Clinical trial NCT02298491
Conditions: CNS Sarcoidosis
Sponsor: University of Maryland, Baltimore
Start date: 2016-05-01; Completion date: 2020-11-01
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to see if treatment with H.P. Acthar® Gel will result in the improvement and long-term stabilization of clinical and radiographic abnormalities that occur in patients with CNS sarcoidosis. In addition, it will also look at whether treatment will be also associated with improvement in measures of quality of life. The treatment of CNS sarcoidosis involves the use of either corticosteroids such as prednisone or potent immunosuppressive agents such as methotrexate, both which can induce severe long term side effects. The adverse effects of steroids may be avoided by treatment with adrenocorticotropic hormone (ACTH), which is available for patient use as H.P. Acthar® Gel. The efficacies of H.P. Acthar® Gel in the treatment of CNS sarcoidosis and the impact on quality of life have not been previously studied. In addition, little is known regarding the expression of immune markers in CNS sarcoidosis and the association of such markers with disease activity and response to treatment.

Detailed description:
Sarcoidosis is a chronic and frequently progressive systemic disease that affects the central nervous system (CNS) in approximately 5% of patients. The hallmark of the disease is the development of chronic inflammation with formation of non-caseating granulomas that can involve the brain parenchyma and meninges and appear as contrast-enhancing mass lesions on magnetic resonance imaging. The granulomas are primarily comprised of proinflammatory T cells (Th1 cells and Th17 cells) and macrophages which accumulate during the early stages of granuloma formation. The inflammation that is generated by these cells is modulated by anti-inflammatory responses mediated by Th2 cells and regulatory T (Treg) cells that later appear and populate the outer regions of the granuloma. The presence of Treg cells are of particular interest since these cell are also detected in high numbers in peripheral blood and the immune suppression that results may underlie the occurrence of anergy in patients with the disease. The treatment of CNS sarcoidosis involves the use of either corticosteroids or potent immunosuppressive agents, both which can induce severe long-term side effects. The adverse effects of steroids may be avoided by treatment with adrenocorticotropic hormone (ACTH), which is available for patient use as H.P. Acthar® Gel. The efficacy of H.P. Acthar® Gel in the treatment of CNS sarcoidosis and the impact on quality of life have not been previously examined. In addition, little is known regarding the expression of immune markers in CNS sarcoidosis and the association of such markers with disease activity and response to treatment. These issues, therefore, will be explored in the context of this proposal.

Arms: arm 1: None
Interventions: intervention 1: H.P. Acthar Gel
Intervention descriptions: intervention 1: 80 IU subcutaneously daily for 10 days then followed by 80 IU subcutaneously three times per week through Month 12

Protocol documents:
Prot_000.pdf: 
 
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Investigator initiated study (IIS)  
Principal Investigator: Walter Royal, III, MD 
 
Institution and department: University of Maryland School of Medicine 
Department of Neurology 
 
 
 
 
 
 
 
 
Date:  July 30, 2014 Amend 1 
 
 
1. Title of the proposed study: Clinical Biomarkers of Disease Activity and 
Treatment Response in Patients with CNS Sarcoidosis Treated with H.P. 
Acthar® Gel 
 
2. Hypothesis/Hypotheses: 
 
a. Treatment with H.P. Acthar® Gel will result in the improvement and long-term 
stabilization of clinical and radiographic abnormalities that occur in patients with 
CNS sarcoidosis.  
b. Treatment will be also associated with improvement in measures of quality of life. 
c. Specific immunological abnormalities will be observed in patients pre-treatment 
that will serve a biomarkers of disease activity. These abnormalities will also 
improve with treatment.  
   
3. Rationale for the study:  Sarcoidosis is a chronic and frequently progressive 
systemic disease that affects the central nervous system (CNS) in approximately 5% 
of patients (Stern et al., 1985). The hallmark of the disease is the development of 
chronic inflammation with formation of non-caseating granulomas that can involve 
the brain parenchyma and meninges and appear as contrast-enhancing mass 
lesions on magnetic resonance imaging (Miller et al., 1988). The granulomas are 
primarily comprised of proinflammatory T cells (Th1 cells and Th17 cells) and 
macrophages which accumulate during the early stages of granuloma formation 
(Agostini et al., 2002; Co et al., 2004).  The inflammation that is generated by these 
cells is modulated by anti-inflammatory responses mediated by Th2 cells and 
regulatory T (Treg) cells (Agostini et al., 2002; Miyara et al., 2006) that later appear 
and populate the outer regions of the granuloma. The presence of Treg cells are of 
particular interest since these cell are also detected in high numbers in peripheral 
blood and the immune suppression that results may underlie the occurrence of 
anergy in patients with the disease (Miyara et al., 2006). The treatment of CNS 


 
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sarcoidosis involves the use of either corticosteroids or potent immunosuppressive 
agents, both which can induce severe long-term side effects (Moller, 2003; Stern et 
al., 2010). The adverse effects of steroids may be avoided by treatment with 
adrenocorticotropic hormone (ACTH) (Arnason et al., 2013), which is available for 
patient use as H.P. Acthar® Gel. The efficacy of H.P. Acthar® Gel in the treatment of 
CNS sarcoidosis and the impact on quality of life have not been previously 
examined. In addition, little is known regarding the expression of immune markers in 
CNS sarcoidosis and the association of such markers with disease activity and 
response to treatment. These issues, therefore, will be explored in the context of this 
proposal. 
 
 
4. Patient population and estimated sample size: 
a. Patients with a diagnosis of CNS sarcoidosis (n=10) will be recruited for these 
studies. 
 
 
 
5. Study design: 
All patients will be recruited from the inpatient and outpatient services of the 
University of Maryland School of Medicine Department of Neurology. 
Criteria for enrollment 
a. A highly probable diagnosis of sarcoidosis, as determined using the WASOG 
Sarcoidosis Organ Assessment Instrument (Judson et al., 2014), with 
involvement limited to the central nervous system.  
b. At the time of enrollment, a history of clinical deterioration based on the 
development of new symptoms or worsening previously present symptoms with 
confirmation by clinical examination and objective clinical testing. 
c. If on steroids, on a stable dose of the medication for at least 1 month3 months. 
Assessments 
a. Administration of questionnaires 
1. Patient Determined Disease Steps (PDDS):  a disability measurement 
2. Montreal Cognitive Assessment (MoCA) and  Symbol-Digit Modalities test 
(SDMT):  cognitive assessments 
3. Fatigue Assessment Scale (FAS) 
4. Short Form-36 Health Survey (SF-36):  measures quality of life 
5. Work Productivity and Activities Impairment—General Health (WPAI-GH):  
measures health-related work productivity loss 
6. Beck Depression Inventory-II (BDI-II):  a depression scale 


 
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b. Brain MRI with and without gadolinium 
c. Phlebotomy 
d. Lumbar puncture 
 
Treatment 
a. Acthar 80 units subcutaneously per day for 10 days, followed by Acthar 80 units 
subcutaneously 3 times per week through month 12 
b. Continuation of the patient’s previously prescribed CNS sarcoidosis maintenance 
regimen, as appropriate. 
c. Acthar dose may be adjusted based on the patient’s tolerability at the discretion 
of the investigator. 
 
Assessments baseline/screening, 4 weeks, 6 months and 12 months post-
treatment 
a. Administration of questionnaires 
i. 
Patient Determined Disease Steps (PDDS)  
ii. 
Montreal Cognitive Assessment (MoCA) and  Symbol-Digit Modalities test 
(SDMT) 
iii. 
Fatigue Assessment Scale (FAS) 
iv. 
Short Form-36 Health Survey (SF-36) 
v. 
Work Productivity and Activities Impairment—General Health (WPAI-GH) 
vi. 
Beck Depression Inventory-II (BDI-II) 
vii. 
Treatment Satisfaction Questionnaire for Medication (TSQM) 
b. Brain MRI 
c. Phlebotomy 
Assessments at baseline/screening, 3 months and 12 months post-treatment 
a. Lumbar puncture- 3 to 4 teaspoons(15 to 20 ml) of CSF fluid per lumbar puncture  
b. Immunological assessments 
Laboratory Assessments 
a. The following immunological assessments will be performed 
i. 
Flow cytometry of mononuclear cells in blood and cerebrospinal fluid 
(CSF) 
ii. 
Activation of peripheral blood mononuclear cells in culture to assess for T 
cell and monocyte activation responses and for secreted cytokines and 
chemokines 
iii. 
Bio-Plex analysis of levels of secreted cytokines and chemokines in blood, 
CSF and in cell culture supernatants 
 
Safety Assessments 


 
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a. Labs: specific monitoring of serum calcium, potassium, creatinine, cortisol 
responses and levels, glucose and HbA1c, 1, 25-dihydroxyvitamin D levels 
b. Symptoms and signs: specific monitoring for gastrointestinal symptoms 
(abdominal pain, bloody or black stools, nausea, vomiting or hematemesis), 
fatigue, edema, hypertension, mood changes, infectious complications 
 
 


 
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b. Table 1 lists the testing that will be performed on blood (plasma) and CSF 
samples  
Blood 
CSF 
CBC with differential 
Red blood cell count 
Comprehensive chemistry panel 
White blood cell count 
Angiotensin converting-enzyme level Protein 
C-Reactive Protein 
Glucose 
Cortisol (checked 4-24 hours after 
the Acthar dose) 
Angiotensin converting-enzyme level 
Hemoglobin A1C 
IgG index 
1, 25-dihydroxyvitamin D 
Oligoclonal bands 
25-hydroxyvitamin D 
Myelin basic protein 
 
Protein electrophoresis 
 
 
 


 
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c. Immune phenotyping of peripheral blood and CSF mononuclear cells, including 
analysis of Treg cells, and analysis of specific proinflammatory and anti-
inflammatory subsets by staining for intracytoplasmic cytokine will be performed 
using flow cytometry as previously described (Royal, III et al., 2009; Royal, III et 
al., 2007). The cell markers and cytokines for which the cells will be labeled are 
described in table 2. 
Table 2: Markers for Analyzing Mononuclear Cells by Flow Cytometry 
Cell type 
Function 
Markers 
T Cells  
 
 
1. CD4+ 
 
 
a. Th1 
Proinflammatory 
CD3+CD4+Interferon (IFN)-γ 
b. Th17 
Proinflammatory 
CD3+CD4+Interleukin (IL)-17+ 
c. Th2 
Anti-inflammatory 
CD3+CD4+IL-4+ 
d. Treg 
Anti-inflammatory 
CD3+CD25+CD127Low 
2. CD8+ (cytotoxic) 
Proinflammatory 
CD3+CD8+ 
Monocytes (Shi and 
Pamer, 2011)  
 
 
1. Classical 
Proinflammatory 
(antibacterial) 
CD14++CD16- 
2. Intermediate  
Proinflammatory (more 
differentiated phenotype) 
CD14+CD16+ 
3. Non-classical 
Proinflammatory (antiviral) 
CD14+CD16++ 
 
d. In vitro activation assays will be performed to assess peripheral blood 
mononuclear cell proliferative responses and secretion of cytokines, chemokines 
and other soluble immune factors using approaches that are well established in 
the lab of the PI (Royal, III et al., 2012), including analyses soluble plasma 
markers of monocyte activation (Royal W III et al, Clinical and Laboratory 
Assessments of Monocyte Function and Associations with Cognition and Gender 
among HIV Infected Individuals in Nigeria, Annual Meeting of the International 
Society of NeuroVirology, Washington, D.C. October 31, 2013). The cytokines 
and chemokines are listed in table 3 and will be detected in the University of 
Maryland Cytokine Core Laboratory by Bio-Plex Assay (Bio-Rad). 
Table 3: Soluble Plasma and CSF Markers 
Cell type 
Cytokine/Chemokine Marker(s) 
T Cells (Pan) 
IL-2, soluble IL-2 receptor, CXCL8, CCL22 
1. CD4+ 
 
a. Th1 
IFN-γ, IL-12, IL-18 
b. Th17 
IL-17 
c. Th2 
IL-4, IL-13, IL-10 
d. Treg 
IL-6, TGF-β 
2. CD8+ (cytotoxic) 
IFN-γ IL-12, IL-18 
Monocytes  
TNF-α, IL-1β, IL-10, CCL5, CCL2, CCL-3, CCL4, soluble 
CD14, soluble CD16, β2-microblobulin, neopterin, 
chitotriosidase 


 
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6. Primary end-points: 
 
a. Change in total number of lesions and in the number and size of 
enhancing lesions 1, 3, 6 months  and 12 months relative to baseline 
 
7. Secondary end-points: 
a. Change in PDDS, MoCA, SDMT, SF-36, WPAI-GH and BDI-II at 4 weeks, 
6 months  and 12 months relative to baseline 
b. TSQM scores at 4 weeks and change in TSQM scores at 6 months and 12 
months versus baseline 
8. Exploratory endpoints 
a. Change in levels of immune markers at 4 weeks, 6 months and 12 months 
versus baseline 
 
 
9. Estimated time line: 
a. Months 0-15: Enrollment and assessment 
b. Months 14-18:  Initial analysis of clinical laboratory data for presentation at 
scientific meetings and for publication  
c. Months 18-24:  Manuscript preparation and submission 
 
 
 
 
 


 
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Schedule of Events (table 4) 
Table 4.  Schedule of 
Events 
Screening/ 
Baseline 
Follow-up (post treatment initiation) 
1 mo. 
3 mos. 
6 mos. 
12 mos. 
Informed consent 
x 
 
 
 
 
Medical history 
x 
 
 
 
 
Physical exam 
x 
x 
x 
x 
x 
Neurological exam 
x 
x 
x 
x 
x 
Vital signs 
x 
x 
x 
x 
x 
Clinical laboratory testing 
x 
x 
x 
x 
x 
Pregnancy test 
x 
 
 
 
 
Inclusion/exclusion criteria 
x 
 
 
 
 
MRI 
x 
x 
x 
x 
x 
Phlebotomy 
x 
x 
x 
x 
x 
PDDS 
x 
x 
x 
x 
x 
MoCA/SDMT 
x 
x 
x 
x 
x 
SF-36 
x 
x 
x 
x 
x 
WPAI-GH 
x 
x 
x 
x 
x 
TSQM 
x 
x 
x 
x 
x 
KPSS 
x 
x 
x 
x 
      x 
Lumbar puncture 
x 
 
x 
 
x 
Immune assessments 
x 
 
x 
 
x 
 
 
 


 
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10. Budget (table 5)  
YR 1 
YR 2 
TOTAL 
Clinical laboratory tests ($250) 
 4,500  
 1,500  
6,000 
Pregnancy tests (up to 10 tests; $18 per test) 
 180  
 0  
180 
Other clinical laboratory supplies (250) 
 7,500  
 2,500  
10,000 
Lumbar punctures (includes labs) ($1,200) 
4,500 
15,000 
19,500 
MRI scans (5 per pt.; 10 pts; $1,200 per MRI) 
36,000 
24,000 
60,000 
 
 
 
 
Immune assays  
 
 
 
Flow cytometry 
20,000 
10,000.00 
30,000 
Bio-Plex assays 
22,000 
11,000 
33,000 
In vitro activation assays 
15,000 
7,500 
22,500 
ELISA kits (sCD14: $700, sCD163: $900, 
neopterin: β-microglobulin: $910; 
chitotriosidase: $600): $2,510 
3,110 
1,555 
4,665 
Other Supplies 
 
 
Center For Clinical Trials fee 
1,000 
1,000 
 
 
 
 
Patient reimbursement 
2,400 
600 
3,000 
 
 
 
 
Personnel (3% COLA for year 2) 
 
PI (W. Royal; 5% effort) 
15,000 
15,450 
30,450 
Co-Investigator (B. Stern; 1% effort) 
4,000 
4,120 
8,120 
Coordinator (15% effort) 
20,000 
20,600 
40,600 
Technical (15% effort) 
9,500 
9,785 
19,285 
Administrative (5%) 
3,500 
3,605 
7,105 
 
 
 
 
Total direct costs 
164,690 
123,610 
288,300 
Indirect costs (30%) 
47,703 
34,865 
82,568 
 
 
 
 
IRB fee 
2,000 
1,000 
3,000 
 
TOTAL  
212,393 
158,475 
370,868 
 
 
 
 
 
 
Please submit your curriculum vitae with the investigator initiated concept to your MSL 
and/or email to studyinfo@questcor.com.  
 
 


 
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11. References 
 
Agostini, C, Meneghin, A, Semenzato, G (2002). T-lymphocytes and cytokines in sarcoidosis. 
Curr. Opin. Pulm. Med., 8, 435-440. 
Arnason, BG, Berkovich, R, Catania, A, Lisak, RP, Zaidi, M (2013). Mechanisms of action of 
adrenocorticotropic hormone and other melanocortins relevant to the clinical 
management of patients with multiple sclerosis. Mult. Scler., 19, 130-136. 
Co, DO, Hogan, LH, Il-Kim, S, Sandor, M (2004). T cell contributions to the different phases of 
granuloma formation. Immunol. Lett., 92, 135-142. 
Judson, MA, Costabel, U, Drent, M, Wells, A, Maier, L, Koth, L, Shigemitsu, H, Culver, DA, 
Gelfand, J, Valeyre, D, Sweiss, N, Crouser, E, Morgenthau, AS, Lower, EE, Azuma, A, 
Ishihara, M, Morimoto, S, Tetsuo, YT, Shijubo, N, Grutters, JC, Rosenbach, M, Li, HP, 
Rottoli, P, Inoue, Y, Prasse, A, Baughman, RP, Organ Assessment Instrument 
Investigators TW (2014). The WASOG Sarcoidosis Organ Assessment Instrument: An 
update of a previous clinical tool. Sarcoidosis. Vasc. Diffuse. Lung Dis., 31, 19-27. 
Miller, DH, Kendall, BE, Barter, S, Johnson, G, MacManus, DG, Logsdail, SJ, Ormerod, IE, 
McDonald, WI (1988). Magnetic resonance imaging in central nervous system 
sarcoidosis. Neurology, 38, 378-383. 
Miyara, M, Amoura, Z, Parizot, C, Badoual, C, Dorgham, K, Trad, S, Kambouchner, M, Valeyre, 
D, Chapelon-Abric, C, Debre, P, Piette, JC, Gorochov, G (2006). The immune paradox 
of sarcoidosis and regulatory T cells. J. Exp. Med., 203, 359-370. 
Moller, DR (2003). Treatment of sarcoidosis -- from a basic science point of view. J. Intern. 
Med., 253, 31-40. 
Royal, W, III, Mia, Y, Li, H, Naunton, K (2009). Peripheral blood regulatory T cell measurements 
correlate with serum vitamin D levels in patients with multiple sclerosis. J. 
Neuroimmunol., 213, 135-141. 
Royal, W, III, Wang, H, Jones, O, Tran, H, Bryant, JL (2007). A vitamin A deficient diet 
enhances proinflammatory cytokine, Mu opioid receptor, and HIV-1 expression in the 
HIV-1 transgenic rat. J. Neuroimmunol., 185, 29-36. 
Royal, W, III, Zhang, L, Guo, M, Jones, O, Davis, H, Bryant, JL (2012). Immune activation, viral 
gene product expression and neurotoxicity in the HIV-1 transgenic rat. J Neuroimmunol., 
247, 16-24. 
Shi, C, Pamer, EG (2011). Monocyte recruitment during infection and inflammation. Nat. Rev. 
Immunol., 11, 762-774. 
Stern, BJ, Aksamit, A, Clifford, D, Scott, TF (2010). Neurologic presentations of sarcoidosis. 
Neurol. Clin., 28, 185-198. 
Stern, BJ, Krumholz, A, Johns, C, Scott, P, Nissim, J (1985). Sarcoidosis and its neurological 
manifestations. Arch. Neurol., 42, 909-917. 


 
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