COPDNCT03680495
Steroid Resistance During COPD Exacerbations With Respiratory Failure
An observational study of COPD and Emphysema or COPD, run by University of Colorado, Denver at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 40 to 89 years
- Conditions the study is for
- COPD, Emphysema or COPD, COPD Exacerbation
- What is being tested?
- Methylprednisolone
- How many people
- 46 participants
- Where
- 1 siteUnited States
- Study dates
- 21 Jul 2017to Jan 2021
- How long will I take part?
- 2 Months
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 to 89 years
- All sexes
- No healthy volunteers
- Adult, Older adult
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.
Who may be able to join
- 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)
Show all 19Show fewer
- 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
Who cannot join
- 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
Show all 12Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site, 1 recruiting
- Recruiting
University of Colorado Denver
Aurora, Colorado, 80045
William Vandivier, MD, 303-724-6068, Bill.Vandivier@ucdenver.edu
About this study
Official title: Targeting Steroid Resistance During Acute Exacerbations of Chronic Obstructive Pulmonary Disease With Respiratory Failure - The AECOPD Resistance Study
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.
Read the 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.
- Conditions
- COPD, Emphysema or COPD, COPD Exacerbation, COPD Exacerbation Acute, Respiratory Failure, Ventilatory Failure
- Being tested
- Methylprednisolone
- Keywords
- COPD, Steroid Resistance
- Medical subject headings
- Pulmonary Disease, Chronic Obstructive, Emphysema, Respiratory Insufficiency, Hypoventilation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
- 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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Methylprednisolone |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: Once at ≥ 45 days after hospital discharge
Secondary outcomes (6)
Expression of Dual Specificity Phosphatase 1 (DUSP1)
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.
Measured: Once at ≥ 45 days after hospital discharge
Activity of the Mitogen-activated Protein (MAP) Kinase Pathway.
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.
Measured: Once at ≥ 45 days after hospital discharge
Expression of Glucocorticoid-induced leucine zipper (GILZ) and DUSP Isoforms.
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.
Measured: Once at ≥ 45 days after hospital discharge
Role of Phosphoinositide 3-kinase (PI3K) and Histone Deacetylase 2 (HDAC2) in steroid resistance.
The role of HDAC2 in steroid resistance will be examined by measuring HDAC2 expression and histone transacetylase and deacetylase activity in PBMCs.
Measured: Once at ≥ 45 days after hospital discharge
Methylprednisolone pharmacokinetics following an acute exacerbation of chronic obstructive pulmonary disease with respiratory failure.
Measuring methylprednisolone pharmacokinetics in patients following an acute exacerbation of COPD with respiratory failure versus a stable, matched control.
Measured: Once at ≥ 45 days after hospital discharge
Examination of steroid-responsive gene expression patterns following an acute exacerbation of COPD with respiratory failure.
Ribonucleic acid (RNA) sequencing will be performed on PBMCs from patients and controls before and after exposure to methylprednisolone.
Measured: Once at ≥ 45 days after hospital discharge
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Sep 2018
- Study start21 Jul 2017
- Primary completionMar 2020 (estimated)
- Study completionJan 2021 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for COPDStudies of the same condition, open and under way.
- More trials run by University of Colorado, DenverThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Other
- Enrolment
- 46 participants (estimated)
- Target duration
- 2 Months
Sponsor and investigators
- Lead sponsor
- University of Colorado, Denver
- Sponsor type
- University, hospital or other
- Collaborators
- National Jewish Health
- Responsible party
- Sponsor
- Investigators
- William Vandivier, MD, Principal investigator, University of Colorado, Denver
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03680495
- Sponsor's protocol ID
- 16-0256
- Status last verified
- Jan 2020
- First submitted
- 21 Jun 2018
- Last updated
- 18 Jan 2020
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 18 Jan 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Targeting Steroid Resistance During Acute Exacerbations of Chronic Obstructive Pulmonary Disease With Respiratory Failure - The AECOPD Resistance Study
- ClinicalTrials.gov ID
- NCT03680495
- Acronym / sponsor ID
- 16-0256
- Conditions
- COPD, Emphysema or COPD, COPD Exacerbation, COPD Exacerbation Acute, Respiratory Failure, Ventilatory Failure
- Keywords
- COPD, Steroid Resistance
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 46 participants (estimated)
- Lead sponsor
- University of Colorado, DenverUniversity, hospital or other
- Collaborators
- National Jewish Health
- Study start
- 21 Jul 2017 (actual)
- Primary completion
- Mar 2020 (estimated)
- Study completion
- Jan 2021 (estimated)
- First posted
- 21 Sep 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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
- Observational model
- Case-control
- Time perspective
- Other
- Target follow-up
- 2 Months
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| AECOPD with Respiratory Failure | – | Drug: MethylprednisoloneThe 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. |
| Stable COPD | – | Drug: MethylprednisoloneThe 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. |
Who may qualify
- Ages
- 40 to 89 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- 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.
Key inclusion criteria (19 listed)
- Physician diagnosis of COPD
- Age ≥ 40 years of age
- Frequency matched to AECOPD subjects for:
- Systemic steroid use ≤ 30 days prior to return visit
- Infection requiring antibiotics ≤ 1 month prior to return visit
Key exclusion criteria (12 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Methylprednisolone1. 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. | Drug | AECOPD with Respiratory Failure, Stable COPD |
Primary outcome
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).
6 secondary outcomes
Expression of Dual Specificity Phosphatase 1 (DUSP1)
Time frame: Once at ≥ 45 days after hospital discharge
Activity of the Mitogen-activated Protein (MAP) Kinase Pathway.
Time frame: Once at ≥ 45 days after hospital discharge
Expression of Glucocorticoid-induced leucine zipper (GILZ) and DUSP Isoforms.
Time frame: Once at ≥ 45 days after hospital discharge
Role of Phosphoinositide 3-kinase (PI3K) and Histone Deacetylase 2 (HDAC2) in steroid resistance.
Time frame: Once at ≥ 45 days after hospital discharge
Methylprednisolone pharmacokinetics following an acute exacerbation of chronic obstructive pulmonary disease with respiratory failure.
Time frame: Once at ≥ 45 days after hospital discharge
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
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Jan 2020.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
William Vandivier, MD principal investigator
University of Colorado, Denver
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of COPD and Emphysema or COPD, run by University of Colorado, Denver at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 19 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 18 Jan 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Jonathan Zakrajsek (303-724-6066, jonathan.zakrajsek@ucdenver.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jan 2020.