Clinical trial NCT03679598
Conditions: Alpha-1 Antitrypsin Deficiency (AATD) Pi*ZZ, Pi*SZ, Pi*Null, Another Rare Phenotype/Genotype Known to be Associated With Either Low or Functionally Impaired AAT Including F or I Mutations Emphysema or COPD
Sponsor: University of Alabama at Birmingham
Start date: 2019-04-08; Completion date: 2023-12-01
Enrollment: 63 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2, multicenter, double-blind, randomized (1:1), placebo-controlled, 12-week, proof-of-concept study to evaluate the safety and tolerability as well as the mechanistic effect of oral administration of alvelestat (MPH966) in subjects with confirmed AATD defined as Pi\*ZZ, Pi\*SZ, Pi\*null, or another rare phenotype/genotype known to be associated with either low (serum AAT level \<11 μM or \<57.2 mg/dL) or functionally impaired AAT including "F" or "I" mutations.

Detailed description:
Alpha-1 antitrypsin deficiency (AATD) is the most common genetic cause of chronic obstructive pulmonary disease (COPD) and early-onset emphysema. AATD is characterized by low AAT levels; leading to excessive neutrophil elastase (NE) mediated lung destruction. Current treatment requires the periodic infusion of pooled AAT derived from human plasma, but this therapeutic approach (termed augmentation) does not definitively slow the rate of emphysema progressionlung function decline and is very expensive. In addition, it is not clear that the currently recommended dose for augmentation fully controls lung inflammation and destruction. Alvelestat (MPH966, formerly AZD9668) is a potent, selective, and reversible, oral inhibitor of human NE. Suppression of NE is expected to reduce lung damage and may slow disease progression. This study is to establish proof of clinical concept by investigating the mechanistic effect and safety of alvelestat (MPH966) in patients with AATD.

Arms: arm 1: Alvelestat (MPH966) 120mg (4 30mg tablets) twice daily by mouth for 12 weeks arm 2: 4 Placebo tablets twice daily by mouth for 12 weeks
Interventions: intervention 1: Alvelestat (MPH966) intervention 2: Placebo
Intervention descriptions: intervention 1: Alvelestat was developed as treatment for lung diseases like Chronic Obstructive Pulmonary Disease. Alevelestat works by blocking certain proteins in the body that are responsible for inflammation and damage to the lungs that can lead to COPD symptoms. intervention 2: Placebo is a pill or tablet that does not contain any study drug.

Protocol documents:
Prot_002.pdf: 
Page 1 of 59 
Protocol Version 1.4 
Protocol Title: Alvelestat (MPH966) for the Treatment of ALpha-1 ANTitrypsin Deficiency (ATALANTa) 
A Phase 2, multicenter, double-blind, randomized, placebo-controlled study to evaluate efficacy, safety, and 
tolerability of alvelestat (MPH966) in alpha-1 antitrypsin deficiency   
IND: 101,534 
NCT identifier: NCT03679598 
Compound Number: Alvelestat/MPH966 (formerly AZD9668) 
Sponsor Name and Legal Registered Address: National Institutes of Health (NIH)/National Center for 
Advancing Translational Sciences (NCATS), Bethesda, MD 
Document Date: 16/Feb/2021


 
Protocol Version 1.4 
 
 
Page 2 of 59 
Table of Contents 
1. 
Synopsis .........................................................................................................................4 
2. 
Schedule of Activities (SOA) ....................................................................................6 
3. 
Introduction ...................................................................................................................7 
3.1. 
Background .....................................................................................................................7 
3.2. 
Study Rationale ..............................................................................................................8 
4. 
Objectives and Endpoints .........................................................................................9 
5. 
Study Design ...............................................................................................................11 
5.1. 
Overall Design ..............................................................................................................11 
5.2. 
Number of Participants ................................................................................................12 
5.3. 
End of Study Definition ................................................................................................12 
5.4. 
Scientific Rationale for Study Design ........................................................................12 
5.5. 
Justification for Dose ...................................................................................................12 
5.6. 
Preclinical Safety Studies ...........................................................................................13 
5.7. 
Clinical Safety Studies .................................................................................................13 
5.8. 
Benefit-Risk Assessment ............................................................................................14 
6. 
Study Population........................................................................................................16 
6.1. 
Inclusion Criteria ...........................................................................................................16 
6.2. 
Exclusion Criteria .........................................................................................................16 
6.3. 
Lifestyle Restrictions ....................................................................................................18 
6.3.1. 
Meals and Dietary Restrictions ..................................................................................18 
6.3.2. 
Alcohol and Tobacco ...................................................................................................18 
6.3.3. 
Activity ............................................................................................................................18 
6.4. 
Screen Failures ............................................................................................................18 
7. 
Treatments ...................................................................................................................19 
7.1. 
Treatments Administered ............................................................................................19 
7.2. 
Method of Treatment Assignment .............................................................................19 
7.3. 
Blinding ..........................................................................................................................19 
7.4. 
Preparation/Handling/Storage/Accountability ..........................................................20 
7.5. 
Treatment Compliance ................................................................................................20 
7.6. 
Concomitant Therapy ..................................................................................................20 
7.7. 
Treatment After the End of the Study .......................................................................21 
8. 
Discontinuation Criteria ...........................................................................................22 
8.1. 
Discontinuation of Study Treatment ..........................................................................22 
8.1.1. 
Temporary Discontinuation .........................................................................................24 
8.1.2. 
Re-challenge .................................................................................................................24 
8.2. 
Discontinuation From the Study .................................................................................24 
8.3. 
Lost to Follow-up ..........................................................................................................24 
9. 
Study Assessments and Procedures ...................................................................25 
9.1. 
Key Screening Assessments .....................................................................................26 
9.2. 
Efficacy Assessments .................................................................................................26 
9.2.1. 
Blood, Sputum, and Bronchoalveolar Lavage Biomarkers ....................................26 
9.2.2. 
SGRQ-C.........................................................................................................................27 
9.2.3. 
COPD Assessment Test (CAT) .................................................................................27 


 
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9.2.4. 
Modified Medical Research Council (MMRC) ..........................................................27 
9.2.5. 
San Diego Breath Questionnaire (SOBQ) ................................................................28 
9.2.6. 
Pulmonary Function Testing/Spirometry ..................................................................28 
9.2.7. 
Daily respiratory symptom scores and peak flow by electronic diary ..................28 
9.3. 
Safety Assessments ....................................................................................................28 
9.3.1. 
Physical Examinations ................................................................................................28 
9.3.2. 
Vital Signs ......................................................................................................................28 
9.3.3. 
Clinical Safety Laboratory Assessments ..................................................................29 
9.3.4. 
Data Safety Monitoring Board ....................................................................................29 
9.4. 
Adverse Events ............................................................................................................30 
9.4.1. 
Time Period and Frequency for Collecting AE and SAE Information ..................30 
9.4.2. 
Follow-up of an AE and/or SAE .................................................................................30 
9.4.3. 
Adverse Events of Special Interest ...........................................................................30 
9.4.4. 
Regulatory Reporting Requirements for SAE ..........................................................31 
9.4.5. 
Pregnancy .....................................................................................................................31 
9.5. 
Treatment of Overdose ...............................................................................................32 
9.6. 
Pharmacokinetics .........................................................................................................32 
9.7. 
Pharmacodynamics .....................................................................................................32 
10. 
Statistical Considerations .......................................................................................33 
10.1. 
Sample Size Determination ........................................................................................33 
10.2. 
Populations for Analyses ............................................................................................33 
10.3. 
Statistical Analyses ......................................................................................................34 
10.3.1. Efficacy Analyses .........................................................................................................34 
10.3.2. Safety Analyses ............................................................................................................35 
10.3.3. Other Analyses .............................................................................................................36 
10.3.4. Interim Analyses ...........................................................................................................36 
11. 
References ...................................................................................................................37 
12. 
Appendices ..................................................................................................................40 
Appendix 1:  Abbreviations, Trademarks & Glossary .....................................................41 
Appendix 2:  Clinical Laboratory Tests ...............................................................................46 
Appendix 3:  Study Governance Considerations .............................................................47 
Appendix 4:  Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ..................................................................50 
Appendix 5:  Contraceptive Guidance and Collection of Pregnancy Information ..54 
Appendix 6:  Study Organization ..........................................................................................57 
Appendix 7:  Summary of Versions and Changes ...........................................................59 
 


 
Protocol Version 1.4 
 
 
Page 4 of 59 
1. 
Synopsis 
 
Protocol Title: Alvelestat (MPH966) for the Treatment of ALpha-1 ANTitrypsin Deficiency (ATALANTa) 
 
Rationale:  
 
Alpha-1 antitrypsin deficiency (AATD) is the most common genetic cause of chronic obstructive pulmonary 
disease (COPD) and early-onset emphysema.  AATD is characterized by low AAT levels; leading to excessive 
neutrophil elastase (NE) mediated lung destruction.  Current treatment requires the periodic infusion of pooled 
AAT derived from human plasma, but this therapeutic approach (termed augmentation) does not definitively 
slow the rate of lung function decline and is very expensive.  In addition, it is not clear that the currently 
recommended dose for augmentation fully controls lung inflammation and destruction.  Alvelestat (MPH966, 
formerly AZD9668) is a potent, selective, and reversible, oral inhibitor of human NE. Suppression of NE is 
expected to reduce lung damage and may slow disease progression. This study is to establish proof of clinical 
concept by investigating the mechanistic effect and safety of alvelestat (MPH966) in patients with AATD.  
 
Overall Design: 
 
This is a Phase 2, multicenter, double-blind, randomized (1:1), placebo-controlled, 12-week, proof-of-concept 
study to evaluate the safety and tolerability as well as the mechanistic effect of oral administration of alvelestat 
(MPH966) in subjects with confirmed AATD defined as Pi*ZZ, Pi*SZ, Pi*null, or another rare 
phenotype/genotype known to be associated with either low (serum AAT level <11 μM or <57.2 mg/dL) or 
functionally impaired AAT including “F” or “I” mutations. 
 
Objectives and Endpoints: 
 
Objective 
Endpoint 
Primary 
• 
To evaluate the effect of alvelestat (MPH966) 
administered twice daily (bid) for 12 weeks on 
blood markers of neutrophil elastase activity 
• 
Within-individual % change from baseline in 
plasma desmosine/isodesmosine at end of 
treatment with MPH966 
• 
To evaluate the safety and tolerability of alvelestat 
(MPH966) administered twice daily (bid) for 12 
weeks 
• 
Numbers and % of subjects who experience at 
least 1 treatment-emergent adverse event 
• 
Adverse events of special interest (liver function 
abnormalities, corrected QT interval/cardiac, 
infections, and neutropenia) 
Secondary 
• 
To evaluate the effect of alvelestat (MPH966) on 
other 
blood 
pharmacodynamic 
markers 
of 
neutrophil activation and elastase activity 
• 
Change 
from 
baseline 
in 
plasma 
desmosine/isodesmosine at end of treatment 
compared to placebo 
• 
Change from baseline in blood Aα-Val360, NE, EL-
NE, Proteinase 3, and Cathepsin B at end of 
treatment compared to placebo 
• 
To evaluate the effect of alvelestat (MPH966) on 
blood biomarkers of lung tissue degradation 
• 
Change from baseline in blood EL-CG, EL-P3, 
PGP, C6M, C1M, and PRO-C6, at end of 
treatment compared to placebo 


 
Protocol Version 1.4 
 
 
Page 5 of 59 
Objective 
Endpoint 
• 
To evaluate the effect of alvelestat (MPH966) on 
biomarkers of inflammation in blood 
• 
Change from baseline in blood high sensitivity C 
reactive protein, interleukin [IL]-6, IL-8, IL-1β, 
RANTES, fibrinogen, MMPs, and MPO at end of 
treatment compared to placebo 
• 
To evaluate the effect of alvelestat (MPH966) on 
neutrophil activation, elastase, and inflammatory 
activity in lung 
• 
Change 
from 
baseline 
in  
desmosine/isodesmosine, NE, NE activity, Aα-
Val360, EL-NE, Proteinase 3, and Cathepsin B; 
inflammatory biomarkers (IL-6, IL-8, IL-1β, LTB4, 
RANTES, 
PGP) 
at 
end 
of 
treatment 
in 
bronchoalveolar lavage (BAL) compared to 
placebo 
• 
Change 
from 
baseline 
in 
desmosine/isodesmosine, NE, NE activity, Aα-
Val360, EL-NE, Proteinase 3, and Cathepsin B, and 
inflammatory biomarkers (IL-6, IL-8, IL-1β, LTB4, 
RANTES, PGP) at end of treatment in induced 
sputum compared to placebo 
Exploratory 
• 
To evaluate the effect of alvelestat (MPH966) on 
pulmonary function 
• 
Change 
from 
baseline 
in 
pre-and 
post-
bronchodilator forced expiratory volume in 1 
second (FEV1), forced vital capacity (FVC), 
FEV1/FVC (total and percent predicted), and 
maximal mid-expiratory flow at end of treatment 
• 
To evaluate the effect of alvelestat (MPH966) on 
respiratory symptoms, breathlessness, and health 
status 
• 
Change from baseline in St. George’s Respiratory 
Questionnaire (SGRQ), COPD Assessment Test 
(CAT), Modified Medical Research Council 
Questionnaire (MMRC), San Diego Breath 
Questionnaire (SOBQ) and daily symptom scores 
• 
To evaluate PK efficacy relationships in AATD 
• 
PK/pharmacodynamic (PD) relationship with 
efficacy biomarkers in blood and sputum 
 
 


 
Protocol Version 1.4 
 
 
Page 6 of 59 
2. 
Schedule of Activities (SOA) 
Visit # 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
Visit 12 
Visit Description 
Pre-
bronch/ 
Screen 
Baseline 
bronch 
Randomize 
Safety 
F/U 
Safety 
F/U 
4 week 
F/U 
Safety 
F/U 
8 week 
F/U 
Safety F/U 
and Pre-
bronch 
End of study 
bronch 
Study 
End 
Washout End 
Week (from 
randomization) 
-4 to 0 
-1 
0 
+1 
+2 
+4 
+6 
+8 
+10 
+11 
+12 
+16 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
Baseline history 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Interim history and 
adverse event 
recording 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood draw 
(routine/safety) 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Blood draw 
(biomarkers) 
X 
 
X 
 
 
X 
 
X 
 
 
X 
X 
Blood (PK) 
 
 
X@ 
X 
X 
X 
 
X 
X 
 
X 
 
Pregnancy test 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
ECG 
X 
 
X@ 
X 
X 
X 
 
X 
X 
 
X 
X 
Sputum biomarkers 
X 
 
 
 
 
 
 
 
 
 
X 
 
Spiro- pre and post BD 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
Spiro – post BD 
X 
 
 
 
 
 
 
 
X 
 
 
 
PROs# 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
Bronchoscopy 
 
X 
 
 
 
 
 
 
 
X 
 
 
Phone contact 
 
X 
 (day after) 
 
 
 
 
 
 
 
X  
(day after) 
 
 
Electronic diary 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
#Patient reported outcomes to include Modified Medical Research Council questionnaire (MMRC), COPD assessment test (CAT), St George Respiratory Questionnaire (SGRQ), 
San Diego Shortness of Breath Questionnaire; @ pre-dose and between 1 and 2 hours post-dose 


 
Protocol Version 1.4 
 
 
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3. 
Introduction 
 
3.1. 
Background 
 
COPD affects nearly 24 million individuals and is the fourth leading cause of death in the United States1-4.  COPD 
is a heterogeneous disease characterized by progressive airflow obstruction, excessive inflammation, and 
protease/anti-protease imbalance 5,6.  AATD is the most common genetic cause of COPD and emphysema, 
accounting for 1-4% of cases of COPD in the United States and affecting between 70,000-100,000 individuals 7-
9.  AAT is encoded by the SERPINA1 gene and mutations in SERPINA1 cause absence or misfolding of the AAT 
protein, resulting in severely reduced plasma and lung levels of AAT.  The most common variants conveying 
increased risk for COPD associated with AATD are the Pi*ZZ and Pi*(null) (null) phenotypes, accounting for very 
low or absent AAT respectively.  In contrast to the general COPD population, individuals with AATD have early-
onset severe emphysema, a more rapid decline in lung function, and an increased risk for liver dysfunction 10.  
The disease often affects people in the fourth and fifth decades of life, leading to substantial loss of productivity 
and societal contributions7.  Current therapies for AATD include the use of bronchodilators, inhaled 
corticosteroids, and intravenous AAT augmentation using pooled, human plasma derived AAT.  AAT 
augmentation is indicated for individuals with emphysema and AATD, including individuals with the Pi*ZZ, Pi*SZ, 
Pi*Z (null), or Pi*(null) (null) mutations.  AAT augmentation has been shown to slow the loss of lung parenchyma 
as measured by CT lung density, but unfortunately does not definitively affect lung function decline, respiratory 
symptoms, exacerbations, or survival9,11.  Further, AAT augmentation is very expensive with direct annual costs 
exceeding $100,000 per patient including the costs associated with technical expertise required for repeated 
intravenous infusion.  Recent studies also suggest that the currently recommended dose of augmentation does 
not adequately control NE activity, lung inflammation and consequent lung destruction pointing to the need for 
additional NE inhibition to improve outcomes12.    
 
The mechanisms by which AATD leads to COPD and emphysema are based primarily on the paradigm of 
protease-antiprotease imbalance 7,8,13.  AAT is a member of the serine protease inhibitor superfamily of proteins 
which play a role in inactivating NE and other proteases14,15.  AAT reacts with NE much more readily than other 
proteases, including proteinase 3 (PR3), cathepsin G (CatG), and trypsin, and in the lung plays a major role in 
mitigating against NE-mediated elastolysis.  In AATD, individuals not only have quantitatively less AAT, but the 
enzyme is less effective in inhibiting NE16.  NE is a protease stored in the azurophilic granules of neutrophils and 
causes more robust proteolysis and connective tissue degradation compared to other proteases, including CatG 
and PR3, contained in the same azurophilic granules 17.  Under normal circumstances, NE is regulated by AAT, 
however, in conditions like COPD, and in particular AATD, the extracellular free enzyme NE concentration 
exceeds the buffering capacity of AAT 7,15.  Thus, NE causes direct lung tissue destruction and initiates a cascade 
resulting in pulmonary inflammation, mucus overproduction, and further damage to lung tissue and extracellular 
matrix18,19.     
 
Elastin is responsible for the elasticity of the lungs and is the substrate for NE20-22.  Elastin is a highly insoluble 
protein formed by cross-linking tropoelastin with desmosine and isodesmosine (collectively referred to as DES).  
Elastin degradation generates several elastin fragments, including DES20.  As these molecules are found 
exclusively in mature elastin in humans, they are useful biomarkers for measuring lung elastin degradation and 
have been measured in lung tissue, sputum, bronchoalveolar lavage (BAL), urine, and blood in patients with 
AATD20,23-25.  DES as well as other NE-specific markers of elastin or collagen turnover (EL-NE) are associated 
with CT emphysema, lung function, and with other markers of inflammation in COPD and in AATD 26-30.  Further, 
AAT augmentation therapy has been demonstrated to reduce DES levels, validating their use as a marker for 
target modulation in trials targeting NE 31. 
 
MPH966 (previously named AZD9668) is a potent, selective, and orally available neutrophil elastase (NE) 
inhibitor32,33.  It has been developed as treatment for pulmonary diseases characterized by increased protease 
activity and neutrophilic inflammation, including bronchiectasis, cystic fibrosis (CF), and COPD33-38. In Phase 2 
clinical trials, MPH966 improved lung function in bronchiectasis, reduced markers of elastin degradation in CF, 
and reduced inflammatory markers in non-AATD patients with COPD.  MPH966 was well tolerated in these trials 


 
Protocol Version 1.4 
 
 
Page 8 of 59 
and no significant safety concerns were raised. However, in the COPD studies, MPH966 failed to achieve the 
primary efficacy endpoint of lung function improvement, due in part to the heterogeneous nature of population 
enrolled33,34.  AATD leads to the only true unique endotype in COPD 19,39 and is caused by a genetic mutation 
leading to unopposed NE activity which in turn promotes accelerated lung destruction and early-onset 
emphysema7,8.  Thus, AATD related COPD is the most ideally suited disease to test anti-NE therapy, and this 
project will examine the potential benefit of MPH966. 
 
MPH966 has high binding affinity and potently inhibits NE activity with an IC50 of 12 nM and Ki of 9.4 nM for 
human NE32.  MPH966 abrogated acute lung injury in mice and rats and decreased pulmonary inflammation 
(neutrophils and IL-1b) in smoking injury models32.  In chronic smoke exposure models in guinea pigs, MPH966 
prevented airspace enlargement and alveolar remodeling.  In ex vivo experiments, MPH966 inhibited zymosan-
stimulated NE activity in human blood, with an IC95 at plasma concentrations of 300nM32.  A detailed description 
of the chemistry, pharmacology, efficacy, and safety of alvelestat (MPH966) is provided in the Investigator 
Brochure (Version 12).  
 
To date, 12 clinical trials have been conducted using MPH966 in non-CF bronchiectasis, CF, bronchiolitis 
obliterans syndrome, and COPD.  Although none of these trials achieved their primary endpoint, significant 
improvements in FEV1 were observed in non-CF bronchiectasis and improvement in inflammatory markers were 
observed in CF and in non-AATD related COPD.  These trials compared placebo to MPH966 60mg twice per 
day and plasma MPH966 levels averaged 200nM, suggesting the 60mg dose was at the lower end of the dose 
range to achieve adequate target engagement.  Thus, a higher dose of MPH966 is needed to achieve the IC95 
(plasma MPH966 concentration of >300nM). In all previous trials, MPH966 was well tolerated with no treatment 
emergent significant adverse events, ECG or vital sign changes, and no dose related liver function abnormalities 
were observed. 
   
The scientific premise that NE inhibition ameliorates ongoing elastolysis in AATD will be tested.  If MPH966 
blocks NE activity in the lungs of AATD patients with PI*ZZ, Pi*SZ, or PI*(Null) (Null) phenotypes, we predict that 
it will provide the first disease-modifying treatment in AATD and provide a paradigm shifting oral therapeutic 
strategy.  This would transform the care of an orphan disease in a patient population with an unmet medical 
need.  The first stage in the development of alvelestat (MPH966) in AATD-related emphysema is this proof-of-
concept trial. The results of this study will determine progression to phase 3 clinical efficacy studies.    
 
3.2. 
Study Rationale 
 
The aims of this study are to build on the previous alvelestat (MPH966) clinical experience and to confirm 
mechanistic efficacy through elastase inhibition in the AATD population and investigate the safety and tolerability 
of alvelestat (MPH966) in the target population. Clinical efficacy endpoint studies in AATD-related lung disease 
often involve longer-term studies and are therefore inappropriate for decision making at the early stages of 
clinical development. The availability of biomarkers of elastolysis, which have been investigated in AATD, 
correlate with lung damage, and show treatment response over periods of 4 to 12 weeks 23,25,31, enables a study 
design to demonstrate mechanistic effects over an appropriate time period for a proof-of-concept trial. Greater 
efficacy and clinical benefit is expected by targeting patients with AATD-related lung disease, in which neutrophil 
elastase is considered the key pathogenic driver, and by using a dose of alvelestat (MPH966) to maintain 
neutrophil elastase inhibition throughout the 24-hour period. 
 
Biomarkers of inflammation and lung matrix breakdown will be used to provide evidence that the inhibitory effect 
of alvelestat (MPH966) on neutrophil elastase may deliver potential clinical benefit demonstrated by effects on 
the pathogenic progresses that drive disease progression. This potential will be tested in patients receiving 
augmentation, which is the standard of care in many countries, as well as in those not receiving augmentation. 
These efficacy data in combination with safety and tolerability will be used to make progression decisions on 
alvelestat (MPH966) development in AATD.  


 
Protocol Version 1.4 
 
 
Page 9 of 59 
4. 
Objectives and Endpoints 
 
Objective 
Endpoint 
Primary 
• 
To evaluate the effect of alvelestat (MPH966) 
administered twice daily (bid) for 12 weeks on 
blood markers of neutrophil elastase activity 
• 
Within-individual % change from baseline in plasma 
desmosine/isodesmosine at end of treatment with 
MPH966 
• 
To evaluate the safety and tolerability of 
alvelestat (MPH966) administered twice daily 
(bid) for 12 weeks 
• 
Numbers and % of subjects who experience at least 1 
treatment-emergent adverse event 
• 
Adverse events of special interest (liver function 
abnormalities, 
corrected 
QT 
interval/cardiac, 
infections, and neutropenia) 
 
Secondary 
• 
To evaluate the effect of alvelestat (MPH966) 
on other blood pharmacodynamic markers of 
neutrophil activation and elastase activity 
• 
Change 
from 
baseline 
in 
plasma 
desmosine/isodesmosine 
at 
end 
of 
treatment 
compared to placebo 
• 
Change from baseline in blood Aα-Val360, NE, EL-NE, 
Proteinase 3, and Cathepsin B at end of treatment 
compared to placebo 
• 
To evaluate the effect of alvelestat (MPH966) 
on 
blood 
biomarkers 
of 
lung 
tissue 
degradation 
• 
Change from baseline in blood EL-CG, EL-P3, PGP, 
C6M, C1M, and PRO-C6, at end of treatment 
compared to placebo 
• 
To evaluate the effect of alvelestat (MPH966) 
on biomarkers of inflammation in blood 
• 
Change from baseline in blood high sensitivity C 
reactive 
protein, 
interleukin 
[IL]-6, IL-8, IL-1β, 
RANTES, fibrinogen, MMPs, and MPO at end of 
treatment compared to placebo 
• 
To evaluate the effect of alvelestat (MPH966) 
on neutrophil activation, elastase, and 
inflammatory activity in lung 
• 
Change from baseline in  desmosine/isodesmosine, 
NE, NE activity, Aα-Val360, EL-NE, Proteinase 3, and 
Cathepsin B; inflammatory biomarkers (IL-6, IL-8, IL-
1β, LTB4, RANTES, PGP) at end of treatment in 
bronchoalveolar lavage (BAL) compared to placebo 
• 
Change from baseline in desmosine/isodesmosine, 
NE, NE activity, Aα-Val360, EL-NE, Proteinase 3, and 
Cathepsin B, and inflammatory biomarkers (IL-6, IL-8, 
IL-1β, LTB4, RANTES, PGP) at end of treatment in 
induced sputum compared to placebo 
Exploratory 


 
Protocol Version 1.4 
 
 
Page 10 of 59 
Objective 
Endpoint 
• 
To evaluate the effect of alvelestat (MPH966) 
on pulmonary function 
• 
Change from baseline in pre-and post-bronchodilator 
forced expiratory volume in 1 second (FEV1), forced 
vital capacity (FVC), FEV1/FVC (total and percent 
predicted), and maximal mid-expiratory flow at end of 
treatment 
• 
To evaluate the effect of alvelestat (MPH966) 
on respiratory symptoms, breathlessness, 
and health status 
• 
Change from baseline in St. George’s Respiratory 
Questionnaire (SGRQ), COPD Assessment Test 
(CAT), 
Modified 
Medical 
Research 
Council 
Questionnaire 
(MMRC), 
San 
Diego 
Breath 
Questionnaire (SOBQ) and daily symptom scores 
• 
To evaluate PK efficacy relationships in 
AATD 
• 
PK/pharmacodynamic (PD) relationship with efficacy 
biomarkers in blood and sputum 
 


 
Protocol Version 1.4 
 
 
Page 11 of 59 
5. 
Study Design  
 
5.1. 
Overall Design  
 
This will be a multicenter, double-blind, randomized, placebo-controlled trial. One dose of alvelestat (MPH966), 
120 mg bid, will be tested against placebo. These doses are based on PK and PD modelling of alvelestat 
(MPH966) inhibition of human neutrophil elastase.  
 
The participants will be those patients with the AATD at risk for emphysema (Pi*ZZ, Pi*SZ, Pi*null, or another 
rare phenotype/genotype known to be associated with either low (serum AAT level <11 μM or <57.2 mg/dL) or 
functionally impaired AAT including “F” or “I” mutations)  
 
Following a screening period of up to 4 weeks, patients will be dosed with study treatment or placebo for 12 
weeks, with a subsequent 4-week follow-up period for safety and determination of the offset of the mechanistic 
effect of MPH966 on the primary endpoint (desmosine/isodesmosine). 
 
The study is divided into 3 phases:  a screening phase, treatment phase, and washout phase as detailed below: 
Figure 1: 
Study Schematic 
 
 
• 
A screening period from Week -4 to Day -1.  Baseline safety assessments and measurement of DES in 
blood, sputum, and BAL (in those who consent to bronchoscopy) will occur prior to randomization and 
treatment allocation. 
 
• 
A treatment period consisting of alvelestat (MPH966) 120mg bid or placebo for 12 weeks.  Safety 
assessments including tests of liver function, ECG, and chemistries will be assessed at the week 1 and week 
2 visits and then bi-weekly for the remainder of the 12-week treatment period.  Blood will be collected at the 
Week 4, 8, and 12 visit for biomarker analysis.  Sputum will be collected at the week 12 visit. Follow-up BAL 
will be collected at week 11.   
 
• 
A washout period from Week 12 to Week 16.  Blood will be collected for biomarker analysis at week 16. 


 
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5.2. 
Number of Participants 
 
A maximum of 66 participants will be randomized so that approximately 60 evaluable participants complete the 
study.  
 
5.3. 
End of Study Definition 
 
The end of the study is defined as the date of all data being entered into the study database and the database 
being locked and ready for analysis. 
 
5.4. 
Scientific Rationale for Study Design  
 
The aims of this study are to build on the previous alvelestat (MPH966) clinical experience and to confirm its 
mechanistic efficacy through elastase inhibition in the AATD population and to investigate the safety and 
tolerability of alvelestat (MPH966) in the target population.  
 
Clinical efficacy endpoint studies in AATD-related lung disease involve long-term treatment due to the slow rate 
of structural lung and functional decline and are therefore inappropriate for decision making at the early stages 
of drug development. The availability of biomarkers of neutrophil elastase activity (such as 
desmosine/isodesmosine and Aα-Val360), which have been investigated in AATD, correlate with lung damage 
and show treatment response over periods of 4 to 12 weeks, enables a study design to demonstrate mechanistic 
effects over an appropriate time period for a proof-of-concept trial40. Biomarkers of inflammation and lung matrix 
breakdown will be used to provide evidence that the inhibitory effect of alvelestat (MPH966) on neutrophil 
elastase may deliver clinical benefit demonstrated by effects on the pathogenic processes that drive disease 
progression. These efficacy data, in combination with information about safety and tolerability, will be used to 
make progression decisions on further alvelestat (MPH966) development in AATD. 
 
5.5. 
Justification for Dose  
 
Single oral doses of alvelestat (MPH966) 2 mg to 150 mg have been evaluated in healthy subjects. Alvelestat 
(MPH966) is rapidly absorbed (median time to reach peak concentration 0.5 to 1.5 h), with a dose-proportional 
increase in systemic exposure. Multiple dosing shows no clinically relevant accumulation, and the PK profile was 
generally similar between healthy subjects and patients with lung disease. The PK data supported development 
of a model to simulate predicted doses and exposures for this study. 
 
Alvelestat (MPH966) demonstrates dose-dependent inhibition of zymosan-stimulated neutrophil elastase activity 
in clinical studies36. Although at plasma alvelestat (MPH966) concentrations of >100 nM, neutrophil elastase 
inhibition was differentiated from that observed on placebo, plasma concentrations >300 nM, were required to 
give meaningful effects achieving a mean neutrophil elastase inhibition of 92%. Through observed and modelled 
PK, 120 mg bid is anticipated to provide a sufficient range of plasma exposures to achieve neutrophil elastase 
inhibition through PK levels >300 nM and will enable the concentration-effect relationship of alvelestat (MPH966) 
to be characterized.  
 
As summarized below, the preclinical toxicology studies provide adequate safety margins for progressing to the 
120 mg bid dose for 12 weeks in this study. The clinical safety experience with alvelestat to date has shown no 
signals that prevent progression of the proposed dose. The potential concern around transaminase elevation is 
considered monitorable and reversible. The safety of patients will be managed through the exclusion and 
inclusion criteria and safety monitoring approach taking into account the preclinical toxicology data and clinical 
safety information. 
 


 
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5.6. 
Preclinical Safety Studies 
 
The safety margins for alvelestat (MPH966) have been evaluated in preclinical toxicology studies of up to 6 
months in rats, 12 months in dogs, and 3 months in mice. 
   
In rats, the no adverse effect level (NOAEL) was 370 mg/kg/day (1 month gavage) and 500 mg/kg/day (dietary 
1 to 6 month studies). These were the highest doses studied, and no toxicity was observed. 
 
In dog, 1-, 3-, and 12-month toxicology studies at doses of 1.2, 12, and 122 mg/kg showed limited effect at the 
intermediate and high doses, including small decreases in body weight, small increases in plasma creatinine 
and triglycerides, and minor effects on electrocardiogram (ECG) with a transient increase of the QTc by Van de 
Water’s correction formula (QTcV) (<10%). The NOAEL was considered to be 122 mg/kg. In telemetered dogs 
at doses of 50 mg/kg (corresponding to a peak plasma concentration of 39.9 µM), a mean increase of 9% 
(individual increases of 8% to 14%) in QTcV was seen. 
 
In mice, alvelestat (MPH966) was well tolerated at doses up to 2000 mg/kg. Histopathology indicated slight focal 
hepatic necrosis above control. Additional effects in liver included minor increase in glycogen vacuolation at 
2000 mg/kg, slight hypertrophy in males at 1000 mg/kg, and increased incidence above control of inflammatory 
foci in females at 1000 mg/kg. A recovery group indicated possible reversibility, although the interpretation was 
difficult due to the low-grade change. Overall, focal necrosis is regarded as a non-specific response in mice, with 
no signs of progression or persistence and the relevance for humans is likely to be limited. 
 
Preclinical toxicology findings, with the exception of QTc change, would be expected to be driven by area under 
the curve (AUC). Based on preclinical data, a human exposure limit corresponding to the AUC at the NOAEL 
(500 mg/kg) in the rat 6-month study (free AUC of 14.7 µM.h, corresponding to a total human AUC of 25.8 µM.h) 
is considered as acceptable in clinical studies. Significantly higher exposure levels have been evaluated in dogs 
for 12 months without any adverse effects.   
 
The 120 mg bid dose in man is predicted to give an AUC of 11791 nM.h, approximately 53.8-fold lower than that 
at the NOAEL in the 12-month study in dogs and 21.5-fold lower than NOAEL in the 6 month study in rats. The 
AUC is predicted to be approximately 9-fold below the level where liver findings in mice (increase in background 
pathology of likely limited relevance to man) were seen. 
    
An additional consideration when calculating the safety margins in man compared to toxicology studies is the 
differences in plasma protein binding seen across the species. Alvelestat (MPH966) plasma protein binding is 
less in humans than the other species investigated.  For more detailed information on the toxicology and 
nonclinical safety studies conducted to date, please refer to the Investigator’s Brochure. 
 
5.7. 
Clinical Safety Studies 
 
Clinical experience comes from 12 completed healthy volunteer and patient studies in which 1149 subjects have 
received at least 1 dose of alvelestat (MPH966). The highest single dose that has been given is 150 mg and the 
highest repeat dose is 240 mg bid (for 6 months). In clinical studies, 540 COPD patients have received 60 mg 
bid for 3 months and 22 patients with bronchiectasis and 26 patients with cystic fibrosis have received 60 mg bid 
for 28 days. Completed clinical studies to date have not revealed any adverse effects on blood pressure, ECG, 
hematology, or urinalysis that could be linked to any of the observations in toxicology studies. For clinical 
chemistry, there has been 1 patient with bronchiectasis with an instance of transient raised transaminases and 
1 patient with cystic fibrosis with an increase in creatine kinase, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), and lactate dehydrogenase. In the studies in COPD patients, there were 14 instances 
where patients experienced raised ALT or AST to ≥3 × upper limit of normal (ULN) across the studied doses 
(alvelestat [MPH966] 5, 20, and 60 mg bid). Although definitive evidence of dose relationship was lacking, there 
was a suggestion of an increased incidence of liver transaminase elevations in patients on alvelestat (MPH966) 
for which there were no definitive alternative explanations. The highest transaminase elevations occurred in the 


 
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highest alvelestat (MPH966) dose (60 mg bid). There have been no cases of Hy’s law related to alvelestat 
(MPH966) treatment reported in any of the studies to date (including up to 240 mg bid). The liver abnormalities 
noted to date with alvelestat, including from study MPH966-2-01 have been infrequent (only 5 liver-related 
adverse events have been reported and no SAE/AESI of liver abnormalities have been reported in study 
MPH966-2-01) and rarely above 3x ULN. Furthermore, all abnormal liver changes that have been observed have 
been reversible either with or without study drug interruption.  
 
Alvelestat (MPH966) is currently being administered in 3 ongoing clinical studies. In a study in patients with 
bronchiolitis obliterans syndrome associated with chronic graft versus host disease following allogenic 
hematopoietic stem cell transplantation (NCT02669251), doses of up to 240 mg bid are being given. To date, 7 
patients have received 240 mg bid dose for up to 6 months. One patient underwent dose reduction to 180 mg 
bid following a SAE of severe gastroenteritis and renal failure that was considered unrelated to alvelestat 
(MPH966). A second patient had elevation of transaminases with temporary treatment discontinuation on a dose 
of 60 mg bid. The event was considered related to alvelestat (MPH966), and drug was restarted at the dose of 
60 mg bid at recovery following a 2-week temporary discontinuation. In an ongoing blinded study in AATD-related 
lung disease (MPH966-2-01, NCT03636347) 50 participants have been randomized to date to alvelestat (either 
120 mg bid, 240 mg bid) or placebo (1:1:1) for 12 weeks duration, no safety signals have been identified. 
 
For more detailed information on clinical safety studies conducted to date, please see additional details below 
and also refer to the current Investigator’s Brochure. 
 
5.8. 
Benefit-Risk Assessment 
 
Patients with AATD-related lung disease present at a younger age and show more rapid progression that non-
AATD COPD. The most common symptoms are shortness of breath, wheeze, chronic cough, and sputum 
production with a propensity for recurrent respiratory infections and bronchiectasis. Available therapies consist 
of chronic symptomatic treatment for COPD with bronchodilators and inhaled corticosteroids as well as 
management of acute exacerbations. None of these affect the progressive decline in lung function that may lead 
to severe structural damage, loss of lung function, and the need for lung volume reduction or transplantation in 
a select group. Augmentation with AAT protein is used in severe cases, with some evidence for effect on 
progression of lung damage. However, the costs of administration and the inconvenience for patients of a weekly 
intravenous therapy mean there is a high unmet need for more effective and convenient therapy.  
 
Alvelestat (MPH966) is a potent, selective, and reversible inhibitor of human neutrophil elastase. Efficacy has 
been demonstrated in in vivo models of lung inflammation and elastase-induced lung injury32. Across clinical 
studies in COPD, cystic fibrosis, and bronchiectasis, there has been some evidence for effects on elastin 
breakdown, inflammatory biomarkers, and lung function. The extent of these effects was not consistent in all 
studies. This may be due to the heterogeneity of the pathogenesis and/or the doses used (maximum 60 mg bid) 
that would not be expected to adequately inhibit neutrophil elastase, allowing inflammatory “escape”. Greater 
efficacy and clinical benefit is expected by targeting patients with AATD-related lung disease, in which neutrophil 
elastase is considered the key pathogenic driver, and by using a dose of alvelestat (MPH966) to maintain 
neutrophil elastase inhibition throughout the 24-hour period.  
 
Alvelestat (MPH966) has been previously evaluated in clinical studies of up to 12 weeks in duration as a potential 
novel oral treatment to control the symptoms and exacerbations of COPD and reduce the progression and 
severity of the disease. Alvelestat (MPH966) has also been evaluated in studies in 2 other airway diseases 
characterized by neutrophilic inflammation: bronchiectasis37 and cystic fibrosis35. Both studies were of 28 days 
in duration.  
 
Headache was the most frequently reported AE in 8 of the 12 completed studies to date. In healthy volunteer 
studies, headache was reported more commonly in the avelestat (MPH966) group than the placebo group. 
Headache was generally mild in intensity (although 1 subject had severe headache), and there was no evidence 
of a dose–related relationship. In studies with cystic fibrosis and bronchiectasis, headache was also generally 


 
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reported more commonly in the alvelestat (MPH966) group compared to placebo. In the BREEZE 
(D0520C00012) and MISTRAL (D0520C00020) COPD studies, headache remained one of the most common 
AEs reported and was the most commonly reported treatment-related AEs (3 patients in the alvelestat [MPH966] 
60 mg group) in the MISTRAL study. Headache has also been the most frequently reported adverse event 
particularly in the 240 mg bid dose group in study MHP966-2-01. 
 
In the Phase 2b COPD program, there were 14 reported events of raised ALT or AST to ≥3 × ULN across the 
studied doses (alvelestat [MPH966]) 5, 20, and 60 mg bid); there were no cases of Hy’s law during the treatment 
period. Although definitive evidence of dose relationship was lacking, there was a suggestion of an increased 
incidence of liver transaminase elevations in patients on alvelestat (MPH966) for which there were no definitive 
alternative explanations. The highest transaminase elevations occurred in the highest alvelestat (MPH966) dose 
(60 mg bid). Elevations in hepatic biochemistry assessments (transaminases) observed in patients in the 
alvelestat (MPH966) studies were confounded by alcohol or by concomitant medication, but an effect of 
alvelestat (MPH966) cannot be excluded at this time. A significant proportion (49%) of adult patients with Pi*ZZ 
AATD have been shown to have small increases in levels of ALT41 and some develop cirrhosis. It is therefore 
possible that patients with AATD may be more susceptible to liver function AEs. Therefore, exclusion criteria for 
clinically relevant hepatic fibrosis, in-study monitoring, and study treatment discontinuation criteria are in place 
to protect the safety of the subjects and liver abnormalities are included as adverse events of special interest 
(AESI). 
 
There were no other clinically relevant changes in clinical chemistry data in the completed studies with alvelestat 
(MPH966). There were also no clinically relevant changes in urinalysis were observed in the completed studies 
with alvelestat (MPH966). There were no changes in ECG or vital signs data that indicated a clear treatment 
effect of alvelestat (MPH966). However, in light of the minor changes in QTc in the dog toxicology, exclusion 
criteria and regular ECG monitoring at the time of peak concentrations of study treatment and discontinuation 
criteria will be applied in the study. Clinically significant changes in ECG are also included as an AESI. 
 
Mutations in ELAINE, the gene that encodes neutrophil elastase, are associated with cyclical neutropenia, 
severe congenital neutropenia, and susceptibility to recurrent infection. To date, no increases in rate or severity 
of infection or neutropenia have been reported with alvelestat. However, for this initial study in AATD, patients 
with neutropenia will be excluded, new onset of neutropenia will constitute a patient stopping criterion, and 
infections will be an AESI to monitor the safety profile as higher doses are explored in a new population. 
 
There have been no liver abnormalities in the current study, and those noted to date with alvelestat in study 
MPH966-2-01, also in alpha-1 antitrypsin deficiency, have also been infrequent (only 5 liver-related adverse 
events have been reported and no SAE/AESI) and rarely above 3x ULN. Furthermore, all abnormal liver changes 
that have been observed have been reversible either with or without study drug interruption up to doses of 240 
mg bid for 12 weeks. 
 
At present, based on the cumulative review of the data and with no new safety issues seen in the ongoing studies 
with dosing up to 240 mg bid of alvelestat (MPH966), the safety profile of alvelestat (MPH966) remains 
unchanged and the benefit-risk balance continues to support the clinical development of alvelestat (MPH966). 
The potential or theoretical safety concerns on liver function, QTc changes, and susceptibility to infection are 
manageable through exclusion criteria, monitoring, study treatment discontinuation criteria, and independent 
safety review through the DSMB, as detailed in Appendix 7.  
 
More detailed information about the known and expected benefits and risks and reasonably expected AEs of 
alvelestat (MPH966) may be found in the current version of the alvelestat (MPH966) Investigator’s Brochure. 


Protocol Version 1.4 
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6.
Study Population
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as protocol waivers 
or exemptions, are not permitted. 
6.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if ALL of the following criteria apply: 
Type of Participant and Disease Characteristics 
1. Capable of giving signed informed consent as described in Appendix 3, which includes compliance with the 
requirements and restrictions listed in the informed consent form and in this protocol
2. Age ≥18 and ≤80 years
3. Patients with a confirmed diagnosis of AATD: Pi*ZZ, Pi*SZ, Pi*null, or another rare phenotype/genotype
known to be associated with either low (serum AAT level <11 μM or <57.2 mg/dL) or functionally impaired
AAT including “F” or “I” mutations.
4. FEV1 ≥25% predicted
5. Patients will be eligible if they are either a) are not currently receiving augmentation treatment and have not
received augmentation in the 12 weeks prior to screening or b) have received weekly infusions of
augmentation at 60 mg/kg for at least 12 weeks prior to screening and intend to continue augmentation
through the study period.
6. Male or female sex
a. Male participants must agree to use a highly effective contraception as detailed in Appendix 5 during 
the treatment period and for at least 4 days after the last dose of study treatment and refrain from 
donating sperm during this period
b. Female participants are eligible to participate if not pregnant; not breastfeeding; and at least one of
the following conditions is met:
i.
Not a woman of childbearing potential as defined in Appendix 5
OR 
ii.
A woman of childbearing potential who agrees to follow the contraceptive guidance in
Appendix 5. During the treatment phase and for at least 4 days after the last dose of study 
medication.  
6.2. 
Exclusion Criteria 
Participants are excluded from the study if ANY of the following criteria apply: 
Excluded Medical Conditions 
1. Subjects with Pi*MZ, Pi*FM, Pi*MS, Pi*SS, or other AATD phenotypes/genotypes not known to be
independently associated with emphysema.
2. Any clinically diagnosed lung disease other than COPD such as diffuse interstitial lung diseases, cystic
fibrosis, or clinically significant bronchiectasis as determined by the Investigator
3. Acute exacerbation of underlying lung disease requiring oral steroids and/or antibiotics within 4 weeks of
baseline
4. Acute or chronic hepatitis, including hepatitis B, hepatitis C (positive serologies, including hepatitis B and C
antibody)
5. HIV infection or other immunodeficiency or with an absolute neutrophil count ≤1.0 × 109/L
6. Abnormal liver biochemistry (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl
transferase) >1.5 × upper limit of normal or total bilirubin > upper limit of normal (unless Gilbert’s disease
with normal conjugated bilirubin)


 
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7. Any of the following laboratory abnormalities are present at baseline: 
a. Platelet count <150×109/L 
b. Serum albumin ≤ 3.5 g/dL 
c. INR ≥1.2 
d. CPK ≥ ULN. 
8. History or current evidence of cirrhosis (on biopsy or imaging), esophageal varices, ascites or hepatic 
encephalopathy. 
9. Evidence of other forms of chronic liver disease based on diagnostic testing as per the guidelines (i.e. 
autoimmune liver disease, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson’s disease, 
Hemochromatosis or iron overload). 
10. Patients with nonalcoholic fatty liver disease (NAFLD) as diagnosed by any imaging modality (or use of 
drugs associated with NAFLD for more than 2 weeks in the year prior to screening).  
11. Subjects with a history of significant alcohol consumption for a period of more than 3 consecutive months 
within 1 year prior to screening, defined as average of >20g/ day in female subjects and >30g/ day in male 
subjects. 
12. Fibrosis-4 (FIB-4) score >3.25 
13. Any of the following cardiovascular conditions within 6 months prior to the screening visit:  
a. Myocardial infarction or unstable angina 
b. Coronary artery bypass surgery, balloon angioplasty, percutaneous coronary intervention, or carotid 
revascularization procedure 
c. Uncontrolled hypertension  
d. Stroke or transient ischemic attack 
14. Congestive heart failure (New York Heart Association III/IV) with left ventricular ejection fraction < 40% 
15. Any clinically significant 12-lead electrocardiogram abnormalities at screening or baseline, including 
corrected QT interval by Fridericia’s correction method >450 ms or history of significant cardiac dysrhythmia, 
including long QT syndrome 
16. History of cancer within the last 5 years, except for well-treated basal cell carcinoma and squamous cell 
carcinoma of the skin 
17. Other documented comorbidities or laboratory abnormalities that in the opinion of the Investigator could affect 
the outcome of the study assessments, participant safety, or ability of the participant to comply with the 
requirements of the protocol 
 
Excluded Prior/Concomitant Therapy 
 
18. Daily use of prednisone (>10mg daily), or other systemic glucocorticoids at comparable or higher equivalent 
dose, or use of other immunosuppressant therapies are prohibited  
19. Immunomodulating monoclonal antibodies within 6 months prior to screening are prohibited 
20. Daily use of non-steroidal anti-inflammatory drugs (NSAIDs) is prohibited.  Daily use of acetaminophen up 
to 2 g per day and aspirin up to 325 mg per day is permitted. 
21. Initiation of drugs known for hepatotoxic potential within the 28 days prior to screening including but not 
limited to: statins, NSAIDS, amoxicillin/clavulanate, PDE inhibitors (theophylline, roflumilast), and anti-
epileptics.  Subjects on established treatment for more than 28 days prior to screening will not be excluded. 
Requirement for medications mainly metabolized by CYP2C9 and with narrow therapeutic index (eg, 
warfarin, phenytoin) is prohibited 
 
Excluded Prior/Concurrent Clinical Study Experience 
 
22. Participation in any clinical investigation using medical devices or non-biologic treatments within 4 weeks or 
5 half-lives of the drug (whichever is longer) prior to the initial dosing (or longer if required by local regulations) 
is prohibited 
23. Participation in any clinical investigation using biologic treatment within 6 months of screening is prohibited 
24. Previous participation in a gene therapy study for AATD at any time is prohibited 


 
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Other Exclusions 
 
25. History of hypersensitivity to alvelestat (MPH966) or any of its excipients or the class of neutrophil elastase 
inhibitors  
26. Known hypersensitivity to medications used in the study procedures (e.g. midazolam, fentanyl, and lidocaine 
for bronchoscopy) 
 
6.3. 
Lifestyle Restrictions 
 
6.3.1. 
Meals and Dietary Restrictions 
 
There are no specific restrictions in respect of mealtimes and administration of study treatment. 
 
6.3.2. 
Alcohol and Tobacco 
 
Tobacco cessation is encouraged but is not required for the study duration. 
 
Participants should avoid alcohol during the 12 week active study period. 
 
6.3.3. 
Activity 
 
Subjects should not participate in unaccustomed or more vigorous exercise than usual routine in the 48 hours 
before each blood sample for laboratory safety tests. 
 
6.4. 
Screen Failures 
 
Screen failures are defined as participants who consent to participate in the clinical study but are not 
subsequently randomized. A minimal set of screen failure information is required to ensure transparent reporting 
of screen failure participants to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, available eligibility criteria, and any SAEs.  Individuals who do not meet the criteria for 
participation in this study (screen failures) may be rescreened after discussion with and approval by the Data 
Coordinating Center (DCC) and/or Principal Investigator (PI).  
 
The screening period may be extended beyond 28 days in the following circumstances after discussion with 
and approval of the DCC and/or PI: 
 
• 
All screening inclusion/exclusion criteria are met but the participant’s schedule, including genetic testing, 
prevented randomization within the screening period. 
• 
The participant experiences an acute exacerbation of COPD during the screening period. 
 
Additionally, individual laboratory parameters or screening tests may be repeated, within the screening period, if 
the result is considered aberrant or not clinically consistent with the patient’s health status. Decisions to re-test 
should be made in conjunction with the study PI. 
 
Participants who have individual laboratory parameters re-tested should have the results entered in the electronic 
case report form (eCRF).  


 
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7. 
Treatments 
 
Study treatment is defined as the investigational treatment or placebo.  
 
7.1. 
Treatments Administered 
 
Study Treatment Name: 
Alvelestat 120 mg 
Placebo 
Dosage Formulation: 
Tablet 
Tablet 
Unit Dose Strength(s) / 
Dosage Level(s): 
4 × 30 mg Alvelestat 
4 × 30 mg Placebo 
Route of Administration  
Oral 
Oral 
Dosing Instructions: 
To be taken bid, 12 hours apart and with water 
Packaging and Labeling: 
Study treatment will be provided in boxes. Each box will contain 
treatment for 7 days and will be labeled as required per U.S. 
regulations. 
Manufacturer: 
Mereo BioPharma 4 Ltd., 1 Cavendish Place, London, W1G 0QF, UK 
 
7.2. 
Method of Treatment Assignment  
 
All participants will be centrally randomized 1:1 to the 120 mg and placebo arms using an interactive web 
response system (IWRS). A unique number will be assigned to each participant and will be linked to 
randomization numbers using a randomization list produced by the DCC. These randomization numbers will be 
linked to the 2 treatment regimens, and the randomization scheme will be stratified according to genotype (Pi*ZZ, 
Pi*SZ, Pi*(Null) (Null)) and clinical center. 
 
7.3. 
Blinding  
 
This is double-blind study. The investigators, participants, Mereo and NCATS will remain blinded to the study 
treatment allocation until the end of the study. The randomization list will be kept secure from the study team, 
investigators, and participants throughout the conduct of the study and until unblinding is authorized by the DCC. 
The DSMB will be unblinded according to the DSMB charter. 
 
The IWRS will be programmed with blind-breaking instructions. The study blind may be broken for a medical 
emergency in which the knowledge of the specific blinded study treatment will affect the immediate management 
of the participant’s condition. In this case, the DCC, the NCATS Medical Monitor, and Mereo must be notified 
within 24 hours after breaking the blind. The date and reason that the blind was broken must be recorded in the 
source documentation and case report form (CRF), as applicable. 
 


 
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7.4. 
Preparation/Handling/Storage/Accountability 
 
Only participants enrolled in the study may receive study treatment, and only authorized site staff may supply or 
administer study treatment. All study treatments must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labelled storage conditions with access limited to 
the Investigator and authorized site staff. 
 
The Investigator, institution, or the head of the medical institution (where applicable) is responsible for study 
treatment accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, and final disposition 
records). 
 
Further guidance and information for the final disposition of unused study treatment are provided in the Manual 
of Procedures (MOP).  
 
7.5. 
Treatment Compliance   
 
The per-protocol dosage, timing, and mode of administration of study treatment may not be changed. Any 
departures from the intended regimen must be recorded in the electronic eCRF and reported to the DCC. 
 
7.6. 
Concomitant Therapy 
 
Treatment for Respiratory Disease 
 
Bronchodilators are allowed as prescribed. However, they should be withheld for the required time before 
spirometry as detailed in the MOP. 
 
Other regular medications for treatment of airways disease (e.g., inhaled bronchodilators or inhaled 
corticosteroids) are permitted provided the subject has been on a stable dose for 1 month before baseline. 
 
Systemic Corticosteroids 
 
Regular systemic steroids are not permitted during the study, unless clinically indicated to treat acute 
exacerbation. 
 
Vaccines 
 
Patients should be vaccinated against pneumococcus and receive annual influenza vaccination.  
 
CYP2C9 Substrates 
 
MPH966 has a weak potential to inhibit CYP2C9. Therefore, medications that are metabolized mainly by 
CYP2C9 and have a narrow therapeutic index are prohibited. Narrow therapeutic index CYP2C9 substrates 
include 
warfarin 
and 
phenytoin 
(a 
complete 
list 
is 
included 
in 
the 
MOP 
or 
online 
at 
http://medicine.iupui.edu/clinpharm/ddis/main-table/). 
 
Enhanced clinical monitoring in patients receiving sensitive/moderate sensitive CYP2C9 for enhanced clinical 
effect should be considered. Moderate sensitive substrates include tolbutamide and glimepiride. 
 
Therapies Known to Cause Liver Function Abnormalities 
 
Daily treatment with acetaminophen at doses greater than 2 g per day or non-steroidal anti-inflammatory drugs 
(NSAIDs) is not permitted during the study. Acetaminophen at doses of up to 2 g per day and aspirin up to 325 
mg per day are permitted during the study.  


 
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Initiation of drugs known for hepatotoxic potential within the 28 days prior to screening including but not limited 
to: statins, amoxicillin/clavulanate, PDE inhibitors (theophylline, roflumilast), and anti-epileptics is exclusionary.  
Subjects on established treatment for more than 28 days prior to screening will not be excluded. 
 
During the course of the study, if medications are required, a concomitant medication’s hepatotoxicity and 
alternative treatments, if possible, should be considered. In the event that no alternatives are available and the 
medication is required to treat the medical condition, the Investigator should discuss the subjects’ ongoing 
participation in the trial with the study PI and/or DCC at the earliest possible opportunity.   
 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or herbal 
supplements) that the participant is receiving at the time of enrolment or receives during the study must be 
recorded along with: 
 
• 
Reason for use 
• 
Dates of administration including start and end dates 
• 
Dosage information including dose and frequency 
 
The DCC and/or study PI should be contacted if there are any questions regarding concomitant or prior therapy. 
 
7.7. 
Treatment After the End of the Study  
 
Alvelestat (MPH966) will not be provided after the end of the study.  


 
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8. 
Discontinuation Criteria  
 
8.1. 
Discontinuation of Study Treatment  
 
In considering discontinuation of the study treatment, the Investigator should give particular consideration of the 
following: 
 
Liver Test Abnormalities 
 
The following monitoring schedule is proposed when a case of acute liver function abnormalities or worsening 
of a liver function abnormality is reported: 
 
• 
If ALT or AST are between 1.5 to 3 × ULN, regular monitoring (every 2 weeks at a minimum) is required 
until event resolution and patient can continue on study treatment during this period. 
 
• 
If ALT or AST are ≥3 × ULN, repeat the test within 48 to 72 hours and the study treatment will be 
temporarily discontinued while awaiting repeat tests results; if the repeat tests is again ≥3 × ULN or 
≥2 × pre-treatment level, testing needs to be repeated at least twice weekly until event resolution or a 
return to baseline value while the study treatment is withheld.  
 
• 
If AST or ALT are ≥5x ULN, a repeat value should be obtained within 24-48 hours. If the repeat ALT 
and AST values is ≥5 x ULN, the drug should be discontinued and the patient followed until the 
laboratory values normalize or stabilize, in addition to initiating potential (Drug Induced Liver Injury) DILI 
evaluation. 
 
Discontinue Alvelestat (MPH966) for the following hepatic adverse events:  
 
• 
Regardless of the magnitude of the transaminase elevation, if the bilirubin is elevated (any level) in 
addition to the presence of signs and symptom(s) such as rash, eosinophilia, nausea, vomiting, or right 
upper quadrant pain, 
 
• 
INR ≥1.5 and TB ≥2x ULN, irrespective of the magnitude of ALT or AST elevation.  
 
• 
TB elevation ≥2x ULN, and ALP ≥2x ULN for cholestatic liver injury. 
 
For each scenario, initiate potential DILI evaluation for alternative etiologies and obtain a hepatology 
consult. Liver biopsy should be considered for DILI. The complete liver profile including PT/INR must be 
repeated within 48-72 hours after first abnormal value is obtained. Follow the patient until laboratory 
parameters stabilize or normalize. Study medication can be restarted only if an alternative etiology is 
“definitively” identified and liver tests have returned to baseline.  Testing for alternative etiologies can 
include serology tests (hepatitis A, hepatitis B, hepatitis C, Cytomegalovirus (CMV), Epstein-Barr Virus 
(EBV), Herpes Simplex Virus (HSV), varicella zoster virus (VZV), parvovirus, toxoplasmosis), imaging, and 
pathology assessments (creatine phosphokinase, clotting) as appropriate to the clinical situation.  
 
Clinically significant liver function abnormalities should be reported as an AE/AESI. 
  


 
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When the following abnormal liver test conditions are met, study treatment MUST be discontinued, the DCC and 
study PI informed, and further steps discussed: 
 
• 
ALT/AST >5 × ULN on 2 consecutive tests within 24 to 48 hours OR 
 
• 
ALT or AST >3 × ULN and total bilirubin >2 × ULN OR 
 
• 
ALT or AST >3 × ULN and international normalized ratio (INR) >1.5 OR  
 
• 
ALT or AST >3 × ULN the appearance of worsening fatigue, nausea, vomiting, right upper quadrant 
pain/tenderness, fever, rash, or eosinophilia 
 
ECG Abnormalities 
 
If a clinically significant finding is identified (including but not limited to changes from baseline in QTcF after 
enrolment), the Investigator or qualified designee will determine if the participant can continue in the study and 
if any change in participant management is needed. This review of the ECG printed at the time of collection must 
be documented. Any new clinically relevant finding should be reported as an AE. 
 
When the following ECG change conditions are met, study treatment MUST be discontinued, the DCC and study 
PI informed, and further steps discussed: 
 
• 
Absolute QTcF >500 ms or >60 ms increase from baseline as confirmed with 3 consecutive ECGs taken 
in a 30-minute period with at least 5 minutes between each ECG. The mean of the 3 ECGs will be used 
for decision making. 
 
Other Laboratory Parameters 
 
Study treatment MUST be discontinued if the following laboratory parameters criteria are met: 
 
• 
Absolute neutrophil count less than or equal to 1.0 x 109/L on 2 consecutive repeat tests within 48 to 72 
hours. 
 
Other 
 
Study treatment MUST be discontinued if the following other criteria are met: 
 
• 
Significant safety issues (as judged by the Site Investigator). This includes AEs considered unacceptable 
by the patient and/or the Investigator 
• 
Any other protocol deviation that results in a significant risk to subject’s safety 
 
• 
Pregnancy as confirmed by positive urine test at any time during the study 
 
• 
Withdrawal of informed consent 
 
Participants may voluntarily discontinue investigational treatment for any reason at any time. Participant decision 
on discontinuation of study treatment does not imply an automatic withdrawal from the study.  
 
Refer to the Schedule of Activities (SoA) for data to be collected at the time of treatment discontinuation and 
follow-up and for any further evaluations that need to be completed. 
 


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8.1.1. 
Temporary Discontinuation  
Study treatment dosing may be temporarily suspended in the event of: 
•
Clinically important laboratory abnormalities
•
Other intercurrent illnesses including acute exacerbations of COPD, major surgery, or gastrointestinal
problems
•
Use of prohibited treatment
•
Any other protocol deviation that results in a significant risk to the participant’s safety
After a laboratory abnormality leading to a delay of dosing normalizes sufficiently, study treatment may resume 
at the discretion of the Site Investigator in consultation with the Study PI as needed. Similarly, study treatment 
may resume after the medication leading to suspension of dosing is discontinued. A decision to discontinue 
study treatment and/or to reinstitute study treatment should be conveyed to the Study PI and the DCC. The 
Investigator may suspend study treatment at any time, without consultation with the Study PI if the urgency of 
the situation requires immediate action and if this is determined to be in the participant’s best interest. However, 
the Study PI and DCC should be contacted as soon as possible in any case of study treatment discontinuation. 
8.1.2. 
Re-challenge 
Resumption of study treatment after temporary discontinuation should always be discussed with the DCC and 
study PI. 
Re-challenge should be performed one time only if the study medication was held due to AST or ALT ≥3x ULN. 
Re-challenge should only occur after the ALT or AST return to pretreatment baseline value. 
In the specific case of liver tests meeting the study treatment discontinuation criteria in Section 8.1, no re-
challenge is permitted. 
8.2. 
Discontinuation From the Study 
The Investigator should consider the following when withdrawing a participant from the study: 
•
A participant may withdraw from the study at any time at his/her own request, or may be withdrawn at
any time at the discretion of the Investigator for safety, behavioral, or administrative reasons.
•
If the participant withdraws consent for disclosure of future information, the DCC may retain and continue
to use any data collected before such the withdrawal of consent.
•
If a participant withdraws from the study, he/she may request destruction of any samples taken and not
tested, and the Investigator must document this in the site study records and notify the DCC.
8.3. 
Lost to Follow-up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for scheduled visits and is 
unable to be contacted by the study site.  


 
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The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
 
• 
The site must attempt to contact the participant and reschedule the missed visit as soon as possible and 
counsel the participant on the importance of maintaining the assigned visit schedule and ascertain 
whether or not the participant wishes to and/or should continue in the study. 
 
• 
In cases in which the participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and mail a certified 
letter to the participant’s last known mailing address. These contact attempts should be documented in 
the participant’s file. 
 
• 
Should the participant continue to be unreachable, he/she will be considered to have withdrawn from the 
study with a primary reason of lost to follow-up.  
 
9. 
Study Assessments and Procedures 
 
• 
Study procedures and their timing are summarized in the SOA.  
 
• 
Adherence to the study design requirements, including those specified in the SOA, is essential and 
required for study conduct. 
 
• 
All screening evaluations must be completed and reviewed to confirm that potential participants meet all 
eligibility criteria. The Investigator will maintain a screening log to record details of all participants 
screened and to confirm eligibility or record reasons for screening failure, as applicable.  
 
• 
. 
 
• 
Sample handling: Routine bloodwork and laboratory measurements used for safety monitoring and 
eligibility assessment (CMP, coagulation measurements, CBC, pregnancy testing, etc.) will be processed 
and measured using local laboratory.  Samples (blood, sputum, BAL) used for PK or biomarker 
assessment will undergo initial processing at the local site but will be shipped to a central lab (Dr. Wells) 
at UAB for curation and analysis.  The procedure is detailed in the MOP. 
 
• 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the samples. 
 
• 
Biomarker samples (blood, sputum, and BAL) will be stored for up to 60 months after the end of the study. 
 


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9.1. 
Key Screening Assessments 
FIB-4 Score 
The FIB-4 test combines age with 3 standard biochemical values (platelets, ALT, and AST) as a non-invasive 
test to assess fibrosis and enable exclusion of participants who may be at greater risk of liver AEs 
(https://www.mdcalc.com/fibrosis-4-fib-4-index-liver-fibrosis). The following formula will be used: 
Using a cut-off value of 1.45, a FIB-4 score <1.45 has been shown to have a negative predictive value of 90% 
for advanced fibrosis. In contrast, a FIB-4 >3.25 would have a 97% specificity and a positive predictive value of 
65% for advanced fibrosis42. FIB-4 index has been shown to be superior to other scoring systems for 
differentiating between advanced and mild fibrosis.   
9.2. 
Efficacy Assessments 
9.2.1. 
Blood, Sputum, and Bronchoalveolar Lavage Biomarkers 
Blood 
Blood will be collected as per the SOA, and samples will be collected and processed as described by the MOP. 
Sputum 
Sputum will be collected from induced samples (refer to the MOP for processing details).  Sputum induction will 
not be undertaken if the baseline FEV1 for the procedure is less than 1 L. Further details of sputum induction will 
be included in the MOP.  Sputum induction is considered an aerosol generating procedure (AGP) and sites 
should use local guidance on conducting AGP as part of clinical research in the COVID-19 era.  
Bronchoalveolar Lavage (BAL) 
BAL will be collected in the subset of participants who agree to participate in the bronchoscopy sub-study.  
Samples will be collected at two time points as per the SOA, and samples will be collected and processed as 
described by the MOP.  Bronchoscopy and BAL is considered an aerosol generating procedure (AGP) and sites 
should use local guidance on conducting AGP as part of clinical research in the COVID-19 era. 
Blood, sputum, and BAL efficacy biomarkers (see Table below) will be taken at the time points as detailed in 
the SoA to evaluate their association with the observed mechanism of action responses to neutrophil 
elastase inhibition, including response of neutrophil elastase activity, inflammation, and lung damage to 
alvelestat (MPH966). 
The samples will be collected and processed as described in the MOP. 


 
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Samples may be stored for a maximum of 60 months following the end of study at a facility selected by the 
Sponsor to enable further analysis of biomarker responses to alvelestat (MPH966).  
 
Biomarkers of Efficacy Collected in Blood and Sputum 
 
Biomarker 
Blood 
Sputum 
BAL 
Neutrophil Elastase Related Biomarkers 
 
Desmosine/Isodesmosine 
X 
X 
X 
Aα-Val360 
X 
X 
X 
NE 
X 
X 
X 
EL-NE 
X 
X 
X 
Proteinase 3 
X 
 
X 
Cathepsin B 
X 
 
X 
Lung Damage Biomarkers 
EL-CG 
X 
 
X 
EL-P3 
X 
 
X 
PGP 
X 
X 
X 
C6M 
X 
 
X 
C1M 
X 
 
X 
PRO-C6 
X 
 
X 
Inflammatory Biomarkers 
Hs-CRP 
X 
 
 
IL-6  
X 
X 
X 
IL-8 
X 
X 
X 
RANTES 
X 
X 
 
IL-1β 
X 
X 
 
Fibrinogen 
X 
 
 
LTB-4 
 
X 
X 
MMPs 
X 
X 
X 
MPO 
X 
X 
X 
 
In addition, samples will be stored and analysis may be performed on additional biomarker variants thought to 
play a role in neutrophil elastase–induced lung damage to evaluate their association with observed neutrophil 
activation responses to alvelestat (MPH966). 
 
9.2.2. 
SGRQ-C  
 
The St. George’s Respiratory Questionnaire (SGRQ-C) will be administered at time points as detailed in the 
SoA. This is a questionnaire that measures health impairment in patients with COPD43. It consists of 3 parts: a 
symptom score, an activity score, and an impact score. A total score is also produced.  
 
9.2.3. 
COPD Assessment Test (CAT) 
 
The CAT is an 8 item questionnaire used to report health status in COPD44.  It will be administered at time 
points as shown in the SOA.  
 
9.2.4. 
Modified Medical Research Council (MMRC) 
 
The MMRC will be administered at time points as detailed in the SoA and is used to measure dyspnea on a 5-
point scale45.  
 


 
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9.2.5. 
San Diego Breath Questionnaire (SOBQ) 
 
The SOBQ assesses patient reported dyspnea46.  The SOBQ will be administered at time points as detailed in 
the SoA.  
 
9.2.6. 
Pulmonary Function Testing/Spirometry 
 
Pulmonary function testing (FEV1, FVC, FEV1/FVC, and maximal mid-expiratory flow) will be performed at the 
times specified in the SoA according to ATS guidelines.  Further details on the spirometry procedure can be 
found in the Specific MOP. Spirometry is considered an aerosol generating procedure (AGP) and sites should 
use local guidance on conducting AGP as part of clinical research in the COVID-19 era. 
 
9.2.7. 
Daily respiratory symptom scores and peak flow by electronic diary  
 
Participants will complete a 2 week baseline period of diary entries after screening and prior to randomization to 
establish a baseline.  Participants will then complete the daily diary throughout the 16 week treatment period.  
Study sites will review diary entries at each clinic visit to confirm compliance and query possible adverse events.  
 
9.3. 
Safety Assessments 
 
Planned time points for all safety assessments are provided in the SoA. 
 
9.3.1. 
Physical Examinations 
 
• 
A complete physical examination will include, at a minimum, assessments of the cardiovascular, 
respiratory, gastrointestinal, integumentary, and neurological systems. Height and weight will also be 
measured and recorded. 
 
• 
A brief physical examination will include, at a minimum, assessments of the lungs, heart, abdomen, and 
skin. 
 
• 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
 
9.3.2. 
Vital Signs 
 
Vital signs will be measured in a semi-supine position after 5 minutes of rest and will include temperature, systolic 
and diastolic blood pressure, heart rate, respiratory rate, and pulse oximetry.  
 
• 
Oral or tympanic temperature. 
 
• 
Blood pressure and pulse measurements will be assessed with a completely automated device. Manual 
techniques will be used only if an automated device is not available. 
 
• 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (e.g., television, cell phones). 
 
• 
Pulse oximetry will be measured using a sensor placed on the participant’s fingertip or earlobe.  Oxygen 
saturation (SpO2) will be recorded.  
 


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Electrocardiograms 
•
12-lead ECG will be obtained as outlined in the SoA using an ECG machine that automatically calculates 
the heart rate and measures PR, QRS, QT, and QTc intervals. Refer to Section 8.1 for QTc withdrawal 
criteria and additional QTc readings that may be necessary.
•
Single ECGs will be performed at all scheduled time points, with the exception of when a change from 
baseline occurs that meets drug discontinuation criteria (Section 8.1). In this situation, a triplicate 
measurement is required to confirm the finding and for discontinuation decisions.
•
When a triplicate ECG is required, 3 consecutive ECG tracings should be taken in a 30-minute period
with at least 5 minutes between each ECG.
•
QTc value will be calculated using the Fridericia formula (QTc=QT/3√RR).
9.3.3. 
Clinical Safety Laboratory Assessments 
•
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SOA for the timing
and frequency.
•
The Investigator must review the laboratory report, document this review, and record any clinically
relevant changes occurring during the study in the AE section of the CRF. The laboratory reports must
be filed with the source documents. Clinically significant abnormal laboratory findings are those that are
not associated with the underlying disease, unless judged by the Investigator to be more severe than
expected for the participant's condition.
•
All laboratory tests with values considered clinically significantly abnormal during participation in the study
or within 28 days after the last dose of study treatment should be repeated until the values return to
normal or baseline, with a frequency based on the judgement of the Site Investigator. If such values do
not return to normal/baseline within a period of time judged reasonable by the Investigator, the etiology
should be identified and the DCC notified.
The monitoring schedule proposed for a case of acute liver function abnormalities or worsening of a
liver function abnormality is reported is listed in Section 8.1 (Liver Test Abnormalities).
•
Clinically significant liver function abnormalities should be reported as an AE/AESI.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted in
accordance with the MOP and the SOA.
9.3.4. 
Data Safety Monitoring Board 
Safety will be regularly reviewed by an independent DSMB who will have the option to unblind masked group 
data as necessary.  
At any time, the DSMB may choose to recommend pausing, modifying, or stopping enrolment. 
Full details of composition, operational aspects, and data to be reviewed and recommendations to be made by 
the DSMB will be described in the DSMB charter. 


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9.4. 
Adverse Events 
The definitions of an AE, SAE, SUSAR, and UP can be found in Appendix 4. 
An AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the participant's 
legally authorized representative).  
The Investigator and any designees are responsible for detecting, documenting, and reporting events that meet 
the definition of an AE or SAE and remain responsible for following AEs that are serious, considered related to 
the study treatment or the study, or that caused the participant to discontinue the study treatment (see 
Section 8.1). 
9.4.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the signing of the ICF until the follow-up visit at the time points specified 
in the SoA. 
All SAEs will be recorded and reported to the DCC within 24 hours, as indicated in Appendix 4. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures for 
completing and transmitting SAE reports are provided in Appendix 4. 
9.4.2. 
Follow-up of an AE and/or SAE 
After the initial AE/SAE report, the Investigator is required to proactively follow each participant at subsequent 
visits/contacts. All SAEs and non-serious AESIs (as defined in Section 9.4.3), will be followed until resolution, 
until stabilization, until the event is otherwise explained, or until the participant is lost to follow-up (as defined in 
Section 8.3). Further information on follow-up procedures is given in Appendix 4. 
9.4.3. 
Adverse Events of Special Interest 
Some AEs, regardless of their severity or outcome, will be expedited due to the relevance for subject safety or 
study treatment safety profile. These events should be reported to the DCC within 24 hours, as indicated in 
Appendix  4. The AESIs for alvelestat (MPH966) are: 
•
Liver function abnormalities defined as:
a)
Any occurrence of (i) ALT or AST elevations >5 × ULN or (ii) ALT or AST >3 × ULN and total bilirubin
>2 × ULN or INR >1.5 or the appearance of worsening fatigue, nausea, vomiting, RUQ
pain/tenderness, fever, rash, or eosinophilia.
b) Any occurrence of <5 × ULN or ALT or AST <3 × ULN and total bilirubin <2 × ULN where the tests
have been repeated within 48 to 72 hours and the elevation confirmed on at least 2 separate
occasions.
For participant safety and to ensure that the hepatotoxic potential of the study treatment to be determined, a 
standardized procedure for identification, monitoring, and evaluation of liver events must be followed as 
outlined in Section 9.3.3 and Section 8.1.  


 
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• 
ECG/Cardiac Events 
 
If a study subject experiences any of the following cardiovascular events, the event should be reported 
immediately as an AESI and the study treatment discontinued: 
 
a) Absolute QTcF >500 ms or >60 ms increase from baseline. 
 
b) Any clinically significant cardiac abnormality on ECG. 
 
• 
Infection 
 
Any new infection that requires the use of systemic antimicrobial treatment (antibiotics, anti-viral, anti-
fungal, or anti-mycobacterial) should be investigated with clinically relevant diagnostic tests.   
 
Acute exacerbations of COPD are considered AESI. 
 
• 
Neutropenia 
 
a) Absolute neutrophil count less than or equal to 1.0 × 109/L on 2 consecutive repeat tests within 48 to 
72 hours.  
 
9.4.4. 
Regulatory Reporting Requirements for SAE 
 
• 
Prompt notification by the Investigator to the DCC of an SAE is essential so that legal obligations and 
ethical responsibilities towards the safety of participants and the safety of a study treatment under clinical 
investigation are met.  
 
• 
The DCC, the NCATS Medical Monitor, as well as Mereo have a legal responsibility to notify both the 
local regulatory authority and other regulatory agencies about the safety of a study treatment under 
clinical investigation.  
• 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSARs) according to local regulatory requirements and will be forwarded to Investigators as necessary. 
 
• 
An Investigator who receives an Investigator safety report describing an SAE or other specific safety 
information (e.g. summary or listing of SAEs) will file it along with the Investigator’s Brochure and will 
notify the IRB/IEC, if appropriate according to local requirements. 
 
9.4.5. 
Pregnancy 
 
• 
Details of all pregnancies in female participants and female partners of male participants will be collected 
after the start of study treatment and until 5 half-lives (4 days) after the last dose. 
 
• 
If a pregnancy is reported, the Investigator should inform the DCC within 24 hours of learning of the 
pregnancy and should follow the procedures outlined in Appendix 5. 
 
• 
Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, congenital anomalies, 
ectopic pregnancy) are considered SAEs. 
 


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Partner Pregnancies 
Pregnancy outcomes must be collected for the female partners of the subjects who took study treatment in this 
study. Pregnancy itself is not regarded as an AE unless there is suspicion that the study treatment may have 
interfered with the effectiveness of a contraceptive medication. If a pregnancy is reported for a subject’s partner, 
study treatment will be immediately discontinued. The outcome of all pregnancies (spontaneous miscarriage, 
elective termination, normal birth, or congenital abnormality) must be followed and documented. A follow-up 
report should be sent with any new information regarding the pregnancy and the outcome of the birth.  
9.5. 
Treatment of Overdose 
For this study, any dose of alvelestat (MPH966) greater than 120 mg bid within a 24-hour time period will be 
considered an overdose. 
There is no specific treatment for an overdose. Any treatment should be supportive as indicated by the subject's 
condition. 
In the event of an overdose, the Investigator/treating physician should: 
1. Contact the DCC and study PI immediately.
2. Closely monitor the participant for AE/SAE and laboratory abnormalities until alvelestat (MPH966) can
no longer be detected systemically (at least 3 days).
3. Obtain a plasma sample for PK analysis within 3 days from the date of the last dose of study treatment if
requested by the DCC and/or study PI (determined on a case-by-case basis).
4. Document the quantity of the excess dose as well as the duration of the overdosing in the CRF.
Decisions regarding dose interruptions or modifications will be made by the Investigator in consultation with the 
Study PI as necessary based on the clinical evaluation of the participant. 
9.6. 
Pharmacokinetics 
Sparse PK sampling will be performed before and after study treatment dosing as detailed in the SoA and MOP. 
•
Blood samples of approximately 3 mL will be collected for measurement of blood concentrations of
alvelestat (MPH966) as specified in the SoA. Instructions for the collection and handling of biological
samples will be provided by the DCC. The actual date and time (24-hour clock time) of each sample will
be recorded.
9.7. 
Pharmacodynamics  
Pharmacocodynamic markers form the primary, and some secondary and exploratory efficacy endpoints in 
this study and are covered in Section 9.2.1. 


 
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10. 
Statistical Considerations  
 
10.1. 
Sample Size Determination  
 
Over the course of the study, approximately 60 participants will be randomized in a 1:1 ratio to receive one of 
the following:  120mg alvelestat (MPH966) BID or placebo.  Randomization will be stratified by study site and by 
AAT genotype/phenotype.   
 
The study will be powered for within-individual change in plasma desmosine/isodesmosine as the primary 
endpoint at Week 12 compared to baseline.  A sample size of 30 participants in the MPH966 treatment group 
will give us >90% power to detect a 15% mean decrease of plasma DES from baseline to 12 weeks follow-up in 
patients treated with MPH966 (within subject change) using a two-sided paired t-test at α=0.05. This 15% mean 
decrease has been observed in trials of standard dose augmentation versus placebo 31.  A recent study of double 
dose versus single dose augmentation revealed a within subject decrease in plasma DES from 0.42 +/-0.03 
ng/ml to 0.38 +/- 0.03 ng/ml 12. We will have 80% power to detect a comparable difference in DES in those who 
have alvelestat added to augmentation.   
 
For comparing the mean change in DES between the two groups (placebo vs. MPH966), and assuming that 
there is no placebo effect over 12 weeks, a two-sided two sample t-test at α=0.05 with a sample size of 60 (30 
per group) reveals that we will have 82% power to detect a 15% difference in mean change in plasma DES.  
 
Other secondary endpoints (BAL and sputum DES, other serum, sputum and BAL inflammatory markers, patient-
reported outcomes, and pulmonary function) will be examined within and between group with paired t-tests or 
mixed effect modeling as appropriate.   
 
We will also examine the association between DES at baseline and response to treatment as measured by 
change in pulmonary function (FEV1) over 12 weeks within the MPH966 treatment group. With a sample size of 
30, we will have 80% power to detect a 0.12 regression correlation coefficient of DES at baseline in predicting 
the change of FEV1 over 12 weeks when the standard deviation of DES is 0.10 and α=0.05.  
 
By including a 10% attrition rate over 12 weeks, the required sample size is inflated to 66 (33 per group) to 
achieve the estimated powers. If we observe attrition rate less than we expected, we will have more statistical 
power to detect the expected differences. As one interim analysis will be conducted only for safety concerns (see 
Data Safety and Monitoring Plan), no adjustments to the Type I error is considered for estimating statistical 
powers. 
 
10.2. 
Populations for Analyses 
 
For purposes of analysis, the following populations are defined: 
 
Population 
Description 
Enrolled Set 
The Enrolled Set will include all participants who sign the ICF. 
Randomized Set 
The Randomized Set will include all subjects who signed the ICF and were 
subsequently randomized into the study, regardless of study treatment 
administration.   
Full Analysis Set 
The Full Analysis Set will serve as the primary population for the analysis of 
efficacy and will consist of all randomized subjects who took at least 1 dose 
of double-blind study treatment and have at least 1 evaluable change from 
baseline in plasma desmosine/isodesmosine levels. Subjects will be 
analyzed according to randomized treatment. 


 
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Population 
Description 
Per-Protocol Set 
The Per-Protocol Set includes all participants from the Full Analysis Set who 
have been treated according to the protocol and fulfil the following criteria: 
1. All inclusion/exclusion criteria satisfied 
2. Absence of relevant protocol violations with respect to factors likely 
to affect the efficacy of treatment where the nature of protocol 
violation will be defined before breaking the blind 
3. Adequate study medication compliance, which will be determined 
before breaking the blind 
Subjects will be analysed according to randomized treatment. 
Safety Set 
All randomized participants who take at least 1 dose of study treatment. 
Participants will be analysed according to randomized treatment. 
PK Set  
The PK Set will include all participants in the Safety Set who have at least 1 
evaluable serum concentration. 
 
10.3. 
Statistical Analyses  
 
The statistical analysis will be performed using SAS® version 9.4 or higher. The main population for efficacy 
analysis will be the Full Analysis Set; supportive analyses will also be performed using the Per-Protocol Set.  
 
Continuous data will be presented using descriptive summaries (e.g., mean, standard deviation, minimum, 
maximum, median, lower quartile, and upper quartile). Categorical variables will be presented by the number of 
observations and relative (%) frequency.   
Unless otherwise stated, baseline value for any variable will be the last value taken prior to the first dose of study 
medication. 
 
Unless otherwise stated, all statistical tests will be 2-sided and conducted at the 5% level. All presented 
confidence intervals will be 2-sided 95% confidence intervals. 
 
The Statistical Analysis Plan (SAP) will be developed and finalized before database lock and will describe the 
selection of participants to be included in the analyses and procedures for accounting for missing, unused, and 
spurious data. Below is a summary of planned statistical analyses of the primary and secondary endpoints. 
 
10.3.1. 
Efficacy Analyses 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Within individual % change from baseline in plasma desmosine/isodesmosine levels at 12 
weeks will be calculated. An analysis of covariance (ANCOVA) model with baseline plasma 
desmosine/isodesmosine levels as a covariate and treatment and sputum strata as factors 
will be used to generate least squared means and least squared mean differences between 
treatment groups.   
Secondary 
The biomarker correlation analysis will be done using stepwise approach:  
The parameters in BAL, sputum, and blood during treatment will be compared to the baseline 
values for active and placebo patients separately to evaluate natural variability of the 
markers.  
 
The time-matched biomarker values will be compared between placebo and active groups 
to assess the differences outside natural variability and time to significant change for the 
responsive biomarkers.  
 


 
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Endpoint 
Statistical Analysis Methods 
Multiple models, including non-parametric models, will be considered within this frame 
incorporating different covariates and data transformations. PD parameters such as area 
under the effect-time curve will also be considered. 
 
Principal component multifactorial analysis and/or cluster analysis may be employed to 
simplify the comparison and to explore the treatment effect. Decisions will be made on review 
of data and prior to database lock.  
 
Correlation of select biomarkers shown to be responsive to treatment with time-matched 
drug concentrations and PK parameters, if available, may be used to evaluate exposure-
response relationship.  
Exploratory 
Observed values and change from baseline in FEV1, FVC, FEV1/FVC (total and percent 
predicted) and maximal mid-expiratory flow will be presented by treatment group and study 
visit. Change from baseline at Week 12 will be analysed using an ANCOVA model. 
 
Observed values and change from baseline for the total and component scores of the 
SGRQ-C will be presented by treatment group and study visit. Change from baseline in total 
score at Week 12 will be analysed using an ANCOVA model. 
 
Correlation of select biomarkers shown to be responsive to treatment with time-matched 
drug concentrations and PK parameters, if available, will be used to evaluate exposure-
response relationship. 
 
 
 
10.3.2. 
Safety Analyses 
 
All safety analyses will be performed on the Safety Set.  
 
Endpoint 
Statistical Analysis Methods 
Primary 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Summaries will be by system organ class and preferred term. Treatment-emergent AEs 
are defined as any AE occurring or worsening on or after the first dose of study medication. 
If a participant experiences the same preferred term multiple times, the event will be 
counted only once overall and by the greatest severity. 
 
The frequency and incidence of treatment-emergent AEs will be presented by system 
organ class and preferred term for each treatment group (number and percentage of 
participants experiencing at least 1 AE per preferred term as well as the number of 
observed events per preferred term). Separate tables will be presented by severity and by 
relationship. All AEs will be presented in full in a comprehensive listing including participant 
number, treatment regimen, severity, seriousness, action taken, outcome, relationship to 
treatment, onset/stop, and duration. Details of SAEs and AEs leading to withdrawal will be 
listed separately. 
 
Adverse Events of Special Interest 
AESIs, including liver function abnormalities, ECG/cardiac events, infections, and 
neutropenia, will be tabulated and summarized by treatment group and overall. 
Secondary 
Vital Signs 


 
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Endpoint 
Statistical Analysis Methods 
Vital signs will be summarized as observed values and change from baseline by treatment 
group and overall. 
 
Physical Examination 
Physical examination results will be listed by subject ID and body system. 
 
ECG 
ECG parameters will be summarized as observed values and change from baseline by 
treatment group and study visit. 
 
Abnormal findings (“normal”, “abnormal, not clinically significant”, and “abnormal, clinically 
significant”) will be summarized by the number and percentage within each category, and 
change from baseline will be summarized by shift tables. 
 
Clinical Laboratory 
Laboratory parameters will be summarized as observed values and change from baseline 
by treatment group and study visit. 
 
Values outside the normal range will be summarized by the number and percentage within 
each category, and change from baseline will be summarized by shift tables. 
 
Safety and PK Relationships 
The safety correlation analysis with drug concentration may be done for the safety 
parameters shown to be sensitive to alvelestat exposure. The comparison of exposure will 
be done between groups with non-clinically significant changes and clinically significant 
changes in safety parameters using graphic and statistical methods where data allow.  
 
Exploratory 
The details will be described in the SAP finalized before database lock. 
 
 
10.3.3. 
Other Analyses  
 
PK, PD, and biomarker exploratory analyses will be described in the SAP finalized before database lock.  
 
10.3.4. 
Interim Analyses  
 
No interim analysis for efficacy is planned for this study.  An interim safety analysis will be conducted when 30 
subjects have completed the study. 


 
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11. 
References 
 
1. 
Vestbo J, Hurd SS, Agusti AG, et al. Global strategy for the diagnosis, management, and prevention of 
chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2013;187:347-
65. 
2. 
Centers for Disease C, Prevention. Chronic obstructive pulmonary disease among adults--United 
States, 2011. MMWR Morb Mortal Wkly Rep 2012;61:938-43. 
3. 
Qaseem A, Wilt TJ, Weinberger SE, et al. Diagnosis and management of stable chronic obstructive 
pulmonary disease: a clinical practice guideline update from the American College of Physicians, American 
College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med 
2011;155:179-91. 
4. 
Vogelmeier CF, Criner GJ, Martinez FJ, et al. Global Strategy for the Diagnosis, Management, and 
Prevention of Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary. Arch Bronconeumol 
2017;53:128-49. 
5. 
Barnes PJ. Chronic obstructive pulmonary disease. N Engl J Med 2000;343:269-80. 
6. 
Wells JM, O'Reilly PJ, Szul T, et al. An aberrant leukotriene A4 hydrolase-proline-glycine-proline 
pathway in the pathogenesis of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 
2014;190:51-61. 
7. 
Stoller JK, Aboussouan LS. Alpha1-antitrypsin deficiency. Lancet 2005;365:2225-36. 
8. 
Stoller JK, Aboussouan LS. A review of alpha1-antitrypsin deficiency. Am J Respir Crit Care Med 
2012;185:246-59. 
9. 
Greulich T. Alpha-1-Antitrypsin Deficiency: Disease Management and Learning from Studies. COPD 
2017;14:S8-S11. 
10. 
Silverman EK, Sandhaus RA. Clinical practice. Alpha1-antitrypsin deficiency. N Engl J Med 
2009;360:2749-57. 
11. 
Chapman KR, Burdon JG, Piitulainen E, et al. Intravenous augmentation treatment and lung density in 
severe alpha1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial. Lancet 
2015;386:360-8. 
12. 
Campos MA, Geraghty P, Holt G, et al. The Biological Effects of Double-Dose Alpha-1 Antitrypsin 
Augmentation Therapy. A Pilot Clinical Trial. Am J Respir Crit Care Med 2019;200:318-26. 
13. 
Cosio MG, Bazzan E, Rigobello C, et al. Alpha-1 Antitrypsin Deficiency: Beyond the 
Protease/Antiprotease Paradigm. Ann Am Thorac Soc 2016;13 Suppl 4:S305-10. 
14. 
Ferrarotti I, Corsico AG, Stolk J, et al. Advances in Identifying Urine/Serum Biomarkers in Alpha-1 
Antitrypsin Deficiency for More Personalized Future Treatment Strategies. COPD 2017;14:56-65. 
15. 
Greene CM, Marciniak SJ, Teckman J, et al. alpha1-Antitrypsin deficiency. Nat Rev Dis Primers 
2016;2:16051. 
16. 
Duvoix A, Roussel BD, Lomas DA. Molecular pathogenesis of alpha-1-antitrypsin deficiency. Rev Mal 
Respir 2014;31:992-1002. 
17. 
Chamba A, Afford SC, Stockley RA, Burnett D. Extracellular proteolysis of fibronectin by neutrophils: 
characterization and the effects of recombinant cytokines. Am J Respir Cell Mol Biol 1991;4:330-7. 
18. 
Wells JM, Gaggar A, Blalock JE. MMP generated matrikines. Matrix Biol 2015;44-46:122-9. 
19. 
Russell DW, Wells JM, Blalock JE. Disease phenotyping in chronic obstructive pulmonary disease: the 
neutrophilic endotype. Curr Opin Pulm Med 2016;22:91-9. 


 
Protocol Version 1.4 
 
 
Page 38 of 59 
20. 
Luisetti M, Ma S, Iadarola P, et al. Desmosine as a biomarker of elastin degradation in COPD: current 
status and future directions. Eur Respir J 2008;32:1146-57. 
21. 
Pelham F, Wewers M, Crystal R, Buist AS, Janoff A. Urinary excretion of desmosine (elastin cross-
links) in subjects with PiZZ alpha-1-antitrypsin deficiency, a phenotype associated with hereditary 
predisposition to pulmonary emphysema. Am Rev Respir Dis 1985;132:821-3. 
22. 
Turino GM, Lin YY, He J, Cantor JO, Ma S. Elastin degradation: an effective biomarker in COPD. 
COPD 2012;9:435-8. 
23. 
Ma S, Turino GM, Lin YY. Quantitation of desmosine and isodesmosine in urine, plasma, and sputum 
by LC-MS/MS as biomarkers for elastin degradation. J Chromatogr B Analyt Technol Biomed Life Sci 
2011;879:1893-8. 
24. 
Deslee G, Woods JC, Moore CM, et al. Elastin expression in very severe human COPD. Eur Respir J 
2009;34:324-31. 
25. 
Ma S, Lin YY, Turino GM. Measurements of desmosine and isodesmosine by mass spectrometry in 
COPD. Chest 2007;131:1363-71. 
26. 
Stolk J, Veldhuisen B, Annovazzi L, et al. Short-term variability of biomarkers of proteinase activity in 
patients with emphysema associated with type Z alpha-1-antitrypsin deficiency. Respir Res 2005;6:47. 
27. 
Bihlet AR, Karsdal MA, Sand JM, et al. Biomarkers of extracellular matrix turnover are associated with 
emphysema and eosinophilic-bronchitis in COPD. Respir Res 2017;18:22. 
28. 
He J, Turino GM, Lin YY. Characterization of peptide fragments from lung elastin degradation in chronic 
obstructive pulmonary disease. Exp Lung Res 2010;36:548-57. 
29. 
Senior RM, Griffin GL, Mecham RP, Wrenn DS, Prasad KU, Urry DW. Val-Gly-Val-Ala-Pro-Gly, a 
repeating peptide in elastin, is chemotactic for fibroblasts and monocytes. J Cell Biol 1984;99:870-4. 
30. 
Stolz D, Leeming DJ, Kristensen JH, et al. Systemic Biomarkers of Collagen and Elastin Turnover Are 
Associated With Clinically Relevant Outcomes in COPD. Chest 2017;151:47-59. 
31. 
Ma S, Lin YY, He J, Rouhani FN, Brantly M, Turino GM. Alpha-1 antitrypsin augmentation therapy and 
biomarkers of elastin degradation. COPD 2013;10:473-81. 
32. 
Stevens T, Ekholm K, Granse M, et al. AZD9668: pharmacological characterization of a novel oral 
inhibitor of neutrophil elastase. J Pharmacol Exp Ther 2011;339:313-20. 
33. 
Vogelmeier C, Aquino TO, O'Brien CD, Perrett J, Gunawardena KA. A randomised, placebo-controlled, 
dose-finding study of AZD9668, an oral inhibitor of neutrophil elastase, in patients with chronic obstructive 
pulmonary disease treated with tiotropium. COPD 2012;9:111-20. 
34. 
Kuna P, Jenkins M, O'Brien CD, Fahy WA. AZD9668, a neutrophil elastase inhibitor, plus ongoing 
budesonide/formoterol in patients with COPD. Respir Med 2012;106:531-9. 
35. 
Elborn JS, Perrett J, Forsman-Semb K, Marks-Konczalik J, Gunawardena K, Entwistle N. Efficacy, 
safety and effect on biomarkers of AZD9668 in cystic fibrosis. Eur Respir J 2012;40:969-76. 
36. 
Gunawardena KA, Gullstrand H, Perrett J. Pharmacokinetics and safety of AZD9668, an oral neutrophil 
elastase inhibitor, in healthy volunteers and patients with COPD. Int J Clin Pharmacol Ther 2013;51:288-304. 
37. 
Stockley R, De Soyza A, Gunawardena K, et al. Phase II study of a neutrophil elastase inhibitor 
(AZD9668) in patients with bronchiectasis. Respir Med 2013;107:524-33. 
38. 
Nordenmark LH, Taylor R, Jorup C. Feasibility of Computed Tomography in a Multicenter COPD Trial: 
A Study of the Effect of AZD9668 on Structural Airway Changes. Adv Ther 2015;32:548-66. 
39. 
Woodruff PG, Agusti A, Roche N, Singh D, Martinez FJ. Current concepts in targeting chronic 
obstructive pulmonary disease pharmacotherapy: making progress towards personalised management. Lancet 
2015;385:1789-98. 


 
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Page 39 of 59 
40. 
Ma S, Lin YY, Cantor JO, et al. The Effect of Alpha-1 Proteinase Inhibitor on Biomarkers of Elastin 
Degradation in Alpha-1 Antitrypsin Deficiency: An Analysis of the RAPID/RAPID Extension Trials. Chronic 
Obstr Pulm Dis 2016;4:34-44. 
41. 
Nelson DR, Teckman J, Di Bisceglie AM, Brenner DA. Diagnosis and management of patients with 
alpha1-antitrypsin (A1AT) deficiency. Clin Gastroenterol Hepatol 2012;10:575-80. 
42. 
Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict 
significant fibrosis in patients with HIV/HCV coinfection. Hepatology 2006;43:1317-25. 
43. 
Meguro M, Barley EA, Spencer S, Jones PW. Development and Validation of an Improved, COPD-
Specific Version of the St. George Respiratory Questionnaire. Chest 2007;132:456-63. 
44. 
Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and first validation of 
the COPD Assessment Test. Eur Respir J 2009;34:648-54. 
45. 
Comstock GW, Tockman MS, Helsing KJ, Hennesy KM. Standardized respiratory questionnaires: 
comparison of the old with the new. Am Rev Respir Dis 1979;119:45-53. 
46. 
Eakin EG, Resnikoff PM, Prewitt LM, Ries AL, Kaplan RM. Validation of a new dyspnea measure: the 
UCSD Shortness of Breath Questionnaire. University of California, San Diego. Chest 1998;113:619-24. 
47. 
Damilakis J, Adams JE, Guglielmi G, Link TM. Radiation exposure in X-ray-based imaging techniques 
used in osteoporosis. Eur Radiol 2010;20:2707-14. 
 


 
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12. 
Appendices 


 
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Appendix 1:  Abbreviations, Trademarks & Glossary 
Abbreviation 
Description 
AAT 
Alpha-1antitrypsin 
AATD 
Alpha-1 antitrypsin deficiency 
Aα-Val360 
Fragment from neutrophil elastase cleavage of elastin at Aα-Val360 site 
AcPGP 
Acetylated Proline-Glycine-Proline 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BAL 
Bronchoalveolar lavage 
bid 
Twice (2 times) a day 
C1M 
MMP-derived collagen type I breakdown fragment 
C6M 
MMP-derived collagen type VI breakdown fragment 
CAT 
COPD assessment test 
Cat g 
Cathepsin G 
CF 
Cystic fibrosis 
CFR 
United States Code of Federal Regulations 
CMP 
Complete metabolic profile 
CMV 
Cytomegalovirus 
CONSORT 
Consolidated Standards of Reporting Trials 
COPD 
Chronic obstructive pulmonary disease 
CRF 
Case report form 
CRO 
Clinical Research Organization 
CT 
Computerized or computed tomography 


 
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CYP2C9 
Cytochrome P450 2C9 
DCC 
Data Coordinating Center 
DES 
Desmosine 
dL 
Decilitre 
DSMB 
Data Safety Monitoring Board 
EBV 
Epstein-Barr virus 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EL-CG 
Elastin degradation mediated by Cathepsin G 
EL-NE 
Elastin degradation mediated by NE 
EL-P3 
Elastin like polypeptide 3 
EOT 
End of treatment 
EP-3 
Elastin peptide 3 
FEV1 
Forced expiratory volume in 1 second 
FEV1/FVC 
Forced expiratory volume in 1 second divided by the forced vital capacity 
FVC 
Forced vital capacity 
FIB-4 
Fibrosis-4 
FU 
Follow-up 
FVC 
Forced vital capacity 
g 
Gram 
GCP 
Good Clinical Practice 
h 
Hour 
hCG 
Human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 
hsCRP 
High-sensitivity C-reactive protein 
HRT 
Hormone replacement therapy 


 
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HSV 
Herpes simplex virus 
Hy’s Law 
a rule of thumb that a patient is at high risk of a fatal drug-induced liver injury (DILI) 
if given a medication that causes hepatocellular injury (not cholestatic injury) with 
jaundice 
IC50 
the concentration of an inhibitor where the response (or binding) is reduced by half 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IL-1β 
Interleukin 1 beta 
IL-6 
interleukin-6 
IL-8 
interleukin-8 
IND 
Investigational new drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IWRS 
Interactive web response system 
Ki 
Inhibitory constant 
kPa 
kiloPascal, a unit of force 
LSM 
Liver stiffness measurement 
LTB4 
Leukotriene b4 
MedDRA 
Medical Dictionary for Regulatory Activities 
mGy 
milliGray, a unit of radiation 
mg/dL 
Milligrams per decilitre 
mIU 
Milli International Units 
MMP 
Matrix metalloproteinase 
MMRC 
Modified medical research council 
MOP 
Methods of procedures 
MPO 
Myeloperoxidase 


 
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MS 
Millisecond 
mSV 
milliSever 
NCATS 
National Center for Advancing Translational Science 
NCT 
National Clinical Trial 
NE 
Neutrophil elastase 
NIH 
National Institutes of Health 
NOAEL 
No observed adverse effect level 
NSAID 
Non-steroidal anti-inflammatory drug 
Pa 
Pascal 
PD 
Pharmacodynamics 
PI 
Principal investigator 
Pi*ZZ 
Alpha-1 ZZ genotype 
Pi*SZ 
Alpha-1 SZ genotype 
Pi*Null, Null 
Alpha-1 Null genotype 
PGP 
P-glycoprotein 
PK 
Pharmacokinetics 
PR 
time from the onset of the P wave to the start of the QRS complex on ECG 
PR3 
Proteinase 3 
PROs 
Patient reported outcomes 
PRO-C6 
Released C-terminal pro-peptide of type VI collagen 
QRS 
Represents ventricular depolarization on ECG 
QT 
The duration of ventricular depolarization and repolarization on ECG 
QTc 
Corrected QT interval 
QTcF 
QTc by Fridericia’s correction method 
QTcV 
QTc by Van de Water’s correction formula 
RANTES 
Regulated on activation, normal T cell expressed and secreted 


 
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RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical analysis software 
SGRQ-C 
St. George’s Respiratory Questionnaire compact version 
SoA 
Schedule of Activities 
SOB 
Shortness of breath 
SOP 
Standard operating procedure 
SOBQ 
Shortness of breath questionnaire 
Sp02 
Pulse oximetry 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
Total bilirubin 
ug 
Microgram 
ULN 
Upper limit of normal 
uM 
Micromolar 
UPs 
Unanticipated problems 
VZV 
Varicella zoster virus 
WBC 
White blood cell 
Wk. 
Week 
 
 


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Appendix 2:  Clinical Laboratory Tests 
•
The tests detailed in the table below will be performed by the local laboratories.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 6.1 or 
Section 6.2, respectively.
•
Additional tests may be performed at any time during the study as determined necessary by the
Investigator or required by local regulations.
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count 
RBC Count 
Hemoglobin 
Hematocrit 
MCV 
MCH 
%Reticulocytes 
WBC count with 
differential (% and 
absolute counts): 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Prothrombin Time (PT) 
Partial prothromboplastin time 
(PTT) 
International normalized ratio 
(INR) 
Clinical 
Chemistry1 
Blood urea 
nitrogen 
Potassium 
AST/Serum 
glutamic-
oxaloacetic 
transaminase 
(SGOT) 
Total and direct bilirubin 
Creatinine and 
estimated 
glomerular 
filtration rate 
clearance  
Sodium 
ALT/Serum 
glutamic-pyruvic 
transaminase 
(SGPT) 
Total protein 
Alkaline 
phosphatase 
Calcium 
Other 
Screening 
Tests 
•
Urine pregnancy test during the study (as needed for women of childbearing potential)
•
Serum human chorionic gonadotropin pregnancy test (as needed for women of
childbearing potential) 
•
Alpha-1 antitrypsin blood protein levels
•
Serology (HIV antibody, hepatitis B surface antigen and hepatitis B antibody, and hepatitis
C virus antibody)
•
All study-required laboratory assessments will be performed at the local laboratory, with
the exceptions of the samples (blood, sputum, BAL) that will be sent to a central laboratory
for curation and analysis.
•
The results of each test must be entered into the CRF as guided by the CRF Completion
Guidelines.
1 Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver 
stopping or monitoring event are given in Section 8.1. All events of ALT ≥3 × ULN and bilirubin ≥2 × ULN 
(>35% direct bilirubin) or ALT ≥3 × ULN and INR >1.5, if INR is measured, which may indicate severe liver 
injury (possible Hy’s Law), must be reported as an SAE. 2 Local urine testing will be standard. 
Investigators must document their review of each laboratory safety report. 


 
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Appendix 3:  Study Governance Considerations 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with: 
o Consensus ethical principles derived from international guidelines including the Declaration of Helsinki 
and Council for International Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines. 
o Applicable International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. 
o Applicable laws and regulations under the IND. 
 
• 
The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB by the Investigator and reviewed and approved by the IRB & 
Competent Authority/Regulatory Authority before the study is initiated.  
 
• 
Any amendments to the protocol will require IRB approval before implementation of changes made to the 
study design, except for changes necessary to eliminate an immediate hazard to study participants.  
 
• 
The Investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB annually or more frequently in 
accordance with the requirements, policies, and procedures established by the IRB. 
o Notifying the IRB of SAEs or other significant safety findings as required by IRB procedures. 
o Overall conduct of the study at the site and adherence to requirements of 21 CFR, ICH guidelines, the 
IRB, and all other applicable local regulations. 
 
Financial Disclosure 
Principal Investigators and Site Investigators will provide the DCC and the Sponsor with sufficient, accurate 
financial information in accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 1 year after 
completion of the study. 
 
Informed Consent Process 
• 
The Site Investigator or his/her representative will explain the nature of the study to the participant or 
his/her legally authorized representative and answer all questions regarding the study.  
 
• 
Participants must be informed that their participation is voluntary. Participants will be required to sign a 
statement of informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB or study site.  
 
• 
The source documentation and CRF must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
 
• 
Participants must be re-consented to the most current version of the ICF(s) during their participation in 
the study. 
 
• 
A copy of the ICF(s) must be provided to the participant or his/her legally authorized representative.  


 
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Data Management 
 
The study will use an electronic data entry system (eDES), a web-based platform used for data entry, 
curation, archiving, and notification.  The eDES was developed and is managed by the DCC. 
 
CRFs can be printed from the eCRF generated by and available through the eDES.  The Site Investigator 
/ Site PI will be responsible for data entry into the system.  The DCC will monitor for data quality and will 
query sites as needed.   
 
Oversight for the study will be done via risk-based monitoring. 
 
The DCC will centrally monitor sites can provide on-site monitoring if needed for any high risk clinical site 
(e.g. those with data anomalies or a higher frequency of errors, protocol violations, or dropouts relative 
to other site).   
 
If adverse events require hospitalization, study participants will be cared for by the hospital staff at the 
local sites as per local policy. The study team will monitor the status of the patient while hospitalized, but 
will not be required to provide all aspects of care for these individuals 
 
Data Protection 
 
Participants will be assigned a unique identifier by the DCC. Any participant records or datasets that are 
transferred to the DCC will contain the identifier only; participant names or any information that would 
make the participant identifiable will not be transferred.  
 
 
The participant must be informed that his/her personal study-related data will be used by the DCC in 
accordance with local data protection law. The level of disclosure must also be explained to the 
participant.  
 
 
The participant must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the DCC, Mereo BioPharma, by 
appropriate IRB members, and by inspectors from regulatory authorities. 
Data Quality Assurance 
 
All participant data relating to the study will be recorded on printed or electronic CRF unless transmitted 
to the DCC or designee electronically (eg, laboratory data). The Investigator is responsible for verifying 
that data entries are accurate and correct by physically or electronically signing the CRF.  
 
 
The Investigator must maintain accurate documentation (source data) that supports the information 
entered in the CRF.  
 
 
The Investigator must permit study-related monitoring, audits, IRB review, and regulatory agency 
inspections and provide direct access to source data documents.  
 
 
The Sponsor or designee is responsible for the data management of this study, including quality checking 
of the data.  
 
 
Records and documents, including signed ICF, pertaining to the conduct of this study must be retained 
by the Investigator for 25 years after study completion unless local regulations or institutional policies 
require a longer retention period. No records may be destroyed during the retention period without the 
written approval of the NIH. No records may be transferred to another location or party without written 
notification to the NIH and the DCC.  


 
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Source Documents 
 
Source documents provide evidence for the existence of the participant and substantiate the integrity of 
the data collected. Source documents are filed at the Investigator’s site. 
 
 
Data reported on the CRF or entered in the electronic CRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The Investigator 
may need to request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
 
 
Definition of what constitutes source data can be found in the Study Manual and Monitoring Plan. 
 
Study and Site Closure 
The NIH, Mereo, UAB, the FDA, the IRB, or a designee may stop the study or study site participation in the study 
for medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, regulations, and 
GCP.  
 


 
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Appendix 4:  Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and 
Reporting 
AE Definition 
• 
An AE is any untoward medical occurrence in a clinical trial subject administered a medicinal product and 
which does not necessarily have a causal relationship with this treatment. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal 
product. 
 
Events Meeting the AE Definition  
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (e.g., ECG, radiological scans, vital signs measurements), including those that worsen from 
baseline, considered clinically significant in the medical and scientific judgment of the Investigator (i.e., not 
related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency 
and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even though it may have been 
present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an intentional 
overdose taken with possible suicidal/self-harming intent. Such overdoses should be reported regardless 
of sequelae. 
• 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as an AE/SAE. 
Such instances will be captured in the efficacy assessments. However, the signs, symptoms, and/or clinical 
sequelae resulting from lack of efficacy will be reported as AE/SAE if they fulfil the definition of an AE/SAE.  
 
Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments which are 
associated with the underlying disease, unless judged by the Investigator to be more severe than expected 
for the participant’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the disease/disorder 
being studied, unless more severe than expected for the participant’s condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the procedure 
is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience admission 
to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start 
of the study that do not worsen. 
 
Unanticipated Problem (UP) Definition 
• 
In general, an AE observed during the conduct of a study should be considered an Unanticipated Problem 
(UP) involving risk to human subjects, and reported to the IRB, only if it were unexpected, serious, and 
would have implications for the conduct of the study (e.g., requiring a significant, and usually safety-related, 
change in the protocol such as revising inclusion/exclusion criteria or including a new monitoring 
requirement, informed consent, or investigator’s brochure).   
• 
An individual AE occurrence ordinarily does not meet these criteria because, as an isolated event, its 
implications for the study cannot be understood.  


 
Protocol Version 1.4 
 
 
Page 51 of 59 
• 
AEs listed in the Investigator’s Brochure (IB) are not by definition UPs because they have been previously 
observed with a drug, and would not be considered unexpected and thus would not be unanticipated 
problems.  
• 
Possible exceptions would include situations in which the specificity or severity of the event is not consistent 
with the description in the investigator’s brochure, or it can be determined that the observed rate of 
occurrence for a serious, expected AE in the clinical trial represents a clinically important increase in the 
expected rate of occurrence 
 
Events Meeting UP Definition  
• 
A single occurrence of a serious, unexpected event that is uncommon and strongly associated with drug 
exposure (such as angioedema, agranulocytosis, hepatic injury, or Stevens-Johnson syndrome).  
• 
A single occurrence, or more often a small number of occurrences, of a serious, unexpected event that is 
not commonly associated with drug exposure, but uncommon in the study population (e.g., tendon rupture, 
progressive multifocal leukoencephalopathy).  
• 
Multiple occurrences of an AE that, based on an aggregate analysis, is determined to be an unanticipated 
problem. There should be a determination that the series of AEs represents a signal that the AEs were not 
just isolated occurrences and involve risk to human subjects (e.g., a comparison of rates across treatment 
groups reveals higher rate in the drug treatment arm versus a control).  
• 
An AE that is described or addressed in the investigator’s brochure, protocol, or informed consent 
documents, but occurs at a specificity or severity that is inconsistent with prior observations. For example, 
if transaminase elevation is listed in the investigator’s brochure and hepatic necrosis is observed in study 
subjects, hepatic necrosis would be considered an unanticipated problem involving risk to human subjects.  
• 
A serious AE that is described or addressed in the investigator’s brochure, protocol, or informed consent 
documents, but for which the rate of occurrence in the study represents a clinically significant increase in 
the expected rate of occurrence (ordinarily, reporting would only be triggered if there were a credible 
baseline rate for comparison).  
• 
Any other AE or safety finding (e.g., based on animal or epidemiologic data) that would cause the sponsor 
to modify the investigator’s brochure, study protocol, or informed consent documents, or would prompt 
other action by the IRB to ensure the protection of human subjects.  
 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions are met (e.g., 
hospitalization for signs/symptoms of the disease under study, death due to progression of disease). 
 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. 
Results in death or; 
b. 
Is life-threatening or; 
The term “life-threatening” in the definition of “serious” refers to an event in which the participant was at risk of 
death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it 
were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization or; 
In general, hospitalization signifies that the participant has been detained (usually involving at least an overnight 
stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate 
in the physician’s office or outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfils any other serious criteria, the event is serious. When in doubt as 
to whether “hospitalization” occurred or was necessary, the AE should be considered serious. 


 
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Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE. 
d. 
Results in persistent disability/incapacity or; 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and accidental trauma (eg, sprained 
ankle) that may interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
e. 
Is a congenital anomaly/birth defect or; 
f. 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate in 
other situations such as important medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the participant or may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definition. These events should usually be 
considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, 
or development of drug dependency or drug abuse. 
 
 
 
Recording AEs and SAEs 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation (e.g., 
hospital progress notes, laboratory, and diagnostics reports) related to the event. 
• 
The Investigator will then record all relevant AE/SAE information in the CRF. 
• 
It is not acceptable for the Investigator to send photocopies of the participant’s medical records to the DCC 
in lieu of completion of the AESI/AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by the DCC. In 
this case, all participant identifiers, with the exception of the participant number, will be blinded on the 
copies of the medical records before submission to the DCC. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other 
clinical information. In such cases, the diagnosis (not the individual signs/symptoms) will be documented 
as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the study and 
assign it to one of the following categories:  
• 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and not interfering with 
everyday activities. 
• 
Moderate: An event that causes sufficiently discomfort and interferes with normal everyday activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe should not 
be confused with an SAE. Severe is a category utilized for rating the intensity of an event; and both AEs 
and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least one of the predefined outcomes as described in the 
definition of an SAE, NOT when it is rated as severe. 


 
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Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between study treatment and each occurrence of 
each AE/SAE. 
• 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or arguments to 
suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The Investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as 
the temporal relationship of the event to study treatment administration will be considered and investigated. 
• 
The Investigator will also consult the Investigator’s Brochure and/or Product Information, for marketed 
products, in his/her assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she has reviewed the 
AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the Investigator has minimal information to 
include in the initial report to. However, it is very important that the Investigator always make an 
assessment of causality for every event before the initial transmission of the SAE data to the DCC. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information and send an SAE 
follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting requirements. 
Follow-up of AE and SAE 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or 
evaluations as medically indicated or as requested by the DCC to elucidate the nature and/or causality of 
the AE or SAE as fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized follow-up period, the Investigator 
will provide the DCC with a copy of any postmortem findings including histopathology. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The Investigator will submit any updated SAE data to the DCC within 24 hours of receipt of the information. 
SAE Reporting to DCC via eCRF 
• 
SAEs will be reported to the DCC via the eCRF. 
• 
Initial reporting can be updated when additional information is obtained but this should not delay 
submission. 
 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
• 
An adverse reaction (AR) is any untoward or unfavorable medical occurrence in a clinical research study 
participant, including any abnormal sign (e.g. abnormal physical exam or laboratory finding), symptom, or 
disease, temporally associated with the participants’ involvement in the research, whether or not considered 
related to participation in the research. 
• 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed. 
• 
SUSAR events are AR events that fulfil criteria for seriousness (outlined in SAE above).  SUSARs should 
be reported to the DCC, NIH/NCATS, Mereo, and the FDA using the instructions listed for SAE reporting. 
 
 


 
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Appendix 5:  Contraceptive Guidance and Collection of Pregnancy Information 
 
Alvelestat (MPH966) has a low genotoxic potential and reproductive toxicology studies have not demonstrated 
any effects in either the reproductive function or in embryo-fetal development. Therefore, the following 
precautions are required to protect women of childbearing potential and female partners of males in the study. 
 
Definitions 
Woman of Childbearing Potential  
 
A woman is considered fertile following menarche and until becoming postmenopausal unless permanently 
sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy. 
 
Women in the following categories are not considered women of childbearing potential 
 
1. Premenopausal female with one of the following: 
a) Documented hysterectomy 
b) Documented bilateral salpingectomy 
c) Documented bilateral oophorectomy 
 
Note: Documentation can come from the site personnel’s: review of participant’s medical records, medical 
examination, or medical history interview. 
 
2. Premenarchal  
 
3. Postmenopausal female 
a) A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. 
A high follicle stimulating hormone level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormone replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single follicle stimulating hormone 
measurement is insufficient.  
b) Females on HRT and whose menopausal status is in doubt will be required to use 1 of the non-
hormonal highly effective contraception methods if they wish to continue their HRT during the study. 
Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status before study 
enrolment. 
Contraception Guidance 
Male participants 
Male participants with female partners of childbearing potential are eligible to participate if they agree to the 
following:  
1. Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent on a long-
term and persistent basis) and agree to remain abstinent for duration of study and for 4 days from last 
dose  
2. Female partner is using a highly effective contraceptive method  
3. Agree to use a male condom plus an additional method with a failure rate of <1% per year as described 
in the table below when having penile-vaginal intercourse with a woman of childbearing potential.   
4. Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal 
intercourse or use a male condom during each episode of penile penetration and for 4 days from last 
dose. 
5. Refrain from donating sperm for duration of study and for 4 days from last dose. 


 
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Highly Effective Contraceptive Methods That Are User Dependent  
Failure rate of <1% per year when used consistently and correctlya.  
Combined (estrogen and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationb  
• 
Oral  
• 
Intravaginal  
• 
Transdermal  
Progestogen-only hormonal contraception associated with inhibition of ovulationb  
• 
Oral  
• 
Injectable  
Highly Effective Methods That Are User Independent  
• 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
Vasectomized partner  
(A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the woman of childbearing potential and the absence of sperm has been confirmed. If not, 
an additional highly effective method of contraception should be used.)  
Sexual abstinence  
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatment. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant.)  
NOTES:  
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for participants participating in 
clinical studies.  
b) Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the 
efficacy of the contraceptive method. In this case, 2 highly effective methods of contraception should be 
utilized during the treatment period and for at least 4 days from last dose.  
 
Female participants 
Female participants of reproductive potential are eligible to participate if they agree to use a highly effective 
method of contraception consistently and correctly as described in the table above.  
Pregnancy Testing  
Women of childbearing potential should only be included after a confirmed menstrual period and a negative 
highly sensitive serum pregnancy test. 
 
Additional pregnancy testing should be performed at regular intervals as per the SoA during the treatment 
period and at 28 days after the last dose of study treatment. 
 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when pregnancy is 
otherwise suspected. 
 
Pregnancy testing, with a sensitivity of 5 mIU/mL will be performed and assayed at the study site.  


 
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Collection of Pregnancy Information  
Male participants with partners of reproductive potential who become pregnant  
 
Investigator will attempt to collect pregnancy information on any female partner of a male study participant 
who becomes pregnant while participating in this study. This applies only to participants who receive study 
treatment. 
 
If a pregnancy is reported for a subject’s partner, study treatment will be immediately discontinued.  
 
After obtaining the necessary signed ICF from the pregnant female partner directly, the Investigator will 
record pregnancy information on the appropriate form and submit it to the DCC within 24 hours of learning 
of the partner’s pregnancy. 
 
Partner will also be followed to determine the outcome of the pregnancy. Information on the status of the mother 
and child will be forwarded to the DCC. 
 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any termination 
of the pregnancy will be reported regardless of fetal status (presence or absence of anomalies) or indication 
for procedure. 
 
Female participants who become pregnant  
 
Investigator will collect pregnancy information on any female participant who becomes pregnant while 
participating in this study. 
 
Information will be recorded on the appropriate form and submitted to the DCC within 24 hours of learning of 
a participant's pregnancy. 
 
Participant will be followed to determine the outcome of the pregnancy. The Investigator will collect follow-up 
information on participant and neonate, which will be forwarded to the DCC. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. 
 
Any termination of pregnancy will be reported, regardless of fetal status (presence or absence of 
anomalies) or indication for procedure. 
 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or elective 
termination of a pregnancy will be reported as an AE or SAE. 
A spontaneous abortion is always considered to be an SAE and will be reported as such. 
 
Any SAE occurring as a result of a post-study pregnancy that is considered reasonably related to the study 
treatment by the Investigator will be reported to the DCC as described in Appendix 4. While the Investigator is 
not obligated to actively seek this information in former study participants, he/she may learn of an SAE through 
spontaneous reporting. 
 
Any female participant who becomes pregnant while participating will be withdrawn from the study. 
 
 
 
 
 


 
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Appendix 6:  Study Organization 
UAB 
Name 
Title 
Contact  
Study PI, Medical 
Oversight 
Mark Dransfield, MD 
Professor 
205-996-0101 
mdransfield@uabmc.edu 
Study PI, DCC Oversight 
Chichi Aban, PhD 
Professor 
205-934-2782 
caban@uab.edu 
Sub-Investigator 
Mike Wells, MD 
Associate 
Professor 
205-996-0101 
jmwells@uabmc.edu 
Sub-Investigator 
 Gary Cutter, PhD 
Professor 
205-975-5048 
cutterg@uab.edu 
Financial and 
Subcontracting Oversight 
Casondra Matthews 
Clinical Research 
Administrator III 
205-934-5555 
casondramatthews@uabmc.edu 
Regulatory Oversight 
Elizabeth Westfall 
MPH 
Director-Clinical 
Research 
Administration 
205-934-9282 
ewestfall@uabmc.edu 
NIH/NCATS 
NCATS Oversight 
Bobbie Ann Austin, 
PhD 
Program Officer 
Ph: 301.435.0824 
bobbieann.mount@nih.gov 
NHLBI Oversight and 
Medical Monitor 
Antonello (Tony) 
Punturieri, MD, PhD 
Program Director, 
DLD at NHLBI 
Ph: (301) 592-8573 
punturieria@nhlbi.nih.gov 
Mereo BioPharma 
Mereo BioPharma Medical 
Expert and Sponsor 
Signatory 
Jackie Parkin 
Therapeutic Area 
Head 
Mereo BioPharma 4 Ltd. 
1 Cavendish Place 
London, W1G 0QF 
Mereo BioPharma Clinical 
Operations Oversight 
William Moore 
Clinical Operations 
Lead 
Participating Centers 
Cleveland Clinic 
Jamie Stoller, MD, MS 
Umur Hatipoglu, MD 
Site PI 
 
Site Sub-Inv 
stollej@ccf.org 
 
HATIPOU@ccf.org 
Temple University 
Wissam Chatila, MD 
Site PI 
Wissam.Chatila@tuhs.temple.edu 
University of Texas Tyler 
Megan Devine, MD 
Site PI 
Megan.Devine@uthct.edu 
Medical University of 
South Carolina 
Charlie Strange, MD 
Site PI 
StrangeC@musc.edu 
National Jewish Health 
Sandy Sandhaus, MD, 
PhD 
Site PI 
Rsandhaus@alphanet.org 
University of North 
Carolina at Chapel Hill 
M. Brad Drummond, 
MD, MHS 
Site PI 
brad_drummond@med.unc.edu 


 
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University of Utah 
Cheryl Pirozzi, MD 
Site PI 
Cheryl.Pirozzi@hsc.utah.edu 
Columbia University 
Jeanine M. D'Armiento, 
MD, PhD 
Site PI 
jmd12@cumc.columbia.edu 
Data Safety Monitoring Board 
Brendan McGuire, MD 
Gastroenterologist, 
UAB 
bmcguire@uabmc.edu 
Robert Reed, MD 
Pulmonologist, 
University of Maryland 
rreed@som.umaryland.edu 
Amber Salter, PhD 
Statistician, 
Washington University 
amber@wustl.edu 
 
 
 


 
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Appendix 7:  Summary of Versions and Changes 
Protocol 
Version 
Date 
Summary of Change 
Original 
1.0 
September 5, 2018 
Not Applicable 
Revision 1 
1.1 
October 26, 2018 
Eligibility and safety modifications per FDA request (see 
also Table of Protocol changes October 26, 2018) 
Revision 2 
1.2 
July 31, 2019 
Eligibility and safety modifications (see also Table of 
Protocol changes July 31, 2019) 
Revision 3 
1.3 
February 18, 2020 
Eligibility modifications to include participants on 
augmentation therapy and safety updates (also see 
Table of Protocol changes February 18, 2020 
Revision 4 
1.4 
February 10, 2021 
Eligibility modifications to include participants with other 
rare genotypes/phenotypes at increased risk for 
emphysema. (also see Table of Protocol changes 
February 16, 2021) 
 

SAP_003.pdf: 
Statistical Analysis Plan 
 ATALANTa Study 
1 
Statistical Analysis Plan 
TRIAL FULL TITLE 
Alvelestat (MPH966) for the Treatment of ALpha-1 
ANTitrypsin Deficiency (ATALANTa) 
NCT identifier 
SAP VERSION 
1.0 
SAP VERSION DATE 
June 21, 2023 
TRIAL STATISTICIANS 
Inmaculada Aban, PhD; Gary Cutter, PhD; Huichien Kuo, 
MPH  
TRIAL CHIEF 
INVESTIGATOR 
Mark Dransfield, MD Mike Wells, MD 
SAP AUTHOR 
Inmaculada Aban, PhD; Gary Cutter, PhD; Huichien Kuo, 
MPH 
NCT03679598


Statistical Analysis Plan 
 ATALANTa Study 
2 
 
Table of Contents 
Table of Contents.................................................................................................... 2 
1 
Abbreviations and Definitions ........................................................................... 5 
2 
Introduction ...................................................................................................... 8 
2.1 
Preface ....................................................................................................... 8 
2.2 
Purpose ...................................................................................................... 8 
3 
Study Objectives ............................................................................................... 8 
3.1 
Primary Objectives: ..................................................................................... 8 
3.2 
Secondary Objectives .................................................................................. 8 
3.3 
Exploratory Objectives ................................................................................ 8 
3.4 
General Study Design and Plan ................................................................... 8 
3.5 
Inclusion-Exclusion Criteria and General Study Population ......................... 9 
3.5.1 Inclusion Criteria ........................................................................................ 9 
3.5.2 Exclusion Criteria ..................................................................................... 10 
3.5.3 Sample Size .............................................................................................. 12 
3.6 
Treatment Administration and Blinding .................................................... 12 
3.7 
Study Procedures and Flowchart ............................................................... 13 
4 
Endpoints ....................................................................................................... 15 
4.1 
Primary Efficacy Endpoints ........................................................................ 15 
4.2 
Primary Safety Endpoints .......................................................................... 15 
4.3 
Secondary Efficacy Endpoints .................................................................... 15 
4.4 
Exploratory Endpoints .............................................................................. 15 
4.5 
Study Variables ......................................................................................... 16 
4.5.1 Key Screening Assessments ...................................................................... 16 
4.5.2 Blood, Sputum, and Bronchoalveolar Lavage Biomarkers ........................... 16 
4.5.3 Functional and Quality of Life Instruments ................................................ 17 
4.5.4 Safety Assessments .................................................................................. 18 
5 
Analysis Sets ................................................................................................... 20 


Statistical Analysis Plan 
 ATALANTa Study 
3 
 
6 
General Aspects for Statistical Analyses .......................................................... 20 
6.1 
General Methods ...................................................................................... 20 
6.2 
Key Definitions ......................................................................................... 21 
6.3 
Covariates and Subgroups ........................................................................ 22 
6.4 
Missing Data ............................................................................................ 22 
6.5 
Multi-center Studies ................................................................................. 22 
6.6 
Multiple Testing ....................................................................................... 22 
7 
Demographic, Other Baseline Characteristics, Medication and Protocol 
Deviations ............................................................................................................. 22 
7.1 
Subject Disposition ................................................................................... 22 
7.2 
Demographic and Baseline Variables ........................................................ 23 
7.3 
Medical History and Concomitant Diseases ............................................... 23 
7.4 
Medications .............................................................................................. 24 
7.5 
Protocol Deviations .................................................................................. 25 
8 
Efficacy Analyses ............................................................................................ 25 
8.1 
Primary Efficacy Endpoint Analyses: .......................................................... 25 
8.2 
Secondary Efficacy Endpoint Analyses: ...................................................... 26 
8.3 
Exploratory Efficacy Endpoint Analyses: .................................................... 27 
8.4 
Analysis of Pharmacokinetics .................................................................... 27 
8.5 
Correlation of PK Exposure with Efficacy (PD) and Safety ........................... 28 
8.5.1 Presentation of Concentration Data .......................................................... 28 
8.5.1.1 
Handling of Missing Data ................................................................ 28 
8.5.1.2 
Listing, Presentation and Summary of PK Data ................................ 28 
9 
Safety Analyses ............................................................................................... 29 
9.1 
Extent of Exposure ................................................................................... 29 
9.2 
Treatment Compliance ............................................................................. 29 
9.3 
Safety Outcomes ...................................................................................... 29 
9.3.1 Primary Safety Outcomes .......................................................................... 29 
9.3.2 Secondary Safety Outcomes ...................................................................... 30 


Statistical Analysis Plan 
 ATALANTa Study 
4 
 
9.3.3 Exploratory Safety Outcomes .................................................................... 30 
10 Changes from Analysis Planned in the Protocol ............................................... 30 
11 Interim Analyses ............................................................................................. 31 
12 References ...................................................................................................... 31 
13 Reporting Conventions ................................................................................... 31 
14 Listing of Tables, Figures, and Listings ........................................................... 32 
14.1 Listing of Tables ....................................................................................... 32 
14.2 Listing of Figures ...................................................................................... 36 
14.3 Listings .................................................................................................... 39 
 
 
 


Statistical Analysis Plan 
 ATALANTa Study 
5 
 
1 Abbreviations and Definitions 
Abbreviation 
Description 
AAT 
Alpha-1antitrypsin 
AATD 
Alpha-1 antitrypsin deficiency 
Aα-Val360 
Fragment from neutrophil elastase cleavage of elastin at Aα-Val360 site 
AcPGP 
Acetylated Proline-Glycine-Proline 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BAL 
Bronchoalveolar lavage 
bid 
Twice (2 times) a day 
C1M 
MMP-derived collagen type I breakdown fragment 
C6M 
MMP-derived collagen type VI breakdown fragment 
CAT 
COPD assessment test 
Cat g 
Cathepsin G 
CF 
Cystic fibrosis 
CFR 
United States Code of Federal Regulations 
CMP 
Complete metabolic profile 
CMV 
Cytomegalovirus 
CONSORT 
Consolidated Standards of Reporting Trials 
COPD 
Chronic obstructive pulmonary disease 
CRF 
Case report form 
CRO 
Clinical Research Organization 
CT 
Computerized or computed tomography 
CYP2C9 
Cytochrome P450 2C9 
DCC 
Data Coordinating Center 
DES 
Desmosine 
dL 
Decilitre 
DSMB 
Data Safety Monitoring Board 
EBV 
Epstein-Barr virus 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EL-CG 
Elastin degradation mediated by Cathepsin G 
EL-NE 
Elastin degradation mediated by NE 
EL-P3 
Elastin like polypeptide 3 
EOT 
End of treatment 
EP-3 
Elastin peptide 3 
FAS 
Full Analysis Set 
FEV1 
Forced expiratory volume in 1 second 
FEV1/FVC 
Forced expiratory volume in 1 second divided by the forced vital capacity 
FVC 
Forced vital capacity 
FIB-4 
Fibrosis-4 
FU 
Follow-up 
FVC 
Forced vital capacity 
g 
Gram 
GCP 
Good Clinical Practice 
h 
Hour 
hCG 
Human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 


Statistical Analysis Plan 
 ATALANTa Study 
6 
 
Abbreviation 
Description 
hsCRP 
High-sensitivity C-reactive protein 
HRT 
Hormone replacement therapy 
HSV 
Herpes simplex virus 
Hy’s Law 
a rule of thumb that a patient is at high risk of a fatal drug-induced liver injury 
(DILI) if given a medication that causes hepatocellular injury (not cholestatic 
injury) with jaundice 
IC50 
the concentration of an inhibitor where the response (or binding) is reduced by 
half 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IL-1β 
Interleukin 1 beta 
IL-6 
interleukin-6 
IL-8 
interleukin-8 
IND 
Investigational new drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IWRS 
Interactive web response system 
Ki 
Inhibitory constant 
kPa 
kiloPascal, a unit of force 
LSM 
Liver stiffness measurement 
LTB4 
Leukotriene b4 
MedDRA 
Medical Dictionary for Regulatory Activities 
mGy 
milliGray, a unit of radiation 
mg/dL 
Milligrams per decilitre 
mIU 
Milli International Units 
MMP 
Matrix metalloproteinase 
MMRC 
Modified medical research council 
MOP 
Methods of procedures 
MPO 
Myeloperoxidase 
MS 
Millisecond 
mSV 
milliSever 
NCATS 
National Center for Advancing Translational Science 
NCT 
National Clinical Trial 
NE 
Neutrophil elastase 
NIH 
National Institutes of Health 
NOAEL 
No observed adverse effect level 
NSAID 
Non-steroidal anti-inflammatory drug 
Pa 
Pascal 
PD 
Pharmacodynamics 
PI 
Principal investigator 
Pi*ZZ 
Alpha-1 ZZ genotype 
Pi*SZ 
Alpha-1 SZ genotype 
Pi*Null, Null 
Alpha-1 Null genotype 
PGP 
P-glycoprotein 
PKS 
Pharmacokinetics Set 
PK 
Pharmacokinetics 
PPS 
Per Protocol Set 
PR 
time from the onset of the P wave to the start of the QRS complex on ECG 
PR3 
Proteinase 3 
 
 


Statistical Analysis Plan 
 ATALANTa Study 
7 
 
Abbreviation 
Description 
PROs 
Patient reported outcomes 
PRO-C6 
Released C-terminal pro-peptide of type VI collagen 
QRS 
Represents ventricular depolarization on ECG 
QT 
The duration of ventricular depolarization and repolarization on ECG 
QTc 
Corrected QT interval 
QTcF 
QTc by Fridericia’s correction method 
QTcV 
QTc by Van de Water’s correction formula 
RANTES 
Regulated on activation, normal T cell expressed and secreted 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAF 
Safety Set 
SAP 
Statistical Analysis Plan 
SAS 
Statistical analysis software 
SGRQ-C 
St. George’s Respiratory Questionnaire compact version 
SoA 
Schedule of Activities 
SOB 
Shortness of breath 
SOP 
Standard operating procedure 
SOBQ 
Shortness of breath questionnaire 
Sp02 
Pulse oximetry 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
Total bilirubin 
ug 
Microgram 
ULN 
Upper limit of normal 
uM 
Micromolar 
UPs 
Unanticipated problems 
VZV 
Varicella zoster virus 
WBC 
White blood cell 
Wk. 
Week 
 
 
 
 


Statistical Analysis Plan 
 ATALANTa Study 
8 
 
2 Introduction 
2.1 Preface 
This is a Phase 2, multicenter, double-blind, randomized (1:1), placebo-controlled, 12-week, 
proof-of-concept study to evaluate the safety and tolerability as well as the mechanistic 
effect of oral administration of Alvelestat (MPH966) in subjects with confirmed AATD defined 
as Pi*ZZ, Pi*SZ, Pi*null, or another rare phenotype/genotype known to be associated with 
either low (serum AAT level <11 μM or <57.2 mg/dL) or functionally impaired AAT including 
“F” or “I” mutations. 
2.2 Purpose  
The purpose of this Statistical Analysis Plan (SAP) is to provide detailed descriptions of the 
statistical methods, data derivations and data displays for the ATALANTa study; to ensure 
that the data listings, summary tables and figures which will be produced, and the statistical 
methodologies that will be used, are complete and appropriate to allow valid conclusions 
regarding the study objectives.  
3 Study Objectives 
3.1 Primary Objectives: 
• 
To evaluate the effect of Alvelestat (MPH966) administered twice daily (bid) for 12 
weeks on blood markers of neutrophil elastase activity 
• 
To evaluate the safety and tolerability of Alvelestat (MPH966) administered twice 
daily (bid) for 12 weeks 
3.2 Secondary Objectives 
• 
To evaluate the effect of Alvelestat (MPH966) on other blood pharmacodynamic 
markers of neutrophil activation and elastase activity 
• 
To evaluate the effect of Alvelestat (MPH966) on blood biomarkers of lung tissue 
degradation 
• 
To evaluate the effect of Alvelestat (MPH966) on biomarkers of inflammation in blood 
3.3 Exploratory Objectives 
• 
To evaluate the effect of Alvelestat (MPH966) on respiratory symptoms, 
breathlessness, and health status 
• 
To evaluate PK efficacy relationships in AATD 
• 
To evaluate the effect of Alvelestat (MPH966) on neutrophil activation, elastase, and 
inflammatory activity in lung. This was a secondary outcome but now exploratory 
depending on data available for analyses due to sputum and BAL being optional. 
3.4 General Study Design and Plan 
This will be a multicenter, double-blind, randomized, placebo-controlled trial. One dose of 
Alvelestat (MPH966), 120 mg bid, will be tested against placebo. These doses are based on 
PK and PD modelling of Alvelestat (MPH966) inhibition of human neutrophil elastase.  


Statistical Analysis Plan 
 ATALANTa Study 
9 
 
 
The participants will be those patients with the AATD at risk for emphysema (Pi*ZZ, Pi*SZ, 
Pi*null, or another rare phenotype/genotype known to be associated with either low [serum 
AAT level <11 μM or <57.2 mg/dL] or functionally impaired AAT including “F” or “I” mutations)  
 
Following a screening period of up to 4 weeks, patients will be dosed with study treatment or 
placebo for 12 weeks, with a subsequent 4-week follow-up period for safety and determination 
of the offset of the mechanistic effect of MPH966 on the primary endpoint 
(desmosine/isodesmosine). 
 
The study is divided into 3 phases:  a screening phase, treatment phase, and washout phase 
as detailed below: 
 
• 
A screening period from Week -4 to Day -1.  Baseline safety assessments and 
measurement of DES in blood, sputum, and BAL (in those who consent to bronchoscopy) 
will occur prior to randomization and treatment allocation. 
 
• 
A treatment period consisting of Alvelestat (MPH966) 120mg bid or placebo for 12 weeks.  
Safety assessments including tests of liver function, ECG, hematology, and chemistries 
will be assessed at the week 1 and week 2 visits and then bi-weekly for the remainder of 
the 12-week treatment period.  Blood will be collected at the Week 4, 8, and 12 visit for 
biomarker analysis.  Sputum will be collected at the week 12 visit. Follow-up BAL will be 
collected at week 11.   
 
• 
A washout period from Week 12 to Week 16.  Blood will be collected for biomarker 
analysis at week 16. 
 
3.5 Inclusion-Exclusion Criteria and General Study Population 
3.5.1 Inclusion Criteria  
Figure 1: Study Schematic 
 


Statistical Analysis Plan 
 ATALANTa Study 
10 
 
Participants are eligible to be included in the study only if ALL of the following criteria apply: 
 
Type of Participant and Disease Characteristics 
 
1. Capable of giving signed informed consent as described in Appendix 3, which includes 
compliance with the requirements and restrictions listed in the informed consent form 
and in this protocol 
2. Age ≥18 and ≤80 years 
3. Patients with a confirmed diagnosis of AATD: Pi*ZZ, Pi*SZ, Pi*null, or another rare 
phenotype/genotype known to be associated with either low (serum AAT level <11 μM 
or <57.2 mg/dL) or functionally impaired AAT including “F” or “I” mutations. 
4. FEV1 ≥25% predicted 
5. Patients will be eligible if they are either a) are not currently receiving augmentation 
treatment and have not received augmentation in the 12 weeks prior to screening or 
b) have received weekly infusions of augmentation at 60 mg/kg for at least 12 weeks 
prior to screening and intend to continue augmentation through the study period. 
6. Male or female sex 
a. Male participants must agree to use a highly effective contraception as detailed in 
Appendix 5 during the treatment period and for at least 4 days after the last dose 
of study treatment and refrain from donating sperm during this period 
b. Female participants are eligible to participate if not pregnant; not breastfeeding; 
and at least one of the following conditions is met:   
i. 
Not a woman of childbearing potential as defined in Appendix 5  
OR 
ii. A woman of childbearing potential who agrees to follow the contraceptive 
guidance in Appendix 5. During the treatment phase and for at least 4 days after 
the last dose of study medication.  
 
3.5.2 Exclusion Criteria 
 
Participants are excluded from the study if ANY of the following criteria apply: 
 
Excluded Medical Conditions 
 
1. Subjects with Pi*MZ, Pi*FM, Pi*MS, Pi*SS, or other AATD phenotypes/genotypes not 
known to be independently associated with emphysema. 
2. Any clinically diagnosed lung disease other than COPD such as diffuse interstitial lung 
diseases, cystic fibrosis, or clinically significant bronchiectasis as determined by the 
Investigator 
3. Acute exacerbation of underlying lung disease requiring oral steroids and/or antibiotics 
within 4 weeks of baseline 
4. Acute or chronic hepatitis, including hepatitis B, hepatitis C (positive serologies, 
including hepatitis B and C antibody) 
5. HIV infection or other immunodeficiency or with an absolute neutrophil count ≤1.0 × 
109/L 
6. Abnormal liver biochemistry (alanine aminotransferase, aspartate aminotransferase, 
gamma-glutamyl transferase) >1.5 × upper limit of normal or total bilirubin > upper limit 
of normal (unless Gilbert’s disease with normal conjugated bilirubin) 
7. Any of the following laboratory abnormalities are present at baseline: 
a. 
Platelet count <150×109/L 
b. 
Serum albumin ≤ 3.5 g/dL 
c. 
INR ≥1.2 
d. 
CPK ≥ ULN. 


Statistical Analysis Plan 
 ATALANTa Study 
11 
 
8. History or current evidence of cirrhosis (on biopsy or imaging), esophageal varices, 
ascites or hepatic encephalopathy. 
9. Evidence of other forms of chronic liver disease based on diagnostic testing as per the 
guidelines (i.e. autoimmune liver disease, primary biliary cirrhosis, primary sclerosing 
cholangitis, Wilson’s disease, Hemochromatosis or iron overload). 
10. Patients with nonalcoholic fatty liver disease (NAFLD) as diagnosed by any imaging 
modality (or use of drugs associated with NAFLD for more than 2 weeks in the year 
prior to screening).  
11. Subjects with a history of significant alcohol consumption for a period of more than 3 
consecutive months within 1 year prior to screening, defined as average of >20g/ day 
in female subjects and >30g/ day in male subjects. 
12. Fibrosis-4 (FIB-4) score >3.25 
13. Any of the following cardiovascular conditions within 6 months prior to the screening 
visit:  
a. 
Myocardial infarction or unstable angina 
b. 
Coronary artery bypass surgery, balloon angioplasty, percutaneous coronary 
intervention, or carotid revascularization procedure 
c. 
Uncontrolled hypertension  
d. 
Stroke or transient ischemic attack 
14. Congestive heart failure (New York Heart Association III/IV) with left ventricular 
ejection fraction < 40% 
15. Any clinically significant 12-lead electrocardiogram abnormalities at screening or 
baseline, including corrected QT interval by Fridericia’s correction method >450 ms or 
history of significant cardiac dysrhythmia, including long QT syndrome 
16. History of cancer within the last 5 years, except for well-treated basal cell carcinoma 
and squamous cell carcinoma of the skin 
17. Other documented comorbidities or laboratory abnormalities that in the opinion of the 
Investigator could affect the outcome of the study assessments, participant safety, or 
ability of the participant to comply with the requirements of the protocol 
 
Excluded Prior/Concomitant Therapy 
 
18. Daily use of prednisone (>10mg daily), or other systemic glucocorticoids at comparable 
or higher equivalent dose, or use of other immunosuppressant therapies are prohibited  
19. Immunomodulating monoclonal antibodies within 6 months prior to screening are 
prohibited 
20. Daily use of non-steroidal anti-inflammatory drugs (NSAIDs) is prohibited.  Daily use 
of acetaminophen up to 2 g per day and aspirin up to 325 mg per day is permitted. 
21. Initiation of drugs known for hepatotoxic potential within the 28 days prior to screening 
including but not limited to: statins, NSAIDS, amoxicillin/clavulanate, PDE inhibitors 
(theophylline, roflumilast), and anti-epileptics.  Subjects on established treatment for 
more than 28 days prior to screening will not be excluded. Requirement for medications 
mainly metabolized by CYP2C9 and with narrow therapeutic index (eg, warfarin, 
phenytoin) is prohibited 
 
Excluded Prior/Concurrent Clinical Study Experience 
 
22. Participation in any clinical investigation using medical devices or non-biologic 
treatments within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to the initial 
dosing (or longer if required by local regulations) is prohibited 
23. Participation in any clinical investigation using biologic treatment within 6 months of 
screening is prohibited 
24. Previous participation in a gene therapy study for AATD at any time is prohibited 
 
Other Exclusions 


Statistical Analysis Plan 
 ATALANTa Study 
12 
 
 
25. History of hypersensitivity to Alvelestat (MPH966) or any of its excipients or the class 
of neutrophil elastase inhibitors  
26. Known hypersensitivity to medications used in the study procedures (e.g. midazolam, 
fentanyl, and lidocaine for bronchoscopy) 
3.5.3 Sample Size  
Over the course of the study, target enrolment is 66 with the goal of 60 completers. Participants 
will be randomized in a 1:1 ratio to receive one of the following:  120mg Alvelestat (MPH966) 
BID or placebo.  Randomization will be stratified by AAT genotype/phenotype.   
The study will be powered for within-individual change in plasma desmosine/isodesmosine 
(DES) as the primary endpoint at Week 12 compared to baseline. A sample size of 30 
participants in the MPH966 treatment group will give us >90% power to detect a 15% mean 
decrease of plasma DES from baseline to 12 weeks follow-up in patients treated with MPH966 
(within subject change) using a two-sided paired t-test at α=0.05. The calculation is based on 
an assumed correlation value of 0.5, baseline mean DES value of 0.466 and standard 
deviation of 0.09.  This 15% mean decrease has been observed in trials of standard dose 
augmentation versus placebo (Ma S, 2013).  A recent study of double dose versus single dose 
augmentation revealed a within subject decrease in plasma DES from 0.42 +/-0.03 ng/ml to 
0.38 +/- 0.03 ng/ml (Campos MA, 2019). We will have >99% power to detect a comparable 
difference in DES in those who have Alvelestat added to augmentation if we assume their 
observed SD=0.03 and 85% power if we double their assumed SD, i.e., SD=0.06. Power will 
not be enough (~50%) to detect this difference if we use our original SD value of 0.9. 
For comparing the mean change in DES between the two groups (placebo vs. MPH966), and 
assuming that there is no placebo effect over 12 weeks, a two-sided two sample t-test at 
α=0.05 with a sample size of 60 (30 per group) reveals that we will have 82% power to detect 
a 15% difference in mean change in plasma DES.  
By including a 10% attrition rate over 12 weeks, the required sample size is inflated to 66 (33 
per group) to achieve the estimated powers. If we observe attrition rate less than we expected, 
we will have more statistical power to detect the expected differences. As one interim analysis 
will be conducted only for safety concerns (see Data Safety and Monitoring Plan), no 
adjustments to the Type I error are considered for estimating statistical powers. 
All participants will be centrally randomized 1:1 to the 120 mg and placebo arms using an 
interactive web response system (IWRS). A unique number will be assigned to each 
participant and will be linked to randomization numbers using a randomization list produced 
by the DCC. These randomization numbers will be linked to the 2 treatment regimens, and the 
randomization scheme will be stratified according to genotype (Pi*ZZ, Pi*SZ, Pi*(Null) (Null)) 
3.6 Treatment Administration and Blinding 
 
Treatments Administered 
Study Treatment Name: 
 
Alvelestat 120 mg 
Placebo 
Dosage Formulation: 
 
Tablet 
Tablet 


Statistical Analysis Plan 
 ATALANTa Study 
13 
 
Unit Dose Strength(s) / 
Dosage Level(s): 
 
4 × 30 mg Alvelestat 
4 × 30 mg Placebo 
Route of Administration  
Oral 
 
Oral 
Dosing Instructions: 
 
To be taken bid, 12 hours apart and with water 
Packaging and Labeling: 
 
Study treatment will be provided in boxes. Each box 
will contain treatment for 7 days and will be labeled 
as required per U.S. regulations. 
 
Manufacturer: 
Mereo BioPharma 4 Ltd., 1 Cavendish Place, 
London, W1G 0QF, UK 
 
 
 
 
This is double-blind study. The investigators, participants, Mereo and NCATS will remain 
blinded to the study treatment allocation until the end of the study. The randomization list will 
be kept secured from the study team, investigators, and participants throughout the conduct 
of the study and until unblinding is authorized by the DCC. The DSMB will be unblinded 
according to the DSMB charter. 
 
The IWRS will be programmed with blind-breaking instructions. The study blind may be 
broken for a medical emergency in which the knowledge of the specific blinded study 
treatment will affect the immediate management of the participant’s condition. In this case, 
the DCC, the NCATS Medical Monitor, and Mereo must be notified within 24 hours after 
breaking the blind. The date and reason that the blind was broken must be recorded in the 
source documentation and case report form (CRF), as applicable. 
3.7 Study Procedures and Flowchart 
Study procedures and their timing are summarized in the Schedule of events (SOA) – see 
Figure 2.


Statistical Analysis Plan 
 ATALANTa Study 
14 
 
Figure 2: SCHEDULE OF ACTIVITIES (SOA) 


Statistical Analysis Plan 
 ATALANTa Study 
15 
 
4 Endpoints 
4.1 Primary Efficacy Endpoints 
Within-individual % change from baseline in plasma desmosine/isodesmosine at end of 
treatment with MPH966 
4.2 Primary Safety Endpoints 
1. 
Numbers and % of subjects who experience at least 1 treatment-emergent adverse 
event 
2. 
Adverse events of special interest (liver function abnormalities, corrected QT 
interval/cardiac, infections, and neutropenia) 
4.3 Secondary Efficacy Endpoints 
Blood pharmacodynamic markers of neutrophil activation and elastase activity. Change 
from baseline in the following outcomes at end of the treatment within patient and 
compared to placebo: 
1. Plasma desmosine/isodesmosine (only change compared to placebo; within-
individual change is the primary outcome) 
2. Plasma Aa-Val-360 
3. Serum NE activity 
4. Plasma proteinase 3  
5. Plasma cathepsin B 
6. Plasma CRP 
7. Plasma IL-6 
8. Plasma IL-8 
9. Plasma IL-1b 
10. Plasma RANTES 
11. Plasma LTB4 
12. Plasma MMP9 
13. Plasma MMP12 
14. Plasma MPO 
15. Plasma PGP 
16. Plasma PK/PD (LCG/DDS) 
The above list was revised from the original protocol as a result of lack of data from sputum 
and BAL collections due to restrictions during the COVID pandemic. Data on NE may not be 
available on all subjects. 
4.4 Exploratory Endpoints 
1. Change from baseline in pre-and post-bronchodilator forced expiratory volume in 1 
second (FEV1), forced vital capacity (FVC), FEV1/FVC (total and percent predicted), 
and maximal mid-expiratory flow at end of treatment . Data may not be sufficient to 
perform this analyses due lack of spirotmetry data. 
2. Change from baseline in St. George’s Respiratory Questionnaire (SGRQ) (overall and 
per domain), COPD Assessment Test (CAT), Modified Medical Research Council 


Statistical Analysis Plan 
 ATALANTa Study 
16 
 
Questionnaire (MMRC), San Diego Breath Questionnaire (SOBQ) and daily symptom 
scores 
3. PK/pharmacodynamic (PD) relationship with efficacy biomarkers in blood and sputum. 
Due to the COVID pandemic, protocol was revised to make sputum collection optional. 
Only correlation of PK/PD with blood will be done. 
 
 
4.5 Study Variables 
4.5.1 Key Screening Assessments 
 
FIB-4 Score 
 
The FIB-4 test combines age with 3 standard biochemical values (platelets, ALT, and AST) as 
a non-invasive test to assess fibrosis and enable exclusion of participants who may be at 
greater risk of liver AEs (https://www.mdcalc.com/fibrosis-4-fib-4-index-liver-fibrosis). The 
following formula will be used: 
 
 
 
Using a cut-off value of 1.45, a FIB-4 score <1.45 has been shown to have a negative 
predictive value of 90% for advanced fibrosis. In contrast, a FIB-4 >3.25 would have a 97% 
specificity and a positive predictive value of 65% for advanced fibrosis42. FIB-4 index has been 
shown to be superior to other scoring systems for differentiating between advanced and mild 
fibrosis.   
 
4.5.2 Blood, Sputum, and Bronchoalveolar Lavage Biomarkers 
 
Blood  
 
Blood will be collected as per the SOA, and samples will be collected and processed as 
described by the MOP. 
 
Sputum (this is optional due to COVID as reflected in the revised protocol Version 1.4) 
 
Sputum will be collected from induced samples (refer to the MOP for processing details).  
Sputum induction will not be undertaken if the baseline FEV1 for the procedure is less than 1 
L. Further details of sputum induction will be included in the MOP.  Sputum induction is 
considered an aerosol generating procedure (AGP) and sites should use local guidance on 
conducting AGP as part of clinical research in the COVID-19 era. 
 
Bronchoalveolar Lavage (BAL) (this is optional due to COVID as reflected in the revised 
protocol) 
 


Statistical Analysis Plan 
 ATALANTa Study 
17 
 
BAL will be collected in the subset of participants who agree to participate in the bronchoscopy 
sub-study.  Samples will be collected at two time points as per the SOA, and samples will be 
collected and processed as described by the MOP.  Bronchoscopy and BAL is considered an 
aerosol generating procedure (AGP) and sites should use local guidance on conducting AGP 
as part of clinical research in the COVID-19 era. 
 
Blood, sputum, and BAL efficacy biomarkers (see Table 1) will be taken at the time points as 
detailed in the SoA to evaluate their association with the observed mechanism of action 
responses to neutrophil elastase inhibition, including response of neutrophil elastase activity, 
inflammation, and lung damage to Alvelestat (MPH966). 
 
The samples will be collected and processed as described in the MOP.  
 
Samples may be stored for a maximum of 60 months following the end of study at a facility 
selected by the Sponsor to enable further analysis of biomarker responses to Alvelestat 
(MPH966).  
 
Table 1 Biomarkers of Efficacy Collected in Blood (list below has been revised to 
exclude biomarkers from Sputum and BAL) 
Biomarker 
Collected at Visit Number 
(see Figure 1 for week corresponding to visit number) 
Plasma desmosine/isodesmosine 
1, 3, 6, 8, 11, 12 
Plasma Aa-Val-360 
1, 3, 6, 8, 11, 12 
Serum NE activity 
1, 3, 6, 8, 11, 12 
Plasma proteinase 3  
3, 11 
Plasma cathepsin B 
3, 11 
Plasma CRP 
3, 11 
Plasma IL-6 
3, 11 
Plasma IL-8 
3, 11 
Plasma IL-1b 
3, 11 
Plasma RANTES 
3, 11 
Plasma LTB4 
3, 11 
Plasma MMP9 
3, 11 
Plasma MMP12 
3, 11 
Plasma MPO 
3, 11 
Plasma PGP 
1, 3, 11 
Plasma PK/PD (LCG/DDS) 
3, 4, 5, 6, 8, 9, 11, 12 
 
In addition, samples will be stored and analysis may be performed on additional biomarker 
variants thought to play a role in neutrophil elastase–induced lung damage to evaluate their 
association with observed neutrophil activation responses to Alvelestat (MPH966). 
 
Biomarker data are reported as concentration results, measured using a specific assay with a 
working range defined by the two limits: Lower limit of quantification (LLOQ) and Upper limit 
of quantification (ULOQ). Values which fall below the LLOQ or above the ULOQ are reported 
as <LLOQ * dilution factor (dilution factor: if sample diluted and concentration measured still 
below LLOQ) and > ULOQ * dilution factor, respectively. In case of censored values (values 
below the LLOQ and/or values above the ULOQ), the values, reported as <LLOQ will be 
imputed as 0.5*LLOQ and values reported as >ULOQ will be imputed as 1.5*ULOQ. 
4.5.3 Functional and Quality of Life Instruments 


Statistical Analysis Plan 
 ATALANTa Study 
18 
 
• 
SGRQ-C  
 
The St. George’s Respiratory Questionnaire (SGRQ-C) will be administered at time points as 
detailed in the SoA. This is a questionnaire that measures health impairment in patients with 
COPD. It consists of 3 parts: a symptom score, an activity score, and an impact score. A total 
score is also produced.  
 
• 
COPD Assessment Test (CAT) 
 
The CAT is an 8 item questionnaire used to report health status in COPD.  It will be 
administered at time points as shown in the SOA.  
 
• 
Modified Medical Research Council (MMRC) 
 
The MMRC will be administered at time points as detailed in the SoA and is used to measure 
dyspnea on a 5-point scale.  
 
• 
San Diego Breath Questionnaire (SOBQ) 
 
The SOBQ assesses patient reported dyspnea.  The SOBQ will be administered at time 
points as detailed in the SoA.  
 
• 
Pulmonary Function Testing/Spirometry 
 
Pulmonary function testing (FEV1, FVC, FEV1/FVC, and maximal mid-expiratory flow) will be 
performed at the times specified in the SoA according to ATS guidelines.  Further details on 
the spirometry procedure can be found in the Specific MOP. Spirometry is considered an 
aerosol generating procedure (AGP) and sites should use local guidance on conducting AGP 
as part of clinical research in the COVID-19 era. 
 
 
4.5.4 Safety Assessments 
 
Planned time points for all safety assessments are provided in the SoA. 
 
• 
Physical Examinations 
 
o A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, integumentary, and neurological 
systems. Height and weight will also be measured and recorded. 
o A brief physical examination will include, at a minimum, assessments of the lungs, 
heart, abdomen, and skin indicating normal vs abnormal 
o Investigators should pay special attention to clinical signs related to previous 
serious illnesses. 
 
• 
Vital Signs 
 
Vital signs will be measured in a semi-supine position after 5 minutes of rest and will include 
temperature, systolic and diastolic blood pressure, heart rate, respiratory rate, and pulse 
oximetry.  
 
o Oral or tympanic temperature. 


Statistical Analysis Plan 
 ATALANTa Study 
19 
 
o Blood pressure and pulse measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device is 
not available. 
o Blood pressure and pulse measurements should be preceded by at least 5 minutes 
of rest for the participant in a quiet setting without distractions (e.g., television, cell 
phones). 
o Pulse oximetry will be measured using a sensor placed on the participant’s fingertip 
or earlobe.  Oxygen saturation (SpO2) will be recorded.  
 
• 
Electrocardiograms 
 
o 12-lead ECG will be obtained as outlined in the SoA using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals. Refer to the Protocol for QTc withdrawal criteria and additional QTc 
readings that may be necessary. 
o Single ECGs will be performed at all scheduled time points, with the exception of 
when a change from baseline occurs that meets drug discontinuation criteria. In 
this situation, a triplicate measurement is required to confirm the finding and for 
discontinuation decisions. 
o When a triplicate ECG is required, 3 consecutive ECG tracings should be taken in 
a 30-minute period with at least 5 minutes between each ECG. 
o QTc value will be calculated using the Fridericia formula (QTc=QT/3√RR).  
 
• 
Clinical Safety Laboratory Assessments 
 
o The Investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE section 
of the CRF. The laboratory reports must be filed with the source documents. 
Clinically significant abnormal laboratory findings are those that are not associated 
with the underlying disease, unless judged by the Investigator to be more severe 
than expected for the participant's condition. 
o All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 days after the last dose of study treatment 
should be repeated until the values return to normal or baseline, with a frequency 
based on the judgement of the Site Investigator. If such values do not return to 
normal/baseline within a period of time judged reasonable by the Investigator, the 
etiology should be identified and the DCC notified. 
o The monitoring schedule proposed for a case of acute liver function abnormalities 
or worsening of a liver function abnormality is reported is listed in the Protocol (Liver 
Test Abnormalities). 
o Clinically significant liver function abnormalities should be reported as an 
AE/AESI.  
o All protocol-required laboratory assessments must be conducted in accordance 
with the MOP and the SOA.  
 
 


Statistical Analysis Plan 
 ATALANTa Study 
20 
 
 
5 Analysis Sets 
For purposes of analysis, the following populations are defined in Table 2. Subjects to be 
included in the analysis sets will be done prior to breaking the blind. 
 
Table 2: Definition of Analysis Sets 
Population 
Description 
Enrolled Set 
The Enrolled Set will include all participants who sign the ICF. 
Randomized Set  
The Randomized Set will include all subjects who signed the 
ICF and were subsequently randomized into the study, 
regardless of study treatment administration.   
Full Analysis Set (FAS) 
The Full Analysis Set will serve as the primary population for 
the analysis of efficacy and will consist of all randomized 
subjects who took at least 1 dose of double-blind study 
treatment and have at least 1 evaluable change from baseline 
in plasma desmosine / isodesmosine levels. Subjects will be 
analysed according to randomized treatment. 
Per-Protocol Set (PPS) 
The Per-Protocol Set includes all participants from the Full 
Analysis Set who have been treated according to the protocol 
and fulfil the following criteria: 
1. All inclusion/exclusion criteria satisfied 
2. Absence of major protocol violations with respect to 
factors likely to affect the efficacy of treatment where 
the nature of protocol violation will be defined before 
breaking the blind 
3. Adequate study medication compliance – to be 
determined before breaking the blind.  
Subjects will be analysed according to randomized treatment. 
Safety Set (SAF) 
All randomized participants who take at least 1 dose of study 
treatment. Participants will be analysed according to treatment 
taken. 
PK Set (PKS) 
The PK Set will include all participants in the Safety Set who 
have at least 1 evaluable serum concentration. 
 
6 General Aspects for Statistical Analyses  
6.1 General Methods 
Database lock will occur once all subjects complete the final study visit (Safety follow up at 
Week 16) or terminate early from the study. All analyses will be performed after data lock 
and cleaning. Statistical analysis will be performed using SAS® version 9.4 or higher. The 
main population for efficacy analysis will be the Full Analysis Set; supportive analyses will 
also be performed using the Per-Protocol Set.  
Continuous data will be presented using descriptive summaries (e.g., mean, standard 
deviation, minimum, maximum, median, lower quartile, and upper quartile). Categorical 
variables will be presented by the number of observations and relative (%) frequency.   


Statistical Analysis Plan 
 ATALANTa Study 
21 
 
Unless otherwise stated, baseline value for any variable will be the last value taken prior to 
the first dose of study medication. In general, all data will be listed, sorted by site, treatment 
and subject, and when appropriate by visit number within subject.  All summary tables will be 
structured with a column for Active, Placebo and Total, and will be annotated with the total 
population size relevant to that table/treatment, including any missing observations. 
 
As a Phase II study, no adjustments for Type I errors (see Section 6.6) will be done. All tests 
will be 2-sided and conducted at the 5% level. Confidence intervals will be 2-sided 95% 
confidence intervals. 
 
Biomarker data are reported as concentration results, measured using a specific assay with a 
working range defined by the two limits: Lower limit of quantification (LLOQ) and Upper limit 
of quantification (ULOQ). Values which fall below the LLOQ or above the ULOQ are reported 
as <LLOQ * dilution factor (dilution factor: if sample diluted and concentration measured still 
below LLOQ) and > ULOQ * dilution factor, respectively. All results for the above biomarker 
parameters, if collected, will be summarised on the respective populations by descriptive 
statistics stratified by treatment and time-point, and including the geometric mean and 
coefficient of variation. Changes in the biomarker concentrations from baseline (Study Day 1 
pre-dose) will be also summarised at each post-baseline time-point. In the summary table, the 
frequency (n, %) of values below the LLOQ and above the ULOQ, respectively, will be 
included. In case of values below the LLOQ and/or values above the ULOQ, the values, 
reported as <LLOQ will be imputed as 0.5*LLOQ and values reported as >ULOQ will be 
imputed as 1.5*ULOQ. 
6.2 Key Definitions 
 
Table 3: Definitions of Terminology 
Terminology 
Definition 
Baseline value 
defined as the last non-missing value prior to first study treatment 
dose 
End of Treatment (EOT) 
Visit 
visit refers to the final day of study treatment administration including 
cases of premature discontinuation of the study treatment. 
End of Treatment (EOT) 
Value 
Last non-missing post-baseline value under study treatment. 
Treatment Period 
duration that a subject is under treatment in the study between the 
date of first study treatment intake and the date of last study 
treatment intake. 
Study duration (in days), 
time to day of last visit or 
the day of study termination 
Calculated as: 
Date of Safety follow-up (FU) visit (or EOT visit in case of premature 
discontinuation) – Date of Baseline (Day 0) + 1. 
Study Completion and 
Withdrawal 
• 
A subject will be defined as “completed the study” if subject 
completes the follow-up at Week 16 – either having completed, 
all or partially, the protocol defined visits before Week 16. 
• 
Termination/withdrawal at a different time point will be 
considered as study discontinuation/withdrawal. 
EndPoint value 
considered the value at Week 12 or EOT value (last non-missing 
post-baseline value under treatment) 
Relative change from 
baseline 
defined as percentage change from baseline 
Calculated as: 
[(Post-baseline value – Value at baseline)/ Value at baseline]x100% 


Statistical Analysis Plan 
 ATALANTa Study 
22 
 
Absolute change from 
baseline 
Calculated as: 
Absolute change = Post-baseline value – Value at baseline 
 
Efficacy Offset Period 
Change from Week 12 to end of study follow-up at Week 16 
6.3 Covariates and Subgroups 
Prespecified covariates have been provided in the above efficacy analyses. Covariates to be 
included in the primary and secondary efficacy analyses on change in the biomarkers are 
baseline values, age and smoking history. Although we have stratified randomization by 
genotype, we will not include genotype as a covariate in the main analyses. Depending on 
available data, we may be able to compare outcomes between genotypes, but this will be 
exploratory in nature. 
Due to the change in protocol to drop augmentation therapy from the exclusion criterion, 
subgroup analyses between those enrolled with and without augmentation will be performed 
as secondary analyses. 
6.4 Missing Data 
Missingness will be assessed and tabulated by treatment group along with reasons for 
missingness to assess any differential missingness between the treatment arms. Patients 
impacted by COVID-19 that are related to study discontinuations, missing assessments, and 
missing visits due to COVID-19 will be created, sorted by patient number, randomized 
treatment and discontinuation date or visit, as applicable. All data will be listed and sorted by 
treatment and patient number within treatment. 
The efficacy analyses relating to change from baseline will be based on all the available post-
baseline measurements. For sensitivity analyses, we will perform a best-case (i.e., replacing 
missing by best value) and worst-case (i.e., replacing missing with worst value) scenario 
analyses with respect to the primary outcome and if the results match with the primary 
analyses, we will stop additional sensitivity analyses. 
6.5 Multi-center Studies 
This study was a multi-center study.  Data will be analyzed by combining data from all study 
centers.  No investigation of center effects is planned. 
6.6 Multiple Testing 
As a signal-seeking study, unless otherwise stated, all statistical tests will be 2-sided and 
conducted at the 5% level. All presented confidence intervals will be 2-sided 95% confidence 
intervals. No adjustment for multiplicity will be made for the primary and secondary efficacy 
variables. 
7 Demographic, Other Baseline Characteristics, Medication and 
Protocol Deviations 
7.1 Subject Disposition  


Statistical Analysis Plan 
 ATALANTa Study 
23 
 
The following flowchart (Figure 3) will be used to summarize the subject disposition in the 
study and by treatment. Numbers will be obtained based on the following CRFs: 
Inclusion/Exclusion, Randomization, Study Treatment Termination or Completion, and Study 
Termination or Completion. 
Listings of the following will be provided. 
• 
screen failures and reasons for failures  
• 
discontinuation from study drug with reasons 
• 
early discontinuation from study participation with reasons 
7.2 Demographic and Baseline Variables 
Demographic characteristics will be based on the information provided at the screening Visit.  
 
The characteristics will be presented by treatment arm, genotype and overall: 
 
• 
Age (years) at study entry - continuous 
• 
Sex - categorical 
• 
Childbearing potential status (female subjects only) - categorical 
• 
Race - categorical 
• 
Height (cm) at baseline - continuous 
• 
Weight (kg) at baseline - continuous 
• 
Alcohol use history - categorical 
• 
Smoking history - categorical/ continuous (packs/year) 
7.3 Medical History and Concomitant Diseases 
 
Figure 3: Disposition of Enrolled Participants by Treatment Group 


Statistical Analysis Plan 
 ATALANTa Study 
24 
 
Medical history will be defined as any clinically significant past medical conditions that ended 
before screening. Medical history will be summarised for the SAF by treatment arm and overall 
with number and percentage of subjects with at least one medical history item, and number 
and percentage of subjects by system organ class (SOC) and preferred term (PT). The terms 
will be sorted by descending frequency across all subjects of SOC and then, within SOC, by 
descending frequency across all subjects for PT. 
 
Relevant AATD medical history will be based on the information provided at the screening 
visit. The characteristics will be presented by treatment arm and overall for the SAF. The 
following will be tabulated: 
 
• 
Genotype of AATD 
• 
Alpha-1 level (mg/dl) 
• 
COPD (yes/no) 
• 
Liver Disease (yes/no) 
• 
Cirrhosis (yes/no) 
• 
Augmentation Therapy (yes/no) 
o Continue augmentation therapy for study duration (yes/no) 
• 
Asthma (yes/no) 
• 
Lung cancer (yes/no) 
• 
Bronchiectasis (yes/no) 
• 
CV issue in last 6 months (yes/no) 
• 
Severe/uncontrolled CHF (yes/no) 
• 
Supplemental oxygen use (yes/no) 
If yes on supplemental oxygen 
o amount prescribed (≤1 liter/min, 2 liters/min, 3 liters/min, 4 liters/min, ≥5 
liters/min) 
o duration per day (<12 hrs/day vs 12-23 hrs/day) 
o years prescribed (0-2, 3-5, 6+) 
o Screening or Historical FEV1% predicted 
• 
AECOPD within the last year (yes/no) 
If yes, 
o Number of exacerbations 
o Number of hospitalizations related to AECOPD 
 
Medical History ongoing at start of study will be summarised separately. 
7.4 Medications 
Prior medications will be defined as medications started 30 days or more prior to screening 
visit and stopped any day prior to administration of the first dose of study treatment. 
Concomitant medications will be defined as medications started within 30 days prior to 
screening visit and ongoing at or began during or after the administration of the first dose of 
study treatment. Specific list of medications checked (yes/no) at screening and in follow-up 
visits are: 
 


Statistical Analysis Plan 
 ATALANTa Study 
25 
 
• 
SABA 
• 
SAMA 
• 
LABA 
• 
LAMA 
• 
ICS 
• 
Roflumilast 
• 
AAT augmentation 
• 
Azithromycin 
• 
Theophylline 
• 
NSAIDS 
• 
Acetaminophen 
• 
Warfarin/Coumadin 
• 
other anticoagulant 
• 
Clopidogrel 
• 
Aspirin 
 
These medications will be summarized by treatment and by visit. 
7.5 Protocol Deviations 
Protocol deviations will be summarized by treatment, site, and type of deviation; deviations 
that resulted in adverse and serious adverse events; and protocol deviations that resulted in 
termination.  
A raw listing of all protocol deviations will be provided by treatment, site, subject ID, deviation 
date, resulting in AE, SAE, and termination; deviation description; reason for the deviation; 
deviation category; effect on product stability; and deviation resolution. 
Finally, any subjects enrolled but not randomized will also be excluded from the analyses. 
8 Efficacy Analyses 
Analyses on all efficacy outcomes will be based on the 12-week period after 
randomization. Time periods included are baseline, Week 4, Week 8 and Week 12. 
Safety outcomes will include through Week 16. 
Actual values, absolute change in actual values and the relative (percent) change from 
baseline will be summarised with descriptive statistics for continuous variables overall and 
by treatment arms. Relative (percentage) change will be calculated by: 
[(Week or EndPoint value – Baseline Value) / Baseline value)] x 100%. 
Baseline value will be computed as the last non-missing value prior to first study treatment 
dose at baseline visit (V1). 
EndPoint will be computed as: 
• 
Value at Week 12 for the completers (regardless of treatment compliance) or 
• 
EOT value must be last non-missing post-baseline value for those that discontinue 
treatment before Week 12. 
8.1 Primary Efficacy Endpoint Analyses: 
 


Statistical Analysis Plan 
 ATALANTa Study 
26 
 
The primary outcome is the relative change from baseline at week 12 in plasma 
desmosine/isodesmosine levels within treatment group. Within individual relative (percent) 
change from baseline in plasma desmosine/isodesmosine levels will be analyzed using Mixed 
Model Repeated Measures (MMRM). Relative change (percent) from baseline will be 
considered the response variable, with time as main independent fixed effect variable and 
baseline levels, augmentation, age, and smoking history (yes/no) as a fixed effect covariates, 
using an unstructured covariance matrix to model the within-subject errors. Available data from 
all time points will be included. The least squared estimates of the mean at each Week and 
EndPoint will be generated. [Note: Originally, it was planned to use sputum strata and FEV1 
as covariates in the model. However, due to the restrictions of the pandemic, there was limited 
opportunity to collect the required sputum, and therefore will not be included in the analyses.] 
The analysis will be conducted using the SAS ‘proc mixed’, with the below specific code: 
proc mixed data=Data; by TRTP; 
class SUBJID TRTP AVISIT AUGMENTATION SMOKING;  
model PCTCHG = BASE AVISIT AUGMENTATION  AGE SMOKING; 
ddfm=KENWARDROGER; 
repeated AVISIT/ subject=SUBJID type=UN; 
lsmeans AVISIT / pdiff; 
run; 
where PCTCHG is the relative (percent) change from baseline, BASE are baselines values, 
TRT is treatment arm, AVISIT is Weeks, AGE is age at enrollment, SMOKING is yes/no at 
enrollment and AUGMENTATION (yes/no) at enrollment. If imbalances are found between 
treatment groups in baseline characteristics deemed to be clinically important in influencing 
the relative change in the outcome, sensitivity analyses will be performed by including these 
variables as covariates in the above model. P-value<0.05 for the mean difference at Week 12 
will be deemed significant. Estimate including 95% confidence interval of the least squares 
mean difference will also be provided. 
If any issues related to convergence occur and cannot be resolved within the ‘proc mixed’, 
then alternative procedures will be considered (such as ‘proc glimmix’). Other covariance 
structures will also be considered if convergence is an issue with unstructured covariance. 
Transformation of data or alternative distribution for the model will be considered should 
there be evidence of nonnormality of the data. 
8.2 Secondary Efficacy Endpoint Analyses: 
Percent change from baseline in the following outcomes at end of the treatment within 
patient and compared to placebo: 
1. Plasma desmosine/isodesmosine (only relative change compared to placebo; 
within-individual change is the primary outcome) 
2. Plasma Aa-Val-360 
3. Serum NE activity 
4. Plasma proteinase 3  
5. Plasma cathepsin B 
6. Plasma CRP 
7. Plasma IL-6 
8. Plasma IL-8 
9. Plasma IL-1b 


Statistical Analysis Plan 
 ATALANTa Study 
27 
 
10. Plasma RANTES 
11. Plasma LTB4 
12. Plasma MMP9 
13. Plasma MMP12 
14. Plasma MPO 
15. Plasma PGP 
16. Plasma PK/PD (LCG/DDS) 
The same approach, i.e., mixed modelling, will be used to analyse the change from baseline 
within and between treatments for the secondary outcomes using available data based on the 
schedule of collection and analyses. The analysis will be conducted using the SAS ‘proc 
mixed’, with the specific code given below. For each outcome, p-value<0.05 for pairwise 
comparisons of the least squared means between treatment groups will indicate treatment effect. This 
will be done for each outcome. 
proc mixed data=Data; 
class SUBJID TRTP AVISIT SMOKING;  
model PCTCHG = BASE TRT|AVISIT FEV1 AGE SMOKING; 
ddfm=KENWARDROGER; 
repeated AVISIT/ subject=SUBJID type=UN; 
lsmeans TRTP*AVISIT / pdiff; 
run; 
 
8.3 Exploratory Efficacy Endpoint Analyses: 
The following exploratory efficacy endpoints will be analysed using MMRM. For data that may 
not follow a normal distribution, we will consider either using an appropriate transformation to 
approximate normality or using the generalized linear model (e.g., for categorical outcomes) 
utilizing the generalized estimating equations or generalized linear mixed model with random 
intercept to address correlation of repeated measures from the same subject. Appropriate 
distribution based on the outcome will be chosen to fit the chosen model. 
• 
Change from baseline in pre-and post-bronchodilator forced expiratory volume in 1 
second (FEV1), forced vital capacity (FVC), FEV1/FVC (total and percent predicted), 
and maximal mid-expiratory flow at end of treatment. The analyses of this outcome will 
be dependent on the amount of spirometry data available. 
• 
Change from baseline in St. George’s Respiratory Questionnaire (SGRQ) (total and 
subscales), COPD Assessment Test (CAT), Modified Medical Research Council 
Questionnaire (MMRC), San Diego Breath Questionnaire (SOBQ) and daily symptom 
scores 
Pearson (or Spearman rank) correlation of select biomarkers shown to be responsive to 
treatment with time-matched drug concentrations and PK parameters, if available, will be used 
to evaluate exposure-response relationship. 
8.4 Analysis of Pharmacokinetics 
Sparse PK sampling will be performed before and after study treatment dosing as detailed in 
the SoA and MOP. Blood samples of approximately 3 mL will be collected for measurement 
of blood concentrations ofAlvelestat (MPH966) as specified in the SoA. Instructions for the 


Statistical Analysis Plan 
 ATALANTa Study 
28 
 
collection and handling of biological samples will be provided by the DCC. The actual date 
and time (24-hour clock time) of each sample willbe recorded. 
8.5 Correlation of PK Exposure with Efficacy (PD) and Safety  
Correlation of select biomarkers (shown to have significant treatment effect) with time-
matched drug concentrations and PK parameters, if available, may be used to evaluate 
exposure-response relationship.  
 
The safety correlation analysis with drug concentration will be done for the safety 
parameters shown to be sensitive to Alvelestat exposure. The comparison of exposure will 
be done between groups with non-clinically significant changes and clinically significant 
changes in safety parameters using graphic and statistical methods where data allow. 
 
8.5.1 Presentation of Concentration Data 
8.5.1.1 
Handling of Missing Data 
Plasma concentrations below the lower limit of quantification (LLOQ) of the assay are 
designated as NQ (not quantifiable) in the PK data and will be replaced by half value of 
LLOQ in listings. Values above the ULOQ will be replaced by 1.5*ULOQ. This approach will 
be used for non-PK data as well. 
Samples taken far outside the sampling windows and any other protocol deviation related to 
plasma concentration measurements will be discussed but will be excluded from summary 
tables. Missing values due to bad sample or unable to measure will also be excluded for that 
visit. Other non-missing data from the same subject will be included in the analyses. 
8.5.1.2 
Listing, Presentation and Summary of PK Data 
The following presentations of subject plasma concentration data will be provided for 
the Alvelestat (MPH966) treatment group for the PK Set: 
• 
A listing including subject, week/time point treatment and plasma 
concentrations 
• 
A summary table of plasma concentrations at each week/time point (n; Geometric 
mean, SD, coefficient of variation (CV)% calculated as 100% × SD/mean, 
minimum, median and maximum)  
• 
A figure with individual visits 1 to 12 from pre-dose through 1-2h post-dose plasma 
concentration-time profiles on both linear and log-linear scale (Y-axis is the 
concentrations; X-axis is the time e.g. Weeks 1, 4, 8, 12) 
• 
A figure with geometric mean ± SD plasma concentration-time profiles presented 
on both linear and log-linear scales (Y-axis is the Visit x pre dose ( or visit x 1-2 
hours post dose concentrations – 2 separate plots; X-axis is the time e.g. Weeks 
1, 4, 8, 12) 
 
Nominal time points and visit number (planned) will be used for summary and geometric 
mean concentration graphical presentations. The time of collection of the pre-dose 
sample will be set to zero. Mean plasma concentrations will not be presented in the 


Statistical Analysis Plan 
 ATALANTa Study 
29 
 
summary or graphics for the time points with 50% or more of the actual values are below 
the LLOQ or missing. 
9 Safety Analyses 
 
All analyses described in this section will be performed on the SAF and will be presented by 
treatment arm and overall. The results will be descriptive in nature. All data will be summarized 
and listed. 
 
Safety will be assessed on the basis of exposure, compliance, AEs, laboratory parameters, 
vital signs and physical examination.  
9.1 Extent of Exposure 
 
The duration of exposure will be expressed as the time in days from the first dose of treatment 
through to last treatment day (inclusive). Duration of exposure will be summarized for the SAF 
using summary statistics for continuous variables.  
9.2 Treatment Compliance 
From baseline and at subsequent visits while the patient is being treated with the study 
treatment, the patient will be directed to bring back all unused tablets. Compliance will be 
checked by calculating number of pills taken/expected pills to be taken by the Investigator 
during those visits and recorded on the eCRF.  
 
The number and percentage of compliant patients will be presented for the SAF by study visit, 
where compliant is defined as percentage compliance between 80.0% and 100.0% inclusive. 
The following percentage compliance categories will be presented:<80.0%; ≥80.0% to 
≤100.0%; >100.0%. Descriptive statistics for treatment compliance will also be presented. 
9.3 Safety Outcomes 
9.3.1 Primary Safety Outcomes 
The primary safety outcomes of interest are (1) numbers and % of subjects who experience 
at least 1 treatment-emergent adverse event and (2) adverse events of special interest (liver 
function abnormalities, corrected QT interval/cardiac, infections, and neutropenia). AEs will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA). Summaries will be by 
system organ class and preferred term.  We will also present data separately by augmentation. 
 
Treatment-emergent AEs (TEAEs) are defined as any AE occurring on or after the first dose 
of study medication. Listing will be sorted by treatment arm, subject ID, chronologically (start 
and end dates) and then alphabetically by SOC, PT and then verbatim description. The listing 
will include all the distinct levels of SOC, PT and the verbatim Investigator description reported 
in the study. A flag per subject will be included to indicate whether the patient received COVID-
19 vaccination. If a participant experiences the same preferred term multiple times, the event 
will be counted only once overall and by the greatest severity. The frequency and incidence 
of TEAEs will be presented by system organ class and preferred term for each treatment group 
(number and percentage of participants experiencing at least 1 AE per preferred term as well 
as the number of observed events per preferred term). Separate tables will be presented by 
severity and by relationship to study drug. All AEs will be presented in a comprehensive listing 


Statistical Analysis Plan 
 ATALANTa Study 
30 
 
including participant number, treatment regimen, day of onset, severity, seriousness, action 
taken, outcome, relationship to treatment, onset/stop, and duration. Details of SAEs and AEs 
leading to withdrawal will be listed separately.  
 
The frequency and incidence of adverse events of acute exacerbations of COPD will be 
presented (number and percentage of participants experiencing at least 1 AE per preferred 
term as well as the number of observed events per preferred term) and overall. Events that 
started after treatment initiation (TEAEs) up until Week 12 will only be presented, meaning 
that events commencing after the end of treatment and during the safety follow up period will 
not be summarized. 
 
AESIs, including liver function abnormalities, ECG/cardiac events, infections, and 
neutropenia, will be tabulated and summarized by treatment group and overall. 
9.3.2  Secondary Safety Outcomes 
For secondary safety outcomes, 
• Physical examination results will be listed by subject ID and body system. ECG 
parameters will be summarized as observed values and change from baseline by 
treatment group and study visit. 
• Abnormal findings (“normal”, “abnormal, not clinically significant”, and “abnormal, 
clinically significant”) will be summarized by the number and percentage within each 
category and change from baseline will be summarized by shift tables. 
• Laboratory parameters will be summarized as observed values and change from 
baseline by treatment group and study visit. 
• Vital signs (temperature, SBP, DBP, heart rate, respiration rate, oxygen saturation) and 
ECG results will be summarized as observed values and change from baseline by 
treatment group and study visit. 
9.3.3  Exploratory Safety Outcomes 
Safety correlation analysis with drug concentration will be done for the safety parameters 
shown to be sensitive to Alvelestat exposure. The comparison of exposure will be done 
between groups with non-clinically significant changes and clinically significant changes in 
safety parameters using graphic and statistical methods where data allow. 
10 Changes from Analysis Planned in the Protocol  
In Version 1.3 of the protocol, augmentation therapy was removed from the list of not 
allowed treatment. Sample size calculation was revised but sample size remained the same. 
Also, stratified analyses by augmentation therapy will be performed.  
Due to the risk during the COVID pandemic, spirometry as well as sputum and BAL 
collections were changed to optional.   Consequently, all analyses using spirometry, sputum 
biomarkers, and BAL biomarker outcomes and data will no longer be performed in this study.  
Primary analysis in the protocol is based on ANCOVA with outcome being the percent 
change at Week 12 from baseline. However, to minimize the effect of missing data and to 
maximize the information from all visits, the primary analysis is now based on fitting a mixed 
model using change from baseline at all available follow-up visits as outcome with the 
assumption of missing at random for missing data. 


Statistical Analysis Plan 
 ATALANTa Study 
31 
 
11 Interim Analyses  
No interim analysis for efficacy is planned for this study.  An interim safety analysis was 
conducted after 30 subjects have completed the study and presented to the DSMB. 
12  References 
Ma S, Lin YY, He J, Rouhani FN, Brantly M, Turino GM. Alpha-1 antitrypsin augmentation 
therapy and biomarkers of elastin degradation. COPD 2013;10:473-81. 
Campos MA, Geraghty P, Holt G, et al. The Biological Effects of Double-Dose Alpha-1 
Antitrypsin Augmentation Therapy. A Pilot Clinical Trial. Am J Respir Crit Care Med 
2019;200:318-26. 
13 Reporting Conventions 
P-values will be reported to 3 decimal places; p-values less than 0.0005 will be reported as 
“<0.001” and p-values greater than 0.9995 will be reported as “>0.999”.  
 
The mean, standard deviation, and other statistics will be reported to 1 decimal place greater 
than the original data. The minimum and maximum will use the same number of decimal 
places as the original data. Proportions will be presented as 2 decimal places; values greater 
than zero but <0.005 will be presented as “<0.01”.  
 
Estimated parameters, not on the same scale as raw observations (e.g. regression 
coefficients) will be reported to 3 significant figures.


Statistical Analysis Plan 
 ATALANTa Study 
32 
 
14 Listing of Tables, Figures, and Listings 
14.1Listing of Tables 
Table 
Number 
Table Name 
Analysis Set 
 
Patient Disposition 
Enrolled Set 
 
Protocol Deviations 
Randomized Set 
 
Protocol Deviations Related to COVID-19 
Randomized Set 
 
Reasons for Exclusion from Analysis Sets 
 
Subject Demographic and Baseline Characteristics 
Safety Set (SAF) 
 
Subject Demographic and Baseline Characteristics 
Full Analysis Set (FAS) 
 
Subject Demographic and Baseline Characteristics 
Per-Protocol Set (PPS) 
 
Medical History 
Safety Set (SAF) 
 
Ongoing Medical History 
Safety Set (SAF) 
 
AATD Medical History 
Safety Set (SAF) 
 
Prior Medication 
Safety Set (SAF) 
 
Concomitant Medication 
Safety Set (SAF) 
 
Concomitant COPD Medication 
Safety Set (SAF) 
 
Treatment Compliance 
Safety Set (SAF) 
 
Absolute and Relative Change from Baseline in Plasma 
Desmosine/Isodesmosine up to End of Treatment: 
Primary Efficacy Analysis (MMRM) 
Full Analysis Set (FAS) 
 
Absolute and Relative Change from Baseline in Plasma 
Desmosine/Isodesmosine up to End of Treatment: Primary 
Efficacy Analysis (MMRM) 
Per-Protocol Set (PPS) 
 
Absolute and Relative Change from Baseline in Blood Aα- 
Val360 levels up to End of Treatment: Secondary Efficacy 
Analysis (MMRM) 
Full Analysis Set (FAS) 
 
Absolute and Relative Change from Baseline in Serum NE 
activity up to End of Treatment: Secondary Efficacy 
Analysis (MMRM) 
Full Analysis Set (FAS) 
 
Absolute and Relative Change from Baseline in Plasma 
proteinase 3   up to End of Treatment: Secondary Efficacy 
Analysis (MMRM) 
Full Analysis Set (FAS) 
 
Absolute and Relative Change from Baseline in Plasma 
cathepsin B up to End of Treatment: Secondary Efficacy 
Analysis (MMRM) 
Full Analysis Set (FAS) 
 
Absolute and Relative Change from Baseline in Plasma 
CRP up to End of Treatment: Secondary Efficacy Analysis 
(MMRM) 
Full Analysis Set (FAS) 
 
Absolute and Relative Change from Baseline in Plasma IL-
6 up to End of Treatment: Secondary Efficacy Analysis 
(MMRM) 
Full Analysis Set (FAS) 


Statistical Analysis Plan 
 ATALANTa Study 
33 
 
Table 
Number 
Table Name 
Analysis Set 
 
Absolute and Relative Change from Baseline in Plasma IL-
8 up to End of Treatment: Secondary Efficacy Analysis 
(MMRM) 
Full Analysis Set (FAS) 
 
Absolute and Relative Change from Baseline in Plasma IL-
1b up to End of Treatment: Secondary Efficacy Analysis 
(MMRM) 
Full Analysis Set (FAS) 
 
Absolute and Relative Change from Baseline in Plasma 
RANTES up to End of Treatment: Secondary Efficacy 
Analysis (MMRM) 
Full Analysis Set (FAS) 
 
Absolute and Relative Change from Baseline in Plasma 
LTB4 up to End of Treatment: Secondary Efficacy Analysis 
(MMRM) 
Full Analysis Set (FAS) 
 
Absolute and Relative Change from Baseline in Plasma 
MMP9 up to End of Treatment: Secondary Efficacy 
Analysis (MMRM) 
Full Analysis Set (FAS) 
 
Absolute and Relative Change from Baseline in Plasma 
MMP12 up to End of Treatment: Secondary Efficacy 
Analysis (MMRM) 
Full Analysis Set (FAS) 
 
Absolute and Relative Change from Baseline in Plasma 
MPO up to End of Treatment: Secondary Efficacy Analysis 
(MMRM) 
Full Analysis Set (FAS) 
 
Absolute and Relative Change from Baseline in Blood Aα- 
Val360 levels up to End of Treatment: Secondary Efficacy 
Analysis (MMRM) 
Per-Protocol Set (PPS) 
 
Absolute and Relative Change from Baseline in Serum NE 
activity up to End of Treatment: Secondary Efficacy 
Analysis (MMRM) 
Per-Protocol Set (PPS) 
 
Absolute and Relative Change from Baseline in Plasma 
proteinase 3   up to End of Treatment: Secondary Efficacy 
Analysis (MMRM) 
Per-Protocol Set (PPS) 
 
Absolute and Relative Change from Baseline in Plasma 
cathepsin B up to End of Treatment: Secondary Efficacy 
Analysis (MMRM) 
Per-Protocol Set (PPS) 
 
Absolute and Relative Change from Baseline in Plasma 
CRP up to End of Treatment: Secondary Efficacy Analysis 
(MMRM) 
Per-Protocol Set (PPS) 
 
Absolute and Relative Change from Baseline in Plasma IL-
6 up to End of Treatment: Secondary Efficacy Analysis 
(MMRM) 
Per-Protocol Set (PPS) 
 
Absolute and Relative Change from Baseline in Plasma IL-
8 up to End of Treatment: Secondary Efficacy Analysis 
(MMRM) 
Per-Protocol Set (PPS) 
 
Absolute and Relative Change from Baseline in Plasma IL-
1b up to End of Treatment: Secondary Efficacy Analysis 
(MMRM) 
Per-Protocol Set (PPS) 
 
Absolute and Relative Change from Baseline in Plasma 
RANTES up to End of Treatment: Secondary Efficacy 
Analysis (MMRM) 
Per-Protocol Set (PPS) 
 
Absolute and Relative Change from Baseline in Plasma 
LTB4 up to End of Treatment: Secondary Efficacy Analysis 
(MMRM) 
Per-Protocol Set (PPS) 


Statistical Analysis Plan 
 ATALANTa Study 
34 
 
 
Absolute and Relative Change from Baseline in Plasma 
MMP9 up to End of Treatment: Secondary Efficacy 
Analysis (MMRM) 
Per-Protocol Set (PPS) 
 
Absolute and Relative Change from Baseline in Plasma 
MMP12 up to End of Treatment: Secondary Efficacy 
Analysis (MMRM) 
Per-Protocol Set (PPS) 
 
Absolute and Relative Change from Baseline in Plasma 
MPO up to End of Treatment: Secondary Efficacy Analysis 
(MMRM) 
Per-Protocol Set (PPS) 
 
Summary PK Concentrations for Alvelestat (MPH966) 
PK Set 
 
Overall Summary of Adverse Events 
Safety Set (SAF) 
 
Summary of Treatment Emergent Adverse Events 
(TEAEs) by System Organ Class and Preferred Term 
Safety Set (SAF) 
 
Summary of Treatment Related Treatment Emergent 
Adverse Events (TEAEs) by System Organ Class and 
Preferred Term 
Safety Set (SAF) 
 
Summary of Serious Treatment Emergent Adverse Events 
(TEAEs) by System Organ Class and Preferred Term 
Safety Set (SAF) 
 
Summary of Treatment Related Serious Treatment 
Emergent Adverse Events (TEAEs) by System Organ 
Class and Preferred Term 
Safety Set (SAF) 
 
Summary of Treatment Emergent Adverse Events 
(TEAEs) Leading to Permanent Withdrawal of Study Drug 
by System Organ Class and Preferred Term 
Safety Set (SAF) 
 
Summary of Adverse Events of Special Interest (AESIs) 
by System Organ Class and Preferred Term 
Safety Set (SAF) 
 
Summary of Adverse Events Leading to Death by System 
Organ Class and Preferred Term 
Safety Set (SAF) 
 
Summary of Treatment Emergent Adverse Events 
(TEAEs) by System Organ Class, Preferred Term and 
Maximum Intensity 
Safety Set (SAF) 
 
Summary of Adverse Events of Acute Exacerbations of 
COPD up until Week 12 by System Organ Class and 
Preferred Term 
Safety Set (SAF) 
 
Deaths, Listing 
Safety Set (SAF) 


Statistical Analysis Plan 
 ATALANTa Study 
35 
 
Table 
Number 
Table Name 
Analysis Set 
 
Summary of Hematology Laboratory Parameters 
Safety Set (SAF) 
 
Summary of Clinical Chemistry Laboratory Parameters 
Safety Set (SAF) 
 
Summary of Urinalysis Laboratory Parameters 
Safety Set (SAF) 
 
Summary of Vital Sign Parameters 
Safety Set (SAF) 
 
Summary of Electrocardiogram (ECG) Parameters 
Safety Set (SAF) 
 
Summary of Study Drug Compliance 
Safety Set (SAF) 


Statistical Analysis Plan 
 ATALANTa Study 
36 
 
14.2Listing of Figures 
Figure Number 
Figure Name 
Analysis Set 
 
Mean (± SE) Absolute Values and % Change from 
Baseline in Plasma Desmosine/Isodesmosine at 
Scheduled Study Visits 
Full Analysis Set (FAS) 
 
Individual Absolute Values in Plasma 
Desmosine/Isodesmosine at Scheduled Study Visits 
Full Analysis Set (FAS) 
 
Mean (± SE) Absolute Values and % Change from 
Baseline in Plasma Desmosine/Isodesmosine at 
Scheduled Study Visits 
Per-Protocol Set (PPS) 
 
Individual Absolute Values in Plasma 
Desmosine/Isodesmosine at Scheduled Study Visits 
Per-Protocol Set (PPS) 
 
Mean (± SE) Absolute Values and % Change from 
Baseline in Plasma Aa-Val-360 at Scheduled Study 
Visits 
Full Analysis Set (FAS) 
 
Individual Absolute Values Plasma Aa-Val-360  at 
Scheduled Study Visits 
Full Analysis Set (FAS) 
 
Mean (± SE) Absolute Values and % Change from 
Baseline in Serum NE activityat Scheduled Study 
Visits 
Full Analysis Set (FAS) 
 
Individual Absolute Values in Blood Serum NE 
activityat Scheduled Study Visits 
Full Analysis Set (FAS) 
 
Mean (± SE) Absolute Values and % Change from 
Baseline in Plasma proteinase 3   levels at 
Scheduled Study Visits 
Full Analysis Set (FAS) 
 
Individual Absolute Values in  Plasma proteinase 3 
levels at Scheduled Study Visits 
Full Analysis Set (FAS) 
 
Mean (± SE) Absolute Values and % Change from 
Baseline in Plasma cathepsin B  levels at Scheduled 
Study Visits 
Full Analysis Set (FAS) 
 
Individual Absolute Values in Plasma cathepsin B  
levels at Scheduled Study Visits 
Full Analysis Set (FAS) 
 
Mean (± SE) Absolute Values and % Change 
from Baseline in Plasma CRP levels at 
Scheduled Study Visits 
Full Analysis Set (FAS) 
 
Individual Absolute Values in Plasma CRP levels at 
Scheduled Study Visits 
Full Analysis Set (FAS) 
 
Mean (± SE) Absolute Values and % Change 
from Baseline in Plasma IL-6 at Scheduled Study 
Visits 
Full Analysis Set (FAS) 
 
Individual Absolute Values in Plasma IL-6 at 
Scheduled Study Visits 
Full Analysis Set (FAS) 
 
Mean (± SE) Absolute Values and % Change 
from Baseline in Plasma IL-8 at Scheduled 
Study Visits 
Full Analysis Set (FAS) 
 
Individual Absolute Values in Plasma IL-8 levels at 
Scheduled Study Visits 
Full Analysis Set (FAS) 


Statistical Analysis Plan 
 ATALANTa Study 
37 
 
Figure Number 
Figure Name 
Analysis Set 
 
Mean (± SE) Absolute Values and % Change 
from Baseline in Plasma IL-1b at Scheduled 
Study Visits 
Full Analysis Set (FAS) 
 
Individual Absolute Values in Plasma IL-1b at 
Scheduled Study Visits 
Full Analysis Set (FAS) 
 
Mean (± SE) Absolute Values and % Change 
from Baseline in Plasma RANTES at Scheduled 
Study Visits 
Full Analysis Set (FAS) 
 
Individual Absolute Values in Plasma RANTES at 
Scheduled Study Visits 
Full Analysis Set (FAS) 
 
Mean (± SE) Absolute Values and % Change 
from Baseline in Plasma LTB4 at Scheduled 
Study Visits 
Full Analysis Set (FAS) 
 
Individual Absolute Values in Plasma LTB4 at 
Scheduled Study Visits 
Full Analysis Set (FAS) 
 
Mean (± SE) Absolute Values and % Change 
from Baseline in Plasma MMP9 at Scheduled 
Study Visits 
Full Analysis Set (FAS) 
 
Individual Absolute Values in Plasma MMP9 at 
Scheduled Study Visits 
Full Analysis Set (FAS) 
 
Mean (± SE) Absolute Values and % Change 
from Baseline in Plasma MMP12 at Scheduled 
Study Visits 
Full Analysis Set (FAS) 
 
Individual Absolute Values in Plasma MMP12 at 
Scheduled Study Visits 
Full Analysis Set (FAS) 
 
Mean (± SE) Absolute Values and % Change 
from Baseline in Plasma MPO at Scheduled 
Study Visits 
Full Analysis Set (FAS) 
 
Individual Absolute Values in Plasma MPO at 
Scheduled Study Visits 
Full Analysis Set (FAS) 
 
Mean (± SE) Absolute Values and % Change 
from Baseline in Plasma PGP at Scheduled 
Study Visits 
Full Analysis Set (FAS) 
 
Individual Absolute Values in Plasma PGP at 
Scheduled Study Visits 
Full Analysis Set (FAS) 
 
Mean (± SE) Absolute Values and % Change from 
Baseline in Markers of Pulmonary Function at 
Scheduled Study Visits 
Full Analysis Set (FAS) 
 
Mean (± SE) Absolute Values and % Change from 
Baseline in Markers of Pulmonary Function at 
Scheduled Study Visits 
Per-Protocol Set (PPS) 
 
Mean (± SE) Absolute Values and % Change from 
Baseline in SOBQ 
at Scheduled Study Visits 
Full Analysis Set (FAS) 
 
Mean (± SE) Absolute Values and % Change from 
Baseline in MMRC 
at Scheduled Study Visits 
Full Analysis Set (FAS) 
 
Mean (± SE) Absolute Values and % Change from 
Baseline in St George’s Respiratory Questionnaire 
at Scheduled Study Visits 
Per-Protocol Set (PPS) 


Statistical Analysis Plan 
 ATALANTa Study 
38 
 
Figure Number 
Figure Name 
Analysis Set 
 
Individual plasma concentration Profiles for 
Alvelestat (MPH966) vs Time by Treatment – Linear 
Scale 
PK Set 
 
Individual plasma concentration Profiles for 
Alvelestat (MPH966) vs Time by Treatment – Log- 
Linear Scale 
PK Set 
 
Geometric Mean (± SD) plasma concentration 
Profile for Alvelestat (MPH966) vs Time by 
Treatment – Linear Scale 
PK Set 
 
Geometric Mean (± SD) plasma concentration 
Profile for Alvelestat (MPH966) vs Time by 
Treatment – Log-Linear Scale 
PK Set 
 
Box-plot of plasma concentration for Alvelestat 
(MPH966) vs Time (pre-dose and by visit post-dose) 
by Treatment   
PK Set 


Statistical Analysis Plan 
 ATALANTa Study 
39 
 
14.3Listings 
Listing Number 
Listing Name 
Analysis Set 
 
Patient Disposition – Screen Failures 
Enrolled Set 
 
Patient Disposition 
Randomized  Set 
 
Patients Impacted by COVID-19 Related Study 
Discontinuations 
Randomized  Set 
 
Missing Assessments Due to COVID-19 
Randomized  Set 
 
Missing Visits Due to COVID-19 
Randomized  Set 
 
Protocol Deviations 
Randomized  Set 
 
Protocol Deviations Related to COVID-19 and Related 
Measures 
Randomized  Set 
 
Inclusion/ Exclusion Criteria 
Randomized  Set 
 
Exclusion from Analysis Sets 
 
Demographics 
Randomized  Set 
 
Pregnancy Test 
Randomized  Set 
 
Medical History (Prior and Ongoing) 
Safety Set (SAF) 
 
AATD Medical History 
Safety Set (SAF) 
 
Alcohol History 
Randomized  Set 
 
Smoking History 
Randomized  Set 
 
Prior and Concomitant Medications 
Safety Set (SAF) 
 
Randomization and Treatment Administration 
Safety Set (SAF) 
 
Drug Accountability 
Safety Set (SAF) 
 
Primary Efficacy Endpoint: Plasma 
Desmosine/Isodesmosine 
Full Analysis Set (FAS) 
 
Primary Efficacy Endpoint: Plasma 
Desmosine/Isodesmosine, Blood Neutrophil Elastase 
Activity and Blood Aα-Val360 
Full Analysis Set (FAS) 
 
Secondary Efficacy Endpoint: Plasma Aa-Val-360 
Serum NE activity, Plasma proteinase 3,  
Plasma cathepsin B,Plasma CRP, Plasma IL-6, Plasma 
IL-8, Plasma IL-1b, Plasma RANTES, Plasma LTB4, 
Plasma MMP9,Plasma MMP12, Plasma MPO, Plasma 
PGP, Plasma PK/PD (LCG/DDS) 
Full Analysis Set (FAS) 
 
Exploratory Efficacy Endpoints: Absolute and Relative 
Change from Baseline in Indicators of Pulmonary 
Function 
Full Analysis Set (FAS) 
 
Exploratory Efficacy Endpoints: Absolute Change from 
Baseline in St George’s Respiratory Questionnaire 
Full Analysis Set (FAS) 
 
Exploratory Efficacy Endpoints: Absolute Change from 
Baseline in SOBQ 
Full Analysis Set (FAS) 
 
Exploratory Efficacy Endpoints: Absolute Change from 
Baseline in MMRC 
Full Analysis Set (FAS) 
 
Exploratory Efficacy Endpoints: Absolute Change from 
Baseline in CAT 
Full Analysis Set (FAS) 
 
Pharmacokinetic Endpoints: Listing of PK Plasma 
Concentration data 
PK Set 


Statistical Analysis Plan 
 ATALANTa Study 
40 
 
Listing Number 
Listing Name 
Analysis Set 
 
Listing of all Adverse Events 
Safety Set (SAF) 
 
Listing of Hematology Laboratory Parameters 
Safety Set (SAF) 
 
Listing of Clinical Chemistry Laboratory Parameters 
Safety Set (SAF) 
 
Listing of Vital Signs 
Safety Set (SAF) 
 
Listing of Electrocardiogram (ECG) Parameters 
Safety Set (SAF) 
 
Listing of Physical Examination 
Safety Set (SAF) 
 
Listing of Serious Treatment Emergent Adverse Events 
(Serious TEAEs) 
Safety Set (SAF) 
 
Listing of Non-Treatment Emergent Serious Adverse 
Events (SAEs) 
Safety Set (SAF) 
 
Listing of Treatment Emergent Adverse Events (TEAEs) 
Leading to Permanent Withdrawal of Study Drug 
Safety Set (SAF) 
 
Listing of Treatment Emergent Adverse Events (TEAEs) 
with a Preferred Term of Headache 
Safety Set (SAF) 
 
Listing of Treatment Emergent Adverse Events 
(TEAEs) of COPD or exacerbation of COPD 
Safety Set (SAF) 
 
Listing of Patients with at Least One Clinically Significant 
Clinical Chemistry Laboratory Parameter 
Safety Set (SAF) 
 
Listing of Patients with at Least One Clinically Significant 
Hematology Laboratory Parameter 
Safety Set (SAF)