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Genomic Effects of Glucocorticoids in Patients With Systemic Lupus Erythematosus

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04233164
Recruitment Status : Recruiting
First Posted : January 18, 2020
Last Update Posted : April 20, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) )

Brief Summary:

Background:

The immune system is the body s defense against bacteria and other harmful invaders. In people with systemic lupus erythematosus (SLE), the immune system becomes overactive and attacks healthy cells by mistake. Many people use glucocorticoids (GCs) to treat their SLE. GCs can calm down an overactive immune system by changing how the body reads genes. But GCs have side effects that can increase over time. Researchers want to learn more about how GCs work. This may help to develop new and better drugs for treating SLE without the side effects GCs have.

Objective:

To better understand how GCs affect the immune system in people with SLE.

Eligibility:

People age 18-80 with SLE.

Design:

Participants will be screened with a physical exam. They will have a health and medical history. They will have blood and urine tests. They will have an electrocardiogram to measure heart activity. For this, sticky pads are put on their chest, arms, and legs.

Participants will have a methylprednisolone infusion for about 30 minutes. It will be given through a needle in a vein.

Blood will be collected immediately before, 2 hours after, and 4 hours after the start of the infusion. Blood pressure and heart activity will be monitored. Participants will repeat some of the screening tests.

Participants will be contacted twice in the week after the infusion visit. They will discuss any health problems they are having.


Condition or disease Intervention/treatment Phase
Systemic Lupus Erythematous (SLE) Drug: SOLU-MEDROL Early Phase 1

Detailed Description:

Systemic lupus erythematosus (SLE) is a systemic autoimmune syndrome that causes pervasive immune dysregulation in all cells of the innate and adaptive immune system. Most patients with SLE require glucocorticoid treatment at some point of the disease course, but the specific effects of glucocorticoids that lead to therapeutic benefit in this condition are not well understood. In addition, the glucocorticoid dosing regimens that are administered to patients with SLE in clinical practice are arbitrary and not based on detailed knowledge of the effects of glucocorticoids at different doses on cells of the immune system. This study aims to improve our understanding of the effects of glucocorticoids on the immune system of patients with SLE, and to test for possible differences in these effects at a range of clinically relevant doses.

A consistent outcome of glucocorticoid exposure is a significant reprogramming of a cell s transcriptional state. The exact changes, however, vary substantially across cell types. Studies of specific cell populations, therefore, are necessary to gain a realistic view of the transcriptional effects of glucocorticoids. Given that cell composition and molecular behavior are known to differ among pathological states, the study of patients with SLE is necessary to identify the effects of glucocorticoids that are most likely to be responsible for their clinically beneficial effects in this condition.

In this study, participants with SLE, ages 18-80 years, will be randomized to receive a single intravenous infusion of 1 of 2 doses of the glucocorticoid methylprednisolone (1 mg/kg or 250 mg). Blood will be collected at baseline (within 45 days before infusion), immediately before the infusion, and again at 2 and 4 hours after the start of the infusion. Blood samples will be processed for isolation of hematopoietic cell subsets, including neutrophils, B cells, CD4+ T cells, CD8+ T cells, monocytes, natural killer cells, and plasmacytoid dendritic cells. Laboratory studies will be performed on the purified cells, with the goal of understanding the human response to glucocorticoids in vivo at the level of RNA (eg, RNA sequencing [RNA-seq], small-RNA-seq, real-time polymerase chain reaction), DNA (eg, chromatin immunoprecipitation sequencing, methylation analysis, DNA sequencing, genotyping), and protein (eg, flow cytometry, mass spectrometry). At each time point, serum methylprednisolone levels will be measured and flow cytometry for standard cell-lineage markers will be performed.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Genomic Effects of Glucocorticoids in Patients With Systemic Lupus Erythematosus
Actual Study Start Date : March 4, 2020
Estimated Primary Completion Date : February 29, 2024
Estimated Study Completion Date : February 29, 2024


Arm Intervention/treatment
Experimental: 1 mg/kg
The study agent solution will be administered as an IV infusion over 30 minutes, for a total single dose of 1 mg/kg or 250 mg of methylprednisolone.
Drug: SOLU-MEDROL
Methylprednisolone sodium succinate for injection, United States Pharmacopeia grade (USP), sold as SOLU-MEDROL sterile powder by Pfizer, Inc, is an antiinflammatory glucocorticoid that occurs as a white, or nearly white, odorless hygroscopic, amorphous solid. It is very soluble in water and in alcohol, but is insoluble in chloroform and is very slightly soluble in acetone. The study agent solution will be administered as an IV infusion over 30 minutes, for a total single dose of 1 mg/kg or 250 mg of methylprednisolone.

Experimental: 250 mg
The study agent solution will be administered as an IV infusion over 30 minutes, for a total single dose of 1 mg/kg or 250 mg of methylprednisolone.
Drug: SOLU-MEDROL
Methylprednisolone sodium succinate for injection, United States Pharmacopeia grade (USP), sold as SOLU-MEDROL sterile powder by Pfizer, Inc, is an antiinflammatory glucocorticoid that occurs as a white, or nearly white, odorless hygroscopic, amorphous solid. It is very soluble in water and in alcohol, but is insoluble in chloroform and is very slightly soluble in acetone. The study agent solution will be administered as an IV infusion over 30 minutes, for a total single dose of 1 mg/kg or 250 mg of methylprednisolone.




Primary Outcome Measures :
  1. A list of human proteincoding genes and non-coding RNAs that are differentially expressed in response to glucocorticoids in patients with SLE, for each of the studied cell types and doses. [ Time Frame: Infusion visit ]
    A list of human proteincoding genes and non-coding RNAs that are differentially expressed in response to glucocorticoids in patients with SLE, for each of the studied cell types and doses.


Secondary Outcome Measures :
  1. A comparison of the transcriptional response to glucocorticoids between the 2 dose groups. [ Time Frame: Infusion visit ]
    A comparison of the transcriptional response to glucocorticoids between the 2 dose groups.

  2. A list of protein-coding or non-coding transcripts, their corresponding proteins, and the molecular pathways representing the best candidates for targeted therapeutic alternatives to glucocorticoids. [ Time Frame: Infusion visit ]
    A list of protein-coding or non-coding transcripts, their corresponding proteins, and the molecular pathways representing the best candidates for targeted therapeutic alternatives to glucocorticoids.

  3. Validation of the targets identified by functional studies. [ Time Frame: Infusion visit ]
    Validation of the targets identified by functional studies.

  4. For each cell type, a list of protein-coding or non-coding transcripts that are shared and a list of transcripts that are different, between patients with SLE and the previously studied healthy controls, at baseline or in response to glucocortic... [ Time Frame: Infusion visit ]
    For each cell type, a list of protein-coding or non-coding transcripts that are shared and a list of transcripts that are different, between patients with SLE and the previously studied healthy controls, at baseline or in response to glucocorticoids.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

    1. Aged 18-80 years.
    2. Has a diagnosis of SLE based on the 1997 Update of the 1982 American College of Rheumatology Revised Criteria for Classification of SLE.
    3. Currently enrolled in study 94-AR-0066.
    4. Able to provide informed consent.
    5. Willing to allow genetic testing.
    6. Has a primary care physician or other healthcare provider who will manage all health conditions related or unrelated to the study objectives.
    7. If receiving immunosuppressive therapies other than glucocorticoids for SLE, then on a stable dose (defined as no increases in dose for the 60 days prior to screening).
    8. If receiving glucocorticoid therapy, then potential participants must be on a daily dose less than or equal to 10 mg/day and agree to undergo a glucocorticoid taper

EXCLUSION CRITERIA:

  1. Body mass index (BMI) < 18 or > 40.
  2. History of a severe allergic reaction to glucocorticoids.
  3. History of a severe adverse cardiovascular or psychiatric event related to glucocorticoid administration.
  4. Use of a glucocorticoid at a prednisone-equivalent dose 10 mg/day in the 15 days prior to screening.
  5. A previously established diagnosis of an active solid or hematologic malignancy.
  6. A previously established diagnosis of untreated osteoporosis. For the purpose of this study, osteoporosis is defined as a dual-energy X-ray absorptiometry (DEXA) scan obtained within 2 years of screening demonstrating a hip or spine bone mineral density T score less than or equal to -2.5 in men or greater than or equal to 50 in postmenopausal women.
  7. A previously established diagnosis of untreated osteopenia with a high fracture risk. For the purpose of this study, osteopenia is defined as a DEXA scan obtained within 2 years of screening demonstrating a hip or spine bone mineral density T score < -1 and > -2.5 in men or greater than or equal to 50 in postmenopausal women. For the purpose of this study, a high fracture risk is defined as a fracture risk assessment tool (FRAX) 10-year risk of major osteoporotic fracture > 20%, or a FRAX 10-year risk of hip fracture > 3%.
  8. A previously established diagnosis of diabetes mellitus or a fasting blood glucose level greater than or equal to 125 mg/dL at the time of screening. For patients without a previously established diagnosis of diabetes mellitus and a fasting blood glucose level < 125 mg/dL at the time of screening, no additional screening tests (e.g., HbA1c or oral glucose tolerance test) will be performed. A history of glucocorticoid-induced hyperglycemia that is not present at the time of screening in the absence of treatment will not be considered an exclusion criterion.
  9. Cancer chemotherapy within the 5 years prior to screening.
  10. Surgery requiring general anesthesia in the 8 weeks prior to screening.
  11. History of an infection requiring IV antibiotics in the 30 days prior to screening.
  12. A positive test for HIV or hepatitis A, B, or C virus infection.
  13. A positive or indeterminate test for active or latent tuberculosis (interferon gamma release assay [IGRA]) without evidence of prior treatment.
  14. History of chronic or possible latent untreated parasitic, amebic, fungal, or mycobacterial infections.
  15. Use of desmopressin in the 30 days prior to screening.
  16. Use of one of the following cytochrome P450 isozyme (CYP) 3A4 inducers in the 30 days prior to screening: nafcillin, rifabutin, rifampin, St. John s wort, or troglitazone.
  17. Use of one of the following CYP3A4 inhibitors in the 30 days prior to screening: clarithromycin, itraconazole, or ketoconazole.
  18. Use of belimumab or rituximab within the past 180 days.
  19. Vaccination within the past 30 days.
  20. Pregnancy, current or in the 90 days prior to screening.
  21. Currently breastfeeding.
  22. Any electrocardiogram (ECG) abnormality that is clinically significant.
  23. Any condition that, in the opinion of the investigator, contraindicates participation in this study.

Laboratory evaluations that will be used to establish eligibility are listed in sections 6 and 7, below. For exclusion criteria that involve previously established diagnoses, such as active malignancy, osteoporosis, or diabetes mellitus, any previously obtained diagnostic studies will be considered, but diagnostic testing for the sole purpose of establishing eligibility will not be performed.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04233164


Contacts
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Contact: Yenealem Temesgen-Oyelakin, R.N. (301) 451-4990 yenealem.temesgen-oyelakin@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Sponsors and Collaborators
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Investigators
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Principal Investigator: Luis M Franco, M.D. National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Additional Information:
Publications:
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Responsible Party: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
ClinicalTrials.gov Identifier: NCT04233164    
Other Study ID Numbers: 200032
20-AR-0032
First Posted: January 18, 2020    Key Record Dates
Last Update Posted: April 20, 2020
Last Verified: March 27, 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) ):
Immunosuppressive Drugs
Methylprednisolone
PREDNISONE
Steroids
Autoimmunity
Additional relevant MeSH terms:
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Lupus Erythematosus, Systemic
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Methylprednisolone
Methylprednisolone Hemisuccinate
Methylprednisolone Acetate
Prednisolone
Prednisolone acetate
Prednisolone hemisuccinate
Prednisolone phosphate
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Neuroprotective Agents
Protective Agents
Antineoplastic Agents, Hormonal
Antineoplastic Agents