Phase I/II Multicenter, Open-label Trial to Evaluate the Safety and Pharmacokinetics of Alpha-1 MP in Patients With Alpha1-Antitrypsin Deficiency
Phase: PHASE1
Conditions: Alpha1-Antitrypsin Deficiency
Sponsor: Grifols Therapeutics LLC

Official Title: 
Phase I/II Multicenter, Open-label Trial to Evaluate the Safety and 
Pharmacokinetics of Alpha-1 MP in Patients with Alpha1-Antitrypsin 
Deficiency 
NCT Number: 
     NCT02870309 
Document Date:    Protocol Version 1.3: 05 July 2016 

Protocol 
Phase I/II Multicenter, Open-label Trial to Evaluate 
the Safety and Pharmacokinetics of Alpha-1 MP in 
Patients with Alpha1-Antitrypsin Deficiency 
Sponsor: Grifols Japan K.K. 
Protocol No.: GTI1401 
Version No.: 1.3 (for Ver1.5J) 
Prepared on: 05 July 2016 

Phase I/II Multicenter, Open-label Trial to Evaluate the Safety and Pharmacokinetics of 
Alpha-1 MP in Patients with Alpha1-Antitrypsin Deficiency 
SIGNATURE/APPROVAL PAGE 
Sponsor 
, MD 
Grifols Therapeutics Inc. 
USA 
Date 
Confidentiality Statement 
The information contained in this protocol is confidential and the proprietary property of 
GrifolsJapan K.K. and Grifols Therapeutics Inc. This information is provided only for those who 
are directly involved in this clinical trial (investigators, subinvestigators, clinical trial 
collaborators, investigational drug storage managers, institutional review boards, etc.). Therefore, 
this information may not be disclosed to third parties not involved in this clinical trial without prior 
authorization of Grifols Japan K.K. and Grifols Therapeutics Inc. unless such disclosure is required 
for practical reasons, such as to obtain consent from trial participants. In addition, prior 
consultation of Grifols Japan K.K. and Grifols Therapeutics Inc. is required for publication of any 
part of or the entire results of this clinical trial at academic societies or in journals, etc. 

1 
PROTOCOL SYNOPSIS
Title of Study 
Phase I/II Multicenter, Open-label Trial to Evaluate the Safety and 
Pharmacokinetics of Alpha-1 MP in Patients with Alpha1-Antitrypsin 
Deficiency 
Protocol 
Identification 
No. 
GTI1401 
Investigational 
Drug Code 
Alpha-1 MP 
Type of Study 
(Phase of 
Development) 
Clinical pharmacology study/Exploratory study (Phase I/II) 
Study Objective 
To evaluate the safety and pharmacokinetics of weekly intravenous infusions 
of 60 mg/kg of Alpha-1 MP for 8 weeks in subjects with alpha1-antitrypsin 
deficiency 
Study Design 
This study is a multicenter, open-label trial to evaluate the safety and 
pharmacokinetics of weekly intravenous infusions of 60 mg/kg of Alpha-1 MP 
for 8 weeks. 
Subject Selection 
Study 
population 
Subjects: Adult patients with alpha1-antitrypsin deficiency 
Target sample size:  A minimum of 3 subjects 
Inclusion 
criteria 
1.
Subjects aged ≥20 years at the time of providing informed consent
2.
Subjects with clinically apparent pulmonary emphysema diagnosed by CT
scan
3.
Subjects with documented serum alpha1-PI levels of <50 mg/dL as
measured by nephelometry. In subjects with no previously documented
serum alpha1-PI levels, their serum alpha1-PI levels measured by
nephelometry during the screening period must be <50 mg/dL.
4.
Subjects whose percentage of forced expired volume in 1 second/Forced
vital capacity (FEV1/FVC) after inhalation of a bronchodilator is <70%
during the screening period
5.
Subjects who are willing and able to provide signed written informed
consent
Exclusion 
criteria 
1.
Subjects with moderately or severely deteriorated lung function in the 4
weeks before the Week 1 (baseline) visit
2.
Subjects whose percentage of forced expired volume in 1 second (%FEV1)
after inhalation of a bronchodilator is <30% during the screening period
3.
Subjects who have undergone lung transplantation or liver transplantation
4.
Subjects who have undergone any lung surgery (excluding lung biopsy) in
the past 2 years
5.
Subjects with increased liver enzymes (AST, ALT, and ALP) ≥2.5 times
the upper limit of normal

2 
6.
Subjects with severe complications, including but not limited to,
congestive heart failure and liver cirrhosis
7.
Subjects who have developed any malignant tumor (including malignant
melanoma; however, other forms of skin cancer are excluded) in the past
5 years
8.
Pregnant women, breastfeeding women, or women of childbearing
potential who do not intend to use effective contraceptive methods
throughout the trial period or male subjects who have a partner who is of
childbearing potential and is unwilling to use effective contraceptive
methods throughout the trial period.
9.
Subjects with a past history of HAV, HBV, HCV, or HIV infection, or
subjects currently presenting with clinical signs or symptoms suggestive
of such infection
10. Subjects with a smoking history in the past 6 months, or subjects tested
positive for urinary cotinine levels at the screening visit
11. Subjects participating in another clinical trial within 4 weeks before the
Week 1 (baseline) visit
12. Subjects with a history of anaphylactic or severe systemic reactions to any
plasma derived alpha1-PI product or other blood products
13. Subjects who have continuously received any systemic steroid therapy at
a prednisone-equivalent dose >5 mg/day within 4 weeks before the Week
1 (baseline) visit (Note: inhaled steroids are not regarded as systemic
steroids)
14. Subjects who have used any systemic or aerosolized antibiotic drug for the
treatment of COPD exacerbation within 4 weeks before the Week 1
(baseline) visit
15. Subjects with a previous or current diagnosis of selective, severe IgA 
deficiency
16. Subjects who are mentally challenged and cannot independently give
consent
17. Subjects who have difficulty in adhering to the protocol or its procedures
in the opinion of the investigator
18. Subjects who have medical conditions that may confound the results of
this clinical trial or may endanger these subjects during their participation
in this clinical trial in the opinion of the investigator
Investigational 
Drug 
Alpha-1 MP: Sterile, lyophilized preparation (each vial contains 
approximately 1000 mg of functionally active alpha1-PI) 
Endpoints 
Safety 
evaluation 
To evaluate adverse events (nature, severity, frequency) occurring after the 
start of investigational drug administration until the end of the follow-up 
period (i.e., 1 week after the last dose for subjects entering the extension trial 
[Study No. GTI1401-OLE] after this clinical trial; 4 weeks after the last dose 
for subjects not entering the extension trial), all clinically unfavorable signs 

3 
(including abnormal changes in clinical laboratory values [blood chemistry, 
hematology, urinalysis] and vital signs [blood pressure, pulse rate, respiratory 
rate, body temperature]) and symptoms will be investigated. In addition, 
COPD exacerbations and pulmonary function tests (FEV1 and FVC) will be 
evaluated. 
Pharmaco
kinetic 
evaluation 
To evaluate alpha1-PI trough concentrations, samples will be collected prior to 
infusion at Weeks 1 (baseline), 7, and 8 and at Week 9 visits. For PK 
parameters (AUC0-7 days, Cmax, tmax, and t½), blood samples for PK evaluation 
will be collected at 10 time points until the 7th day after the last dose in Week 
8 (i.e., immediately before dosing, and at immediately post-infusion [0], 0.25, 
2, 4, 8, 24, 48, 120, and 168 hours after dosing [Week 9]). 
Study Centers 
and 
Investigators 
Refer to Attachment “Study Centers and Investigators List” 
Study Period 
January 2016 to March 2017. 

4 
List of Abbreviation
Abbreviation
Full expression without abbreviation
°C 
degree Celsius 
°F 
degree Fahrenheit 
AATD 
Alpha1-Antitrypsin Deficiency  
ADR 
Adverse Drug Reaction  
AE 
Adverse Events  
Alpha-1 MP 
Alpha1-Proteinase Inhibitor (human), Modified 
Process  
alpha1-PI 
Alpha1-Proteinase Inhibitor  
ALT 
Alanine Aminotransferase  
AST 
Aspartate Transaminase  
ATS 
American Thoracic Society  
AUC 
Area under the concentration-time curve  
B19V 
Parvovirus B19  
ChAMP 
Pharmacokinetic Comparability of Alpha-1 MP 
Study  
Cmax 
Maximum concentration  
COPD 
Chronic Obstructive Pulmonary Disease  
CRF 
Case Report Form  
CRA 
Clinical Research Associate  
CRO 
Contract Research Organization  
CT 
Computed Tomography 
CV 
Coefficient of variation  
dL 
Deciliter  
DNA 
Deoxyribonucleic Acid  
ERS 
European Respiratory Society  
FEV1 
Forced Expired Volume in 1 second  
FVC 
Forced Vital Capacity  
GCP 
Good Clinical Practice  
HAV 
Hepatitis A Virus  
HBV 
Hepatitis B Virus  
HCV 
Hepatitis C Virus  
HIV 
Human Immunodeficiency Virus  
IB 
Investigator’s Brochure  
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICF 
Informed Consent Form  
IgA 
Immunoglobulin A  

5 
IgG 
Immunoglobulin G  
IgM 
Immunoglobulin M  
IRB/EC 
Institutional Review Board / Ethics Committee  
IUD 
Intrauterine Device  
IUS 
Intrauterine Contraceptive System 
IV 
Intravenous  
kg 
Kilogram  
μM 
Micromolar  
MDI 
Metered dose inhaler  
MedDRA® 
Medical Dictionary for Regulatory Activities  
mg 
Milligram  
mL 
Milliliter  
NaCl 
Sodium chloride  
NAT 
Nucleic Acid Amplification Technology  
NE 
Neutrophil Elastase 
PFT 
Pulmonary Function Test  
PI*MM 
Proteinase inhibitor homozygote for normal M allele 
 
PI*(null)(null) 
Proteinase inhibitor homozygote for (null) allele 
 
PI*SZ 
Proteinase inhibitor heterozygote for S and Z deficiency alleles 
 
PI*Z 
Proteinase inhibitor Z deficiency allele  
PI*ZZ 
Proteinase inhibitor homozygote for Z deficiency allele 
Homozygote for Z (Deficiency) Allele of the Alpha1-Proteinase Inhibitor 
Gene 
pH 
Potential of hydrogen; acidity / alkalinity measure  
 
PK 
Pharmacokinetics  
RNA 
Ribonucleic Acid  
SAE 
Serious Adverse Event  
SAP 
Statistical Analysis Plan  
SD 
Standard deviation  
SPARK 
Alpha-1 MP Safety and Pharmacokinetic Study   
STAMP 
Safety and Tolerability of Alpha-1 MP study  
t½ 
Terminal half-life  
TEAE 
Treatment-Emergent Adverse Event  
tmax 
Time to reach Cmax  

6 
Table of Contents 
1.
INTRODUCTION ....................................................................................................................... 10 
1.1 Alpha1-Antitrypsin Deficiency ......................................................................................................... 10 
1.2 Alpha1-PI Replacement Therapy ...................................................................................................... 10 
1.3 Alpha-1 MP: Human Alpha1-Proteinase Inhibitor from a Modified Manufacturing Process ........... 11 
1.4 Rationale for this Clinical Trial ........................................................................................................ 12 
2.
STUDY ADMINISTRATIVE STRUCTURE ............................................................................ 13 
3.
STUDY OBJECTIVES ................................................................................................................ 14 
3.1 Primary Objective ............................................................................................................................. 14 
3.2 Secondary Objective ......................................................................................................................... 14 
3.3 Exploratory Objective ...................................................................................................................... 14 
4.
INVESTIGATIONAL PLAN ...................................................................................................... 15 
4.1 Study Design and Plan ...................................................................................................................... 15 
4.1.1 
Design and Plan of this Clinical Trial ...................................................................................... 15 
4.1.2 
Type of Study ........................................................................................................................... 17 
4.1.3 
Phase of Development ............................................................................................................. 17 
4.2. Selection of Subject Population ........................................................................................................ 17 
4.2.1 
Inclusion Criteria ..................................................................................................................... 17 
4.2.2 
Exclusion Criteria .................................................................................................................... 18 
4.3. Investigational Drug ......................................................................................................................... 20 
4.3.1 
Investigational Drug ................................................................................................................ 20 
4.3.1.1 
Investigational drug code ......................................................................................................... 20 
4.3.1.2 
Investigational drug name ........................................................................................................ 20 
4.3.1.3 
Content and dosage form ......................................................................................................... 20 
4.3.1.4 
Composition of the Preparation ............................................................................................... 20 
4.3.2 
Investigational Drug Labeling ................................................................................................. 20 
4.3.2.1 
Packaging ................................................................................................................................. 20 
4.3.2.2 
Labeling ................................................................................................................................... 20 
4.3.3 
Dose and Dosage Regimen ...................................................................................................... 22 
4.3.3.1 
Dose and dosage regimen ........................................................................................................ 22 
4.3.3.2 
Rationale for the dose .............................................................................................................. 22 
4.3.3.3 
Rationale for the dosage regimen............................................................................................. 22 
4.3.4 
Storage of the Investigational Drug ......................................................................................... 23 
4.3.5 
Accountability of the Investigational Drug .............................................................................. 23 
4.4 Assignment Method .......................................................................................................................... 23 
4.4.1 
Subject Number ....................................................................................................................... 23 
4.4.2 
Blinding ................................................................................................................................... 24 
4.4.3 
Schedule for Investigational Drug Administration to Each Subject ........................................ 24 
4.4.4 
Treatment Compliance ............................................................................................................. 24 
4.5 Concomitant Medications and Other Restrictions ............................................................................ 24 

7 
4.5.1 
Prohibited Medications (Before Trial Entry) ........................................................................... 25 
4.5.2 
Prohibited Concomitant Medications ...................................................................................... 25 
4.6. Endpoints .......................................................................................................................................... 25 
4.6.1 
Exacerbation of Chronic Obstructive Pulmonary Disease (COPD) ........................................ 26 
4.6.2 
Pulmonary Function Test (PFT) ............................................................................................... 26 
4.7. Evaluation ......................................................................................................................................... 27 
4.7.1 
Evaluation Period ..................................................................................................................... 27 
4.7.2 
Observation and Measurement ................................................................................................ 27 
4.7.2.1 
Screening period ...................................................................................................................... 27 
4.7.2.2 
Treatment period ...................................................................................................................... 29 
4.7.2.3 
Visit for follow-up/study completion (Week 12) (for subjects not entering the extension trial 
[GTI1401-OLE]) ...................................................................................................................................... 34 
4.7.3 
Laboratory Tests and Testing Procedures ................................................................................ 35 
4.7.3.1 
Viral safety assessment ............................................................................................................ 36 
4.7.4 
Measurement of Serum Alpha1-PI Concentrations .................................................................. 36 
4.7.5  Volume of Blood Sampling ...................................................................................................... 37 
4.8 Screening Failures ............................................................................................................................ 37 
5 
ADVERSE EVENTS (AES) ........................................................................................................ 38 
5.1 Warnings/Precautions ....................................................................................................................... 38 
5.2 Monitoring of Adverse Events .......................................................................................................... 38 
5.3 Definitions and Handling of Adverse Events ................................................................................... 39 
5.3.1 
Definition of Adverse Events (AEs) ........................................................................................ 39 
5.3.2 
Definition of Suspected Adverse Drug Reactions (ADRs) ...................................................... 39 
5.3.3 
Causal Relationship of Adverse Events ................................................................................... 39 
5.3.4 
Severity of Adverse Events/ Suspected Adverse Drug Reactions ............................................ 40 
5.3.5 
Expectedness of Adverse Events/ Suspected Adverse Drug Reactions ................................... 41 
5.3.6 
Seriousness of Adverse Events/Adverse Drug Reactions; Serious Adverse Events (SAEs) ... 41 
5.3.7 
Recording of Adverse Events .................................................................................................. 42 
5.3.8 
Method and Duration of Follow-up of Subjects Experiencing Adverse Events ...................... 43 
5.3.9 
Events of Special Interest ........................................................................................................ 43 
5.4 Reporting of Serious Adverse Events (SAEs)/Pregnancies .............................................................. 43 
5.4.1 
Reporting of Serious Adverse Events (SAEs).......................................................................... 43 
5.4.2 
Reporting of Pregnancies ......................................................................................................... 45 
6. 
TRIAL DISCONTINUATION CRITERIA AND PROCEDURES FOR INDIVIDUAL 
SUBJECTS ........................................................................................................................................... 45 
6.1 Discontinuation Criteria ................................................................................................................... 45 
6.2 Discontinuation Procedures .............................................................................................................. 46 
7. 
TRIAL COMPLETION, DISCONTINUATION, OR INTERRUPTION .............................. 48 
7.1 Completion of the Clinical Trial ....................................................................................................... 48 
7.2 Discontinuation or Interruption of the Clinical Trial ........................................................................ 48 

8 
7.2.1 
Discontinuation or Interruption of the Clinical Trial by the Sponsor ...................................... 48 
7.2.2 
Discontinuation or Interruption of the Clinical Trial at a Study Center ................................... 48 
8 
STATISTICAL METHODS AND DETERMINATION OF TARGET SAMPLE SIZE ....... 50 
8.1 Statistical Analysis Plan ................................................................................................................... 50 
8.1.1 
Analysis Sets ............................................................................................................................ 50 
8.1.2 
Descriptive Statistics................................................................................................................ 50 
8.1.3 
Statistical Analysis of PK Parameters ...................................................................................... 50 
8.2 Determination of Target Sample Size ............................................................................................... 50 
9.
CASE REPORT FORMS ............................................................................................................ 51 
9.1 Completion and Reporting of Case Report Forms ........................................................................... 51 
9.2 Guidance for Completion of Case Report Forms ............................................................................. 51 
9.3 Identification of Data to be Recorded Directly on Case Report Forms and to be Considered to be 
Source Data ............................................................................................................................................... 51 
10.
PROTOCOL ADHERENCE, DEVIATIONS OR MODIFICATIONS, AND
AMENDMENTS .................................................................................................................................. 53 
10.1 Protocol Adherence .......................................................................................................................... 53 
10.2 Protocol Deviations or Modifications ............................................................................................... 53 
10.3 Protocol Amendments ...................................................................................................................... 54 
11 TRIAL MANAGEMENT ............................................................................................................ 55 
11.1 Investigator, Other Trial Staff, External Committees ....................................................................... 55 
11.2 Quality of Data ................................................................................................................................. 55 
11.2.1 Sponsor .................................................................................................................................... 55 
11.2.1.1 
Quality Control .................................................................................................................... 55 
11.2.1.2 
Quality Assurance ................................................................................................................ 55 
11.2.2 Study Centers ........................................................................................................................... 55 
11.3 Management of Documents .............................................................................................................. 56 
11.4 Retention of Records ........................................................................................................................ 56 
11.4.1 Retention of Records at the Study Center ................................................................................ 56 
11.4.2 Retention of Records by the Sponsor....................................................................................... 57 
11.4.3 Retention of Records at Other Organizations .......................................................................... 58 
11.5 Access to Information through Monitoring ...................................................................................... 58 
11.6 Access to Information for Auditing or Inspection ............................................................................ 59 
11.6.1 Source Documents ................................................................................................................... 59 
12.
ETHICS .................................................................................................................................... 60 
12.1 Declaration of Helsinki ..................................................................................................................... 60 
12.2 Adherence to the Drugs and Medical Devices Law and the GCP Ordinance ................................... 60 
12.3 Institutional Review Board (IRB) ..................................................................................................... 60 
12.3.1 Review of the Conduct of this Clinical Trial .............................................................................. 60 
12.3.2 Review of the Continuation of this Clinical Trial .................................................................... 60 

9 
12.4 Informed Consent of Subjects .......................................................................................................... 60 
12.4.1 Timing and Method of Obtaining Informed Consent .............................................................. 60 
12.4.1.1 
Preparation of written information and informed consent form .......................................... 61 
12.4.1.2 
Revision of the written information and informed consent form ......................................... 61 
12.4.1.3 
Information to be included in the written information ......................................................... 62 
12.4.1.4 
Method of obtaining informed consent ................................................................................ 63 
12.5 Protection of the Privacy of Subjects ............................................................................................... 64 
13.
FINANCING ............................................................................................................................ 65 
13.1 Compensation for Health Injury and Insurance ................................................................................ 65 
13.2 Payments to Subjects and Planned Trial-related Expenses ............................................................... 65 
14 
PUBLICATION POLICY ....................................................................................................... 65 
14.1 Use of the Data on this Clinical Trial ............................................................................................... 65 
14.2 Publication of the Trial Results ........................................................................................................ 66 
15.
PLANNED TRIAL PERIOD .................................................................................................. 66 
16.
LITERATURE REFERENCES.............................................................................................. 67 

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1.
INTRODUCTION
1.1 
Alpha1-Antitrypsin Deficiency
Alpha1-antitrypsin deficiency (AATD) is a genetic disorder in which mutations of the 
SERPINA1 gene (a member of the SERPIN, serine protease inhibitor gene family) lead to a 
reduced serum level of the serine protease inhibitor called alpha1-proteinase inhibitor 
(alpha1-PI) or, historically, alpha1-antitrypsin.  AATD manifests clinically as pulmonary 
emphysema, chronic obstructive pulmonary disease (COPD), and liver cirrhosis (1-3).   
The most frequent mutation causing severe AATD is called PI*Z and was first described in a 
Swedish patient with emphysema (4).  PI*MM (normal) individuals have serum alpha1-PI 
levels in the range of 20 to 53 µM; however, PI*ZZ (homozygous abnormal) individuals with 
AATD have serum alpha1-PI levels in the range of 2 to 10.2 µM (5).  The estimated world-
wide prevalence of PI*ZZ and PI*SZ (heterozygous abnormal) individuals is approximately 
163,700 and 903,000, respectively (6).   
Like other hereditary disorders, AATD is relatively rare (e.g., has orphan drug designation); 
however, it is extremely rare among Asians.  In 2000, a survey supported by the Japanese 
Ministry of Health and Welfare identified only 16 individuals in Japan with documented 
AATD (7).  AATD in Japanese patients exhibits unique features compared to AATD in 
Caucasians, including the lack of a PI*Z variant and a high incidence of the Siiyama deficiency 
AATD variant (7).  In Japanese patients homozygous for the Siiyama variant, serum alpha1-PI 
levels are in the range of 2.1 to 7.7 µM (7). Japanese normal individuals have serum alpha1-PI 
levels in the range of 21 to 34 μM (94 to 150 mg/dL as measured by nephelometry, which is 
used as the laboratory test standard values [8]). 
1.2 
Alpha1-PI Replacement Therapy 
Within the lung airways, neutrophil recruitment is thought to be an important component of 
continuing inflammation and progression of COPD (9).  When neutrophils phagocytize, an 
array of enzymes, including proteases such as neutrophil elastase (NE) may destroy tissue.  
Alpha1-PI is the most abundant circulating tissue inhibitor of NE (10,11) and constitutes an 
important part of the lung’s protective protease inhibitory shield and maintenance of the 
normal protease:antiprotease balance in the lungs (12).  In AATD, there appears to be an 
inadequate protective protease inhibitory shield (12-14), a disruption of the normal 
protease:antiprotease balance (12,15,16) and an unopposed action of NE leading to 
destruction of lung matrix and the development of emphysema (12-14,17-19). 

11 
Augmentation therapy with intravenous (IV) alpha1-PI is administered in patients with AATD 
to increase the low serum concentrations in this patient population.  This usage is intended to 
bolster the protective protease inhibitory shield against increased numbers of lung neutrophils 
releasing increased concentrations of NE, leading to a corrected protease:antiprotease 
imbalance (16,20-22). The restored antiprotease shield then protects the lung from elastolytic 
damage and slows or prevents the development of pulmonary emphysema (23,24).   
The serum level of alpha1-PI in normal individuals ranges from approximately 20 to 53 μM 
(5), and the historical serum alpha1-PI therapeutic target trough level of 11 μM was proposed 
as a “protective threshold” to prevent the development of progressive lung disease (20,21).  
This was based on a comparison of the apparent risk of emphysema among AATD individuals 
(PI*null/null, PI*ZZ, and PI*SZ) which Gadek and colleagues at the National Heart, Lung, 
and Blood Institute had conducted, and they inferred “that the hypothetical ‘threshold’ level 
of serum alpha1-antitrypsin necessary to protect against lung proteolysis resides in the range 
of ~ 35% of normal” (20).  Subsequently, it was demonstrated that augmentation with 60 
mg/kg alpha1-PI administered by weekly IV infusions consistently achieved trough serum 
alpha1-PI concentrations above 11 μM (22).  As previously noted, Japanese patients 
homozygous for the Siiyama AATD variant have serum alpha1-PI levels in the range of 2.1 to 
7.7 µM (Section 1.1), which is below the suggested 11 μM “protective threshold” serum 
alpha1-PI level.   
 
 
1.3 
Alpha-1 MP: Human Alpha1-Proteinase Inhibitor from a 
Modified Manufacturing Process 
Alpha1-PI (human), Prolastin®, was licensed for use as augmentation therapy for AATD at a 
dose of 60 mg/kg weekly, in the United States (US) in 1987 and in Germany in 1988.  
Prolastin is currently authorized in 14 European Union countries as well as in Switzerland and 
Brazil.  Subsequently, Grifols incorporated modifications into the Prolastin manufacturing 
process to produce alpha1-PI (human), modified process (Alpha-1 MP).  This modified 
process results in an increased yield of alpha1-PI and a product with twice the alpha1-PI 
concentration with an improved pathogen safety profile and higher purity compared to 
Prolastin.  Alpha-1 MP is approved for 60 mg/kg weekly IV administration in the US, 
Canada, Columbia, Argentina, and Tarky for the treatment of patients with severe AATD and 
clinically evident emphysema under the trade name Prolastin®-C.   
Two studies have examined Alpha-1 MP at the 60 mg/kg dose given weekly by IV infusion to 
AATD subjects.  The STAMP (Safety and Tolerability of Alpha-1 MP) study was a multi-
center, open-label study to evaluate the safety and tolerability of Alpha-1 MP.  In the 

12 
STAMP study, 38 subjects with AATD were treated with Alpha-1 MP at 60 mg/kg for 20 
weeks.  Suspected adverse drug reactions (ADRs; i.e., drug-related adverse events [AEs]) 
were chills, malaise, headache, rash, and hot flush. The ChAMP (pharmacokinetic 
Comparability of Alpha-1 MP) study was a multi-center, randomized, double-blind, crossover 
study to evaluate the pharmacokinetic (PK) comparability of Alpha-1 MP and Prolastin in 24 
subjects with AATD.  The study consisted of two 8-week double-blind treatment periods 
during which study subjects received either 60 mg/kg of Alpha-1 MP or 60 mg/kg of 
Prolastin, weekly by IV infusion, followed by 60 mg/kg weekly of Alpha-1 MP in an 8-week 
open-label treatment phase.  Alpha-1 MP was determined to be pharmacokinetically 
equivalent to Prolastin, and the elimination half-life of Alpha-1 MP was 146 hours (i.e., 6 
days) as measured by functional activity assay.  The only suspected ADR for Alpha-1 MP in 
the ChAMP study was mild pruritis/itching.   
Subsequent to the STAMP and ChAMP studies, the SPARK (Alpha-1 MP Safety and 
PhARmacoKinetic) study was conducted to assess the safety and PK of weekly IV infusions of 
Alpha-1 MP at 120 mg/kg compared to the US-approved 60 mg/kg dose in 30 subjects with 
AATD.  The study was a crossover design; thus, subjects received Alpha-1 MP at either 60 or 
120 mg/kg for 8 weeks and then were switched to the alternate dose for an additional 8 weeks. 
Subjects completed a 2-week washout period prior to switching to the alternate dose. Results 
from the study showed that steady-state serum concentrations of Alpha-1 MP were dose-
proportional between the 60 mg/kg and 120 mg/kg doses.  The weekly dose of 120 mg/kg 
Alpha-1 MP provided an average mean trough level of alpha1-PI of 27.7 µM, which was within 
the reported range of alpha1-PI serum levels (20 to 53 µM) in normal, non-AATD individuals. 
Both the 60 mg/kg and 120 mg/kg weekly doses of Alpha-1 MP were safe and well tolerated. 
1.4 
Rationale for this Clinical Trial 
Japanese patients with AATD exhibit very different genotypes of AATD compared to the rest 
of the world, and the number of Japanese patients with AATD is extremely small (see Section 
1.1).  These subjects can exhibit symptoms of emphysema-typed COPD and therefore, will 
have clinically evident emphysema and along with alpha1-PI deficiency. The safety and PK of 
augmentation therapy with Alpha-1 MP to increase serum alpha1-PI levels has not been 
evaluated in Japanese patients with AATD.  Thus, Grifols Japan K.K. is conducting a study 
to assess the safety and PK of 60 mg/kg Alpha-1 MP administered by weekly IV infusions 
over 8 weeks in Japanese subjects with AATD. 

13 
2.
STUDY ADMINISTRATIVE STRUCTURE
Please refer to Appendix 2 for the study administrative studructure of this study such as; 
–
SPONSOR
–
CONTRACT RESEARCH ORGANIZATION
–
STUDY CENTERS
–
LABORATORY TESTING SERVICES, TRANSPORTER, INVESTIGATIONAL DRUG
MANUFACTURER

14 
3. STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of this study is to evaluate the safety of 60 mg/kg Alpha-1 MP 
administered by weekly IV infusions over 8 weeks in Japanese subjects with AATD.  
 
 
3.2 
Secondary Objective 
The secondary objective of this study is to evaluate the trough level of total alpha1-PI for 
weekly IV infusions of 60 mg/kg Alpha-1 MP in Japanese subjects with AATD. 
 
 
3.3 
Exploratory Objective 
The following PK parameters for Alpha1-PI are to be measured at steady state at the end of 
the 8-week treatment period.   
• AUC0-7 days 
 
Area under the concentration-time curve (AUC) from Day 0 to Day 7, calculated at 
 
steady state at the end of the 8-week treatment period.   
• Cmax 
 
Maximum concentration 
• tmax   
 
The observed time to reach Cmax  
• t½ 
 
Terminal half-life 
 
 
 

15 
4. INVESTIGATIONAL PLAN 
4.1 
Study Design and Plan 
4.1.1 
Design and Plan of this Clinical Trial 
This study is a multicenter, open-label trial to evaluate the safety and pharmacokinetics of 
weekly intravenous infusions of 60 mg/kg of the investigational drug in subjects with AATD. 
The trial will be conducted at approximately 5 medical institutions in Japan, aiming to enroll a 
minimum of 3 adult subjects or more. The trial will consist of a screening period scheduled 
within 3 weeks before trial entry, an open-label treatment period for 8 weeks, and a PK 
evaluation period for 1 week. At the Week 9 visit when the PK evaluation period is completed, 
subjects will be asked whether they would like to participate in an extension trial (GTI1401-
OLE). For subjects not intending to participate in the extension trial, the date of follow-up/study 
completion visit (30 days [4 weeks] after the last dose of the investigational drug) will be 
arranged. Subjects will participate in this trial for approximately 14 weeks from the start of the 
screening period through the completion of the trial. 
 
At the screening visit (scheduled within 3 weeks before trial entry), after providing informed 
consent (agreement based on adequate explanation and understanding of the treatment plan), 
subjects will be evaluated for eligibility for participation during the screening period (refer to 
Section 4.2.1 “Inclusion Criteria” and Section 4.2.2 “Exclusion Criteria”). Subjects considered 
eligible will enter the 8-week treatment period to receive a total of 8 weekly intravenous 
infusions of 60 mg/kg of Alpha-1 MP. The initial intravenous infusion will be given at the Week 
1 (baseline) visit. During the treatment period, subjects will receive weekly intravenous 
infusions of Alpha-1 MP at the Weeks 1 (baseline), 2, 3, 4, 5, 6, 7, and 8 visits. After the last 
intravenous infusion of Alpha-1 MP at the Week 8 visit, subjects will enter the 1-week PK 
evaluation period. During this PK evaluation period, subjects will visit the study center to 
undergo blood sampling for PK evaluation at the PK1 visit (the next day of the Week 8 visit), 
the PK2 visit (2 days after the Week 8 visit), the PK5 visit (5 days after the Week 8 visit), and 
at the Week 9 visit. At 30 days after the last dose (Week 8), subjects will visit the study center 
for follow-up/study completion (Week 12). All subjects will undergo blood sampling for the 
measurement of alpha1-PI trough concentrations at the Weeks 1 (baseline), 7, and 8 visits (blood 
samples will be collected before dosing) as well as at the Week 9 visit. 
 
Blood samples for the evaluation of PK parameters will be collected from Week 8 to Week 9. 
The blood sample collected before the infusion of Alpha-1 MP at the Week 8 visit and the blood 
sample for PK evaluation collected at the Week 9 visit (7 days after the infusion at the Week 8 
visit) will be also used for the measurement of alpha1-PI trough concentrations for Weeks 8 and 

16 
9. For details of the total of 10 sequential PK blood sampling time points, refer to Section 4.7.2.2 
and Appendix 1. 
 
At the Week 9 visit, subjects will be asked whether they would like to participate in the 
extension trial (GTI1401-OLE). Subjects intending to participate in the extension trial will be 
able to continue the treatment with intravenous infusions of 60 mg/kg of Alpha-1 MP for at 
least another year (subjects will be further asked whether they would like to continue the 
treatment at yearly intervals) for the purpose of evaluation of the safety of long-term Alpha-1 
MP treatment. Subjects not intending to enter the extension trial will visit the study center for 
follow-up/study completion at 30 days (4 weeks) after the last dose of Alpha-1 MP (Week 12). 
 
The entire design of this clinical trial is shown in Figure 4-1, and its schedule is provided in 
Appendix 1. 
 
 
Figure 4-1 Overall study schema 
 
 

17 
4.1.2 
Type of Study 
Safety and clinical pharmacology study 
 
 
4.1.3 
Phase of Development 
Phase II 
 
 
4.2. 
Selection of Subject Population 
Eligible subjects must provide written consent to participate in this clinical trial of their own 
free will after being fully informed of the contents of the trial based on the written information 
and informed consent form. 
 
After obtaining written informed consent from each subject, the investigator or subinvestigator 
will screen the subject within 21 days before the first investigational drug infusion. The 
investigator will assess subject eligibility based on the inclusion criteria and the exclusion 
criteria below. 
 
4.2.1 
Inclusion Criteria 
1. Subjects aged ≥20 years at the time of providing informed consent 
2. Subjects with clinically apparent pulmonary emphysema diagnosed by CT scan 
3. AATD subjects with documented serum alpha1-PI levels of <50 mg/dL (i.e., 11 µM) as 
measured by nephelometry. In subjects with no previously documented serum alpha1-PI 
levels, their serum alpha1-PI levels measured by nephelometry during the screening 
period must be <50 mg/dL. 
4. Subjects whose percentage of forced expired volume in 1 second/forced vital capacity  
(FEV1/FVC) after inhalation of a bronchodilator is <70% during the screening period 
[equivalent to the criterion for the diagnosis of COPD] 
5. Subjects who are willing to and able to provide signed written informed consent 
 
<Rationale for establishing the inclusion criteria> 
1. This criterion has been established as the target age group of subjects for this clinical trial. 
2. This criterion has been established to include subjects with clinically evident emphysema 
based on the diagnostic criteria for designated intractable diseases with clinically evident 
pulmonary emphysema in this clinical trial. This CT scan will measure lung density. 
3. This criterion has been established to enroll only subjects with alpha1-PI deficiency in 
this clinical trial. 

18 
4. This criterion has been established to specify the acceptable levels of percentage of 
FEV1/FVC for this clinical trial [equivalent to the criterion for the diagnosis of COPD]. 
5. This criterion has been established because written consent to participate in this clinical 
trial from each patient is required. 
 
4.2.2 
Exclusion Criteria 
1. Subjects with moderately or severely deteriorated lung function in the 4 weeks before the 
Week 1 (baseline) visit 
2. Subjects whose percentage of forced expired volume in 1 second (%FEV1) after 
inhalation of a bronchodilator is <30% during the screening period 
3. Subjects who have undergone lung transplantation or liver transplantation 
4. Subjects who have undergone any lung surgery (excluding lung biopsy) in the past 2 years 
5. Subjects with increased liver enzymes (AST, ALT, and ALP) ≥2.5 times the upper limit 
of normal 
6. Subjects with severe complications including but not limited to congestive heart failure 
and liver cirrhosis 
7. Subjects who have developed any malignant tumor (including malignant melanoma; 
however, other forms of skin cancer are excluded) in the past 5 years 
8. Pregnant women, breastfeeding women, or women of childbearing potential who do not 
intend to use effective contraceptive methods (use of oral, injection, or implant hormonal 
contraceptives; placement of an intrauterine device (IUD) or intrauterine contraceptive 
system; concomitant use of spermatocidal foam, gel, film, cream, suppository and 
condoms or cervical caps; male sterilization; or abstinence) throughout the trial period or 
male subjects who have a partner who is of childbearing potential and is unwilling to use 
effective contraceptive methods throughout the trial period. 
9. Subjects with a past history of HAV, HBV, HCV, or HIV infection, or subjects currently 
presenting with clinical signs or symptoms suggestive of such infection 
10. Subjects with a smoking history in the past 6 months, or subjects tested positive for 
urinary cotinine levels at the screening visit 
11. Subjects participating in another clinical trial within 4 weeks before the Week 1 (baseline) 
visit 
12. Subjects with a history of anaphylactic or severe systemic reactions to any plasma derived 
alpha1-PI product or other blood products 
13. Subjects who have continuously received any systemic steroid therapy at a prednisone-
equivalent dose >5 mg/day within 4 weeks before the Week 1 (baseline) visit (Note: 
inhaled steroids are not regarded as systemic steroids) 
14. Subjects who have used any systemic or aerosolized antibiotic drug for the treatment of 
COPD exacerbation within 4 weeks before the Week 1 (baseline) visit 

19 
15. Subjects with a previous or current diagnosis of selective, severe IgA deficiency 
16. Subjects who are mentally challenged  and cannot independently give consent   
17. Subjects who have difficulty in adhering to the protocol or its procedures in the opinion 
of the investigator 
18. Subjects who have medical conditions that may confound the results of this clinical trial 
or may endanger other subjects during the participation in this clinical trial in the opinion 
of the investigator 
 
<Rationale for establishing the exclusion criteria> 
1. This criterion has been established to exclude subjects with this medical condition 
because the condition will affect pulmonary function tests (PFTs) and clinical laboratory 
tests, thereby precluding appropriate safety evaluation. 
2. This criterion has been established to determine the range of percentage of forced expired 
volume in 1 second (%FEV1) to be excluded. 
3. Same as 1 above. 
4. Same as 1 above. 
5. This criterion has been established to exclude subjects with any underlying disease that 
may affect clinical laboratory values and safety evaluation. 
6. Same as 5 above. 
7. Same as 5 above. 
8. This criterion has been established because animal reproduction studies have not been 
conducted with Alpha1-PI, the safety of Alpha1-PI in pregnant women and their fetuses 
as well as its effects on fertility have not been established yet, and no results on the 
excretion of Alpha1-PI into breast milk are available. 
9. Same as 1 above. 
10. This criterion has been established to exclude smokers who may be at risk for further 
deterioration of lung function and lung damage. 
11. This criterion has been established to exclude any effect on the evaluation of adverse 
events and safety of this investigational drug. 
12. Same as 11 above. 
13. This criterion has been established to reduce clinical changes associated with the use of 
concomitant drugs and exclude factors that may affect symptomatic improvement. 
14. Same as 1 above. 
15. Same as 11 above. 
16. This criterion has been established to exclude subjects in whom it is difficult to confirm 
whether they intend to consent or not. 
17. This criterion has been established to exclude subjects who cannot adhere to the protocol. 
18. Same as 11 above. 
 

20 
4.3. 
Investigational Drug 
4.3.1 
Investigational Drug 
4.3.1.1 
Investigational drug code 
 
 
Alpha-1 MP 
 
4.3.1.2 
Investigational drug name 
 
 
Alpha-1 MP 
 
4.3.1.3 
Content and dosage form 
Alpha-1 MP is a stable, sterile, lyophilized preparation of human alpha1-PI, also known as α1-
antitrypsin. Alpha-1 MP is supplied as a white to beige, lyophilized powder contained in a glass 
vial. Each vial of Alpha-1 MP contains the labeled amount of functionally active alpha1-PI in 
milligrams per vial (each vial contains approximately 1,000 mg of functionally active alpha1-
PI). Alpha-1 MP contains no preservatives. Alpha-1 MP is reconstituted using a dissolving 
solution (20 mL of water for injection) as instructed in the Pharmacy Manual. Alpha-1 MP must 
be administered by an intravenous route. 
 
Further information on the investigational drug is provided in the investigator’s brochure. 
 
4.3.1.4 
Composition of the Preparation 
The composition of the preparation per vial is shown in Table 4-1. 
 
Table 4-1  Composition of Alpha-1 MP Preparation 
Component 
Content (per vial) 
Quality standards 
Alpha1-Proteinase Inhibitor 
(Human) 
Nominal 1,000 mg 
WHO Standard 
NaH2PO4 
0.4 mmol 
United States Pharmacopeia 
NaCl 
2.0 mmol 
United States Pharmacopeia 
 
 
4.3.2 
Investigational Drug Labeling 
4.3.2.1 
Packaging 
An individual package contains 10 labeled, transparent vials. 
 
4.3.2.2 
Labeling 
The labels for the investigational drug on an individual package and a vial include the following 
information: the statements “For Investigational Use”, investigational drug name, protocol No., 

21 
instructions for use, expiration date, serial number, storage conditions, quantity, and sponsor’s 
name and address. Sample labels on an individual package and a vial are shown below. 
 
 
GRIFOLS 
Protocol: GTI1401 
 
Alpha1-Proteinase Inhibitor (Human), Modified Process  
(Alpha-1 MP) 
 
Contents: 
• 
10 Alpha-1 MP Vials 
• 
12 Filter Needles 
• 
12 Transfer Needles 
SHIP AND STORE AT TEMPERATURES NOT TO EXCEED 25°C.  
DO NOT FREEZE. 
Reconstitute with 20 mL Sterile Water for Injection for a vial. 
For intravenous administration only. 
Dosage per Protocol. 
For Clinical Trial Use Only. 
Site No.: _______________________________ 
Investigator’s Name: _____________________ 
 
LOT 
EXP. 
mg α1-PI / vial 
 
Grifols Japan K.K. 
Level 19 Hilton Plaza West Office Tower 
2-2-2 Umeda, Kita-ku, Osaka 530-0001, Japan 
 
Figure 4-2 Sample Labeling for the Investigational Drug 
 
 

22 
Protocol: GTI1401 
 
Alpha1-Proteinase Inhibitor (Human), Modified Process  
(Alpha-1 MP) 
 
Store at temperatures not to exceed 25°C. Do not freeze. 
Reconstitute with 20 mL Sterile Water for Injection 
For intravenous administration only. Dosage per Protocol. 
For Clinical Trial Use Only. 
 
Site No.: _______________________________ 
Investigator’s Name: _____________________ 
Patient ID: _____________________________ 
 
LOT 
EXP. 
mg α1-PI / vial 
 
Grifols Japan K.K. 
Level 19 Hilton Plaza West Office Tower 
2-2-2 Umeda, Kita-ku, Osaka 530-0001, Japan 
 
Figure 4-3 Sample Labeling for the Investigational Drug 
 
 
4.3.3 
Dose and Dosage Regimen 
4.3.3.1 
Dose and dosage regimen 
Subjects will receive a total of 8 IV infusions of 60 mg/kg Alpha-1 MP administered weekly. 
The prescribed infusion rate for Alpha-1 MP is not to exceed 0.08 mL/kg/min as determined 
by the response and comfort of the subject. The recommended dose for this trial takes 
approximately 15 minutes per IV bag to infuse (based on ~70 kg subject).  
 
4.3.3.2 
Rationale for the dose 
The recommended dose of Alpha-1 MP (commercially available as Prolastin-C) is 60 mg/kg 
body weight administered once weekly.  Alpha-1 MP is currently approved for 60 mg/kg 
weekly IV administration in the US, Canada, Columbia, Argentina, and Turkey.  As such, 
Alpha-1MP at a dose of 60 mg/kg body weight will be used in this study.   
 
4.3.3.3 
Rationale for the dosage regimen 
Given that Alpha-1 MP has a serum half-life of approximately one week in Caucasians (see 
Section 1.3), weekly infusion is the preferable treatment regimen. Furthermore, the 
recommended dose of Alpha-1 MP is 60 mg/kg body weight administered once weekly.  In 

23 
this study, subjects will receive IV-administered Alpha-1 MP once weekly for 8 weeks for a 
total of 8 infusions. 
 
4.3.4 
Storage of the Investigational Drug 
Alpha-1 MP should be stored at a temperature not to exceed 25°C.  Do not freeze.  Alpha-1 
MP must be stored in a secure area accessible only to designated study site personnel until 
dispensed for the study subject.  
Alpha-1 MP should be kept at room temperature after reconstitution and should be 
administered within 3 hours after reconstitution. 
Additional details are provided in the Pharmacy Manual. 
 
4.3.5 
Accountability of the Investigational Drug 
Alpha-1 MP is to be used only for the study in accordance with the directions given in this 
protocol.  The Primary Pharmacist responsible for management of the Investigational 
Product at the site, is responsible for the distribution of Alpha-1 MP in accordance with 
directions given in the protocol and Pharmacy Manual. 
The Primary Pharmacist is responsible for maintaining accurate records of Alpha-1 MP for 
his/her site.  Alpha-1 MP inventory/dispensing documentation verifying the receipt, 
dispensing, destruction, or return must be maintained and kept current by the Investigator, or 
designee. The inventory must be made available for inspection by the study monitor.  Alpha-
1 MP supplies must be accounted for by the study monitor and inventory/dispensing logs 
must be verified by the monitor prior to Alpha-1 MP return or destruction.  Written 
documentation of all used and unused inventory is required.  At the end of the study, a copy 
of the inventory/dispensing log(s) will be retrieved by the monitor and returned to Grifols 
Japan K.K. 
 
 
4.4 
Assignment Method 
4.4.1 
Subject Number 
Within each study site, subjects in the study will receive a consecutive subject number. 
Subject numbers are generated beginning with the study center number (2 digits, assigned by 
the sponsor) followed consecutively with a unique number for each subject (2 digits, starting 
with 10).  For example, if the Investigator’s center number is 10, subject numbers will be 
1001, 1002, 1003, etc., in consecutive order.  Subject numbers, once assigned, will not be 
reused at any center. 

24 
4.4.2 
Blinding 
This study is an open-label trial; thus, blinding procedures are not applicable. 
 
4.4.3 
Schedule for Investigational Drug Administration to Each Subject 
Subjects will receive a total of 8 IV infusions of 60 mg/kg Alpha-1 MP administered weekly.  
Weekly infusions of Alpha-1 MP will be performed at the Investigator’s study site under the 
care and supervision of the treating Investigator, or designee, during scheduled study visits at 
Weeks 1 (Baseline), 2, 3, 4, 5, 6, 7, and 8.  Subjects will receive their first infusion of 
Alpha-1 MP at the Week 1 (Baseline) Visit and their last infusion at the Week 8 Visit. 
Each week, designated study site personnel will prepare an infusion bag of Alpha-1 MP at the 
calculated volume based on the subject’s body weight, and the subject will receive the 
contents of the infusion bag via IV administration.   
The prescribed infusion rate for Alpha-1 MP is not to exceed 0.08 mL/kg/min as determined 
by the response and comfort of the subject. The recommended dose for this trial takes 
approximately 15 minutes per IV bag to infuse (based on ~70 kg subject). After completion of 
the infusion bag, each subject will receive a minimum of 25 mL of 0.9% Sodium Chloride for 
Injection to flush the IV line.   
For each infusion, the total infusion volume prepared, total infusion time, total volume 
infused, and, if necessary, any infusion interruption with explanation will be documented. 
Complete details are provided in the Pharmacy Manual. 
 
4.4.4 
Treatment Compliance 
The volume of the Alpha-1 MP administered will be documented in the subject’s source 
documentation and case report form (CRF).  Reasons for any deviation from the 
administration of less than 100% of the prepared Alpha-1 MP dose (i.e., volume) must be 
recorded in the CRF and in the subject’s source documentation.  
 
4.5 
Concomitant Medications and Other Restrictions 
Concomitant medications must be recorded in the subject’s source documentation and CRF, 
including the trade or generic names of the medication, dose, route of administration, 
duration, and frequency. 
 
 

25 
4.5.1 
Prohibited Medications (Before Trial Entry) 
Use of the following medications, as specified below, would exclude a subject from 
participating in this study: 
• Systemic steroids above a stable dose equivalent to 5 mg/day prednisone (e.g., 10 mg 
every 2 days) within 4 weeks prior to the Week 1 (Baseline) Visit (Note: inhaled steroids 
are not considered systemic steroids)   
• Systemic or aerosolized antibiotics for a COPD exacerbation within the 4 weeks prior to 
the Week 1 (Baseline) Visit 
 
 
4.5.2 
Prohibited Concomitant Medications 
Use of the following medications is prohibited during study participation: 
• Any other alpha1-PI treatment 
• Investigational products not part of this study 
 
 
4.6. 
Endpoints 
No efficacy variables will be assessed for this the study.  The variables to be assessed for 
this study are as follows: 
• Adverse events, ADRs, serious AEs (SAEs), and discontinuations due to AEs or SAEs 
• Vital signs (heart rate, blood pressure, respiratory rate, and temperature) 
• COPD exacerbations 
• Pulmonary function tests : 
– 
Forced Expiratory Volume in 1 second (FEV1) 
– 
Forced Vital Capacity (FVC) 
• Clinical laboratory parameters: 
– 
Chemistry 
– 
Hematology 
– 
Urinalysis 
• Alpha1-PI trough level 
• PK parameters: 
– 
AUC0-7 days 
– 
Cmax 
– 
tmax   
– 
t½ 

26 
4.6.1 
Exacerbation of Chronic Obstructive Pulmonary Disease (COPD) 
All COPD exacerbations occurring during the study will be recorded.  The subject will be 
assessed for signs and symptoms of exacerbations at each study visit.  Given that COPD 
exacerbations are part of the natural history of AATD, COPD exacerbations will not be 
reported as AEs unless a COPD exacerbation meets the criteria of an SAE.  If an 
exacerbation meets criteria for an SAE, it will be reported as such, and the standard of care 
should be followed.  Results from standard of care should be obtained and reported.   
This study will use the definition of exacerbation published in the “Outcomes for COPD 
pharmacological trials: from lung function to biomarkers,” a report from an American 
Thoracic Society (ATS)/European Respiratory Society (ERS) Task Force (25).  The 
definition of an exacerbation of COPD is an increase in respiratory symptoms (dyspnea, 
increased cough, and/or production of sputum) over baseline that usually requires medical 
intervention.  Exacerbation severity is defined as:   
• Mild: which involves an increase in one or more respiratory symptoms (dyspnea, cough, 
and/or sputum) that is controlled by the subject with an increase in the usual medication. 
• Moderate: which requires treatment with systemic steroids and/or antibiotics. 
• Severe: which describes exacerbations that require hospitalization (an emergency 
department stay > 24 hours is considered a hospitalization). 
 
 
4.6.2 
Pulmonary Function Test (PFT) 
Pulmonary function tests (i.e., spirometry), including FEV1 (absolute and present predicted) 
and FVC, will be performed according to ATS/ERS guidelines (26) at Screening Visit and 
Weeks 5, 9 and 12 (Appendix 1).  Pulmonary function tests at Week 5 should be conducted 
prior to Alpha-1 MP infusion.  At each visit in which PFTs are scheduled, testing will be 
performed pre-infusion both pre- and post-bronchodilator administration.  The post-
bronchodilator PFT should be performed 15 to 30 minutes after bronchodilator 
administration.  For each PFT, 4 puffs of metered dose inhaler (MDI) salbutamol as a short-
acting bronchodilator should be administered.  The same bronchodilator should be used 
throughout the study.   
 
 

27 
4.7. 
Evaluation 
4.7.1 
Evaluation Period 
This clinical trial will consist of the screening period scheduled within 3 weeks before trial 
entry; the open-label treatment period for 8 weeks; the PK evaluation period for 1 week; the 
Week 9 visit (at this visit, subjects will be asked whether or not they would like to enter an 
extension trial [GTI1401-OLE]); and the follow-up/study completion visit for subjects not 
intending to enter the extension trial (30 days [4 weeks] after the last dose of Alpha-1 MP). 
Subjects will participate in this trial for approximately 14 weeks from the start of the screening 
period through the completion of the trial (refer to Appendix 1 “Trial Schedule”). 
 
 
4.7.2 
Observation and Measurement 
The trial procedures and evaluations at each visit are described below. For a summary of the 
scheduled visits and the trial procedures and evaluations at each visit, refer to Appendix 1 “Trial 
Schedule.” Unscheduled visits may be requested for subjects to ensure their safety if necessary. 
 
4.7.2.1 
Screening period 
Prior to collection of screening evaluation data or the start of the trial, written consent must be 
obtained from all candidate subjects. Trial entry will start after the subjects sign their informed 
consent forms. Subject eligibility will be evaluated during the screening period. 
The screening visit will occur within 3 weeks before the Week 1 (baseline) visit. 
 
Visit 
Trial Procedures and Evaluations 
Screening 
(within 3 weeks) 
• 
Informed consent 
• 
Eligibility evaluation based on the inclusion/exclusion 
criteria 
• 
PFT (FEV1 and FVC) before and after administration of a 
bronchodilator (refer to Section 4.6.2) 
• 
Assignment of subject numbers 
• 
Medical history 
• 
Age, sex,  
• 
CT scan (This CT scan [densitometry] will be performed for 
documentation of emphysema at each study site, and CT scan 
data will be evaluated centrally for lung density at Vida 
Diagnostics, Inc.; see CT Scan Manual for detailed 
procedures) 
• 
Body height 

28 
• 
Body weight 
• 
Physical examination (excluding breast and urogenital 
examination) 
• 
Laboratory tests (refer to Section 4.7.3) 
Urine samples: Urinalysis 
Urine pregnancy test: To be performed only in 
women of childbearing potential. 
Only women tested negative for 
pregnancy can continue the trial. 
Urinary cotinine level: Subjects tested positive for 
urinary 
cotinine 
are 
considered 
ineligible. 
Blood samples: Blood chemistry, hematology 
 
• 
Alpha1-PI measurement: To be performed in subjects with no 
previously documented alpha1-PI levels as measured by 
nephelometry (if it is unknown whether the subject’s alpha1-
PI level is <50 mg/dL or not) 
• 
COPD exacerbation (refer to Section 4.6.1) 
• 
Adverse events (AEs) 
• 
Concomitant medications 
• 
12-lead ECG 
 
 

29 
4.7.2.2 
Treatment period 
During the 8-week treatment period, subjects will receive a total of 8 weekly intravenous 
infusions of 60 mg/kg of Alpha-1 MP. Weekly infusions of Alpha-1 MP will be given at the 
scheduled Week 1 (baseline), 2, 3, 4, 5, 6, 7, and 8 visits at each study center. Visit dates after 
the Week 1 (baseline) visit will be arranged at 1-week intervals as specified in the protocol 
according to the actual date of the Week 1 (baseline) visit (±1 day). 
 
Subjects meeting all of the inclusion criteria and not meeting any of the exclusion criteria will 
make the Week 1 (baseline) visit within 21 days after the screening visit. Subjects considered 
eligible will receive the initial intravenous infusion (intravenous drip) of Alpha-1 MP at the 
Week 1 (baseline) visit. 
The 1-week PK evaluation period will start at the Week 8 visit and end at the Week 9 visit. At 
the Week 8 visit, subjects will undergo blood sampling for PK evaluation immediately before 
the intravenous infusion of Alpha-1 MP; immediately after the intravenous infusion; and at 15 
minutes, 2, 4, and 8 hours after completion of the intravenous infusion. Subjects will visit the 
study center 1 day (PK1), 2 days (PK2), and 5 days (PK5) after the Week 8 visit to provide PK 
evaluation blood samples at 24 ± 4 hours (1 day), 48 ± 4 hours (2 days), and 120 hours ± 1 day 
(5 days), respectively, after the intravenous infusion of Alpha-1 MP at the Week 8 visit. The 
date of Week 9 visit will be scheduled in the week specified in the protocol according to the 
actual date of the Week 1 (baseline) visit (±1 day). 
 
Visit 
Trial Procedures and Evaluations 
Week 1 
(Baseline) 
[Before intravenous infusion of Alpha-1 MP] 
• 
Reevaluation of the inclusion/exclusion criteria 
• 
Body weight: Recorded body weight will be used to calculate 
the Alpha-1 MP dose administered at the Week 
1 (baseline) visit. This recorded body weight 
will be used for dose calculation until the next 
scheduled body weight measurement. 
• 
Laboratory tests (refer to Section 4.7.3) 
Urine samples: Urinalysis 
 
Blood samples: 
Viral safety assessment: Blood samples for viral nucleic 
acid amplification (NAT) and 
viral serologic test will be 
collected 
at 
the 
Week 
1 
(baseline) visit. However, the 
collected samples will be tested 
only if the subject shows 
clinical signs or symptoms 

30 
suggestive of viral infection 
during the trial period. All 
collected blood samples will be 
stored until completion of the 
tests 
in 
this 
clinical 
trial 
(GTI1401) and the extension 
trial (GTI1401-OLE). 
Blood chemistry, hematology, alpha1-PI concentrations 
 
• 
COPD exacerbation (refer to Section 4.6.1) 
• 
Adverse events 
• 
Concomitant medications 
• 
Vital signs (pulse rate, blood pressure, respiratory rate, and 
body temperature) immediately before the start of 
intravenous infusion of Alpha-1 MP 
 
[At the time of intravenous infusion (intravenous drip) of Alpha-
1 MP] 
• 
Intravenous infusion of Alpha-1 MP 
• 
Vital signs (pulse rate, blood pressure, respiratory rate, and 
body temperature) immediately after the completion of 
intravenous infusion of Alpha-1 MP 
• 
12-lead ECG immediately after the end of intravenous 
infusion of Alpha-1 MP 
• 
Observation of the subject for at least 30 minutes after the 
intravenous infusion 
 
Weeks 2,3,4,6 
[Before intravenous infusion of Alpha-1 MP] 
• 
COPD exacerbation (refer to Section 4.6.1) 
• 
Adverse events 
• 
Concomitant medications 
• 
Vital signs (pulse rate, blood pressure, respiratory rate, and 
body temperature) immediately before the start of 
intravenous infusion of Alpha-1 MP 
 
[At the time of intravenous infusion of Alpha-1 MP] 
• 
Intravenous infusion of Alpha-1 MP 
• 
Vital signs (pulse rate, blood pressure, respiratory rate, and 
body temperature) immediately after the completion of 
intravenous infusion of Alpha-1 MP 
• 
Observation of the subject for at least 30 minutes after the 
intravenous infusion 

31 
Week 5 
[Before intravenous infusion of Alpha-1 MP] 
• Body weight: Recorded body weight will be used to calculate 
the Alpha-1 MP dose administered at the Week 
5 visit. This recorded body weight will be used 
for the weekly dose calculations thereafter. 
• Laboratory tests (refer to Section 4.7.3) 
Urine samples: 
Urinalysis 
Urine pregnancy test: 
To be performed only in women 
of childbearing potential. Only 
women 
tested 
negative 
for 
pregnancy can continue the trial. 
Urinary cotinine level: Subjects tested positive for 
urinary cotinine due to smoking 
must be withdrawn from the 
trial. 
 
Blood samples: Blood chemistry, hematology 
 
• PFT (FEV1 and FVC) before and after administration of a 
bronchodilator (refer to Section 4.6.2) 
• COPD exacerbation (refer to Section 4.6.1) 
• Adverse events 
• Concomitant medications 
• Vital signs (pulse rate, blood pressure, respiratory rate, and 
body temperature) immediately before the start of intravenous 
infusion of Alpha-1 MP 
 
[At the time of intravenous infusion of Alpha-1 MP] 
• Intravenous infusion of Alpha-1 MP 
• Vital signs (pulse rate, blood pressure, respiratory rate, and 
body temperature) immediately after the completion of 
intravenous infusion of Alpha-1 MP 
• Observation of the subject for at least 30 minutes after the 
intravenous infusion 
 
Week 7 
[Before intravenous infusion of Alpha-1 MP] 
• COPD exacerbation (refer to Section 4.6.1) 
• Adverse events 
• Concomitant medications 
• Laboratory tests (refer to Section 4.7.3) 
Blood samples: Alpha1-PI trough concentrations 

32 
• Vital signs (pulse rate, blood pressure, respiratory rate, and 
body temperature) immediately before the start of intravenous 
infusion of Alpha-1 MP 
 
[At the time of intravenous infusion of Alpha-1 MP] 
• Intravenous infusion of Alpha-1 MP 
• Vital signs (pulse rate, blood pressure, respiratory rate, and 
body temperature) immediately after the completion of 
intravenous infusion of Alpha-1 MP 
• Observation of the subject for at least 30 minutes after the 
intravenous infusion 
 
Week 8 
(At the start of the 
PK evaluation 
period) 
[Before intravenous infusion of Alpha-1 MP] 
• COPD exacerbation (refer to Section 4.6.1) 
• Adverse events 
• Concomitant medications 
• Laboratory tests (refer to Section 4.7.3) 
Blood samples: Alpha1-PI trough concentrations (To be 
used as a PK sample immediately before the start 
of intravenous infusion [refer to the description 
below]) 
• Vital signs (pulse rate, blood pressure, respiratory rate, and 
body temperature) immediately before the start of intravenous 
infusion of Alpha-1 MP 
 
[At the time of intravenous infusion of Alpha-1 MP] 
• Intravenous infusion of Alpha-1 MP 
• Vital signs (pulse rate, blood pressure, respiratory rate, and 
body temperature) immediately after the completion of 
intravenous infusion of Alpha-1 MP 
• Observation of the subject for at least 30 minutes after the 
intravenous infusion 
 
[PK sampling time points] 
• Immediately before the intravenous infusion 
• Immediately after the intravenous infusion (after flushing the 
infusion line with physiological saline) (at 0 hours) 
• At 15 minutes after completion of the intravenous infusion 
• At 2 hours after completion of the intravenous infusion 

33 
• At 4 hours after completion of the intravenous infusion 
• At 8 hours after completion of the intravenous infusion 
• At 24 ± 4 hours (1 day after completion of the intravenous 
infusion) 
• At 48 ± 4 hours (2 days after completion of the intravenous 
infusion) 
• At 120 hours ± 1 day (5 days after completion of the 
intravenous infusion) 
• At 168 hours ± 1 day (7 days after completion of the 
intravenous infusion) (Week 9) 
 
 
PK1, PK2, and 
PK5 
 
• COPD exacerbation (refer to Section 4.6.1) 
• Adverse events 
• Concomitant medications 
 
[PK sampling time points] 
After the intravenous infusion of Alpha-1 MP at the Week 8 
visit: 
• At 24 ± 4 hours (1 day after completion of the intravenous 
infusion) [PK1] 
• At 48 ± 4 hours (2 days after completion of the intravenous 
infusion) [PK2] 
• At 120 hours ± 1 day (5 days after completion of the 
intravenous infusion) [PK5] 
 
Week 9 
(At the completion 
of the PK 
evaluation 
period/clinical 
trial) 
At the Week 9 visit, subjects will be given an explanation about 
the extension trial (GTI1401-OLE) and asked whether or not 
they would like to enter the trial. 
 
For subjects intending to enter the extension trial and 
considered eligible for participation in the trial, the Week 9 visit 
will be the visit for study completion for GTI1401 as well as the 
screening/Week 1 visit for the extension trial. Subjects entering 
the extension trial will continue the treatment with intravenous 
infusions of 60 mg/kg of Alpha-1 MP weekly for at least 
another year for the purpose of evaluation of the safety of long-
term Alpha-1 MP treatment (subjects will be further asked 
whether or not they would like to continue the treatment at 
yearly intervals). 
 
• Physical examination (excluding breast and urogenital 
examination) 

34 
• Laboratory tests (refer to Section 4.7.3) 
Urine samples: Urinalysis 
Urine pregnancy test: To be performed only in 
women 
of 
childbearing 
potential 
Urinary cotinine level 
Blood samples: Alpha1-PI trough concentrations (To be 
used as a PK sample at 168 hours after 
completion of the intravenous infusion [7 
days after completion of the intravenous 
infusion at the Week 8 visit]) 
Blood chemistry, hematology 
 
• PFT (FEV1 and FVC) before and after administration of a 
bronchodilator (refer to Section 4.6.2) 
• COPD exacerbation (refer to Section 4.6.1) 
• Adverse events 
• Concomitant medications 
• Vital signs (pulse rate, blood pressure, respiratory rate, and 
body temperature) 
• 12-lead ECG (Note: For subjects to be enrolled in the 
GTI1401-OLE, this 12-lead ECG will be performed prior to 
the Alpha-1 MP infusion for GTI1401-OLE). 
 
 
 
4.7.2.3 
Visit for follow-up/study completion (Week 12) (for subjects not entering the 
extension trial [GTI1401-OLE]) 
Subjects not entering the extension trial (GTI1401-OLE) will visit the study center at 30 days 
(4 weeks) after completion of the last intravenous infusion of the investigational drug (Week 8) 
and at 3 weeks after the Week 9 visit to complete the follow-up/study completion examinations 
(Week 12). The date of Week 12 visit will be scheduled in the week specified in the protocol 
according to the actual date of the Week 1 (baseline) visit (±1 day). 
 
 

35 
 
Visit 
Trial Procedures and Evaluations 
Visit for follow-
up/study completion 
(Week 12) 
(for subjects not 
entering the 
extension trial 
[GTI1401-OLE]) 
• Physical examination (excluding breast and urogenital 
examination) 
• Laboratory tests (refer to Section 4.7.3) 
Urine samples: Urinalysis 
Urine pregnancy test: To be performed only in 
women of childbearing potential. 
Urinary cotinine level 
Blood samples: Blood chemistry, hematology 
• PFT (FEV1 and FVC) before and after administration of a 
bronchodilator (refer to Section 4.6.2) 
• COPD exacerbation (refer to Section 4.6.1) 
• Adverse events 
• Concomitant medications 
• Vital signs (pulse rate, blood pressure, respiratory rate, and 
body temperature) 
 
 
4.7.3 
Laboratory Tests and Testing Procedures 
Detailed procedures for laboratory tests are provided in the Laboratory Manual for this clinical 
trial. Table 3-1 summarizes the laboratory tests to be performed in the clinical trial. 
 
Table 4-2  Laboratory Tests, Procedure Name, Description, and Laboratory 
Test 
Parameter 
Laboratory 
Hematology 
Hemoglobin, hematocrit, platelet count, red blood 
cell count, white blood cell count and differential 
counts 
Central 
laboratorya 
Blood chemistry 
Sodium, potassium, creatinine, calcium, blood urea 
nitrogen, bicarbonate, albumin, AST, ALT, alkaline 
phosphatase, glucose, total protein, total bilirubin 
Central 
laboratorya 
Urinalysis 
pH, protein, glucose, blood and microscopic 
evaluation of blood cells 
Microscopy will be performed when indicated. 
Central 
laboratorya 
Urinary cotinine 
Cotinine level 
Local 
laboratory 

36 
Urine pregnancy 
test 
To be performed only in women of childbearing 
potential. 
Only women tested negative for pregnancy can 
continue the trial. 
Local 
laboratory 
Viral NAT 
Before the intravenous infusion of Alpha-1 MP at the 
Week 1 (baseline) visitb: 
Collection of samples for storage 
HAV RNA, HBV DNA, HCV RNA, HIV RNA, 
parvovirus B19 (B19V) DNA 
Central 
laboratorya 
Viral serologic 
test 
Before the intravenous infusion of Alpha-1 MP at the 
Week 1 (baseline) visitb: 
Collection of samples for storage 
Differentiation 
of 
HAV 
antibody 
(IgM/IgG), 
differentiation of HBV core antibody (IgM/IgG), 
HCV antibody, HIV-1/-2 +Group O antibody, 
differentiation of B19V antibody (IgM/IgG) 
Central 
laboratorya 
Alpha1-PI 
concentration 
Blood sample collected for the measurement of serum 
alpha1-PI concentration 
Central 
laboratorya 
a: The central laboratory will be at LSI Medience Corporation. 
b: Refer to Section 4.7.3.1 These blood samples will be stored until completion of the tests in this 
clinical trial (GTI1401) and the extension trial (GTI1401-OLE).  
 
 
4.7.3.1 
Viral safety assessment 
Virus safety retain samples (viral NAT and viral serology; see Table 4-2) will be collected at 
the Week 1 (Baseline) Visit prior to infusion and will be stored until all analyses in support of 
the this study (GTI1401) and the open-label extension study (GTI1401-OLE) are complete.  
These virus safety retain samples will be tested only if a subject exhibits clinical signs and 
symptoms consistent with a viral infection while participating in the study.  Additional 
samples for viral NAT and viral serology may be collected and tested if the subject exhibits 
clinical signs and symptoms consistent with a viral infection while participating in the study. 
 
 
4.7.4 
Measurement of Serum Alpha1-PI Concentrations 
All subjects will have a blood sample collected for the measurement of trough alpha1-PI 
levels at Weeks 1, 7 and 8 (prior to the infusions of Alpha-1 MP) and through Week 9 for PK 
evaluation. All samples for measurement of alpha1-PI concentration will be analyzed using an 
antigenic content assay that is validated according to current regulatory and industry 
expectations.   

37 
4.7.5  Volume of Blood Sampling 
For laboratory tests (hematology and Blood chemistry), viral tests (Viral NAT and Viral serologic 
test) and alpha1-PI concentration (alpha1-PI trough concentration and samples for PK measurement), the 
following volume of blood per a subject will be taken throughout the study. 
 
Blood sampling 
Volume (mL) 
Times 
Total volume (mL) 
Laboratory tests – Screening 
9 
1 
9 
Laboratory tests – Week 1 to 
Study Completion 
6 
4 
24 
Viral tests 
34.5 
1 
34.5 
alpha1-PI concentration 
4 
12 
48 
Grand Total over 8 weeks 
115.5 
 
 
 
4.8 
Screening Failures 
Screening evaluations will be used to determine the eligibility of each subject for enrollment.  
Subjects who fail to meet eligibility criteria during screening evaluations will be considered 
screen failures and will not participate in the study. 
 
 
 
 
 

38 
5 
ADVERSE EVENTS (AEs) 
5.1 
Warnings/Precautions 
Alpha-1 MP is human alpha1-PI produced by a modification of the Prolastin process and is 
approved as Prolastin-C for 60 mg/kg weekly IV administration in the US, Canada, Columbia, 
Argentina, and Turkey.  For complete Alpha-1 MP safety information, refer to the current 
Alpha-1 MP IB.   
Immunoglobulin E-mediated anaphylactic reactions to plasma-derived, alpha1-PI preparations 
may occur in recipients (27) with or without documented prior histories of severe allergic 
reactions to blood products.  Very rarely, an anaphylactoid reaction may occur in subjects 
with no prior history of severe allergic reactions to plasma-derived alpha1-PI administration 
(28).  
Individuals with selective IgA deficiency should not receive alpha1-PI since these subjects 
may experience severe reactions, including anaphylaxis, to IgA which may be present in the 
preparation.   
It is not known whether alpha1-PI is excreted in human breast milk, can cause fetal harm 
when administered to pregnant women, or can affect reproductive capacity.  Subjects who 
are pregnant must not enter the study, and subjects who become pregnant during the study 
must be withdrawn. 
Overdose with plasma-derived alpha1-PI has not been reported.  In an overdose situation, 
supportive care should be given and the subject managed accordingly.   
The manufacturing process for all Grifols plasma-derived products begins with the screening 
of plasma donors and the testing of individual plasma donations and plasma manufacturing 
pools for specific markers of viral infection.  To provide additional assurance of the 
pathogen safety margin of the final product, in vitro laboratory spiking studies were 
performed to validate the capacity of key steps of the Alpha-1 MP manufacturing process to 
inactivate and/or remove pathogenic agents.   
 
5.2 
Monitoring of Adverse Events 
Subjects must be carefully monitored for AEs.  This monitoring includes clinical and 
laboratory tests and physical signs.  Adverse events should be assessed in terms of their 
seriousness, severity, and causal relationship to the investigational product. 
 

39 
5.3 
Definitions and Handling of Adverse Events 
5.3.1 
Definition of Adverse Events (AEs) 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product or study treatment and which does not necessarily 
have a causal relationship with this administration.  An AE can therefore be any unfavorable 
and unintended sign (including any abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
 
5.3.2 
Definition of Suspected Adverse Drug Reactions (ADRs) 
All noxious and unintended responses to a medicinal product or study treatment related to any 
dose should be considered suspected ADRs.  The phrase “responses to a medicinal product” 
means that a causal relationship between a medicinal product or study treatment and an AE is 
at least a reasonable possibility, that is, the relationship cannot be ruled out.   
 
5.3.3 
Causal Relationship of Adverse Events 
The Investigator is required to provide a causality assessment for each AE reported to the 
Sponsor.  The Sponsor will consider the Investigator’s causality assessment. Assessment of 
the causal relationship to the study drug will be made according to the following 
classifications based on Karch FE, et al. (29): 
Definite: An event that follows a reasonable temporal sequence from administration of the 
treatment or in which the treatment level has been established in body fluids or tissues, that 
follows a known response pattern to the suspected treatment, and that is confirmed by 
improvement on stopping the treatment (dechallenge), and reappearance of the event on 
repeated exposure (rechallenge). 
Probable: An event that follows a reasonable temporal sequence from administration of the 
treatment that follows a known response pattern to the suspected treatment, that is confirmed 
by dechallenge, and that could not be reasonably explained by the known characteristics of 
the patient’s clinical state. 
Possible: An event that follows a reasonable temporal sequence from administration of the 
treatment, that follows a known response pattern to the suspected treatment, but that could 
have been produced by the patient’s clinical state or other modes of therapy administered to 
the patient. 

40 
Doubtful/Unlikely: An event that follows a reasonable temporal sequence from 
administration of the treatment; that does not follow a known response pattern to the 
suspected treatment; but that could not be reasonably explained by the known characteristics 
of the patient’s clinical state. 
Unrelated: Any event that does not meet the criteria above. 
The operational tool to decide the AE causal relationship is based on algorithms by Karch FE 
et al. and Naranjo CA et al. (29,30). 
When an AE is classified, assessing causal relationship by the Investigator, as “definitive”, 
“probable”, “possible” or “doubtful/unlikely”, the event will be defined as a suspected ADR.  
When the causal relationship is labeled “Unrelated”, then it will be considered that the AE is 
not imputable to the study treatment and it is not a suspected ADR. 
In addition, when a causal relationship between the study treatment and the AE cannot be 
ruled out by the Investigator and/or Sponsor, it means that the AE cannot be labeled 
“unrelated”. 
For any subject, all AEs that occur at any time from the beginning of Alpha-1 MP 
administration until the final visit of the clinical trial will be considered as TEAEs. 
 
5.3.4 
Severity of Adverse Events/ Suspected Adverse Drug Reactions 
AEs and suspected ADRs will be classified depending on their severity according to the 
following definitions: 
Mild: 
an AE which is well tolerated by the subject, causing minimum degree of malaise and 
without affecting normal activities. 
Moderate:  an AE that interferes with the subject’s normal activities. 
Severe:  
an AE that prevents the subject from performing their normal activities. 
 
AE and suspected ADR severity gradation must be distinguished from AE and suspected 
ADR seriousness gradation, which is defined according to event consequence. For example, 
headache can be mild, moderate, or severe but unusually is serious in all these cases. 
The Investigator will be responsible for assessing the AE and suspected ADR severity during 
the clinical trial, taking into account current criteria included in this section. 
 
 

41 
5.3.5 
Expectedness of Adverse Events/ Suspected Adverse Drug Reactions 
An AE or suspected ADR is considered “unexpected” if the nature, seriousness, severity or 
outcome of the reaction(s) is not consistent with the reference information. The expectedness 
of an event shall be determined by the Sponsor according to the reference document (i.e., IB).  
Events not listed in the IB are considered “unexpected” and those listed are considered 
“expected.” When new serious ADRs (potentially related SAEs)  are received, it is the 
Sponsor’s responsibility to determine whether the events are “unexpected” for expedited 
safety reporting purposes. 
 
5.3.6 
Seriousness of Adverse Events/Adverse Drug Reactions; Serious 
Adverse Events (SAEs) 
An AE or suspected ADR is considered “serious” if, in the view of either the Investigator or 
Sponsor, it results in any of the following outcomes:  
1. Death 
2. Life-threatening AE (life-threatening in the definition of “serious” refers to an event in which 
the subject 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) 
3. In-patient hospitalization or prolongation of existing hospitalization 
4. A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions  
5. A congenital anomaly/ birth defect 
6. An important medical event (important medical event in the definition of “serious” refers to 
those events which may not be immediately life-threatening, or result in death, or hospitalization, 
but from medical and scientific judgment may jeopardize the subject or/and may require medical 
or surgical intervention to prevent one of the other outcomes listed above) 
 
This definition permits either the Sponsor or the Investigator to decide whether an event is 
“serious”.  If either the Sponsor or the Investigator believes that the event is serious, the 
event must be considered “serious” and evaluated by the Sponsor for expedited reporting.  
A distinction should be drawn between serious and severe AEs. The term “severe” is used to 
describe the intensity (severity) of a specific event; the event itself, however, may be of 
relative minor medical significance (such as severe headache). This is not the same as 
“serious”, which is defined on subject/event outcome or action criteria usually associated with 
events that pose a threat to a subject’s life or functioning. Seriousness (not severity) is a 
medical term while severity is a subjective term.  

42 
According to the medical criteria, an AE or a suspected ADR can be classified as serious, 
although it does not fulfill the conditions fixed in this section, if it is considered important 
from a medical point of view. 
 
5.3.7 
Recording of Adverse Events 
All AEs and SAEs occurring after the subject has signed the ICF through the End of Study 
must be fully recorded in the subject’s CRF and SAE form if applicable.  If no AE has 
occurred during the study period, this should also be indicated in the CRF. 
It is responsibility of the Investigator to ensure that AEs are appropriately recorded. 
At each visit, AEs will be elicited by asking the individual a non-leading question such as 
“Do you feel different in any way since the last visit?”.  Moreover, AEs will also be 
collected through directly observed events or spontaneously volunteered by the subject.  
Clearly related signs, symptoms and abnormal diagnostic procedures should preferably be 
grouped together and recorded as a single diagnosis or syndrome wherever possible. 
The following variables must be recorded on the AE CRF entry: 
1. The verbatim term (a diagnosis is preferred) 
2. Date/time of onset 
3. Date/time of resolution 
4. Severity (mild, moderate, severe) 
5. Causality (unrelated, doubtful/unlikely, possible, probable, definite)* 
6. Seriousness (yes, no) 
7. Action taken (with regard to investigational product) 
8. Other action (to treat the event) 
9. Outcome and sequel (follow-up on AE) 
*Causality assessment will be only made when the AE occurs after the subject has 
initiated at least one infusion of the investigational product. Any AE occurring before 
subject's exposure to investigational product will be always labeled as "unrelated". 
 
In addition to the Investigator’s own description of the AEs, each AE will be encoded by the 
Sponsor (or Contract Research Organization [CRO]) according to the Medical Dictionary for 
Regulatory Activities (MedDRA®). 
For example, a laboratory test abnormality considered clinically relevant, e.g., causing the 
subject to withdraw from the study, requiring treatment or causing apparent clinical 
manifestations, or judged relevant by the Investigator, should be reported as an AE.  Each 

43 
event must be described in detail along with start and stop dates, severity, relationship to 
investigational product, action taken and outcome. Each event must be adequately supported 
by documentation as it appears in the subject’s medical or case file. 
 
5.3.8 
Method and Duration of Follow-up of Subjects Experiencing Adverse 
Events 
In so far as is possible, all individuals will be followed up until the AE or suspected ADR has 
been resolved.  If an AE/suspected ADR/SAE is present when the subject has completed the 
study, the course of the event must be followed until the final outcome is known, or the event 
has been stabilized and no further change is expected and the Investigator decides that no 
further follow-up is necessary. 
 
5.3.9 
Events of Special Interest 
All COPD exacerbations occurring during the study will be recorded.  Each subject will be 
assessed for signs and symptoms of exacerbations at each study visit (Section 4.6.1).  Given 
that COPD exacerbations are part of the natural history of AATD, COPD exacerbations will 
not be reported as AEs unless a COPD exacerbation meets the criteria of a SAE (Section 
5.3.6).  If an exacerbation meets criteria for a SAE, it will be reported as such (Section 
5.4.1), and the standard of care should be followed.  Results from standard of care should be 
obtained and reported. 
 
 
5.4 
Reporting of Serious Adverse Events (SAEs)/Pregnancies 
5.4.1 
Reporting of Serious Adverse Events (SAEs) 
The investigator must report all serious adverse events (SAEs) that occur up to the end of this 
clinical trial after each subject has signed the informed consent form for participation in this 
clinical trial (refer to Section 5.3.6). SAEs should be reported by using designated report forms. 
If the investigator becomes aware of an SAE, the investigator must send a signed and dated 
SAE report form that completely describes the SAE to the sponsor within 24 hours. 
 
Each SAE should be followed up until it resolves or becomes stable. After initial reporting of 
an SAE, all related information on the follow-up and outcome of the SAE should be provided 
for the CMIC Co., Ltd. (CMIC) to which the sponsor entrusts the pharmacovigilance duties for 
this clinical trial. as instructed below via the SAE report form (see Appendix 3.1 and 3.2) in a 
timely manner (within 24 hours of both of identification for already obtained information and 

44 
awareness for new related information). In addition, additional information/report may be 
requested by the sponsor or CMIC HOLDINGS Co., Ltd. (CHD) to which the sponsor entrusts 
the development-related duties for this clinical trial. 
 
All SAE report forms should be submitted by email to the Eastern Japan Pharmacovigilance 
Division of the CMIC Co., Ltd. (CMIC), which is the devision of the affiliate company of CHD 
in responsible for pharmacovogilance, as shown below. 
 
Eastern Japan Pharmacovigilance Division, CMIC Co., Ltd 
Email: 
 
FAX: 
 (back-up only) 
 
 
After receiving the SAE information, CMIC will send a provisional assessment in English to 
both Grifols Global Pharmacoviligence and Grifols Japan within 24 hours. The following 
required information should be provided to Grifols Global Pharmacoviligence to perform the 
preliminary reportability assessment: 
• Day 0 of SAE notification (Actual date when CMIC receives the SAE notification from 
the investigator) 
• Patient (ID or subject no., gender, and date of birth) 
• SAE verbatim term 
• SAE seriousness criteria 
• Relationship of the SAE to the study drug 
• SAE onset date 
• Outcome of the SAE 
• Brief summary of the SAE/additional details (if applicable) 
 
CMIC will translate the source documents to English and send them to Grifols Global 
Pharmacoviligence and Grifols Japan by day 2 post-SAE notification for unexpected fatal or 
life-threatening cases/day 7 post-SAE notification for all other cases. Grifols Global 
Pharmacoviligence will process the case in the Grifols safety database and create a narrative 
and Company assessment. The CIOMS report will be provided by Grifols Global 
Pharmacoviligence to CMIC and Grifols Japan by day 4 post-SAE notification for unexpected 
fatal or life-threatening cases)/day 10 post-SAE notification for all other cases. CMIC will 
translate the CIOMS report to Japanese and create the appropriate files for submission to the 
PMDA. After approval by Grifols Japan, CMIC will transfer the final files to Grifols Japan 
for Grifols Japan to submit the case to the authorities. Grifols Japan will send the 
acknowledgment of the submission to CMIC and Grifols Global Pharmacoviligence. 
 

45 
5.4.2 
Reporting of Pregnancies 
Pregnancy itself is not an “adverse event,” but if a female subject becomes pregnant during the 
trial period, the subject should be withdrawn from the trial (administration of the investigational 
drug should be discontinued immediately) and the subject should be followed up to collect 
information on the exposure to the investigational drug in regard to the gestation and pregnancy 
status. The investigator should report all pregnancies that occur up to the end of this clinical 
trial after each subject has signed the informed consent form for participation in this clinical 
trial to the sponsor. 
 
Any pregnancy that is not confirmed at the entry to this clinical trial and occurs during the trial 
period will not be regarded as an adverse event unless it is suspected of being related to the 
investigational drug. However, if a female subject or the partner of a male subject becomes 
pregnant, the investigator should complete a pregnancy report (see Appendix 3.3) form and 
send it to the sponsor as soon as possible. A copy of the report form should be retained at the 
study center for the purpose of follow-up until completion of the pregnancy (delivery, 
miscarriage, abortion). 
 
For any pregnancy resulting in a live birth (delivery of a neonate), the neonate should be 
followed up until 1 month after birth. Any deformity, complication, abnormal outcome, or birth 
defect observed in the neonate must be reported as an SAE within 24 hours of awareness by the 
investigator or those involved in the trial. 
 
 
6. TRIAL 
DISCONTINUATION 
CRITERIA 
AND 
PROCEDURES FOR INDIVIDUAL SUBJECTS 
6.1 
Discontinuation Criteria 
The investigator or subinvestigator will discontinue a subject who meets any of the criteria for 
discontinuation/dropout shown below and cannot continue the trial, and take appropriate action 
for the benefit of the subject. If a subject is withdrawn from the trial, the investigator will ask 
the subject to visit the study center for study termination and follow up any adverse event that 
has not been resolved. 
The investigator or subinvestigator will enter the date of discontinuation, the reason for 
discontinuation, and comments in a case report form. The date of discontinuation should be the 
day of determination or confirmation of discontinuation by the investigator or subinvestigator 
for subjects . 
 

46 
(1) 
When a subject or the subject’s legally acceptable representative requests 
withdrawal of consent or discontinuation of the trial 
(2) 
When a subject develops any complication, or when a subject has any medical 
condition that may pose unnecessary risks or harm in the subject because of its 
severity, duration, or the need for changes in therapy in the opinion of the 
investigator 
(3) 
When a subject develops an adverse event, which requires discontinuation of the 
trial in the opinon of the investigator or subinvestigator 
(4) 
When a subject develops HAV, HBV, HCV, B19V, or HIV infection during the 
trial period. When a subject shows clinical signs or symptoms suggestive of viral 
infection and is confirmed by viral safety assessment to have developed any of the 
infections described above 
(5) 
When a subject has a positive test for urinary cotinine due to smoking 
(6) 
When a subject has exacerbated symptoms of an underlying disease, which requires 
discontinuation of the trial in the opinon of the investigator or subinvestigator 
(7) 
When a female subject has become pregnant (refer to Section 5.4.2) 
(8) 
When a subject fails to visit the study center for required tests, and it is difficult to 
continue the trial in the opinion of the investigator or subinvestigator 
(9) 
When a subject is found in significant violation of a protocol 
(10) 
Other cases which require discontinuation of the trial in the opinon of the 
investigator or subinvestigator 
(11) 
When the sponsor informs of discontinuation of the entire trial or discontinuation 
of the trial in a study center 
 
 
6.2 
Discontinuation Procedures 
When discontinuing this clinical trial according to the discontinuation criteria during the period 
between the start of investigational drug administration and the completion of the follow-up 
period, the investigator or subinvestigator should follow the procedures below: 
 
(1) 
The investigator or subinvestigator should provide appropriate medical care or take 
appropriate measures to ensure the safety of the subject. 
(2) 
The investigator or subinvestigator should investigate the contents of the 
investigation, observation, and examination performed at the time of trial 
discontinuation, the date of discontinuation, the reason for discontinuation, the 
action taken after discontinuation, and the course after discontinuation, and enter 
the information in a case report form. 

47 
(3) 
When administration of the investigational drug is discontinued due to the 
development of an adverse event, the investigator or subinvestigator should follow 
the procedures described in Section 5.3 “Definitions and Handling of Adverse 
Events (AEs).” 
(4) 
If a subject who has received Alpha-1 MP at any dose discontinues this clinical 
trial early, this subject will not be replaced by a new subject. 
(5) 
If a subject who has received Alpha-1 MP at any dose discontinues this clinical 
trial early, this subject will be asked to return to the study center for the follow-
up/study completion procedures scheduled at the Week 12 visit (refer to Section 
4.7.2.3 “Visit for follow-up/study completion” and Appendix 1). This visit should 
be made at the timing as close as possible to 4 weeks (i.e., 30 days) after the last 
dose of the investigational drug in the subject. If no follow-up investigation can be 
made for reasons such as “failed to return,” the investigator or subinvestigator 
should contact the subject whenever possible and enter the method for 
communication, the date of communication, the condition of the subject, and the 
reason for not having returned in a case report form. If attempting to comminucate 
with the subject but unable to identify the location of the subject, the investigator 
or subinvestigator should also enter the fact, the method for communication, and 
the date of communication in a case report form. 
 
 

48 
7. TRIAL COMPLETION, DISCONTINUATION, OR 
INTERRUPTION 
7.1 
Completion of the Clinical Trial 
(1) 
When this clinical trial is completed, the investigator should report the completion 
of the trial in writing to the head of each study center. 
(2) 
When receiving the report of the completion of the trial, the head of each study 
center should inform the institutional review board and the sponsor of the fact in 
writing. 
 
 
7.2 
Discontinuation or Interruption of the Clinical Trial 
The sponsor, the institutional review board, and/or the regulatory authority may discontinue or 
interrupt the entire clinical trial or the trial in a specific study center.  
 
7.2.1 
Discontinuation or Interruption of the Clinical Trial by the Sponsor 
The sponsor should discontinue or interrupt the entire clinical trial in the following cases: 
(1) 
If the development of the investigational drug is discontinued 
(2) 
If there is any ethically or medically unavoidable reason, such as to ensure the 
safety of subjects 
 
 
7.2.2 
Discontinuation or Interruption of the Clinical Trial at a Study Center 
(1) 
If the sponsor becomes aware of any serious noncompliance*1 or persistent 
noncompliance*2 related to the GCP Ordinance, the protocol, or the clinical trial 
contract by an investigator or subinvestigator or a study center through monitoring 
and/or auditing, and considers that such noncompliance has interfered with the 
proper conduct of the trial (except for the cases stipulated in Article 46 of the GCP 
Ordinance), the sponsor should cancel the clinical trial contract with the study 
center and discontinue the trial at the study center. 
*1 Serious noncompliance refers to any violation that may compromise the human 
rights, safety, and welfare of subjects and the reliability of this clinical trial. 
*2 Persistent noncompliance refers to any repeated noncompliance to which no 
appropriate action has been taken in spite of the request for improvement by the 
sponsor irrespective of its seriousness. 
(2) 
The sponsor should discuss whether or not to continue this clinical trial in all or 
some of the study centers in the following cases: 

49 
1) If a study center(s) cannot respond to any necessary modification in the protocol 
2) If the sponsor cannot accept an approval condition(s) proposed by the head of a 
study center based on the opinion of the institutional review board of the study 
center 
3) If the institutional review board of a study center considers that the clinical trial 
should not be continued and the head of the study center requests discontinuation 
of the trial 
(3) 
If deciding to discontinue or interrupt this clinical trial, the sponsor should 
immediately report the fact and the reason for discontinuation or interruption to the 
head of a study center. The head of the study center should immediately report the 
fact to the investigator and the institutional review board in writing. 
(4) 
If judging that it is absolutely necessary to discontinue or interrupt the clinical trial 
at a study center for any ethically or medically unavoidable reason, such as to 
ensure the safety of subjects, the investigator may discontinue or interrupt the trial 
at the study center. At this time, the investigator should immediately report to the 
head of the study center in writing, and the head of the study center should 
immediately report to the sponsor and the institutional review board in writing. 
(5) 
In the case of discontinuation of the clinical trial or withdrawel of a study center, 
the investigator should return all trial-related materials (excluding documents to be 
continously retained at the study center) to the sponsor. The investigator should 
retain all the documents to be continously retained at the study center until a 
notification of destruction is received from the sponsor. 
(6) 
For the procedures for discontinuation of the clinical trial in invidual subjects, refer 
to the procedures stipulated in Section 6. “Trial Discontinuation Criteria and 
Procedures for Individual Subjects.” 
 
 

50 
8 
STATISTICAL METHODS AND DETERMINATION 
OF TARGET SAMPLE SIZE 
8.1 
Statistical Analysis Plan 
Data handling and evaluation procedures will be described in the Statistical Analysis Plan 
(SAP). 
 
 
8.1.1 
Analysis Sets 
The Safety Population will include all subjects who receive any amount of Alpha-1 MP. 
 
 
8.1.2 
Descriptive Statistics 
Demographic and baseline characteristics, safety variables, and alpha1-PI levels will be summarized using 
the safety population.  For continuous variables, mean, standard deviation, median, minimum, and 
maximum will be provided.  For categorical/qualitative data, absolute and relative frequency counts will be 
provided. 
All subject data will be presented in data listings. 
 
8.1.3 
Statistical Analysis of PK Parameters 
Descriptive statistics, including n, mean, standard deviation (SD), % coefficient of variation (CV), median, 
minimum, and maximum, will be calculated for each PK parameter determined from alpha1-PI concentration 
data by the antigenic content assay. All PK parameters will be calculated using non-compartmental methods 
with WinNONLIN software (Pharsight Corporation, Cary, NC), which will be further described in the SAP.      
 
 
8.2 
Determination of Target Sample Size 
The targeted sample size is a minimum of 3 subjects. Sample size was chosen based on 
clinical considerations and the number of available Japanese patients with AATD, not on a 
formal sample size calculation. 
 

51 
9. CASE REPORT FORMS 
9.1 
Completion and Reporting of Case Report Forms 
(1) 
After completion of the treatment perod or the follow-up period in each subject, 
the investigator or subinvestigator should immediately complete a case report form 
according to the “Procedure for Completion, Modification, or Revision of Case 
Report Forms” provided by the sponsor, and submit the form with a signature or 
name and seal to the sponsor. When this clinical trial is discontinued, the 
investigator or subinvestigator should immediately complete a case report form for 
each subject. The investigator should retain copies of the completed forms. 
(2) 
 A clinical trial collaborator(s) appointed from the “List of Subinvestigators and 
Clinical Trial Collaborators” by the head of a study center is allowed to translate 
any date from source documents to case report forms. The investigator should 
check all entries on each case report form, confirm that none of the case report 
forms include any problems, and sign or affix the investigator’s name and seal on 
them with the date of confirmation. 
 
 
9.2 
Guidance for Completion of Case Report Forms 
(1) 
Subject identification codes should be used to identify individual subjects. 
(2) 
Case report forms should be completed using a pen or ballpoint pen (black or blue 
ink). 
(3) 
Any test report or photograph should be affixed on a case report form with a tally 
impression. 
(4) 
For any observation, investigation, or examiantion that has not been performed, 
this item should beslash mark 
(5) 
Every entry on a case report form should be consistent with its source document. 
 
 
9.3 
Identification of Data to be Recorded Directly on Case 
Report Forms and to be Considered to be Source Data 
Data to be recorded directly on case report forms and to be considered to be source data include 
the following: 
 
[Assessment results and comments] 
 
Results of the assessments specified in the protocol and comments 
 
Comments about subject demographics 

52 
 
Results of the assessments of severity, seriousness, and causal relationship of 
adverse events, and comments or reasons 
 
Other comments to complement data 
 
 

53 
10. PROTOCOL 
ADHERENCE, 
DEVIATIONS 
OR 
MODIFICATIONS, AND AMENDMENTS 
10.1 Protocol Adherence 
This clinical trial will be conducted in compliance with the protocol based on the agreement 
between the investigator and the sponsor. 
(1) 
After examining the ethical and scientific validity of the contents of the 
protocol, the investigator will prove that he/she has agreed on the contents of 
the protocol and agreed to adhere to the protocol by affixing his/her signature, 
or his/her name and seal, with a date on a written separate agreement along 
with the sponsor’s signing oficial. 
(2) 
The investigator and the sponsor will submit the approved protocol to the head 
of the study center to obtain the approval of the protocol from the institutional 
review board. 
(3) 
The sponsor will obtain documents related to the instructions and decisions of 
the head of the study center (including a copy of a dated approval letter of the 
institutional review board). Approval of the conduct of the clinical trial by the 
head of the study center and the institutional review board will be regarded as 
approval of the protocol at the study center. 
(4) 
The sponsor should not supply the study center with the investigational drug 
before concluding a trial contract based on the documents related to the 
instructions and decisions of the head of the study center. 
(5) 
If the investigator is replaced by a new investigator or if any amendment is 
made to the protocol, the new investigator will prove that he/she has agreed 
on the contents of the protocol and agreed to adhere to the protocol again 
through the above procedures. 
 
 
10.2 Protocol Deviations or Modifications 
(1) 
The investigator or subinvestigator should not implement any deviation from 
the protocol or any modification to the protocol without obtaining prior written 
agreement between the investigator and the sponsor and written approval 
based on prior review by the institutional review board, except when there are 
medically unavoidable reasons, such as the need to eliminate immediate 
hazards to the subjects, or when the modification(s) involves only 
administrative aspects of the trial. 
(2) 
The investigator or subinvestigator will record all deviations from the protocol. 

54 
(3) 
The investigator or subinvestigator will prepare a document explaining the 
reason for any noncompliance with the protocol for medically unavoidable 
reasons, such as the need to eliminate immediate hazards to the subjects, 
submit the document to the sponsor, and retain a copy of the document. 
(4) 
When considering it appropriate to make an amendment(s) to the protocol 
based on the contents of a deviation(s) or a modification(s) and the reasons for 
them, the investigator may recommend such amendment to the Sponsor. 
 
 
10.3 Protocol Amendments 
(1) 
The sponsor will discuss with the medical expert and make a modification(s) 
or an amendment(s) to the protocol as needed in the following cases: 
1) When the sponsor becomes aware of any information on the quality, 
efficacy, or safety of the investigational drug or other important information 
that would interfere with the proper conduct of the clinical trial. 
Independently from the protocol amendments discussed here, the sponsor 
may make a modification(s) or an amendment(s) to protocol attachments 
regarding minor matters not related to the core of the protocol (e.g., trial 
organization name, administrative matters). 
2) When a modification(s) is made to the protocol for medically avoidable 
reasons. 
3) When the head of the study center recommends a protocol amendment based 
on the opinion of the institutional review board of the study center 
 
(2) 
Approval of protocol amendment 
When any amendment is made to the protocol, approval for the protocol 
amendment will be obtained from the study center according to Section 10.1 
“Protocol Adherence.” 
 
 

55 
11 TRIAL MANAGEMENT 
11.1 Investigator, Other Trial Staff, External Committees 
The information on the major trial staff members involved in the conduct of this clinical trial 
(the names and addresses of the investigator, monitors, clinical laboratory(ies), other technical 
department(s) and/or institutions, as well as members of a clinical trial committee if established, 
etc.) is provided in Section 2 “Study Administrative Structure.” 
 
The investigator and the trial staff members will receive appropriate training for this clinical 
trial study group, the kick-off meeting at the study center, or other individual institutions. 
 
 
11.2 Quality of Data 
11.2.1 
Sponsor 
11.2.1.1 
Quality Control 
The sponsor will apply quality control based on standard operating procedures to each stage of 
data handling to ensure that all trial-related data are reliable and have been processed correctly. 
 
11.2.1.2 
Quality Assurance 
The sponsor will implement monitoring and auditing according to the agreed monitoring 
procedure and auditing procedure stipulated by the sponsor to conduct this clinical trial in 
compliance with the protocol, the standard operating procedures, the standards stipulated in 
Clause 3 of Article 14 (Marketing Approval of Drugs, etc.) and Article 80-2 (Handling of 
Clinical Trials) of the Law for Ensuring the Quality, Efficacy, and Safety of Drugs and Medical 
Devices (hereinafter referred to as the Drugs and Medical Devices Law), and the GCP 
Ordinance (including revised ordinances and related notifications). The clinical research 
associate (CRA) will visit each study center periodically to verify whether the clinical trial is 
being conducted in compliance with the protocol, GCP, and other legal requirements described 
above. The means to confirm that the case report forms have been adequately and clearly 
completed at each study center include cross-checking the case report form entries with source 
documents and clarification of administrative matters. The verification method using data query 
is described in the Data Management Plan. 
 
 
11.2.2 
Study Centers 
The study centers will apply quality control based on standard operating procedures to conduct 
this clinical trial and generate, record, and report data in compliance with the GCP Ordinance 

56 
and the protocol. In addition, the study centers will undergo investigations by representatives 
of the Minister of Health, Labour and Welfare or the sponsor (inspection, direct access, etc.) for 
the purpose of investigation and verification of records, etc. to be retained at the study centers. 
 
 
11.3 Management of Documents 
Trial data will be recorded on the case report forms and updated at all times by the clinical trial 
collaborator directly responsible for the trial data at the study center. Entries on the case report 
forms must be able to be verified against source documents. For any data to be recorded directly 
on case report forms, the case report forms are considered to be source data. 
 
The representative of the sponsor or the person appointed by the sponsor will periodically 
monitor the data included in the case report forms at each study center, and compare them with 
source documents to verify the integrity of the data. Examples of source documents include 
medical records of individual subjects, which are separate documents from the case report forms. 
 
All adverse events and serious adverse events must be recorded. All serious adverse events will 
be recorded on SAE forms. Original forms of recorded SAE will be retained at each study center, 
and copies of the original forms will be provided for designated personnel according to the 
procedures at each study center. 
 
 
11.4 Retention of Records 
11.4.1 
Retention of Records at the Study Center 
The person responsible for record retention appointed by the head of the study center will retain 
the following essential documents and records that are required to be retained at the study center 
by GCP at the place designated by the study center until at least the date of marketing approval 
granted for the test drug. If the sponsor discontinues the clinical trial, the person responsible for 
record retention will retain these essential documents and records until the date on which 3 
years have elapsed after the day of discontinuation. However, if the sponsor needs retention for 
a longer period of time than the above periods, the study center should discuss the retention 
period and the retention method with the sponsor. 
 
[Documents to be retained by the institutional review board] 
 
Written procedures of the institutional review board 
 
Member list 
 
Documents reviewed by the institutional review board (protocol, case report forms, 

57 
written information and informed consent forms, investigator’s brochure, list of 
subinvestigators and clinical trial collaborators, documents explaining payments 
related to the clinical trial, documents explaining compensation for subject health 
injury, reports on the safety of subjects, etc., other documents considered 
necessary by the investigator or the institutional review board) 
 
Notifications sent from the head of the study center or the investigator to the 
institutional review board (notifications regarding clinical trial discontinuation, 
interruption, completion) 
 
Minutes of the institutional review board (written opinions, etc. of the evaluation 
committee used as reference at reviews will be also retained) 
 
[Documents to be retained by the clinical trial office or the investigator] 
 
Procedures for conducting the clinical trial 
 
Source documents 
 
Protocol 
 
Written agreements, informed consent/assent forms (consent document for 
investigation for definitive diagnosis and consent document for participation of 
the clinical trial), other documents prepared by the medical institution personnel 
as stipulated by the GCP Ordinance 
 
Documents obtained from the institutional review board 
 
Documents obtained as stipulated by the GCP Ordinance 
 
Records about the management of the investigational drug and other trial-related 
records 
 
The investigational drug is categorized as a specified biological product; therefore, each study 
center should retain the following records for the period stipulated by the Drugs and Medical 
Devices Law (for 20 years) by affixing the sticker accompanied by the investigational drug to 
a blood product management record that is used to manage other blood products. 
[Information to be retained as a specified biological product] 
 
Manufacturing number 
 
Dates of administration 
 
Name and address of each patient 
 
 
11.4.2 
Retention of Records by the Sponsor 
The person responsible for record retention appointed by the sponsor will retain the following 
essential documents and records that are required to be retained by the sponsor by GCP 
according the sponsor’s procedures until the date on which 5 years have elapsed after the day 

58 
of marketing approval granted for the test drug. If the sponsor discontinues the clinical trial, the 
person responsible for record retention will retain these essential documents and records until 
the date on which 3 years have elapsed after the day of discontinuation. 
The investigational drug is categorized as a specified biological product; therefore, the sponsor 
should retain the following records for the period stipulated by the Drugs and Medical Devices 
Law (for 30 years). 
[Information to be retained as a specified biological product] 
 
Records about the manufacturing of the investigational drug 
 
Name and address of the study centers 
 
Records of distribution of the investigational drug to each study center (including 
manufacturing number) 
 
Records of disposal of the investigational drug 
 
11.4.3 
Retention of Records at Other Organizations 
The central laboratory and other organizations involved in this clinical trial will retain written 
agreements and documents to be retained stipulated in the written agreements until at least the 
day of marketing approval for the test drug. If the sponsor discontinues the clinical trial, these 
organizations will retain the written agreements and the documents to be retained stipulated in 
the written agreements until the date on which 3 years have elapsed after the day of 
discontinuation. Records should be retained appropriately at each organization according to the 
written operating procedures confirmed by the sponsor. 
 
 
11.5 Access to Information through Monitoring 
Trial data will be recorded on the case report forms and updated at all times by the clinical trial 
collaborator directly responsible for the trial data at the study center, and the integrity of the 
records will be verified by the clinical research associate (CRA). The representative of the 
sponsor or the CRA appointed by the sponsor may investigate the records. 
 
As stipulated in GCP, the CRA will verify whether the data recorded on the case report forms 
are consistent and in compliance with the protocol and whether the data entered are complete 
and consistent through direct access to source documents of the investigator. “Source 
documents” include subject files describing the date of visit, laboratory test results, concomitant 
treatment, vital signs, medical history, physical examination, adverse events, investigational 
drug distribution records, and other appropriate information, and the files should be retained 
separately from the case report forms. The investigator will agree to solve any issues detected 
through the CRA’s monitoring in cooperation with the CRA. 
 

59 
11.6 Access to Information for Auditing or Inspection 
The investigator and study centers should permit monitoring and auditing by the sponsor and 
inspection by the institutional review board and the regulatory authority, and provide direct 
access to all trial-related records including the source documents shown below. 
After discussing the method, timing, and schedule of direct access with the investigator or 
subinvestigator and the clinical trial office in advance, the CRA and the auditor will verify 
through direct access that all trial-related records have been sorted and retained appropriately 
in accordance with the “Good Clinical Practice (GCP Ordinance, Ministry of Health and 
Welfare Ordinance No.28 dated March 27, 1997)” and that the contents of the records are 
accurate and complete. 
 
11.6.1 
Source Documents 
In this clinical trial, the following documents and records will be defined as source documents: 
(1) Medical records (including laboratory test slips, etc.) 
(2) Records of diagnostic imaging (films, records, etc.) 
(3) Records of pulmonary function tests 
(4) Laboratory test reports 
(5) Prescription records 
(6) Medical procedure records 
(7) Subject screening list, etc. 
(8) Documents regarding investigational drug management 
(9) Informed consent documents 
(10) Other medical data that allow confirmation of entries on the case report forms 
 
 
 
 

60 
12. ETHICS 
12.1 Declaration of Helsinki 
This clinical trial will be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki “Ethical Principles for Medical Research Involving Human 
Subjects” adopted by the World Medical Association General Assembly in Helsinki in 1964 
and amended by the World Medical Association General Assembly in Fortaleza in 2013. 
 
 
12.2 Adherence to the Drugs and Medical Devices Law and the 
GCP Ordinance 
This clinical trial will be conducted in compliance with the standards stipulated in Clause 3 of 
Article 14 and Article 80-2 of Drugs and Medical Devices Law and the GCP Ordinance 
(including revised ordinances and related notifications). 
 
 
12.3 Institutional Review Board (IRB) 
12.3.1 Review of the Conduct of this Clinical Trial 
Prior to the conduct of the trial in each study center, the institutional review board will review 
the protocol, case report forms, and written information and informed consent forms, etc. as 
well as the appropriateness of the conduct of this clinical trial in terms of its ethical and 
scientific validity. 
 
 
12.3.2 Review of the Continuation of this Clinical Trial 
The institutional review board will review whether this clinical trial is being conducted 
appropriately at the study center at least once per year to examine whether or not to continue 
the trial. 
 
 
12.4 Informed Consent of Subjects 
12.4.1 Timing and Method of Obtaining Informed Consent 
The investigator or subinvestigator will fully explain the contents of this clinical trial to each 
subject by using a written information and informed consent form to obtain written consent of 
his/her own free will from the subject at the time of screening prior to any trial-related procedure, 
and provide the subject with a copy of the signed and dated informed consent form and the 

61 
written information used for explanation. 
If information becomes available that may be relevant to the subject’s willingness to continue 
participation in the trial, the investigator or subinvestigator will inform the subject of the 
information immediately, confirm whether the subject is willing to continue participation in the 
trial, and then obtain written consent of his/her own free will from the subject in the same 
manner. For subjects withdrawing their consent, the investigator or subinvestigator will ask 
them why they withdrew their consent and whether they agree on the use of their trial data 
obtained so far, and document the communication of this information. 
 
12.4.1.1 
Preparation of written information and informed consent form 
With the cooperation of the sponsor, the investigator or subinvestigator will prepare written 
information and an informed consent form to be used to obtain informed consent for the 
participation in this clinical trial from subjects. These documents will be revised as needed. 
These prepared or revised documents will be submitted to the sponsor and approval of the 
institutional review board of the study center will be obtained in advance. 
The written information should include the following: the objectives and methods of the clinical 
trial; the expected clinical benefits and risks or inconveniences for the subject; the availability 
of alternative treatments for the subject and their important potential benefits and risks; the 
statement that the subject may refuse to participate or withdraw from the clinical trial, at any 
time, without penalty or loss of benefits to which the subject is otherwise entitled; and other 
information. 
The language used in the written information should be understandable to the subject and should 
be as non-technical as possible, and the written information should not contain any language 
that causes the subject to waive or to appear to waive any legal rights, or that releases or appears 
to release the investigator, the subinvestigator, the clinical trial collaborator, the study center, 
or the sponsor from liability for negligence. 
It is necessary to combine written information with an informed consent form, and these 
documents should be prepared or revised in accordance with the GCP Ordinance (Ministry of 
Health and Welfare Ordinance No.28 dated March 27, 1997) and the ethical principles that have 
their origin in the Declaration of Helsinki. 
 
12.4.1.2 
Revision of the written information and informed consent form 
If any new important information becomes available that may be relevant to the subject’s 
consent, the investigator should immediately revise the written information and informed 
consent form, report the revision to the head of the study center, and obtain approval for the 
revised written information and informed consent form from the institutional review board in 
advance. In addition, the investigator or subinvestigator should also inform subjects already 
participating in the trial of the new information immediately to confirm whether they are willing 
to continue their participation in the trial, and use the revised informed consent form and other 

62 
written information to provide explanations again to obtain written consent for continuation of 
the participation in the trial of their own free will from the subjects. 
(1) If any new important information becomes available that may be relevant to the subject’s 
consent, the investigator should immediately revise the written information and 
informed consent form based on the information with the cooperation of the sponsor. 
The investigator should obtain approval for the revised written information and 
informed consent form from the institutional review board in advance. 
(2) The investigator or subinvestigator should also inform subjects already participating in 
the trial of the new information immediately, and use the revised informed consent form 
and other written information to provide explanations again to obtain written consent 
for continuation of the participation in the trial of their own free will from the subjects. 
When consent is obtained from a subject again, the informed consent form with the 
subject’s name and seal, or signature, and date will be retained (such as by affixing the 
form on the medical record) and the date of consent will be entered on the case report 
form. 
(3) The investigator or subinvestigator will provide a copy of the new informed consent 
form with the subject’s name and seal, or signature, and date and the written information 
to the subject. 
 
12.4.1.3 
Information to be included in the written information 
The written information should include at least the following information as required by Clause 
1 of Article 51 of the GCP Ordinance: 
(1) That the clinical trial involves research 
(2) The purpose of the clinical trial 
(3) The name, title, and contact information of the investigator or subinvestigator 
(4) Trial methods (including the research aspects of the trial, subject selection criteria) 
(5) The expected clinical benefits and risks or inconveniences 
(6) The availability of alternative treatments for the target disease in this clinical trial and 
their important potential benefits and risks 
(7) The expected duration of the subject’s participation in the clinical trial 
(8) That the subject’s participation in the clinical trial is voluntary and that the subject may 
refuse to participate or withdraw from the clinical trial, at any time, without penalty or 
loss of benefits to which the subject is otherwise entitled 
(9) That the CRA, the auditors, the institutional review board (IRB), and the regulatory 
authorities will be granted direct access to the subject’s medical information, without 
violating the confidentiality of the subject, and that by signing an informed consent form, 
the subject is authorizing such access. 
(10) That the subject’s privacy will remain confidential even if the results of the clinical trial 
are published 

63 
(11) The contact information of the study center for further information regarding the clinical 
trial and the rights of the subject and for inquiry or contact in the event of trial-related 
injury 
(12) The compensation and/or treatment available to the subject in the event of trial-related 
injury 
(13) The type of the institutional review board that investigates and reviews the 
appropriateness, etc. of the clinical trial; the matters that are investigated and reviewed 
in each institutional review board; and other matters regarding the institutional review 
board in relation to the clinical trial. That the subject can see the procedures, etc. of the 
institutional review board. 
(14) The planned number of subjects involved in the clinical trial 
(15) That the subject will be informed in a timely manner if information becomes available 
that may be relevant to the subject’s willingness to continue participation in the clinical 
trial 
(16) The foreseeable circumstances and/or reasons under which the subject’s participation in 
the clinical trial may be terminated 
(17) The anticipated expenses, if any, to the subject for participating in the clinical trial 
(18) The anticipated prorated payment, if any, to the subject for participating in the clinical 
trial 
(19) The subject’s responsibilities 
(20) Other necessary matters in relation to the protection of the human rights of the subject 
 
12.4.1.4 
Method of obtaining informed consent 
(1) Prior to the participation of each subject in the clinical trial, the investigator or 
subinvestigator will fully explain the contents of the trial to the subject by using the 
written information approved by the institutional review board to obtain written consent 
of his/her own free will from the subject. 
(2) The investigator or subinvestigator should provide the subject ample time and 
opportunity to inquire about details of the trial and to decide whether or not to participate 
in the trial before obtaining informed consent from the subject. At this time, the 
investigator or subinvestigator, or the clinical trial collaborator should answer all 
questions about the trial to the satisfaction of the subject. 
(3) The investigator or subinvestigator who provided explanations and the subject should 
affix their names and seals to or sign, and date the informed consent form. If a clinical 
trial collaborator provided supplemental explanations, the clinical trial collaborator 
should also affix his/her name and seal to or sign, and date the informed consent form. 
(4) After obtaining informed consent for the participation in the clinical trial from the 
subject, unless otherwise stipulated by the study center, before the participation of the 
subject in the trial, the investigator or subinvestigator should immediately provide a 

64 
copy of the informed consent form and the written information to the subject after 
retaining the informed consent form with their names and seals, or signatures, and date 
(such as by affixing the form on the medical record) and recording the date of informed 
consent on the case report form. 
(5) The investigator or subinvestigator should ask whether the subject is being treated by 
any primary physician. If the subject is being treated by his/her primary physician, the 
investigator or subinvestigator should inform the primary physician of the participation 
of the subject in the trial before the start of investigational drug administration with the 
subject’s consent. In addition, the name and the medical institution of the primary 
physician and the date of report should be recorded in the medical record. 
 
 
12.5 Protection of the Privacy of Subjects 
With regard to the conduct of this clinical trial, due consideration will be given to the protection 
of the privacy of subjects at the time of handling of their case report forms, informed consent 
forms, source documents, and other data including the personal information of the subjects as 
well as at the time of publication of the clinical trial results. 
The investigator or subinvestigator should use subject identification codes and not use medical 
record numbers when entering any information that can identify individual subjects on the case 
report forms, etc. If other documents or materials (laboratory test slips, packages of the 
investigational drug, etc.) include any information that can identify individual subjects, such as 
subject name, such information should be masked so that individual subjects cannot be 
identified before submission of the document or material to the sponsor. 
The investigator or subinvestigator will inform subjects that the monitors, the auditors, the 
institutional review board (IRB), and the regulatory authorities pay due attention to the 
confidentiality of subjects with respect to their personal information obtained through direct 
access to source documents, etc. and their personal information provided at the time of drug 
marketing (importing) approval application. 
The investigator will prepare and retain a subject identification code list (including subject 
names corresponding to subject identification codes) that is used to identify individual subjects. 
 
 
 
 

65 
13. FINANCING 
13.1 Compensation for Health Injury and Insurance 
(1) 
If a subject suffers any injury directly resulting from the use of the study drug or a 
study procedure (“trial-related health injury”), the study center will provide the 
subject with adequate treatment and other appropriate measures. Among the medical 
expenses required for the treatment, the sponsor will pay for medical expenses that 
are not covered by the health insurance, provided the subject has followed the 
directions given by the lnvestigator, and the trial-related health injury is not due to the 
natural progression of any condition exsisting before the subject participated in the 
study. No other compensation will be offered. 
(2) 
If any trial-related health injury occurs and results in legal liability, except when the 
study center is liable, the sponsor will be legally liable to the trial-related health injury. 
If it is not clear who will be legally liable to the trial-related health injury, the study 
center and the sponsor should discuss in good faith to solve the issue. 
(3) 
The sponsor has taken out an insurance policy to cover trial-related health injury. 
(4) 
If any health injury results from the intention or negligence of a subject or a study 
center, the health injury should be discussed based on the trial contract. 
 
 
13.2 Payments to Subjects and Planned Trial-related Expenses 
Any expense for testing or diagnostic imaging for a subject during the trial period will be paid 
by the sponsor as an expense for medical treatment designed for evaluation. Expenses such as 
transportation expenses for a subject should be paid with approval of the institutional review 
board after discussion by the study center and the sponsor. Methods for payment will be 
discussed with the study center and determined. 
 
 
14 PUBLICATION POLICY 
14.1 Use of the Data on this Clinical Trial 
All of unpublished information that was provided by the sponsor related to the investigational 
drug, including but not limited to clinical applications, formulation, manufacturing method 
and other academic data should be treated as confidential. Investigator can use the 
information only for the purposes of this trial.  In addition, all information about the trial, 
including the study results, is the confidential information of the sponsor. If you want to use 
for any purpose other than this trial, or disclose to a third party, you must obtain written 
consent from the sponsor previously. 

66 
14.2 Publication of the Trial Results 
Any of the information obtained in this study, it is not allowed to publish without prior 
consultation with the sponsors. For the method of the publication, the sponsor will determine 
after the end of the trial. 
Sponsor is committed to honoring the principles of academic freedom while, at the same time, 
protecting its confidential information, the subjects, and the integrity of the study, and the 
study documentation all in compliance with applicable law. Institution and/or Investigator 
recognize that, with respect to any study that is part of a multi-site study, there is a need for a 
coordinated approach to any publication or presentation of results from the sites. Accordingly, 
the Institution/Investigator shall not publish or present any results from this study to any third 
parties until: (1) Sponsor publishes the results; (2) Institution and/or Investigator receives 
written notification from Sponsor that publication of the results is no longer planned; or (3) 
twelve (12) months following the close of Study, whichever occurs first.   
Institution and/or Investigator shall submit to Sponsor for its review a copy of any proposed 
publication at least thirty (30) calendar days prior to the planned date of submission for 
publication or presentation. Institution and Investigator shall consider in good faith all 
comments received from Sponsor during the review period and shall delete Sponsor’s 
confidential information (other than study results).  
If Sponsor determines that the publication contains patentable subject matter which requires 
protection, Sponsor may require the delay of submission for publication or presentation for an 
additional period of time for the purpose of filing patent applications or otherwise take 
measures to protect such information.   
Institution and/or the Investigator shall acknowledge Sponsor’s support in all publications and 
presentations.     
 
 
15. PLANNED TRIAL PERIOD 
January 1, 2016 (IRB submission) to March 31, 2017 (Data lock) 
 
 

67 
16. LITERATURE REFERENCES 
1. 
Mulgrew AT, Taggart CC, McElvaney NG. Alpha-1-antitrypsin deficiency: current 
concepts. Lung 2007;185:191-201. 
2. 
Kohnlein T, Welte T. Alpha-1 antitrypsin deficiency: pathogenesis, clinical presentation, 
diagnosis, and treatment. Am J Med 2008 Jan;121(1):3-9. 
3. 
Fregonese L, Stolk J.  Hereditary alpha-1-antitrypsin deficiency and its clinical 
consequences.  Orphanet J of Rare Diseases 2008;3(16):1-9. 
4. 
Eriksson S. Pulmonary emphysema and alpha1-antitrypsin deficiency. Acta Medica 
Scandinavica 1964;175:197-205. 
5. 
McElvaney NG, Stoller JK, Buist AS, et al. Baseline characteristics of enrollees in the 
National Heart, Lung and Blood Institute Registry of α1-antitrypsin deficiency. Chest 
1997;111:394-403. 
6. 
de Serres FJ, Blanco I, Fernández-Bustillo E. PI S and PI Z alpha-1 antitrypsin deficiency 
worldwide. A review of existing genetic epidemiological data. Monaldi Arch Chest Dis 
2007;67(4):184-208. 
7. 
Seyama K.  State of alpha1-antitrypsin deficiency in Japan. Respirology 2000;5: S35-
S38. 
8. 
Test instructions – test: α1-antitrypsin 
http://data.medience.co.jp/compendium/module_detail.cgi?field=06&m_class=02&s_cla
ss=0013. Last checked: 18 March 2015. 
9. 
Woolhouse IS, Bayley DL, Stockley RA. Sputum chemotactic activity in chronic 
obstructive pulmonary disease: effect of α1-antitrypsin deficiency and the role of 
leukotriene B4 and interleukin 8. Thorax 2002;57:709-14. 
10. Carrell RW, Jeppsson JO, Laurell CB, et al. Structure and variation of human α1-
antitrypsin. Nature 1982;298(5872):329-334. 
11. Travis J. Structure, function, and control of neutrophil proteinases. Am J Med 1988; 
84(6A):37-42. 
12. Gadek JE, Fells GA, Zimmerman RL, et al. Antielastases of the human alveolar structures: 
implications for the protease-antiprotease theory of emphysema. J Clin Invest 
1981;68:889-98. 

68 
13. Janoff A. Elastases and emphysema. Current assessment of the protease-antiprotease 
hypothesis. Am Rev Respir Dis 1985;132(2):417-33. 
14. Hubbard RC, Fells G, Gadek J, et al. Neutrophil accumulation in the lung in α1-antitrypsin 
deficiency: spontaneous release of leukotriene B4 by alveolar macrophages. J Clin Invest 
1991;88: 891-7. 
15. American Thoracic Society/European Respiratory Society Statement: Standards for the 
diagnosis and management of individuals with Alpha-1 antitrypsin deficiency. Am J 
Respir Crit Care Med 2003;168:818-900. 
16. Crystal RG. α1-Antitrypsin deficiency, emphysema, and liver disease: Genetic basis and 
strategies for therapy. J Clin Investigation 1990;85:1343-52. 
17. Janoff A, Sloan B, Weinbaum G, et al. Experimental emphysema induced with purified 
human neutrophil elastase: tissue localization of the instilled protease. Am Rev Respir Dis 
1977;115(3):461-78. 
18. Senior RM, Tegner H, Kuhn C, et al. The induction of pulmonary emphysema with human 
leukocyte elastase.  Am Rev Respir Dis 1977;116(30):469-75. 
19. Stockley RA, Mannino D, Barnes PJ. Burden and pathogenesis of chronic obstructive 
pulmonary disease. Proc Am Thorac Soc 2009;6:524-6. 
20. Gadek JE, Klein HG, Holland PV, et al. Replacement therapy of alpha 1-antitrypsin 
deficiency: reversal of protease-antiprotease imbalance within the alveolar structures of 
PiZ subjects. J Clin. Invest 1981;68:1158-65. 
21. Gadek JE, Crystal RG. α1-Antitrypsin Deficiency In: The Metabolic Basis of Inherited 
Disease. Stanbury, JB, Wyngaarden JB, Fredrickson DS et al. (Eds) 5th Ed. McGraw-Hill, 
NY 1983. pp. 1450-67. 
22. Wewers MD, Casolaro MA, Sellers SE, et al. Replacement therapy for alpha1-antitrypsin 
deficiency associated with emphysema. N Engl J Med 1987;316(17):1055-62. 
23. Alpha-1-Antitrypsin Deficiency Registry Study Group. Survival and FEV1 decline in 
individuals with severe deficiency of α1-Antitrypsin. Am J Respir Crit Care Med 
1998;158:49-59. 
 
 

69 
24. Seersholm N, Wencker M, Banik N, et al. Does α1-antitrypsin augmentation therapy slow 
the annual decline in FEV1 in patients with severe hereditary α1-antitrypsin deficiency? 
Wissenschaftliche Arbeitsgemeinschaft zur Therapie von Lungenerkrankungen (WATL) 
α1-AT study group. Eur Respir J 1997;10(10):2260-63. 
25. Cazzola M, MacNee W, Martinez FJ, et al. Outcomes for COPD pharmacological trials: 
from lung function to biomarkers. Eur Respir J 2008;31(2):416-68. 
26. Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J 
2005;26:319-38. 
27. Meyer FJ, Wencker M, Teschler H, et al. Acute allergic reaction and demonstration of 
specific IgE antibodies against α-1-protease inhibitor. Eur Respir J 1998;12:996-7. 
28. Wencker M, Banik N, Buhl R, et al. Long-term treatment of α1-antitrypsin deficiency-
related pulmonary emphysema with human α1-antitrypsin. Eur Respir J 1998;11:428-33. 
29. Karch FE, Lasagna L. Toward the operational identification of adverse drug reactions. 
Clin Pharmacol Ther 1977; 21: 247-54. 
30. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of 
adverse drug reactions. Clin Pharmacol Ther 1981; 30: 239-45. 
 

70 
APPENDIX 1 
Trial Schedule (Examinations, Observations, Tests, and Evaluations and their Timing) 
Trial period 
Screening 
Treatmenta 
Follow-up 
Visita 
Day −21 
to the day 
before 
Week 1 
Week 1 
(baseline) 
Week 
2 
Week
3 
Week 
4 
Week 
5 
Week 
6 
Week 
7 
Week 
8 
PK1 
PK2 
PK5 
Week 9 
(Study 
completion)b 
Week 12 
(Study 
completion)c 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Assignment of subject number 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Age, sex, 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT Scan (densitometry) 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
(excluding breast and urogenital examination) 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Body height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
Xe 
 
 
 
Xe 
 
 
 
 
 
 
 
 
Blood sampling for viral safety assessmentf 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
(Only in women of childbearing potential) 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
Urinary cotinine level 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
Blood and urine sampling for laboratory tests 
(Hematology, blood chemistry, urinalysis) 
X 
X g 
 
 
 
X g 
 
 
 
 
 
 
X 
X 
Vital signs 
(Pulse rate, blood pressure, respiratory rate, 
body temperature)h 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
12-lead ECG 
X 
X 
 
 
 
 
 
 
 
 
 
 
(X) 
 
Pulmonary function tests before and after 
administration of a bronchodilator (FEV1 and 
FVC)i 
X i 
 
 
 
 
X i 
 
 
 
 
 
 
X i 
X i 
Blood sampling for alpha1-PI concentration 
measurement 
X j 
X g 
 
 
 
 
 
X g 
X k 
X k 
X k 
X k 
X k 
 
Intravenous infusion of Alpha-1 MPl 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Observation of subjects after infusion of Alpha-
1 MPm 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Evaluation of COPD exacerbations 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Evaluation of adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Evaluation of concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

71 
a: The date of individual visits will be determined in relation to the date of the Week 1 (baseline) visit. The date of all visits after the screening visit and the 
Week 1 (baseline) visit will be arranged within a time window of ± 1 day. The PK evaluation period will start at the Week 8 visit and end at the Week 9 visit. 
b: At the Week 9 visit, subjects will be asked whether or not they would like to enter the extension trial (GTI1401-OLE). For subjects eligible for participation 
in the extension trial, the Week 9 visit will be the study completion visit for this clinical trial (GTI1401). 
c: Subjects not entering the extension trial (GTI1401-OLE) and subjects who receive Alpha-1 MP at any dose and discontinue this clinical trial early will be 
asked to return to the study center for the follow-up/study completion procedures and evaluations scheduled at the Week 12 visit. This visit should be made 
at the timing as close as possible to 4 weeks (i.e., 30 days) after the last dose of the investigational drug in the subject. 
d: CT densitometry scan should be performed anytime from the Screening Visit to the Week 1 (Baseline) Visit; if the CT densitometry scan is performed at the 
Week 1 (Baseline) Visit, then it must be performed prior to the first Alpha-1 MP infusion. This CT scan will measure lung density.  
e: Body weight will be used to calculate the Alpha-1 MP dose, and this recorded body weight will be used for dose calculation until the next scheduled body 
weight measurement. 
f: Blood samples for viral safety assessment (viral NAT and viral serologic test) will be collected before the intravenous infusions of Alpha-1 MP at the Week 
1 (baseline) visit. However, the collected samples will be tested only if the subject shows clinical signs or symptoms suggestive of viral infection during the 
trial period. Only in this case will additional blood samples for viral NAT and viral serologic test be collected. All these collected blood samples will be 
stored until completion of all the tests in this clinical trial (GTI1401) and the extension trial (GTI1401-OLE). 
g: Sampling will be performed before each intravenous infusion of Alpha-1 MP. 
h: Vital signs will be checked immediately before and after each intravenous infusion of Alpha-1 MP. 
i: Pulmonary function tests after administration of a bronchodilator will be performed 15 to 30 minutes after administration of a bronchodilator. For a short-
acting bronchodilator, subjects will receive 4 puffs of salbutamol given by an MDI and spacer in each pulmonary function testing. The same bronchodilator 
as that used at the start of the trial should be used throughout the trial period. 
j: Sampling will be performed in subjects with no previously documented alpha1-PI levels as measured by nephelometry (if it is unknown whether the subject’s 
alpha1-PI level is <50 mg/dL or not). 
k: Sampling time points of PK samples: 1) Immediately before the intravenous infusion; 2) Immediately after the intravenous infusion (after flushing the 
infusion line with physiological saline) (at 0 hours); 3) At 15 minutes after completion of the intravenous infusion; 4) At 2 hours after completion of the 
intravenous infusion; 5) At 4 hours after completion of the intravenous infusion; 6) At 8 hours after completion of the intravenous infusion; 7) At 24 ± 4 
hours (1 day after completion of the intravenous infusion); 8) At 48 ± 4 hours (2 days after completion of the intravenous infusion); 9) At 120 hours ± 1 day 
(5 days after completion of the intravenous infusion); and 10) At 168 hours ± 1 day (7 days after completion of the intravenous infusion) (Week 9). 
l: Weekly intravenous infusions of 60 mg/kg of Alpha-1 MP will be given under the supervision of the investigator or a designated person at each study center. 
m: Subjects will be observed for at least 30 minutes after each intravenous infusion of Alpha-1 MP. 

72 
APPENDIX 2 
 
A2.1 Sponsor 
1) Sponsor 
 
Grifols Japan K.K. 
Level 19, Hilton Plaza West Office Tower 
2-2-2 Umeda, Kita-ku, Osaka 530-0001, Japan 
TEL: 
  FAX:
 
 
2) 
 
 
Grifols Japan K.K. 
Level 19, Hilton Plaza West Office Tower 
2-2-2 Umeda, Kita-ku, Osaka 530-0001, Japan 
TEL: 
  FAX: 
 
 
3) 
 
 
Japan Anti-Tuberculosis Association 
1-3-12 Misaki-cho, Chiyoda-ku, Tokyo, Japan 
TEL: 
  FAX:
 
<Main duties> 
To give the sponsor medical advice on the following matters when necessary: 
(i) 
Appropriateness of the investigational plan, the protocol, etc. 
(ii) 
Action to be taken against adverse events and evaluation of them 
(iii) 
Appropriateness of subject data handling and result assessment after 
completion of the trial 
(iv) 
Appropriateness of the clinical study report 
(v) 
Other medical issues concerning the trial 
 
A2.2 Contract Research Organization 
In this clinical trial, trial-related duties will be entrusted to the contract research organization 
below: 
CMIC HOLDINGS Co., Ltd. 
 
1-1-1 Shibaura, Minato-ku, Tokyo 105-0023, Japan 
TEL: 03-6779-8000 (main switchboard) 
 

73 
Monitor (CRA) and Medical Monitor 
Refer to Attachment. 
 
<Main duties> 
(i) 
Duties related to the selection of study centers and investigators 
(ii) 
Duties related to negotiations and confirmation with investigators and study 
centers 
(iii) 
Duties related to the request for study centers to conduct the trial and the 
conclusion of a trial contract with each study center 
(iv) 
Duties related to the completion or discontinuation of the trial at study centers 
(v) 
Duties related to trial monitoring 
(vi) 
Duties related to supplying and retrieving of the investigational drug 
(vii) 
Duties related to the collection of case report forms and data verification 
against source documents 
(viii) Duties related to the confirmation of GCP essential documents at study 
centers 
(ix) 
Quality control functions as part of the entrusted duties 
(x) 
Duties related to data management 
(xi) 
Duties related to statistical analysis 
(xii) 
Medical writing (protocol, written information and informed consent form, 
clinical study report, etc.) 
(xiii) Duties related to auditing 
(xiv) Safety Information handling and reporting 
(xv) 
Duties related to the medical monitoring 
 
A2.3 Grifols Therapeutics Inc., USA  
Grifols Therapeutics Inc. 
 
4201 Research Commons 
79 T.W. Alexander Drive 
Research Triangle Park, NC 27709 USA 
TEL: 
    FAX:
 
 
In this clinical trial, several trial-related duties will be provided by Grifols 
Therapeutics Inc. or will be carried out by CMIC HOLDINGS Co., Ltd. in 
conjunction with Grifols Therapeutics Inc. as listed below: 
1) Medical Monitor 
Refer to Attachment. 
 

74 
 
Other duties to be performed by Grifols Therapeutics Inc. in conjunction with the 
CMIC HOLDINGS Co., Ltd. 
(i) 
Duties related to statistical analysis 
(ii) 
Duties related to supplying and retrieving of the investigational drug 
(iii) 
Medical writing (protocol, written information and informed consent form, 
clinical study report, etc.) 
 
A2.4 Study Centers 
Study centers 
Refer to Attachment. 
 
Investigators 
Refer to Attachment. 
 
<Main duties> 
(i) 
Preparation of written information and informed consent forms 
(ii) 
Selection of subjects and informed consent procedure 
(iii) 
Agreement on and adherence to the protocol 
(iv) 
Control of the investigational drug 
(v) 
Administration of the investigational drug to subjects 
(vi) 
Conduct of various tests 
(vii) 
Entering data into case report form and confirmation of the data in the case 
report forms 
(viii) Preparation and retention of study records 
 
 
A2.5 Laboratory Testing Services, Transporter, Investigational Drug 
Manufacturer 
1) Laboratory testing services  
LSI Medience Corporation 
, 
 
3-30-1 Shimura, Itabashi-ku, Tokyo 174-8555, Japan 
TEL: 03-5943-9270  FAX: 03-5375-9211 
<Main duties> 
(i) 
Collection of laboratory test samples 
(ii) 
Measurement of laboratory test parameters 
(iii) 
Reporting of test results to study centers and the sponsor 
(iv) 
Assurance of the testing methods and data quality 

75 
(vi) 
Transportation and interim storage of viral safety assessment samples 
 
2) Transportation and storage of the investigational drug 
TNT Express Worldwide (Japan) Inc. 
, 
 
TOC Ariake East Tower 6th floor, 3-5-7 Ariake, Koto-ku, Tokyo, Japan 
 
3) Investigational drug manufacturer 
Grifols Therapeutic Inc. 
 
4201 Research Commons 
79 T.W. Alexander Drive 
Research Triangle Park, NC 27709 USA 
TEL: 
    FAX:
 
 
A2.6 Central Evaluation of lung density of CT Scan Image 
Vida Diagnostics 
2500 Crosspark Road 
W250 BioVentures Center 
Coralville, IA 52241 
TEL: +1-855-900-VIDA (8432)   FAX: +1-610-602-5941 
 
 
 

76 
Attchement 1 
 
1. List of Investigational Sites and Investigators 
 
Investigational Sites 
(Address & Tel#) 
Department 
Principal Investigator 
 
 
 Japan 
Tel: 
 
 
 
 
Masaru Suzuki 
 
 
 
Tel: 
 
 
 
 
Kuniaki Seyama 
 
 
 
 
Tel: 
 
 
 
 
 
 
2. Medical Monitor 
 
To be updated. 
 
 
 
, Grifols Therapeutics Inc. 
4210 Research Commons 
79 TW Alexander Drive, RTP, NC 27709 
TEL: 
    FAX:
 
 
 
3. Monitor (CRA) 
, 
 
1-1-1 Shibaura, Minato-ku, Tokyo 105-0023, Japan 
CMIC HOLDINGS Co., Ltd. 
TEL: 
, FAX: 
 
 
 

77 
APPENDIX 3 
A3.1 SAE Report Form 
 

78 

80 
A3.2 Supplemental Event Form 
 
 
 

83 
 
 
Emergency contact: 
CMIC HOLDINGS Co., Ltd. 
Business Innovation Unit (BIU) 
1-1-1 Shibaura, Minato-ku, Tokyo 105-0023, Japan 
TEL: 
 FAX: 
 
 
 (Mobile phone No. 080-xxxx-xxxx)