Steroid Resistance During COPD Exacerbations With Respiratory Failure

• ClinicalTrials.gov Identifier: NCT03680495
• Recruitment Status: Unknown
• First Posted: September 21, 2018
• Last Update Posted: January 18, 2020
• Sponsor: University of Colorado, Denver
• Collaborator: National Jewish Health
• Information provided by (Responsible Party): University of Colorado, Denver

Study Description

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.

Condition or disease	Intervention/treatment
COPD; Emphysema or COPD; COPD Exacerbation; COPD Exacerbation Acute; Respiratory Failure; Ventilatory Failure	Drug: Methylprednisolone

Detailed Description:

Chronic obstructive pulmonary disease (COPD) is a cigarette smoke-induced disease of the lungs that affects millions of people in the United States and worldwide. COPD is the 3rd leading cause of death, making it one our most important public health problems. Perhaps most importantly, COPD confines many people to their homes, tethers them to oxygen lines, and destroys their independence. Like many diseases of chronic inflammation, the course of COPD is marred by intermittent disease flares that need more intensive treatment. In COPD, disease flares are called acute exacerbations of COPD (AECOPDs). AECOPDs are characterized by increased shortness of breath, wheezing or cough that leads to urgent, and sometimes emergent, treatment with inhaled bronchodilators, antibiotics and steroids. AECOPDs can be devastating to many because they worsen quality of life and lung function, frequently lead to hospitalization, and increase the risk of death. For instance, the death rate can reach 25-30% when COPD patients are admitted to the intensive care unit with respiratory failure (i.e. needing ventilator support). Accordingly, our research is focused on improving outcomes in the sickest patients admitted to the hospital with an AECOPD.

Oral or intravenous steroids (glucocorticoids) have been the mainstay of treatment for over 40 years, but virtually no research has been done to determine the optimal therapy for the sickest patients who are admitted to the intensive care unit. Results from the few clinical studies suggest that steroid resistance is increased in these critically-ill patients and that many physicians under- or over-dose steroids. For example, patients hospitalized with an AECOPD (without respiratory failure) are effectively treated with steroids (such as prednisone) dosed as low as 40mg/day. In contrast, two recent clinical studies showed that ~80mg/day of prednisone was ineffective for AECOPD patients hospitalized with respiratory failure (those who require ventilatory support), while in a second study ~160mg/day of methylprednisolone improved outcomes. The investigators recent epidemiologic study showed that 66% of patients admitted with an AECOPD and respiratory failure between 2003-2008 were treated with >240mg/day of methylprednisolone, a dose that increases steroid-related side effects. The investigators hypothesize that there is a stepwise increase in steroid resistance with COPD<AECOPD<AECOPD with respiratory failure. A newly launched team of investigators is focused on establishing the presence of steroid resistance, defining the cause(s), devising new treatments to combat this problem and optimizing therapy for these vulnerable patients.

Steroids suppress inflammation by inducing anti-inflammatory genes, such as the dual-specificity phosphatase (DUSP) family - including DUSP1. DUSP1 inhibits inflammatory cytokines by removing phosphates from p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases, which turns them off. Preliminary data show that DUSP1 is decreased in alveolar macrophages from COPD patients, suggesting the central hypothesis that steroid resistance is increased in AECOPDs with respiratory failure due to impaired glucocorticoid-mediated induction of DUSP1. To address this hypothesis, the investigators will inject 23 AECOPD patients with respiratory failure and 23 matched stable COPD subjects with 60mg of methylprednisolone to: 1) determine the presence of corticosteroid resistance in AECOPDs, 2) determine the role of DUSP1, and 3) examine alternative mechanisms driving steroid resistance. The goal of The AECOPD Resistance Study is to identify targets associated with steroid resistance in AECOPDs with respiratory failure to pave the way for new treatments based upon novel mechanisms.

Study Design

• Study Type: Observational [Patient Registry]
• Estimated Enrollment: 46 participants
• Observational Model: Case-Control
• Time Perspective: Other
• Target Follow-Up Duration: 2 Months
• Official Title: Targeting Steroid Resistance During Acute Exacerbations of Chronic Obstructive Pulmonary Disease With Respiratory Failure - The AECOPD Resistance Study
• Actual Study Start Date: July 21, 2017
• Estimated Primary Completion Date: March 2020
• Estimated Study Completion Date: January 2021

Groups and Cohorts

Group/Cohort	Intervention/treatment
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; 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.
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; 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.

Outcome Measures

Primary Outcome Measures :

1. Presence of steroid resistance in patients recently admitted with an acute exacerbation of chronic obstructive pulmonary disease with respiratory failure. [ Time Frame: Once at ≥ 45 days after hospital discharge ]
   The ability of methylprednisolone to suppress interleukin-8 (IL-8) release from lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs).

Secondary Outcome Measures :

1. Expression of Dual Specificity Phosphatase 1 (DUSP1) [ Time Frame: Once at ≥ 45 days after hospital discharge ]
   Baseline expression and induction of Dual Specificity Phosphatase 1 (DUSP1) in peripheral blood monocytes from patients recently admitted with an acute exacerbation of chronic obstructive pulmonary disease with respiratory failure versus stable, matched controls.
2. Activity of the Mitogen-activated Protein (MAP) Kinase Pathway. [ Time Frame: Once at ≥ 45 days after hospital discharge ]
   Differences in Mitogen-activated Protein (MAP) Kinase Pathway activity in peripheral blood monocytes from patients recently admitted with an acute exacerbation of chronic obstructive pulmonary disease with respiratory failure versus stable, matched controls.
3. Expression of Glucocorticoid-induced leucine zipper (GILZ) and DUSP Isoforms. [ Time Frame: Once at ≥ 45 days after hospital discharge ]
   Baseline expression and induction of Glucocorticoid-induced Leucine Zipper (GILZ) and DUSP isoforms in peripheral blood monocytes from patients recently admitted with an acute exacerbation of chronic obstructive pulmonary disease with respiratory failure versus stable, matched controls.
4. Role of Phosphoinositide 3-kinase (PI3K) and Histone Deacetylase 2 (HDAC2) in steroid resistance. [ Time Frame: Once at ≥ 45 days after hospital discharge ]
   The role of HDAC2 in steroid resistance will be examined by measuring HDAC2 expression and histone transacetylase and deacetylase activity in PBMCs.
5. Methylprednisolone pharmacokinetics following an acute exacerbation of chronic obstructive pulmonary disease with respiratory failure. [ Time Frame: Once at ≥ 45 days after hospital discharge ]
   Measuring methylprednisolone pharmacokinetics in patients following an acute exacerbation of COPD with respiratory failure versus a stable, matched control.
6. Examination of steroid-responsive gene expression patterns following an acute exacerbation of COPD with respiratory failure. [ Time Frame: Once at ≥ 45 days after hospital discharge ]
   Ribonucleic acid (RNA) sequencing will be performed on PBMCs from patients and controls before and after exposure to methylprednisolone.

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.

Eligibility Criteria

• Ages Eligible for Study: 40 Years to 89 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• 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.

Criteria

Inclusion Criteria for AECOPD with Ventilatory Failure Cohort:

• 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

Inclusion Criteria for Stable COPD Cohort:

• 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)

Exclusion Criteria for AECOPD with Ventilatory Failure Cohort:

• 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

Exclusion Criteria for Stable COPD Cohort:

• 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

Contacts and Locations

Contacts

Contact: Jonathan Zakrajsek; 303-724-6066; jonathan.zakrajsek@ucdenver.edu

Contact: Fernando Diaz del Valle; 303-724-6067; fernando.diazdelvalle@ucdenver.edu

Locations

United States, Colorado

University of Colorado Denver; Recruiting

Aurora, Colorado, United States, 80045

Contact: William Vandivier, MD 303-724-6068 Bill.Vandivier@ucdenver.edu

Sponsors and Collaborators

University of Colorado, Denver

National Jewish Health

Investigators

• Principal Investigator: William Vandivier, MD; University of Colorado - Anschutz Medical Campus

More Information

Additional Information:

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT03680495
• Other Study ID Numbers: 16-0256
• First Posted: September 21, 2018
• Last Update Posted: January 18, 2020
• Last Verified: January 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by University of Colorado, Denver:

COPD; Steroid Resistance

Additional relevant MeSH terms:

Pulmonary Disease, Chronic Obstructive; Respiratory Insufficiency; Hypoventilation; Emphysema; Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Pathologic Processes; Signs and Symptoms, Respiratory; Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Hemisuccinate; 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