A Multi-Center, Open-Label Study to Evaluate the Long-term Safety of Weekly Intravenous Infusions of Alpha1-Proteinase Inhibitor (Human) in Japanese Subjects With Alpha1 Antitrypsin Deficiency
Phase: PHASE1
Conditions: Alpha1-Antitrypsin Deficiency
Sponsor: Grifols Therapeutics LLC

Official Title: 
A Multi-Center, Open-Label Study to Evaluate the Long-term Safety
of Weekly Intravenous Infusions of Alpha1-Proteinase Inhibitor
(Human) in Japanese Subjects With Alpha1 Antitrypsin Deficiency
NCT Number:           NCT02870348 
Document Date:    Protocol Version: 2.1: January 21, 2019

 
 
 
 
 
 
 
Protocol 
 
 
A Multi-Center, Open-Label Study to Evaluate the 
Long-term Safety of Weekly Intravenous Infusions 
of Alpha1-Proteinase Inhibitor (Human) in Japanese 
Subjects with Alpha1-Antitrypsin Deficiency 
 
 
 
 
 
 
Sponsor: Grifols Japan K.K. 
 
 
 
 
 
 
 
Protocol No.: GTI1401-OLE 
Version No.: 2.1 (for Ver2.1J) 
Prepared on: January 21, 2019 
 
 
 

1 
PROTOCOL SYNOPSIS 
Title of Study 
A Multi-Center, Open-Label Study to Evaluate the Long-term Safety of 
Weekly Intravenous Infusions of Alpha1-Proteinase Inhibitor (Human) in 
Japanese Subjects with Alpha1-Antitrypsin Deficiency 
Protocol 
Identification No. 
GTI1401-OLE 
Investigational 
Drug Code 
Alpha-1 MP 
Type of Study 
(Phase of 
Development) 
Clinical safety study (Phase I/II) 
Study Objective 
To evaluate the long-term safety of 60 mg/kg. Alpha-1 MP administered by 
weekly IV infusions for approximately one year (52 weeks) or longer (can 
be renewed annually with the consent of the subjects) in adult subjects with 
AATD in Japan. 
Study Design 
This study is a multi-center, open-label study to evaluate the long-term 
safety of weekly IV infusions of 60 mg/kg Alpha-1 MP in adult subjects 
with AATD in Japan who have completed the Study GTI1401.  
Subject Selection 
Study 
Population 
Subjects: 
Adult subjects with alpha1-antitrypsin deficiency 
Target sample size:  A minimum of 3 subjects 
Inclusion 
Criteria 
1. Subjects who complete participation in the Study GTI1401 
 (i.e., who have completed the study through the Week 9 Visit) 
2. Subjects who will and are able to provide written informed consent. 
Exclusion 
Criteria 
1. Subjects with newly diagnosed severe concomitant disease including, 
but not limited to, congestive heart failure and liver cirrhosis. 
2. Subjects with newly diagnosed malignant tumor (including malignant 
melanoma; however, other forms of skin cancer are allowed). 
3. Female subjects who are pregnant, breastfeeding or, if of child-bearing 
potential, unwilling to practice a highly effective method of 
contraception throughout the study or male subjects who have a partner 
who is of child-bearing potential and is unwilling to practice a highly 
effective method of contraception throughout the study. 
4. Subjects with clinical signs and symptoms of active viral infection of 
HAV, HBV, HCV, or HIV at the Week 9 Visit of the Study GTI1401 
and confirmed by testing. 

2 
5. Subjects with current evidence of smoking or has a positive urine 
cotinine test at the Week 9 Visit in the Study GTI1401 that is due to 
smoking. 
6. Subjects who currently participate in a study of another investigational 
product (other than Alpha-1 MP). 
7. Subjects who have difficulty in adhering to the protocol or its 
procedures, in the opinion of the investigator. 
8. 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 
Variables 
The safety variables to be assessed for this study are as follows  
(No efficacy variables will be assessed for this study): 
 Adverse events (AEs), serious AEs (SAEs), adverse drug reactions 
(ADRs), and discontinuations due to AEs or SAEs 
 Vital signs (heart rate, blood pressure, respiratory rate, and 
temperature) 
 Chronic Obstructive Pulmonary Disease (COPD) exacerbations  
 Pulmonary function tests (PFTs): 
– Forced Expiratory Volume in 1 second (FEV1) 
– Forced Vital Capacity (FVC) 
 Clinical laboratory parameters: 
– Hematology 
– Chemistry 
– Urinalysis 
 Alpha1-PI level 
Exploratory 
Variable 
 Computed Tomography (CT) scan (densitometry) 
CT scan (densitometry) data will be accumulated for future 
evaluation of lung density 
Study Centers 
and Investigators 
Refer to Attachment “Study Centers and Investigators List” 
Study Period 
March 1, 2016 to March 31, 2022 
Remarks 
This study will be switched to a post-marketing study  
after Alpha-1 MP is approved in Japan. 
 
 

3 
LIST OF ABBREVIATION 
Abbreviation 
Meaning of Abbreviation (In Japanese) 
°C 
Degree Celsius （摂氏） 
°F 
Degree Fahrenheit （華氏） 
AATD 
Alpha1-Antitrypsin Deficiency （α1-アンチトリプシン欠乏症）  
ADR 
Adverse Drug Reaction （薬物有害反応、副作用） 
AE 
Adverse Events （有害事象） 
Alpha-1 MP 
Alpha1-Proteinase Inhibitor (human), Modified Process  
（製法を改良したヒトalpha1-proteinase inhibitor） 
alpha1-PI 
Alpha1-Proteinase Inhibitor （alpha1-プロテイナーゼインヒビター） 
ALT 
Alanine Aminotransferase （アラニンアミノ基転移酵素 ） 
AST 
Aspartate Transaminase （アスパラギン酸アミノ基転移酵素 ） 
ATS 
American Thoracic Society （米国胸部疾患学会 ） 
B19V 
Parvovirus B19 （パルボウィルスB19 ） 
ChAMP 
Pharmacokinetic Comparability of Alpha-1 MP Study  
（Alpha-1 MP の薬物動態の相互比較性試験 ） 
COPD 
Chronic Obstructive Pulmonary Disease （慢性閉塞性肺疾患） 
CRF 
Case Report Form （症例報告書） 
CRA 
Clinical Research Associate （治験モニター） 
CRO 
Contract Research Organization （医薬品開発業務受託機関） 
CT 
Computed Tomography（コンピューター断層撮影） 
CV 
Coefficient of Variation （変動係数） 
DNA 
Deoxyribonucleic Acid （デオキシリボ核酸） 

4 
dL 
Deciliter （デシリットル） 
ERS 
European Respiratory Society （欧州呼吸器学会） 
Ext 
Extension （継続） 
FEV1 
Forced Expired Volume in 1 second （1 秒量: 1 秒間の努力呼気量） 
FVC 
Forced Vital Capacity （努力性肺活量） 
GCP 
Good Clinical Practice （医薬品の臨床試験の実施の基準） 
HAV 
Hepatitis A Virus （A 型肝炎ウィルス） 
HBV 
Hepatitis B Virus （B 型肝炎ウィルス） 
HCV 
Hepatitis C Virus （C 型肝炎ウィルス） 
HIV 
Human Immunodeficiency Virus （ヒト免疫不全ウィルス） 
IB 
Investigator’s Brochure （治験薬概要書） 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
（日米欧医薬品規制調和国際会議） 
ICF 
Informed Consent Form （患者同意説明文書） 
IgA 
Immunoglobulin A （免疫グロブリンA） 
IgG 
Immunoglobulin G （免疫グロブリンG） 
 
Abbreviation 
Meaning of Abbreviation (In Japanese) 
IgM 
Immunoglobulin M （免疫グロブリンM） 
IRB/EC 
Institutional Review Board / Ethics Committee  
（治験審査委員会／倫理委員会） 
IUD 
Intrauterine Device （子宮内避妊用具） 
IUS 
Intrauterine Contraceptive System（子宮内避妊システム ） 

5 
IV 
Intravenous （静脈内） 
kg 
Kilogram （キログラム） 
μM 
Micromolar （マイクロモル濃度） 
MDI 
Metered Dose Inhaler （定量噴霧式吸入器） 
MedDRA® 
Medical Dictionary for Regulatory Activities （ICH 国際医薬用語集） 
mg 
Milligram （ミリグラム） 
mL 
Milliliter （ミリリットル） 
NaCl 
Sodium Chloride （塩化ナトリウム） 
NAT 
Nucleic Acid Amplification Technology （核酸増幅法） 
NE 
Neutrophil Elastase（好中球エラスターゼ） 
OLE 
Open Label Extension 
PFT 
Pulmonary Function Test （肺機能検査） 
PI*MM 
Proteinase Inhibitor homozygote for normal M allele 
〔Proteinase Inhibitor 対立遺伝子M（正常）のホモ接合体〕 
PI*(null)(null) 
Proteinase Inhibitor homozygote for (null) allele 
〔Proteinase Inhibitor の対立遺伝子ヌル（零＝欠損）のホモ接合体〕 
PI*SZ 
Proteinase Inhibitor heterozygote for S and Z deficiency alleles 
〔Proteinase Inhibitor の対立遺伝子S（欠乏）及びZ（欠乏）のホモ接合
体〕 
PI*Z 
Proteinase Inhibitor Z deficiency allele 
〔Proteinase Inhibitor 遺伝子のZ（欠乏）の対立遺伝子〕 
PI*ZZ 
Proteinase Inhibitor homozygote for Z deficiency allele 
Homozygote for Z (Deficiency) Allele of the Alpha1-Proteinase Inhibitor 
Gene  
〔Proteinase Inhibitor の対立遺伝子Z（欠乏）のホモ接合体〕 
PK 
Pharmacokinetic/Pharmacokinetics （薬物動態） 
RNA 
Ribonucleic Acid （リボ核酸 ） 
SAE 
Serious Adverse Event （重篤な有害事象） 
SAP 
Statistical Analysis Plan （統計解析計画書） 
SD 
Standard Deviation （標準偏差） 
SPARK 
Alpha-1 MP Safety and Pharmacokinetic Study  

6 
（Alpha-1 MP の安全性及び薬物動態試験 ） 
STAMP 
Safety and Tolerability of Alpha-1 MP study 
（Alpha-1 MP の安全性及び忍容性試験） 
TEAE 
Treatment-Emergent Adverse Event （治療中に発生した有害事象） 
 
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  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 ....................................................................................................... 16 
4.1.3  Phase of Development .......................................................................................... 16 
4.2  Selection of Subject Population ................................................................................... 17 
4.2.1  Inclusion Criteria .................................................................................................. 17 
4.2.2  Exclusion Criteria ................................................................................................. 17 
4.3  Investigational Drug .................................................................................................... 18 
4.3.1  Investigational Drug ............................................................................................. 18 
4.3.1.1  Investigational Drug Code ....................................................................................................... 18 
4.3.1.2  Investigational Drug Name ...................................................................................................... 19 
4.3.1.3  Content and Dosage Form ....................................................................................................... 19 
4.3.1.4  Composition of the Preparation ............................................................................................... 19 
4.3.2  Investigational Drug Labeling .............................................................................. 19 
4.3.2.1  Packaging ................................................................................................................................ 19 
4.3.2.2  Labeling ................................................................................................................................... 19 
4.3.3  Dose and Dosage Regimen .................................................................................. 21 
4.3.3.1  Dose and Dosage Regimen ...................................................................................................... 21 
4.3.3.2  Rationale for the Dose ............................................................................................................. 21 
4.3.3.3  Rationale for the Dosage Regimen .......................................................................................... 21 
4.3.4  Storage of the Investigational Drug ...................................................................... 21 
4.3.5  Accountability of the Investigational Drug .......................................................... 21 

7 
4.4  Assignment Method ..................................................................................................... 22 
4.4.1  Subject Number .................................................................................................... 22 
4.4.2  Blinding ................................................................................................................ 22 
4.4.3  Schedule for Investigational Drug Administration to Each Subject .................... 22 
4.4.4  Treatment Compliance ......................................................................................... 23 
 
4.5  Concomitant Medications and Other Restrictions ....................................................... 24 
4.5.1  Prohibited Concomitant Medications during the Study ....................................... 24 
4.6  Endpoints ..................................................................................................................... 24 
4.6.1  Exacerbation of Chronic Obstructive Pulmonary Disease (COPD) ..................... 25 
4.6.2  Pulmonary Function Test (PFT) ........................................................................... 26 
4.6.3  CT Densitometry .................................................................................................. 26 
4.7  Evaluation .................................................................................................................... 27 
4.7.1  Evaluation Period ................................................................................................. 27 
4.7.2  Observation and Measurement ............................................................................. 27 
4.7.2.1  Screening / Ext Week 1 Visit of the 1st year ............................................................................ 28 
4.7.2.2  The 1st Visit of the 2nd year (at the Ext Week 53), the 3rd year (at the Ext Week 105), the 4th year 
(at the Ext Week 157), the 5th year (at the Ext Week 209), and the 6th year (at the Ext Week 
261) ......................................................................................................................................... 29 
4.7.2.3 
Weekly On-Site Infusion Visits .............................................................................................. 30 
4.7.2.4 
Quarterly Visits: Ext Weeks 12, 24, 36, and 48 of the 1st year (Ext Weeks 64, 76, 88, and 100 
of the 2nd year, Ext Weeks 116, 128, 140, and 152 of the 3rd year, Ext Weeks 116, 128, 140, 
and 152 of the 3rd year, Ext Weeks 168, 180, 192, and 204 of the 4th year, Ext Weeks 220, 232, 
244, and 256 of the 5th year, and Ext Weeks 272, 284, 296, and 308 of the 6th year). ............ 31 
4.7.2.5 
Bi-Annual Visits No.1:  the Ext Week 26 of the 1st year (the Ext Week 78 of the 2nd year, the 
Ext Week 130 of the 3rd year, the Ext Week 182 of the 4th year, the Ext Week 234 of the 5th 
year, and the Ext Week 286 of the 6th year). ........................................................................... 32 
4.7.2.6 
Bi-Annual Visits No.2:  Ext Week 52 of the 1st year (Ext Week 104 of the 2nd year, Ext Week 
156 of the 3rd year, Ext Week 208 of the 4th year, Ext Week 260 of the 5th year and Ext Week 
312 of the 6th year). ................................................................................................................. 33 
4.7.2.7   End of Study / Follow-Up Assessments................................................................................. 35 
4.7.3  Laboratory Tests and Testing Procedures ............................................................ 36 
4.7.3.1  Viral Safety Assessment .......................................................................................................... 37 
4.7.4  Drug Concentration Measurements ...................................................................... 37 
4.7.5  Volume of Blood Sampling .................................................................................. 38 
4.8  Screening Failures ....................................................................................................... 38 
5. ADVERSE EVENTS (AES) ........................................................................................... 39 
5.1  Warnings/Precautions .................................................................................................. 39 
5.2  Monitoring of Adverse Events .................................................................................... 39 
5.3  Definitions and Handling of Adverse Events .............................................................. 40 
5.3.1  Definition of Adverse Events (AEs) ..................................................................... 40 
5.3.2  Definition of Suspected Adverse Drug Reactions (ADRs) .................................. 40 

8 
5.3.3  Causal Relationship of Adverse Events................................................................ 40 
5.3.4  Severity of Adverse Events/ Suspected Adverse Drug Reactions ........................ 42 
5.3.5  Expectedness of Adverse Events/ Suspected Adverse Drug Reactions ............... 42 
5.3.6  Seriousness of Adverse Events/Adverse Drug Reactions; Serious Adverse Events 
(SAEs) .................................................................................................................. 43 
5.3.7  Recording of Adverse Events ............................................................................... 44 
5.3.8  Method and Duration of Follow-Up of Subjects Experiencing Adverse Events . 45 
5.3.9  Events of Special Interest ..................................................................................... 45 
5.4  Reporting of Serious Adverse Events (SAEs) / Pregnancies ...................................... 45 
5.4.1  Reporting of Serious Adverse Events (SAEs) ...................................................... 45 
5.4.2  Reporting of Pregnancies ...................................................................................... 47 
6. TRIAL 
DISCONTINUATION 
CRITERIA 
AND 
PROCEDURES 
FOR 
INDIVIDUAL SUBJECTS ............................................................................................ 48 
6.1  Discontinuation Criteria .............................................................................................. 48 
6.2  Discontinuation Procedures ......................................................................................... 49 
7. TRIAL COMPLETION, DISCONTINUATION, OR INTERRUPTION ................. 50 
7.1  Completion of the Clinical Trial .................................................................................. 50 
7.2  Discontinuation or Interruption of the Clinical Trial ................................................... 50 
7.2.1  Discontinuation or Interruption of the Clinical Trial by the Sponsor................... 50 
7.2.2  Discontinuation or Interruption of the Clinical Trial at a Study Center ............... 50 
8. STATISTICAL METHODS AND DETERMINATION OF TARGET SAMPLE 
SIZE ................................................................................................................................. 52 
8.1  Statistical Analysis Plan .............................................................................................. 52 
8.1.1  Analysis Sets ......................................................................................................... 52 
8.1.2  Descriptive Statistics ............................................................................................ 52 
8.2  Determination of Target Sample Size ......................................................................... 52 
9. CASE REPORT FORMS ............................................................................................... 53 
9.1  Completion and Reporting of Case Report Forms ...................................................... 53 
9.2  Guidance for Completion of Case Report Forms ........................................................ 53 
9.3  Identification of Data to Be Recorded Directly on Case Report Forms and to Be 
Considered to Be Source Data ................................................................................... 54 
10. PROTOCOL ADHERENCE, DEVIATIONS OR MODIFICATIONS, AND 
AMENDMENTS ........................................................................................................... 55 
10.1  ProtocolAdherence .................................................................................................... 55 
10.2  Protocol Deviations or Modifications ........................................................................ 55 
10.3  Protocol Amendments ............................................................................................... 56 
11. TRIAL MANAGEMENT ............................................................................................... 57 
11.1  Investigator, Other Trial Staff, External Committees ............................................... 57 

9 
11.2  Quality of Data .......................................................................................................... 57 
11.2.1  Sponsor ............................................................................................................... 57 
11.2.1.1  Quality Control ...................................................................................................................... 57 
11.2.1.2  Quality Assurance ................................................................................................................. 57 
11.2.2  Study Centers ...................................................................................................... 58 
11.3  Management of Documents ....................................................................................... 58 
11.4  Retention of Records ................................................................................................. 58 
11.4.1  Retention of Records at the Study Center .......................................................... 58 
11.4.2  Retention of Records by the Sponsor ................................................................. 60 
11.4.3  Retention of Records at Other Organizations ..................................................... 60 
11.5  Access to Information through Monitoring ............................................................... 60 
11.6  Access to Information for Auditing or Inspection ..................................................... 61 
11.6.1  Source Documents .............................................................................................. 61 
12. ETHICS ............................................................................................................................ 62 
12.1  Declaration of Helsinki ............................................................................................. 62 
12.2  Adherence to the Drugs and Medical Devices Law and the GCP Ordinance ........... 62 
12.3  Institutional Review Board (IRB) .............................................................................. 62 
12.3.1  Review of the Conduct of This Clinical Trial .................................................... 62 
12.3.2  Review of the Continuation of This Clinical Trial ............................................. 62 
12.4  Informed Consent of Subjects ................................................................................... 62 
12.4.1  Timing and Method of Obtaining Informed Consent ......................................... 62 
12.4.1.1  Preparation of Written Information and Informed Consent Form ......................................... 63 
12.4.1.2  Revision of the Written Information and Informed Consent Form ....................................... 64 
12.4.1.3  Information to Be Included in the Written Information......................................................... 64 
12.4.1.4  Method of Obtaining Informed Consent ................................................................................ 66 
12.5  Protection of the Privacy of Subjects ........................................................................ 67 
13. FINANCING .................................................................................................................... 68 
13.1  Compensation for Health Injury and Insurance ......................................................... 68 
13.2  Payments to Subjects and Planned Trial-Related Expenses ...................................... 68 
14. PUBLICATION POLICY .............................................................................................. 69 
14.1  Use of the Data on This Clinical Trial ....................................................................... 69 
14.2  Publication of the Trial Results ................................................................................. 69 
15. PLANNED TRIAL PERIOD ......................................................................................... 70 
16. LITERATURE REFERENCES..................................................................................... 71 
 

10 
1. INTRODUCTION 
In addition to the information provided below, please also refer to the Investigator’s Brochure 
(IB) and any additional data supplied by the sponsor. 
 
 
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 
versus antiprotease balance in the lungs (12). In AATD, there appears to be an inadequate 

11 
protective protease inhibitory shield (12-14), a disruption of the normal protease versus 
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). 
 
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 versus 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 in 1987 and in Germany in 1988.  
 
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 and higher 
purity compared to Prolastin. Alpha-1 MP is approved for 60 mg/kg weekly IV administration 
in the US, Canada, Colombia, Argentina, Turkey, Chile and Australia for the treatment of 
patients with severe AATD and clinically evident emphysema under the trade name Prolastin®-
C.   

12 
Prolastin and Prolastin-C are together licensed in a total of 22 countries, with Prolastin 
[produced by the original process] authorized in several European countries. 
 
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 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 Alpha-1 MP or 60 mg/kg 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 pruritus/itching. 
 
Subsequent to the STAMP and ChAMP studies, the SPARK (Alpha-1 MP Safety and 
PhARmacoKinetic) study was conducted to assess the safety and pharmacokinetics (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 
The safety and PK of augmentation therapy with Alpha-1 MP to increase serum alpha1-PI levels, 
at a dosing regimen of 60 mg/kg in weekly IV infusions over 8 weeks, will be evaluated in 
patients with AATD (the Study GTI1401, a Phase 1/2 study) in Japan. The current study is an 
extension of the Study GTI1401 to evaluate the long-term safety of 60 mg/kg Alpha-1 MP. 
 
 

13 
2. STUDY ADMINISTRATIVE STRUCTURE 
Please refer to Appendix 2 for the administrative structure of this study including: 
– 
Sponsor 
– 
Contract research organization 
– 
Study centers 
– 
Laboratory testing services, courier, investigational drug manufacturer 
 
 

14 
3. STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of this study is to evaluate the long-term safety of 60 mg/kg Alpha-1 MP 
administered by weekly IV infusions for approximately one year (52 weeks) or longer (can be 
renewed annually with the consent of the subjects) in adult subjects with AATD in Japan.  
 
 
3.2 
Exploratory Objective 
The CT scan (densitometry) will be performed, and CT scan data will be accumulated for future 
evaluation of lung density.  
 

15 
4. INVESTIGATIONAL PLAN 
4.1 
Study Design and Plan 
4.1.1 Design and Plan of This Clinical Trial 
This is a multi-center, open-label study to evaluate the long-term safety of weekly IV infusions 
of 60 mg/kg Alpha-1 MP in adult subjects with AATD in Japan who have completed the Study 
GTI1401. The Study GTI1401 is being conducted to evaluate the safety and PK of Alpha-1 MP 
in subjects with AATD in Japan. In the current study, the GTI1401-OLE, subjects will be 
administered 60 mg/kg Alpha-1 MP by weekly IV infusion for approximately 1 year or longer 
to assess the long-term safety of Alpha-1 MP in subjects with AATD.  
 
Unless the sponsor informs of discontinuation of this OLE trial, basically this trial can be 
renewed annually with the consent of the subjects. 
 
This study will be conducted at three centers in Japan. 
 
At the Week 9 Visit of the Study GTI1401, after giving consent, on the same day, subjects will 
be assessed for eligibility at the Screening/Extension (Ext) Week 1 Visit for this extension study, 
the Study GTI1401-OLE (see Section 4.2 for study inclusion and exclusion criteria). If eligible, 
subjects will be administered weekly IV infusions of 60 mg/kg Alpha-1 MP continuously. The 
Week 9 Visit of the Study GTI1401 will be the End of Study Visit for the subjects who are 
enrolled in the Study GTI1401-OLE.  
 
Subjects in the Study GTI1401-OLE will have the option to remain in the Study GTI1401-OLE 
and continue to receive weekly IV infusions of 60 mg/kg Alpha-1 MP for up to a total of 6 
years. The option for continuing the Study GTI1401-OLE for another year will be renewed 
annually with the consent of the subjects. The annual renewal for participation for another year 
will occur at the Ext Week 52, for the next 2nd year; at the Ext Week 104, for the next 3rd year; 
at the Ext Week 156, for the next 4th year, at the Ext Week 208, for the next 5th year; and at the 
Ext Week 260, for the next 6th year.  
 
If a subject gives consent for remaining in the Study GTI1401-OLE, the subjects will skip the 
End of Study / Follow-Up Assessment and continue to receive weekly IV infusions of 60 mg/kg 
Alpha-1 MP for the next year. 
 
A subject may choose to withdraw from the Study GTI1401-OLE at any time. If subjects choose 
to withdraw from the Study GTI1401-OLE, they will be asked to complete the End of Study / 

16 
Follow-Up Assessments, which will be scheduled as close as possible to 30 days (a ±2 days 
window is allowed) after the last Alpha-1 MP infusion. 
 
Remarks: This study will be switched to a post-marketing study after Alpha-1 MP is approved 
in Japan. 
 
A Schedule of Study Procedures is provided in Appendix 1. 
 
 
4.1.2 Type of Study 
Clinical safety study 
 
 
4.1.3 Phase of Development 
Phase I/II 
 
 
 
 
 

17 
 
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 
in the informed consent form. 
The investigator will assess subject eligibility based on the inclusion criteria and the exclusion 
criteria below. 
 
 
4.2.1 Inclusion Criteria 
A subject must meet all the following inclusion criteria to be eligible for participation in this 
study: 
1. 
Subjects who complete participation in the Study GTI1401 (i.e., have completed the 
study through the Week 9 Visit).  
2. 
Subjects who will and are able to provide written informed consent.  
 
<Rationale for establishing the inclusion criteria> 
1. 
The Study GTI1401-OLE is an open-label safety extension study of the Study 
GTI1401. 
2. 
Subjects' documented consent to participate in the study is required  
 
 
4.2.2 Exclusion Criteria 
A subject who has completed the Study GTI1401 but meets any of the following exclusion 
criteria is NOT eligible for participation in the study. 
1. 
Subjects with newly diagnosed severe concomitant disease including, but not limited 
to, congestive heart failure and liver cirrhosis. 
2. 
Subjects with newly diagnosed malignant tumor (including malignant melanoma; 
however, other forms of skin cancer are allowed). 
3. 
Female subjects who are pregnant, breastfeeding or, if of child-bearing potential, 
unwilling to practice a highly effective method of contraception (oral, injectable or 
implanted hormonal methods of contraception, placement of an intrauterine device 
[IUD] or intrauterine system [IUS], condom or occlusive cap with spermicidal 
foam/gel/film/cream/suppository, male sterilization, or abstinence) throughout the 
study or male subjects who have a partner who is of child-bearing potential and is 
unwilling to practice a highly effective method of contraception throughout the study.  

18 
4. 
Subjects with clinical signs and symptoms of HAV, HBV, HCV, or HIV viral 
infection at the Week 9 Visit of the Study GTI1401 and confirmed by testing. 
5. 
Subjects with current evidence of smoking or has a positive urine cotinine test at the 
Week 9 Visit in the Study GTI1401 that is due to smoking. 
6. 
Subjects who currently participate in a study of another investigational product (other 
than Alpha-1 MP). 
7. 
Subjects who have difficulty in adhering to the protocol or its procedures, in the 
opinion of the investigator. 
8. 
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. 
 
<Rationale for establishing the exclusion criteria> 
1. 
To eliminate predisposition of underlying disease that could impact clinical 
laboratory assessments and subject safety 
2. 
Same as above [#1] 
3. 
For subject safety: Animal reproduction studies have not been conducted with Alpha-
1 MP. It is not known whether Alpha-1 MP can cause fetal harm when administered 
to a pregnant woman or can affect reproduction capacity. 
4. 
To eliminate confounding factors that could impact physical assessment and clinical 
laboratory values, thereby impacting safety assessment 
5. 
To eliminate confounding factors that could cause further decline in lung function 
and damage to the lungs 
6. 
To exclude any confounding effect on the evaluation of adverse events and safety of 
this investigational drug 
7. 
To eliminate noncompliance by the subject and other confounders to the safety 
assessments 
8. 
To eliminate impact that may confound the safety assessment. 
 
 
4.3 
Investigational Drug 
4.3.1 Investigational Drug 
4.3.1.1 
Investigational Drug Code 
 
 
Alpha-1 MP 
 

19 
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 
alpha1-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., 
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. 

20 
GRIFOLS 
Protocol: GTI1401-OLE 
 
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. 
1-2-8, Toranomon, Minato-ku, Tokyo, 105-0001, Japan 
 
Figure 4-1  Sample Labeling for the Investigational Drug (Package) 
 
Protocol: GTI1401-OLE 
 
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. 
1-2-8, Toranomon, Minato-ku, Tokyo, 105-0001, 
Japan 
 
Figure 4-2  Sample Labeling for the Investigational Drug (Vial) 

21 
4.3.3 Dose and Dosage Regimen 
4.3.3.1 
Dose and Dosage Regimen 
Subjects will receive an IV infusion 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, Colombia, Argentina, Turkey, Chile and Australia.   
 
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.   
 
 
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 
to the study subject.  
 
Alpha-1 MP should be kept at room temperature after reconstitution and should be administered 
within 3 hours after reconstitution. 
 
Additional storage 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. 
 

22 
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. 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 retain the subject number from the Study 
GTI1401. 
 
If a subject will change to a different study site in the course of the Study GTI1401-OLE due 
to his/her convenience, a new subject number will be assigned at the new study site based on 
its site number. In this case, in order to identify the subject as the same person, the matter of 
transition of the subject should be documented in each case report form of both sites as 
memorandum. 
 
 
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 
At the Week 9 Visit of the Study GTI1401, subjects will be given the option to participate in 
the Study GTI1401-OLE. If subjects give the consent for participation, on the same day, 
subjects will be assessed for eligibility at the Screening / Ext Week 1 Visit for this extension 
study, the GTI1401-OLE. If eligible, the subjects will receive their first IV infusion of 60 mg/kg 
Alpha-1 MP for the Study GTI1401-OLE at the Ext Week 1. Subjects will continue to receive 
weekly IV infusions of 60 mg/kg Alpha-1 MP for approximately one year (52 weeks) or longer. 
 
 
 

23 
If a subject gives consent for remaining in the Study GTI1401-OLE at the Ext Week 52 for the 
next 2nd year, at the Ext Week 104 for the next 3rd year, at the Ext Week 156 for the next 4th 
year, at the Ext Week 208 for the next 5th year, and at the Ext Week 260 for the next 6th year, 
the subject will continue to receive weekly IV infusions of 60 mg/kg Alpha-1 MP for the next 
year. 
 
Each week, designated study site personnel will prepare an infusion bag of Alpha-1 MP for 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 
approximately 0.08 mL/kg/min (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.  
 
 

24 
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. 
 
 
4.5.1 Prohibited Concomitant Medications during the Study 
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 
The variables to be assessed for this trial are as follows 
 
Safety 
Variables 
 
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: 
– 
Hematology, Chemistry, Urinalysis 
 
Alpha1-PI level 
Exploratory 
Variable 
 
CT scan (densitometry) 
CT scan (densitometry) data will be accumulated for future 
evaluation of lung density. 
 
 
 
 

25 
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: 
It 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: 
It requires treatment with systemic steroids and/or antibiotics. 
 
Severe: 
It describes exacerbations that require hospitalization (an emergency department stay > 
24 hours is considered a hospitalization) 
 
 
 
 

26 
4.6.2 Pulmonary Function Test (PFT) 
Pulmonary function tests (PFT; i.e., spirometry), including FEV1 (absolute and percent 
predicted) and FVC, will be performed according to ATS/ERS guidelines (26) at the Ext Week 
26 and 52 of the 1st year (at the Ext Week 78 and 104 of the 2nd year, at the Ext Week 130 and 
156 of the 3rd year, at the Ext Week 182 and 208 of the 4th year, at the Ext Week 234 and 260 
of the 5th year and at the Ext Week 286 and 312 of the 6th year). Pulmonary function tests at the 
Ext Week 26 and 52 of the 1st year (at the Ext Week 78 and 104 of the 2nd year, at the Ext Week 
130 and 156 of the 3rd year, at the Ext Week 182 and 208 of the 4th year, at the Ext Week 234 
and 260 of the 5th year and at the Ext Week 286 and 312 of the 6th year) should be conducted 
prior to Alpha-1 MP infusion. At each visit in which PFTs are scheduled, testing will be 
performed before 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.   
 
 
4.6.3 CT Densitometry 
The CT densitometry will be performed for measuring lung density; see CT Scan Manual for 
detailed procedures. 
 
 
 
 

27 
4.7 
Evaluation 
4.7.1 Evaluation Period 
This study consists of a Screening / Ext Week 1 Visit in which the treatment regimen will be 
initiated as part of a 52-week open-label treatment period. After the treatment period, there will 
be an End of Study / Follow-Up Assessments scheduled as close as possible to 30 days (a ±2 
days window is allowed) after the last Alpha-1 MP infusion. The total duration of study 
participation for subjects who complete the study will be approximately 56 weeks (a 52-week 
treatment period + 30 days).  
 
The study can be renewed annually with the consent of the subjects.  
If a subject gives consent for remaining in the Study GTI1401-OLE at the Ext Week 52 for the 
next 2nd year, at the Ext Week 104 for the next 3rd year, at the Ext Week 156 for the next 4th 
year, at the Ext Week 208 for the next 5th year, and at the Ext Week 260 for the next 6th year, 
the subject will continue to receive weekly IV infusions of 60 mg/kg Alpha-1 MP for the next 
year.  
 
If subjects plan to conclude their participation in the study (GTI1401-OLE) at the Ext Week 52 
of the 1st year, at the Ext Week 104 of the 2nd year, at the Ext Week 156 of the 3nd year, at the 
Ext Week 208 of the 4th year, and at the Ext Week 260 of the 5th year or earlier before the Ext 
Week 52 of the 1st year, the Ext Week 104 of the 2nd year, the Ext Week 156 of the 3rd year, at 
the Ext Week 208 of the 4th year, at the Ext Week 260 of the 5th year or at the Ext Week 312 of 
the 6th year, they will be asked to complete the End of Study / Follow-Up Assessments, which 
will be scheduled as close as possible to 30 days (a ±2 days window is allowed) after the last 
Alpha-1 MP infusion. 
 
 
4.7.2 Observation and Measurement 
The following is a description of the procedures/assessments to take place at each study visit.  
See the Schedule of Study Procedures in Appendix 1 for a summary of study visits and the 
procedures and assessments to be conducted at each visit. Unscheduled visits may be conducted 
if deemed necessary for the purpose of subject safety. 
 
 
 

28 
4.7.2.1 
Screening / Ext Week 1 Visit of the 1st year 
At the Week 9 Visit of the Study GTI1401, subjects will be given the option for participation 
in the Study GTI1401-OLE. If subjects opt to participate, on the same day, they will be assessed 
for eligibility at the Screening / Ext Week 1 Visit of the 1st year for this extension study. Subjects 
who satisfy the inclusion and exclusion criteria will receive their first IV infusion of Alpha-1 
MP at this visit. 
 
Informed consent must be obtained for all prospective subjects prior to the collection of any 
screening assessments or the conduct of any study procedures. All subjects will start their 
participation in the study by signing the Informed Consent Form (ICF).    
 
The Screening / Ext Week 1 Visit of the 1st year will occur on the same day as the Week 9 Visit 
of the prior study (GTI1401). The procedures performed at the Week 9 Visit of the Study 
GTI1401 will be used for the Screening / Ext Week 1 Visit for the first year of the Study 
GTI1401-OLE. 
 
Additional procedures and assessments will be performed during the Screening / Ext Week 1 
Visit of the 1st year, including: 
Visit 
Trial Procedures and Evaluations 
Screening / Ext 
Week 1 Visit of 
the 1st year 
 
Prior to Alpha-1 MP Infusion 
• Informed consent 
• Determine eligibility by assessment of inclusion/exclusion criteria 
• Subject number confirmed 
• Body weight:  
Recorded body weight will be used to calculate the Alpha-1 MP 
dose administration at the OLE-Week 1 Visit (OLE-baseline). 
This recorded body weight will be used for dose calculation until 
the next scheduled body weight measurement. 
 
• Vital signs immediately before the start of Alpha-1 MP infusion 
(heart rate, blood pressure, respiratory rate, and temperature) 
 
Alpha-1 MP Infusion: 
• Administer Alpha-1 MP infusion 
• Vital signs immediately after the completion of Alpha-1 MP infusion 
(heart rate, blood pressure, respiratory rate, and temperature) 
 
 

29 
4.7.2.2 
The 1st Visit of the 2nd year (at the Ext Week 53), the 3rd year (at the Ext Week 
105), the 4th year (at the Ext Week 157), the 5th year (at the Ext Week 209), 
and the 6th year (at the Ext Week 261) 
The following procedures and assessments will be performed in the 1st Visit of the 2nd year (at 
the Ext Week 53), the 3rd year (at the Ext Week 105), the 4th year (at the Ext Week 157), the 5th 
year (at the Ext Week 209) and the 6th year (at the Ext Week 261). [Those are the same as 
Section 4.7.2.3 Weekly On-site Infusion Visits.] 
 
Visit 
Trial Procedures and Evaluations 
The 1st Visit of 
the 2nd year or 
longer 
 
(The 2nd year) 
Ext Week 53 
 
[The 3rd year] 
Ext Week 105 
 
[The 4th year] 
Ext Week 157 
 
[The 5th year] 
Ext Week 209 
 
[The 6th year] 
Ext Week 261 
Prior to Alpha-1 MP Infusion:  
• AE assessment [see Section 5] 
• Concomitant medications assessment 
• COPD exacerbation assessment [see Section 4.6.1] 
• Vital signs immediately before the start of Alpha-1 MP infusion 
(heart rate, blood pressure, respiratory rate, and temperature)  
 
Alpha-1 MP Infusion: 
• Administer Alpha-1 MP infusion 
• Vital signs immediately after the completion of Alpha-1 MP infusion 
(heart rate, blood pressure, respiratory rate, and temperature) 
 
 
 

30 
4.7.2.3 
Weekly On-Site Infusion Visits 
Subjects will return to the clinical site for weekly IV infusions throughout the study and will 
undergo the following procedures and assessments. 
 
Visit 
Trial Procedures and Evaluations 
Weekly On-Site 
Infusion Visits 
Prior to Alpha-1 MP Infusion:  
• AE assessment [see Section 5] 
• Concomitant medications assessment 
• COPD exacerbation assessment [see Section 4.6.1] 
• Vital signs immediately before the start of Alpha-1 MP infusion 
(heart rate, blood pressure, respiratory rate, and temperature)  
 
Alpha-1 MP Infusion: 
• Administer Alpha-1 MP infusion 
• Vital signs immediately after the completion of Alpha-1 MP infusion  
(heart rate, blood pressure, respiratory rate, and temperature)  
 
 
 
 
 

31 
4.7.2.4 
Quarterly Visits: Ext Weeks 12, 24, 36, and 48 of the 1st year (Ext Weeks 64, 
76, 88, and 100 of the 2nd year, Ext Weeks 116, 128, 140, and 152 of the 3rd 
year, Ext Weeks 116, 128, 140, and 152 of the 3rd year, Ext Weeks 168, 180, 
192, and 204 of the 4th year, Ext Weeks 220, 232, 244, and 256 of the 5th year, 
and Ext Weeks 272, 284, 296, and 308 of the 6th year). 
In addition to Alpha-1 MP infusion and the procedures performed during Weekly On-Site 
Infusion Visits (see Section 4.7.2.3), the following procedures and assessments will be 
performed during the quarterly on-site visits at Ext Weeks 12, 24, 36, and 48 of the 1st year (at 
Ext Weeks 64, 76, 88, and 100 of the 2nd year, Ext Weeks 116, 128, 140, and 152 of the 3rd year, 
Ext Weeks 168, 180, 192, and 204 of the 4th year, Ext Weeks 220, 232, 244, and 256 of the 5th 
year, and Ext Weeks 272, 284, 296, and 308 of the 6th year). 
 
Visit 
Trial Procedures and Evaluations 
Quarterly Visits: 
 
 Ext Weeks 12, 
24, 36, and 48  
 
[the 2nd year] 
Ext Weeks 64, 
76, 88, and 100  
 
[the 3rd year] 
Ext Weeks 116, 
128, 140, and 152 
 
[the 4th year] 
Ext Weeks 168, 
180, 192, and 204 
 
[the 5th year] 
Ext Weeks 220, 
232, 244, and 256 
 
[the 6th year] 
Ext Weeks 272, 
284, 296, and 308 
Prior to Alpha-1 MP Infusion: 
• Body weight:  
Recorded body weight will be used to calculate the Alpha-1 MP 
dose administration. This recorded body weight will be used for 
dose calculation until the next scheduled body weight 
measurement. 
 
• Alpha1-PI level 

32 
4.7.2.5 
Bi-Annual Visits No.1:  the Ext Week 26 of the 1st year (the Ext Week 78 of 
the 2nd year, the Ext Week 130 of the 3rd year, the Ext Week 182 of the 4th 
year, the Ext Week 234 of the 5th year, and the Ext Week 286 of the 6th year). 
In addition to Alpha-1 MP infusion and the procedures performed during Weekly On-Site 
Infusion Visits (see Section 4.7.2.3), the following procedures and assessments will be 
performed bi-annually at the Ext Week 26 of the 1st year, at the Ext Week 78 of the 2nd year, at 
the Ext Week 130 of the 3rd year, at the Ext Week 182 of the 4th year, at the Ext Week 234 of 
the 5th year and at the Ext Week 286 of the 6th year. 
 
Visit 
Trial Procedures and Evaluations 
Bi-Annual Visits 
No.1  
 
Ext Week 26 
 
[the 2nd year] 
Ext Week 78 
 
[the 3rd year] 
Ext Week 130 
 
[the 4th year] 
Ext Week 182 
 
[the 5th year] 
Ext Week 234 
 
[the 6th year] 
Ext Week 286 
Prior to Alpha-1 MP Infusion: 
• Laboratory assessments [see Section 4.7.3]: 
– Urine: 
 Urine pregnancy test  
(Potential child-bearing females only; results must be 
negative for the subject to continue in the study) 
 Urinalysis 
 Urine cotinine 
– Blood: 
 Hematology 
 Chemistry 
• Physical examination (excludes breast and genitourinary) 
• Pre- and post-bronchodilator PFTs (FEV1 and FVC) 
   
 
 
 
 
 
[see Section 4.6.2]  
 
 
 
 

33 
4.7.2.6 
Bi-Annual Visits No.2:  Ext Week 52 of the 1st year (Ext Week 104 of the 
2nd year, Ext Week 156 of the 3rd year, Ext Week 208 of the 4th year, Ext Week 
260 of the 5th year and Ext Week 312 of the 6th year). 
In addition to Alpha-1 MP infusion and the procedures performed during Weekly On-Site 
Infusion Visits (see Section 4.7.2.3), the following procedures and assessments will be 
performed bi-annually at the Ext Week 52 of the 1st year, at the Ext Week 104 of the 2nd year, 
at the Ext Week 156 of the 3rd year, at the Ext Week 208 of the 4th year, at the Ext Week 260 
of the 5th year, and at the Ext Week 312 of the 6th year. 
 
Subjects in the Study GTI1401-OLE will have the option to remain in the Study GTI1401-OLE 
and continue to receive weekly IV infusions of 60 mg/kg Alpha-1 MP for another year at the 
Ext Week 52 for the next 2nd year and at the Ext Week 104 for the next 3rd year, at the Ext Week 
156 for the next 4th year, at the Ext Week 208 for the next 5th year, and at the Ext Week 260 for 
the next 6th year. The option for continuing the Study GTI1401-OLE for another year will be 
renewed annually with the consent of the subjects.  
 
Informed consent must be obtained for all prospective subjects prior to the collection of any 
screening assessments or the conduct of any study procedures for the second year or longer.  
All subjects will start their participation in the study for the second year or longer by signing 
the Informed Consent Form (ICF). 
 
 

34 
 
Visit 
Trial Procedures and Evaluations 
Bi-Annual Visits: 
No.2 
 
Ext Week 52  
 
[the 2nd year] 
 Ext Week 104 
 
[the 3rd year] 
Ext Week 156 
 
[the 4th year] 
 Ext Week 208 
 
[the 5th year] 
Ext Week 260 
 
[the 6th year] 
 Ext Week 312 
Prior to Alpha-1 MP Infusion: 
• Laboratory assessments [see Section 4.7.3]: 
– Urine: 
 Urine pregnancy test  
(Potential child-bearing females only; results must be 
negative for the subject to continue in the study) 
 Urinalysis 
 Urine cotinine 
– Blood: 
 Hematology 
 Chemistry 
 Viral safety retain samples  
(Viral nucleic acid technology [NAT] and viral 
serology). 
 
• Physical examination (excludes breast and genitourinary) 
• Pre- and post-bronchodilator PFTs (FEV1 and FVC)  
   
 
 
 
 
  
[see Section 4.6.2]  
• CT densitometry 
 
• Informed consent to remain in GTI1401-OLE for another year 
(except the Ext Week 312 of the 6th year). 
 
If a subject gives consent for remaining in the Study GTI1401-
OLE, the subject will skip the End of Study / Follow-Up 
Assessments scheduled and continue to receive weekly IV 
infusions of 60 mg/kg Alpha-1 MP for another year. 
 
 
 
 

35 
4.7.2.7   End of Study / Follow-Up Assessments 
If a subject decides not to remain in the Study GTI1401-OLE at the Ext Week 52 of the 1st year 
and at the Ext Week 104 of the 2nd year, at the Ext Week 156 of the 3nd year, at the Ext Week 
208 of the 4th year, at the Ext Week 260 of the 5th year, or the Ext Week 312 of the 6th year he 
or she will complete the End of Study / Follow-Up Assessments scheduled as close as possible 
to 30 days (a ±2 days window is allowed) after the last Alpha-1 MP infusion. The following 
procedures and assessments will be performed during this visit: 
 
If a subject decides to conclude the OLE trial earlier before the Ext Week 52 of the 1st year, 
the Ext Week 104 of the 2nd year, the Ext Week 156 of the 3rd year, the Ext Week 208 of the 
4th year, the Ext Week 260 of the 5th year, or the Ext Week 312 of the 6th year, he or she will 
be asked to complete the End of Study / Follow-Up Assessments, which will be scheduled 
as close as possible to 30 days (a ±2 days window is allowed) after the last Alpha-1 MP 
infusion. 
 
Visit 
Trial Procedures and Evaluations 
End of Study / 
Follow-Up 
Assessments  
• Laboratory assessments [see Section 4.7.3]: 
– Urine: 
 Urine pregnancy test  
(Potential child-bearing females only) 
 Urinalysis 
 Urine cotinine 
– Blood: 
 Hematology 
 Chemistry 
 Viral safety retain samples  
(Viral nucleic acid technology [NAT] and viral serology) 
 
• CT densitometry:  
 
CT scan should only be conducted if it is more than 6 months 
from previous CT scan. 
 
• Physical examination (excludes breast and genitourinary)  
• Pre- and post-bronchodilator PFTs (FEV1 and FVC) 
 
 
 
 
 
  
[see Section 4.6.2] 
• COPD exacerbation assessment [see Section 4.6.1] 
• AE assessment [see Section 4.2] 
• Concomitant medications assessment 
• Vital signs 
 (heart rate, blood pressure, respiratory rate, and temperature)  

36 
4.7.3 Laboratory Tests and Testing Procedures 
Detailed descriptions of laboratory test procedures are located in the study Laboratory Manual.  
Table 4-2 provides a summary of the laboratory tests conducted for this study. 
 
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, glucose, 
albumin, total protein, total bilirubin 
aspartate aminotransferase (AST),  
alanine transaminase (ALT),  
alkaline phosphatase  
Central 
laboratorya 
Urinalysis 
pH, protein, glucose, blood, and Microscopic 
evaluation will be performed only with cause  
Central 
laboratorya 
Urinary cotinine 
Cotinine level 
Local 
laboratory 
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 Ext Week 52 visitb, at the Ext Week 104 visitb at 
the Ext Week 156 visitb, at the Ext Week 208 visitb, 
at the Ext Week 260 visitb, and at the Ext Week 312 
visitb: 
Collection of samples for storage 
Hepatitis A virus (HAV) RNA,  
Hepatitis B virus (HBV) DNA,  
Hepatitis C virus (HCV) RNA,  
Human immunodeficiency virus (HIV) RNA, 
Parvovirus B19 (B19V) DNA 
Central 
laboratorya 

37 
Viral serologic 
test 
Before the intravenous infusion of Alpha-1 MP at 
the Ext Week 52 visitb, at the Ext Week 104 visitb, 
at the Ext Week 156 visitb, at the Ext Week 208 
visitb, at the Ext Week 260 visitb, at the Ext Week 
312 visitb: 
Collection of samples for storage 
Differentiation of HAV antibody 
(immunoglobulin M [IgM]/immunoglobulin G 
[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: Central lab: LSI Medience Corporation 
b: Section 4.7.3.1. These retain samples will be stored until all analyses in support of studies GTI1401 
and GTI1401-OLE are complete. 
 
4.7.3.1 
Viral Safety Assessment 
Virus safety retain samples (viral NAT and viral serology) collected at the Week 1 (Baseline) 
Visit of the Study GTI1401 prior to infusion will be used as baseline virus safety retain samples 
for GTI1401-OLE. In the Study GTI1401-OLE, virus safety retain samples (viral NAT and 
viral serology; see Table 4-2) will be collected prior to infusion at the Ext Week 52 of the 1st 
year, at the Ext Week 104 of the 2nd year, and at the Ext Week 156 of the 3rd year, at the Ext 
Week 208 of the 4th year, at the Ext Week 260 of the 5th year, and at the Ext Week 312 of the 
6th year. These samples will be stored until the subject has completed the Study GTI1401-OLE.  
 
Viral NAT and viral serology 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 Drug Concentration Measurements 
All subjects will have a blood sample collected quarterly at Ext Weeks 12, 24, 36 and 48 of the 
1st year, at Ext Weeks 64, 76, 88 and 100 of the 2nd year, at Ext Weeks 116, 128, 140 and 152 
of the 3rd year, at Ext Weeks 168, 180, 192 and 204 of the 4th year, at Ext Weeks 220, 232, 244 
and 256 of the 5th year, and at Ext Weeks 272, 284, 296 and 308 of the 6th year for the 
measurement of trough alpha1-PI levels prior to the IV infusions of 60 mg/kg Alpha-1 MP. 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. 

38 
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 trough concentration measurements, the following volumes of blood per 
subject will be taken during the study planned 56 weeks including End of Study / Follow-Up 
Assessment if a subject completes the study at the end of the 1st year. 
 
Blood sampling 
Volume (mL) 
Times 
Total volume (mL) 
Laboratory tests 
6 
3 
18 
Viral tests 
34.5 
1 
34.5 
Alpha1-PI concentration 
4 
4 
16 
Grand Total over 56 weeks 
68.5 
 
 
4.8 
Screening Failures 
Screening evaluations (the Week 9 Visit of the Study GTI1401) 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. 
 
 
 
 

39 
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, Colombia, 
Argentina, Turkey, Chile and Australia. 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 immunoglobulin A (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. 
 

40 
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 subject 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. 
 

41 
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. 
 
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 treatment-emergent 
adverse events (TEAE). 
 
 
 
 

42 
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. 
 
 
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. 
 
 
 
 

43 
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.  
 
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. 
 
 

44 
5.3.7 Recording of Adverse Events 
All AEs and SAEs occurring after the subject has signed the ICF through the End of Study / 
Follow-Up Assessments 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 the 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 event 

45 
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 an SAE (Section 5.3.6). If an 
exacerbation meets criteria for an 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 SAEs that occur after signing the study ICF through the End of 
Study / Follow-Up Assessments (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 by email. 
 
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 development-related duties 
for this clinical trial, as instructed below via the SAE report form (see Appendix 3.1 and 3.2) 

46 
form in a timely manner (within 24 hours of both of identification for already obtained 
information and awareness for new related information). In addition, additional 
information/report may be requested by the sponsor or CMIC. 
 
All SAE report forms should be submitted by email to the Eastern Japan Pharmacovigilance 
Division of CMIC, which is responsible for pharmacovigilance, 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 Pharmacovigilance and Grifols Japan within 24 hours. The following 
required information should be provided to Grifols Global Pharmacovigilance to perform the 
preliminary reportable 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 
Pharmacovigilance 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 
Pharmacovigilance 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 
Pharmacovigilance 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 Pharmacovigilance. 

47 
5.4.2 Reporting of Pregnancies 
Pregnancy itself is not an AE, 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 in a study subject subsequent to informed 
consent signature through the End of Study / Follow-Up Assessments 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 form (see Appendix 3.3) 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. 
 
 

48 
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 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. 
 
(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 to 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 AE which requires discontinuation of the trial in the 
opinion 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 opinion 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 opinion 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 
 

49 
6.2 
Discontinuation Procedures 
When discontinuing a subject from 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, and should also document the date of discontinuation, the reason for 
discontinuation, the action taken after discontinuation, and the course after 
discontinuation in a case report form. 
(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 be asked to return to the study center for the End of Study / 
Follow-Up Assessments (refer to Section 4.7.2.7 “End of Study / Follow-Up 
Assessments” and Appendix 1).  
• This visit should be made as close as possible to 30 days (a ±2 days window is 
allowed) 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 should document 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 attempts to communicate with the subject are made, but the 
investigator is unable to identify the location of the subject, the investigator or 
subinvestigator should document the fact, the method for communication, and 
the date of communication in a case report form. 
 
 

50 
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 (IRB) 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 Good Clinical Practice (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. 

51 
(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: 
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 withdrawal of a study center, the 
investigator should return all trial-related materials (excluding documents to be 
continuously retained at the study center) to the sponsor. The investigator should 
retain all the documents to be continuously 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 individual subjects, refer 
to the procedures stipulated in Section 6. “Trial Discontinuation Criteria and 
Procedures for Individual Subjects.” 
 
 

52 
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 
(SD), 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. 
 
 
8.2 
Determination of Target Sample Size 
Sample size of this study (GTI1401-OLE) will be contingent on the number of subjects who 
enter and complete the Study GTI1401 and who consent to enter this extension study. Sample 
size was chosen based on clinical considerations and the number of available Japanese patients 
with AATD, not on a formal sample size calculation. 
 
 
 
 
 

53 
9. CASE REPORT FORMS 
9.1 
Completion and Reporting of Case Report Forms 
(1) 
After completion of the treatment 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 
data 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 examination that has not been performed, this 
item should be slash mark (date and initial should be included on blank pages that are 
slashed through). 
(5) 
Every entry on a case report form should be consistent with its source document. 
 
 
 
 

54 
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 
 
Results of the assessments of severity, seriousness, and causal relationship of adverse 
events, and comments or reasons 
 
Other comments to complement data 
 
 

55 
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 
official. 
(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. 
(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. The investigator or 

56 
subinvestigator will also 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.” 
 
 

57 
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. 
 
 

58 
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 
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 AEs and SAEs must be recorded. All serious adverse events will be recorded on SAE forms. 
Original forms of recorded SAEs 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. 

59 
 [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, 
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 
 
 

60 
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 
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 CRA. The representative of the sponsor or the CRA appointed 
by the sponsor may investigate the records. 
 

61 
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. 
 
 
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 
 

62 
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, 

63 
and provide the subject with a copy of the signed and dated informed consent form and the 
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. 
 

64 
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 
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 

65 
(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 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 
(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 
 
 
 

66 
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 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 should record 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. 
 
 
 
 

67 
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 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. 
 
 
 
 

68 
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 Investigator, and the trial-related health injury is not due to 
the natural progression of any conditions existing 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. 
 
 
 
 

69 
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. 
 
 
14.2 Publication of the Trial Results 
None of the information obtained in this study is allowed to be published 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.   
 

70 
Institution and/or the Investigator shall acknowledge Sponsor’s support in all publications and 
presentations.     
 
 
 
15. PLANNED TRIAL PERIOD 
 
March 1, 2016 to March 31, 2022 
 
 

71 
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: 709-714. 

72 
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: 889-898. 
13. Janoff A.: Elastases and emphysema. Current assessment of the protease-antiprotease 
hypothesis.  
Am Rev Respir Dis 1985; 132(2): 417-433. 
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: 891-897. 
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 Invest 1990; 85: 1343-1352. 
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): 461-478. 
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): 469-475. 

73 
19. Stockley RA, Mannino D, Barnes PJ.: Burden and pathogenesis of chronic obstructive 
pulmonary disease.  
Proc Am Thorac Soc 2009; 6: 524-526. 
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: 1158-1165. 
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. 1450-1467. 
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): 1055-1062. 
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. 
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): 2260-2263. 
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): 416-468. 
26. Miller MR, Hankinson J, Brusasco V, et al.: Standardisation of spirometry.  
Eur Respir J 2005; 26: 319-338. 
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: 996-997. 

74 
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: 428-433. 
29. Karch FE, Lasagna L.: Toward the operational identification of adverse drug reactions. 
Clin Pharmacol Ther 1977; 21: 247-254. 
30. Naranjo CA, Busto U, Sellers EM, et al.: A method for estimating the probability of 
adverse drug reactions.  
Clin Pharmacol Ther 1981; 30: 239-245. 
 

75 
Appendix 1 
Schedule of Study Procedures 
Visits 
Screening /  
Ext Week 1 Visit  
of the 1st year 
The 1st Visit of  
the 2nd year or 
longer 
[The 2nd year] 
Ext Week 53 
[The 3rd year] 
Ext Week 105 
[The 4th year] 
Ext Week 157 
[The 5th year] 
Ext Week 209 
[The 6th year] 
Ext Week 261 
Weekly  
On-Site 
Infusion Visits  
Ext Week 2 to 
Ext Week 52 
 
Ext Week 54 to 
Ext Week 104  
Ext Week 106 
to Ext Week 
156 
Ext Week 158 
to Ext Week 
208 
 
Ext Week 210 
to Ext Week 
260  
Ext Week 262 
to Ext Week 
312 
Quarterly 
Visits  
Ext Weeks 12, 
24, 36, 48 
Ext Weeks 64, 
76, 88, 100 
Ext Weeks 116, 
128, 140, 152 
Ext Weeks 168, 
180, 192, 204 
Ext Weeks 220, 
232, 244, 256 
Ext Weeks 272, 
284, 296, 308 
Bi-Annual Visits 
End of Study / 
Follow-Up 
Assessments b  
Procedures / Assessments 
Screening 
Initiation 
of 
Infusion 
[No.1] 
Ext Week 
26 
Ext Week 
78 
Ext Week 
130 
Ext Week 
182 
Ext Week 
234 
Ext Week 
286 
[No.2] 
Ext Week 
52 
Ext Week 
104 
Ext Week 
156 
Ext Week 
208 
Ext Week 
260 
Ext Week 
312 
Informed consent 
X 
 
 
 
 
 
X l  
 
Inclusion / Exclusion criteria 
X 
 
 
 
 
 
 
 
Subject number confirmed 
X 
 
 
 
 
 
 
 
Weight c 
X 
 
 
 
X 
 
 
 
CT Scan (densitometry) d 
 
 
 
 
 
 
X 
X  
Collection of virus safety retain samples c 
 
 
 
 
 
 
X 
X 
Physical exam 
(excludes breast and genitourinary) f 
 
 
 
 
 
X 
X 
X 

76 
Urine pregnancy test 
(potential child-bearing females only) f 
 
 
 
 
 
X 
X 
X 
Urine cotinine f 
 
 
 
 
 
X 
X 
X 
Urinalysis f 
 
 
 
 
 
X 
X 
X 
Blood for hematology and chemistry 
laboratory assessments f 
 
 
 
 
 
X 
X 
X 
Vital signs (heart rate, blood pressure, 
respiratory rate, and temperature) g 
 
X 
X 
X 
X 
X 
X 
X 
Pre- and post-bronchodilator PFTs 
(FEV1 and FVC) h 
 
 
 
 
 
X 
X 
X 
Blood for alpha1-PI level i 
 
 
 
 
X 
 
 
 
Alpha-1 MP IV infusion j 
 
X 
X 
X 
X 
X 
X 
 
COPD exacerbation assessment f 
 
 
X 
X 
X 
X 
X 
X 
Adverse event assessment f, k 
 
 
X 
X 
X 
X 
X 
X 
Concomitant medications assessment f 
 
 
X 
X 
X 
X 
X 
X 
 
a:  Time period is relative to the Screening / Ext Week 1 Visit.  A ±1 day window is allowed for all study visits after the Screening / Ext Week 1 Visit. The Screening / Ext 
Week 1 Visit and initiation of treatment for the current study (GTI1401-OLE) occurs on the same day as the Week 9 Visit of GTI1401 only for those subjects who give the 
consent for participation in the Study GTI1401-OLE. The procedures performed at the Week 9 Visit of the Study GTI1401 will be used for the Screening / Ext Week 1 
Visit of the Study GTI1401-OLE. Blood samples for virus safety testing (viral NAT and viral serology) collected at the Week 1 (Baseline) Visit of the Study GTI1401 will 
be used as baseline virus safety retain samples for the Study GTI1401-OLE.  
b:  Subjects who receive any amount of Alpha-1 MP and discontinue early from the study will be requested to complete the End of Study / Follow-Up Assessments scheduled 
at the timing as close as possible to 30 days (a ±2 days window is allowed) after their last administration of Alpha-1 MP. If a subject gives consent for remaining in the 
Study GTI1401-OLE, the subject will skip the End of Study / Follow-Up Assessments and continue to receive weekly IV infusions of 60 mg/kg Alpha-1 MP for another 
year. 
c:  Each recorded weight will be used to calculate the Alpha-1 MP infusion dose for the scheduled visit and subsequent weekly Alpha-1 MP infusions until the next scheduled 
weight is measured. 

77 
d:  This CT scan will measure lung density. As for the End of Study / Follow-Up Assessments, CT scan should only be conducted if it has passed more than 6 months from 
previous CT scan. 
e:  Virus safety retain samples (viral NAT and viral serology) will be collected prior to infusion at the Ext Week 52 of the 1st year, at the Ext Week 104 of the 2nd year, at the 
Ext Week 156 of the 3rd year, at the Ext Week 208 of the 4th year, at the Ext Week 260 of the 5th year, and at the Ext Week 312 of the 6th year, but will be tested only if a 
subject exhibits clinical signs and symptoms consistent with a viral infection. Additional blood 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. 
f:  To be conducted prior to Alpha-1 MP infusion (except the End of Study / Follow-Up Assessments). 
g:  Vital signs will be performed prior to and after each infusion of Alpha-1 MP (except the End of Study / Follow-Up Assessments). 
h:  Pulmonary function tests at the Ext Week 26 and 52 of the 1st year (at the Ext Week 78 and 104 of the 2nd year, and at the Ex Week 130 and 156 of the 3rd year, at the Ext 
Week 182 and 208 of the 4th year, at the Ext Week 234 and 260 of the 5th year and at the Ext Week 286 and 312 of the 6th year) should be conducted prior to Alpha-1 MP 
infusion. The post-bronchodilator PFT should be performed 15 to 30 minutes after bronchodilator administration. For each PFT, four puffs of MDI salbutamol as a short-
acting bronchodilator should be administered. The same bronchodilator should be used throughout the study.   
i:  Alpha1–PI level as measured by nephelometry.   
j:  Weekly infusions of 60 mg/kg Alpha-1 MP will be performed at the Investigator site.  
k:  Adverse event assessment includes AEs, SAEs, ADRs, and discontinuation due to AEs or SAEs. 
l:  Informed consent should be done at the Ext Week 52 and at the Ext Week 104, at the Ext Week 156, at the Ext Week 208, and at the Ext Week 260 for the next year (except 
the Ext Week 312). 
 

78 
APPENDIX 2 
A2.1 Sponsor 
1) 
Sponsor 
 
 
Grifols Japan K.K. 
1-2-8, Toranomon, Minato-ku, Tokyo, 105-0001, Japan 
TEL: 
  
FAX: 
 
 
2) 
 
 
 
Grifols Japan K.K. 
1-2-8, Toranomon, Minato-ku, Tokyo, 105-0001, Japan 
TEL: 
 
 
FAX: 
 
 
3) 
 
 
 
<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 
 
 
 
 

79 
A2.2 Contract Research Organization 
In this clinical trial, trial-related duties will be entrusted to the contract research organization 
below: 
 
 
CMIC Co., Ltd. 
1-1-1 Shibaura, Minato-ku, Tokyo 105-0023, Japan 
TEL: 
 (main switchboard) 
 
Monitor (CRA) 
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 
 
 
 

80 
A2.3 Grifols Therapeutics LLC., USA  
 
 
Grifols Therapeutics LLC. 
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 LLC. 
or will be carried out by the CMIC Co., Ltd. in conjunction with Grifols Therapeutics LLC. 
as listed below: 
1) 
Medical Monitor 
Refer to Attachment. 
 
Other duties to be performed by Grifols Therapeutics LLC. in conjunction with the CMIC 
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 

81 
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:
  FAX:
 
<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 
(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 Therapeutics LLC. 
4201 Research Commons 
79 T.W. Alexander Drive 
Research Triangle Park NC 27709, USA 
TEL: 
    FAX: 
 
 
A2.6 Central Evaluation of CT Scan Image 
Vida Diagnostics 
2500 Crosspark Road 
W250 BioVentures Center 
Coralville, IA 52241 
TEL: 
   FAX: 
 
 

82 
Attachment 1 
 
1. List of Investigational Sites and Investigators 
 
Investigational Sites 
(Address & Tel#) 
Department 
Principal Investigator 
Hokkaido University Hospital 
Kita 14 Nishi 5, Kita-ku,Sapporo  
060-8648 Japan 
Tel: 
 
 
 
 
Juntendo University Hospital 
3-1-3 Hongo, Bunkyo-ku, Tokyo  
113-8431 Japan 
Tel: 
 
 
 
 
Hirosaki University Hospital 
53 Honcho, Hirosaki, Aomori, 
036-8563 Japan 
Tel: 
 
 
 
 
 
 
 
2. Medical Monitor 
, M.D., Ph.D 
, 
Artage Inc. 
5-15-25 Minamiazabu, Minato-ku,  
Tokyo 106-0047, JAPAN 
TEL/FAX: 
 
 
 
, M.D., FCCP 
,  
Grifols Therapeutics LLC 
4210 Research Commons 
79 T.W. Alexander Drive, Research Triangle Park NC 27709, USA 
TEL: 
    FAX: 
 
 
 

83 
3. Monitor (CRA) 
 
Orphan Drug Trial Department 
Academia Clinical Research Division 
CMIC Co., Ltd. 
1-1-1 Shibaura, Minato-ku, Tokyo 105-0023, Japan 
TEL: 
,  
FAX: 
 
 
 

84 
APPENDIX 3 
A3.1 SAE Report Form 
 

85 

86 
 
 
 
 
 

87 
A3.2 Supplemental Event Form 
 
 
 
 

88 
A3.3 Pregnancy Report Form 
 
  

89 
 
 
 
 

90 
 
 
Emergency contact: 
 
 
Orphan Drug Trial Department 
Academia Clinical Research Division 
CMIC Co., Ltd. 
1-1-1 Shibaura, Minato-ku, Tokyo 105-0023, Japan 
TEL:
  
FAX: 
 
(Mobile phone No. 
)