Characterizing Matrix Metalloproteinase-12 (MMP12) in Sputum

Emphysema Clinical Trial

Official title:

Characterizing Mmp12 In Sputum And Its Relationship To Emphysema And Inflammatory Endotypes

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04761393
• Other study ID #: FIRH_Xe007
• Status: Recruiting
• Start date: November 29, 2022
• Est. completion date: March 2024

Study information

• Verified date: January 2024
• Source: McMaster University
• Contact: Sarah Svenningsen, PhD
• Phone: 905-522-1155
• Email: svennins[@]mcmaster.ca
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The hypothesis is that in patients with emphysema, a high MMP12 sputum and/or blood level correlates with airspace enlargement and with increased sputum Th2 immune biomarkers.

Description:

Since MMP-12 apparently has a preponderant role in the genesis of emphysema and probably in airspace enlargement, its inhibition may result in an interesting targeting point in view to find specific therapies in obstructive diseases. There is abundant evidence in animal models that shows how MMP-12 blockade inhibits the development of emphysema and airway remodeling. Unfortunately, the results have not been conclusive in human models. In the last years, pulmonary imaging biomarkers that measure airspace enlargement have been developed. In particular, the apparent diffusion coefficient (ADC), quantified by inhaled hyperpolarized gas MRI, reflects alveolar airspace size. ADC provides information consistent with histopathological findings that may be used to estimate lung disease progression and treatment response.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 45
• Est. completion date: March 2024
• Est. primary completion date: February 2024
• Gender: All
• Age group: 40 Years to 85 Years

Eligibility

Inclusion Criteria (COPD):

• =40 years of age
• Current or ex-smokers with a >10 pack year smoking history
• Have a post-bronchodilator forced expired volume in 1 second (FEV1)/forced expired vital capacity (FVC) ratio of <70% and a post-bronchodilator FEV1 value from =30% predicted (GOLD 1, 2 and 3), (Global Initiative for Obstructive Lung disease)
• Have a radiologist confirmed pulmonary emphysema diagnosis based on CT

Inclusion criteria for normal controls:

• No clinically significant medical condition or a history of asthma, COPD, cystic fibrosis, or other significant respiratory disorder including significant occupational or environmental exposures with ongoing respiratory symptoms.
• No current or past smoking history
• Have a post-bronchodilator FEV1/FVC ratio of >70% Exclusion Criteria: Any potential subject who meets any of the following criteria will be excluded from

participating in the study:

• Patients with other non-COPD airway diseases
• Patients with very severe COPD (FEV1<30% predicted)
• Patients with an intercurrent exacerbation
• Patients with life expectancy less than 3 months
• Pregnant or breastfeeding
• Undergoing immunomodulatory or biologic treatment
• Use of systemic steroids in the last month
• Hospitalization in the last 12 months due to exacerbation
• Known cardiovascular comorbidity under treatment or with hospitalizations of this cause in the last year
• That they cannot perform spirometry
• Active malignancy
• Realization of lung surgery during the study period
• History of alcohol and drug abuse that prevents compliance with follow-up
• History of bronchial thermoplasty
• Participating in another study concomitantly
• MRI Related: patients who have implanted mechanically, electrically or magnetically activated device or any metal in their body which cannot be removed, including but not limited to pacemakers, artificial limb, metallic fragments of foreign body, shunt, surgical staples (including clips or metallic sutures and/or ear implants).

Related Conditions & MeSH terms

• Emphysema
• Pulmonary Emphysema

Intervention

Procedure:
• Hyperpolarized 129Xe (Xenon) diffusion-weighted MRI
Participants will inhale a one litre gas mixture containing hyperpolarized 129Xe mixed with nitrogen (N2) or helium (4He) from a one litre dose bag. Breath-hold will be up to 16 seconds

Locations

Country	Name	City	State
Canada	Firestone Institute for Respiratory Health, St. Joseph's Healthcare	Hamilton	Ontario

Sponsors (2)

Lead Sponsor	Collaborator
McMaster University	Foresee Pharmaceuticals Co Inc

Country where clinical trial is conducted

Canada, 

References & Publications (3)

Nair P, Ochkur SI, Protheroe C, Radford K, Efthimiadis A, Lee NA, Lee JJ. Eosinophil peroxidase in sputum represents a unique biomarker of airway eosinophilia. Allergy. 2013 Sep;68(9):1177-84. doi: 10.1111/all.12206. Epub 2013 Aug 9. — View Citation

Ostridge K, Williams N, Kim V, Bennett M, Harden S, Welch L, Bourne S, Coombs NA, Elkington PT, Staples KJ, Wilkinson TM. Relationship between pulmonary matrix metalloproteinases and quantitative CT markers of small airways disease and emphysema in COPD. Thorax. 2016 Feb;71(2):126-32. doi: 10.1136/thoraxjnl-2015-207428. Epub 2015 Dec 8. — View Citation

Shukla Y, Wheatley A, Kirby M, Svenningsen S, Farag A, Santyr GE, Paterson NA, McCormack DG, Parraga G. Hyperpolarized 129Xe magnetic resonance imaging: tolerability in healthy volunteers and subjects with pulmonary disease. Acad Radiol. 2012 Aug;19(8):941-51. doi: 10.1016/j.acra.2012.03.018. Epub 2012 May 15. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Blood and sputum matrix metalloproteinase-12 (MMP12) levels	Measure sputum and blood MMP12 levels	Baseline
Primary	Quantify their alveolar destruction using Computed Tomography (CT) and magnetic resonance imaging (MRI)	The relative area of the Computed Tomography (CT) attenuation histogram with attenuation of 950 HU or less (RA950) and the 15th percentile of the CT attenuation histogram (HU15) will be generated to quantify emphysema.; For analysis of 129Xe diffusion-weighted MR images we will employ the same approach as described by Kirby and colleagues to quantify the apparent diffusion coefficient (ADC) and generate ADC maps12 to assess airspace size.	Baseline
Primary	Measure other T2 activity biomarkers in sputum	Sputum: enumeration of Free eosinophils granules (FEG) by none, few moderate and many	Baseline
Primary	Measure other T2 activity biomarkers in sputum supernatant	Sputum supernatant: Levels of (interleukin) IL-4, IL-5 and IL-13, eosinophil peroxidase, transforming growth factor (TGF)-beta, Phospho-Smad2 and Phospho-Smad3 (SMAD=Small Mothers Against Decapentaplegic gene)	Baseline
Primary	Measure other T2 activity biomarkers in blood	Ferritin in microgram per litre (ug/L)	Baseline
Primary	Measure other T2 activity biomarkers in blood	C reactive protein (CRP) in milligram/litre (mg/L)	Baseline
Primary	Compare type-2 (T2) activity biomarkers with healthy individuals in sputum	Sputum: enumeration of Free eosinophils granules (FEG) as few, moderate and many.	Baseline
Primary	Compare type-2 (T2) activity biomarkers with healthy individuals in blood	Ferritin in microgram per litre (ug/L)	Baseline
Primary	Compare type-2 (T2) activity biomarkers with healthy individuals in blood	C reactive protein (CRP) in milligram/litre (mg/L)	Baseline
Primary	Compare type-2 (T2) activity biomarkers with healthy individuals in sputum supernatant	Sputum supernatant: Levels of IL-4, IL-5 and IL-13, eosinophil peroxidase, TGF-beta, Phospho-Smad2 and Phospho-Smad3.	Baseline