ClinicalTrials.gov
ClinicalTrials.gov Menu

Genomic Responses of Human Immune and Non-Immune Cells to Glucocorticoids

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: NCT02798523
Recruitment Status : Recruiting
First Posted : June 14, 2016
Last Update Posted : November 2, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

Brief Summary:

Background:

The immune system defends the body against bacteria and other harmful invaders. But it can overact and attack healthy cells by mistake. The group of drugs called glucocorticoids (GCs) can calm down an overactive immune system. But they often cause negative side effects. Researchers want to learn how human genes respond to GCs. Genes live inside each cell of the body. They tell our cells how to function. Researchers hope the results of this study will show them how to develop better drugs that will have the benefits of GCs without the side effects.

Objectives:

To study how human genes respond to glucocorticoid drugs.

Eligibility:

Healthy adult volunteers ages 18 64.

Design:

Participants will be screened with a medical history and physical exam. They will have a heart test and blood tests.

The study visit will last about 6 hours.

Participants will have medical history, physical exam, and 3 blood draws.

Participants will have a skin biopsy. An injection will numb the skin on one arm. Then a tool will remove a piece of skin about as big as a pencil eraser.

A GC cream will be applied to the other arm.

Participants will get the GC study drug for 30 minutes. It will be a liquid that will drip through a needle placed in an arm vein.

Participants will have a skin biopsy of the arm that had the cream applied.

Participants will have follow-up calls 1 and 4 days later. They will be asked about reactions or other health problems.


Condition or disease Intervention/treatment Phase
Normal Physiology Drug: Solu-Medrol (methylprednisolone sodium succinate) Drug: Topical methylprenisolone 0.1% Phase 1

Detailed Description:

Glucocorticoids are among the most frequently prescribed immunosuppressive and anti-inflammatory medications worldwide. Long-term use, however, is complicated by serious non-immunologic side effects. Ongoing in vitro experiments with human primary cells in our laboratory suggest that there are indeed fundamental differences in the genomic response of immune and non-immune cells to glucocorticoids. These and other aspects of drug action at the genomic level have not been completely characterized. This study will attempt to generate a list of human genes and non-coding RNAs that are differentially expressed and regulated in response to glucocorticoids between immune and non-immune cells. These data will be used to identify transcripts, their corresponding proteins, and the molecular pathways that are best candidates for targeted intervention. Potential targets could be validated with small interfering RNA (siRNA) libraries, with the long-term goal of developing small-molecule or nanoparticlefacilitated RNA interference (RNAi) interventions that reproduce the therapeutic action of glucocorticoids in immune cells while avoiding their harmful side effects on other tissues.

Healthy volunteers will undergo baseline blood collection prior to receiving a single intravenous dose of 250 milligrams of methylprednisolone sodium succinate. Blood will be collected in one of two regimens: 1 and 2 hours or 2 and 4 hours after the start of the infusion. A skin punch biopsy may be obtained before healthy volunteers receive IV methylprednisolone. If so, topical methylprednisolone will be applied to a limited area of skin, contralateral to the site of the baseline skin biopsy, and an affitional skin biopsy will be obtained 4 hours after drug administration, from the area where topical methylprednisolone was applied. Follow-up phone calls 1 day and 1 week after discharge will document any adverse effects related to the drug or skin biopsy. Total length of individual study participation is 1-5 weeks.

Blood samples will be processed for isolation of hematopoietic cell sub-population (neutrophils, B cells, CD4+ T cells, CD8+ T cells, monocytes, and natural killer [NK] cells). Laboratory studies will be performed in the purified cells, with the goal of understanding the human response to glucocorticoids in vivo at the level of RNA (e.g., RNA sequencing, small -RNA-sequencing, real-time PCR), DNA (e.g., ChIP-seq, methylation analysis, DNA sequencing, genotyping, and protein (e.g., flow cytometry, mass spectrometry). At each time point, serum methylprednisolone levels will be measured and flow cytometry for standard lineage markers will be performed. Skin biopsies will be subjected to RNA isolation for RNA sequencing and small-RNA sequencing. A fragment of each skin biopsy will undergo fibroblast isolation and culture for in vitro exposure to glucocorticoids and for the generation of induced pluripotent stem (iPS) cells.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Genomic Responses of Human Immune and Non-Immune Cells to Glucocorticoids
Study Start Date : June 10, 2016
Estimated Primary Completion Date : August 1, 2019
Estimated Study Completion Date : August 1, 2023


Arm Intervention/treatment
Experimental: 1
Following collection of a 3-mm skin punch biopsy sample and a preinfusion whole-blood sample, volunteers will receive a single intravenous dose of 250 milligrams (mg) of methylprednisolone sodium succinate infused over 15 minutes, and a single application of topical methylprednisolone 0.1% to a small area (2 x 2 cm) of the skin. Whole blood samples will then be obtained serially, at 2 and 4 hours after the start of drug administration. A second skin punch biopsy will be performed 4 hours after the start of drug administration, in the area of skin where topical methylprednisolone was applied.
Drug: Solu-Medrol (methylprednisolone sodium succinate)

Methylprednisolone sodium succinate for injection, USP (SOLU-MEDROL sterile powder, Pfizer, Inc.) is an anti-inflammatory glucocorticoid which occurs as a white, or nearly white, odorless hygroscopic, amorphous solid. It is very soluble in water and in alcohol; it is insoluble in chloroform and is very slightly soluble in acetone.

125-milligram Act-O-Vial (AOV) System: Each 2 mL AOV (when mixed) contains methylprednisolone sodium succinate equivalent to 125 milligrams methylprednisolone; also 1.6 mg monobasic sodium phosphate anhydrous; and 17.4 mg dibasic sodium phosphate dried.


Drug: Topical methylprenisolone 0.1%
1 g Advantan emulsion 0.1% (Bayer) contains methylprednisolone aceponate (21-acetoxy-11beta-hydroxy-6alpha-methyl-17-propionyloxy-1,4-pregnadiene-3,20-dione) 1 mg, as the active ingredient. It is an oil-in-water emulsion containing medium chain triglycerides, caprylic-capric-stearic triglyceride, polyoxyethylene alcohol 2-stearylether, polyoxyethylene alcohol-21-stearylether, benzyl alcohol, disodium edetate, glycerol, and purified water.




Primary Outcome Measures :
  1. A list of human genes and non-coding RNAs that are differentially expressed and regulated in response to glucocorticoids between immune and non-immune cells [ Time Frame: 3 years ]

Secondary Outcome Measures :
  1. A list of protein-coding and noncoding transcripts, their corresponding proteins, and the molecular pathways representing the best candidates for targeted therapeutic alternatives to glucocorticoids [ Time Frame: 3 years ]
  2. Validation of such targets with small interfering RNA (siRNA) libraries [ Time Frame: 3 years ]


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.


Ages Eligible for Study:   18 Years to 64 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria
  • INCLUSION CRITERIA:

    1. Age 18 to 64 years
    2. Willingness to have samples stored for future research
    3. Willingness to undergo genetic testing

EXCLUSION CRITERIA:

  1. Body Mass Index less than 18 or greater than 35
  2. Difficult peripheral venous access (as determined by study staff at screening)
  3. History of severe allergic reaction to glucocorticoids
  4. History of autoimmune or autoinflammatory disease
  5. Active solid or hematologic malgnancy
  6. History of a skin condition (such as psoriasis, pemphigus, or atopic dermatitis) that could affect the results of the transcriptional analysis of the skin biopsy samples
  7. Diabetes mellitus
  8. Cancer chemotherapy within the past 5 years
  9. Surgery within the past 8 weeks
  10. History of recent (within the past 30 days) infection
  11. A positive test for human immunodeficiency virus, or hepatitis A, B or C virus infection (viral markers hepatitis screen, which includes HBsAg, anti-HCV IgG, anti-HAV IgM).
  12. A positive or indeterminate test for latent tuberculosis (interferon gamma release assay)
  13. History of parasitic, amebic, fungal or mycobacterial infections, or other possible latent infections
  14. Coagulation test (PT and PTT) results outside of normal range
  15. History of a bleeding disorder
  16. Use of a glucocorticoid (including topical or inhaled), a nonsteroidal anti-inflammatory drug (including aspirin), an anti-epileptic drug, an anticoagulant, a statin, fluoxetine, diltiazem, amiodarone, clarithromycin, ketoconazole, or St. John s wort, within the past 30 days
  17. Vaccination within the past 30 days
  18. Receipt of an immunosuppressant or immunomodulatory drug within the past 30 days
  19. Pregnancy, current or within the past 90 days
  20. Current breastfeeding
  21. Complete blood count (CBC) and/or acute care panel values are both outside of the NIH Department of Laboratory Medicine normal reference range and deemed clinically significant by the principal investigator (PI)
  22. Any Electrocardiogram (ECG) abnormality that is clinically significant
  23. Any condition that, in the investigator s opinion, may put the participant at undue risk or compromise the study s scientific objectives
  24. Participation in a clinical protocol which includes an intervention that, in the opinion of the investigator, may affect the results of the current study

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): NCT02798523


Contacts
Contact: Katherine N Howe, P.A.-C (240) 669-2747 kate.howe@nih.gov

Locations
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 Allergy and Infectious Diseases (NIAID)
Investigators
Principal Investigator: Luis M Franco, M.D. National Institute of Allergy and Infectious Diseases (NIAID)

Additional Information:
Publications:
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT02798523     History of Changes
Other Study ID Numbers: 160126
16-I-0126
First Posted: June 14, 2016    Key Record Dates
Last Update Posted: November 2, 2018
Last Verified: October 31, 2018

Studies a U.S. FDA-regulated Drug Product: Yes

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) ):
Methylprednisolone
Immunologic
Infusion
Topical
Intravenous

Additional relevant MeSH terms:
Glucocorticoids
Prednisolone acetate
Methylprednisolone acetate
Methylprednisolone
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Neuroprotective Agents
Protective Agents
Antineoplastic Agents, Hormonal
Antineoplastic Agents