A 12-week Study Treating Participants Who Have alpha1-antitrypsin-related COPD With Alvelestat (MPH966) or Placebo.

Study Overview
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Brief Summary
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The purpose of this study is to investigate the effect of alvelestat (an oral neutrophil elastase inhibitor) on blood and sputum biomarkers in patients with PiZZ, null or rare variant phenotype/genotype alpha-1 anti-trypsin deficient lung disease. Change in a number of different blood and sputum biomarkers related to lung damage, inflammation and elastase activity will be measured over a 12 week period. The effect on lung function and respiratory symptoms will also be measured.

Official Title
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A Phase 2, Proof-of-concept, Multicentre, Double-blind, Randomised, Dose-ascending, Sequential Group, Placebo-controlled Study to Evaluate the Mechanistic Effect, Safety, and Tolerability of 12 Weeks Twice Daily Oral Administration of Alvelestat (MPH966) in Participants With Alpha-1 Antitrypsin Deficiency.

Conditions
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Alpha 1-Antitrypsin Deficiency, Emphysema, COPD

Intervention / Treatment
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* Drug: Placebo Oral Tablet
* Drug: Alvelestat oral tablet - dose 1
* Drug: Alvelestat oral tablet - dose 2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with a confirmed diagnosis of alpha-1-anti-trypsin deficiency and a PiZZ, null or other rare geno/phenotype and serum anti-alpha1 antitrypsin levels of less than 11uM FEV1 ≥20% predicted Computerised tomography (CT) scan evidence of emphysema Non-smokers Exclusion Criteria: Primary diagnosis of bronchiectasis An ongoing acute exacerbation of the underlying lung disease Underlying liver disease or abnormal liver function tests Previous augmentation therapy within 6 months of dosing

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: placebo-controlled, dose ascending, sequential group
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo oral tablet<br> | Drug: Placebo Oral Tablet<br>* twice daily administration<br>|
| Active Comparator: Alvelestat oral tablet - dose 1<br>MPH966 | Drug: Alvelestat oral tablet - dose 1<br>* twice daily administration<br>* Other names: MPH966;|
| Active Comparator: Alvelestat oral tablet - dose 2<br>MPH966 | Drug: Alvelestat oral tablet - dose 2<br>* twice daily administration<br>* Other names: MPH966;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline on blood biomarkers of neutrophil elastase activity compared to baseline and placebo | Within-individual change from baseline up to end of treatment in: Blood neutrophil elastase activity Blood Aα-Val 360 levels Plasma desmosine/isodesmosine levels | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline on other blood biomarkers of neutrophil elastase activity | Frequency of neutrophil elastase levels below the limit of detection from baseline to end of treatment | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PiZZ or Null, Neutrophil elastase inhibitor, Alpha-1, Alvelestat, AZD9668, MPH966, Rare variant genotype, Astraeus, AATD, Alpha 1-Antitrypsin Deficiency, Lung Disease