Clinical trial NCT02953821
Conditions: Lupus Erythematosus, Systemic
Sponsor: Mallinckrodt
Start date: 2016-12-16; Completion date: 2019-10-25
Enrollment: 172 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial is to study Acthar Gel in participants with active systemic lupus erythematosus (SLE).

The doctor will assign eligible patients to one of two groups (like flipping a coin).

Participants will receive the treatment assigned to their group for 24 weeks:

* Acthar Gel
* Placebo Gel, which looks like Acthar Gel, but has no medicine in it.

The doctor or his staff will take measurements and ask questions to:

* see how well the gel is working
* see how safe it is for patients with SLE

Detailed description:
This trial was initiated (started recruiting) in October 2016, but first patient was not enrolled (randomized) until December, 2016.

Arms: arm 1: Participants receive Acthar Gel every other day for 4 weeks, and then twice per week for 20 weeks arm 2: Participants receive Placebo Gel every other day for 4 weeks, and then twice per week for 20 weeks
Interventions: intervention 1: Acthar Gel intervention 2: Placebo Gel
Intervention descriptions: intervention 1: 1 mL (80 Units) given by a shot under the skin (via subcutaneous injection) intervention 2: 1 mL (0 Units) given by a shot under the skin (via subcutaneous injection)

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
CLINICAL STUDY PROTOCOL 
A Multicenter, Randomized, Double Blind, Placebo Controlled Study to 
Assess the Efficacy and Safety of 
Acthar® Gel in Subjects With 
Persistently Active Systemic Lupus Erythematosus Despite Moderate Dose 
Corticosteroids 
 
Protocol Number: MNK14304067 
Date of Original Protocol: 02 June 2016 
Date of Protocol Revision: 04 August 2016 
Date of Protocol Revision:  26 August 2016 
Date of Protocol Revision: 01 June 2017  
 
 
 
 
Mallinckrodt ARD, Inc. 
675 McDonnell Boulevard 
Hazelwood, MO 63042 
United States of America 
 
 
 


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Table of Contents 
1 
DISCLOSURE STATEMENT ............................................................................................ 7 
1.1 
Restricted Distribution of Documents ............................................................................ 7 
2 
CONTACTS ....................................................................................................................... 8 
2.1 
Emergency Contacts ....................................................................................................... 8 
2.2 
Additional Contacts ........................................................................................................ 9 
3 
SPONSOR SIGNATURE ................................................................................................. 10 
4 
INVESTIGATOR SIGNATURE .......................................................................................11 
5 
SUMMARY OF CHANGES ............................................................................................ 12 
6 
ABBREVIATIONS .......................................................................................................... 13 
7 
SYNOPSIS ....................................................................................................................... 15 
8 
STUDY SCHEMATIC AND SCHEDULE OF EVENTS ................................................ 19 
8.1 
Study Schematic ........................................................................................................... 19 
8.2 
Schedule of Study Events ............................................................................................. 20 
9 
ETHICAL CONSIDERATIONS ...................................................................................... 22 
9.1 
Institutional Review Board/Independent Ethics Committee ........................................ 22 
9.2 
Ethical Conduct of the Study ........................................................................................ 22 
9.3 
Subject Information and Consent ................................................................................. 22 
10 BACKGROUND INFORMATION AND RATIONALE ................................................. 23 
10.1 Systemic Lupus Erythematosus .................................................................................... 23 
10.2 Product Description ...................................................................................................... 27 
10.3 Dosage and Administration .......................................................................................... 27 
10.4 Rationale ....................................................................................................................... 27 
10.5 Risks and Benefits ........................................................................................................ 28 
11 OBJECTIVES ................................................................................................................... 29 
11.1 Primary Objective ......................................................................................................... 29 
11.2 Secondary Objectives ................................................................................................... 29 
11.3 Exploratory Objectives ................................................................................................. 29 


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11.4 Approximate Duration of Subject Participation ........................................................... 29 
12 STUDY DESIGN ............................................................................................................. 29 
12.1 Description ................................................................................................................... 29 
12.2 Approximate Duration of Study ................................................................................... 30 
12.3 Approximate Number of Subjects ................................................................................ 30 
13 SELECTION OF SUBJECTS .......................................................................................... 30 
13.1 Inclusion Criteria .......................................................................................................... 30 
13.2 Exclusion Criteria ......................................................................................................... 32 
13.3 Screen Failure ............................................................................................................... 34 
14 PRIOR AND CONCOMITANT MEDICATIONS/TREATMENTS ................................ 35 
14.1 Permitted Concomitant Medications ............................................................................ 35 
14.2 Prohibited Concomitant Medications ........................................................................... 35 
15 PROCEDURES ................................................................................................................ 36 
15.1 Screening Visit (Study Days -28 to -1) Procedures ...................................................... 36 
15.2 Randomization Visit (Week 0) and First Dose Procedures .......................................... 37 
15.3 Week 2 (± 3 days) and 6 (± 3 days) Procedures ........................................................... 38 
15.4 Week 4 (± 3 days) and 20 (± 5 days) Procedures ......................................................... 38 
15.5 Week 8 (± 3 days) and 16 (± 5 days) Procedures ......................................................... 39 
15.6 Week 12 (± 5 days) Procedures .................................................................................... 39 
15.7 Week 24 (± 5 days)/Early Termination Procedures ...................................................... 40 
15.8 Follow-up Visit - Week 28 (± 5 days) .......................................................................... 41 
16 INVESTIGATIONAL MEDICINAL PRODUCT (Study Drug)...................................... 41 
16.1 Methods of Assigning Subjects to Treatment Groups .................................................. 41 
16.1.1 
Randomization and Stratification ............................................................................. 41 
16.1.2 
IXRS ......................................................................................................................... 42 
16.2 Emergency Identification of Investigational Medicinal Product .................................. 42 
16.3 Dosing Procedures ........................................................................................................ 43 
16.3.1 
Treatment Discontinuation ....................................................................................... 43 
16.4 Storage of Clinical Supplies ......................................................................................... 44 
16.5 Drug Accountability ..................................................................................................... 44 


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16.6 Compliance Monitoring................................................................................................ 44 
17 EFFICACY ASSESSMENTS AND PROCEDURES ...................................................... 44 
17.1 Physician Completed Assessments ............................................................................... 44 
17.1.1 
Systemic Lupus Erythematosus Disease Activity Index-2000 ................................. 45 
17.1.2 
British Isles Lupus Assessment Group 2004 ............................................................ 45 
17.1.3 
Physicians Global Assessment ................................................................................. 45 
17.1.4 
SELENA Flare Index ................................................................................................ 46 
17.1.5 
Cutaneous Lupus Erythematosus Disease Area and Severity Score- Activity ......... 46 
17.1.6 
28 Joint Count ........................................................................................................... 46 
17.2 SLE Responder Index ................................................................................................... 46 
 .................................................................... 
 
 
............................................................... 
 
 
...................................................................................
19 SAFETY ASSESSMENTS AND PROCEDURES .......................................................... 48 
19.1 Adverse Events ............................................................................................................. 48 
19.2 Medical and Surgical History ....................................................................................... 48 
19.3 Current Medical Conditions ......................................................................................... 49 
19.4 Physical Examination ................................................................................................... 49 
19.5 Height and Weight ........................................................................................................ 49 
19.6 Vital Signs .................................................................................................................... 49 
19.7 Clinical Laboratory Tests (Chemistry, Hematology and Urinalysis), HbA1c, IGRA, 
 Pregnancy Tests, 
; and C3, C4, 
and anti-ds DNA antibodies.......................................................................................... 50 
19.8 Hospital Admissions ..................................................................................................... 52 
............................................................................. 
 
 
 ................................................................................................................. 
 
 
................................................................................................... 52 
21 STATISTICAL METHODS AND PLANNED ANALYSIS ............................................ 52 
21.1 General Considerations ................................................................................................ 52 
21.2 Analysis Populations .................................................................................................... 53 
21.3 Efficacy Endpoints ....................................................................................................... 53 


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21.3.1 
Primary Efficacy Endpoint ....................................................................................... 53 
21.3.2 
Secondary Efficacy Endpoints .................................................................................. 53 
21.3.3 
Exploratory Endpoints .............................................................................................. 54 
21.4 Safety Endpoints ........................................................................................................... 54 
21.5 Subject Characteristics ................................................................................................. 54 
21.5.1 
Demographics ........................................................................................................... 54 
21.5.2 
Medical and Surgical History ................................................................................... 54 
21.5.3 
Prior and Concomitant Medications ......................................................................... 55 
21.5.4 
Subject Disposition and Exposure to Study Drug .................................................... 55 
21.6 Efficacy Analysis .......................................................................................................... 55 
21.7 
.......................................................... 55 
21.8 Safety Analysis ............................................................................................................. 56 
21.8.1 
Adverse Events ......................................................................................................... 56 
21.8.2 
Clinical Laboratory Tests; 
 
 ................................................................................................................. 56 
21.8.3 
Vital Signs ................................................................................................................ 56 
21.8.4 
Hospital Admissions ................................................................................................. 56 
21.8.5 
Other Safety Analysis ............................................................................................... 57 
21.9 
............................................................................................... 57 
21.10 Interim Analysis............................................................................................................ 57 
21.11 Statistical Power and Sample Size Considerations ...................................................... 57 
21.12 Deviations From Statistical Analysis Plan ................................................................... 57 
22 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ......................................... 57 
22.1 Safety ............................................................................................................................ 57 
22.2 Definitions .................................................................................................................... 58 
22.3 Adverse Event and Serious Adverse Event Classifications .......................................... 60 
22.4 Adverse Event and Serious Adverse Event Recording and Reporting ......................... 61 
22.5 Adverse Events of Special Interest ............................................................................... 63 
22.6 Pregnancy Reporting .................................................................................................... 64 
23 SUBJECT DISCONTINUATION OR WITHDRAWAL ................................................. 64 
23.1 Subject Withdrawal ...................................................................................................... 64 
24 STUDY SUSPENSION, TERMINATION, AND COMPLETION ................................. 66 


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25 PROTOCOL AMENDMENTS ........................................................................................ 66 
26 QUALITY CONTROL AND ASSURANCE ................................................................... 66 
26.1 Study and Study Site Discontinuation Criteria ............................................................. 66 
27 DIRECT ACCESS, DATA HANDLING, AND RECORD-KEEPING ............................ 67 
27.1 Investigator ................................................................................................................... 67 
27.2 Sponsor ......................................................................................................................... 67 
28 SUBJECT INJURY .......................................................................................................... 68 
29 RECORDS RETENTION ................................................................................................ 68 
30 BIOLOGICAL SAMPLES ............................................................................................... 68 
31 PUBLICATION POLICY ................................................................................................. 68 
31.1 Sponsor’s Publication Policy ........................................................................................ 68 
31.2 Investigator’s Ability to Publish ................................................................................... 69 
32 REFERENCES ................................................................................................................. 70 
33 Attachments ...................................................................................................................... 74 
33.1 Attachment 1: Clinical Laboratory Tests ...................................................................... 74 
 
List of Tables 
Table 8-1: 
Schedule of Study Events ............................................................................... 20 
Table 22-1:  
Adverse Event Relationships .......................................................................... 60 
Table 22-2:  
Adverse Event Severity Grades ...................................................................... 60 
Table 22-3: 
Reporting Requirements for Adverse Events .................................................. 62 
 
List of Figures 
Figure 8-1: 
Study Overview .............................................................................................. 19 
 


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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 
2.1 Emergency Contacts 
Role in Study  
Name  
Contact Information  
Primary Contact: 
Medical Monitor 
 MD 
Toll Free Number:
  
Toll Number 
 
Email: 
   
FAX: 
 
Secondary Cintact: 
Medical Monitor 
 
 MD 
Toll Free Number: 
  
Toll Number 
 
Email: 
 
FAX: 
 
 
Please see next page for additional telephone contact numbers in Section 2.2. 
Please see Section 22.4 for detailed information regarding the Serious Adverse Event (SAE) 
Reporting Requirements for this study. 
SAE reporting fax: 
 
SAE confirmation email:  
 
 


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2.2 Additional Contacts 
 
 
 
Role in Study 
Name 
Contact Information 
Clinical Trial 
Manager 
 
Telephone:  
 
E-mail:
 
Clinical Technical 
Lead  
 PhD 
Telephone:
  
E-mail: 
 


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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) 
 
 
 
 


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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 SUMMARY OF CHANGES 
 
1. Updated the pharmacovigilance email address. 
2. Updated the approximate number of study centers from 45 to 60. 
3. Updated the Schedule of Events to include: a) footnote “e” (positive urine test after 
randomization confirmed by serum pregnancy test) and b) footnote “f”(autoantibody 
testing at screening). 
4. Added new inclusion criterion #8, and removed original inclusion criteria # 8 and # 9 
in Section 13.1. 
5. Updated the reporting of adverse events for physical examinations done between 
screening and randomization in Section 19.4. 
6. Updated clinical laboratory tests in Section 19.7. 
7. Updated subject withdrawal criteria in Section 23.1. 
 
 
 


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6 ABBREVIATIONS 
Abbreviation Term 
2x/week 
Twice a week 
ACTH 
Adrenocorticotropic hormone 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
BAFF 
B cell activity factor 
BILAG-2004 
British Isles Lupus Assessment Group-2004 
CFR 
Code of Federal Regulations 
CLASI 
Cutaneous Lupus Erythematosus Disease Area and Severity Score 
CNS 
Central nervous system 
CTX-I 
C-terminal crosslinking telopeptide of Type I collagen 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
FDA 
Food and Drug Administration 
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 
hSLEDAI 
Hybrid Systemic Lupus Erythematosus Disease Activity Index 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ID 
Identification 
IEC 
Independent Ethics Committee 
IFN-alpha 
Interferon alpha 
Ig 
Immunoglobulin 
IGRA 
Interferon gamma release assay 
IL 
Interleukin 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
IV 
Intravenous, intravenously 
IXRS 
Interactive Phone/Web Response System 
MCR 
Melanocortin receptor 
mITT 
Modified intent-to-treat 
MM 
Medical monitor 
NSAID 
Nonsteroidal anti-inflammatory drugs 
PGA 
Physician’s Global Assessment 
PINP 
N-terminal propeptide of Type I collagen 


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Abbreviation Term 
QOL 
Quality of life 
SAE 
Serious adverse event 
SC 
Subcutaneous, subcutaneously 
SELENA 
Safety of Estrogens in Lupus Erythematosus National Assessment 
SFI 
SELENA Flare Index 
SLE 
Systemic Lupus Erythematosus 
SLEDAI-2K 
Systemic Lupus Erythematosus Disease Activity Index-2000 
SRI 
Systemic Lupus Erythematosus Responder Index 
sVCAM-1 
Soluble vascular cell adhesion molecule-1 
TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 
U 
Unit(s) 
US 
United States 
ULN 
Upper limit of normal 
WPAI 
Work Productivity and Activity Impairment Questionnaire 
 
 
 


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7 SYNOPSIS  
Study Title: A Multicenter, Randomized, Double Blind, Placebo Controlled Study to Assess the Efficacy 
and Safety of 
Acthar® Gel in Subjects With Persistently Active Systemic Lupus Erythematosus Despite 
Moderate Dose Corticosteroids 
Protocol Number: MNK14304067 
Type: Phase 4 (US)/ Phase 2 (Outside the US) 
Condition/Disease:  
Systemic Lupus Erythematosus 
Approximate Number of Subjects: 162 
 
Approximate Duration of Subject Participation: 32 weeks 
Approximate Number of Study Centers:  
60 globally 
Approximate Duration of Study: 3 years 
 
Design:  
This is a randomized, placebo controlled, double blind study. Following a screening period of up to 28 days, 
subjects with persistently active systemic lupus erythematosus (SLE) and moderate to severe rash and/or 
arthritis despite receiving corticosteroids (7.5 mg to 30 mg per day of prednisone or equivalent) for ≥ 4 weeks 
prior to screening, will be randomized in a 1:1 ratio to receive 1 mL (80 Units [U]) of Acthar or matching 
placebo. At randomization, subjects will be stratified by prednisone equivalent dose (≤ 20 mg/day vs > 20 
mg/day) and by location (United States [US] or outside the US). During Weeks 1 to 4, 1 mL (80 U) of Acthar 
or volume matched placebo will be administered subcutaneously (SC) every other day. For the remainder of 
the study (Weeks 5 to 24), Acthar 1 mL (80 U) or volume matched placebo will be administered SC 
2x/week. The primary efficacy endpoint is the SLE Responder Index (SRI) at Week 16. Corticosteroid taper 
will be encouraged between Weeks 16 and 24. All subjects will have a follow-up visit 28 (± 5) days after the 
last dose of study drug.  
Objectives:  
Primary Objective 
 
To determine the ability of Acthar to reduce disease activity as measured by SRI, in subjects with 
SLE requiring moderate dose corticosteroids for persistently active disease.  
Secondary Objectives 
 
To assess the impact of Acthar on disease activity, measured by the Systemic Lupus Erythematosus 
Disease Activity Index-2000 (SLEDAI-2K), British Isles Lupus Assessment Group-2004 (BILAG-
2004), and Physician’s Global Assessment (PGA), in subjects with SLE requiring moderate dose 
corticosteroids for persistently active disease. 
 
To assess the time to response to Acthar in subjects with SLE requiring moderate dose 
corticosteroids for persistently active disease. 
 
To further assess the safety and tolerability of Acthar in subjects with SLE requiring moderate dose 
corticosteroids for persistently active disease. 
Exploratory Objectives 
 
 
 
 
 
  
Entry Criteria:  
Male or nonpregnant, nonlactating female subjects 18 years of age or older with a diagnosis of SLE 
according to the American College of Rheumatology revised criteria (fulfilled ≥ 4 criteria) and active disease 
defined as total SLEDAI-2K score ≥ 6 and clinical SLEDAI-2K (excluding laboratory domains) score of ≥ 4 
at the time of screening and randomization (points for arthritis and/or rash must be present at both screening 


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Study Title: A Multicenter, Randomized, Double Blind, Placebo Controlled Study to Assess the Efficacy 
and Safety of 
 Acthar® Gel in Subjects With Persistently Active Systemic Lupus Erythematosus Despite 
Moderate Dose Corticosteroids 
Protocol Number: MNK14304067 
Type: Phase 4 (US)/ Phase 2 (Outside the US) 
Condition/Disease:  
Systemic Lupus Erythematosus 
and randomization), and a BILAG-2004 score of A or B in the in the mucocutaneous and/or musculoskeletal 
body systems at screening and randomization. Subjects must have a documented history of a positive 
antinuclear antibody (ANA) or a screening result of a positive ANA test by immunofluorescent assay (IFA) 
with a titer ≥ 1:80 or an equivalent assay; or a documented history or positive screening result of elevated 
anti-dsDNA or ENA antibodies (e.g., anti-Smith, SSA, SSB, RNP).. Subjects with Type 1 or Type 2 
diabetes, active central nervous system manifestations of SLE or active lupus nephritis, tuberculosis, history 
of hepatitis, peptic ulcer, active infection, or any contraindication for Acthar will be excluded. Subjects must 
exhibit disease activity despite being on a stable daily dose of a corticosteroid (7.5 mg to 30 mg per day 
[inclusive] of prednisone or prednisone equivalent) for at least 4 weeks prior to the Screening Visit.  
Subjects may be taking antimalarials and nonsteroidal anti-inflammatory drugs if they are on a stable dose 
for at least 4 weeks prior to the Screening Visit and will remain on that dose throughout the study. Subjects 
may be taking methotrexate, azathioprine, and/or mycophenolate mofetil if they are on a stable dose for at 
least 8 weeks prior to the Screening Visit and will remain on that dose throughout the study. Subjects must 
not have received any steroid injection (intramuscular, intraarticular, or intravenous) within the 4 weeks prior 
to the Screening Visit. Subjects must not have received cyclosporine, oral corticosteroid doses > 30 mg per 
day of prednisone or equivalent, or any non-biologic investigational drug within the 3 months prior to the 
Screening Visit. Subjects must not have received intravenous immunoglobulin or plasmapheresis within the 
4 months prior to the Screening Visit. Subjects must not have received cyclophosphamide, abatacept, B cell 
targeted therapies (anti-CD-22 agents [epratuzumab] or belimumab), B cell depleting therapy (rituximab or 
other anti-CD20 agents, or anti-CD52 agents [alemtuzumab]), or any biologic investigational agent within 
the 6 months prior screening.  
Concomitant Medications and Treatments:  
Subjects must remain on stable daily dose of prednisone or prednisone equivalent through Week 16 of the 
study. Taper of corticosteroid is encouraged between Weeks 16 and 24 as clinically indicated. 
All other background medications for SLE must remain stable throughout the study. 
No new immunosuppressant therapies or other new treatments for SLE may be initiated during the study. 
Subjects are not permitted to receive live or live-attenuated vaccines during the study.  
All medications and nondrug therapies (eg, blood transfusions, oxygen supplementation) taken from 30 days 
prior to the Screening Visit and throughout the study will be recorded.  
Study Drug and Treatment Administration:  
Acthar is a sterile preparation of purified adrenocorticotropic hormone (ACTH) analogue formulated in a gel 
for repository administration. 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 SC every other day from Week 0 to 4 and 2x/week from 
Weeks 5 to 24. 
Treatment B: Placebo 1 mL administered SC every other day from Week 0 to 4 and 2x/week from Weeks 5 
to 24. 
Efficacy Evaluations: 
The following efficacy assessments will be evaluated: SRI, SLEDAI-2K, BILAG-2004, PGA, Safety of 
Estrogens in Lupus Erythematosus National Assessment (SELENA) Flare Index (SFI), Cutaneous Lupus 
Erythematosus Disease Area and Severity Score (CLASI), 28 Joint Count, and prednisone usage after 
Week 16. 


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Study Title: A Multicenter, Randomized, Double Blind, Placebo Controlled Study to Assess the Efficacy 
and Safety of
 Acthar® Gel in Subjects With Persistently Active Systemic Lupus Erythematosus Despite 
Moderate Dose Corticosteroids 
Protocol Number: MNK14304067 
Type: Phase 4 (US)/ Phase 2 (Outside the US) 
Condition/Disease:  
Systemic Lupus Erythematosus 
 
 
 
Safety Evaluations:  
The following safety assessments will be evaluated: adverse events, physical examination, clinical laboratory 
tests, pregnancy testing, vital signs, 
 and hospital admissions. 
 
 
 
Statistical Methods: 
Analysis Populations 
 
The Modified Intent-to-Treat (mITT) Population will include all randomized subjects who receive at 
least 1 dose of study drug and who contribute any postbaseline efficacy data to the study.  
 
The Per-Protocol Population will include the subset of the mITT population who complete the study as 
per protocol, have no missing primary endpoint data, and do not have any major protocol deviations.  
 
The Safety Population will include all subjects who receive 1 or more doses of study drug. 
Sample Size  
It is expected that approximately 270 subjects will be screened to randomize a total of 162 subjects into 1 of 
the 2 treatment groups: 1 mL (80 U) of Acthar every other day for 4 weeks followed by 1 mL (80 U) of 
Acthar 2 times per week for 20 weeks or 1 mL of placebo every other day for 4 weeks followed by 1 mL of 
placebo 2 times per week for 20 weeks in a 1:1 ratio (81 per group). The primary efficacy analysis will 
compare the SRI response rate in the Acthar group to the SRI response rate in the placebo group. Assuming 2 
subjects might not qualify for the mITT analysis population after randomization, with 80 mITT subjects in 
each treatment group (160 total) and a response rate of 30% in the placebo group and 55% in the Acthar 
group, the study will have a 90% power to detect a treatment difference at the 0.05 level of significance.  
Statistical Analysis  
The safety analyses will be performed using the safety population. The efficacy 
 
analyses will be performed using the mITT and per protocol populations. Analyses performed on the mITT 
population will be considered primary.  
Summaries for continuous variables will include standard statistics (n, mean, SD, median, relevant 
percentiles, minimum, and maximum). Categorical data will be summarized using frequency tables that will 
present the subject counts and the percent of subjects falling into that category. All statistical tests will be 2-
sided with a significance level of 0.05. The statistical analysis plan will describe in further detail the analyses 
for primary, secondary, 
 efficacy endpoints.  
Efficacy Analysis 
Subjects will be included in the efficacy analyses based on their treatment assignment. The primary endpoint 
is the proportion of SRI responders at Week 16. The proportions of SRI responders for the 2 treatment 
groups will be summarized descriptively by visit and treatment group in tabular format and compared using a 
2-sided Pearson’s chi-square test at a significance level of 0.05. If the responder or nonresponder count falls 
to equal or below 5 in either treatment group, 2-sided Fisher’s exact test will be used instead. All quantitative 
secondary and exploratory endpoints will be analyzed using analysis of covariance models with treatment 


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Study Title: A Multicenter, Randomized, Double Blind, Placebo Controlled Study to Assess the Efficacy 
and Safety of 
Acthar® Gel in Subjects With Persistently Active Systemic Lupus Erythematosus Despite 
Moderate Dose Corticosteroids 
Protocol Number: MNK14304067 
Type: Phase 4 (US)/ Phase 2 (Outside the US) 
Condition/Disease:  
Systemic Lupus Erythematosus 
group as a factor and the baseline value of the corresponding endpoint as a covariate. Mixed model with 
repeated measurements will be performed as deemed necessary. Secondary and exploratory endpoints that 
are proportions will be analyzed using Pearson’s chi-square test or Fisher’s exact tests.  
 
 
 
 
 
 
 
Safety Analysis 
Treatment-emergent adverse events and serious adverse events will be summarized using the MedDRA by 
preferred term within system organ class. 
Hospital admissions and the reason for each admission will be listed and summarized descriptively by visit 
and treatment. The cumulative number of hospital admissions will be compared between treatment groups at 
Week 24 with a 2-sided Pearson’s chi-square test or Fisher’s exact test at a significance level of 0.05. 
Other safety data will be listed and summarized descriptively or graphically, as appropriate. 
 
 
 
  
 


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Screening
(Days -28 to -1)
Randomized Controlled Double-blind Treatment
(24 Weeks)
Acthar 1 mL (80 U) QOD x 4 weeks then 2x/week x 20 weeks
PRIMARY ENDPOINT 
(Week 16)
PBO Acthar 1 mL QOD x 4 weeks then 2x/week x 20 weeks
Stable steroid dose (7.5 to 30 mg)
Attempt steroid 
taper
Follow up
(28  5 days)
 
8 STUDY SCHEMATIC AND SCHEDULE OF EVENTS 
8.1 Study Schematic 
Figure 8-1: 
Study Overview 
 
 


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8.2 Schedule of Study Events 
Table 8-1: 
Schedule of Study Events 
 
Assessment/Procedure 
Screening  
(Day-28 to Day -1) 
Randomization 
Dosing 
Treatment Period 
Follow-up  
Week 
 
0 
0 
2 (± 3 
days) 
4 (± 3 
days) 
6 (± 3 
days) 
8 (± 3 
days) 
12 (± 5 
days) 
16 (± 5 
days) 
20 (± 5 
days) 
24 (± 5 
days)/Early 
Termination 
28 (± 5 
days) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria Review 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Current Medical Condition Review 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete Physical Examination 
X 
 
 
 
 
 
 
 
 
 
X 
 
Limited Physical Examination 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Height and Weighta  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signsb 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
X 
 
Clinical Laboratory Testsc  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lipid Panel 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
HbA1c 
X 
 
 
 
 
 
 
X 
 
 
X 
 
Serum Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
X 
 
Urine Pregnancy Testd 
 
X 
 
 
 
 
X 
 
X 
 
 
X 
IGRA for TB 
X 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis Serologye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
C3, C4 and anti-ds DNA antibodies 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serology (ANA, ENA)f 
X 
 
 
 
 
 
 
 
 
 
 
 


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Assessment/Procedure 
Screening  
(Day-28 to Day -1) 
Randomization 
Dosing 
Treatment Period 
Follow-up  
Week 
 
0 
0 
2 (± 3 
days) 
4 (± 3 
days) 
6 (± 3 
days) 
8 (± 3 
days) 
12 (± 5 
days) 
16 (± 5 
days) 
20 (± 5 
days) 
24 (± 5 
days)/Early 
Termination 
28 (± 5 
days) 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
SLEDAI-2K 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
BILAG-2004 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
PGA 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
SFI 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
CLASI-Activity 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
28 Joint Count 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
Hospital Admissions 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
IXRS Contact 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study Drug and Diary Training 
 
X 
 
 
 
 
 
 
 
 
 
 
Study Drug Accountability and Diary Review 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense Study Drug and Diary  
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Administer First Dose 
 
 
X 
 
 
 
 
 
 
 
 
 
Adverse Events and Concomitant Treatments 
X 
aHeight at screening only. 
bBlood pressure, respiratory rate,  pulse rate and body temperature. For blood pressure, an average of 3 readings after the subject has been seated for ≥ 5 minutes at 
The Screening and Randomization Visits. Single readings after subject has been seated for ≥ 5 minutes at all other time points. 
c Chemistry, hematology assays,  and urinalysis (see Attachment 1). 
 
dPositive urine test after randomization will be confirmed by serum pregnancy test. 
eHepatitis B surface antigen, Hepatitis B core antibody (HBcAb), hepatitis C virus antibody (HCV Ab), hepatitis C polymerase chain reaction([(HCV PCR] for 
subjects positive for HCV Ab only). 
fAutoantibody testing  (ANA, ENA) may be performed if history is unavailable. 
 


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9 ETHICAL CONSIDERATIONS 
This clinical study is designed to comply with ICH Guidance on General Considerations for 
Clinical Trials and applicable national and local regulations. 
9.1 Institutional Review Board/Independent Ethics Committee 
It is the responsibility of the investigator to obtain the approval of the Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC) before the start of the study. The 
investigator will provide Mallinckrodt with a statement of compliance from the IRB/IEC and/or 
the United States (US) Department of Health and Human Services general assurance number. 
A copy of the approval letter along with a roster of IRB/IEC members and compliance letter 
and/or the US Department of Health and Human Services general assurance number (if 
applicable) will be 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). 
9.2 Ethical Conduct of the Study 
The study will be conducted in full compliance with applicable international, national and 
local regulatory requirements; US Food and Drug Administration (FDA) regulations including 
21 CFR 314.106 and 312.120, (where applicable); and ICH guidelines for GCP and in 
accordance with the ethical principles that have their origins in the Declaration of Helsinki. 
9.3 Subject Information and Consent 
The ICF must be approved by the sponsor and the IRB/IEC before any subject provides 
consent. The investigator will provide Mallinckrodt with a copy of the IRB/IEC-approved ICF 
and a copy of the IRB/IEC’s written approval before the start of the study. 
At the Screening Visit, subjects will read the ICF and a 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.  


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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 by national and local regulations including confidentiality. All versions 
of each subject's signed ICF must be kept on file by the site for possible inspection by 
regulatory authorities and/or authorized Mallinckrodt personnel. Signed copies of the 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. 
10 BACKGROUND INFORMATION AND RATIONALE 
10.1 Systemic Lupus Erythematosus 
Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease characterized by 
excess production of proinflammatory cytokines and formation of autoantibodies resulting in 
immune complex deposition, and tissue damage. A range of organ systems may be involved 
(Von Feldt, 1995). The frequency of SLE varies by race and ethnicity, with higher rates 
reported among black and Hispanics, particularly women aged 14 to 64 years (Helmick et al, 
2008).  
SLE currently carries an average 10 year survival rate that exceeds 90% (Kasitanon et al, 
2006; Trager and Ward, 2001). Before 1955, the 5 year survival rate was less than 50%. 
Decreased mortality rates associated with SLE can be attributed to earlier diagnosis (including 
milder cases), improvement in disease-specific treatments, and advances in general medical 
care. According to the Centers for Disease Control and Prevention, one third of SLE-related 
deaths in the US occur in patients younger than 45 years, making this a serious issue despite 
declining overall mortality rates. In 1976, Urowitz first reported bimodal mortality in early vs 
late SLE, noting that SLE-related deaths usually occur within the first 5 to10 years of 
symptom onset (Urowitz, 1976). 


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A number of medications are used in the treatment of SLE including nonsteroidal anti-
inflammatory drugs (NSAIDs), antimalarials, glucocorticoids, and immunosuppressive agents. 
In general, low dose glucocorticoids are used for nonorgan-threatening disease (cutaneous, 
musculoskeletal, serositis, arthritis, and constitutional symptoms) and high dose 
glucocorticoids are reserved for organ threatening disease (eg, cardiopulmonary, hepatic, 
renal, hemolytic anemia, immune thrombocytopenia). Immunosuppressive agents are 
generally reserved for patients with significant organ involvement or patients who have had an 
inadequate response to glucocorticoids. Although the use of glucocorticoids is common in 
SLE, response to treatment is variable, with some patients responding well to low dose 
therapy and others requiring high doses, although a minority of patients does not respond to 
even long courses of high dose therapy (Petri, 2011). While glucocorticoid treatment is 
effective in many cases, side effects are common. 
The primary goal of lupus treatment is to control or halt the inflammatory disease process 
while minimizing side effects. Treatments that reduce or eliminate disease activity without 
adding significant toxicity are needed.  
Belimumab (Benlysta®), a B lymphocyte stimulator inhibitor, is an SLE targeted therapy 
approved by the FDA in 2011. It was the first new SLE drug approved in over 50 years. In the 
BLISS 52 Phase 3 study, approximately 58% of Benlysta patients (10 mg/kg) responded to 
treatment and 19% were able to decrease prednisone to < 7.5 mg/day (Navarra et al, 2011). 
This is compared to approximately 44% of placebo patients who responded to treatment and 
12% were able to decrease prednisone to < 7.5 mg/day. Despite the recent approval of 
Benlysta, a significant unmet need remains for treatments that can improve disease activity 
and decrease dependence on chronic prednisone use. 
As described in the Package Insert, 
Acthar® Gel (repository corticotropin injection, 
hereafter referred to as Acthar) contains a highly purified adrenocorticotropic hormone (ACTH) 
analogue (Mallinckrodt, 2015). It is approved by the FDA for use during an acute exacerbation 
or as maintenance therapy in selected cases of SLE. ACTH is a member of the family of 
structurally related peptides known as melanocortin peptides. Melanocortin peptides, which in 
addition to ACTH include α-, β-, and γ-melanocyte stimulating hormones, are derived from the 
natural protein pro-opiomelanocortin and exert their physiologic effects by binding to cell 
surface G-protein coupled receptors known as melanocortin receptors (MCR) (Mountjoy et al, 
1992). Five subtypes of MCRs have been identified to date (MC1R-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). Stimulation of cortisol by ACTH is mediated by activation of the MC2R expressed on 


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adrenal cortical cells. However, biologic activity of ACTH may extend beyond stimulation of 
adrenal corticosteroid production.  MC1, 3, 4 and 5R are expressed on multiple leukocytes 
subpopulations (eg, T & B cells, macrophages), as well as within target organs (eg, skin, 
kidney, central nervous system [CNS]) relevant to SLE (Catania et al, 2004).  
Experimental evidence suggests that MCR ligands such as ACTH and α-MSH may possess 
steroid-independent anti-inflammatory and immune modulatory activity relevant to SLE 
pathophysiology (Decker et al, 2014; Botte et al, 2014). In a murine model, Acthar has been 
shown to reduce B-cell differentiation and development, and to decrease circulating auto-
antibodies, proteinuria, renal lymphocyte infiltration and glomerular immune complex 
deposition (Decker et al, 2014).  Similarly, other investigators demonstrated that alpha-MSH 
attenuated manifestations of pristine-induced lupus in mice (Botte et al, 2014).  Effects of 
Acthar on human B cell function were studied in vitro using peripheral blood B cells isolated 
from healthy human subjects. Acthar dose dependently inhibited interluekin-4/CD40 ligand-
induced B-cell proliferation and immunoglobulin G production without enhancing cell death. 
These data suggest direct effects of Acthar on human B-cell function and provide supportive 
evidence for steroid independent effects of Acthar when used as a treatment for SLE, an 
autoimmune disease characterized by B-cell activation and humoral autoimmunity (Olsen et 
al, 2015). Historically, ACTH preparations have been used as a treatment option in SLE, with 
and without corticosteroids (cortisone or prednisone) (Harris-Jones, 1956). 
In a recent publication (Fiechtner et al, 2014), the results of an open label, single arm study 
supported the use of Acthar as a treatment for SLE. A total of 10 female patients with chronic, 
moderate to severe SLE who were receiving a stable dose of prednisone (or equivalent) ≤ 
 20 mg/day and/or stables doses of azathioprine, antimalarials, mycophenolate 
mofetil/mycophenolic acid, or methotrexate were enrolled. Patients self-administered a 1 mL 
SC injection daily of Acthar (80 Units [U]) over 10 days with an optional 5 day rescue period 
for partial or nonresponders. All patients were assessed weekly from baseline (Day 0) through 
Week 4 (Day 28). There were significant improvements at all follow-up visits in Systemic 
Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) scores and other measures 
of disease activity. These results suggested that Acthar may be a therapeutic option for SLE 
patients and may provide significant disease activity reduction. 
The sponsor recently completed a pilot study to explore the effects of Acthar on disease 
activity in SLE (Furie et al, 2015; Becker et al, 2016). The study consisted of 2 treatment 
periods: an 8 week double blind, placebo controlled period followed by an optional 44 week 
open label period, and was performed to examine the effects of Acthar in patients with steroid 
dependent, persistently active SLE with arthritic and/or cutaneous involvement. Subjects 
received 0.5 mL (40 U) SC daily or 1 mL (80 U) SC every other day of Acthar or volume 


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matched placebo for 4 weeks, followed by dose tapering to 2 times per week (2x/week) during 
Weeks 5 to 8. Subjects who completed the double blind period were given the option to 
continue into the 44 week open label extension period where all subjects received Acthar. 
From Weeks 9 to 20, Acthar regimen adjustments were permitted based on safety and efficacy 
with a goal of achieving a stable Acthar regimen by no later than Week 28, which was to be 
maintained for the remainder of the open label extension. 
The majority of patients in this study were white (63.9%), while 33% were black or African-
American and 16.7% were of Hispanic or Latino ethnicity. Mean baseline Hybrid Systemic 
Lupus Erythematosus Disease Activity Index (hSLEDAI) total scores ranged from 8.7 to 11.3 
across treatment groups and mean total British Isles Lupus Assessment Group-2004 (BILAG-
2004) total scores ranged from 13.1 to 18.6. 
A novel responder index that had not been validated was used as the primary endpoint. It was 
defined as the proportion of patients responding to treatment at Week 4, with response defined 
by a decrease in hSLEDAI score from 4 to 0 for arthritis, or from 2 to 0 for rash, with no 
worsening in other organ systems as assessed by BILAG-2004. Although the primary 
endpoint was not met in this pilot study, Acthar was associated with significant improvements 
in several measures of disease activity, including hSLEDAI and BILAG-2004. The response 
to treatment with Acthar was seen as early as Week 6 for improvements from baseline in total 
hSLEDAI score, and by Week 8 significant improvements were seen in the remaining 
measures of disease activity (total BILAG-2004, improvement in BILAG A and B 
mucocutaneous and musculoskeletal scores, Cutaneous SLE Disease Area and Severity Score 
(CLASI)-Activity, and both tender and swollen joint count). Furthermore, in post hoc 
analyses, the proportion of responders as defined by the SLE Responder Index (SRI), a widely 
accepted and validated composite index (Furie et al, 2009), was significantly higher in the 
combined Acthar group than in the combined Placebo group at Week 8. 
In the open label extension, hSLEDAI, BILAG, and Physician’s Global Assessment (PGA) 
scores generally decreased over time from Week 8 for both treatment groups (Acthar/Acthar 
and Placebo/Acthar). Subjects randomized to Acthar during the double blind period who 
continued on Acthar throughout the 44 week open label extension had a durable response to 
therapy, while subjects who crossed over from placebo to Acthar experienced improvements 
in several measures of disease activity during the open label extension.  These improvements 
were generally comparable to the improvements seen with Acthar treatment from the blinded 
period of the trial by 12 to16 weeks after Acthar was initiated.  A notable proportion of 
subjects were able to taper exogenous corticosteroid therapy by Week 52 (Furie et al, 2015; 
Becker et al, 2016). 


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In general, Acthar was safe and well tolerated at the doses administered in this pilot study. In 
the double blind period, the most commonly reported treatment-emergent adverse event 
(TEAE) was increased weight, for which the incidence in the combined placebo cohort was 
comparable to that in the Acthar 0.5 mL (40 U) and Acthar 1 mL (80 U) cohorts. Two patients 
treated with Acthar had serious TEAEs (moderate viral infection and Klebsiella sepsis), and 4 
patients (11.1% overall, 16.0% of the combined Acthar cohort) reported 4 TEAEs leading to 
study drug withdrawal. There were no unexpected adverse events in the open label extension. 
10.2 Product Description 
Acthar is a sterile preparation of a purified ACTH analogue formulated in 16% gelatin to provide 
a prolonged release after intramuscular or subcutaneous (SC) injection. Acthar contains 0.5% 
phenol, not more than 0.1% cysteine (added), sodium hydroxide and/or acetic acid to adjust 
pH, and water for injection. Acthar is obtained from processing porcine pituitary using an 
FDA approved process. Acthar is currently labeled for use during an exacerbation or as 
maintenance therapy in selected cases of SLE (Mallinckrodt, 2015). 
Placebo is a sterile preparation of 16% gelatin for intramuscular or SC injection. Placebo 
contains 0.5% phenol, not more than 0.1% cysteine, sodium hydroxide and/or acetic acid to 
adjust pH, and water for injection. The placebo formulation is identical to Acthar except that it 
contains no active medication. 
10.3 Dosage and Administration 
Investigational medicinal product (IMP) or study drug will be used to denote active drug 
(Acthar) and/or volume matched placebo. 
Following a screening period of up to 28 days, subjects with persistently active disease SLE 
despite treatment with moderate dose corticosteroids will be randomized to receive either 
Acthar or placebo. Acthar 1 mL (80 U) or placebo (1 mL) will be administered as SC doses 
every other day for 4 weeks, followed by Acthar 1 mL (80 U) or placebo (1 mL) SC doses 
2x/week for an additional 20 weeks.  
10.4 Rationale 
Recent studies (Fiechtner et al, 2014; Furie et al, 2015; Becker et al, 2016) support the 
efficacy of Acthar as a treatment for SLE. This study will provide additional data to support 
the efficacy and safety of Acthar in SLE, 
 
 


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The Acthar dose and dosing regimen for this study are based on results from the pilot Phase 4 
study exploring the efficacy, safety and pharmacodynamics of Acthar in subjects with SLE 
and a history of persistently active disease (Furie et al, 2015; Becker et al, 2016). In that study, 
subjects received 0.5 mL (40 U) SC daily or 1 mL (80 U) SC every other day of Acthar or 
volume matched placebo for 4 weeks, followed by dose tapering to 2x/week during Weeks 5 
to 8. Subjects who completed the double blind period were given the option to continue into 
the 44 week, open label extension period where all subjects received Acthar. From Weeks 9 to 
20, Acthar regimen adjustments were permitted based on safety and efficacy with a goal of 
achieving a stable Acthar regimen, no later than Week 28, which was to be maintained for the 
remainder of the open label period. 
The Acthar dosing regimens studied during the pilot trial led to clinically meaningful 
improvements in disease activity measures such as hSLEDAI and BILAG-2004 as early as  
8 weeks after initiation of Acthar in the double blind period, and 12 to16 weeks after initiating 
Acthar therapy in the open label extension. In general, Acthar was safe and well tolerated at 
the doses administered in the double blind and open label extension periods. No unexpected 
adverse events were observed. These results support the efficacy of Acthar as a treatment 
option in steroid dependent patients with persistently active SLE.  
10.5 Risks and Benefits 
The common adverse reactions for Acthar are similar to those of corticosteroids and include 
fluid retention, alteration in glucose tolerance, elevation in blood pressure, behavioral and 
mood changes, increased appetite and weight gain. For a complete reference of known 
potential risks please refer to the Acthar product labeling (Mallinckrodt, 2015). 
SLE is a chronic, autoimmune disease characterized by excess production of autoantibodies, 
immune complex deposition and pro-inflammatory cytokines that can cause inflammation and 
tissue damage in a range of organ systems. Although early diagnosis and advances in disease-
specific therapies have improved 5- to 10-year survival rates to more than 90% (Kasitanon et 
al, 2006; Trager and Ward, 2001), there remain significant unmet needs in the management of 
SLE, particularly among patients with persistent, treatment-refractory disease (Holloway et al, 
2014). Preclinical data (Decker et al, 2014; Olsen et al, 2015) support the potential for Acthar 
to reduce circulating autoantibodies and disease activity. Additionally, a recently published 
case series (Fiechtner, 2014) and the safety and efficacy data generated from a recently 
completely randomized controlled double blind pilot study with an optional open label 
extension (Furie et al, 2015; Becker et al, 2016) support the potential benefits of Acthar for 
reducing disease activity in the patient population to be studied.  


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11 OBJECTIVES 
11.1 Primary Objective 
The primary objective of this study is: 
 
To determine the ability of Acthar to reduce disease activity as measured by SRI in 
subjects with SLE requiring moderate dose corticosteroids for persistently active 
disease.  
11.2 Secondary Objectives 
The secondary objectives of this study are: 
 
To assess the impact of Acthar on disease activity, measured by the SLEDAI-2K, 
BILAG-2004, and PGA, in subjects with SLE requiring moderate dose corticosteroids 
for persistently active disease. 
 
To assess the time to response to Acthar in subjects with SLE requiring moderate dose 
corticosteroids for persistently active disease. 
 
To further assess the safety and tolerability of Acthar in subjects with SLE requiring 
moderate dose corticosteroids for persistently active disease. 
11.3 Exploratory Objectives 
 
 
 
 
 
  
11.4 Approximate Duration of Subject Participation 
Subjects will participate in the study for a total of up to approximately 32 weeks, including a 
screening period of up to 28 days, an active treatment period of 24 weeks, and a follow-up 
visit 28 (± 5) days after the last dose of study drug.  
12 STUDY DESIGN 
12.1 Description 
This is a randomized, placebo controlled, double blind study. Following a screening period of 
up to 28 days, subjects with persistently active SLE and moderate to severe rash and/or arthritis 
despite receiving corticosteroids (7.5 mg to 30 mg per day of prednisone or equivalent) for ≥ 4 
weeks prior to screening, will be randomized in a 1:1 ratio to receive 1 mL (80 U) of Acthar or 


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matching placebo. At randomization, subjects will be stratified by prednisone equivalent dose 
(≤ 20 mg/day vs > 20 mg/day). During Weeks 1 to 4, 1 mL (80 U) of Acthar or volume 
matched placebo will be administered SC every other day. For the remainder of the study 
(Weeks 5 to 24), Acthar 1 mL (80 U) or volume matched placebo will be administered SC 
2x/week. The primary efficacy endpoint is the SRI at Week 16. Corticosteroid taper may be 
attempted and is encouraged between Weeks 16 and 24 if medically appropriate; the taper rate 
and schedule will be at the discretion of the individual investigator. All subjects will have a 
follow-up visit 28 (± 5) days after the last dose of study drug.   
12.2 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 3 years to complete.  
12.3 Approximate Number of Subjects 
It is expected that approximately 270 subjects will be screened and 162 subjects will be 
randomized at approximately 60 sites globally. 
13 SELECTION OF SUBJECTS 
13.1 Inclusion Criteria 
Subjects must meet all of the following criteria for inclusion in the study at the Screening 
Visit and the Randomization 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 Screening Visit and can be male or female. 
3. Female subjects must be of nonchildbearing potential (history of hysterectomy, bilateral 
oophorectomy, or bilateral tubal ligation; or postmenopausal with no history of menstrual 
flow in the 12 months prior to the Screening Visit); or if of childbearing potential must be 
nonpregnant, nonlactating and agree to use effective contraception when with a male 
partner throughout study participation (through the Follow-up Visit). Acceptable forms of 
contraception include hormonal measures (oral contraceptive pills, contraceptive patch, 
contraceptive ring, injections), intrauterine devices, double barrier method (condom plus 
diaphragm, condom or diaphragm plus spermicidal gel or foam), and abstinence.  
4. Male subjects with a female partner of childbearing potential must have been surgically 
sterilized (vasectomy) or agree to use a double barrier for contraception (condom plus 


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diaphragm, condom or diaphragm plus spermicidal gel or foam) or remain abstinent 
throughout their study participation (through the Follow-up Visit). 
5. Subjects must have a diagnosis of SLE according to the American College of Rheumatology 
revised criteria (fulfilled ≥ 4 criteria) (Hochberg, 1997; Tan et al, 1982). 
6. Subjects must have active SLE as demonstrated by a SLEDAI-2K score of  ≥ 6 at the 
Screening Visit and a clinical SLEDAI (excluding laboratory results) score ≥ 4 at the 
Screening and Randomization Visits. Points for arthritis and/or rash must be present at both 
the Screening and Randomization Visits. 
7. Subjects must have moderate to severe rash and/or arthritis as demonstrated by BILAG-2004 
score A or B in the in the mucocutaneous and/or musculoskeletal body systems at both 
Screening and Randomization Visits. 
8. A documented history of positive antinuclear antibody (ANA)  
OR 
A screening result of positive ANA test by immunofluorescent assay (IFA) with titer ≥ 
1:80 or an equivalent assay  
OR  
A documented history or positive screening result of elevated anti-dsDNA or ENA 
antibodies (e.g., anti-Smith, SSA, SSB, RNP). 
9. Subjects must have been on prednisone (or prednisone equivalent) for ≥ 8 weeks prior to the 
Screening Visit and on a stable dose of 7.5 mg to 30 mg of prednisone (or prednisone 
equivalent) for ≥ 4 weeks prior to the Screening Visit. 
10. Subjects must have a mean systolic blood pressure ≤ 150 mm Hg and a diastolic blood 
pressure of ≤ 90 mm Hg determined by the average of 3 seated readings taken at least 5 
minutes apart at the Screening and Randomization Visits. 
11. Subjects using antimalarials and NSAIDs must have been on a stable dose for at least 4 
weeks prior to the Screening Visit and remain on that dose throughout the study. 
12. Subjects using methotrexate, azathioprine and/or mycophenolate mofetil must have been a 
stable dose for at least 8 weeks prior to the Screening Visit and remain on that dose 
throughout the study. 
13. Subjects must be able to communicate effectively with study personnel. 
14. Subjects must be able and willing to follow all protocol requirements and study 
restrictions. 
15. Subjects must be able and willing to return for all study visits. 
 


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13.2 Exclusion Criteria 
Subjects are ineligible for study participation if they meet any of the following criteria at the 
Screening Visit or the Randomization 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 is unwilling to receive, or is intolerant of, SC injections. 
3. Subject has a history of sensitivity to ACTH preparations (including but not limited to 
Acthar and Synacthen). 
4. Subject has a history of sensitivity to porcine protein products. 
5. Subject has severe active lupus nephritis defined as serum creatinine > 2.5 mg/dL or 
protein creatinine ratio > 1.5 g/g, or subject has required hemodialysis within 3 months 
prior to the screening visit or is likely to require hemodialysis throughout the study. 
6. Subject has active CNS manifestations of lupus (as evidenced by seizures, psychoses, 
organic brain syndrome, cerebrovascular accident, cerebritis, or CNS vasculitis) within the 
3 months prior to the Screening Visit or develops CNS lupus between the Screening Visit 
and the first dose of study drug 
7. Subject has Type 1 or Type 2 diabetes mellitus or is taking hypoglycemic medication (a 
history of gestational diabetes mellitus is not exclusionary). Subjects must not have 
glycosylated hemoglobin (HbA1c)  6.5 at the Screening Visit. 
8. Subject has received any steroid injection (intramuscular, intraarticular or intravenous 
[IV]) within 4 weeks prior to the Screening Visit (use of topical and/or inhaled steroids is 
not exclusionary). 
9. Subject has received oral prednisone > 30 mg per day or equivalent, cyclosporine, or any 
nonbiologic investigational drug within 3 months prior to the Screening Visit. 
10. Subject has received IV immunoglobulin (Ig) or plasmapheresis within 4 months prior to 
the Screening Visit. 


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11. Subject has received cyclophosphamide, abatacept, B cell targeted therapy (anti-CD-22
[epratuzumab] or belimumab), B cell depleting therapy (rituximab or other anti-CD20
agent, or anti-CD52 agent [alemtuzumab]), or any biologic investigational agent within 6
months prior to the Screening Visit.
12. Subject has any known contraindication(s) to Acthar (Mallinckrodt, 2015) including, but
not limited to:

Any known history of scleroderma, osteoporosis, or ocular herpes simplex. For the
purposes of this study, osteoporosis is defined as evidence of vertebral or long bone
fracture, or lumbar T-score > 2.0 SD below the mean of the reference population.

Any primary adrenocortical insufficiency, or adrenal cortical hyperfunction.

Any current congestive heart failure (defined as New York Heart Association
Functional Class III to IV).

Peptic ulcer (within 24 weeks prior to the Screening Visit).

Recent major surgery (within 24 weeks prior to the Screening Visit).
13. Subject has a history of chronic active hepatitis including active or chronic hepatitis B, or
acute or chronic hepatitis C. Subjects must have negative Hepatitis B surface antigen
(HBsAg) or Hepatitis B core antibody (HBcAb) and negative Hepatitis C virus antibody
(HCV) or HCV polymerase chain reaction (PCR) < 25 IU/mL (HCV PCR will be
automatically analyzed if HCV is positive) at the Screening Visit.
14. Subject has a history of tuberculosis (TB) infection, any signs/symptoms of TB, or any
close contact with an individual with an active TB infection.  Subjects must not have a
positive or indeterminate interferon gamma release assay (IGRA) for TB at the Screening
Visit.
15. Subject has a clinically significant infection requiring administration of IV antibiotics or
hospitalization in the 4 weeks prior to the Screening Visit or between the Screening Visit
and the first dose of study drug.
16. Subject has known immune compromised status (not related to SLE or therapies for SLE),
including but not limited to, individuals who have undergone organ transplantation or who
are known to be positive for the human immunodeficiency virus.
17. 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.


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18. 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.
19. 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). 
20. 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) ≤ 1000 cells/μL.

Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin
 2 times upper limit of normal (ULN).
21. Subject has any other clinically significant disease, disorder or laboratory abnormality
(including those listed on the Prescribing Information Section 5: Warnings and
Precautions [Mallinckrodt, 2015]) which, in the opinion of the investigator (by its nature
or by being inadequately controlled), might put the patient at risk due to participation in
the study, or may influence the results of the study or the subject’s ability to complete the
study.
13.3 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 Randomization Visit must not 
exceed 28 days, inclusive of any repeat screening procedures.  
Subjects who do not meet all of the eligibility criteria at the Screening or Randomization 
Visits will be deemed a screen failure and the reason for the screen failure will be 
documented. A subject who is a screen failure at the Screening or Randomization Visit may be 
rescreened. The subject must repeat all screening procedures. The period from the start of 
rescreening related procedures to the first dose of study drug must not exceed 28 days. 
Subjects may be rescreened only once. 


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14 PRIOR AND CONCOMITANT MEDICATIONS/TREATMENTS 
The start and stop date, dose, unit, frequency, route of administration, and indication for all 
prior (taken within the 30 days prior to the Screening Visit) and concomitant (taken from the 
Screening Visit through the Follow-up Visit) medications and nondrug therapies (eg, blood 
transfusions, oxygen supplementation) received will be recorded.  
In addition, all prior treatments for SLE will be recorded with start and stop date, dose, unit, 
frequency and route of administration. 
14.1 Permitted Concomitant Medications 
The use of antimalarials and NSAIDs is permitted provided the subject has been on a stable 
dose for at least 4 weeks prior to the Screening Visit and will remain on that dose throughout 
the study. 
The use of methotrexate, azathioprine and mycophenolate mofetil is permitted provided the 
subject has been on a stable dose for at least 8 weeks prior to the Screening Visit and will 
remain on that dose throughout the study. 
The use of topical and/or inhaled corticosteroids is allowed during the study. 
14.2 Prohibited Concomitant Medications 
The following treatments will not be permitted during the study: 
 
Administration of live or live-attenuated vaccines. 
 
Oral prednisone (or equivalent) > 30 mg/day. 
 
Steroid injections (intramuscular, intraarticular, or IV). 
 
IV Ig or plasmapheresis. 
 
Cyclosporine. 
 
Cyclophosphamide. 
 
Abatacept. 
 
B cell targeted therapy, anti-CD-22 (epratuzumab) or belimumab.  
 
B cell depleting therapy (rituximab or other anti-CD20 agent, or anti-CD52 agent 
[alemtuzumab]). 
 
Any other new immunosuppressant therapy or any other new treatment for SLE 
(initiated after the Screening Visit). 


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 
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. 
15 PROCEDURES 
The detailed schedule of study procedures is summarized in the Schedule of Study Events 
(Table 8-1). What follows is a general outline of required procedures and a suggested order for 
completion. 
15.1 Screening Visit (Study Days -28 to -1) Procedures 
Screening assessments must be performed within 1 to 28 days prior to the Week 0 Visit.  
The following procedures will be performed at the Screening Visit: 
 Informed consent. 
 Inclusion/exclusion criteria. 
 SLEDAI-2K and BILAG-2004. 
 Medical and surgical history, including the first day of the last menstrual period for 
women of childbearing potential. 
 Demographics. 
 Complete physical examination. 
 Height and Weight.  
 Vital signs. 
 12-lead electrocardiogram (ECG). 
 Clinical laboratory tests (chemistry, hematology, and urinalysis). 
 Lipid panel. 
 HbA1c. 
 Serum pregnancy test.  
 Hepatitis serology.  
 IGRA test for TB.  


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 C3, C4 and anti-ds DNA antibodies. 
 Serology (ANA, ENA; if history is unavailable) 
 Contact the Interactive Phone/Web Response System (IXRS). 
 Adverse events and concomitant medications. 
 
Subjects will be allowed to repeat any screening procedure once, if necessary, if it is within 
the screening window. 
15.2 Randomization Visit (Week 0) and First Dose Procedures 
All evaluations will occur prior to the first dose of study drug, except as noted. 
 Inclusion/exclusion criteria review. 
 
 
 
 
 28 Joint Count, SLEDAI-2K, BILAG-2004, PGA, and CLASI -Activity. 
 Current medical condition review. 
 Limited physical examination. 
 Weight. 
 Vital signs. 
 Clinical laboratory tests.  
 Lipid panel. 
 Urine pregnancy test. 
 C3, C4, and anti-ds DNA antibodies. 
 
  
 
  
 
 
 
  
 Subject diary and study drug administration training. 
 Contact IXRS and dispense study drug kits. 


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 Study drug administration under supervision of study staff and observation for at least 
1 hour thereafter.  
 Adverse events and concomitant medications. 
15.3 Week 2 (± 3 days) and 6 (± 3 days) Procedures 
 SLEDAI-2K.   
 Current medical condition review. 
 Limited physical examination. 
 Weight. 
 Vital signs. 
 Clinical laboratory tests 
 
  
 C3, C4, and anti-ds DNA antibodies. 
 Hospital admissions. 
 Subject diary review. 
 Study drug accountability. 
 Contact IXRS and dispense study drug kits.  
 Adverse events and concomitant medications. 
15.4 Week 4 (± 3 days) and 20 (± 5 days) Procedures 
 28 Joint Count, SLEDAI-2K, BILAG-2004, PGA, CLASI- Activity, and Safety of 
Estrogens in Lupus Erythematosus National Assessment (SELENA) Flare Index (SFI). 
 Current medical condition review. 
 Limited physical examination. 
 Weight. 
 Vital Signs. 
 Clinical laboratory tests.  
 C3, C4, and anti-ds DNA antibodies. 
 Hospital admissions. 
 Subject diary review. 


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 Study drug accountability. 
 Contact IXRS and dispense study drug kits.  
 Adverse events and concomitant medications. 
15.5 Week 8 (± 3 days) and 16 (± 5 days) Procedures 
 
 
 
 
 28 Joint Count, SLEDAI-2K, BILAG-2004, PGA, CLASI-Activity, and SFI. 
 Current medical condition review. 
 Limited physical examination. 
 Weight. 
 Vital Signs. 
 Clinical laboratory tests.  
 Urine pregnancy test. 
 C3, C4 and anti-DS DNA antibodies. 
 
  
 
  
 Serum cortisol and aldosterone. 
 Hospital admissions. 
 Subject diary review. 
 Study drug accountability. 
 Contact IXRS and dispense study drug kits.  
 Adverse events and concomitant medications. 
15.6 Week 12 (± 5 days) Procedures 
 28 Joint Count, SLEDAI-2K, BILAG-2004, PGA, CLASI-Activity, and SFI. 
 Current medical condition review. 
 Limited physical examination. 
 Weight. 


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 Vital Signs. 
 Clinical laboratory tests.  
 Lipid panel. 
 C3, C4 and anti-DS DNA antibodies. 
 HbA1c. 
 
 
 Hospital admissions. 
 Subject diary review. 
 Study drug accountability. 
 Contact IXRS and dispense study drug kits.  
 Adverse events and concomitant medications. 
15.7 Week 24 (± 5 days)/Early Termination Procedures 
 
 
 
 
 28 Joint Count, SLEDAI-2K, BILAG-2004, PGA, CLASI-Activity, and SFI. 
 Current medical condition review. 
 Complete physical examination. 
 Weight. 
 Vital Signs. 
 12-lead ECG. 
 Clinical laboratory tests.  
 Lipid panel. 
 Serum pregnancy test. 
 HbA1c. 
 
 
 C3, C4 and anti-DS DNA antibodies. 
 
  


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 Hospital admissions. 
 Subject diary review. 
 Study drug accountability. 
 Contact IXRS 
 Adverse events and concomitant medications. 
 
15.8 Follow-up Visit - Week 28 (± 5 days) 
The following procedures will be completed at the follow-up visit 28 (± 5) days after the final 
dose of study drug: 
 Current medical condition review. 
 Limited physical examination. 
 Weight. 
 Vital signs. 
 Clinical laboratory tests. 
 Urine pregnancy test. 
 Adverse events and concomitant medications. 
16 INVESTIGATIONAL MEDICINAL PRODUCT (Study Drug) 
16.1 Methods of Assigning Subjects to Treatment Groups 
16.1.1 Randomization and Stratification 
Subjects will be randomized according to computer-generated allocation scheme to receive 
either Acthar 1 mL (80 U) or placebo 1 mL administered every other day for 4 weeks followed 
by 2x/week for 20 weeks. The randomization will be stratified by location (US or outside the 
US) and prednisone equivalent dose (≤ 20 and > 20 mg/day). For each stratum, a separate 
randomization scheme will be produced. 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. 


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16.1.2 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, they do not need a new subject ID number. At the 
Randomization Visit, qualified subjects who meet all of the eligibility criteria will be 
randomized into the study.  
The investigator or designee must contact the IXRS to report a subject as a screen failure if 
the subject does not meet eligibility criteria prior to randomization. 
The investigator or designee must contact IXRS to record each subject visit, to receive the 
study drug 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. 
16.2 Emergency Identification of Investigational Medicinal Product 
In case of an emergency during the Randomized Treatment Period, 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 by the IXRS vendor. 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 that the blind was broken and provide the date, time, and reason 
for breaking the blind.  


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16.3 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: 
 Acthar 1 mL (80 U) SC doses every other day for 4 weeks, followed by 1 mL (80 U) 
SC 2x/week for an additional 20 weeks. 
 Placebo (1 mL) SC doses every other day for 4 weeks, followed by 1 mL SC 2x/week 
for an additional 20 weeks. 
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. 
16.3.1 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 (Class III or IV) 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) that cannot be managed by the adjustment of concomitant medications 
such as insulin and oral hypoglycemic agents.  
 
Development of any other adverse event (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. 
Missed doses of study drugshould be discussed with the medical monitor. 


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16.4 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. 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. 
16.5 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 
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.  
16.6 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. 
17 EFFICACY ASSESSMENTS AND PROCEDURES 
Efficacy assessments will be evaluated at times specified in the Schedule of Study Events 
(Table 8-1). Below is a general instruction of the administration of these assessments. Specific 
instructions and questionnaires/forms (where appropriate) will be provided in a separate 
document. 
17.1 Physician Completed Assessments 
The SLEDAI-2K, BILAG-2004, PGA, SFI, CLASI-Activity and 28 Joint Count are 
assessments to be completed by the investigator or designee. When these assessmentsare 
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. 


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17.1.1 Systemic Lupus Erythematosus Disease Activity Index-2000 
The SLEDAI-2K is a modified version of a composite score based on the presence or absence 
of clinical signs, clinical symptoms, and immunologic laboratory results taken within 10 days 
of the evaluations (Bombardier et al, 1992; Gladman et al, 2002). Disease activity is based on 
24 questions weighted across 9 organ systems with total scores ranging from 0 to 105 but are 
generally < 20 with very active disease. The Clinical SLEDAI-2K score is derived without the 
inclusion of points attributed to laboratory test results. 
17.1.2 British Isles Lupus Assessment Group 2004  
The BILAG scores disease involvement within each organ system based upon the intent to 
treat premise (Isenberg et al, 2005). The major difference between the BILAG and other 
disease activity indices is that disease activity in different organs/systems is reported 
separately. Specific manifestations in 9 organ systems are scored (there are a total of 97 
items). Each item is rated as 0 (not present), 1 (improving), 2 (same), 3 (worse), or 4 (new) in 
the last 4 weeks compared with the previous 4 weeks. 
The numerical scores are used to categorize each organ system by an alphabetical score: ‘A’ 
reflecting severe disease requiring increases in prednisone to > 20 mg daily and/or addition of 
immunosuppressive agents, ‘B’ indicated less active disease, requiring low-dose prednisone 
and/or symptomatic treatment with NSAIDs and/or antimalarials, ‘C’ reflecting mild disease 
requiring only symptomatic therapy, ‘D’ reflecting previous organ system involvement 
without current disease activity, and ‘E’ reflecting no prior or no current disease involvement 
in that organ system.  
BILAG 2004 is a revised version of the original BILAG. The revised index removed the 
vasculitis section, placing individual clinical features more appropriately within the other 
organs or systems. It now incorporates sections on gastrointestinal disease and has an 
ophthalmology section, both missing from the original. Furthermore, some items related to 
damage were removed. 
17.1.3 Physicians Global Assessment 
PGA is a 100 mm visual analogue scale anchored at 0 (none) and 3 (severe) with intermediate 
lines at 1 (mild) and 2 (moderate). It was designed for physicians to provide an overall 
assessment of a patient’s wellbeing (Petri et al, 1999). 


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17.1.4 SELENA Flare Index 
The SFI categorizes SLE flare as mild, moderate or severe based on the following 6 variables 
(Buyon et al, 2005): 
 
Change in SELENA SLEDAI score from the most recent assessment to current.  
 
Change in signs or symptoms of disease activity.  
 
Change in prednisone dosage.  
 
Use of new medication for disease activity or hospitalization.  
 
Change in PGA score.  
 
Hospitalization for SLE activity. 
A severe flare is defined as 1 or more of the following: a) SLEDAI score greater than 12; b) 
new or worsening CNS involvement, vasculitis, glomerulonephritis, myositis, 
thrombocytopenia (platelet count < 60,000/mL), or hemolytic anemia (hemoglobin level  
< 70 g/L or decrease in hemoglobin level > 30 g/L), each requiring doubling of corticosteroid 
dosage to a final dosage > 0.5 mg/kg per day or acute hospitalization; c) any manifestation 
requiring an increase in dosage of prednisone or equivalent drug to greater than 0.5 mg/kg per 
day, or initiation of therapy with cyclophosphamide, azathioprine, mycophenolate mofetil, or 
methotrexate; d) hospitalization for lupus activity; and e) PGA score  greater than 2.5 points. 
17.1.5 Cutaneous Lupus Erythematosus Disease Area and Severity Score- 
Activity 
The CLASI was developed to specifically track cutaneous activity and damage in SLE (Klein 
et al, 2010). The CLASI uses separate activity and damage scores as indicators of disease 
burden. The activity score reflects ongoing inflammation that can be treated, with points given 
for the presence of erythema, scale, mucous membrane lesions, recent hair loss, and 
inflammatory alopecia. The damage score represents the irreversible aftermath of 
inflammation. Only the CLASI activity score will be used in the study. 
17.1.6 28 Joint Count 
The 28 Joint Count includes assessment of swelling and tenderness in the shoulders, elbows, 
wrists, metacarpophalangeal joints, proximal interphalangeal joints and knees.  
17.2 SLE Responder Index 
An SRI responder is defined as a subject with a 4 point reduction from baseline in SLEDAI-
2K, with no new BILAG A and no more than 1 new BILAG B organ domain scores compared 


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with baseline, and no worsening in PGA (≤ 10% increase from baseline) (Furie et al, 2009). 
This index will be calculated by the sponsor. 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 


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19 SAFETY ASSESSMENTS AND PROCEDURES 
The following safety assessments will be evaluated: AEs, physical examinations, clinical 
laboratory test results (chemistry, lipid panel, hematology, and urinalysis), HbA1c, vital signs, 
 medical history, weight, concurrent medical conditions, and 
hospital admissions. All safety assessments will be performed at times outlined in the 
Schedule of Study Events (Table 8-1). Additional (unscheduled) safety assessments may be 
performed as needed. 
19.1 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 21 for additional details on the handling of AEs and SAEs. 
19.2 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.  


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19.3 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.  
19.4 Physical Examination 
A complete physical examination will be performed at the Screening and Week 24/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 visits.  
The findings of the physical examinations completed prior to the Randomization visit will be 
recorded as Medical History..  
19.5 Height and Weight 
Height will be collected at screening only. Weight will be collected at all visits. 
19.6 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 Randomization Visits, blood pressure will be 
measured 3 times, with at least 5 minutes between assessments after the subject has been 
seated for a minimum of 5 minutes prior to the initial blood pressure assessment. 
The investigator may perform additional unscheduled vital sign measurements to evaluate or 
manage a suspected AE. These unscheduled vital sign measurements should be obtained after 
the subject has been seated for at least 5 minutes, if possible. Unscheduled vital signs will be 
recorded.  
The date and time for all vital sign assessments will be recorded.  
 


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Screening/Randomization  
A subject with systolic blood pressure  150 mm Hg and diastolic blood pressure  90 mm Hg 
(average of 3 assessments) at the Screening or Randomization Visits does not qualify for the 
study. 
On Study Assessments 
If an on-study systolic blood pressure is  150 mm Hg and diastolic blood pressure is 
 90 mm Hg, an AE will be recorded if the investigator determines the change is clinically 
significant or requires a change in the subject’s clinical management.  
19.7 Clinical Laboratory Tests (Chemistry, Hematology and Urinalysis), 
HbA1c, IGRA, Direct Coombs test, Pregnancy Tests, 
 
; and C3, C4, and anti-ds DNA antibodies 
The clinical laboratory tests are listed in Attachment 1. All clinical laboratory tests will be 
done at a central laboratory facility except urine pregnancy (at the site) and 
 
 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. 
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 Follow-up Visits. A positive urine test after randomization will be 
confirmed by a serum pregnancy test. Urine pregnancy tests will be done at other 
specified 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 Randomization) or withdrawn from the study. Any 


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female subject that becomes pregnant during the study will be immediately withdrawn 
and the pregnancy reported as per Section 21.6. 
If applicable, the subject’s agreement to use contraception throughout their study 
participation, and for 28 days after ending study participation, will be documented. 
 A lipid panel (high density lipoprotein, low density lipoprotein, triglycerides, and total 
cholesterol) will be done at the Screening, Randomization, Week 12, and Week 24 
Visits. 
 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. Additional HbA1c tests will be done at specified times during 
the protocol. 
 
 
 
 C3, C4, and anti-ds DNA antibody samples will be taken at specified times during 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 at the 
Randomization Visit and throughout the study will be assessed by the investigator for clinical 
significance. If the out of range value is deemed clinically significant by the investigator, an 
AE will be recorded.  


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19.8 Hospital Admissions 
The number of hospital admissions and the reason for each admission will be collected at 
specified times in the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
21 STATISTICAL METHODS AND PLANNED ANALYSIS 
21.1 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.
 
 
 
Unless otherwise specified, all statistical tests will be two-sided with a significance level of 
0.05. Summary statistics will be provided for all study variables with descriptive statistics 
(number of observations, mean, SD, median, minimum, and maximum) for numerical (or 
continuous) variables. Frequency and percentages will be calculated for categorical variables. 


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All data will be summarized by treatment groups as appropriate. Data summary and analyses 
will be performed with SAS 9.2 or higher. 
21.2 Analysis Populations 
 The Modified Intent-to-Treat (mITT) Population will include all randomized subjects 
who receive at least 1 dose of study drug and who contribute any postbaseline efficacy 
data to the study.  
 
The Per-Protocol Population will include the subset of the mITT population who 
complete the study as per protocol, have no missing primary endpoint data, and do not 
have any major protocol deviations.  
 The Safety Population will include all subjects who receive 1 or more doses of study 
drug. 
The safety analyses will be performed using the safety populations. The efficacy and 
pharmacodynamic analyses will be performed using the mITT and Per Protocol populations; 
analyses performed on the mITT population will be considered primary. 
21.3 Efficacy Endpoints 
21.3.1 Primary Efficacy Endpoint 
The primary efficacy endpoint will be proportion of responders as assessed by SRI at 
Week 16. 
21.3.2 Secondary Efficacy Endpoints 
 
Change from baseline over time in SLEDAI-2K (Week 0 to 16).  
 
Time to first response as assessed by SRI. 
 
Change from baseline over time in total BILAG-2004 (Week 0 to 16).  
 
Change from baseline over time in PGA (Week 0 to 16).  
 
Proportion of subjects with decrease from baseline of ≥ 4 points in SLEDAI-2K over 
time (Week 0 to 16).  
 
Change from baseline in CLASI-Activity score over time (Week 0 to 16) in subjects 
with CLASI-Activity at baseline. 
 
Change from baseline (Week 0 to 16) in 28 Joint Count (tender and swollen) in subjects 
with tender and swollen joints at baseline. 


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21.3.3 Exploratory Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
21.4 Safety Endpoints 
 Summary of general safety profile, including adverse events (serious and non-serious), 
vital signs and laboratory assessments by study period and over the entire study. 
21.5 Subject Characteristics 
21.5.1 Demographics 
The demographic information will be summarized for each analysis population by treatment 
group. 
21.5.2 Medical and Surgical History 
Prior medical conditions or procedures will be summarized by body system and treatment 
group. 


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21.5.3 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.  
21.5.4 Subject Disposition and Exposure to Study Drug 
Subject disposition will be summarized. The number of subjects who complete the study and 
who do not complete the study along with the reasons for discontinuation from the study will 
be summarized.  
21.6 Efficacy Analysis 
Subjects will be included in the efficacy analyses based on their treatment assignment. The 
primary endpoint is the proportion of SRI responders at Week 16. The proportions of SRI 
responders for the 2 treatment groups will be summarized descriptively by visit and treatment 
group in tabular format and compared using a 2-sided Pearson’s chi-square test at a 
significance level of 0.05. If the responder or nonresponder count falls to equal or below 5 in 
either treatment group, 2-sided Fisher’s exact test will be used instead. All quantitative 
secondary and exploratory endpoints will be analyzed using analysis of covariance models 
with treatment group as a factor and the baseline value of the corresponding endpoint as a 
covariate. Mixed model with repeated measurement will be performed as deemed necessary.  
Secondary and exploratory endpoints that are proportions will be analyzed using Pearson’s 
chi-square test or Fisher’s exact tests.  
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 non-
responder. A similar approach will be applied to secondary efficacy endpoints that are 
proportions; missing will be classified as not satisfying the conditions described for that 
endpoint. A full description of missing data imputation method for all endpoints will be 
described in the statistical analysis plan. 
 
 
 
 
 
 


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21.8 Safety Analysis  
All subjects who receive at least 1 dose of study drug will be included in the safety analyses.  
21.8.1 Adverse Events 
Adverse events will be coded using MedDRA (version 19.0 or higher) by preferred term 
within system organ class. The number of AEs and the number of subjects reporting AEs will 
be listed and summarized descriptively by body system, preferred term, severity, and causality 
for each treatment group. Only TEAEs (events that are new in onset or aggravated in severity 
following treatment) will be included in all summaries. SAEs (including death) will be 
summarized.  
21.8.2 Clinical Laboratory Tests; 
 and C3, C4, and 
anti-ds DNA Antibodies 
Clinical laboratory tests (hematology, lipid panel, blood chemistry, and urinalysis); 
 
 and C3, C4, and anti-ds DNA antibodies results will be listed by subject and 
summarized by visit and treatment group. Categorical laboratory results will be presented with 
the frequency and percentage in each category by treatment group. Change from baseline at 
each visit will also be summarized. Shift tables will be generated if applicable. Select 
laboratory parameters may be presented graphically. Abnormal laboratory values will be 
identified and analyzed.  
21.8.3 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.  
21.8.4 Hospital Admissions 
Hospital admissions and the reason for each admission will be listed and summarized 
descriptively by visit and treatment. The cumulative number of hospital admissions will be 
compared between treatment groups at Week 24 with a 2-sided Pearson’s chi-square test or 
Fisher’s exact test at a significance level of 0.05. 


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21.8.5 Other Safety Analysis 
Other safety assessments including physical examinations, weight, pregnancy testing, and 
HbA1c will be listed and summarized descriptively or graphically, as appropriate.  
 
 
 
 
  
21.10 Interim Analysis 
Blinded aggregate data analyses will be completed when 25%, 50% and 75% of subjects 
complete Week 16. No other interim analyses are planned for this study. 
21.11 Statistical Power and Sample Size Considerations 
It is expected that approximately 270 subjects will be screened to randomize a total of 162 
subjects into 1 of the 2 treatment groups: 1 mL (80 U) of Acthar every other day for 4 weeks 
followed by 1 mL (80 U) of Acthar for 20 weeks or 1 mL of placebo every other day for 4 
weeks followed by 1 mL of placebo 2 times per week for 20 weeks in a 1:1 ratio (81 per 
group). The primary efficacy analysis will compare the SRI response rate in the Acthar 1 mL 
(80 U) group to the SRI response rate in the placebo group. Assuming 2 subjects might not 
qualify for the mITT analysis population after randomization, with 80 mITT subjects in each 
treatment group (160 total) and a response rate of 30% in the placebo group and 55% in the 
Acthar group, the study will have a 90% power to detect a treatment difference at the 0.05 
level of significance.  
21.12 Deviations From Statistical Analysis Plan 
Any deviations from the planned statistical analysis will be described and justified in the final 
clinical study report as appropriate. 
22 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
22.1 Safety 
For safety information about Acthar refer to the most recent version of the Prescribing 
Information (Mallinckrodt, 2015) and the Investigators Brochure (Mallinckrodt, 2016).  


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22.2 Definitions 
Adverse Event  
An AE is any untoward or undesirable medical occurrence in a subject who is administered 
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 the Investigator’s Brochure. 
SLE Activity Changes 
All changes in SLE activity that are unequivocally due to progression of disease should not be 
reported as an AE unless they result in a SAE as defined below.  
Serious Adverse Event  
An SAE is defined as any untoward medical occurrence that at any dose results in any of the 
following outcomes: 
 Death. 
 A life-threatening AE. 
 Inpatient hospitalization or prolongation of existing hospitalization. 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
 Results in a congenital anomaly/birth defect. 


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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. 
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. 


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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). 
22.3 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 22-1). 
Table 22-1:  
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 22-2. 
Table 22-2:  
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 
 


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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. 
22.4 Adverse Event and Serious Adverse Event Recording and Reporting 
AEs and SAEs will be recorded from signing of the ICF through completion of the Follow-up 
Visit. The investigator is required to record the AE or SAE regardless of the severity of the 
event or its relationship to study treatment. The investigator must follow up on all AEs and 
SAEs reported to have occurred through the Follow-up Visit until the event has resolved or 
stabilized or at such time the investigator refers the subject to a nonstudy physician. The 
investigator will document the further follow-up information in the subject’s source 
document.  
During the period specified above, the investigator will: 
 Record all AEs and SAEs from the signing of the ICF through the completion of the 
Follow-up Visit. 
 Report all SAEs on an SAE Report Form to Global Pharmacovigilance. 
 Report all pregnancies to Global Pharmacovigilance on the Pregnancy Surveillance 
Form. 
 Submit any Expedited Safety Report or Suspected Unexpected Serious Adverse 
Reaction from Global Pharmacovigilance to the IRB/IEC. 
The reporting requirements for AEs are summarized in Table 22-3. 


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Table 22-3: 
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 Global Pharmacovigilance.  
 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 at 
+1 314-654-5759 or email at PVClinical@mallinckrodt.com within 24 hours of first 
knowledge of the event even if the experience does not appear to be related to the IMP. 
 The investigator, or designee, will receive acknowledgement of receipt of the SAE 
Report Form from Mallinckrodt. 
 Should the investigator or designee have any difficulty in sending the SAE Report, 
they may contact Mallinckrodt contacts listed in Section 2.2. 


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 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 are 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 or e-mail it to Mallinckrodt at +1 314-654-5759 or 
PVClinical@mallinckrodt.com within 24 hours of receipt. The investigator(s) or designee will 
receive acknowledgement of receipt for each SAE Report Form from Mallinckrodt. 
 The investigator or designee is required to provide all related information/supporting 
documentation of an SAE until the SAE is resolved or stabilized or the subject has 
been referred to a nonstudy physician for follow-up treatment.  
The investigator(s) or designee is required to submit the Safety Alert to the responsible 
IRB/IEC.  
The sponsor will ensure that any Expedited Safety Report or Suspected Unexpected Serious 
Adverse Reaction are submitted to the FDA and other regulatory agencies as appropriate. 
22.5 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 that are considered SAEs or lead to 
treatment discontinuation. 
 
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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22.6 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. The investigator must report the 
pregnancy by submitting the appropriate form to Global Pharmacovigilance (fax at 
+1 314-654-5759 or email at PVClinical@mallinckrodt.com) 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 Global Pharmacovigilance (fax at +1 314-654-
5759 or email at PVClinical@mallinckrodt.com ) 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 Global 
Pharmacovigilance (fax at +1 314-654-5759 or email at PVClinical@mallinckrodt.com) 
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 Global 
Pharmacovigilance (fax at +1 314-654-5759 or email at PVClinical@mallinckrodt.com), 
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 Global Pharmacovigilance (fax at +1 314-654-5759 or email at 
PVClinical@mallinckrodt.com ) 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 
Pharmacovigilance (fax at +1 314-654-5759 or email atPVClinical@mallinckrodt.com ) 
within 24 hours of the study site becoming aware of the follow-up information. 
23 SUBJECT DISCONTINUATION OR WITHDRAWAL 
23.1 Subject Withdrawal 
Subjects who discontinue, or are withdrawn from the study for any reason, will be considered 
early termination. All subjects who terminate early will be required to have the Early 
Termination safety assessments (see Section 14.7) to assess their continued well-being.  


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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. 
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 study drug. In addition, subjects who experience any of the adverse events described in 
Section 15.3.1 will be discontinued. 
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 the 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 13.2) or fails 
to meet an inclusion criteria (Section 13.1) during the study that is not considered to be an AE 
or is noncompliant (eg, has a positive pregnancy), the subject will be discontinued from study 
drug. Discontinuation from study drug is also mandated for safety and/or tolerability issues as 
outlined in Section 15.3.1). 
Worsening of Disease Activity 
Subjects may be withdrawn if, in the opinion of the investigator, there is a lack of efficacy 
during the study.  


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Other 
If the above reasons are not applicable, please use the “Other” option and provide the 
appropriate reason for subject withdrawal. 
24 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.  
25 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.  
26 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 IB, 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. 
26.1 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. 


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 The decision on the part of the sponsor to suspend or discontinue testing or evaluation 
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. 
27 DIRECT ACCESS, DATA HANDLING, AND RECORD-KEEPING 
27.1 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 randomized. 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. 
27.2 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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28 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. 
29 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.  
 
 
 
 
 
 
 
  
31 PUBLICATION POLICY 
31.1 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 


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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. 
31.2 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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32 REFERENCES 
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (5th 
Edition). 2013. Washington, DC. 
Becker, P.; Furie, R.; Mitrane, M.; Zhao, E. Repository Corticotropin Injections (RCI) 
Attenuates Disease Activity in Patients with Persistently Active Systemic Lupus 
Erythematosus (SLE) Requiring Corticosteroids: Results From a 44 Week Open-Label 
Extension Study.  To be presented at the 2016 Annual Congress of Rheumatology; June 2016; 
London, England. 
Bombardier, C.; Gladman, D.D.; Urowitz, M.B.; Caron, C.; Chang, C.H. Description of the 
SLEDAI: A Disease Activity Index for Lupus Patients. The Committee on Prognosis Studies 
in SLE. Arthritis Rheum. 1992, 35, 630-640. 
Botte, D.A.C.; Noronha, I.L.; Malheiros, D.M.A.C.; Peixoto, T.V.; de Mello, S.B.V. Alpha-
melanocyte Stimulating Hormone Ameliorates Disease Activity in Induced Murine Lupus-like 
Model. Clin. Exp. Immun. 2014, 177, 381-390. 
Buyon, J.P.; Petri, M.A.; Kim, M.Y.; Kaluniam, K.C.; Grossman, J.; Hahn, B.H.; et al. The 
Effect of Combined Estrogen and Progesterone Hormone Replacement Therapy on Disease 
Activity in SLE: A Randomized Trial. Ann. Internal Med. 2005, 142, 953-962. 
Catania, A.; Gatti, S.; Colombo, G.; Lipton, J.M. Targeting Melanocortin Receptors as a 
Novel Strategy to Control Inflammation. Pharmacol. Rev. 2004, 56, 1-29. 
Decker, D.; Grant, C.; Oh, L.; Becker, P.; Young, D.; Jordan, S. Immunomodulatory Effects of 
H. P. Acthar Gel on B Cell Development in the NZB/W F1 Mouse Model of Systemic Lupus 
Erythematosus. Lupus, 2014, 23, 802-12. 
Fiechtner, J.J.; Montroy, T. Treatment of Moderately to Severely Active Systemic Lupus 
Erythematosus With Adrenocorticotropic Hormone: A Single-site, Open-label Trial. Lupus. 
2014, 23, 905-12. 
Furie, R.A.; Das, M.; Li, D.; Smythe, S.; Mathura, E.; Becker, P. Repository Corticotropin 
Injections (H.P. Acthar® Gel) Attenuates Disease Activity in Patients With Persistently Active 
Systemic Lupus Erythematosus (SLE) Requiring Corticosteroids,  Arthritis Rheumatol. 2015, 
67, S10. 


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Furie, R.A.; Petri, M.A.; Wallace, D.J.; Ginzler E.M.; Merrill, J.T.; Stohl, W.; et al. Novel 
Evidence-Based Systemic Lupus Erythematosus Responder Index. Arthritis Rheum. 2009, 61, 
1143-1151. 
Getting, S.J. Targeting Melanocortin Receptors as Potential Novel Therapeutics. Pharmacol. 
Ther. 2006, 111, 1-15. 
Gladman, D.D.; Ibanez, D.; Urowitz, M.B. Systemic Lupus Erythematosus Disease Activity 
Index 2000.J. Rheumatol. 2002, 29, 288-291. 
Gordon, C.; Isenberg, D.; Lerstrom, K.; Norton, Y.; Enkeleida, N.; Pushparajah, D.S. The 
Substantial Burden of Systemic Lupus Erythematosus on the Productivity and Careers of 
Patients: a European Patient-driven Online Survey. Rheumatol. 2013, 52, 2292-2301.  
Harris-Jones, J.N. The role of ACTH and Cortisone in the Treatment of Systemic Lupus 
Erythematosus. Postgrad. Med. J. 1956, 32, 145-149. 
Helmick, C.G.; Felson, D.T.; Lawrence, R.C.; Gabriel, S.; Hirsh, R.; Kwoh, C. K.; et al. 
Estimates of the Prevalence of Arthritis and Other Rheumatic Conditions in the United States. 
Part I. Arthritis Rheum. 2008; 58, 15-25. 
Hochberg, M.C. Updating the American College of Rheumatology Revised Criteria for the 
Classification of Systemic Lupus Erythematosus. Arthritis Rheum. 1997, 40, 1725. 
Holloway, L.; Humphrey, L.; Heron, L.; Pilling, C.; Kitchen, H.; Hojbjerre, L.; et al. Patient-
reported Outcome Measures for Systemic Lupus Erythematosus Clinical Trials: A Review of 
Content Validity, Face Validity, and Psychometric Performance. Health Qual. Life Outcomes. 
2014, 12, 116. 
Isenberg, D. A.; Rahman, A.; Allen E.; Farwell, V.; Akl, M.; Bruce, I.M. BILAG 2004. 
Development and Initial Validation of the British Isles Lupus Assessment Group’s Disease 
Activity Index for Patients with Systemic Lupus Erythematosus. Rheumatol. 2005, 44, 902-
906. 
Jolly, M.; Pickard, A.S.; Wilke, C.; Mikolaitis, R.A.; Teh, L-S.; McElhine, K.; et al. Lupus-
specific Health Outcomes Measure for US Patients: The Lupus QOL.-US Version. Ann. 
Rheum. Dis. 2010, 69, 29-33. 
Kasitanon, N.; Magder, L.S.; Petri, M. Predictors of Survival in Systemic Lupus 
Erythematosus. Medicine (Baltimore). 2006, 85, 147-156. 


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Klein, R.S.; Morganroth, P.A.; Werth, V.P. Cutaneous Lupus and the CLASI instrument. 
Rheum. Dis. North Am. 2010, 36, 33-51. 
Mallinckrodt Inc. Acthar Data Compendium. RD-010-00 internal data on file. 
Mallinckrodt Inc. H.P. Acthar® Gel; Package Insert: Hazelwood, MO, 2015. 
Mallinckrodt Inc. H.P. Acthar® Gel; Investigator’s Brochure: Hazelwood, MO, 2016. 
McElhone, K.; Abbott, J. Shelmerdine, J.; Bruce, J.; Ahmad, Y.; Gordon, C.; et al. 
Development and Validation of Disease-specific Health-related Quality of Life Measure, the 
Lupus QOL, for Adults With Systemic Lupus Erythematosus. Arthritis Care Res. 2007, 57, 
972-979. 
Mountjoy, K.G.; Robbins, L.S.; Mortrud, M.T.; Cone, R.D. The Cloning of a Family of Genes 
That Encode the Melanocortin Receptors. Science. 1992, 257, 1248-1251. 
Navarra, S.V.; Guzmán, R.M.; Gallacher, A.E.; Hall, S.; Levy, R.A.; Jimenez, R.E.; et al. 
Efficacy and Safety of Belimumab in Patients With Active Systemic Lupus Erythematosus: A 
Randomized, Placebo-controlled, Phase 3 Trial. Lancet. 2011, 377, 721-731. 
Olsen, N.J.; Decker, D.A.; Becker, P.A.; McAloose, C.A.; Benko, A.L.; Kovacs, W.J. Direct 
Effects of HP Acthar Gel on Human B Lymphocyte Activation In Vitro. Arthritis Res. Ther. 
2015, 17, 300. 
Petri, M.; Buyon, J.; Kim, M.; Classification and Definition of Major Flares in Systemic 
Lupus Erythematosus Clinical Trials. Lupus. 1999, 8, 685-691. 
Petri, M. Clinical Research in Systemic Lupus Erythematosus: Immediate Relevance to 
Clinical Practice. Int. J. Rheum. Dis. 2011, 14, 1-5. 
Schiöth, H.B.; Muceniece, R.; Wikberg, J.E.; Chhajlani, V. Characterization of melanocortin 
receptor subtypes by radioligand binding analysis. Eur. J. Pharmacol. 1995, 15, 311-317. 
Tan, E.M.; Cohen, A.S.; Fries, J.F., Masi, A.T.; McShane, D.J.; Rothfield, N.F.; at al. The 
1982 Revised Criteria for the Classification of Systemic Lupus Erythematosus. Arthritis 
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Trager, J.; Ward, M.M. Mortality and Causes of Death in Systemic Lupus Erythematosus. 
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Urowitz, M.B.; Bookman, A.A.; Koehler, B.E.; Gordon, D.A.; Smythe, H.A.; Ogryzlo, M.A.; 
The Bimodal Mortality Pattern of Systemic Lupus Erythematosus. Am. J. Med. 1976, 60, 221-
225. 
Von Feldt, J.M. Systemic Lupus Erythematosus. Recognizing its Various Presentations. 
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Productivity and Activity Impairment Questionnaire – A General Health Version in Patients 
With Rheumatoid Arthritis. Arthritis Res. Ther. 2010, 12, R177. 
 
 


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33 Attachments 
33.1 Attachment 1: Clinical Laboratory Tests  
Serum Chemistry 
Alanine aminotransferase (ALT) 
Creatine phosphokinase 
Albumin (total) 
Creatinine 
Alkaline phosphatase  
Glucose 
Aspartate aminotransferase (AST) 
Phosphorus 
Bilirubin (total) 
Potassium 
Bicarbonate 
Protein, total 
Blood urea nitrogen 
Sodium 
Calcium 
Uric acid 
Chloride 
 
Lipid Profile 
 
High density lipoprotein 
Triglycerides 
Low density lipoprotein 
Total cholesterol 
Hematology Assays 
Direct Coombs Test (local laboratory) 
Mean corpuscular volume 
Hematocrit 
Platelet count 
Hemoglobin 
Red blood cell count 
Haptoglobin 
Reticulocyte count 
Mean corpuscular hemoglobin 
White blood cell count, including differential  
Mean corpuscular hemoglobin concentration 
 
Urinalysis 
Color 
Ketones 
Clarity 
Protein 
Albumin 
pH 
Bilirubin 
Specific gravity 
Blood 
Protein:creatinine ratio 
Creatinine 
Microscopy (WBC/ high power field (HPF), RBC/HPF 
and urinary casts) 
Glucose 
Diabetes Screen 
HbA1c 
 
Hormones 
Serum and urine beta-human chorionic gonadotropin (pregnancy test; conducted on site)  
Other 
C3, C4, and ant-ds DNA antibodies 
 


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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)