Steroid Resistance During COPD Exacerbations With Respiratory Failure

NCT03680495 | Unknown DMC FDA Drug

• 1 other identifier: 16-0256
• Study Type: observational
• Target: 46
• Locations: 1 country
• Sites: 1

Brief Summary

Chronic obstructive pulmonary disease (COPD) is a lung disease caused by cigarette smoke that affects millions of people. In the United States, COPD is the 3rd leading cause of death making it one of our most important public health problems. Some people with COPD get disease flares that are called acute exacerbations of COPD - or AECOPDs for short. When people get an AECOPD they experience increased shortness of breath, wheezing and cough; symptoms that often require urgent or emergent treatment by healthcare providers. In the most severe, life-threatening situations, people with AECOPDs are put on a ventilator in the emergency department and admitted to the intensive care unit. Most AECOPDs can be treated with low doses of medications called steroids. This is good because high doses of steroids can cause unwanted side effects. Unfortunately, recent studies suggest that the sickest people, those admitted to the intensive care unit needing ventilator support, need higher doses of steroids because they may have resistance to these important medications. The investigators are studying steroid resistance during very severe AECOPDs so that we can eventually develop better and safer therapies for these vulnerable people.

Conditions

COPD; Emphysema or COPD; COPD Exacerbation; COPD Exacerbation Acute; Respiratory Failure; Ventilatory Failure

Keywords

COPD; Steroid Resistance

Outcome Measures

Primary Outcomes (1)

• Presence of steroid resistance in patients recently admitted with an acute exacerbation of chronic obstructive pulmonary disease with respiratory failure.

  The ability of methylprednisolone to suppress interleukin-8 (IL-8) release from lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs).

  Once at ≥ 45 days after hospital discharge

Secondary Outcomes (6)

• Expression of Dual Specificity Phosphatase 1 (DUSP1)

  Once at ≥ 45 days after hospital discharge

• Activity of the Mitogen-activated Protein (MAP) Kinase Pathway.

  Once at ≥ 45 days after hospital discharge

• Expression of Glucocorticoid-induced leucine zipper (GILZ) and DUSP Isoforms.

  Once at ≥ 45 days after hospital discharge

• Role of Phosphoinositide 3-kinase (PI3K) and Histone Deacetylase 2 (HDAC2) in steroid resistance.

  Once at ≥ 45 days after hospital discharge

• Methylprednisolone pharmacokinetics following an acute exacerbation of chronic obstructive pulmonary disease with respiratory failure.

  Once at ≥ 45 days after hospital discharge

Study Arms (2)

AECOPD with Respiratory Failure

The AECOPD cohort will be hospitalized for an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) with respiratory failure requiring invasive or non-invasive mechanical ventilation. We will be following patients from admission through to discharge, and during a follow-up visit (\~2 months from discharge). During the follow-up visit we will be administering 60mg of methylprednisolone once to study possible steroid resistance.

Drug: Methylprednisolone

Stable COPD

The Stable COPD cohort will not have had an AECOPD within the past 6 months and will be frequency matched to the AECOPD cohort. The Stable COPD cohort will have one research visit where we will administer 60mg of methylprednisolone once to study possible steroid resistance.

Drug: Methylprednisolone

Interventions

Methylprednisolone DRUG

1\. Methylprednisolone is a steroid (corticosteroid) similar to a product produced in the adrenal glands. It is used to help relieve inflammation (swelling, heat, redness, and pain) and is used to treat certain medical issues including COPD.

AECOPD with Respiratory Failure; Stable COPD

Eligibility Criteria

• Age: 40 Years - 89 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

The AECOPD Cohort will be selected from University of Colorado Hospital inpatient units during an exacerbation of their COPD requiring respiratory failure. The COPD Cohort will be selected from the pulmonary clinics at the University of Colorado Hospital.

You may qualify if:

• Emergency Department (ED) or ICU physician diagnosis of an acute exacerbation of COPD
• Age ≥ 40 years of age
• Need for ventilator support in the ED or ICU during the first 24 hours
• Physician diagnosis of COPD
• Age ≥ 40 years of age
• Frequency matched to AECOPD subjects for:
• Age (± 10 year increments)
• Current/Former smoking status (former smoker = no smoking for ≥ 1 month)
• Lung function (FEV1% predicted by ± 10% increments)

You may not qualify if:

• Systemic steroid use ≤ 30 days prior to return visit
• Infection requiring antibiotics ≤ 1 month prior to return visit
• Hemoglobin \< 8.0 g/dl
• Acute pulmonary embolism
• Diabetes
• History of immunodeficiency, interstitial lung disease, neuromuscular disorder or heart failure with respiratory exacerbation
• Tracheostomy
• Drugs that induce cytochrome P450 3A enzyme activity (e.g. barbiturates, phenytoin or carbamazepine) or drugs that inhibit cytochrome P450 3A activity (e.g. ketoconazole and chronic macrolide antibiotics)
• Age ≥ 90 year of age
• Known pregnancy
• Nursing mothers
• Prisoners
• Systemic steroid use ≤ 30 days prior to return visit
• Infection requiring antibiotics ≤ 1 month prior to return visit
• Hemoglobin \< 8.0 g/dl

Sponsors & Collaborators

• University of Colorado, Denver: lead
• National Jewish Health: collaborator

Study Sites (1)

University of Colorado Denver

Aurora, Colorado, 80045, United States

RECRUITING

Biospecimen

Retention: SAMPLES WITH DNA

Collection of whole blood, serum, plasma, PBMCs, urine, nasal cells, and microbiome from the mouth, sinonasal passage, lung and stool.

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive; Emphysema; Respiratory Insufficiency; Hypoventilation

Interventions

Methylprednisolone

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Respiration Disorders; Signs and Symptoms, Respiratory; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• William Vandivier, MD

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jonathan Zakrajsek

CONTACT

303-724-6066; jonathan.zakrajsek@ucdenver.edu

Fernando Diaz del Valle

CONTACT

303-724-6067; fernando.diazdelvalle@ucdenver.edu

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: OTHER
• Target Duration: 2 Months
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 21, 2018
• First Posted: September 21, 2018
• Study Start: July 21, 2017
• Primary Completion: March 1, 2020
• Study Completion: January 1, 2021
• Last Updated: January 18, 2020

Record last verified: 2020-01

Locations

US (1)