Open Label Study to Evaluate Efficacy and Safety of Short-Term, Adjunctive Adrenocorticotropic Hormone (ACTH) Gel in Rheumatoid Arthritis
Phase: NA
Conditions: Rheumatoid Arthritis
Sponsor: Dana Ascherman

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Open Label Study to evaluate Efficacy and Safety of Short-Term, Adjunctive Adrenocorticotropic 
Hormone (ACTH) Gel Therapy in Rheumatoid Arthritis.  
Protocol Version: 0.01 / 04/Apr/2022 
Clinical Trials.gov: NCT02030028 
 
Principal Investigator:  
Dana Ascherman, MD 
 
 
 
 
University of Pittsburgh  
 
 
 
 
Division of Rheumatology and Clinical Immunology 
 
 
 
 
Seventh Floor, Biomedical Science Tower, South Wing 
 
 
 
 
200 Lothrop Street 
 
 
 
 
Pittsburgh, PA 15261 
 
 
 
 
412-383-8734 
 
Trial design: open label for 12 weeks 
Dose/Route/Regimen: ACTHAR gel 80u subcutaneously twice weekly 
Target population: 20 refractory adult Rheumatoid arthritis patients  
 
Glossary of terms in protocol: 
RA = rheumatoid arthritis  
CDAI = clinical disease activity index  
DAS = disease activity score 
ESR = Erythrocyte sedimentation rate 
CRP = C-reactive protein  

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A. Background and Rationale: 
Adrenocorticotropic hormone (ACTH) gel (repository corticotropin injection) (ACTHAR) is 
a long-acting full sequence ACTH that includes other pro-opiomelanocortin peptides (1-
6). ACTH is thought to have anti-inflammatory prospects as well as immunomodulatory 
effects mediated through melanocortin receptors (2). ACTH gel is FDA approved for 
several immune-mediated disorders including rheumatoid arthritis (RA), multiple 
sclerosis, systemic lupus erythematosus, polymyositis, nephrotic syndrome, and 
infantile spasm syndromes (1-6).  
 
RA is a chronic systemic autoimmune inflammatory arthropathy of unknown etiology 
(7).  The worldwide prevalence is approximately 1% of adults of all races. Disease onset 
occurs most often between the ages of 20 and 60 years, with peak occurrences at 50 to 
60 years. The prevalence of RA varies with sex and age, and is higher in women than in 
men. Affected subjects experience considerable morbidity, including symptoms such as 
joint stiffness, pain and swelling, rapid loss of function, joint destruction, permanent 
deformity as well as a reduced life expectancy.  
 
The treatment of RA has seen a dramatic paradigm shift over the past decade with the 
introduction of biologic response modifiers (5 that inhibit tumor necrosis factor, 1 
inhibitor of interleukin-1, 1 that blocks interleukin-6, 1 that inhibits B-cells, and 1 that 
blocks co-stimulatory pathways), plus most recently an oral agent that blocks Janus 

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Kinase pathways.  In addition, treatment with standard oral medications such as triple 
oral disease modifying drugs (DMARDs) also are effective options (7).   Despite these 
advances, a large percentage of our patients require daily therapy with oral prednisone 
and/or don’t respond to these current therapies. Thus, safe new therapies are still 
needed for this common immune-mediated inflammatory disease.  
 
B. Hypothesis and Specific Aims: 
 
Hypothesis: Patients with RA, who are receiving stable doses of background 
medications will have an improvement in disease activity (as measured by CDAI) when 
treated with 12 weeks of subcutaneous ACTHAR.  
Specific aim 1:  
To determine the efficacy and safety of ACTH gel in refractory RA  
 
 
 
patients.  
Specific aim 2:  
To determine the potential mechanisms of action of ACTH gel,  
 
 
 
pending review of efficacy data.  
 
C. STUDY Design: 
The proposed trial design would be open-label with a subcutaneous dose of ACTHAR 80 
units, twice a week, for 12 weeks. The entry criteria would be: 
1. 
RA diagnosis by ACR criteria 
2. 
Active disease (CDAI > 10) (8, 9, 10) 
3. 
Have received at least are biologic agent for at least 6 months 

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4. 
May or may not be receiving oral daily steroids (less than or equal 
 
to 20 mg/day) of prednisone equivalent  
5. 
No current active infections requiring antibiotics 
6. 
Patients must be on stable doses of RA therapies (e.g., 
 
methotrexate or other RA therapies for at least 4 weeks prior to 
 
baseline visit) 
Table 1.  Proposed Study Visits and Study Activities   
 
Screening 
Baseline 
2wk 
4wk 
8wk 
12wk 
16wk 
Informed Consent 
X 
 
 
 
 
 
 
Dispense 
medication 
 
X 
 
X 
X 
X 
 
Clinical Labs* 
X 
 
X 
X 
X 
X 
X 
AE Monitoring 
 
 
X 
X 
X 
X 
X 
Efficacy 
assessments  
 
X 
X 
X 
X 
X 
X 
Research Labs 
(PBMC’s, serum, 
plasma, RNA) 
 
X 
X 
X 
X 
X 
X 
*CBC, glucose, creatinine, ESR, CRP, ALT 
 
Patient population and estimated sample size: Patients will be recruited from UPMC 
Rheumatology Outpatient Clinics. A pilot study of 20 patients will provide initial 
information on efficacy of this agent in refractory RA patients. For the year ending in 
Spring 2012, we had over 4,000 unique, active RA patients in our outpatient clinics.  We 
have 35 Rheumatologists who practice at UPMC in Western, PA.  
 

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Primary end-points: 
 
1. Changes in CDAI at week-12 (9); we propose a 20% improvement after 12 
 
week of therapy compared to baseline as a positive response.  
 
Secondary end points: 
 
1. Changes in DAS28-CRP (9, 10) 
 
2. Changes in acute phase reactants (ESR, CRP) 
 
3. Changes in fatigue, as measured by FACIT (11).   
 
D. Data Analysis: 
We will determine the frequency of subjects who have at least a 20% improvement in 
CDAI from baseline to week 12 visit.  We will document the frequency and events of 
adverse event.   For secondary endpoints we will also determine frequency of subjects 
what have at least 20% improvement in DAS28-CRP, fatigue, ESR and CRP from baseline 
to week 12.  
E. Data captured and Database: 
The Division of Rheumatology and Clinical Immunology has experience spanning four 
decades in the development, maintenance and refinement of disease-specific databases 
of longitudinal cohorts of patients with rheumatic diseases.  In the past few years we 
have developed a web-based database that we plan to use for this investigator-initiated 
trial.  The key characteristics of the Rheumatic Disease Musculoskeletal System (RDMS) 
are: 1) the ability for longitudinal data collection and database management of data 

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from multiple clinic visits;  2) the ability to use multiple methods of data entry (e.g., 
web-based, tablet-based, or manual from hard copy) that permit secure data collection 
at various UPMC clinics,  other institutions or Academic Medical Centers; 3) data 
capture and synthesis in real-time has the ability to provide immediate feed-back to 
clinic staff and patients with regards to the data collected and trends over time; 4) 
flexibility to meet the needs of diverse researchers and their research questions through 
a modular design allowing for customization of data collection specific to individual 
study questions; 5) adaptability for future research studies through the addition of new 
forms or disease-specific modules; 6) easy accessibility of data for analysis by research 
team members with limited programming and statistical training such as coordinators, 
fellows and faculty; 7) capability for automated downloading and database integration 
of discrete well-defined clinical data, such as medication data, laboratory data and 
imaging data, from other electronic UPMC systems (e.g., EPIC electronic medical record 
system, Medical Archival Record System (MARS)); 8) patient data is separated into 
different data modules (e.g., Health Insurance Portability and Accountability Act (HIPAA) 
identifiers, demographic information, generic connective tissue disease data and 
disease-specific data) with restricted user access and linkage between the HIPAA 
information and other data based on a unique 8-digit subject ID number; 9) a set of 
common definitions for terms and data collection forms used in the database and the 
establishment of a committee to oversee the common definitions and forms; and 10) a 
research biospecimen and sample tracking system module. 
 

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F. Exploratory future objectives:  
Once the clinical trial is completed we will consider what mechanistic studies to pursue. 
We plan to collect appropriate samples and store in -80% freezer in one of the 
Rheumatology Division’s freezers.  
 
G. Proposed time line: 
Estimated time line (including IRB approval, study initiation, enrollment, study 
completion and submission of publication): 
 
 
2 year trial  
 6-month start-up (develop forms; IRB submission) 
 18-month recruitment and follow-up 
 
H. References: 
1. Catania A, Gatti S, Colombo G, Lipton JM: Targeting melanocortin receptors as a novel 
strategy to control inflammation. Pharmacological Reviews 2004; 56:1-29  
2. Catania A, Lonati C, Sordis A, et al: The melanocortin system in control of inflammation. The 
Scientific World Journal 2010; 10:1840-1855. 
3. Questcor Pharmaceuticals, Inc. H.P. Acthar GelSummary of Product Characteristics (SPC), 
June, 2011.  
4. Gong, R. The renaissance of corticotropin therapy in proteinuric nephropathies. Nat Rev 
Nephrol 2011, 8(2):122-128. 

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5. Levine, T: Treating refractory dermatomyositis or polymyositis with adrenocorticotropic 
hormone gel: a retrospective case series. Drug Des Devel Ther 2012, 6: 133-139. 
6. Arnason BG, Berkovich, R, Catania, A, Lisak RP, Zaidi M: Mechanisms of action of 
adrenocorticotropic hormone and other melanocortins relevant to the clinical management of 
patients with multiple sclerosis. Multiple Sclerosis Journal 2012, 
http://msj.sagepub.com/content/early/2012/10/01/1352458544 
7. Moreland LW, O’Dell JR, Paulus HE, Curtis JR, Bathon JM, St Clair EW, Bridges SL, Jr., Zhang J, 
McVie T, Howard G, van der Heijde D, Cofield SS: A randomized comparative effectiveness 
study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid 
arthritis: the treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis Rheum 2012, 
64(9):2824-2835. http://www.ncbi.nlm.nih.gov/pubmed/22508468 
8. Salaffi F, Cimminio MA, Leardini G, Gasparini S, Grass W: Disease activity assessment of 
rheumatoid arthritis in daily practice: validity, internal consistency, reliability and congruency of 
the Disease Activity Score including 28 joints (DAS28) compared with the Clinical Disease 
Activity Index (CDAI). Clin Exp Rheumatol 2009, 27(4): 552-559. 
9. Gaujoux-Viala C, Mouterde G, Baillet A, Claudepierre P, Fautrel B, Le Loet X, Maillefert JF: 
Evaluating disease activity in rheumatoid arthritis: which composite index is best? A systematic 
literature analysis of studies comparing the psychometric properties of the DAS, DAS28, SDAI 
and CDAI. Joint Bone Spine 2012, 79(2):149-155. 
http:www.ncbi.nlm.nih.gov/pubmed/21680221 
10. Anderson J, Caplan L, Yazdany J, Robbins MI, Neogi T, Michaud K, Saag KG, O’Dell JR, Kazi S: 
Rheumatoid Arthritis Disease Activity Measures: American College of Rheumatology 

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Recommendations for Use in Clinical Practice. Arthritis Care Res (Hoboken) 2012, 64(5):640-
647. 
11. Webster K, Cella D, Yost K: The Functional Assessment of Chronic Illness Therapy (FACIT) 
Measurement System: properties, applications, and interpretation. Health Qual Life Outcomes 
2003, 1:79.