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 : May 9, 2018
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.
To study how human genes respond to glucocorticoid drugs.
Healthy adult volunteers ages 18 64.
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|
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|
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.
- 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 ]
- 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 ]
- Validation of such targets with small interfering RNA (siRNA) libraries [ Time Frame: 3 years ]
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
|Contact: Katherine N Howe, P.A.-C||(240) email@example.com|
|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 firstname.lastname@example.org|
|Principal Investigator:||Luis M Franco, M.D.||National Institute of Allergy and Infectious Diseases (NIAID)|