Mechanism(s)of Airflow Limitation in Moderate-severe Persistent Asthma

NCT00576069 | Recruiting DMC

• 1 other identifier: 20070934
• Study Type: observational
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to evaluate the site and mechanisms responsible for expiratory airflow limitation in chronic, treated, non-smoking, stable asthmatics with moderate to severe persistent expiratory airflow obstruction. Treatment will include inhaled corticosteroids and long acting beta2agonists and long acting muscarinic antagonists. We are interested in determining whether the large and/or small airways are the predominant site of airflow limitation. We are also interested in determining whether intrinsic small airways obstruction and/or loss of lung elastic recoil is responsible for expiratory airflow limitation and to what extent may be attributed to loss of lung elastic recoil vs decreased airway conductance in peripheral airways. We are also interested to evaluate the role of varying doses of inhaled corticosteroids to suppress large and small airway inflammation using exhaled nitric oxide as surrogate markers of inflammation. For comparison purposes, spirometry and measurements of exhaled nitric oxide will also be obtained if possible during a naturally occurring exacerbation of asthma. High resolution thin section CT of the lung will also be obtained. Analysis will evaluate integrity of the lung parenchyma as to absence and or presence of emphysema and extent of emphysema using voxel quantification. We will also investigate optical coherence tomography to detect clinically unsuspected emphysema. We will also obtain autopsy material when available in asthmatics who expire. Will also measure serum periostin as a marker of inflammation by collaborating with Genetech in San Francisco.

Conditions

Asthma

Keywords

asthma; lung function; inflammation

Outcome Measures

Primary Outcomes (4)

• use exhaled nitric oxide as a surrogate marker of large airway vs small airway/lung inflammation following various doses of inhaled corticosteroids

  20-60 days

• determine site of airflow limitation, whether predominantly large and /or small airways using expiratory flow volume curves obtained before and after asthmatics breathe a 80% helium-20% oxygen gas mixture

  20-60 days

• investigate the mechanisms that limit expiratory airflow: intrinsic airway obstruction vs loss of lung elastic recoil

  20-60 days

• determine the extent of asthma and distribution of emphysema

  at autopsy or post lung transplantation

  within 10 days following death or explanted lung if lung transplant obtained

Secondary Outcomes (3)

• dynamic hyperinflation

  20-60 days

• Evaluate large and small airways and lung parenchyma in autopsied or transplanted lung in asthmatics and look for unsuspected emphysema

  June 2018

• Optical Coherence Tomography

  June 2015

Study Arms (1)

asthma, quality of life, lung function

All Asthmatics will be treated with 1 of 3 long acting beta 2 agonist + corticosteroid using low or medium dose of inhaled (Advair) fluticasone or equivalent corticosteroid 200-500mcg/day plus salmeterol 100 mcg/day or (Symbicort) budesonide 320-640 mcg +formoterol 18 mcg/day or (Dulera) mometasone 400-800mcg + formoterol 20 mcg/day. In addition tiotropium 18ucg/day will be used. Additionally, albuterol 0.083%/ipratropium 0.02% solution or MDI HFA for acute exacerbation.Will measure lung function and asthma quality of life questionaire

Drug: budesonide/formoterol; Drug: fluticasone/salmeterol; Drug: mometasone/formoterol; Drug: Prednisone

Interventions

budesonide/formoterol DRUG

2 inhalations 2X/daily in treated arm/group. No placebo group

Also known as: symbicort 80/4.5, symbicort 160/4.5, budesonide 80 or 160ug/formoterol 4.5ug, 2 inhalations bid, spiriva handihaler or respihaler

asthma, quality of life, lung function

fluticasone/salmeterol DRUG

fluticasone 100ug/salmeterol 50ug, 1 inhalation bid noplacebo fluticasone 250ug/salmeterol 50ug, 1 inhalations bid no placebo Spiriva handihaler daily or respihaler 2 inhalations daily no placebo group

Also known as: advair 100/50, advair 250/50

asthma, quality of life, lung function

mometasone/formoterol DRUG

200/5 mcg two puffs bid 100/5 mcg two puffs bid Breo Ellipta once daily Spiriva capsule handihaler once daily or Spiriva respihaler 2 in no placebo group

Also known as: Dulera

asthma, quality of life, lung function

Prednisone DRUG

0-15 mg daily as needed

Also known as: medrol

asthma, quality of life, lung function

Eligibility Criteria

• Age: 10 Years - 95 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Chronic Asthmatics

You may qualify if:

• Current non-smoking (\<10 pack yr smoking history)
• Stable, treated asthmatics
• Age 12-95 yr
• post 180ug albuterol by MDI: FEV 1/FVC \< 70% and FEV 1 \<80% predicted

You may not qualify if:

• Pregnancy

Sponsors & Collaborators

• Gelb, Arthur F., M.D.: lead

Study Sites (1)

Arthur F Gelb Medical Corporation

Lakewood, California, 90712, United States

RECRUITING

Related Publications (16)

• Gelb AF, Zamel N. Unsuspected pseudophysiologic emphysema in chronic persistent asthma. Am J Respir Crit Care Med. 2000 Nov;162(5):1778-82. doi: 10.1164/ajrccm.162.5.2001037.

  PMID: 11069812 BACKGROUND

• Gelb AF, Licuanan J, Shinar CM, Zamel N. Unsuspected loss of lung elastic recoil in chronic persistent asthma. Chest. 2002 Mar;121(3):715-21. doi: 10.1378/chest.121.3.715.

  PMID: 11888951 BACKGROUND

• Gelb AF, Gutierrez CA, Weisman IM, Newsom R, Taylor CF, Zamel N. Simplified detection of dynamic hyperinflation. Chest. 2004 Dec;126(6):1855-60. doi: 10.1378/chest.126.6.1855.

  PMID: 15596684 BACKGROUND

• Gelb AF, Flynn Taylor C, Shinar CM, Gutierrez C, Zamel N. Role of spirometry and exhaled nitric oxide to predict exacerbations in treated asthmatics. Chest. 2006 Jun;129(6):1492-9. doi: 10.1378/chest.129.6.1492.

  PMID: 16778266 BACKGROUND

• Gelb AF, Taylor CF, Nussbaum E, Gutierrez C, Schein A, Shinar CM, Schein MJ, Epstein JD, Zamel N. Alveolar and airway sites of nitric oxide inflammation in treated asthma. Am J Respir Crit Care Med. 2004 Oct 1;170(7):737-41. doi: 10.1164/rccm.200403-408OC. Epub 2004 Jun 30.

  PMID: 15229098 BACKGROUND

• Gelb AF, Zamel N, Krishnan A. Physiologic similarities and differences between asthma and chronic obstructive pulmonary disease. Curr Opin Pulm Med. 2008 Jan;14(1):24-30. doi: 10.1097/MCP.0b013e3282f197df.

  PMID: 18043272 BACKGROUND

• Gelb AF, Moridzadeh R, Singh DH, Fraser C, George SC. In moderate-to-severe asthma patients monitoring exhaled nitric oxide during exacerbation is not a good predictor of spirometric response to oral corticosteroid. J Allergy Clin Immunol. 2012 Jun;129(6):1491-8. doi: 10.1016/j.jaci.2012.03.036. Epub 2012 May 2.

  PMID: 22560478 RESULT

• Gelb AF, Yamamoto A, Mauad T, Kollin J, Schein MJ, Nadel JA. Unsuspected mild emphysema in nonsmoking patients with chronic asthma with persistent airway obstruction. J Allergy Clin Immunol. 2014 Jan;133(1):263-5.e1-3. doi: 10.1016/j.jaci.2013.09.045. Epub 2013 Nov 28. No abstract available.

  PMID: 24290280 RESULT

• Gelb AF, Singh DH, Moridzadeh R, Fraser C, Tran D, Verbanck S, George SC. Age-stratified comparison of large and peripheral airway/alveolar nitric oxide levels in children and young adults. J Allergy Clin Immunol. 2013 Nov;132(5):1222-4. doi: 10.1016/j.jaci.2013.05.045. Epub 2013 Aug 6. No abstract available.

  PMID: 23932460 RESULT

• Gelb AF, Yamamoto A, Verbeken EK, Nadel JA. Unraveling the Pathophysiology of the Asthma-COPD Overlap Syndrome: Unsuspected Mild Centrilobular Emphysema Is Responsible for Loss of Lung Elastic Recoil in Never Smokers With Asthma With Persistent Expiratory Airflow Limitation. Chest. 2015 Aug;148(2):313-320. doi: 10.1378/chest.14-2483.

  PMID: 25950858 RESULT

• Gelb AF, Nadel JA. Understanding the pathophysiology of the asthma-chronic obstructive pulmonary disease overlap syndrome. J Allergy Clin Immunol. 2015 Sep;136(3):553-5. doi: 10.1016/j.jaci.2015.06.013. No abstract available.

  PMID: 26343939 RESULT

• Gelb AF, Christenson SA, Nadel JA. Understanding the pathophysiology of the asthma-chronic obstructive pulmonary disease overlap syndrome. Curr Opin Pulm Med. 2016 Mar;22(2):100-5. doi: 10.1097/MCP.0000000000000236.

  PMID: 26717511 RESULT

• Gelb AF, Yamamoto A, Verbeken E, Grigorian SR, Nadel JA. Asthma and emphysema overlap in nonsmokers. Ann Allergy Asthma Immunol. 2020 Dec;125(6):711-713. doi: 10.1016/j.anai.2020.08.010. Epub 2020 Aug 10. No abstract available.

  PMID: 32791102 DERIVED

• Gelb AF, Yamamoto A, Verbeken EK, Schein MJ, Moridzadeh R, Tran D, Fraser C, Barbers R, Elatre W, Koss MN, Glassy EF, Nadel JA. Further Studies of Unsuspected Emphysema in Nonsmoking Patients With Asthma With Persistent Expiratory Airflow Obstruction. Chest. 2018 Mar;153(3):618-629. doi: 10.1016/j.chest.2017.11.016. Epub 2017 Nov 29.

  PMID: 29197547 DERIVED

• Gelb AF, George SC, Camacho F, Fraser C, Flynn Taylor C, Shakkottai S. Increased nitric oxide concentrations in the small airway of older normal subjects. Chest. 2011 Feb;139(2):368-375. doi: 10.1378/chest.10-1157. Epub 2010 Aug 12.

  PMID: 20705799 DERIVED

• Gelb AF, George SC, Silkoff PE, Krishnan A, Fraser C, Taylor CF, Shinar CM, Maginot T. Central and peripheral airway/alveolar sites of exhaled nitric oxide in acute asthma. Thorax. 2010 Jul;65(7):619-25. doi: 10.1136/thx.2009.132696.

  PMID: 20627920 DERIVED

MeSH Terms

Conditions

Asthma; Inflammation

Interventions

Budesonide, Formoterol Fumarate Drug Combination; Formoterol Fumarate; Fluticasone-Salmeterol Drug Combination; Mometasone Furoate; Mometasone Furoate, Formoterol Fumarate Drug Combination; Prednisone; Methylprednisolone

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Ethanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Amines; Budesonide; Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Drug Combinations; Pharmaceutical Preparations; Salmeterol Xinafoate; Albuterol; Phenethylamines; Ethylamines; Fluticasone; Androstadienes; Androstenes; Androstanes; Pregnadienediols; Pregnadienes; Prednisolone; Pregnadienetriols

Study Officials

• Arthur F Gelb, MD

  Arthur F Gelb Medical Corporation

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Arthur F Gelb, MD

CONTACT

562-633-2204; afgelb@msn.com

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: INDIV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: December 17, 2007
• First Posted: December 18, 2007
• Study Start: October 25, 2007
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2027
• Last Updated: October 26, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will share

Locations

US (1)