 
15.2. 
Emergency Identification of Investigational Medicinal Product ............. 37 
15.3. 
Dosing Procedures ................................................................................... 38 
15.3.1. 
Treatment Discontinuation ....................................................................... 38 
15.4. 
Storage of Clinical Supplies ..................................................................... 38 
15.5. 
Drug Accountability ................................................................................. 38 
15.6. 
Compliance Monitoring ........................................................................... 39 
16. 
EFFICACY ASSESSMENTS .................................................................. 40 


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16.1. 
Subject Completed Assessments .............................................................. 40 
16.1.1. 
MS Impact Scale (Version 1) ................................................................... 40 
16.2. 
Investigator (or Designee) and Blinded Rater Completed Assessments .. 40 
16.2.1. 
Expanded Disability Status Score/Functional Systems Score ................. 40 
16.3. 
Clinical Global Impression of Improvement............................................ 41 
17. 
SAFETY ASSESSMENTS AND PROCEDURES ................................. 42 
17.1. 
Adverse Events......................................................................................... 42 
17.2. 
Medical and Surgical History................................................................... 42 
17.3. 
Current Medical Conditions ..................................................................... 42 
17.4. 
Physical Examination ............................................................................... 42 
17.5. 
Height and Weight ................................................................................... 43 
17.6. 
Vital Signs ................................................................................................ 43 
17.7. 
Clinical Laboratory Tests (Chemistry, Hematology, Urinalysis, HbA1c, 
Hepatitis Serology, IGRA, and Pregnancy Tests) .................................... 43 
18. 
QUALITY OF LIFE/ HEALTH OUTCOME ASSESSMENTS ............. 45 
 
 
 
 
 
 
19. 
STATISTICAL METHODS AND PLANNED ANALYSIS .................. 46 
19.1. 
General Considerations ............................................................................ 46 
19.2. 
Analysis Populations ................................................................................ 46 
19.3. 
Endpoints ................................................................................................. 46 
19.3.1. 
Primary Efficacy Endpoint ....................................................................... 46 
19.3.2. 
Primary Safety Endpoint .......................................................................... 46 
19.3.3. 
Secondary Efficacy Endpoints ................................................................. 46 
19.3.4. 
Exploratory Endpoints ............................................................................. 47 
19.4. 
Subject Characteristics ............................................................................. 47 
19.4.1. 
Demographics .......................................................................................... 47 
19.4.2. 
Medical and Surgical History................................................................... 47 
19.4.3. 
Prior and Concomitant Medications......................................................... 47 
19.4.4. 
Subject Disposition and Exposure to Study Drug .................................... 47 
19.5. 
Efficacy Analysis ..................................................................................... 47 


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19.6. 
Safety Analysis ........................................................................................ 48 
19.6.1. 
Adverse Events......................................................................................... 48 
19.6.2. 
Clinical Laboratory Tests ......................................................................... 48 
19.6.3. 
Vital Signs ................................................................................................ 48 
19.6.4. 
Other Safety Analysis .............................................................................. 49 
19.7. 
Quality of Life/ Health Outcomes Analysis ............................................. 49 
19.8. 
Interim Analysis ....................................................................................... 49 
19.9. 
Statistical Power and Sample Size Considerations .................................. 49 
19.10. 
Missing Data ............................................................................................ 49 
19.11. 
Deviations From the Statistical Analysis Plan ......................................... 50 
20. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ................ 51 
20.1. 
Safety........................................................................................................ 51 
20.2. 
Definitions ................................................................................................ 51 
20.3. 
Adverse Event and Serious Adverse Event Classifications ..................... 52 
20.4. 
Adverse Event and Serious Adverse Event Recording and Reporting .... 53 
20.5. 
Adverse Events of Special Interest .......................................................... 55 
20.6. 
Pregnancy Reporting ................................................................................ 56 
21. 
SUBJECT DISCONTINUATION OR WITHDRAWAL ....................... 57 
21.1. 
Subject Withdrawal .................................................................................. 57 
22. 
STUDY SUSPENSION, TERMINATION, AND COMPLETION ........ 58 
23. 
PROTOCOL AMENDMENTS ............................................................... 59 
24. 
QUALITY CONTROL AND ASSURANCE .......................................... 60 
24.1. 
Study and Study Site Discontinuation Criteria ........................................ 60 
25. 
DIRECT ACCESS, DATA HANDLING, AND RECORD-KEEPING .. 61 
25.1. 
Investigator ............................................................................................... 61 
25.2. 
Sponsor ..................................................................................................... 61 
26. 
SUBJECT INJURY .................................................................................. 62 
27. 
RECORDS RETENTION ........................................................................ 63 
28. 
BIOLOGICAL SAMPLES ...................................................................... 64 
29. 
PUBLICATION POLICY ........................................................................ 65 
29.1. 
Sponsor’s Publication Policy ................................................................... 65 


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29.2. 
Investigator’s Ability to Publish .............................................................. 65 
30. 
REFERENCES ......................................................................................... 66 
31. 
ATTACHMENTS .................................................................................... 69 
31.1. 
Attachment 1: Clinical Laboratory Tests ................................................. 69 
 
List of Tables and Figures 
Figure 1: 
Study Overview ........................................................................................ 19 
Table 1: 
Schedule of Study Events ........................................................................ 20 
Table 2: 
Adverse Event Relationships ................................................................... 53 
Table 3: 
Adverse Event Severity Grades ............................................................... 53 
Table 4: 
Reporting Requirements for Adverse Events ........................................... 54 
 


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1. 
DISCLOSURE STATEMENT 
1.1. 
Restricted Distribution of Documents 
This document contains information that is confidential and proprietary to the sponsor. This 
information is being provided to the investigator solely for the purpose of evaluating and/or 
conducting a clinical study for the sponsor. The investigator may disclose the contents of this 
document only to study personnel under his/her supervision, institutional review boards 
(IRBs)/independent ethics committees (IECs), or duly authorized representatives of regulatory 
agencies for this purpose under the condition that they maintain confidentiality. The contents 
of this document may not be used in any other clinical study, disclosed to any other person or 
entity, or published without the prior written permission of the sponsor. The foregoing shall 
not apply to disclosure required by any regulations; however, the investigator will give 
prompt notice to the sponsor of any such disclosure. All other nonpublic information provided 
by the sponsor, as well as any information that may be added to this document, also is 
confidential and proprietary to the sponsor and must be kept in confidence in the same manner 
as the contents of this document. 
 
 


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2. 
CONTACTS 
Current medical monitor and sponsor contacts will be provided in a separate document. 
Please see Section 20.4 for detailed information regarding the Serious Adverse Event (SAE) 
Reporting Requirements for this study. Specific contact information for SAE reporting will be 
provided in a separate document. 
 
 


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3. 
SPONSOR SIGNATURE 
My signature, in conjunction with the signature of the investigator, confirms the agreement of 
both parties that the clinical study will be conducted in accordance with the protocol and 
applicable laws and other 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) (where applicable), all applicable national and local regulations, 
protections for privacy, and generally accepted ethical principles for human research such as 
the Declaration of Helsinki. 
Nothing in this document is intended to limit the authority of a physician to provide 
emergency medical care. 
 
 
 
 
Sponsor Signature 
 
Date of Signature 
(DD Month YYYY) 
 
 
 
 PhD 
 
 
Sponsor Name (print) 
 
 
 
 
Digitally signed by 
 
Reason: I am approving this document 
Date: 2019.08.15 13:46:19 -04'00'


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4. 
INVESTIGATOR SIGNATURE  
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) (where appropriate), all applicable national and 
local regulations, 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. 
 
 
 
 
 
Investigator’s Signature 
 
Date of Signature 
(DD Month YYYY) 
 
 
 
 
 
 
Investigator’s Name and Title (print) 
 
 
 
 
 


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5. 
ABBREVIATIONS 
Abbreviation 
Term 
ACTH 
Adrenocorticotropic hormone 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
 
 
CGI-I 
Clinical Global Impression of Improvement Scale 
CI 
Confidence interval 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
EDSS 
Expanded Disability Index Scale 
FSS 
Functional Systems Score 
HbA1c 
Glycosylated hemoglobin 
HBsAg 
Hepatitis B surface antigen 
HBcAb 
Hepatitis B core antibody 
HCV 
Hepatitis C virus antibody 
HCV PCR 
Hepatitis C virus polymerase chain reaction 
HIPAA 
Health Insurance Portability and Accountability Act 
 
 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ID 
Identification 
IEC 
Independent Ethics Committee 
IGRA 
Interferon gamma release assay 
IMP 
Investigational medicinal product 
IVIg 
Intravenous immunoglobulin 
IVMP 
Intravenous methylprednisolone 
IXRS 
Interactive Phone/Web Response System 
JC virus 
John Cunningham virus 
LOCF 
Last observation carried forward 
MCR 
Melanocortin receptor 
mITT 
Modified intent-to-treat 
MM 
Medical monitor 
MS 
Multiple sclerosis 
MSIS-29 
Multiple Sclerosis Impact Scale Version 1 
QD 
Per day, daily 
QOL 
Quality of life 
RRMS 
Relapsing-remitting multiple sclerosis 
SAE 
Serious adverse event 
SC 
Subcutaneous 
TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 


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Abbreviation 
Term 
U 
Unit(s) 
ULN 
Upper limit of normal 
 
 
 
 
 


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6. 
SYNOPSIS  
Study Title: A Multicenter, Randomized, Double Blind, Placebo Controlled Parallel Group, Pilot Study to 
Assess the Efficacy and Safety of Acthar® in Subjects With Relapsing-remitting Multiple Sclerosis  
Protocol Number: MNK14274069 
Type: Phase 4 
Condition/Disease:  
Relapsing-remitting Multiple Sclerosis  
Approximate Number of Subjects: 66 
Approximate Duration of Subject Participation: 13 
weeks 
Approximate Number of Study Centers: 20 
Approximate Duration of Study: 22 months 
Design:  
This is a multicenter, multiple dose study to estimate the response rate, and examine the safety of, Acthar in 
subjects with relapsing-remitting multiple sclerosis (RRMS) who have not responded to high dose intravenous 
methylprednisolone (IVMP), oral prednisone, or oral methylprednisolone. Approximately 66 subjects will be 
randomized.  
Subjects with RRMS who have experienced a relapse and who will receive 3 to 5 days (given over a period of 
up to 7 days) of treatment with high dose IVMP (1g/day), oral prednisone (1,250 mg per day [QD]), or oral 
methylprednisolone (1,000 mg QD) within 28 days of the onset of relapse symptoms are candidates for the 
current study. The Screening Visit will take place during the initial 28 days of the 42-day screening period and 
subjects will be assessed with the Expanded Disability Index Scale (EDSS)/ Function Systems Score (FSS) 
prior to treatment with IVMP, oral prednisone, or oral methylprednisolone. At 14 (± 1) days following the 
initiation of high dose IVMP, oral prednisone, or oral methylprednisolone, subjects will be re-assessed with 
the EDSS/FSS and subjects who do not improve by at least 1 point in 1 or more functions of the FSS will be 
randomized on a 1:1 basis to receive subcutaneous (SC) Acthar 1 mL (80 units [U]) QD or SC matching 
placebo 1 mL QD for 14 days. The improvement on an FSS subscale will be relevant to the symptoms 
associated with the relapse based on the judgement of the treating physician. Subjects will be evaluated for 
treatment response using the EDSS and other standard measures up to 42 days after the start of study drug 
dosing. 
Objectives:  
Primary Objectives 
 
To generate an estimate of the response rate for Acthar in subjects with RRMS who have not 
responded to high dose IVMP, oral prednisone, or oral methylprednisolone.  
 
To assess the safety and tolerability of Acthar in subjects with RRMS who have not responded to 
high dose IVMP, oral prednisone, or oral methylprednisolone.  
Secondary Objective 
 
To assess the effect of Acthar on quality of life (QOL) in subjects with RRMS who have not 
responded to high dose IVMP, oral prednisone, or oral methylprednisolone.  


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Study Title: A Multicenter, Randomized, Double Blind, Placebo Controlled Parallel Group, Pilot Study to 
Assess the Efficacy and Safety of Acthar® in Subjects With Relapsing-remitting Multiple Sclerosis  
Protocol Number: MNK14274069 
Type: Phase 4 
Condition/Disease:  
Relapsing-remitting Multiple Sclerosis  
Exploratory Objective 
 
To explore 
 
 
  
Entry Criteria: 
Adult male or female subjects with a diagnosis of clinically RRMS who have experienced a relapse with onset 
≤ 42 days prior to the Baseline Visit. Subject must have started treatment with 3 to 5 days (inclusive, over a 
period of up to 7 days) of 1 g per day of IVMP, 1,250 mg per day of oral prednisone, or 1,000 mg per day of 
oral methylprednisolone within 28 days of the onset of the first relapse symptom. Subjects must have failed to 
obtain an improvement of at least 1 point in 1 or more functions on the FSS 14 days following the first dose of 
high dose IVMP (1g/day for 3 to 5 days), oral prednisone (1,250 mg per day for 3 to 5 days), or oral 
methylprednisolone (1,000 mg per day for 3 to 5 days). Subjects must have an EDSS score of 2.0 to 6.5 
(inclusive) at the Baseline Visit. Subjects must have a mean systolic blood pressure ≤ 140 mm Hg and a mean 
diastolic blood pressure of ≤ 90 mm Hg at the Screening and Baseline Visits. Subject may not have been treated 
with daclizumab, or any immunosuppressants (including but not limited to cyclophosphamide, mitoxantrone, 
or rituximab) in the 6 months prior to the Screening Visit or throughout the study. If subjects are receiving any 
nonexcluded disease modifying treatments, they must have been on a stable dose(s) for 30 days prior to the 
Baseline Visit and plan to remain on that dose(s) throughout the study. Subjects may not have any known 
contraindication(s) to Acthar, history of chronic active hepatitis including active or chronic hepatitis B, or 
acute or chronic hepatitis C, history of tuberculosis (TB) infection or positive TB test, or type 1 or type 2 
diabetes mellitus.  
Concomitant Medications/Nondrug Therapies:  
The following medications/nondrug therapies are not permitted during the study from the Screening Visit 
through Day 42: 
 
Oral corticosteroids (prednisone/prednisone equivalent) in excess of the 3 to 5 days (given over a 
period of up to 7 days) of high dose treatment that is allowed during the screening period. 
 
Parenteral corticosteroids. 
 
Daclizumab, or any immunosuppressant (including but not limited to cyclophosphamide, 
mitoxantrone, or rituximab). 
 
Natalizumab, as long as the subject is currently negative for the John Cunningham (JC) virus 
based on a negative test result within the 6 months prior to the first dose of study drug.   
 
Live or live-attenuated vaccines. 
 
Intravenous immunoglobulin (IVIg). 
 
Any investigational drug, device, or procedure administered as part of a research study.  


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Study Title: A Multicenter, Randomized, Double Blind, Placebo Controlled Parallel Group, Pilot Study to 
Assess the Efficacy and Safety of Acthar® in Subjects With Relapsing-remitting Multiple Sclerosis  
Protocol Number: MNK14274069 
Type: Phase 4 
Condition/Disease:  
Relapsing-remitting Multiple Sclerosis  
All medications and nondrug therapies (eg, blood transfusions, oxygen supplementation) received by subjects 
from the Screening Visit through the Follow-up Visit will be recorded.  
Investigational Medicinal Product and Treatment Administration:  
Acthar is a porcine adrenocorticotropic hormone (ACTH) analogue currently approved by the FDA for the 
treatment of MS exacerbations. Acthar and its matching placebo will be supplied by the sponsor and 
administered SC as follows in this study: 
Treatment A: Acthar 1 mL (80 U) administered QD for 14 days, 
OR 
Treatment B: Placebo 1 mL administered QD for 14 days. 
Efficacy Evaluations: 
The following efficacy assessments will be evaluated: Multiple Sclerosis Impact Scale Version 1 (MSIS-29), 
EDSS/FSS, and Clinical Global Impression of Improvement Scale (CGI-I). 
Safety Evaluations:  
The following safety assessments will be evaluated: adverse events, physical examinations, clinical laboratory 
tests, pregnancy testing, medical history, weight, and vital signs.  
Quality of Life/Health Outcome Evaluations: 
The following QOL and health outcome assessment will be evaluated: 
 
 
  
Statistical Methods: 
Analysis Populations 
 
The Safety Population will include all randomized subjects who receive 1 or more doses of study 
drug. 
 
The Modified Intent-to-Treat (mITT) Population will include all enrolled subjects who receive 1 or 
more doses of study drug and who have at least 1 postbaseline EDSS score.  
 
The Per-Protocol Population will include the subset of the mITT population who complete the 
study as per protocol.  
Sample Size 
It is expected that 66 subjects will be randomized into 1 of 2 treatment groups: 80 U (1 mL) of Acthar per day 
for 14 consecutive days or placebo (1 mL) per day for 14 consecutive days in a 1:1 ratio (33 per group). The 
primary analysis is to generate point estimates and associated 90% confidence intervals (CI) for the response 
rates on EDSS in the Acthar group and the placebo group at Day 42, respectively using a mITT analysis 
population. Assuming 3 subjects will not qualify for the mITT analysis population after randomization in each 
treatment group, there will be 30 mITT subjects in each group. Based on an expected 60% response rate in the 
Acthar group, the study can build a 90% Wilson CI of (45.1%, 73.3%) with approximate precision of 14.1%. 
Based on an expected 25% response rate in the placebo group, the study can build an approximate 90% 
Wilson CI of (15.7%, 41.5%) with approximate precision of 12.9%.  


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Study Title: A Multicenter, Randomized, Double Blind, Placebo Controlled Parallel Group, Pilot Study to 
Assess the Efficacy and Safety of Acthar® in Subjects With Relapsing-remitting Multiple Sclerosis  
Protocol Number: MNK14274069 
Type: Phase 4 
Condition/Disease:  
Relapsing-remitting Multiple Sclerosis  
Endpoint Analyses 
A responder on EDSS is defined as a subject who achieves the following: 
 
≥ 1.0 point improvement on EDSS score compared to baseline if baseline EDSS score was ≤ 5.5. 
 
≥ 0.5 point improvement on EDSS score if the baseline EDSS score was > 5.5.  
A responder on MSIS-29 is defined as a patient who achieves a ≥ 8 point improvement on the physical 
subscale score of MSIS-29 compared to baseline. 
Baseline is defined as the value observed prior to first dose of the study drug (Day 1). 
The primary efficacy endpoint, the response rate on EDSS at Day 42, will be calculated by treatment group. 
Response rates and 90% Wilson CIs will be reported for each treatment group. These analyses will be 
performed for the mITT and Per-Protocol populations. 
Summary statistics (n, mean, SD, median, minimum, and maximum) of the baseline value, the value at each 
scheduled postbaseline evaluation and the corresponding change from baseline for EDSS score will be 
presented by treatment group for all subjects in the mITT population and the Per-Protocol population. 
A subject-by-subject data listing sorted by treatment group and subsequently by subject will be generated for 
all subjects in the mITT population. 
For the secondary endpoints, the response rate endpoints will be analyzed and presented with the same 
approach as described above for the primary efficacy endpoint. The mean score endpoint will be calculated by 
treatment group. Mean, SD, and 90% CI will be presented by treatment group. All secondary efficacy 
analyses will use the mITT population. 
For the exploratory endpoints, 
 
 
 
For all efficacy endpoints, the normality assumption of the data will be examined using appropriate normality 
test. If the test result shows the data is not normally distributed, then median, 10% and 90% percentiles will be 
presented instead of mean, SD and 90% CI.  
Quality of Life/ Health Outcomes  
 
  
Safety 
Treatment-emergent adverse events and serious adverse events will be summarized using the MedDRA by 
preferred term within system organ class. Other safety data will be listed and summarized descriptively or 
graphically, as appropriate. 


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7. 
STUDY SCHEMATIC AND SCHEDULE OF EVENTS 
7.1. 
Study Schematic 
Figure 1: 
Study Overview 


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7.2. 
Schedule of Study Events 
Table 1: 
Schedule of Study Events 
Assessment/Procedure 
Screening (Day −42 to Day −1) 
Baseline a 
Treatment Period 
Follow-up  
Visit 1 
End of Study/ 
Follow-up 
Visit 2/ 
Day 1 
Day 7 
(± 1 
day) 
Day 14 (± 
2 days) b 
Day 21 
(± 2 
days) 
Day 42 
(± 2 days) 
Informed Consent 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria Review 
X 
X 
 
 
 
 
Medical/Surgical History 
X 
 
 
 
 
 
Current Medical Condition Review 
 
X 
X 
 
X 
X 
Demographics 
X 
 
 
 
 
 
Complete Physical Examination 
 
X 
 
 
 
X 
Limited Physical Examination 
X 
 
X 
 
X 
 
Height and Weight c 
X 
X 
 
 
 
X 
Vital Signs d 
X 
X 
X 
 
X 
X 
12-lead ECG 
 
X 
 
 
 
X 
Clinical Laboratory Tests e 
X 
X 
X 
 
X 
X 
HbA1c 
X 
 
 
 
 
 
Serum Pregnancy Test 
X 
 
 
 
 
X 
Urine Pregnancy Test 
 
X 
X 
 
X 
 
Hepatitis Serology 
X 
 
 
 
 
 
IGRA for TB 
X 
 
 
 
 
 
EDSS/FSS 
X 
X 
X 
 
X 
X 


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Assessment/Procedure 
Screening (Day −42 to Day −1) 
Baseline a 
Treatment Period 
Follow-up  
Visit 1 
End of Study/ 
Follow-up 
Visit 2/ 
Day 1 
Day 7 
(± 1 
day) 
Day 14 (± 
2 days) b 
Day 21 
(± 2 
days) 
Day 42 
(± 2 days) 
MSIS-29  
X 
X 
X 
X 
X 
X 
CGI-I 
 
 
X 
 
X 
X 
 
 
X 
 
 
X 
X 
 
 
X 
 
 
X 
X 
 
 
X 
 
 
X 
X 
Study Drug and Diary Training 
 
X 
 
 
 
 
IXRS Contact 
X 
X 
 
 
 
 
Dispense Study Drug 
 
X 
 
 
 
 
Administer First Dose f 
 
X 
 
 
 
 
Study Drug Accountability and Diary 
Review 
 
 
X 
 
X 
  
Adverse Events and Concomitant 
Treatments 
X 
 a The Baseline visit will occur 14 (± 1) days after the first dose of IVMP, oral prednisone or oral 
methylprednisolone. 
b All Day 14 assessments will be done via telephone. 
c Height will be collected at the Screening Visit only. 
d Blood pressure, pulse rate, respiratory rate and body temperature. Blood pressure will be measured in triplicate 
at the Screening and Baseline Visits. 
e Chemistry, hematology, and urinalysis. 
f The first dose will be administered clinic and the subject will be observed for at least 1 hour after dosing. 
 
 


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8. 
ETHICAL CONSIDERATIONS 
This clinical study is designed to comply with International Council for Harmonisation (ICH) 
Guidance on General Considerations for Clinical Trials and applicable national and local 
regulations. 
8.1. 
Institutional Review Board/Independent Ethics Committee 
It is the responsibility of the investigator to obtain the approval of the IRB before the start of 
the study. The investigator will provide Mallinckrodt Inc. with a statement of compliance from 
the IRB and/or the US Department of Health and Human Services general assurance number. 
A copy of the approval letter along with a roster of IRB/Independent Ethics Committee (IEC) 
members and compliance letter 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 serious adverse events (SAE) or other 
significant safety findings per IRB/IEC guidelines. The study protocol, informed consent form 
(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 Code of 
Federal Regulations (CFR), Title 21, Part 56 (where applicable). 
8.2. 
Ethical Conduct of the Study 
The study will be conducted in full compliance with applicable international, national and 
local regulatory requirements; 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. 
8.3. 
Subject Information and Consent 
The ICF must be approved by the sponsor and the IRB before any subject provides consent. 
The investigator will provide Mallinckrodt with a copy of the IRB-approved ICF and a copy 
of the IRB’s written approval before the start of the study. 
At the Screening Visit, subjects will read the ICF and a Health Insurance Portability and 
Accountability Act (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. Subjects unable to give written informed consent must orally assent to the 
procedures, and written informed consent must be obtained from a legally authorized 
representative in accordance with national and local laws, as applicable. 
The ICF must contain all applicable elements of informed consent and the mandatory 
statements as defined in by national and local regulations including confidentiality. All 


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versions of each subject's signed ICF must be kept on file by the site for possible inspection by 
regulatory authorities and/or authorized Mallinckrodt personnel. Signed copies of the 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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9. 
BACKGROUND INFORMATION AND RATIONALE 
9.1. 
Overview 
Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by the 
demyelination of the central nervous system (Fox et al, 2012; Mayo Clinic). The incidence of 
MS in the US is estimated to be 4 cases per 100,000 per year with approximately 2,000 new 
cases diagnosed annually (MS International Federation). MS is more likely to occur in women 
than men (2:1 ratio) and mean age of onset in the US is approximately 33 years (MS 
International Federation). The most common form of MS is relapsing-remitting MS (RRMS) 
where patients experience acute relapses, also referred to as exacerbations, which are defined 
as episodes of worsening neurological function followed by partial or complete recovery 
periods (National MS Society; Nickerson et al, 2015; Ross et al, 2013b). Relapses in MS 
patients are associated with impaired daily abilities, residual disability, and reduced quality of 
life (QOL) (Nickerson et al, 2015; Ross et al, 2013b). 
The goal of treating an MS relapse is to alleviate the symptoms as quickly as possible and to 
promote a complete recovery of the episode. Mild relapses, such as sensory changes or bouts 
of fatigue, can be left to recover over time without treatment. However, more severe relapses 
such as optic neuritis or loss of equilibrium, are primarily treated with corticosteroids or 
adrenocorticotrophic hormone (ACTH) (Ontaneda and Rae-Grant, 2009; Ross et al, 2013a; 
Ross et al, 2013b). ACTH is an alternative treatment for acute relapses in patients who do not 
respond to, or do not tolerate, high dose corticosteroids. 
As described in the Package Insert, Acthar® (repository corticotropin injection, hereafter 
referred to as Acthar) is a porcine ACTH analogue (Mallinckrodt, 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), activation of the JAK-signal transducer and inhibition of nuclear factor-B (Buggy, 
1998; Mountjoy et al, 1992). Five subtypes of MCRs have been identified to date (MC1R-
MC5R), each with different tissue distributions, binding affinity characteristics, and 
physiological roles (Getting, 2006). ACTH binds to all 5 subtypes of MCR (Schioth et al, 
1995) and recent experiments demonstrate that Acthar also has agonist activity for all 5 MCRs 
(Mallinckrodt, Unpublished Data). 
There are several potential mechanisms by which Acthar may impact the pathophysiologic 
processes involved in MS. The MC1R, MC3R, MC4R, and the MC5R are expressed on cell 
types that are relevant to MS, including neurons, microglia, astrocytes, lymphocytes, and 
monocytes/macrophages (Catania et al, 2004; Brzoska et al, 2008; Arnason et al, 2012). The 
therapeutic benefits of Acthar in MS are often ascribed to corticosteroid pathways; however, 
recent evidence suggests that the immune-modulating and anti-inflammatory effects of Acthar 
may also be mediated via corticosteroid-independent melanocortin signaling pathways (Ross 
et al, 2013a; Arnason et al, 2012; Delgado et al, 1998). Melanocortin peptides exert numerous 
anti-inflammatory effects, including attenuation of NF-κB activity, downregulation of pro-
inflammatory cytokines and chemokines, inhibition of inflammatory cell migration, and 
upregulation of anti-inflammatory cytokines. Melanocortins also suppress the activation of 


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Th1 effector cells and promote the development of regulatory T lymphocytes (Catania et al, 
2004; Getting, 2002; Ross et al, 2013a; Taylor et al, 1994; Taylor and Lee, 2011). Thus, 
Acthar may benefit patients with MS through both its effects on melanocortin receptors as 
well as through steroidogenic effects.  
Early placebo controlled studies of Acthar for MS relapses demonstrated faster recovery when 
compared to placebo (Rose et al, 1970). Trials comparing Acthar to corticosteroids in the 
treatment of MS relapses demonstrated similar marked improvement outcomes (Miller et al, 
1961; Thompson et al, 1989). Acthar has been shown to provide positive outcomes and lower 
numbers of adverse events (AE) compared to intravenous methylprednisolone (IVMP) in MS 
patients who failed treatment with methylprednisolone (Berkovich et al, 2012). 
Although IVMP 1 g per day, high dose oral prednisone (1,250 mg per day), or high dose oral 
methylprednisolone (1,000 mg per day) for 3 to 5 days has become the standard of care for 
patients who have experienced MS relapses, many patients do not recover to their baseline 
level of neurological function. In a retrospective study, (Lublin, 2003) showed that MS 
relapses result in sustained accumulation of disability over time. In this study, a total of 224 
patients who had participated in the placebo groups of large clinical trials and who had 
experienced MS relapses were evaluated. Forty-two percent of patients were left with a 
residual deficit of at least 0.5 points on the Expanded Disability Status Scale (EDSS) and 28% 
with a deficit of at least 1.0 EDSS points at a mean of 64 days following the relapse.  
Randomized clinical trials that have examined the response rate of patients who have been 
treated for MS relapse with either IVMP or oral methylprednisolone suggest that between 65% 
and 85% experienced significant improvement (Le Page et al, 2015; Sellebjerg et al, 1998). 
This indicates that 20% to 35% of patients do not experience significant improvement. 
There are very limited treatment alternatives for patients who have experienced a relapse of 
MS and do not respond to corticosteroids. In a randomized, controlled, double blind trial of 
plasma exchange vs sham treatment in patients with acute demyelinating episodes (including 
some MS patients) who had failed to respond to treatment with IVMP, 42.1% responded to 
plasma exchange as compared to only 5.9% who responded to a sham treatment (Weinshenker 
et al, 1999).  
Because a significant number of MS patients with relapse do not respond to corticosteroids, 
and plasma exchange is invasive and often involves a lengthy hospital stay, there remains a 
large unmet need for these patients. The current placebo controlled, pilot study is designed to 
generate response rates in this patient population following treatment with Acthar in order to 
facilitate a sample size calculation for a larger, more definitive study in the future. 
9.2. 
Product Description 
Acthar is a sterile preparation of a purified ACTH analogue formulated in 16% gelatin to 
provide prolonged release after intramuscular or subcutaneous (SC) injection. Acthar contains 
0.5% phenol, not more than 0.1% cysteine (added), sodium hydroxide and/or acetic acid to 
adjust pH, and water for injection. Acthar is obtained from processing porcine pituitary using 
an FDA approved process. 
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 


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adjust pH, and water for injection. The placebo formulation is identical to Acthar except that it 
contains no active medication. 
9.3. 
Dosage and Administration 
Investigational medicinal product (IMP), also referred to as study drug, will be used to denote 
active drug (Acthar) and/or matching placebo. 
Following a screening period of up to 42 days during which subjects will receive either IVMP 
1g per day, oral prednisone 1,250 mg per day, or oral methylprednisolone 1,000 mg/day for 
3 to 5 days, subjects with RRMS unresponsive to corticosteroid therapy with relapse onset 
≤ 42 days prior to the Baseline Visit, will be randomized on a 1:1 basis to receive SC Acthar 
1 mL (80 Units [U]) daily (QD) or SC matching placebo 1 mL QD for 14 days.  
9.4. 
Dose Rationale 
Acthar is currently approved in the US for treatment of acute exacerbations of MS with daily 
intramuscular or SC doses of 80 to 120 U for up to 2 to 3 weeks (Mallinckrodt, 2019). The 
14 day regimen of 1 mL (80 U) was chosen for this study based on feasibility, safety, and 
current prescribing practices. The 1 mL (80 U) dose is lower than the maximum approved 
dose of 120 U.  
9.5. 
Adverse Events 
The most common adverse reactions for Acthar 
 
include fluid retention, alteration in glucose tolerance, elevation of blood pressure, behavioral 
and mood changes, and increased appetite and weight gain. See the current Acthar package 
insert for more specific information on adverse events associated with Acthar (Mallinckrodt, 
). 


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10. 
OBJECTIVES 
10.1. 
Primary Objectives 
The primary objectives of this study are: 
 To generate an estimate of the response rate for Acthar in subjects with RRMS 
who have not responded to high dose IVMP, oral prednisone, or oral 
methylprednisolone.  
 To assess the safety and tolerability of Acthar in subjects with RRMS who have 
not responded to high dose IVMP, oral prednisone, or oral methylprednisolone.  
10.2. 
Secondary Objective 
The secondary objective of this study is: 
 To assess the effect of Acthar on QOL in subjects with RRMS who have not 
responded to high dose IVMP, oral prednisone, or oral methylprednisolone.  
10.3. 
Exploratory Objective 
The exploratory objective of this study is: 
 
 
 
  
10.4. 
Outcome Measures 
The primary efficacy outcome measure is: Score on the Expanded Disability Status Scale 
(EDSS) at Baseline and Day 42.   
The EDSS is a method to score the steps of progressive disability in MS patients. The scale 
ranges from 0 (no disability) to 10 (death) in ½ point increments (0, 0.5, 1.0, 1.5, 2.0, etc).  
It is used by neurologists to track MS disability. Higher scores indicate more disability. Steps 
0-4.5 mean the patient is progressively disabled in eight functions, but still able to walk 
without aid. By Step 6, the patient needs a pair of canes or crutches to walk. By Step 9, the 
patient is unable to get out of bed, but can still talk and eat. 


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11. 
STUDY DESIGN 
11.1. 
Description 
This is a multicenter, multiple dose study to estimate the response rate, and examine the safety 
of, Acthar in subjects with RRMS who have not responded to high dose intravenous 
methylprednisolone (IVMP), oral prednisone, or oral methylprednisolone. Approximately 66 
subjects will be randomized.  
Subjects with RRMS who have experienced a relapse and who will receive 3 to 5 days (given 
over a period of up to 7 days) of treatment with high dose IVMP (1g/day for 3 to 5 days), oral 
prednisone (1,250 mg per day [QD]), or oral methylprednisolone (1,000 mg QD) within 
28 days of the onset of relapse symptoms are candidates for the current study. The Screening 
Visit will take place during the initial 28 days of the 42-day screening period and subjects will 
be assessed with the EDSS/ Function Systems Score (FSS) prior to treatment with IVMP, oral 
prednisone, or oral methylprednisolone. At 14 (± 1) days following the initiation of high dose 
IVMP, oral prednisone, or oral methylprednisolone, subjects will be re-assessed with the 
EDSS/FSS and subjects who do not improve by at least 1 point in 1 or more functions of the 
FSS will be randomized on a 1:1 basis to receive SC Acthar 1 mL (80 U) QD or SC matching 
placebo 1 mL QD for 14 days. The 1 point improvement on an FSS subscale will be relevant 
to the symptoms associated with the relapse based on the judgement of the treating physician. 
Subjects will be evaluated for treatment response using the EDSS and other standard measures 
up to 42 days after the start of study drug dosing.  
11.2. 
Approximate Duration of Subject Participation 
Subjects will participate in the study for a total of up to approximately 13 weeks, including a 
screening period of up to 42 days, and active treatment period of 14 days, and Follow-up 
Visits at 21 (± 2)  and 42 (± 2) days after the start of study drug administration.  
11.3. 
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 sites to identify and enroll eligible subjects. The entire study is expected 
to require approximately 22 months to complete.  
11.4. 
Approximate Number of Subjects 
It is expected that approximately 320 subjects will be screened and 66 subjects will be 
randomized at approximately 20 sites in the US. 


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12. 
SELECTION OF SUBJECTS 
12.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria for inclusion in the study at the Screening 
Visit and the Baseline Visit. 
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 years of age at the Screening Visit and can be male or female. 
3. Female subjects must be of nonchildbearing potential (history of hysterectomy, 
bilateral oophorectomy, bilateral tubal ligation, or postmenopausal with no history of 
menstrual flow in the 12 months prior to the Screening Visit), or if of childbearing 
potential must be nonpregnant, nonlactating and agree to use effective contraception 
with a male partner throughout study participation (through the final Follow-up Visit). 
Acceptable forms of contraception include hormonal measures (oral contraceptive 
pills, contraceptive patch, contraceptive ring, injections), intrauterine devices, double 
barrier methods (condom plus diaphragm, condom or diaphragm plus spermicidal gel 
or foam), and abstinence.  
4. This number left intentionally blank. 
5. Subjects must have a diagnosis of RRMS according to the revised McDonald criteria 
(Polman et al, 2011).  
6. Subjects must have had a relapse with onset ≤ 42 days prior to the Baseline Visit. 
Relapse is defined as new neurological symptom(s) persisting for ≥ 24 hours and 
accompanied by an objective change in neurological examination.  
7. Subject must have started treatment with 3 to 5 days (inclusive, given over a period of 
up to 7 days) of 1 g per day of IVMP, 1,250 mg per day of oral prednisone, or  
1,000 mg per day of oral methylprednisolone within 28 days of the onset of the first 
relapse symptom. 
8. Subjects must have failed to obtain an improvement of at least 1 point in 1 or more 
functions (pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, 
cerebral) on the FSS 14 days following the first dose of high dose IVMP (1g/day for 3 
to 5 days), oral prednisone (1,250 mg per day for 3 to 5 days), or oral 
methylprednisolone (1,000 mg per day for 3 to 5 days). The 1 point improvement in 1 
or more symptoms on the FSS subscale will be relevant to the symptoms associated 
with the relapse based on the judgement of the treating physician. 
9. Subjects must have an EDSS score of 2.0 to 6.5 (inclusive) at the Baseline Visit.  
10. Subjects must have a mean systolic blood pressure ≤ 140 mm Hg and a mean diastolic 
blood pressure of ≤ 90 mm Hg determined by the average of 3 seated readings taken at 
least 5 minutes apart at the Screening and Baseline Visits. 
11. Subjects must be able to communicate effectively with study personnel. 
12. Subjects must be able and willing to follow all protocol requirements and study 
restrictions. 


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13. Subjects must be able and willing to return for all study visits. 
12.2. 
Exclusion Criteria 
Subjects are ineligible for study participation if they meet any of the following criteria at the 
Screening Visit and/or the Baseline Visit: 
1. Subject is from a vulnerable population, as defined by the US CFR Title 45, Part 46, 
Section 46.111(b) and other local and national regulations, including but not limited 
to, employees (temporary, part-time, full time, etc) or a family member of the research 
staff conducting the study, or of the sponsor, or of the clinical research organization, or 
of the IRB/IEC. 
2. Subject has used Acthar for the treatment of MS within the last 6 months. 
3. Subject has only sensory, bowel/bladder, and/or cognitive symptoms of MS associated 
with the most recent relapse. 
4. Subject is unwilling to receive, or is intolerant of, SC injections. 
5. Subject has a history of sensitivity to ACTH preparations or to porcine protein 
products. 
6. Subject has cognitive or behavioral impairment that in the opinion of the investigator 
would impair the ability of the subject to comply with study procedures.  
7. Subject has received < 3 or > 5 days of dosing of IVMP, oral prednisone, or oral 
methylprednisolone during the screening period or who received their doses over a 
period of > 7 days. Divided doses of oral prednisone or oral methylprednisolone are 
acceptable as long as the total daily dose is 1,250 mg or 1,000 mg, respectively. 
8. Subject has been treated with daclizumab, or any immunosuppressants (including but 
not limited to cyclophosphamide, mitoxantrone, or rituximab), in the 6 months prior to 
the Screening Visit or throughout the study. Subjects treated with natalizumab will be 
excluded if they are not currently negative for JC virus based on a negative John 
Cunningham (JC) virus test result in the 6 months prior to the first dose of Acthar. 
9. Subjects receiving any nonexcluded disease modifying treatments (including beta-
interferons, glatiramer acetate, fingolimod, teriflunomide, and dimethyl fumarate) 
must have been on a stable dose(s) for 30 days prior to the Baseline Visit and plan to 
remain on that dose(s) throughout the study.  
10. Subject has any known contraindication(s) to Acthar (Mallinckrodt, 2019) including, 
but not limited to: 
 Any known history of scleroderma, osteoporosis, or ocular herpes simplex. 
 Any current uncontrolled hypertension, primary adrenocortical insufficiency, or 
adrenal cortical hyperfunction. 
 Any current psychoses, infectious disease, or Cushing’s syndrome. 
 Any current congestive heart failure (defined as New York Heart Association 
Functional Class III to IV). 


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 Peptic ulcer (within 24 weeks prior to the Screening Visit). 
 Recent major surgery (within 24 weeks prior to the Screening Visit). 
11. Subject has a history of chronic active hepatitis including active or chronic hepatitis B, 
or acute or chronic hepatitis C. 
12. Subject has a history of tuberculosis (TB) infection, any signs/symptoms of TB, or any 
close contact with an individual with an active TB infection. 
13. Subject has a clinically significant infection requiring intravenous administration of 
antibiotics and hospitalization in the 4 weeks prior to the Screening Visit. 
14. Subject has known immune compromised status, including but not limited to, 
individuals who have undergone organ transplantation or who are known to be 
positive for the human immunodeficiency virus. 
15. Subject has type 1 or type 2 diabetes mellitus (prior diagnosis of gestational diabetes 
mellitus is not exclusionary). 
16. Subject has any solid tumor malignancy currently diagnosed or undergoing therapy, or 
has received therapy for any solid tumor malignancy in the 5 years prior to the Screening 
Visit, with the exception of treated and cured basal cell carcinoma, treated and cured 
squamous cell carcinoma of the skin, and treated and cured carcinoma in situ of the 
cervix. 
17. Subject has a diagnosis of, is undergoing therapy for, or has received therapy for a 
hematologic malignancy in the 5 years prior to the Screening Visit. 
18. Subject has current or recent (within 24 weeks prior to the Screening Visit) drug or 
alcohol abuse as defined in Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition, Diagnostic Criteria for Drug and Alcohol Abuse (American Psychiatric 
Association, 2013). 
19. Subject has any of the following laboratory abnormalities at the Screening Visit: 
 Hemoglobin ≤ 8.0 g/dL. 
 Platelets ≤ 50,000 cells/μL. 
 Absolute neutrophil count (ANC) ≤ 1,000 cells/μL. 
 Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total 
bilirubin  2 times upper limit of normal (ULN). 
 Glycosylated hemoglobin (HbA1c)  6.5%. 
 Positive Hepatitis B surface antigen (HBsAg) or Hepatitis B core antibody 
(HBcAb). 
 
Positive Hepatitis C virus antibody (HCV) and HCV polymerase chain reaction 
(PCR) ≥ 25 IU/mL (HCV PCR will be automatically analyzed if HCV is positive). 
 Positive or indeterminate interferon gamma release assay (IGRA). 
20. Subject has any other clinically significant disease, disorder or laboratory abnormality 
which, in the opinion of the investigator (by its nature or by being inadequately 


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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. 
12.3. 
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 starting 
screening related procedures at the Screening Visit to the Baseline Visit must not exceed 42 
days, inclusive of any repeat screening procedures.  
Subjects who do not meet all of the eligibility criteria at the Screening or Baseline Visits will 
be deemed a screen failure and the reason for the screen failure will be documented.  


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13. 
PRIOR AND CONCOMITANT MEDICATION/NONDRUG 
THERAPIES 
The start and stop date, dose, unit, frequency, route of administration, and indication for all 
prior (taken within the 42 days prior to the first dose of study drug) and concomitant 
medications and nondrug therapies (eg, blood transfusions, oxygen supplementation) received 
will be recorded.  
In addition, all prior treatments for MS during the past 2 years will be recorded with start and 
stop date, dose, unit, frequency and route of administration. 
13.1. 
Prohibited Concomitant Medications/Nondrug Therapies 
The following medications/nondrug therapies are not permitted during the study from the 
Screening Visit through Day 42: 
 Oral corticosteroids (prednisone/prednisone equivalent) in excess of the 3 to 5 days 
(given over a period of up to 7 days) of high dose treatment that is allowed during 
the screening period. 
 Parenteral corticosteroids. 
 Daclizumab, or any immunosuppressant (including but not limited to 
cyclophosphamide, mitoxantrone, or rituximab). 
 Natalizumab (unless the subject is currently negative for JC virus based on  a 
negative JC virus test in the 6 months prior to the first dose of Acthar). 
 Live or live-attenuated vaccines. 
 Intravenous immunoglobulin (IVIg). 
 Any investigational drug, device, or procedure administered as part of a research 
study.  
If any prohibited medication is taken during the study, all pertinent information will be 
recorded in source documents and the electronic case report form (eCRF). The designated 
study medical monitor (MM) must be informed immediately so the sponsor may determine 
whether to continue the subject in the study. 
13.2. 
Required and Allowed Concomitant Medications/Nondrug 
Therapies 
Subject must have started treatment with 3 to 5 days (inclusive, given over a period of up to 
7 days) of IVMP (1 g per day), oral prednisone (1,250 mg/day), or oral methylprednisolone 
(1,000 mg per day) within 28 days of the onset of the first relapse symptom. 
Subjects receiving nonexcluded disease modifying treatment(s) (including beta-interferons, 
glatiramer acetate, fingolimod, teriflunomide, and dimethyl fumarate) must have been in a 
stable dose(s) for ≥ 30 days prior to the Baseline Visit and plan to remain on that dose(s) 
throughout the study.  


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14. 
PROCEDURES/ASSESSMENTS 
The schedule of study procedures/assessments is summarized in the Schedule of Study Events 
(Table 1). 
14.1. 
Screening Visit (Study Days −42 to −14) Procedures/Assessments 
Screening assessments must be performed within 42 and 14 days prior to the Baseline Visit. 
The following procedures will be performed at the Screening Visit: 
 Informed consent. 
 Inclusion/exclusion criteria. 
 Medical and surgical history. 
 Demographics. 
 Limited physical examination. 
 FSS and EDSS. (Exception: these assessments may be performed within a 2 day 
window after the initiation of high dose corticosteroids.) 
 Multiple Sclerosis Impact Scale, Version 1 (MSIS-29). (Exception: this assessment 
may be performed within a 2 day window after the initiation of high dose 
corticosteroids.) 
 Height and Weight.  
 Vital signs. 
 Clinical laboratory tests. 
 HbA1c. 
 Serum pregnancy test.  
 Hepatitis serology.  
 IGRA test for TB (to be performed locally). 
 Contact the Interactive Phone/Web Response System (IXRS). 
 Treat with IVMP (1g QD), oral prednisone (1,250 mg QD), or oral 
methylprednisolone (1,000 mg QD) for 3 to 5 days (given over a period of up to 7 
days). 
 Adverse events and concomitant medications. 
Subjects will be allowed to repeat any screening procedure once, if necessary, if it is within 
the screening window. 
14.2. 
Baseline Visit (Day 1) and First Dose Procedures/Assessments 
Predose evaluations will occur prior to the first dose of study drug and 14 (± 1) days after the 
first dose of IVMP, oral prednisone, or oral methylprednisolone. The investigator or designee 
will complete the following procedures prior to the first study drug dose:  


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 Inclusion/exclusion criteria review; subject must meet all eligibility criteria at 
screening and baseline. 
 MSIS-29, 
 
 
 
 Current medical condition review. 
 Complete physical examination. 
 FSS and EDSS. 
 Weight. 
 Vital signs. 
 12-lead electrocardiogram (ECG). 
 Clinical laboratory tests.  
 Urine pregnancy test. 
 Contact IXRS and dispense study drug kits. 
 Study drug administration under supervision of study staff and observation for at 
least 1 hour thereafter.  
 Adverse events and concomitant medications. 
14.3. 
Day 7 (± 1 Day) Procedures/Assessments 
 MSIS-29.  
 Current medical condition review. 
 Limited physical examination. 
 FSS and EDSS. 
 Global Clinical Impressions Scale (CGI-I). 
 Vital signs. 
 Clinical laboratory tests.  
 Urine pregnancy test. 
 Subject diary review. 
 Study drug accountability. 
 Adverse events and concomitant medications. 
14.4. 
Day 14 (± 2 Days) Procedures/Assessments 
 MSIS-29 (to be administered via telephone). 
 Adverse events and concomitant medications. 


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14.5. 
Day 21 (± 2 Days)/Follow-up Visit 1 
 MSIS-29, 
 
 Current medical condition review. 
 Limited physical examination. 
 FSS and EDSS. 
 CGI-I. 
 Vital signs. 
 Clinical laboratory tests.  
 Urine pregnancy test. 
 Subject diary review. 
 Study drug accountability. 
 Adverse events and concomitant medications. 
14.6. 
Day 42 (± 2 Days) Follow-up Visit 2/Early Termination 
Procedures/Assessments 
The following procedures will be completed at Study Day 42 (± 2 days) or whenever a subject 
terminates early from the study: 
 MSIS-29, 
 
 Current medical condition review. 
 Complete physical examination. 
 FSS and EDSS. 
 CGI-I. 
 Weight. 
 Vital signs. 
 12-lead ECG. 
 Clinical laboratory tests.  
 Serum pregnancy test. 
 Diary review and study drug accountability (if appropriate, for early termination 
only). 
 Adverse events and concomitant medications. 


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15. 
INVESTIGATIONAL MEDICINAL PRODUCT (STUDY DRUG) 
15.1. 
Methods of Assigning Subjects to Treatment Groups 
15.1.1. 
Randomization 
Subjects will be randomized according to a computer-generated allocation scheme to receive 
either Acthar 1 mL (80 U) or placebo 1 mL administered QD for 14 consecutive days. 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. 
15.1.2. 
IXRS 
The investigator or designee will contact IXRS to register subjects at screening. The subject’s 
identification (ID) number will be determined by the IXRS and will be used to identify the 
subjects for the duration of the study within all systems and documentation. 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 Baseline, qualified subjects who meet all of the eligibility criteria will 
be enrolled into the study.  
The investigator or designee must contact the IXRS to report subjects as a screen failure if the 
subject does not meet eligibility criteria predose. 
The investigator or designee must contact IXRS to register the subject at screening, to receive 
the study drug kit 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. 
15.2. 
Emergency Identification of Investigational Medicinal Product 
In case of an emergency during the study, when knowledge of the investigational product 
assignment is required for the medical management of an individual subject, the investigator 
may obtain the treatment assignment of the subject experiencing the emergency. The 
treatment blind for that subject may be broken by accessing the IXRS using instructions 
provided. The investigator must notify the sponsor’s MM or physician designee immediately 
after determining that it is necessary to unblind the treatment assignment. The investigator and 
sponsor should make every effort to document and limit the people who are unblinded to the 
subject’s treatment assignment. The investigator must also indicate in source documents and 
in the eCRF that the blind was broken and provide the date, time, and reason for breaking the 
blind.  


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15.3. 
Dosing Procedures 
Both Acthar and the placebo are supplied as 5 mL multidose vials. Acthar vials contain 80 U 
of ACTH per mL. The vials should not be over pressurized prior to withdrawing the product. 
The vials should be warmed to room temperature before using and will be labeled according 
to all applicable national and local regulations. 
The following treatments will be administered: 
 Treatment A: Acthar 1 mL (80 U) SC QD for 14 days, OR 
 Treatment B: Placebo 1 mL SC QD for 14 days.  
The subject or subject’s caregiver will administer the first dose of Acthar 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. Thereafter, all doses will be administered by 
the subject or the subject’s caregiver at home. 
15.3.1. 
Treatment Discontinuation 
Treatment with study drug should be discontinued if any of the following occur: 
 Development of accelerated hypertension (defined as systolic blood pressure ≥ 180 
and 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 that cannot be managed by the adjustment 
of concomitant medications such as diuretics and antihypertensive medications. 
 Development of diabetic signs/symptoms (ie, HbA1c > 6.5%, or fasting plasma 
glucose > 126 mg/dL, or classic symptoms of hyperglycemia with random plasma 
glucose > 200 mg/dL). 
 Subjects who undergo plasma exchange or IVIg due to lack of efficacy will be 
considered treatment failures and will be withdrawn from the study. 
 Development of any other AE of at least moderate intensity and possibly, probably 
or definitely related to study drug that cannot be managed by the adjustment of 
concomitant medications. 
15.4. 
Storage of Clinical Supplies 
Acthar and placebo will be maintained in a temperature controlled, secure locked area with 
restricted access at the study site.  
Study drug will be supplied in kits containing the appropriate amount of vials according to the 
treatment group to which the subject is assigned. Study drug will be stored under refrigeration 
between 2° to 8°C (36° to 46°F). Please refer to the Pharmacy Manual for complete 
information regarding storage and accountability of study drug. 
15.5. 
Drug Accountability 
In accordance with ICH requirements, the investigator will, at all times, be able to account for 
all study drug furnished to the study site. A drug accountability record will be maintained for 


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this purpose. The investigator must maintain accurate records indicating dates and quantity of 
study drug received, to whom it was dispensed (subject-by-subject accounting) and accounts 
of any study drug accidentally or deliberately destroyed. All unused study drug not involved 
in immediate subject dosing will be maintained under locked, temperature-controlled storage 
at the study site.  
15.6. 
Compliance Monitoring 
Prior to beginning the administration of study drug, subjects and/or their caregiver will be 
trained on dosing administration and must exhibit proper technique. 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. 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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16. 
EFFICACY ASSESSMENTS  
Efficacy assessments will be evaluated at times specified in the Schedule of Study Events 
(Table 1). Below are general instructions for the administration of these assessments. Specific 
instructions and questionnaires will be provided in a separate document. 
16.1. 
Subject Completed Assessments 
The MSIS-29 is a subject reported outcome measure. When this assessment is required, it 
should be the first assessment done at any visit 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). The study staff should review the 
questionnaire after it completed and encourage the subjects to complete any missing 
information. Subjects may refrain from answering any question. Study staff will record the 
refusal of subjects to answer any questions in the source documents.  
16.1.1. 
MS Impact Scale (Version 1) 
The MSIS-29 measures the physical (20 items) and psychological (9 items) impact of MS 
from the subjects perspective (Hobart et al, 2001). This validated questionnaire will result in a 
total score between 29 and 145 and can provide separate scores for physical and psychological 
impact. The MSIS-29 will be completed by the subject at all required times points during the 
study except on Study Day 14 when the MSIS-29 will be administered via telephone by a call 
center trained in the administration of the MSIS-29 or captured via a web portal. 
16.2. 
Investigator (or Designee) and Blinded Rater Completed 
Assessments 
The EDSS and FSS are to be completed by an appropriately trained blinded rater. The CGI-I 
assessment will be completed by an appropriately trained investigator or designee. When 
these assessments are required, they should be the done immediately after subject reported 
outcome/questionnaire completion (if applicable) and must be completed prior to any study 
drug dosing. The same trained rater should complete these assessments at all required time 
points for a subject. 
16.2.1. 
Expanded Disability Status Score/Functional Systems Score 
The EDSS is a 10 step assessment of neurological impairment/disability in MS ranging from 0 
(normal neurological examination) to 10 (death due to MS) (Kurtzke, 1983) that is completed 
by a blinded rater.  
The FSS is a component of the EDSS that requires the rater to score function in 7 functions 
(pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, cerebral) on a scale 
from 0 (normal) to 5 or 6 (severe impairment) (Kurtzke, 1983). 
Each site will designate 1 primary rater (neurologist or advanced practitioner experienced in 
performing EDSS/FSS) for each subject who will be responsible for performing all EDSS and 
FSS evaluations and who will be blinded to all other study aspects. The blinded rater should 
remain constant for each subject whenever possible. Subjects will be instructed not to discuss 


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MS therapy, any skin reactions, or other therapy side effects they have experienced with the 
blinded rater. The blinded rater will not be involved in any aspects of subject care and 
management other than performing the EDSS/FSS evaluations in subjects in the study.  
16.3. 
Clinical Global Impression of Improvement 
The CGI-I was developed for use in clinical research to provide a brief overview of the 
change in a subject’s global function compared to baseline and regardless of study drug 
treatment (Guy, 1976; Busner and Targum, 2007). It requires a rating from 1 (very much 
improved) to 7 (very much worse). 


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17. 
SAFETY ASSESSMENTS AND PROCEDURES 
The following safety assessments will be evaluated: AEs, physical examinations, clinical 
laboratory test results (chemistry, hematology, and urinalysis), vital signs, medical history, 
current medical condition, and weight. All safety assessments will be performed at times 
outlined in the Schedule of Study Events (Table 1Table71). Additional (unscheduled) safety 
assessments may be performed as needed. 
17.1. 
Adverse Events 
Adverse events will be recorded from signing of the ICF and followed by the investigator 
until the AE is resolved or stabilized. 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 20 for additional details on the handling of AEs and SAEs. 
17.2. 
Medical and Surgical History  
Medical and surgical history will be obtained at the Screening Visit. Medical history will 
include a review of the following systems: general, dermatological, respiratory, 
cardiovascular, gastrointestinal, genitourinary, gynecological, endocrine, musculoskeletal, 
hematological, neuropsychological, immune (allergies), and head, eyes, ears, nose, and throat. 
Historical and current medical conditions including date of last menstrual period for female 
subjects will be recorded.  
17.3. 
Current Medical Conditions 
At each visit after screening, subjects will be asked about any changes in medical conditions, 
specifically new medical conditions and worsening of existing medical conditions. Any 
changes since the Screening Visit will be recorded as AEs, as appropriate.  
17.4. 
Physical Examination 
A complete physical examination will be performed at the Baseline Visit and the Day 
42/Early Termination Visit. The complete physical examination includes 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. 
A limited physical examination, including evaluation of lungs, heart, abdomen, and 
extremities will be done at all other clinic visits.  
The findings of the physical examinations will be recorded. Any change from the Screening 
Visit physical examination that is considered clinically significant by the investigator will be 
recorded as an AE.  


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17.5. 
Height and Weight 
Height will be collected at screening only. Weight will be collected at specified times during 
the study. 
17.6. 
Vital Signs 
Vital signs will be obtained after the subject has been seated for 5 minutes (minimum) and 
will include systolic and diastolic blood pressures, pulse rate, respiratory rate, and body 
temperature. Additionally, at the Screening and Baseline Visits, blood pressure will be 
measured at least 3 times, with 5 minutes between assessments after the subject has been 
seated for a minimum of 5 minutes prior to the initial blood pressure assessment. The date and 
time for all vital sign assessments will be recorded. 
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. 
Screening/Baseline Assessments 
A subject with systolic blood pressure  140 mm Hg and diastolic blood pressure  90 mm Hg 
(average of 3 assessments) at the Screening or Baseline Visits does not qualify for the study. 
On Study Assessments 
If an on study vital sign is not in the site’s standard reference range, an AE will be recorded if 
the investigator determines the change is clinically significant or requires a change in the 
subject’s clinical management.  
17.7. 
Clinical Laboratory Tests (Chemistry, Hematology, Urinalysis, 
HbA1c, Hepatitis Serology, IGRA, and Pregnancy Tests) 
The clinical laboratory tests are listed in Section 31.1. All clinical laboratory tests will be done 
at a central laboratory facility except urine pregnancy (at the site) and IGRA (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 laboratory testing at all visits may be collected under fasted or nonfasted 
conditions. Fasting early morning samples are preferred, but a random daytime sample is 
acceptable. 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. 
Hematology with differential, serum chemistry, and urinalysis samples will be collected at the 
specific times starting at screening and throughout the study.  
In addition: 
 All female subjects of child-bearing potential will have a serum pregnancy test at 
the Screening and Day 42/Early Termination Visits. Urine pregnancy tests will be 


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done at all other visits throughout the study. Results must be available prior to 
dosing with protocol mandated study drug. Subjects with positive results will be 
ineligible for study entry (Screening Visit or Predose) or withdrawn from the study 
if the positive result is obtained before the end of the treatment period. Any female 
subject that becomes pregnant before the end of the treatment period will be 
immediately withdrawn. All subjects who became pregnant after the last dose of 
the treatment will be continued in the study for follow-up visits. All pregnancies 
will be reported as per Section 20.6. 
If applicable, the subject’s agreement to use contraception throughout their study 
participation (through the Follow-up Visit) will be documented. 
 HBsAg and HBcAb will be performed at the Screening Visit. Results of these tests 
must be negative or nonreactive for subjects to qualify for the study.  
 HCV will be performed at the Screening Visit. 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 the Screening Visit. Results of this test must be 
negative for subjects to qualify for the study.  
 HbA1c will be performed at the Screening Visit. HbA1c must be ≤ 6.5% for 
subjects to qualify for the study.  
Out-of-Range Laboratory Values 
Laboratory values from samples collected at the Screening Visit will be evaluated by the 
investigator for eligibility of the subject in the study. Clinical laboratory tests may be repeated 
once to determine subject eligibility. 
Laboratory values that fall outside the reference range from samples collected during the 
study or at study exit or early termination 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.  


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18. 
QUALITY OF LIFE/ HEALTH OUTCOME ASSESSMENTS 
The following QOL/Health Outcome questionnaires are to be completed by the subject. When 
these assessments are required, they should be the second assessment done at any visit (after 
MSIS-29) and must be completed prior to any study drug dosing. Subjects will be provided a 
quiet, private place to complete the assessments. 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). The study staff should review the questionnaires after they are 
completed and encourage the subjects to complete any missing information. Subjects may 
refrain from answering any question. Study staff will record the refusal of subjects to answer 
any questions in the source documents.  
18.1. 
 
 
 
 
 
  
18.2. 
 
 
 
 
 
 
 
 
 
 


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19. 
STATISTICAL METHODS AND PLANNED ANALYSIS 
19.1. 
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. A 
more detailed statistical analysis plan will be provided in a separate document that will be 
finalized prior to database lock. 
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. Data 
summary and analyses will be performed with SAS 9.2 or higher. 
19.2. 
Analysis Populations 
 The Safety Population will include all randomized subjects who receive 1 or more 
doses of study drug. 
 The Modified Intent-to-Treat (mITT) Population will include all enrolled subjects 
who receive 1 or more doses of study drug and who have at least 1 postbaseline 
EDSS score.  
 The Per-Protocol Population will include the subset of the mITT population who 
complete the study as per protocol.  
19.3. 
Endpoints 
19.3.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be the response rate on EDSS and 90% confidence interval 
(CI) on Day 42 for each treatment group.  
19.3.2. 
Primary Safety Endpoint 
The primary safety endpoint will be a summary of general safety profile, including adverse 
events (serious and nonserious), vital signs and laboratory assessments by study period and 
over the entire study. 
19.3.3. 
Secondary Efficacy Endpoints 
 The response rates on MSIS-29 and 90% CIs on Day 7, Day 14, Day 21 and Day 
42 for each treatment group.  
 The response rates on EDSS and 90% CIs on Day 7 and Day 21 for each treatment 
group. 
 CGI-I mean scores and 90% CIs on Day 7, Day 21 and Day 42 for each treatment 
group. 


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19.3.4. 
Exploratory Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
19.4. 
Subject Characteristics 
19.4.1. 
Demographics 
The demographic information will be summarized for each analysis population by treatment 
group. 
19.4.2. 
Medical and Surgical History 
Relevant prior medical conditions or procedures will be summarized by body system and 
treatment group. 
19.4.3. 
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.  
19.4.4. 
Subject Disposition and Exposure to Study Drug 
Subject disposition will be summarized for all randomized subjects. 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.  
19.5. 
Efficacy Analysis 
A responder on EDSS is defined as a subject who achieves the following: 
 ≥ 1.0 point improvement on EDSS score compared to baseline if baseline EDSS 
score was ≤ 5.5. 
 ≥ 0.5 point improvement on EDSS score if the baseline EDSS score was > 5.5.  
A responder on MSIS-29 is defined as a patient who achieves ≥ 8 point improvement on the 
physical subscale score of MSIS-29 compared to baseline. 
Baseline is defined as the value observed prior to first dose of the study drug (Day 1). 
The primary efficacy endpoint, the response rate on EDSS at Day 42, will be calculated by 
treatment group. Response rates and 90% Wilson CIs will be reported for each treatment 
group. These analyses will be performed for the mITT and Per-Protocol populations. 


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Summary statistics (n, mean, SD, median, minimum, and maximum) of the baseline value, the 
value at each scheduled postbaseline evaluation and the corresponding change from baseline 
for EDSS score will be presented by treatment group for all subjects in the mITT population 
and the Per-Protocol population. 
A subject-by-subject data listing sorted by treatment group and subsequently by subject will 
be generated for all subjects in the mITT population. 
For the secondary endpoints, the response rate endpoints will be analyzed and presented with 
the same approach as described above for the primary efficacy endpoint. The mean score 
endpoint will be calculated by treatment group. Mean, SD, and 90% CI will be presented by 
treatment group. All secondary efficacy analyses will use the mITT population. 
For the exploratory endpoints, scores change from baseline will be calculated by treatment 
group. Mean, SD, and 90% CI will be presented by treatment group. All exploratory efficacy 
analyses will use the mITT population. 
For all efficacy endpoints, the normality assumption of the data will be examined using 
appropriate normality test. If the test result shows the data is not normally distributed, then 
median, 10% and 90% percentiles will be presented instead of mean, SD and 90% CI. 
The statistical analysis plan will describe in further detail the analyses for primary, secondary, 
and exploratory efficacy endpoints. 
19.6. 
Safety Analysis  
All subjects who receive at least 1 dose of study drug will be included in the safety analyses. 
Safety data will be summarized descriptively or graphically, as appropriate. 
19.6.1. 
Adverse Events 
Adverse events will be coded using the appropriate version of MedDRA. All AEs will be 
presented in a data listing. Only treatment-emergent adverse events (TEAEs) (events that are 
new in onset or aggravated in severity following treatment) will be included in all summaries. 
TEAEs will be summarized for each treatment group, by system organ class and preferred 
term. Serious adverse events (including death) will be summarized. In addition, adverse 
events will be summarized by severity and relation to study drug.  
19.6.2. 
Clinical Laboratory Tests 
Hematology, blood chemistry, and urinalysis results will be summarized at baseline and at 
each visit by treatment group. Change from baseline to each visit will also be summarized. 
Abnormal laboratory values will be identified and analyzed.  
19.6.3. 
Vital Signs 
Vital sign results (heart rate, diastolic/systolic blood pressures, respiratory rate, and body 
temperature) and corresponding changes from baseline values will be summarized at each 
visit with descriptive statistics by treatment group.  


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19.6.4. 
Other Safety Analysis 
Other safety assessments including physical examinations, weight, and pregnancy testing, will 
be analyzed with appropriate summary statistics.  
19.7. 
Quality of Life/ Health Outcomes Analysis 
The change from baseline in 
 will be 
summarized with mean change, SD, and 90% CI.  
19.8. 
Interim Analysis 
No interim analyses are planned for this study. 
19.9. 
Statistical Power and Sample Size Considerations 
It is expected that 66 subjects will be randomized into 1 of 2 treatment groups: 80 U  
(1 mL) of Acthar per day for 14 consecutive days or placebo (1 mL) per day for 14 
consecutive days in a 1:1 ratio (33 per group). The primary analysis is to generate point 
estimates and associated 90% CIs for the response rates on EDSS in the Acthar group and the 
placebo group at Day 42, respectively using a mITT analysis population. Assuming 3 subjects 
will not qualify for the mITT analysis population after randomization in each treatment group, 
there will be 30 mITT subjects in each group. Based on an expected 60% response rate in the 
Acthar group, the study can build a 90% Wilson CI of (45.1%, 73.3%) with approximate 
precision of 14.1%. Based on an expected 25% response rate in the placebo group, the study 
can build an approximate 90% Wilson CI of (15.7%, 41.5%) with approximate precision of 
12.9%.  
19.10. 
Missing Data 
Given the mITT design, an imputation or some other procedure for handling missing primary 
endpoints is required.  
For the primary efficacy endpoint, subjects who do not provide data to allow classification as 
responders will be considered nonresponders, that is, missing data will be imputed as 
“nonresponder”. A similar approach will be applied to secondary efficacy endpoints that are 
proportions. 
For continuous secondary efficacy endpoints collected directly from the CRF, the method of 
last observation carried forward (LOCF) will be used to impute the missing values. For other 
continuous secondary efficacy endpoints that need to be derived based on patients’ response 
to a questionnaire, if the responses to an entire questionnaire are missing, LOCF will be 
applied; otherwise, the method of handling missing response is described in each individual 
section for the secondary efficacy endpoint analysis. 
 
A full description of missing data imputation method for all endpoints will be described in the 
statistical analysis plan. 


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19.11. 
Deviations From the 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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20. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
20.1. 
Safety 
For safety information about Acthar, refer to the most recent version of the Prescribing 
Information (Mallinckrodt, 20159).  
20.2. 
Definitions 
Adverse Event  
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 IMP abuse. 
 An AE associated with IMP withdrawal. 
 Unexpected Adverse Event. 
An unexpected AE is defined as an AE, the nature and severity of which is not consistent with 
the applicable product information in the most recent version of Acthar Package Insert 
(Mallinckrodt, 2019). 
Serious Adverse Event  
An SAE is defined as any untoward medical occurrence that 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. 
 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 or 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. 


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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 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:  
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). 
20.3. 
Adverse Event and Serious Adverse Event Classifications 
Study Drug Relatedness 
The following classifications should be used when evaluating the relationship of AEs or SAEs 
to study treatment (Table 2). 


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Table 2: 
Adverse Event 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 3. 
Table 3: 
Adverse Event Severity Grades 
Grade 
Definition 
Mild 
Does not interfere with subject's usual function and activities 
Moderate 
Interferes to some extent with subject's usual function and activities 
Severe 
Interferes significantly with subject's usual function and activities 
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 follow-up 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,” 
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. 
20.4. 
Adverse Event and Serious Adverse Event Recording and 
Reporting 
AEs and SAEs will be recorded from signing of the ICF through completion of the final study 
visit. The investigator is required to record the AE or SAE regardless of the severity of the 
event or its relationship to study treatment. Prior to the Baseline Visit/Day 1, only AEs and 
SAEs related to study procedures will be recorded. The investigator must follow up on all 
AEs and SAEs reported until the event has resolved or stabilized or at such time the 


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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 from the signing of the ICF through the completion of the End of 
Study/Early Termination visit. 
Report all SAEs on an SAE Report Form to Global Pharmacovigilance or designee. 
Report all pregnancies to the Global Pharmacovigilance or designee contact on the Pregnancy 
Surveillance Form. 
Submit any Expedited Safety Report or Suspected Unexpected Serious Adverse Reaction 
from Global Pharmacovigilance or designee to the IRB/IEC. 
The reporting requirements for AEs are summarized in Table 4. 
Table 4: 
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 
Adverse Events 
Adverse events 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. For subjects 
incapable of giving consent, the legally acceptable representative may provide information 
regarding the subject’s status. 
All fields on the AE CRF page should be completed for each event with a full description of 
the event and date 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.  
Serious Adverse Events 
Initial Reporting 
Serious adverse events (based on FDA/ICH definition of an SAE) require immediate reporting 
to Mallinckrodt Global Pharmacovigilance or designee.  
For all SAEs, the investigator, or designee, must complete the SAE Report Form with the 
minimum information required by 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. 


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The investigator, or designee, will receive acknowledgement of receipt of the SAE Report 
Form from Mallinckrodt Global Pharmacovigilance or designee. 
Should the investigator or designee have any difficulty in sending the SAE Report, they may 
contact Mallinckrodt Global Pharmacovigilance or designee based on the information in the 
Study Operations Manual. 
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 any Expedited Safety Report or 
Suspected Unexpected Serious Adverse Reaction to the responsible IRB/IEC. 
The sponsor will ensure that any Expedited Safety Report or Suspected Unexpected Serious 
Adverse Reaction is submitted to the 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 it to Mallinckrodt Global Pharmacovigilance or designee within 
24 hours of receipt. The investigator(s) or designee will receive acknowledgement of receipt 
for each SAE Report Form from Mallinckrodt Global Pharmacovigilance or designee. 
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 ensure that any Expedited Safety Report or Suspected Unexpected Serious 
Adverse Reaction is submitted to the FDA and other regulatory agencies as appropriate. 
20.5. 
Adverse Events of Special Interest 
AEs of special interest for this study are outlined below. Adverse events of special interest 
will be followed until resolution or return to baseline.  
 Elevated blood pressure (defined as systolic blood pressure ≥ 180 and diastolic 
blood pressure ≥ 100 mm Hg). 
 Hyperglycemia (HbA1c > 6.5%, or fasting plasma glucose > 126 mg/dL, or classic 
symptoms of hyperglycemia with random plasma glucose > 200 mg/dL). 
 MedDRA System Organ Class infection/infestation of ≥ moderate intensity. 
 AEs considered possibly, probably, or definitely related to study drug treatment of 
≥ moderate intensity. 
 Hy’s Law cases (ALT > 3 x ULN, with total bilirubin > 2 x ULN, no initial signs 
of cholestasis [alkaline phosphatase within the reference range]), and no other 
reason can be found to explain liver injury).  


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20.6. 
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 investigational medicinal product, 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 (subjects may complete follow-
up visits). The investigator must report the pregnancy by submitting the appropriate form to 
Mallinckrodt Global Pharmacovigilance or designee within 24 hours of confirmation of a 
pregnancy (ie, positive serum pregnancy test result). The outcome of pregnancy (eg, 
spontaneous abortion, live birth, still birth, congenital anomalies, birth defects) must be 
reported by submitting the appropriate form to Mallinckrodt Global Pharmacovigilance 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. Both 
maternal and paternal investigational medicinal product exposures are collected.  
If the female partner of a male subject becomes pregnant during the study, the site will 
forward the Pregnancy Notification form and the Pregnancy Report Fax cover page 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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21. 
SUBJECT DISCONTINUATION OR WITHDRAWAL 
21.1. 
Subject Withdrawal 
Subjects who discontinue, or are withdrawn from the study for any reason, will be required to 
enter the follow-up period and have the Early Termination and Follow-up safety assessments 
(see Section 14.5 and Section 14.6) to assess their continued well-being.  
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 study drug but do not complete the study will not be replaced. 
Lack of Efficacy 
Subjects who undergo plasma exchange or receive IVIg following treatment with Acthar due 
to lack of efficacy will be considered treatment failures and will be withdrawn from the study. 
Adverse Event 
If a dosed subject suffers 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 further participation in the study. 
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 used 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 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 
If a subject develops a condition that meets any of the exclusion criteria (Section 12.2) or fails 
to meet an inclusion criteria (Section 12.1) during the study that is not considered to be an AE 
or is noncompliant (eg, has a positive pregnancy during the screening or treatment periods or 
positive drug screening test), the subject will be discontinued from further participation in the 
study. Discontinuation is also mandated for safety and/or tolerability issues as outlined in 
Section 15.3.1. 
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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22. 
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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23. 
PROTOCOL AMENDMENTS 
Any change in the study plan requires a protocol amendment. An investigator must not make 
any changes to the study without IRB/IEC and sponsor approval except when necessary to 
eliminate apparent immediate hazards to the subjects. A protocol change intended to eliminate 
an apparent immediate hazard to subjects may be implemented immediately, but the change 
must then be documented in an amendment, reported to the IRB/IEC within 5 working days, 
and submitted to the appropriate regulatory agency in the required time frame.  


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24. 
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 Investigator’s Brochure, 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. During these study site visits, information recorded in the eCRFs will be verified 
against source documents. 
24.1. 
Study and Study Site Discontinuation Criteria 
The sponsor, investigator, or local and national regulatory authorities may discover conditions 
during the study that indicate that the study or study site should be terminated. This action 
may be taken after appropriate consultation between the sponsor and investigator. Conditions 
that may warrant termination of the study/study site include, but are not limited to: 
 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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25.
DIRECT ACCESS, DATA HANDLING, AND RECORD-KEEPING
25.1. 
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 will be recorded on source documents. The eCRFs must be fully 
completed and include all required data for all subjects enrolled. All eCRF data must be 
submitted to the sponsor throughout and at the end of the study.  
If an investigator retires, relocates, or otherwise withdraws from conducting the study, the 
investigator must notify the sponsor to agree upon an acceptable storage solution. Regulatory 
agencies will be notified with the appropriate documentation. 
Any significant changes in study personnel will require an updated Statement of Investigator 
(ie, FDA form 1572) to be filed with the sponsor. 
The investigator must notify their IRB/IEC of protocol deviations in accordance with local 
regulatory and IRB/IEC requirements. 
25.2. 
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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26. 
SUBJECT INJURY 
In general, subject to specific provisions in the clinical trial agreement, if a subject is injured 
as a direct result of an investigational medicinal product, 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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27. 
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 investigational medicinal product. These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by an agreement with the sponsor. It is the responsibility of the 
sponsor to inform the investigator/institution as to when these documents no longer need to be 
retained. Prior to destruction of any study essential documents, the investigator must first 
obtain written approval from the sponsor.  


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28. 
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 
urine and serum samples for biomarker analysis (if applicable). Urine and serum samples for 
biomarker analysis will be retained at a biologic storage facility for future testing. 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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29. 
PUBLICATION POLICY 
29.1. 
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. 
Exploratory studies, in contrast, serve to set direction for possible future studies. They have 
significant statistical limitations, provide only preliminary information about a disease, 
condition, or product, and are not designed to provide final conclusions on product claims. 
The sponsor does not commit to publish or otherwise communicate the results of every 
exploratory study, because this information is of an exploratory nature and often highly 
proprietary. However, if information from an exploratory study is of significant medical 
importance, the sponsor will publish or otherwise communicate the results. 
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. 
29.2. 
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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30.
REFERENCES
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Vitro and in Vivo and Future Perspectives for the Treatment of Immune-mediated 
Inflammatory Diseases, Endocrine Rev. 2008, 29, 581-602.  
Buggy, J.J. Binding of Alpha-melanocyte Stimulating Hormone to its G-protein Coupled 
Receptor on B-lymphocytes Activates the Jak/STAT Pathway. Biochem. J. 1998, 331, 211-
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Busner, J.; Targum, S.D. The Clinical Global Impressions Scale: Applying a Research Tool in 
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31.
ATTACHMENTS
31.1. 
Attachment 1: Clinical Laboratory Tests 
Serum Chemistry 
Alanine aminotransferase (ALT) 
Chloride 
Albumin (total) 
Creatinine 
Alkaline phosphatase  
Glucose 
Aspartate aminotransferase (AST) 
Phosphorus 
Bilirubin (total) 
Potassium 
Blood urea nitrogen 
Protein, total 
Calcium 
Sodium 
CO2 
Uric acid 
Diabetes Screen 
Hemoglobin A1c 
Hormones 
Serum and urine beta-human chorionic gonadotropin (pregnancy test) 
Hematology Assays 
Hematocrit 
Platelet count 
Hemoglobin 
Red blood cell count 
White blood cell count, including differential 
Absolute neutrophil count 
Urinalysis 
Blood 
Nitrite 
Color, clarity 
Protein 
Glucose 
pH 
Leukocyte esterase 
Specific gravity 
Ketones 
Microscopy, including white blood cells, red blood cells, bacteria, yeasts, casts, and crystals. 
Hepatitis Serology 
Hepatitis B core antibody 
Hepatitis C virus antibody (HCV) 
Hepatitis B surface antigen 
Hepatitis C virus PCR (only if HCV +) 
TB Assay 
Interferon gamma release assay (IGRA)