A Phase 2/3, Open-Label, Repeat-Dose Study of the Pharmacokinetics, Efficacy, and Safety of Prometic Plasminogen Intravenous Infusion in Subjects With Hypoplasminogenemia
Phase: PHASE2
Conditions: Hypoplasminogenemia, Congenital Plasminogen Deficiency
Sponsor: Prometic Biotherapeutics, Inc.

IND Number: 16186 
Protocol Number: 2002C011G 
Prometic Biotherapeutics Inc. 
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CLINICAL PROTOCOL 
2002C011G 
A Phase 2/3, Open-Label, Repeat-Dose Study of the Pharmacokinetics, Efficacy, and Safety of 
Prometic Plasminogen Intravenous Infusion in Subjects with Hypoplasminogenemia 
 
Clinical Development Phase: 
2/3 
 
Sponsor: 
Prometic Biotherapeutics Inc. 
1330 Piccard Drive, Suite 201 
Rockville, MD 20850 
 
Medical Monitor: 
Joseph Parker, MD 
 
Issue Date: 
08August2018 
 
Version: 
Amendment 5 
 
 
CONFIDENTIAL – PROPRIETARY INFORMATION 

IND Number: 16186 
Protocol Number: 2002C011G 
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SIGNATURES 
Sponsor Signature 
 
 
Study Title: 
A Phase 2/3, Open-Label, Repeat-Dose Study of the Pharmacokinetics, 
Efficacy, and Safety of Prometic Plasminogen Intravenous Infusion in 
Subjects with Hypoplasminogenemia 
 
Study Number: 
2002C011G 
 
Version/Date: 
Amendment 5 / 08August2018 
 
Joseph M. 
Digitally signed by Joseph M. 
Parker, MD 
DN: cn=Joseph M. Parker, MD, 
o=ProMetic BioTherapeutics, ou, 
email=j.parker@prometic.com, 
c=US 
Date: 2018.08.08 11:10:43 -04'00' 
Signed:   
 
Joseph Parker, M.D. 
Senior Director, Clinical Development 
Prometic Biotherapeutics Inc. 
 
Date:   
 
Parker, 

IND Number: 16186 
Protocol Number: 2002C011G 
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Signature of Principal Investigator 
 
 
Study Title: 
A Phase 2/3, Open-Label, Repeat-Dose Study of the Pharmacokinetics, 
Efficacy, and Safety of Prometic Plasminogen Intravenous Infusion in 
Subjects with Hypoplasminogenemia 
 
Study Number: 
2002C011G 
 
Version/Date: 
Amendment 5 /08August2018 
 
 
I, the undersigned, have read the protocol and agree to conduct this protocol in accordance with 
ethical principles that have their origin in the Declaration of Helsinki and are consistent with the 
International Conference on Harmonisation (ICH) guidelines for Good Clinical Practice (GCP), 
and all applicable regulatory requirements 
I will provide copies of the protocol and access to all information furnished by the sponsor to study 
personnel under my supervision. I will discuss this material with them to ensure they are fully 
informed about the investigational product and the study. I understand that the study may be 
terminated or enrollment suspended at any time by sponsor with or without cause, or by me if it 
becomes necessary to protect the best interests of the study subjects. 
 
 
 
 
 
Signed:   
 
Name: 
Title: 
Affiliation: 
Address: 
Tel: 
E-mail: 
Date:   
 

IND Number: 16186 
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Protocol Synopsis 
 
Title 
A Phase 2/3, Open-Label, Repeat-Dose Study of the Pharmacokinetics, 
Efficacy, and Safety of Prometic Plasminogen Intravenous Infusion in 
Subjects with Hypoplasminogenemia 
Study Design 
Multicenter, open-label, uncontrolled, repeat-dose 
Indication 
Systemic treatment of Type I plasminogen deficiency 
(hypoplasminogenemia) 
Phase 
2/3 (pivotal) 
Investigational 
Medicinal 
Product 
Plasminogen (Human) Intravenous (IV), lyophilized material 
reconstituted with Water for Injection to produce a sterile suspension 
with a concentration of 5.5 mg/mL 
Objectives 
Primary objectives: 
• To achieve an increase of individual trough plasminogen activity 
by at least an absolute 10% (i.e., 10 U/dL) from baseline in adult 
and pediatric subjects with hypoplasminogenemia during the 12 
weeks of plasminogen replacement therapy in Segment 2; 
• To evaluate the efficacy of plasminogen replacement therapy on 
clinically evident or visible lesions of hypoplasminogenemia 
during 48 weeks of dosing in Segments 2 and 3. 
Secondary objectives: 
• To evaluate the safety and tolerability of plasminogen 
replacement therapy during the 48 weeks of dosing; 
• 
To evaluate the efficacy of plasminogen replacement therapy on 
clinically evident or visible symptoms of hypoplasminogenemia 
during the 12 weeks of dosing in Segment 2. 
• 
To evaluate the effect of plasminogen replacement therapy on 
pharmacokinetics and immunogenicity during the 48 weeks of 
dosing. 
Study Sites 
This study will be conducted in at least 2 sites, including at least 1 site in 
the US and 1 in Norway. 
Study Design 
Approximately 15 subjects aged 2 to 80 years with hypoplasminogenemia 
will be enrolled to ensure a sample size of at least 10 PK-evaluable subjects. 
At least 2 pediatric subjects, aged 2 to 18 years, will be enrolled. An 
evaluable subject for PK is defined as a subject who completes Segment 2 

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of plasminogen replacement therapy (see below) of the study and provides 
at least 3 blood samples to measure trough plasminogen activity levels. 
The study consists of a screening period and 3 segments as illustrated in 
Figure 1. Subjects who have documented individual PK profiles with the 
sponsor (e.g., due to participation in the previous Phase 1 study and received 
6 mg/kg Plasminogen) do not need to undergo Segment 1 and can proceed 
directly to Segment 2. 
Screening 
Subjects will be screened for study eligibility within a period of no more than 
21 days before the start of dosing. Subjects will enter either Segment 1 or 2, 
depending on the availability of their prior individual PK profile. 
Segment 1 
For subjects undergoing Segment 1, each will receive a single dose of 
6.6mg/kg Plasminogen IV infusion on Day -4. Blood samples for PK 
analysis will be drawn prior to infusion and subsequently through 96 hours 
after the infusion to establish individual PK profiles. The sample drawn prior 
to infusion will be used to measure the subject’s baseline plasminogen 
activity and antigen as well as D-dimer levels. The last PK sample (96 hours 
post infusion) will be withdrawn on Week 1, Day 0, before the 
administration of the first dose in Segment 2. The resulting PK profile will 
be used to determine each subject’s dosing interval in Segment 2. 
Segment 2 
Based on individual PK profiles, subjects will receive 6.6 mg/kg 
Plasminogen IV infusion every second, third, or fourth day for 12 weeks 
during Segment 2. Subjects will receive approximately 21 to 42 doses in 
Segment 2. 
For subjects who do not participate in Segment 1 and directly enter Segment 
2, baseline assessments will be conducted before the first dose of 
Plasminogen IV infusion, including a blood sample to measure the baseline 
plasminogen activity and antigen as well as D-dimer levels. Their dosing 
interval will be every second, third, or fourth day, depending on each 
subject’s PK profile on file. 
Subjects who have gone through Segment 1 will start with the every-third- 
day dosing interval until their individual PK results become available. This 
initial dosing regimen is based upon the aggregate PK obtained from the 
Phase 1 study. Once each subject’s individual PK profile becomes available, 
his or her dosing interval will be adjusted to every second, third, or fourth 
day accordingly. 
The first  dose of Plasminogen  IV infusion in this segment will 
beadministered at the study site on Week 1, Day 0. Subjects will visit the 
study sites every 4 weeks and receive the investigational medicinal product 
(IMP) infusion at the study site. The infusions between study visits can be 
administered at the study site or an ancillary site by study personnel or at the 

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subject’s home by a home health nurse, by the subject (i.e., self- 
administration), or by a caregiver/family member (US subjects only). 
Subjects or caregivers may be trained for IMP administration as deemed 
appropriate by the Investigator (US subjects only). The final dose at the 
Week 12 visit (or at study discontinuation) in Segment 2 must be 
administered at the study site to allow for a repeat PK profile. 
Plasma samples will be drawn before IMP administration every 2 weeks to 
measure the trough levels of plasminogen activity and antigen and D-dimer. 
The samples will be obtained at each study visit at Weeks 4, 8 and 12 and by 
a home health nurse at Weeks 2, 6, and 10. Additional samples may be taken 
in addition if needed. 
Subjects will undergo clinical assessments of the disease at each study visit 
depending on the system and organ involvement of hypoplasminogenemia 
and the characteristics of lesions, including but not limited to: photographic 
measurements of visible lesions (e.g., ocular, gingival), spirometry for 
subjects with pulmonary involvement, and imaging study of nonvisible 
lesions (e.g., oropharyngeal, ureteral, bronchial), as deemed appropriate by 
the investigator. 
Safety assessments will include vital signs, physical examination, clinical 
laboratory tests (hematology, chemistry, urinalysis, fibrinogen and 
coagulation panels, and urine pregnancy test for women of childbearing 
potential), AE assessments, virology, and immunogenicity. 
In addition, subjects will be given a diary to record infusions, symptoms, 
concomitant medications and AEs at home between visits. 
At the end of Segment 2, subjects will have the option to participate in 
Segment 3. Subjects for whom there is no perceived or anticipated benefit 
from further dosing would not be enrolled in Segment 3 at the investigator’s 
discretion and based on discussion with the Safety Monitoring Committee 
(SMC, see Section 3.7) and the sponsor. 
Any subject who discontinues the study during or at the end of Segment 2 
should return to the study site for a Safety Follow-up visit 30 days after the 
final IMP dose. 
Segment 3 
Subjects who participate in Segment 3 will continue to receive Plasminogen 
IV for 36 additional weeks in Norway and until product licensing or study 
termination by the sponsor for subjects in the United States. The dose will 
be 6.6 mg/kg with the frequency determined during Segment 2, with the 
option of modification based on clinical response and plasminogen trough 
levels. Subjects (or their caregivers) may be trained to self-administer the 
IMP at home if deemed appropriate by the Investigator. 
Subjects will return to the study sites for assessments every 3 months to 
monitor subjects’ clinical status and plasminogen trough levels. Subjects will 
be given a diary to record the dates of IMP administration, any AEs, 
concomitant medication and other relevant information. Subjects will be 

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given instructions for how to document receipt of IMP and how to return all 
used IMP vials. 
Subjects at the Norway site in Segment 3 should return to the study site for 
a Safety Follow-up visit 30 days after the final IMP dose. 
Due to the delay in product approval, subjects at the United States (US) site 
in Segment 3 will be allowed to enroll in Treatment Protocol 2002C018G 
and continue ongoing IMP treatment without any break in treatment. If 
subjects decide to enter Treatment Protocol 2002C018G, then they will 
return to the study site and complete the End of Study visit and sign an 
informed consent/assent for that study and stop participation in the current 
study. If subjects decide to not enter Treatment Protocol 2002C018G, then 
they will stop IMP and return to the study site for a Safety Follow-up visit 
30 days after the final IMP dose. 
Stopping rules 
Any subject who experiences any of the following occurrences will suspend 
the IMP treatment until further assessments: 
• Anaphylactic response to study drug administration 
• 
A significant AE that, in the investigator’s opinion, necessitates 
suspension of treatment 
• 
Confirmed presence of neutralizing antibodies (in at least 2 
measurements) in association with diminished plasminogen activity 
that obviates the potential benefit of plasminogen replacement 
therapy 
• 
Thrombotic or uncontrolled bleeding event requiring hospitalization 
The SMC will review safety data on an ongoing basis and will determine if 
a subject should stop treatment, or if there are unforeseen events (e.g., 
thromboembolic event) that would warrant halting or stopping the study. 
Such an event will be discussed with FDA before enrolling further subjects. 
Duration 
For each subject, the estimated duration of study participation is no more 
than 21 days for screening, 4 days for Segment 1, 12 weeks for Segment 2, 
and 40 weeks (36 weeks Treatment and 4 weeks Safety Follow-up) for 
subjects who participate in Segment 3 in Norway. 
For those subjects who participate in Segment 3 in the United States, it will 
be dependent on product approval and sponsor decision. A Safety Follow- 
up visit is required 30 days after the final IMP dose. However, due to the 
delay in product approval, subjects at the US site will be allowed to enroll in 
Treatment Protocol 2002C018G and continue ongoing IMP treatment 
without any break in treatment. If subjects decide to enter Treatment 
Protocol 2002C018G, then they will return to the study site and complete the 
End of Study visit and sign an informed consent/assent for that study and 
stop participation in the current study. If subjects decide to not enter 
Treatment Protocol 2002C018G, then they will stop IMP and return to the 
study site for a Safety Follow-up visit 30 days after the final IMP dose. 

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Administration & 
Dosage 
IMP Preparation 
Plasminogen (Human) Intravenous lyophilized material will be reconstituted 
with sterile Water for Injection to yield a solution of 5.5 mg/mL for IV 
infusion. 
Infusion 
Only eligible and enrolled subjects will receive IMP. The entire dose of the 
Plasminogen IV solution should be calculated on the basis of each subject’s 
body weight and infused over 10 to 30 minutes. 
Dose and Dosing Interval 
In Segment 1, a single dose of 6.6 mg/kg Plasminogen will be administered 
to each subject. However, subjects who have documented individual PK 
profiles with the sponsor (e.g., due to participation in the previous Phase 1 
study and received 6.6 mg/kg Plasminogen) do not need to undergo Segment 
1 and can proceed directly to Segment 2. 
In Segment 2, repeated doses of 6.6 mg/kg Plasminogen will be administered 
every second, third, or fourth day, depending on individual PK profile. 
Subjects will receive a range of 21 to 42 doses in Segment 2. 
The dosage and dosing interval in Segment 3 will be the same as Segment 
2, with the possibility of modification based on discussion between the 
Investigator and the sponsor. 
Inclusion criteria 
1. Subject or legal guardian has provided informed consent (as well as 
assent by subjects with ages dictated by local Investigational Review 
Board [IRB] guidelines). 
2. Subject is male or female between the ages of 2 and 80 years (inclusive). 
3. Subject has a documented history of lesions and symptoms consistent 
with a diagnosis of hypoplasminogenemia. 
4. Subject has plasminogen activity level ≤ 45%. 
5. Subject has documented vaccination to hepatitis A virus (HAV) and 
hepatitis B virus (HBV), or has received the first dose of HAV and HBV 
vaccine prior to the first dose of IMP and is scheduled to receive the 
second vaccine dose. If subject has documented vaccination more than 
1 year before screening but has a negative antibody titer to HAV and/or 
HBV at screening, subject is required to begin a re-vaccination series 
with the first dose of HAV and/or HBV vaccine prior to the first dose 
of IMP and is scheduled to receive the second vaccine dose. No 
revaccination is required if the documented vaccination took place 
within 1 year of screening. 
6. Subject agrees to use contraceptive methods from screening through 14 
days after last dose of study  treatment  (unless documented as 
biologically or surgically sterile (e.g., postmenopausal, vasectomized), 
or has not reached reproductive age. 

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Exclusion Criteria 
1. Subject has a history of anaphylactic reactions to blood or blood 
products that may interfere with participation in the study in the opinion 
of the investigator. 
2. Subject has uncontrolled hypertension. 
3. Subject has clinical or laboratory evidence of an intercurrent infection 
as evidenced by symptoms including fever, tachycardia, or other 
systemic signs and symptoms. (Note: Subjects with an intercurrent 
clinically significant infection cannot participate; however, once the 
infection has resolved according to the investigator, they can be re- 
screened if enrollment is still open.) 
4. Subject is pregnant and/or lactating. 
5. Subject has a malignancy, except for basal or squamous cell skin cancer, 
within 3 years before screening. 
6. Subject is a previous organ transplant recipient. 
7. Subject is in receipt of exogenous plasminogen (ocular or IV), such as 
laboratory grade plasminogen, fresh frozen plasma, or Prometic 
Plasminogen (Human) within 2 weeks of the screening visit. 
8. Subject has a psychiatric disorder, other mental disorder, or any other 
medical disorder that impairs the subject’s ability to provide informed 
consent or to comply with the requirements of the study protocol. 
9. Subject has evidence of renal dysfunction defined as of > 2 X the upper 
limit of normal (ULN) in serum creatinine. 
10. Subject has evidence of hepatic dysfunction defined as > 3 x ULN in 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), or 
alkaline phosphatase (ALP). 
11. Subject has participated in another IRB-approved interventional clinical 
trial of a drug, biologic, or device within 30 days before the first dose 
of the IMP. 
12. Subject has a chronic or acute clinically significant intercurrent illness 
(e.g., cardiac, hepatic, renal, endocrine, neurologic, hematologic, 
neoplastic, immunological, and skeletal) that the investigator 
determines could interfere with the assessments in this study. 
Criteria of 
Evaluation 
Pharmacokinetics: 
Blood samples will be drawn and analyzed for plasminogen activity and 
plasminogen antigen levels using validated assays at a central laboratory. 
Segment 1 
Blood samples are drawn on Day -4 before the IMP infusion to establish 
baseline levels for plasminogen activity, antigen, and D-dimer and at the 
following time points after the end of the infusion: between 5 and 15 
minutes, 6 hours (± 30 minutes), 24 hours (± 2 hours, Day -3), 48 hours (± 
2 hours, Day -2), 72 hours (± 2 hours, Day -1), and 96 hours (± 2 hours, 

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Day 0). An individual PK profile will be developed based on these time 
points. 
Subjects who have had individual PK profile for 6.6 mg/kg Plasminogen 
with the sponsor, due to participation in the prior Phase 1 study, do not 
participate in Segment 1. 
Segment 2 
For subjects who do not undergo Segment 1, blood samples are drawn to 
measure plasminogen activity and antigen levels on Week 1, Day 0, before 
the first dose of the IMP is given, to establish the baseline levels. 
For all subjects, blood samples will be drawn every 2 weeks before IMP 
infusion to measure trough levels through the final dose. 
A full PK profile will also be done for all subjects at the end of Segment 
2 (Week 12 visit) to evaluate the stability of individual PK profile after 12 
weeks of IMP administration. As plasminogen is a consumable clotting 
factor, if significant lesion burden is present at the start of the study or if 
neutralizing antibody develops, a subject’s PK profile may be altered by 
the end of the 12-week treatment period. At the Week 12 visit, blood 
samples are drawn before the IMP infusion and at the following time 
points after the end of the infusion: between 5 and 15 minutes, 6 hours (± 
30 minutes), 24 hours (± 2 hours), 48 hours (± 2 hours), 72 hours (± 2 
hours), and 96 hours (± 2 hours, Day 0). The PK profile will be developed 
for each subject and compared with his or her prior PK profile(s). 
Furthermore, additional PK analyses may be performed at other time 
points during Segment 2 as needed, such as when a subject’s trough level 
or antibody test suggests the appearance of neutralizing antibody against 
the IMP. 
Segment 3 
Blood samples will be drawn at each study visit every 3 months before 
IMP infusion to measure trough levels. 
Efficacy: 
All subjects will be clinically evaluated by the investigator for the clinical 
manifestation and severity of hypoplasminogenemia. 
• Visible lesions (ocular, gingival) will be evaluated using 
photographs. 
• Nonvisible lesions (e.g., ureteral, oropharyngeal, and bronchial) 
may be evaluated via imaging studies, such as computed 
tomography [CT] scans, X-ray, or other imaging techniques, as 
deemed appropriate by the Investigator. 
• Functionality of affected organs may be assessed as deemed 
appropriate by the Investigator. Respiratory tract involvement 
may be assessed by spirometry to measure forced vital capacity 

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(FVC), forced expiratory volume in 1 second (FEV1), peak 
expiratory flow (PEF), and FEV1/FVC ratio. 
• Clinical Global Impression scales 
• 
Quality of life assessment 
Safety 
Assessments 
Physical examinations, vital signs, and clinical laboratory tests will be 
assessed at each study visit. 
Virology will be assessed at Screening, Baseline, and every 12 weeks during 
dosing and at Study Discontinuation which is 30 days after the final dose of 
the IMP. An archive sample for virology will be taken at Baseline. 
Immunogenicity testing will be assessed at Screening and every 4 weeks 
during Segment 2, every 12 weeks during Segment 3 and at Study 
Discontinuation which is 30 days after the final dose of the IMP. 
At each IMP infusion during Segments 1 and 2 Study Visits, the study 
personnel will assess AEs and vital signs. Subjects will be provided a diary 
to record AEs and infusions between visits. 
All treatment-emergent AEs and SAEs will be documented, including 
assessments of their severity and relatedness to the IMP. 
Laboratory abnormalities, physical examination findings, and vital sign 
abnormalities that are clinically significant, as judged by the investigator, 
will be reported as AEs. 
Statistical 
Methods 
Analysis datasets 
Safety population: Includes any subject who receives at least one dose of 
the IMP and provides safety data for at least one non-screening visit. 
PK population: Includes any subject who has completed Segment 2 dosing 
and have provided sufficient samples for PK assessments. 
Full Analysis Set (FAS): Includes any subject who receives at least 1 dose 
of the IMP and provided data for at least one post-baseline efficacy 
assessments. 
Pharmacokinetic Analysis 
The primary PK endpoint is the number and percentage of subjects who 
achieve the target plasminogen activity trough levels for at least 3 
measurements in 12 weeks during Segment 2. The target trough level is 
defined as an increase in plasminogen activity level of at least an absolute 
10% (10 U/dL) from the subject’s individual baseline level. Baseline is 
defined as the plasminogen activity level measured before the first dose of 
IMP at Segment 1, Day -4 for subjects who undergo Segment 1 or at 
Segment 2, Day 0 for those who do directly enter Segment 2. Primary 
endpoint success is defined as at least 80% of evaluable subjects (i.e., 8 or 
more) achieving the target trough levels for at least 3 measurements in 12 
weeks. 

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The secondary PK endpoints include individual PK profiles at the end of 
Segment 2, compared with their PK profiles at baseline, and trough 
plasminogen activity and antigen levels during Segment 2 and Segment 3. 
Plasminogen activity and antigen levels will be presented by individual 
subjects and summarized descriptively (number of subjects, mean, 
standard deviation [SD], coefficient of variation [CV], medium, 
minimum, maximum, geometric mean and associated CV). Individual and 
median profiles of the concentration-time data will be plotted using 
nominal times. Median profiles may be presented on both linear-linear and 
linear-log scales. 
Standard PK parameters, including area under the curve (AUC), clearance 
(CL), mean residence time (MRT), volume of distribution (Vd) and 
terminal half-life (t1/2) will be calculated using non-compartmental 
analysis and baseline-adjusted plasminogen activity levels derived from 
Segment 1 data and, if a subject is suspected to develop neutralizing 
antibody to the IMP, plasminogen activity levels at the end of Segment 2. 
Additional PK compartmental analysis may be performed and best-fit 
model will be used for further individual PK prediction. 
D-dimer is monitored as a potential pharmacodynamic marker to better 
understand if there is a relationship between the levels of D-dimer in 
subjects over time and the subject’s potential response to therapy. 
Safety Analysis 
For analysis of safety and tolerability, TEAEs and SAEs will be 
summarized descriptively. Clinical laboratory tests (hematology, 
biochemistry, urinalysis, fibrinolysis/coagulation) will be presented in 
summary and shift tables. The numbers of subjects who had changes from 
baseline in viral tests and immunogenicity tests will be presented in 
individual subject listings and summary tables. 
Efficacy Analysis 
The primary efficacy endpoint is: 
Overall clinical success in number and size of lesions as measured by 
photographic or other imaging modality depending on the organ 
system affected or change in affected organ functionality at 48 weeks 
The secondary efficacy endpoints are 
• Overall clinical success in number and size of lesions as measured 
by photographic or other imaging modality depending on the organ 
system affected or change in affected organ functionality at 12 
weeks 
• CGI scores at 12 and 48 weeks 
• Quality of life scores at 12 and 48 weeks 

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Clinical success is considered achieved if 50% of subjects with visible or 
other measureable lesions demonstrate at least a 50% improvement in 
lesion number/size or functionality impact from baseline at 12 and/or 48 
weeks. Visible lesions are defined as lesions which can imaged and 
analyzed with digital photography. Other measureable lesions are defined 
as lesions whose dimensions can be assessed by medical imaging studies 
(e.g., computed tomography, magnetic resonance imaging, ultrasound, 
etc.) or organ specific functional assessments (e.g., spirometry, 
audiogram, oximetry, etc.). 
All efficacy results will be presented descriptively by individual subjects, 
including summarized hypoplasminogenemia symptoms over time 
recorded in subject diaries. 
The small sample size and high variability of disease presentation do not 
allow formal statistical analyses. 

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Table of Contents 
Protocol Synopsis .......................................................................................... 4 
Table of Contents ........................................................................................ 14 
List of In-text Tables ................................................................................... 17 
List of In-text Figures ................................................................................. 17 
List of Abbreviations and Definitions of Terms ....................................... 18 
1 
Introduction ........................................................................................ 20 
1.1 
Background .......................................................................................................20 
1.1.1 
Overview of Hypoplasminogenemia ..............................................................20 
1.1.2 
Current Treatment for Hypoplasminogenemia ...............................................20 
1.2 
Pre-clinical Experience with Plasminogen ........................................................21 
1.3 
Clinical Experience with Plasminogen..............................................................22 
1.4 
Benefit Versus Risk and Study Rationale .........................................................24 
1.5 
Dose Rationale ..................................................................................................25 
2 
Study Objectives ................................................................................. 27 
2.1 
Primary Objectives ............................................................................................27 
2.2 
Secondary Objectives ........................................................................................27 
3 
Study Design ....................................................................................... 27 
3.1 
Overall Study Design ........................................................................................27 
3.2 
Treatment, Dosage, and Duration. .....................................................................30 
3.2.1 
Inclusion Criteria ............................................................................................31 
3.2.2 
Exclusion Criteria ...........................................................................................32 
3.3 
Measures to Minimize or Avoid Bias. ...............................................................33 
3.3.1 
Randomization ................................................................................................33 
3.3.2 
Blinding ..........................................................................................................33 
3.4 
Study Procedures ...............................................................................................33 
3.4.1 
Procedures by Visit .........................................................................................36 
Screening .....................................................................................................36 
Baseline Assessments (Either Segment 1, Day -4 or Segment 2, Day 0) ...36 
Segment 1, Week 0, Day -4 (Participants Only) .........................................37 
Segment 1, Week 0, Day -3, Day -2, and Day -1 (Participants Only) ........38 

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Segment 2, Week 1, Day 0 ..........................................................................38 
Segment 2, Week 2, Week 6, Week 10 .......................................................38 
Segment 2, Weeks 4 and 8 ..........................................................................39 
Segment 2, Week 12 or Discontinuation.....................................................39 
Segment 3 ....................................................................................................40 
End of Study Visit for US Subjects Only....................................................41 
Safety Follow-up Visit ................................................................................41 
3.4.2 
Description of Assessments ............................................................................42 
Informed Consent/Assent ............................................................................42 
Demographics .............................................................................................42 
Medical History and Disease History and Symptoms.................................42 
Prior Medications and Treatments ..............................................................43 
Plasminogen Genetic Test ...........................................................................43 
PK Analyses for Plasminogen Activity and Antigen Levels ......................43 
Clinical Laboratory Tests ............................................................................44 
Vital Signs ...................................................................................................45 
Physical Examination ..................................................................................45 
Antibodies to Plasminogen .........................................................................45 
Virology ......................................................................................................45 
Subject Diary ...............................................................................................45 
Clinical Assessments ...................................................................................45 
Clinical Global Impression – Global Improvement (CGI-I) Scale .............46 
Quality of life assessment ...........................................................................46 
3.5 
Stopping Rules and Withdrawal ........................................................................47 
3.5.1 
Study Termination ..........................................................................................47 
3.5.2 
Stopping Rules ................................................................................................47 
3.5.3 
Withdrawal and Replacement of Subjects ......................................................47 
3.6 
Safety Monitoring Committee ...........................................................................48 
3.7 
Subject Identification ........................................................................................48 
3.8 
Treatment Compliance ......................................................................................48 
3.9 
Protocol Deviations ...........................................................................................49 
4 
Restrictions ......................................................................................... 49 

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4.1 
Concomitant and Prohibited Medications .........................................................49 
4.2 
Other Restrictions ..............................................................................................49 
5 
Reporting of Adverse Events ............................................................ 49 
5.1 
Definitions .........................................................................................................50 
5.1.1 
Adverse Event .................................................................................................50 
5.1.2 
Adverse Drug Reaction ...................................................................................50 
5.1.3 
Serious Adverse Event ....................................................................................50 
5.1.4 
Assessment of Severity ...................................................................................50 
5.1.5 
Assessment of Causality .................................................................................51 
5.2 
Eliciting and Reporting Adverse Events ...........................................................52 
5.3 
Serious Adverse Event Reporting .....................................................................52 
5.3.1 
SAE Reporting to the CRO .............................................................................52 
5.3.2 
Institutional Review Board/Ethics Committee ...............................................53 
5.3.3 
Expedited SUSAR Reporting (Sponsor Responsibility) ................................53 
5.4 
Pregnancy ..........................................................................................................54 
5.5 
Procedure for Breaking the Blind ......................................................................54 
5.6 
Follow-up of Adverse Events ............................................................................54 
6 
Statistical Analysis ............................................................................. 54 
6.1 
Datasets for Analysis .........................................................................................54 
6.2 
Handling of Missing Data .................................................................................55 
6.3 
Analyses Plan ....................................................................................................55 
6.3.1 
Demographics and Baseline Characteristics ...................................................55 
6.3.2 
Pharmacokinetic/Pharmacodynamic Analysis ................................................55 
6.3.3 
Efficacy Analysis ............................................................................................56 
6.3.4 
Safety Analysis ...............................................................................................57 
6.4 
Sample Size .......................................................................................................57 
6.5 
Interim Analysis ................................................................................................57 
7 
Management of Investigational Medicinal Product ....................... 57 
7.1 
Packaging and Labeling in the US ....................................................................57 
7.2 
Storage ...............................................................................................................58 
7.3 
Accountability ...................................................................................................58 
7.4 
Shipment, Returns, and Destruction ..................................................................59 

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7.5 
Preparation.........................................................................................................59 
7.6 
Administration ...................................................................................................59 
8 
Records Management ........................................................................ 59 
8.1 
Direct Access to Source Data/Documents .........................................................59 
8.2 
Data Collection and Management .....................................................................60 
8.3 
Record Keeping .................................................................................................60 
9 
Quality Control and Quality Assurance .......................................... 61 
9.1 
Quality Control by the Monitoring Team ..........................................................61 
9.2 
Quality Assurance by an Audit Team ...............................................................61 
9.3 
Quality Assurance by Data Management ..........................................................61 
10 
Ethics and Responsibility .................................................................. 62 
10.1 
Investigational Review Board/Ethics Committee .............................................62 
10.2 
Ethical Conduct of the Trial ..............................................................................62 
10.3 
Informed Consent and Assent ...........................................................................63 
10.4 
Changes in the Conduct of the Study ................................................................64 
11 
Confidentiality .................................................................................... 64 
12 
Publication Policy ............................................................................... 65 
13 
Liabilities and Insurance ................................................................... 65 
14 
References ........................................................................................... 65 
15 
Appendices .......................................................................................... 67 
15.1 
Declaration of Helsinki .....................................................................................67 
15.2 
Clinical Laboratory Tests ..................................................................................73 
15.3 
Clinical Global Impression – Global Improvement (CGI-I) .............................74 
15.4 
Quality of life assessment..................................................................................75 
 
 
List of In-text Tables 
Table 1. 
Plasminogen Activity Levels from Cohort 2 (6 mg/kg) of the Phase 1 Study .......... 26 
Table 2. 
Schedule of Events by Visit ....................................................................................... 34 
 
 
List of In-text Figures 
Figure 1. Study Design Diagram .................................................................................................. 30 

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List of Abbreviations and Definitions of Terms 
 
Abbreviation 
Definition 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CFR 
Code of Federal Regulation 
CL 
Clearance 
Cmax 
Maximum concentration 
CRA 
Clinical research associate 
CRO 
Contract research organization 
CT 
Computed tomography 
CV 
Coefficient of variation 
eCRF 
Electronic case report form 
EDTA 
Ethylenediaminetetraacetic acid 
EIA 
Enzyme immunoassay 
FDA 
Food and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Force vital capacity 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GGT 
Gamma glutamyltransferase 
HAV 
Hepatitis A virus 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV-1 
Human immunodeficiency virus Type 1 
HIV-2 
Human immunodeficiency virus Type 2 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug Application 

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INR 
International normalization ratio 
IRB 
Institutional Review Board 
ITT 
Intent to treat 
IV 
Intravenous 
LDH 
Lactic dehydrogenase 
MRT 
Mean residence time 
NAT 
Nucleic acid test 
PAI-1 
Plasminogen activator inhibitor-1 
PEF 
Peak expiratory flow 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QA 
Quality assurance 
QC 
Quality control 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SE 
Standard error 
SMC 
Safety Monitoring Committee 
t1/2 
Half-life 
tmax 
Time to maximum concentration 
ULN 
Upper limit of normal 
US 
United States 
Vd 
Volume of distribution 
WFI 
Water for Injection 
WBC 
White blood cell 

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1 
Introduction 
1.1 
Background 
 
1.1.1 
Overview of Hypoplasminogenemia 
 
Hypoplasminogenemia is a rare autosomal recessive genetic disorder that leads to a variety of 
significant clinical manifestations primarily associated with fibrous depositions on mucous 
membranes throughout the body (Schott et al., 1998). Plasminogen is a naturally occurring protein 
that is synthesized by the liver and circulates in the blood. Plasminogen is activated to form 
plasmin, an enzymatic component of the fibrinolytic system and is the main enzyme involved in 
the lysis of clots and clearance of extravasated fibrin (Collen et al., 1991). Plasmin is also involved 
in wound healing, cell migration, tissue remodeling, angiogenesis and embryogenesis (Castellino 
et al., 2005). 
Hypoplasminogenemia is a multisystem disease that can affect the eyes, ears, nasal and oral 
cavities, sinuses, tracheobronchial tree, genitourinary tract, gastrointestinal tract, and gingiva. The 
most common clinical manifestation of hypoplasminogenemia is ligneous conjunctivitis, which is 
characterized by thick, woody (ligneous) growths on the conjunctiva of the eye. If left untreated, 
ligneous conjunctivitis can lead to blindness. Most affected cases are infants and children showing 
their first clinical manifestation at a median age of approximately 10 months (Schuster et al., 2007; 
Bateman et al., 1986). Ligneous conjunctivitis is believed to be triggered by local infections, 
injury, irritation or inflammation, and various surgical interventions into the eye (Schuster et al., 
2003). 
In addition to ligneous conjunctivitis, hypoplasminogenemia can cause tracheobronchial lesions 
including abnormal membranes with poor pulmonary toilette that can result in chronic obstruction 
of the affected pulmonary segment or even respiratory failure. Hydrocephalus occurs in 
approximately 10% of children with severe hypoplasminogenemia, apparently related to the 
deposition of fibrin in the cerebral ventricular system; treatment may require implantation of a 
shunt which can be complicated by repeated occlusions and may lead to death. Severely impaired 
skin-wound healing has also been reported (Schott et al., 1998). 
Hypoplasminogenemia is listed as a rare disease by the National Institutes of Health (NIH) Office 
of Rare Diseases Research. Prevalence for hypoplasminogenemia is estimated at approximately 
1.6 per 1,000,000 (Tefs et al., 2006). 
1.1.2 
Current Treatment for Hypoplasminogenemia 
There are 2 forms of plasminogen: Glu and Lys. Most literature references of plasminogen 
replacement therapy are based on the Lys form; it is important to note the Prometic plasminogen 

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is the Glu form, which has a longer half-life (approximately 2.5 days in healthy subjects) than Lys- 
plasminogen (0.8 days) (Collen et al., 1991; Claeys et al., 1973). 
Attempted treatments for ligneous conjunctivitis lesions include: surgical removal; high dose 
intravenous corticosteroid treatment; topical treatment with heparin, corticosteroids and alpha- 
chymotrypsin, or cyclosporine; azathioprine; and hyaluronidase. These treatments are not 
consistently or completely successful in either the treatment or the prevention of lesion regrowth 
(Schuster et al., 2007; DeCock et al., 1995; Silva et al., 2006; Rubin et al., 1991). After treatment, 
including surgical removal, the lesions will usually recur. Local administration of fresh frozen 
plasma (which contains plasminogen) and other plasminogen-containing eye drops, however, has 
shown effectiveness in treating eye lesions of ligneous conjunctivitis (Heidemann et al., 2003). 
Furthermore, continued topical administration of plasminogen-containing eye drops can treat the 
lesion and prevent regrowth. Other research shows that systemic administration of plasminogen 
concentrates results in partial resolution of the lesions (Schott et al., 1998; Kraft et al., 2000). A 
6-month-old child treated with Lys-plasminogen preparation as a continuous infusion and later as 
daily bolus injections led to complete regression of ligneous conjunctivitis within 4 weeks and 
normalized hyperviscous secretions in the respiratory tract as well as skin wound healing (Schott 
et al., 1998). Currently, there is no plasminogen replacement product approved for the treatment 
of plasminogen deficiency in the US. 
1.2 
Pre-clinical Experience with Plasminogen 
 
A literature review revealed the following information regarding work done in plasminogen 
deficient animal models. Bugge et al. (1995) generated the first plasminogen-deficient 
homozygous (PLG -/-) knockout mouse model to study the physiological role of plasminogen in 
development, hemostasis, and reproduction. The PLG -/- mice completed embryonic development, 
survived to adulthood and were fertile. However, the PLG -/- mice were predisposed to severe 
thrombosis, and young animals exhibited thrombotic lesions in the liver, stomach, rectum, lungs, 
pancreas and other tissues. Further histological examination of the mice between 5 and 21 weeks 
old revealed formation of fibrin deposits in the liver and ulcerated lesions in the gastrointestinal 
tract compared to controls. The authors concluded that plasminogen plays a critical role in 
fibrinolysis and hemostasis. 
Ploplis et al. (1995) also generated homozygous knockout mice to investigate the effects of 
plasminogen disruption on thrombosis, growth, viability, and fertility in mice. Plasminogen- 
deficient mice survived embryonic development but developed spontaneous fibrin deposition due 
to impaired thrombolysis, suffered retarded growth (weighing significantly less than control and 
heterozygous knockouts), and had reduced fertility and survival. Approximately 20% of the 
homozygous Pg-/- mice developed rectal prolapse. Histological examination revealed fibrin 
deposits in the liver, lungs, and stomach, associated with gastric ulcers in 6 to 12 weeks old Pg-/- 

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mice, but not in the controls or heterozygous littermates. These PLG -/- mice displayed a reduced 
capacity to dissolve spontaneous pulmonary plasma clots within 24 hours. Thus, the most 
prominent phenotype of plasminogen-deficient mice appears to be related to fibrin homeostasis; 
some of the lesions, such as gastric ulcers, indicated that the plasminogen system may play a role 
in the prevention and/or healing of tissue damage. 
Bugge et al. (1996) also investigated the effects of combined homozygous plasminogen and 
fibrinogen deficiencies in mice by interbreeding of lines carrying disrupted plasminogen and 
fibrinogen-binding protein (FIB) genes. The double-deficient mice (PLG -/- and FIB-/-) exhibited 
similar phenotypic survival patterns to control animals. These results demonstrate that the lack of 
fibrinogen prevents animals from early morbidity and premature death associated with a PLG -/- 
deficiency. The authors concluded that the fundamental, and possibly only, essential physiological 
role of plasminogen is fibrinolysis. 
Lijnen et al. (1996) administered bolus injections of purified mouse plasminogen to PLG -/- mice 
and showed that the levels of plasminogen antigen and activity were increased to normal levels. 
Moreover, plasminogen administration was associated with significant restoration of thrombolytic 
potential and markedly reduced fibrin deposition in the liver after 24 hours of treatment. 
These studies in the plasminogen knockout mice (PLG /-) confirm the fundamental role of 
plasminogen in fibrinolysis and help establish the scientific understanding of the symptoms/lesions 
associated with plasminogen deficiency in humans. However, systemic administration of human 
plasminogen to plasminogen knockout mice would result in the development of cross-species anti- 
human antibodies in mice, making the mouse model impractical for studying the pharmacology of 
human plasminogen. No other suitable animal models for studying systemic treatment of 
plasminogen deficiency have yet been identified. 
1.3 
Clinical Experience with Plasminogen 
 
Prometic Biotherapeutics, Inc. (hereafter referred to as the sponsor), is developing Plasminogen 
(Human) Intravenous Lyophilized Solution (the investigational medicinal product [IMP]), for the 
treatment of hypoplasminogenemia. The IMP is derived from pooled plasma donated by US blood 
donors and has undergone multiple steps of viral testing and inactivation. 
The 
clinical 
development 
program 
for 
Plasminogen 
(Human) 
in 
subjects 
with 
hypoplasminogenemia consists of a completed Phase 1, single-ascending-dose study in adolescent 
and adult subjects (2002C005G), an ongoing pivotal Phase 2/3 repeat dose study in pediatric and 
adult subjects (2002C011G), and supportive data from 3 ongoing single-subject, repeat-dose, 
Expanded Access studies (2002C013G, 2002C016G, and 2002C017G). In the Phase 1 study 
2002C005G, 5 subjects received a single IV infusion of Plasminogen (2 mg/kg) and 7 subjects 
received a single IV infusion of Plasminogen (6.0 mg/kg). Both doses were well tolerated. 

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In addition to the Phase 1 study, Prometic provided Plasminogen to an infant with 
hypoplasminogenemia in Germany on the compassionate-use basis. Prometic was contacted by a 
German physician who made a request to obtain Plasminogen for a patient. The patient is a 22- 
month-old child with hypoplasminogenemia. Within 2 weeks after birth, he presented with 
problems with his eyes and respiratory tract and was diagnosed with hypoplasminogenemia. From 
then onward, he has been through various treatments, including surgery in combination with 
antibiotics, and other medications. He had also received fresh frozen plasma infusions as part of 
his treatment. When Prometic was contacted, the patient was in critical condition in a pediatric 
ICU receiving ventilatory and circulatory support. He had a collapsed left lung and right lower 
lobe related to viscous bronchial secretions and to obstructing ligneous lesions in the bronchial 
tree. On 15 September 2015, the physician gave an initial dose of 4 mg/kg the IMP, which was 
increased to 6 mg/kg and then 6.5 mg/kg every second day. The patient was extubated within a 
matter of days. To date, no adverse events (AEs) associated with administration of Plasminogen 
have been observed. 
In the current study, an interim analysis was performed after the first 10 subjects completed 12 
weeks of treatment with a data cutoff at 30 November 2016. All 10 of these subjects achieved 
target PK trough levels demonstrating the ability of Prometic’s Plasminogen (Human) to serve as 
effective replacement therapy. Preliminary efficacy evaluation at 12 weeks revealed that 13 of 14 
visible lesions had resolved, and the remaining lesion had improved from 15 × 5 mm at baseline 
to too small to be measured at 12 weeks. There were no recurrences and no new lesions during 
this period of observation. There were no deaths, serious adverse events (SAEs), or AEs 
resulting in discontinuation of study drug. The most frequent AEs were headache and 
nasopharyngitis. Nausea, diarrhea, rhinorrhea, sinusitis, epistaxis, back pain, pain in extremity, 
and hematuria were also frequent in adult subjects, and upper abdominal pain and cough were 
frequent AEs in pediatric subjects. A US Biologics Licensing Application was submitted based 
on these interim data; this application is under review. As of 14Dec2017 study enrollment is 
complete and all 15 enrolled subjects received at least 48 weeks of treatment. Three subjects in 
Norway completed the study as planned, with the remaining 12 subjects in the US continuing 
treatment until product licensing or study termination by the Sponsor. However, due to the delay 
in product approval, subjects at the US site will be allowed to enroll in Treatment Protocol 
2002C018G and continue ongoing IMP treatment without any break in treatment. If subjects 
decide to enter Treatment Protocol 2002C018G, then they will return to the study site and 
complete the End of Study visit and sign an informed consent/assent for that study and stop 
participation in the current study. If subjects decide to not enter Treatment Protocol 2002C018G, 

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then they will stop IMP and return to the study site for a Safety Follow-up visit 30 days after the 
final IMP dose. 
Subject dosing has been revised throughout the protocol from 6.0 mg/kg to 6.6 mg/kg of 
plasminogen to reflect the true concentration and dosing as agreed with FDA during the 
05Oct2016 Pre-BLA Meeting (CRMTS# 10393). 
Details of these studies can be found in the Investigator’s Brochure (IB). 
1.4 
Benefit Versus Risk and Study Rationale 
 
The prognosis of hypoplasminogenemia is variable depending on the extent, location(s), length, 
and site of the lesions. A number of patients have died or have suffered loss of affected organ 
functions, such as sight and dentition, as a result of hypoplasminogenemia (Mehta and Shapiro, 
2008). The one clearly documented effective therapy that leads to resolution and halts re-formation 
of ophthalmologic lesions is systemic or topical plasminogen concentrates (Heidemann et al., 
2003; Watts et al., 2002; Pergantou et al., 2011; Tabarra et al., 2004). There is no effective licensed 
local or systemic plasminogen replacement therapy available for hypoplasminogenemia. 
Prometic is developing purified human plasminogen as replacement therapy from its proprietary 
PPPS plasma fractionation process for the systemic treatment of hypoplasminogenemia. This rare 
disease represents an area of unmet medical need, where optimal treatment is likely to be systemic 
replacement of plasminogen to reduce or resolve the clinical manifestations in patients and to 
prevent or suppress lesion recurrence. Prior to generation of this material by Prometic, no purified 
Glu-plasminogen has been available for evaluation in plasminogen deficient subjects. We 
hypothesize based on pharmacokinetic data in the Phase 1 study using Glu-plasminogen that a 
trough level of >10% plasminogen activity above baseline is achievable with every other day or 
every third day dosing. Potential clinical benefit will be assessed during Segment 2 and Segment 
3 to monitor and correlate plasminogen replacement therapy with clinical response in visibly 
evident lesions. 
In support of this strategy, results from a case study indicate the benefit of repeat dosing as 
demonstrated in a named patient in Germany treated with Prometic’s plasminogen. The 
plasminogen deficient subject had a collapsed left lung and right lower lobe related to viscous 
bronchial secretions and to obstructing ligneous lesions in the bronchial tree. Pharmacokinetic 
results for this subject showed that the trough values 10% above baseline were achieved with the 
current dosing regimen. The subject was extubated within a matter of days of administration of 
intravenous Plasminogen (Human). To date, no adverse events have been observed associated with 
administration of Plasminogen (Human) in this subject. 
This is a Phase 2/3 pivotal study of Prometic Plasminogen (Human) Intravenous Lyophilized 
solution. 

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As the IMP is derived from pooled plasma, there are potential safety risks associated with the IMP, 
including a low inherent risk of transmission of blood-borne pathogens. These are unlikely, given 
current viral donor testing and robust virus elimination/inactivation processes performed during 
manufacturing. The IMP was well tolerated in the Phase 1 single-dose study at 2 mg/kg and 6 
mg/kg. 
Additionally, there is a risk that subjects will develop antibodies to exogenous plasminogen since 
plasminogen deficiency is a heterogeneous disease with a variety of genetic mutations resulting in 
altered plasminogen protein. It is unknown if such antibodies will be neutralizing and perhaps 
interfere with the efficacy of Plasminogen (Human). The effects of potential neutralizing 
antibodies will be assessed during the study. 
Given the absence of effective licensed treatment for hypoplasminogenemia, the potential 
benefits of this study to the affected population and study participants outweigh the risk of their 
participation. 
1.5 
Dose Rationale 
 
A successful outcome for this study is defined as achieving a trough level of plasminogen that is 
at least 10% above the subject’s baseline level for at least 3 measurements during the 12 weeks of 
treatment in Segment 2. Table 1 shows the results of a single IV infusion of Plasminogen 6 mg/kg, 
in the 5 adult subjects in Cohort 2 of the Phase 1 study. Red highlighted cells indicate when a 
trough level less than 10% above the baseline level was obtained at 72 or 96 hours, while orange 
cells indicate a value exceeding but close to the desired >10% level. All subjects achieved a trough 
level at 48 hours above the 10% level over baseline. These data are used to establish the dosing 
regimens in this Phase 2/3 study. For example, if Subjects 2, 6 and 7 were to enter the Phase 2/3 
study, they would require dosing every second day to routinely avoid a trough level <10% above 
baseline, while Subjects 1 and 8 would require dosing every 3 days. This data may be augmented 
by PK modeling of repeat dosing to aid the investigator with the selection of the appropriate dose 
for the subject. 
Therefore, subjects who enter the Phase 2/3 study will be commenced on an initial regimen of 
6.6 mg/kg every 2, 3, or 4 days, with the decision based on each subject’s individual known PK 
profile if they have been dosed in Cohort 2 at 6 mg/kg in the Phase 1 study. New subjects will 
undergo a PK study (Segment 1) with blood samples taken up to 96 hours after injection and will 
be started on an every-third-day dosing regimen at 6.6 mg/kg until their individual PK results are 
available, at which time dosing will tailored accordingly (Section 3.2). A change in dosing interval 
to provide an increase or decrease in the trough levels may be required at the discretion of the 
principal investigator (PI) and the Sponsor, based on the actual results in each individual patient. 

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Table 1. Plasminogen Activity Levels from Cohort 2 (6 mg/kg) of the Phase 1 Study 
 
Time 
Subject # 1 
Subject # 2 
Subject # 6 
Subject # 7 
Subject # 8 
Plg 
% 
Increase 
from 
Baseline 
Plg 
% 
Increase 
from 
Baseline 
Plg 
% 
Increase 
from 
Baseline 
Plg 
% 
Increase 
from 
Baseline 
Plg 
% 
Increase 
from 
Baseline 
Baseline 
30 
- 
52 
- 
33 
- 
19 
- 
4 
- 
5-15 
min 
162 
132 
146 
94 
110 
77 
95 
76 
86 
82 
1 h 
160 
130 
126 
74 
105 
72 
98 
79 
84 
80 
6 h 
126 
96 
109 
57 
93 
60 
80 
61 
79 
75 
24 h 
90 
60 
79 
27 
69 
36 
55 
36 
53 
49 
48 h 
65 
35 
74 
22 
56 
23 
41 
22 
32 
28 
72 h 
53 
23 
55 
3 
46 
13 
33 
14 
21 
17 
96 h 
42 
12 
49 
- 
39 
6 
28 
9 
17 
13 
Abbreviations: Plg=plasminogen, min=minutes. 
At the end of Segment 2, subjects will be asked to participate in long-term therapy in Segment 3, 
if this is deemed appropriate by the Investigator, Safety Monitoring Committee (SMC), and 
Sponsor. Plasminogen deficiency is a life-long disorder, and continued plasminogen replacement 
therapy to suppress lesion development and/or worsening disease is likely necessary for patients 
with a history of frequent or recurrent lesions. 

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2 
Study Objectives 
2.1 
Primary Objectives 
 
The primary objectives of the study are: 
• To achieve an increase of individual trough plasminogen activity by at least an absolute 
10% (i.e., 10 U/dL) from baseline in adult and pediatric subjects with 
hypoplasminogenemia during the 12 weeks of plasminogen replacement therapy in 
Segment 2; and 
• To evaluate the efficacy of plasminogen replacement therapy on clinically evident or 
visible symptoms of hypoplasminogenemia during the 48 weeks of dosing in Segments 2 
and 3. 
2.2 
Secondary Objectives 
 
The secondary objectives of the study are: 
• To evaluate the safety and tolerability of plasminogen replacement therapy during the 48 
weeks of dosing; and 
• To evaluate the efficacy of plasminogen replacement therapy on clinically evident or 
visible symptoms of hypoplasminogenemia during the 12 weeks of dosing in Segment 2; 
and 
• 
To evaluate the effect of plasminogen replacement therapy on pharmacokinetics and 
immunogenicity during the 48 weeks of dosing. 
 
3 
Study Design 
3.1 
Overall Study Design 
 
Approximately 15 subjects aged 2 to 80 years with hypoplasminogenemia will be enrolled to 
ensure a sample size of at least 10 PK-evaluable subjects. At least 2 pediatric subjects, aged 2 to 
18 years, will be enrolled. An evaluable subject for PK is defined as a subject who completes 
Segment 2 of plasminogen replacement therapy (see below) of the study and provides at least 3 
blood samples to measure trough plasminogen activity levels. 
The study consists of a screening period and 3 segments as illustrated in Figure 1. Subjects who 
have documented individual PK profiles with the sponsor (e.g., due to participation in the previous 
Phase 1 study and received 6 mg/kg Plasminogen) do not need to undergo Segment 1 and can 
proceed directly to Segment 2. 

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Screening 
Subjects will be screened for study eligibility within a period of no more than 21 days before the 
start of dosing. Subjects will enter either Segment 1 or 2, depending on the availability of their 
prior individual PK profile. 
Segment 1 
For subjects undergoing Segment 1, each will receive a single dose of 6.6 mg/kg Plasminogen IV 
infusion on Day -4. Blood samples for PK analysis will be drawn prior to infusion and 
subsequently through 96 hours after the infusion to establish individual PK profiles. The sample 
drawn prior to infusion will be used to measure the subject’s baseline plasminogen activity and 
antigen as well as D-dimer levels. The last PK sample (96 hours post infusion) will be withdrawn 
on Week 1, Day 0, before the administration of the first dose in Segment 2. The resulting PK 
profile will be used to determine each subject’s dosing interval in Segment 2. 
Segment 2 
Based on individual PK profiles, subjects will receive 6.6 mg/kg Plasminogen IV infusion every 
second, third, or fourth day for 12 weeks during Segment 2. Subjects will receive approximately 
21 to 42 doses in Segment 2. 
For subjects who do not participate in Segment 1 and directly enter Segment 2, baseline 
assessments will be conducted before the first dose of Plasminogen IV infusion, including a blood 
sample to measure the baseline plasminogen activity and antigen as well as D-dimer levels. Their 
dosing interval will be every second, third, or fourth day, depending on each subject’s PK profile 
on file. 
Subjects who have gone through Segment 1 will start with the every-third-day dosing interval until 
their individual PK results become available. This initial dosing regimen is based upon the 
aggregate PK obtained from the Phase 1 study. Once each subject’s individual PK profile becomes 
available, his or her dosing interval will be adjusted to every second, third, or fourth day accordingly. 
The first dose of Plasminogen IV infusion in this segment will be administered at the study site on 
Week 1, Day 0. Subjects will visit the study sites every 4 weeks and receive the IMP infusion at 
the study site. The infusions between study visits can be administered at the study site or an 
ancillary site by study personnel or at the subject’s home by a home health nurse, by the subject 
(i.e., self-administration), or by a caregiver/family member (US subjects only). Subjects or 
caregivers may be trained for IMP administration as deemed appropriate by the Investigator (US 
subjects only). Subjects administering IMP at home (home administration in the US only) are not 
required to take vital signs with the infusion. Vitals for home administration subjects will only be 
taken when the nurse draws trough levels (Week 2, 6, and 10) and when the subject returns to the 
site for visits (Week 4, 8, and 12) and every 12 weeks thereafter in Segment 3. The final dose at 

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the Week 12 visit (or at study discontinuation) in Segment 2 must be administered at the study site 
to allow for a repeat PK profile. 
Plasma samples will be drawn before IMP administration every 2 weeks to measure the trough 
levels of plasminogen activity and antigen and D-dimer. The samples will be obtained at each 
study visit at Weeks 4, 8 and 12 and by a home health nurse at Weeks 2, 6 and 10. Additional 
samples may be taken in addition if needed. 
Subjects will undergo clinical assessments of the disease at each study visit depending on the 
system and organ involvement of hypoplasminogenemia and the characteristics of lesions, 
including but not limited to: photographic measurements of visible lesions (e.g., ocular, gingival), 
spirometry for subjects with pulmonary involvement, and imaging study of nonvisible lesions 
(e.g., oropharyngeal, ureteral, bronchial), as deemed appropriate by the investigator. 
Safety assessments will include vital signs, physical examination, clinical laboratory tests 
(hematology, chemistry, urinalysis, fibrinogen and coagulation panels, and urine pregnancy test 
for women of childbearing potential), AE assessments, virology, and immunogenicity. 
In addition, subjects will be given a diary to record infusions, symptoms, concomitant medications 
and AEs at home between visits. 
At the end of Segment 2, subjects will have the option to participate in Segment 3. Subjects for 
whom there is no perceived or anticipated benefit from further dosing would not be enrolled in 
Segment 3 at the investigator’s discretion and based on discussion with the Safety Monitoring 
Committee (SMC, see Section 3.7) and the sponsor. 
Any subject who discontinues the study during or at the end of Segment 2 should return to the 
study site for a Safety Follow-up visit 30 days after the final IMP dose. 
Segment 3 
Subjects who participate in Segment 3 will continue to receive Plasminogen IV for an additional 
36 weeks in Norway and until product licensing or study termination by the sponsor for subjects 
in the United States. The dose will be 6.6 mg/kg with the frequency determined during Segment 
2, with the option of modification based on clinical response and plasminogen trough levels. 
Subjects (or their caregivers) may be trained to self-administer the IMP at home if deemed 
appropriate by the Investigator. 
Subjects will return to the study sites for assessments every 3 months to monitor subjects’ clinical 
status and plasminogen trough levels. Subjects will be given a diary to record the dates of IMP 
administration, any AEs, concomitant medication and other relevant information. Subjects will be 
given instructions for how to document receipt of IMP and how to return all used IMP vials. 

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Subjects at the Norway site in Segment 3 should return to the study site for a Safety Follow-up 
visit 30 days after the final IMP dose. 
Due to the delay in product approval, subjects at the US site in Segment 3 will be allowed to enroll in 
Treatment Protocol 2002C018G and continue ongoing IMP treatment without any break in treatment. 
If subjects decide to enter Treatment Protocol 2002C018G, then they will return to the study site and 
complete the End of Study visit and sign an informed consent/assent for that study and stop 
participation in the current study. If subjects decide to not enter Treatment Protocol 2002C018G, then 
they will stop IMP and return to the study site for a Safety Follow-up visit 30 days after the final IMP 
dose. 
Figure 1. Study Design Diagram 
 
 
 
 
 
 
 
 
 
 
 
*End of study = Week 48 in Norway and product licensing or study termination by sponsor in the US. A Safety 
Follow-up visit is required 30 days after the last IMP dose in any segment, Due to the delay in product approval, 
subjects at the US site in Segment 3 will be allowed to enroll in Treatment Protocol 2002C018G and continue ongoing 
IMP treatment without any break in treatment. If subjects decide to enter Treatment Protocol 2002C018G, then they 
will return to the study site and complete the End of Study visit and sign an informed consent/assent for that study and 
stop participation in the current study. If subjects decide to not enter Treatment Protocol 2002C018G, then they will 
stop IMP and return to the study site for a Safety Follow-up visit 30 days after the final IMP dose. 
 
 
3.2 
Treatment, Dosage, and Duration 
 
In Segment 1, a single dose of 6.6 mg/kg Plasminogen will be administered to each subject. 
However, subjects who have documented individual PK profiles with the sponsor (e.g., due to 
participation in the previous Phase 1 study and received 6 mg/kg Plasminogen) do not need to 
undergo Segment 1 and can proceed directly to Segment 2. 
In Segment 2, repeated doses of 6.6 mg/kg Plasminogen will be administered every second, third, 
or fourth day, depending on individual subject’s PK profile. Individual dosing intervals will be 
determined by the longest time point that the subject’s plasminogen activity level remains 10% 
(absolute) above their baseline value. For example, if a subject’s plasminogen activity level 
remains above 10% (absolute %) above their baseline at 48 hours and their activity level at 72 
Treatment: Plasminogen IV infusion 
Screening 
Segment 1 
Single-dose 
6.6 mg/kg PK 
Segment 2 
Multi-dose 
6.6 mg/kg every second, third or 
fourth day 
PK, efficacy, safety 
Segment 3 
Extended treatment 
Safety 
≤21 days 
Day -4 
Week 1 
Day 0 
Week 12 
End of Study* 

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hours drops below 10% (absolute %) then that subject will be dosed every second day. Subjects 
will receive a range of 21 to 42 doses in Segment 2. 
The dosage and dosing interval in Segment 3 will be the same as Segment 2, with the possibility 
of modification based on discussion between the Investigator and the sponsor. In the event that a 
subject does not achieve the expected/optimum clinical response by the completion of Segment 2, 
the principal investigator may reduce the dosing interval during Segment 3 by one day increments 
until the trough plasminogen activity level exceeds 45%. 
For each subject, the estimated duration of study participation is no more than 21 days for screening, 
4 days for Segment 1, 12 weeks for Segment 2, and 40 weeks (36 weeks of treatment and 4 weeks of 
safety follow-up) for Segment 3 for subjects in Norway. For those subjects in the United States who 
participate in Segment 3, it will be dependent on product approval and sponsor decision. A Safety 
Follow-up visit is required 30 days after the final IMP dose. However, due to the delay in product 
approval, subjects at the US site will be allowed to enroll in Treatment Protocol 2002C018G and 
continue ongoing IMP treatment without any break in treatment. If subjects decide to enter Treatment 
Protocol 2002C018G, then they will return to the study site and complete the End of Study visit and 
sign an informed consent/assent for that study and stop participation in the current study. If subjects 
decide to not enter Treatment Protocol 2002C018G, then they will stop IMP and return to the study 
site for a Safety Follow-up visit 30 days after the final IMP dose. 
 
 
3.3 
Subject Population 
 
A total of 15 subjects with hypoplasminogenemia will be enrolled in the study to ensure at least 
10 evaluable subjects. At least 2 pediatric subjects (aged 2 to 18 years) will be enrolled. 
3.3.1 
Inclusion Criteria 
 
Subjects must meet all the criteria below to participate in this study: 
1. Subject or legal guardian has provided informed consent (as well as assent by subjects with 
ages dictated by local Investigational Review Board [IRB] guidelines). 
2. Subject is male or female between the ages of 2 and 80 years (inclusive). 
3. Subject has a documented history of lesions and symptoms consistent with a diagnosis of 
hypoplasminogenemia. 
4. Subject has plasminogen activity level ≤ 45%. 
5. Subject has documented vaccination to hepatitis A virus (HAV) and hepatitis B virus 
(HBV), or has received the first dose of HAV and HBV vaccine prior to the first dose of 
IMP and is scheduled to receive the second vaccine dose. If subject has documented 

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vaccination more than 1 year before screening but has a negative antibody titer to HAV 
and/or HBV at screening, subject is required to begin a re-vaccination series with the first 
dose of HAV and/or HBV vaccine prior to the first dose of IMP and is scheduled to receive 
the second vaccine dose. No revaccination is required if the documented vaccination took 
place within 1 year of screening. 
6. Subject agrees to use contraceptive methods from screening through 14 days after last dose 
of study treatment (unless documented as biologically or surgically sterile (e.g., 
postmenopausal, vasectomized), or has not reached reproductive age. 
 
3.3.2 
Exclusion Criteria 
 
Subjects must meet none of the criteria below: 
1. Subject has a history of anaphylactic reactions to blood or blood products that may interfere 
with participation in the study in the opinion of the investigator. 
2. Subject has uncontrolled hypertension. 
3. Subject has clinical or laboratory evidence of an intercurrent infection as evidenced by 
symptoms including fever, tachycardia, or other systemic signs and symptoms. (Note: 
Subjects with an intercurrent infection cannot participate; however, once the infection has 
resolved as judged by the investigator, they can be re-screened if enrollment is still open.) 
4. Subject is pregnant and/or lactating. 
5. Subject has a malignancy, except for basal or squamous cell skin cancer, within 3 years 
before screening. 
6. Subject is a previous organ transplant recipient. 
7. Subject is in receipt of exogenous plasminogen (ocular or IV), such as laboratory grade 
plasminogen, fresh frozen plasma, or Prometic Plasminogen (Human) within 2 weeks of 
the screening visit. 
8. Subject has a psychiatric disorder, other mental disorder, or any other medical disorder that 
impairs the subject’s ability to provide informed consent or to comply with the 
requirements of the study protocol. 
9. Subject has evidence of renal dysfunction defined as of > 2 X the upper limit of normal 
(ULN) in serum creatinine. 
10. Subject has evidence of hepatic dysfunction defined as > 3 x ULN in alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase 
(ALP). 

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11. Subject has participated in another IRB-approved interventional clinical trial of a drug, 
biologic, or device within 30 days before the first dose of the IMP. 
12. Subject has a chronic or acute clinically significant inter-current illness (e.g., cardiac, 
hepatic, renal, endocrine, neurologic, hematologic, neoplastic, immunological, and 
skeletal) that the investigator determines could interfere with the assessments in this study. 
 
 
 
3.4 
Measures to Minimize or Avoid Bias 
 
3.4.1 
Randomization 
 
Subjects will not be randomized. 
3.4.2 
Blinding 
 
This study will not be blinded. 
3.5 
Study Procedures 
 
The schedule of events is provided in Table 2. 

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Table 2. 
Schedule of Events by Visit 
 
Segment 1a 
Segment 2l 
Segme 
nt 3l 
End of 
Study 
Visit 
for 
Subjec 
ts at 
US 
Site 
Onlyo 
Safety 
Follo 
w-up 
Scree 
ning 
(≤ 21 
days) 
Day - 
4 
Day - 
3, 
Day - 
2, 
Day - 
1 
Wee 
k 1 
Day 
0 
Wee 
k 2b 
 
Wee 
k 4 
Wee 
k 6b 
Wee 
k 8 
Wee 
k 
10b 
Wee 
k 
12c 
Every 
12 
Weeks 
30 
days 
post 
final 
dose 
Informed 
consent/ assent 
X 
Eligibility 
review 
X 
Demographics 
X 
Medical 
history 
X 
Xj 
Xj 
Disease 
history & 
treatment 
X 
Xj 
Xj 
Medication 
history 
X 
Xj 
Xj 
Weight 
X 
Xj 
Xj 
X 
X 
X 
X 
Physical 
examination 
X 
Xj 
Xj 
X 
X 
X 
X 
Urine 
pregnancy 
testd 
X 
Xj 
Xj 
X 
X 
X 
X 
Genetic teste 
X 
Xj 
Xj 
Hematology 
X 
Xj 
Xj 
X 
X 
X 
X 
X 
X 
Biochemistry 
X 
Xj 
Xj 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
Xj 
Xj 
X 
X 
X 
X 
X 
X 
Fibrinolysis & 
coagulation 
panels 
X 
Xj 
Xj 
X 
X 
X 
X 
X 
X 
Virology 
X 
Xj 
Xj 
X 
X 
X 
X 
Retention 
virology 
sample 
Xj 
Xj 
Anti- 
plasminogen 
antibody 
Xj 
Xj 
X 
X 
X 
X 
X 
X 
Plasminogen 
activity and 
antigen, D- 
dimer: trough 
levels 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Plasminogen 
activity and 
antigen, D- 
dimer: spot 
levels 
X 

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Segment 1a 
Segment 2l 
Segme 
nt 3l 
End of 
Study 
Visit 
for 
Subjec 
ts at 
US 
Site 
Onlyo 
Safety 
Follo 
w-up 
Scree 
ning 
(≤ 21 
days) 
Day - 
4 
Day - 
3, 
Day - 
2, 
Day - 
1 
Wee 
k 1 
Day 
0 
Wee 
k 2b 
 
Wee 
k 4 
Wee 
k 6b 
Wee 
k 8 
Wee 
k 
10b 
Wee 
k 
12c 
Every 
12 
Weeks 
30 
days 
post 
final 
dose 
Plasminogen 
activity and 
antigen, D- 
dimer: PK 
profilef 
X 
X 
Xk 
X 
Clinical 
assessmentsg 
Xj 
Xj 
X 
X 
X 
X 
X 
X 
Clinical 
Global 
Impression 
Xj 
Xj 
X 
X 
X 
Xn 
Quality of life 
assessment 
Xj 
Xj 
X 
X 
X 
Xn 
Chest X-ray 
Xj,m 
Xj,m 
Xm 
Vital signsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IMP infusioni 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Subject diary 
X 
X 
X 
X 
X 
X 
X 
AE = adverse event; IMP = investigational medicinal product; PK = pharmacokinetic. 
a. 
For subjects who do not have PK profile for 6 mg/kg Plasminogen on file only. Those who have PK profile on 
file (e.g., they participated in the previous Phase 1, Cohort 2 study) do not need to go through Segment 1 and 
can directly enter Segment 2. 
b. Weeks 2, 6 and 10 visits may be performed at subject’s home by a home health nurse or at an ancillary site in 
lieu of the study site. 
c. 
The Week 12 visit is the end of treatment in Segment 2. Subjects are asked to Segment 3 based on 
Investigator’s and Sponsor’s decision. Subjects who discontinue the study during Segment 2 are required to 
undergo these assessments as well, except IMP infusion. 
d. Women with child-bearing potential only. 
e. 
Genetic test for hypoplasminogenemia is optional. Subjects who already have known test results or who do not 
wish to participate can omit the test. 
f. 
See Section 3.5.2.6 for PK sampling time points. 
g. The types and timing of clinical assessments depend on each subject’s disease presentation and include but are 
not limited to: 1) measurement of visible lesions using photographs, 2) functionality tests (e.g., spirometry), 3) 
imaging of non-visible lesions (e.g., ureteral, oropharyngeal and bronchial) based on the investigator’s 
discretion. See Section 3.5.2.13 for details. 
h. Vital signs are taken within 15 minutes before and 15 minutes after each infusion that takes place at the study 
site and when a home health nurse is present during a visit. 
i. 
At each study visit, the IMP is infused by study staff on site. Between study visits, the IMP is infused at the 
site or an ancillary site, or at home by a home health nurse or self-administered by the subject or a 
caregiver. See Section 3.2 for details. Subjects’ infusions window for both Segment 2 and Segment 3 is +/- 
1 day. 
j. 
For subjects who participate in Segment 1, these baseline assessments are performed on Day -4 only. For 
subjects who do not participate in Segment 1 and are directly entering Segment 2, these baseline assessments 

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are performed on Day 0 only. Any of these assessments that have already been performed at Screening within 
the past 7 days may be omitted. 
k. A pre-infusion sample for PK profile is required for subjects in Segment 1 only (i.e., the 96-hour time point). 
Subjects directly entering Segment 2 do not require PK profile. 
l. 
Visit windows for Segment 2 are +/- 1 day and for Segment 3 are +/- 7 days. Visit windows for the Safety 
Follow-up, 30 days post final dose, are +/-3 days. 
m. A chest X-ray will be performed at baseline and Week 12 at the investigator’s discretion. 
n. The Clinical Global Impression and Quality of life assessment will be performed at the Week 48 Visit only in 
Segment 3. 
o. Subjects who decide to enter Treatment Protocol 2002C018G will return to the study site and complete the End 
of Study visit and sign an informed consent/assent for that study and stop participation in the current study. 
Subjects who decide not to enter Treatment Protocol 2002C018G will stop IMP and return to the study site for 
the Safety Follow-up visit 30 days after the final IMP dose. 
 
 
3.5.1 
Procedures by Visit 
Screening 
• Informed consent/assent 
• Eligibility review 
• Demographics 
• Medical history 
• Disease history and past and current treatment 
• Medications taken in the past year 
• Weight 
• Vital signs (temperature, respiratory rate, BP, and heart rate) 
• Physical examination 
• Blood sample for genetic test (if not on file) 
• Blood and urine samples for clinical laboratory tests (hematology, biochemistry, urinalysis, 
fibrinolysis panel, coagulation panel) (Appendix 15.2) 
• 
Blood samples for plasminogen activity, antigen, D-dimer 
• Blood sample for virology serology (results are not required to begin dosing) 
 
 
Baseline Assessments (Either Segment 1, Day -4 or Segment 2, Day 0) 
The following baseline assessments will occur before the first dose of IMP. For subjects 
participating in Segment 1, the baseline assessments will occur on Day -4. For subjects directly 
entering Segment 2, the assessments will occur on Day 0. 

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Any of the assessments that have been conducted at Screening within 1 week before Baseline may 
be omitted at the Investigator’s discretion, and the results from Screening may be used as Baseline 
values. 
• Weight 
• Vital signs 
• Physical examination 
• Changes in medical history, disease history and current medications 
• Blood and urine samples for clinical laboratory tests (hematology, biochemistry, urinalysis, 
fibrinolysis panel, coagulation panel) 
• Blood samples for plasminogen activity, antigen, D-dimer 
• Retention blood samples for virology (PCR) 
• A blood sample for virology serology 
• A blood sample for anti-plasminogen antibody 
• Clinical assessments (Section 3.5.2.13) 
o Measurements and photographs of visible lesions 
o Imaging of non-visible lesions 
o Functionality testing 
• Clinical Global Impression 
• Quality of life assessment 
• 
Chest X-ray, at the investigator’s discretion 
• Urine pregnancy test (women of childbearing potential) 
 
 
Segment 1, Week 0, Day -4 (Participants Only) 
Segment 1 is required only for subjects without a prior PK profile on file for 6 mg/kg Plasminogen 
(Section 3.1). Baseline assessments (Section 3.5.1.2) should be completed before the IMP 
administration. 
• Vital signs (before and 15 minutes after infusion) 
• IMP infusion 
• Blood samples (post-dose) for PK profile: plasminogen activity, antigen, and D-dimer 
(Section 3.5.2.6) 
• 
Concomitant medications 
• AE assessment 

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Segment 1, Week 0, Day -3, Day -2, and Day -1 (Participants Only) 
• Blood samples for PK profile: plasminogen activity, antigen, and D-dimer (Section 3.5.2.6) 
• 
Concomitant medications 
• 
AE assessment 
 
 
Segment 2, Week 1, Day 0 
For subjects with prior PK profile on file and directly entering Segment 2, the Baseline assessments 
(Section 3.5.1.2) will be completed before the IMP administration, followed by the procedures 
below. 
Any of the assessments that have been conducted at Screening within 2 weeks before this visit 
may be omitted, and the results from Screening may be used as Baseline values. 
• Vital signs (before and 15 minutes after infusion) 
• IMP infusion 
• 
Concomitant medications 
• AE assessment 
• Provision of subject diary and instructions 
For subjects entering Segment 2 after completing Segment 1, Baseline assessments are not needed. 
Instead, the following procedures will be conducted: 
• Prior to IMP infusion, blood samples for trough plasminogen activity, antigen, and D-dimer 
(i.e., the 72-hour sample after first dose) 
• Vital signs (before and 15 minutes after infusion) 
• IMP infusion 
• 
Concomitant medications 
• 
AE assessment 
• 
Provision of subject diary and instructions 
 
 
Segment 2, Week 2, Week 6, Week 10 
These visits will occur either at the study site or ancillary site, or at the subject’s home by a home 
health nurse (US subjects only). 
• Prior to IMP infusion, blood samples for trough plasminogen activity, antigen, and D-dimer 
• Vital signs (before and 15 minutes after infusion) 

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• 
IMP infusion 
 
 
Segment 2, Weeks 4 and 8 
• Clinical assessments (Section 3.5.2.13) 
o Measurements and photographs of visible lesions 
o Imaging of non-visible lesions 
o Functionality testing 
• Clinical Global Impression 
• Quality of life assessment 
• Urine pregnancy test (women of childbearing potential) 
• Prior to IMP infusion, blood and urine samples for clinical laboratory tests (hematology, 
biochemistry, urinalysis, fibrinolysis panel, coagulation panel) 
• Prior to IMP infusion, a blood sample for anti-plasminogen antibody 
• Prior to IMP infusion, blood samples for trough plasminogen activity, antigen, and D-dimer 
• Vital signs (before and 15 minutes after infusion) 
• IMP infusion 
• Concomitant medications 
• 
AE assessment 
• 
Review and provision of subject diary 
 
 
Segment 2, Week 12 or Discontinuation 
The following assessments will be conducted at the study site at Week 12 or at the final visit if a 
subject discontinues treatment: 
• Weight 
• Physical examination 
• Urine pregnancy test (women of childbearing potential) 
• Clinical assessments (Section 3.5.2.13) 
o Measurements and photographs of visible lesions 
o Imaging of non-visible lesions 
o Functionality testing 
• Clinical Global Impression 
• Quality of life assessment 

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• Chest X-ray, at the investigator’s discretion 
• Prior to IMP infusion, blood and urine samples for clinical laboratory tests (hematology, 
biochemistry, urinalysis, fibrinolysis panel, coagulation panel) 
• Prior to IMP infusion, blood samples for virology (serology and PCR) testing 
• Prior to IMP infusion, a blood sample for anti-plasminogen antibody 
• Prior to IMP infusion, blood samples for trough plasminogen activity, antigen, and D-dimer 
• Vital signs (before and 15 minutes after infusion) 
• IMP infusion (not administered if subject is discontinuing treatment) 
• Blood samples for PK profile: plasminogen activity, antigen, and D-dimer (Section 3.5.2.6, 
not conducted if subject is discontinuing treatment) 
• Concomitant medications 
• AE assessments 
• Review and collection of subject diary 
 
 
Segment 3 
The following assessments will be conducted at the study site every 12 weeks for 36 weeks in 
Norway or until the IMP licensing or study termination by the sponsor in the United States. During 
Segment 3, subjects will continue to receive the IMP at the same dosage and interval as Segment 
2, with the possibility of modification based on discussion between the investigator and the sponsor. 
Subjects or their caregivers may administer the IMP at home if properly trained. 
• Weight 
• Vital signs 
• Physical examination 
• Urine pregnancy test (women of childbearing potential) 
• Clinical assessments (Section 3.5.2.13), if indicated 
o Measurements and photographs of visible lesions 
o Imaging of non-visible lesions 
o Functionality testing 
• Prior to IMP infusion, blood and urine samples for clinical laboratory tests (hematology, 
biochemistry, urinalysis, fibrinolysis panel, coagulation panel) 
• Prior to IMP infusion, blood samples for virology (serology and PCR) testing 
• Prior to IMP infusion, blood samples for anti-plasminogen antibody 
• Prior to IMP infusion, blood samples for trough plasminogen activity, antigen, and D-dimer 

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• Vital signs (before and 15 minutes after infusion) 
• IMP infusion 
• Concomitant medications 
• AE assessments 
• Provision and review of subject’s diary 
• Clinical Global Impression (performed at the Week 48 Visit only) 
• Quality of life assessment (performed at the Week 48 Visit only) 
 
 
End of Study Visit for Subjects at the US Site Only 
The following assessments will be conducted for subjects at the US site who decide to enter 
Treatment Protocol 2002C018G: 
• Weight 
• Physical examination 
• Blood and urine samples for clinical laboratory tests (hematology, biochemistry, urinalysis, 
fibrinolysis panel, coagulation panel) 
• Blood sample for virology (serology and PCR) testing 
• Blood sample for anti-plasminogen antibody 
• Blood samples for spot plasminogen activity, antigen, and D-dimer 
• Concomitant medications 
• AE assessment 
• Review and collection of subject diary 
 
 
Safety Follow-up VisitThe following assessments will be conducted 30 days after the last dose of 
IMP has been administered 
• Weight 
• Physical examination 
 
• Blood and urine samples for clinical laboratory tests (hematology, biochemistry, urinalysis, 
fibrinolysis panel, coagulation panel) 
• Blood sample for virology (serology and PCR) testing 
• Blood samples for trough plasminogen activity, antigen, and D-dimer 
• Blood sample for anti-plasminogen antibody 

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• Concomitant medications 
• AE assessment 
• Review and collection of subject diary 
 
 
3.5.2 
Description of Assessments 
 
Informed Consent/Assent 
Informed consent is a process that includes the signing of the Informed Consent Form (ICF) for 
all subjects. Assent will be required from subjects younger than 18 years with consent from their 
legally authorized representative according to state law. Patients should be approached according 
to site policies regarding confidentiality. Potential subjects should be informed about the study 
according to the requirements of International Conference of Harmonisation (ICH) Good Clinical 
Practice (GCP). The informed consent process involves the investigator, and the subject should 
have the opportunity to discuss all aspects of the study, ask questions, consider the ICF/assent and 
statements, and provide an informed decision regarding any potential risks and any potential 
benefits. Both ICFs and assent, if applicable, must be signed prior to any study procedures being 
conducted. The informed consent/assent process continues throughout a subject’s participation in 
the study. Subjects have the right to withdraw from the study for any reason and at any time. A 
separate genetic testing consent will be required. 
Demographics 
Demographic information will be collected, including the subject’s date of birth, race, ethnicity, 
and sex. 
Medical History and Disease History and Symptoms 
A complete medical and surgical history will be obtained. If the subject is biologically or surgically 
unable to reproduce offspring, the reason for sterility should be recorded as a diagnosis (males and 
females). 
At least 1 year of documented general history are recorded. 
As part of the medical history assessment the investigator or designee will obtain a complete and 
detailed documented history regarding the progression of hypoplasminogenemia within at least 1 
year before screening, including any surgeries performed, other treatments, and all symptoms of 
the disease (e.g., ligneous conjunctivitis). In addition, the investigator will interview the subject 
and record any self-reported lifetime history and treatment of the disease, including the date when 
the disease was originally diagnosed. 

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Prior Medications and Treatments 
Documented prior and current medications within at least 1 year before screening will be recorded, 
including non-prescription, prescription, herbal/natural, blood products, and birth control for males 
and females who are able to reproduce at the time of screening. Records will include dates of use, 
indications, routes, doses, and schedules as appropriate. Corresponding diagnoses will also be 
recorded in the medical history with dates of diagnoses. 
Plasminogen Genetic Test 
Optional plasminogen genetic testing will be conducted at screening for those subjects who 
provide written informed consent form for genetic testing. A blood sample will be obtained, 
centrifuged, transferred to, and frozen in a cryovial and stored at -20°C. Genetic testing will be 
conducted by a Central Laboratory using a validated method developed by Machaon. Please see 
Laboratory Manual for more details on processing and shipping of blood samples. The genetic test 
is not necessary if the subject has undergone genetic testing in the past and the test result is 
available. 
PK Analyses for Plasminogen Activity and Antigen Levels 
Blood samples will be drawn and analyzed for plasminogen activity and plasminogen antigen 
levels at a Central Laboratory using validated assays. Plasminogen activity is assessed with a 
chromogenic assay developed and validated at a central specialty laboratory. Plasminogen 
antigen levels are determined by ELISA (Cell Sciences) and validated at a central specialty 
laboratory. For each sample taken for Plasminogen activity and antigen testing in Segments 1, 2, 
and 3 a backup sample will also be taken and stored at the Central Laboratory facility in case of 
repeat testing requirements. No backup sample is needed at the End of Study visit for subjects 
who decide to enter the treatment protocol. 
Segment 1 
Blood samples are drawn on Day -4 before the IMP infusion to establish baseline levels for 
plasminogen activity, antigen, and D-dimer and at the following time points after the end of the 
infusion: between 5 and 15 minutes, 6 hours (± 30 minutes), 24 hours (± 2 hours, Day -3), 48 hours 
(± 2 hours, Day -2), 72 hours (± 2 hours, Day -1), and 96 hours (± 2 hours, Day 0). An individual 
PK profile will be developed based on these time points. 
Subjects who have had individual PK profile for 6 mg/kg Plasminogen with the sponsor, due to 
participation in the prior Phase 1 study, do not participate in Segment 1. 
Segment 2 
For subjects who do not undergo Segment 1, blood samples are drawn to measure plasminogen 
activity and antigen levels on Week 1, Day 0, before the first dose of the IMP is given, to establish 
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For all subjects, blood samples will be drawn every 2 weeks before IMP infusion to measure trough 
levels through the final dose. 
A full PK profile will also be done for all subjects at the end of Segment 2 (Week 12 visit) to 
evaluate the stability of individual PK profile after 12 weeks of IMP administration. As 
plasminogen is a consumable clotting factor, if significant lesion burden is present at the start of 
the study or if neutralizing antibody develops, a subject’s PK profile may be altered by the end of 
the 12-week treatment period. At the Week 12 visit, blood samples are drawn before the IMP 
infusion and at the following time points after the end of the infusion: between 5 and 15 minutes, 
6 hours (± 30 minutes), 24 hours (± 2 hours), 48 hours (± 2 hours), 72 hours (± 2 hours), and 96 
hours (± 2 hours). The PK profile will be developed for each subject and compared with his or her 
prior PK profile(s). 
Furthermore, additional PK analyses may be performed at other time points during Segment 2 as 
needed, such as when a subject’s trough level or antibody test suggests the appearance of 
neutralizing antibody against the IMP or when the dosing frequency has changed. 
Segment 3 
Blood samples will be drawn at each study visit every 3 months before IMP infusion to measure 
trough levels. Plasminogen activity and antigen, D-dimer spot levels will be measured at the End 
of Study visit for subjects who decide to enter Treatment Protocol 2002C018G. 
PK Sample Handling: 
Blood samples will be obtained, centrifuged, and resulting plasma will be transferred to, and frozen 
in a cryovial and stored at -20°C. All samples will be shipped frozen to a Central Laboratory for 
analysis. Details on processing and shipping of blood samples are provided in the Laboratory 
Manual. 
Clinical Laboratory Tests 
 
Specimens for laboratory analysis will be obtained to ascertain if the subject meets eligibility 
criteria and to assess for abnormal changes and possible AEs during the study. The laboratory tests 
include hematology, serum chemistry, urinalysis, fibrinolysis and coagulation panels, and urine 
pregnancy test (as applicable). See Appendix 15.2 for a list of specific tests to be conducted. 
Abnormal laboratory results will be reviewed by the investigator. Clinically significant 
abnormalities or changes from baseline will be reported as AEs, according to the investigator’s 
judgment. However, changes that are associated with clinical improvement (for example, blood 
clot discharged in urine, increases in D-dimer) are not reported as AEs. 
Details of sample collection and shipping will be outlined in the Laboratory Manual provided by 
the Central Laboratory. 

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Vital Signs 
 
Vital signs will be collected to include body temperature, blood pressure, respiratory rate, and 
heart rate. In each subject, the same arm will be used to collect all blood pressure readings, and 
every attempt will be made to use the same equipment and investigator/designee at each visit. 
Physical Examination 
 
The investigator will perform a physical exam to include a gross neurological exam and major 
body systems. The exam will focus on systems and organs known to be affected by 
hypoplasminogenemia. 
Antibodies to Plasminogen 
 
A blood sample will be obtained, centrifuged, and resulting serum sample transferred to and 
frozen in a cryovial, stored at -20°C, and shipped frozen to a Central Laboratory for detection of 
anti-plasminogen antibodies. Testing for anti-plasminogen antibodies is performed by ELISA. If 
neutralizing antibodies are suspected based on the plasminogen activity levels, an assay for 
assessing binding versus non-binding antibodies will be implemented. Details on processing and 
shipping of blood samples are provided in the Laboratory manual. For each sample taken for 
Plasminogen a ntibody testing in Segments 1, 2, and 3 a backup sample will also be taken and 
stored at the Central Laboratory facility in case of repeat testing requirements. No backup 
sample is needed at the End of Study visit for subjects who decide to enter the treatment protocol. 
 
 
Virology 
Screening serology testing will be conducted for HIV-1, HIV-2, HCV, HBV, HAV, and B19 
(Appendix 15.2). Provided the subject meets all inclusion/Exclusion criteria, the subject may begin 
IMP infusion in Segment 1 or 2 without waiting for the virology results. Retention samples for 
virology at baseline will be tested with PCR. 
Subject Diary 
A diary will be provided to subjects during Segments 2 and 3 to record hypoplasminogenemia 
symptoms, IMP administration and any AEs between visits. The diary will be reviewed by the 
study personnel at each visit. Subjects will return the diary at the End of Study visit or Safety 
Follow-Up visit. 
Clinical Assessments 
All subjects will be clinically evaluated by the investigator for the clinical manifestation and 
severity of hypoplasminogenemia at the time points specified in the Schedule of Events table. 

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Measurement of Visible Lesions 
The size (length and width) of visible lesions, such as ocular and gingival lesions, in subjects who 
have ligneous conjunctivitis will be measured and documented using photography at each visit. 
The procedure of photographic measurements is described in the Study Manual. 
Imaging 
Nonvisible lesions (ureteral, oropharyngeal, and bronchial) may be qualitatively evaluated as 
appropriate via imaging studies, such as computed tomography (CT) scans, X-ray, or other suitable 
imaging techniques at the Investigator’s discretion. For example, if there is lung involvement 
suspected, lesions may be monitored via a CT scan obtained at Screening (unless already available 
within the past 6 months) and at the Week 12 visit, and at other time points if warranted. 
Functionality Testing 
Spirometry may be performed in subjects who have respiratory tract involvement of 
hypoplasminogenemia, if deemed appropriate by the investigator. The spirometry will measure 
forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), peak expiratory flow 
(PEF), and FEV1/FVC ratio. If applicable, these tests may be performed at Screening and Baseline 
(before the first dose of IMP), and every 4 weeks subsequently. However, no testing beyond 
Baseline is warranted if the subject’s lung function is within normal limits at Screening and/or 
Baseline. Spirometry does not need to be repeated at Baseline if Screening is within 3 weeks of 
Baseline. Other functional tests appropriate for the affected organ system may be performed and 
analyzed as determined by the PI. 
Clinical Global Impression – Global Improvement (CGI-I) Scale 
The Clinical Global Impression-Global Improvement (CGI-I) Scale is a single, clinician- 
completed scale designed to capture the clinician’s impression of the subject’s disease 
improvement over time (Appendix 15.3). Clinicians are asked to consider their experience in this 
patient population and rate the change relative to the subject’s state at baseline using a 7-point 
scale (1 = very much improved, 7 = very much worse). 
Quality of life assessment 
Subjects are asked to rate their overall quality of life using a 10-point scale (0 = non-functioning, 
10 = normal; Appendix 15.4), adapted from a scale developed by the American Chronic Pain 
Association. 

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3.6 
Stopping Rules and Withdrawal 
 
3.6.1 
Study Termination 
 
The sponsor and/or a principal investigator may elect to terminate the study early as defined by 
the clinical trial agreement. 
Any decision to voluntarily suspend or terminate a clinical trial will be carefully reviewed and 
fully justified. The sponsor will notify the FDA and the IRB of any suspension or termination, 
along with justification for restarting or terminating the study as applicable. 
3.6.2 
Stopping Rules 
 
Any subject who experiences any of the following occurrences will suspend the IMP treatment 
until further assessments: 
• Anaphylactic response to study drug administration 
• 
A significant AE that, in the investigator’s opinion, necessitates suspension of treatment 
• Confirmed presence of neutralizing antibodies (in at least 2 measurements) in association with 
diminished plasminogen activity that obviates the potential benefit of plasminogen 
replacement therapy. 
• 
Thrombotic or uncontrolled bleeding event requiring hospitalization 
The SMC will review safety data on an ongoing basis and will determine if a subject should stop 
treatment, or if there are unforeseen events (e.g., thromboembolic event) that would warrant 
halting or stopping the study. Such events will be discussed with FDA before enrolling further 
subjects. 
3.6.3 
Withdrawal and Replacement of Subjects 
 
Subjects will be withdrawn for the following reasons: 
• The subject withdraws consent (no justification is required); and/or 
• The subject develops a condition that in the investigator’s opinion makes it medically 
necessary that the subject not continue in the study. 
After a discussion between the investigator and sponsor, subjects may be withdrawn for the 
following reasons: 
• An AE that in the investigator’s or sponsor’s opinion requires the subject be withdrawn from 
the study; 
• Violation of eligibility criteria; 
• Major protocol violations or deviations from the treatment plan (e.g., incorrect IMP 
administration); 

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• Lost to follow-up after all attempts at contacting the subject; and/or 
• Death. 
In all cases, the reasons for withdrawal will be recorded in the subject’s source documentation and 
in the Case Report Form (eCRF). It is possible that some subjects may become lost to follow-up 
during the study. Every reasonable effort will be made to contact these subjects; all available 
efficacy and safety data collected for these subjects will be used, even if incomplete. Subjects 
withdrawn from the study may be replaced so that there are at least 10 evaluable subjects. 
Subjects who do not meet the entry criteria at screening will be ineligible for treatment and will be 
deemed screen failures. Subjects who are screen failed will not receive IMP; therefore, no PK or 
safety data will be collected for these subjects, and only demographic information will be collected 
on the eCRF. Subjects who screen fail will be considered screened but not enrolled. A screen failed 
subject may re-enter the study if they pass the re-screening. Only subjects who qualify for 
treatment will be enrolled. 
3.7 
Safety Monitoring Committee 
 
The SMC is composed of the sponsor’s Medical Monitor and an independent Medical Monitor 
and will review the safety data (e.g., AE listings, laboratory data, vital sign data, trough levels) 
biweekly during Segments 1 and 2, as data become available. Formal meetings of the SMC will 
be convened if warranted based on data obtained at any time during Segments 1 and 2. Any AEs 
will be discussed between SMC members in an ongoing basis. The SMC will continue to review 
the safety data periodically during Segment 3. 
3.8 
Subject Identification 
 
Subjects will be identified by their initials and a numerical code in the database. All subjects who 
sign the ICF/assent will receive a Subject Identification Number according to the following format: 
XX-YYY (site number-subject number) to be defined in a Study Manual. The anonymity of 
subjects will be maintained insofar as is required by law and to protect the subjects’ rights to 
privacy. Personally identifying information may only be obtained by the investigator or their 
designee to complete the requirements of the protocol and must be kept by the investigator in 
strictest confidence and may not be released unless required by law. See Section 11 for additional 
information regarding confidentially. 
3.9 
Treatment Compliance 
 
The IMP will be provided by the sponsor and delivered to participating sites. IMP administration 
will be performed and recorded by study personnel or home nurse, or by subjects or their caregivers 
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Subjects will be given instructions how to document the receipt of IMP and how to return the used 
vials for accountability. The subjects will document IMP administration in the study diary. The 
study personnel will review the diary at each visit and document all doses used and missed in the 
CRF. 
3.10 
Protocol Deviations 
 
Every effort should be made to avoid deviations from the protocol during the conduct of the trial. 
When protocol deviations do occur, the Investigator should promptly inform the Monitor, and the 
implications of each deviation must be reviewed and discussed. Any deviation must be 
documented, stating the reasons, date, actions taken, and the impact for the subject and/or trial for 
each deviation. This documentation must be kept in the Sponsor Files and Investigator Files. In 
case of any major protocol deviations (i.e., violations), the investigator and sponsor will decide on 
the further participation of the affected subject, after having discussed all relevant aspects. Such 
deviations will be reported to the IRB by the site according to its local IRB requirements. 
Deviations occurring outside of the study site, by vendors will be documented by the Sponsor and 
supplied to the site for IRB submission. 
 
 
4 
Restrictions 
4.1 
Concomitant and Prohibited Medications 
 
The administration of concomitant medications, in accordance with the standard of care for 
subjects with hypoplasminogenemia, is permitted during the study. Any medications (e.g., 
prescription and non-prescription medications, blood products, herbal/natural products) taken by 
the subject within 30 days prior to Visit 1 (Screening) and/or during the course of the study will 
be recorded in the eCRF, including the dates of use, reason for use, dose, and dosage/schedule. 
Any product containing plasminogen is not allowed from Screening to the end of the study. 
4.2 
Other Restrictions 
 
None. 
 
 
5 
Reporting of Adverse Events 
Adverse events will be recorded from the first dose of IMP administration through 30 days after 
administration of IMP and collected by observation and reporting. AEs will be elicited from 
subjects by asking questions regarding changes in the subject’s status at each visit. 

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5.1 
Definitions 
 
5.1.1 
Adverse Event 
 
An AE is any untoward medical occurrence (whether or not considered to have a causal 
relationship to IMP) in a study subject administered an IMP. Therefore, an AE can be any 
unfavorable and unintended sign (including clinically significant laboratory finding), symptom, or 
disease temporally associated with the use of an IMP, whether or not related to the IMP. 
However, signs and observations that are associated with clinical improvement (such as discharge 
of blood clots in urine), as judged by the investigator, will not be reported as AEs. 
5.1.2 
Adverse Drug Reaction 
 
All noxious and unintended responses to an IMP related to any dose should be considered ADRs. 
The phrase “responses to an IMP” means that a causal relationship between the IMP and the AE 
is at least a reasonable possibility, that is, the relationship cannot be ruled out. 
5.1.3 
Serious Adverse Event 
 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening (i.e., the subject was at immediate risk of death from the AE as it occurred. 
This does not include an event that, had it occurred in a more severe form or was allowed to 
continue, might have caused death). 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the study 
drug) or 
• Is a medically important event or reaction: 
Events that did not result in death or hospitalization but may, based on appropriate medical 
judgment, jeopardize the subject or require intervention, to prevent one of the outcomes in the 
definition of SAE listed above, should also be considered SAEs. 
5.1.4 
Assessment of Severity 
 
The severity of all AEs and SAEs must be assessed according to the following categories: 
• Mild – The AE/SAE is easily tolerated by the subject, causes minimal discomfort and does not 
interfere with everyday activities; or 
• Moderate – The AE/SAE is sufficiently discomforting to interfere with normal everyday 
activities; or 

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• Severe – The AE/SAE prevents the subject from engaging in normal everyday activities. 
The term “severe” is used to describe the intensity of a specific event. The event itself may be of 
relatively minor medical significance (such as a severe headache). “Severe” 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/subject’s life or ability to carry out life functions. Seriousness is a 
medical term, while severity is a subjective term. 
5.1.5 
Assessment of Causality 
 
The following 4-point scale will be used by the investigator to rate the relationship of the adverse 
event to the IMP: 
• Definitely related: A clinical event (including laboratory test abnormality) occurring in a 
plausible time relationship to IMP administration and which cannot be explained by concurrent 
disease or other drugs or chemicals. The response to withdrawal of the drug (de-challenge) 
should be clinically plausible. The event must be definitively associated pharmacologically, 
using a satisfactory re-challenge procedure, if necessary; or 
• Probably related: A clinical event (including laboratory test abnormality) with a reasonable 
time sequence to administration of the drug, unlikely to be attributed to concurrent disease or 
other drugs or chemicals, and which follows a clinically reasonable response on withdrawal 
(de-challenge). Re-challenge information is not required to fulfill this definition; or 
• Possibly related: A clinical event (including laboratory test abnormality) with a reasonable 
time sequence to administration of the drug, but which could also be explained by concurrent 
disease or other drugs or chemicals. Information on drug withdrawal may be lacking or unclear; 
or 
• Not related: An event for which sufficient information exists to conclude that the etiology of 
the event is unrelated to the IMP. 
The degree of certainty with which an AE or SAE is attributed to treatment with IMP (or alternative 
causes, e.g., natural history of underlying diseases, concomitant therapy) will be determined by how 
well the event can be understood with regard to one or more of the following: 
• Known pharmacology of the IMP; 
• Reaction of similar nature being previously observed with this medication or class of 
medications; 
• The event having often been reported in literature for similar medications as related; and/or 
• There is a temporal relationship between IMP administration and the event. 
Refer to the Investigator’s Brochure for all available relevant information about the IMP. 

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The investigators will assign causality at their respective sites during the study. The medical monitor 
responsible for the study will review the assigned causality for all AEs and SAEs prior to data-base 
lock. This assignment will be included in the study database and final study report. 
5.2 
Eliciting and Reporting Adverse Events 
 
The condition of the patient will be monitored throughout the study. At each visit, AEs will be 
elicited using a standard non-leading question such as “How have you been since the last visit / 
during the previous study period?” AEs will also be elicited through the use of Subject Diary 
cards, which the investigator will review in detail with the subject at each visit, ensuring accuracy 
and completeness of entries recorded by the subject. 
Any AE or ADR occurring during the study will be noted in detail on the appropriate pages of the 
eCRF. If the patient reports several signs or symptoms, which represent a single syndrome or 
diagnosis, the latter should be recorded in the eCRF. The investigator will grade the severity of all 
AEs or ADRs (mild, moderate or severe), the seriousness (non-serious or serious) and relatedness, 
as defined in Section 5.1. 
In the event of clinically significant abnormal laboratory findings, the tests will be repeated and 
followed-up, as needed. Diseases, signs and symptoms, and/or laboratory abnormalities already 
existing before the first administration of IMP are not considered as AEs when observed at a later 
stage unless they represent a worsening. 
The investigator should always provide detailed information concerning any abnormalities and the 
nature of, and reasons for any necessary action(s), as well as any other observations or comments, 
which are useful for the interpretation and understanding of the subjects’ AEs or ADRs. 
5.3 
Serious Adverse Event Reporting 
 
All AEs must be evaluated as potential serious adverse events (SAEs). All AEs assessed as serious 
must be reported beginning from the time of first dose of IMP until 30 days post dose. SAEs must 
be followed until the event resolves, the event or sequelae stabilize, or it is unlikely that additional 
information can be obtained after demonstration of due diligence with follow-up efforts (i.e., the 
subject or investigator is unable to provide additional information or, the subject is lost to follow- 
up). 
5.3.1 
SAE Reporting to the CRO 
 
All SAEs will be reported within 24 hours of the investigator becoming aware of the event to the 
Pharmacovigilance (PV) CRO Safety Department submitting the Safety Report 24/7 on the fax 
number below. 
Toll Free Fax US: 1-866-246-1693 

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Toll Free Fax Norway: 800-24-747. 
Full details of SAE reporting to the PV CRO will be defined in the Safety Management Plan. The 
telephone number for ITSI is 1-888-784-2723 in US. Alternately any safety information can be 
sent via email to Prometic_Safety@integratedtsi.com. 
It should be noted that reporting to the PV CRO Safety Department within 24 hours of awareness 
is required for all SAEs regardless of their causal relationship with the IMP. 
The PV CRO Safety Department, together with the sponsor’s medical monitor, will review all 
safety information/documentation and follow up with the investigative site to obtain any other 
required information. Follow-up information should be actively sought by the investigator and 
reported to the PV CRO Safety Department as it becomes available using the Safety Report. 
The sponsor is responsible for reporting SAEs to IND/CTA under the oversight of the FDA and 
NMA (Norwegian Medicines Agency), respectively, as applicable. 
5.3.2 
Institutional Review Board/Ethics Committee 
 
All AEs will be reported to the IRB/EC according to the guidelines of the IRB/EC. However, as a 
general guideline, IRBs/EC need to know about any AEs that are unexpected or of a greater 
severity than what is reported in the IB. Reporting is always required for all SAEs. Any new safety 
data (or other finding) that might affect an IRB/EC’s judgments regarding their risks versus 
benefits analysis should always be reported to the IRB/EC. The sponsor and the CRA will assist 
the investigator in determining which events require reporting and in what timeframes. 
5.3.3 
Expedited SUSAR Reporting (Sponsor Responsibility) 
 
The sponsor will submit a written IND Safety Report (i.e., completed FDA Form 3500A and/or 
CIOMS form) within 15 calendar days of receipt to the responsible review division of the FDA and 
the Norwegian Medicines Agency, as required, for any observed or volunteered SAE that is: 
1) Suspected to be associated with the investigational drug or study treatment(s); and 
2) Unexpected. 
Any SUSARs that will be filed to the IND for the purpose of notifying FDA, and will be filed 
electronically via EudraVigilance for the purpose of notifying the Norwegian Medicines Agency. 
In addition, if the event is fatal or life-threatening and meets the above criteria, a telephone or facsimile 
notification will be sent to the FDA as soon as possible, but no later than 7 calendar days after the 
sponsor’s initial receipt, followed by a completed FDA Form 3500A within 15 calendar days after 
initial receipt. 
Each IND Safety Report will be prominently labeled “IND Safety Report,” and a copy will be 
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For each written IND Safety Report, the sponsor will identify all previously submitted IND Safety 
Reports that addressed a similar adverse event experience and will provide an analysis of the 
significance of the newly reported adverse event in light of the previous, similar report(s). 
If the results of the sponsor’s follow-up investigation show that an adverse event that was initially 
determined to not require a written IND Safety Report does, in fact, meet the requirements for 
reporting, the sponsor will submit a written IND Safety Report as soon as possible, but in no event 
later than 15 calendar days after the determination was made. 
Follow-up information to an IND Safety Report will be submitted to the applicable review division 
of the FDA as soon as the relevant information is available. 
5.4 
Pregnancy 
 
Every effort must be made to avoid a pregnancy during the trial. Contraception should be used in 
accordance with Inclusion Criterion #6, and the techniques discussed at Screening should 
preferably not be changed during the course of the trial. A pregnancy test will be performed at 
Screening and at each study visit. 
In case a subject becomes pregnant during the trial, she has to be withdrawn. Pregnancies occurring 
during the study after exposure to the IMP need to be reported. The pregnancy notification form 
has to be sent to the CRO Safety Department. Follow-up information on the outcome of both mother 
and fetus must also be reported. 
5.5 
Procedure for Breaking the Blind 
 
This is not a blinded study. 
5.6 
Follow-up of Adverse Events 
 
The responsible investigator will follow up each AE until it is resolved or until the medical 
condition of the patient has returned to baseline, and all relevant follow-up information has been 
reported to the sponsor. 
 
 
6 
Statistical Analysis 
6.1 
Datasets for Analysis 
 
Safety population: Includes any subject who receives at least one dose of the IMP and provides 
safety data for at least one non-screening visit. 
PK population: Includes subjects who have completed Segment 2 dosing and have provided 
sufficient samples for PK assessments. 

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Full Analysis Set (FAS): Includes any subject who receives at least 1 dose of the IMP and provided 
data for at least one post-baseline efficacy assessments. 
6.2 
Handling of Missing Data 
 
No missing data will be imputed. Missing plasminogen activity or antigen data will be ignored in 
the calculation of PK parameters. 
6.3 
Analyses Plan 
 
Details will be provided in a Statistical Analysis Plan (SAP), which will be finalized before the 
database lock. 
6.3.1 
Demographics and Baseline Characteristics 
 
Subjects’ demographic and baseline clinical characteristics will be summarized descriptively. 
Continuous variables will be presented as mean, standard deviation, median, and range. 
Categorical parameters will be presented as numbers and percentages. 
6.3.2 
Pharmacokinetic/Pharmacodynamic Analysis 
 
The primary endpoint is the number and percentage of subjects who achieve the target 
plasminogen activity trough levels for at least 3 measurements in 12 weeks during Segment 2. 
Primary endpoint success is defined as at least 80% of evaluable subjects (i.e., 8 or more) achieving 
the target trough levels for at least 3 measurements in 12 weeks. The target trough level is defined 
as an increase in plasminogen activity level of at least an absolute 10% (10 U/dL) from the 
subject’s individual baseline level. Baseline is defined as the plasminogen activity level measured 
before the first dose of IMP at Segment 1, Day -4 for subjects who undergo Segment 1 or at 
Segment 2, Day 0 for those who do directly enter Segment 2. 
The secondary PK endpoints include individual PK profiles at the end of Segment 2, compared 
with their PK profiles at baseline, and trough plasminogen activity and antigen levels during 
Segment 2 and Segment 3. 
Plasminogen activity and antigen levels will be presented by individual subjects and summarized 
descriptively (number of subjects, mean, standard deviation [SD], coefficient of variation [CV], 
medium, minimum, maximum, geometric mean and associated CV). Individual and median 
profiles of the concentration-time data will be plotted using nominal times. Median profiles may 
be presented on both linear-linear and linear-log scales. 
Standard PK parameters, including area under the curve (AUC), clearance (CL), mean residence 
time (MRT), volume of distribution (Vd) and terminal half-life (t1/2) will be calculated using non- 
compartmental analysis and baseline-adjusted plasminogen activity levels derived from Segment 

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1 data and, if a subject is suspected to develop neutralizing antibody to the IMP, plasminogen 
activity levels at the end of Segment 2. 
Additional PK compartmental analysis may be performed and best-fit model will be used for 
further individual PK prediction. 
The summary statistics will include the number of subjects, mean, median, standard deviation, 
minimum, and maximum. The PK parameters will be summarized with the geometric mean and 
95% confidence interval around the geometric mean 
D-dimer is monitored as a potential pharmacodynamic marker to better understand if there is a 
relationship between the levels of D-dimer in subjects over time and the subject’s potential 
response to therapy. 
6.3.3 
Efficacy Analysis 
 
The primary endpoint is: 
Overall Clinical Success in number and size of lesions or change in organ functionality at 48 
weeks 
The secondary efficacy endpoints are: 
• Overall Clinical Success in number and size of lesions or change in organ functionality at 
12 weeks 
• CGI scores at 12 and 48 weeks 
• Quality of life scores at 12 and 48 weeks 
Overall clinical success is defined as 50% of subjects with visible or other measureable lesions 
achieving at least a 50% improvement in lesion number/size or functionality impact from baseline. 
Visible lesions are defined as lesions which can imaged and analyzed with digital photography. 
Other measureable lesions are defined as lesions whose dimensions can be assessed by medical 
imaging studies (e.g. computed tomography, magnetic resonance imaging, ultrasound, etc) or 
functional assessments (e.g. spirometry, audiogram, oximetry, etc). 
Clinical success will be further described as a graded evaluation of potential clinical responses; 
1) Excellent response: > 75% decrease; 2) Good response: > 50% and < 75% reduction; 3) 
Moderate response: > 25% to < 50% reduction; 4) Minimal response: < 25% reduction; 5) No 
response: an increase or no reduction in the size of the lesion. Clinical responses will determined 
by the principal investigator for the assessment of clinical success. 
All efficacy results will be presented descriptively by individual subjects, including summarized 
hypoplasminogenemia symptoms over time recorded in subject diaries. The small sample size and 
high variability of disease presentation do not allow formal statistical analyses. 

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6.3.4 
Safety Analysis 
 
For safety analyses, treatment emergent adverse events (TEAEs) and SAEs will be summarized 
descriptively. 
Clinical 
laboratory 
tests 
(hematology, 
biochemistry, 
urinalysis, 
fibrinolysis/coagulation) will be presented in summary and shift tables. The numbers of subjects 
who had changes from baseline in viral tests and immunogenicity tests will be presented in 
individual subject listings and summary tables. 
6.4 
Sample Size 
 
Approximately 15 subjects with hypoplasminogenemia will be enrolled in this study to achieve at 
least 10 evaluable subjects. No formal calculation was made for sample size because of the rarity 
of the disease. The sample size is based on known patients who have hypoplasminogenemia. 
6.5 
Interim Analysis 
 
The data in this study will be conducted in stages. An initial analysis of the PK data will be 
conducted when at least 10 subjects have completed Segment 2 dosing and have provided 
sufficient samples for PK assessments. The second data analysis will be conducted when all 
subjects have either completed the Week 48 visit or have withdrawn consent and completed the 
final safety visit. The final data analysis will occur when all subjects have completed the final 
safety visit or remain in the study in Segment 3 (US subjects only). Additional details for these 
analyses will be included in the Statistical Analysis Plan (SAP). 
 
 
7 
Management of Investigational Medicinal Product 
7.1 
Packaging and Labeling in the US 
 
The IMP for IV administration is in a lyophilized presentation and will be available in 50 mL vial 
size. Each vial contains 62.5 mg Plasminogen, which will yield a concentration of 5 mg/mL after 
it is reconstituted in 12.5 mL of Water for Injection. The IMP is labeled as below: 
Protocol #: 2002C011G 50 mL 
Plasminogen Human 
LOT NO: 2388 - XXX 
Caution: New Drug-Limited by Federal (US) Law to 
Investigational Use – For Clinical Trial Use Only 
Mfg Date: XXXXXXX Store at ≤ 2 °C to 8 °C 

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Manufactured by ProMetic BioProduction Inc, Laval, Quebec, H7V 1B7 and 
Emergent BioSolutions Inc, Baltimore, MD, 21230 
For ProMetic BioTherapeutics Inc., Rockville, MD, 20850 
There will be a separate IMP manual for Norway which will include the label with expiry 
date. 
7.2 
Storage 
 
The plasminogen IMP must be stored lyophilized at ≤ 2 °C to 8 °C in a secured area until used. 
The temperature in the storage area should be monitored with properly calibrated instruments and 
monitored on a temperature log. Subjects receiving and storing IMP at home can store their IMP 
in a non-monitored refrigerator at home. 
7.3 
Accountability 
 
The principal investigator is responsible for ensuring that accurate inventory records of IMP are 
properly maintained. The principal investigator or designee will inventory all shipments upon 
receipt, acknowledge possession by signing all required documentation, and return the required 
documentation to the sponsor or CRO. The principal investigator must ensure that IMP is kept in 
a secure location onsite per site SOPs and in accordance with required storage conditions. The 
inventory records for the IMP will include: 
• Protocol name, number and sponsor. 
• Product name and description. 
• Trial site and principal investigator name. 
• Product lot number and Expiry Date(s)/Re-test date. 
• Number of vials, sizes received from the Central Drug Repository. 
• Number of vials dispensed, date and time of dispensing and study subject for whom product 
was dispensed. 
• Product balance. 
• Name and title of qualified individual dispensing product. 
These records will be reviewed by the Monitor, and may be reviewed by regulatory agencies. 
All correspondence with the sponsor regarding the stability and product release should be kept with 
the study specific documents at site and/or the pharmacy as applicable. 
The subject identifier (i.e., subject ID number) must be recorded on the IMP Drug Accountability 
Log. All used and unused IMP must be maintained for drug accountability. 

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7.4 
Shipment, Returns, and Destruction 
 
IMP will be shipped from Prometic Biotherapeutics to a selected Central Drug Repository (one in 
the US and one in Norway). The Central Drug Repositories will ship IMP to the sites and/or 
directly to subjects’ homes or treating study nurse office location. Details regarding the drug 
shipping and receipt will be provided in the Pharmacy Manual which will include detailed 
instructions for subjects covering the receipt, storage, preparation of IMP as well as return of used 
and unused vials. Inventory should be entered into the IMP Drug Accountability Log at the Study 
site. At the end of the trial, or upon request of the sponsor, all unused, partially used or empty IMP 
containers will be returned to Prometic Biotherapeutics or the CRO or destroyed at the site after 
accountability has been completed by the Monitor. 
7.5 
Preparation 
 
IMP infusions should be prepared by a pharmacist or a qualified designee (subjects will be trained 
by site personnel for home preparation and infusion). 
IMP must be removed from refrigerated storage and brought to room temperature for reconstitution 
with 12.5 mL of Water for Injection using sterile technique. The IMP should be reconstituted by 
addition of water slowly with swirling until dissolved. After reconstitution, the plasminogen 
solution should be colorless and clear to slightly opalescent. Reconstituted plasminogen must be 
used within 3 hours after reconstitution. 
Please see the Pharmacy Manual for complete details regarding drug reconstitution. 
7.6 
Administration 
 
Only eligible and enrolled subjects will receive IMP. The entire dose of the Plasminogen IV 
solution should be calculated on the basis of each subject’s body weight and infused over a period 
of 10 to 30 minutes. IMP will be administered using a syringe with filter or disk filter according to 
the instructions in the Pharmacy Manual. 
 
 
8 
Records Management 
8.1 
Direct Access to Source Data/Documents 
 
The investigator will permit study-related monitoring, audits, IRB review, and regulatory 
inspection(s), providing direct access to source data and documents. 
The investigator or designee must record study participation details including enrollment, safety, 
and efficacy information for each subject onto source documents. The investigator is responsible 
for maintaining complete and adequate case histories in the source records of each subject. 

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Source data must be preserved for the maximum period of time permitted by local regulations and 
made available by the investigator in the cases described above. 
8.2 
Data Collection and Management 
 
Data generated as per protocol will be entered onto the eCRF in accordance with the ICH Topic 
E6 (R1) Guidelines for GCP (CPMP/ICH/135/95). When the eCRFs have been completed, a 
monitor, with the assistance of the study site coordinator, will verify the source documentation 
records and review the data. 
Subsequent electronic review of the data may result in queries being generated that will be 
forwarded simultaneously to the appropriate investigator or designee and the CRO appointed for 
the study for prompt resolution. Resolutions will be sent back to Data Management in a timely 
fashion. All data modifications resulting from review or querying of the data will be electronically 
tracked. 
Any errors detected by either the CRA or the investigator after query resolution should be 
communicated via eCRF data change forms. In all cases, an investigator or designee signature will 
be required. 
Coding of AEs and SAEs will be performed automatically by the Data Management using the 
MedDRA dictionary. Similarly, coding of all medications will occur using the WHO Drug 
Dictionary. 
The medical monitor or designee will perform a periodic medical review of the coding and of the 
AE profile. 
8.3 
Record Keeping 
 
The investigator is responsible for maintaining all records pertaining to the clinical trial and for 
ensuring complete and accurate documentation. 
The investigator is responsible for maintaining a subject identification log. This confidential 
subject identification log provides the link between named subject source records in the subject 
file and anonymous eCRF data provided to the sponsor. 
The sponsor requires that each investigator retain records (all regulatory documents such as the 
protocol, study approval letters, all eCRFs, drug dispensing and accountability logs, all original 
subject consent forms, and all correspondence pertaining to the conduct of the study) for a period 
of no less than 2 years from the date of final regulatory approval or as per local regulations, 
whichever is longer. If the study is discontinued, or if no application/license is to be filed or if the 
application/license is not approved for such indication, records should be retained for 7 years after 
the investigation is discontinued or as per local regulations, whichever is longer. 

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In all instances, it is prohibited for study documents to be destroyed without prior written 
agreement between the investigator and the sponsor. If the investigator wishes to assign the study 
records to another party, or move them to another location, the sponsor must be notified in writing. 
9 
Quality Control and Quality Assurance 
9.1 
Quality Control by the Monitoring Team 
 
The Clinical Research Associates (CRA) will monitor the data collected throughout the study thus 
providing Quality Control (QC) of the study. Independent monitoring of the clinical study for 
protocol and GCP compliance will be conducted periodically at selected sites by qualified Quality 
Assurance (QA) auditors. 
The investigator must make himself or herself available for CRAs during their visits and ensure 
that CRAs have direct access to all documents that they require, including direct access to the 
subjects’ files. The investigator agrees to cooperate with the CRAs to make certain that any 
problems detected in the course of monitoring visits are resolved. The investigator will permit 
direct access to the source data and documents to the appropriate regulatory authorities to verify 
the accuracy of this data. 
The present study sponsored Prometic Biotherapeutics will be conducted in accordance with ICH 
GCP. The clinical team at the CRO will systematically control the essential documents generated 
during this trial. The trial will be monitored by the clinical team and will be subject to internal 
audits by Quality Assurance. All clinical study monitoring visits and audits by QA will be followed 
by internal reports and corrective actions, if needed. Follow-up letters will be forwarded to sites 
after all visits and any findings should be addressed by the investigator. The follow-up letters 
should be filed with the study correspondence and other essential documentation. 
9.2 
Quality Assurance by an Audit Team 
 
Any study site may be selected for audit at any time by an audit team originating from the sponsor 
or from an external organization acting on behalf of the sponsor. The investigator agrees to 
cooperate with the auditor to ensure that any problems detected in the course of these audit visits 
are resolved. 
9.3 
Quality Assurance by Data Management 
 
The CRO or delegate will be responsible for QA and QC of the database and data management. 

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10 
Ethics and Responsibility 
10.1 
Investigational Review Board/Ethics Committee 
 
Where possible a list of IRB/EC members should be obtained by the investigator and provided to 
the sponsor. The investigator/sponsor will obtain prior approval for this clinical trial, its 
corresponding ICFs, and any material viewed by the subject. The IRB/EC will be provided with 
the following documents for review: 
• Clinical protocol and corresponding ICF(s); 
• Modifications (amendments) to the clinical protocol and corresponding ICFs; 
• Advertisements (i.e., directed at potential research subjects) for study recruitment, and any other 
material presented to a subject. 
• Any other document they request for review 
• Clinical Investigational Drug Brochure 
The IRB/EC must operate in compliance with FDA regulations 21 CFR 50 and 21 CFR 56 and/or EU 
Directives, and in conformance with applicable ICH E6 Guidelines on GCP. IRB/EC review 
documents should refer to the study be exact protocol title and number, and should identify the 
documents reviewed and the date of the review. The investigator is responsible for keeping the 
IRB/EC updated regarding any new safety data. 
10.2 
Ethical Conduct of the Trial 
 
The clinical study will be conducted in accordance with the current IRB/EC-approved clinical 
protocol; ICH E6 Guidelines on GCP; and relevant policies, requirements, and regulations of the 
IRB/EC and applicable federal agencies. Any violations by sites, CRO, or sponsor will also be 
submitted to IRBs and relevant regulatory agencies. 
The IRB/EC and the FDA/ Norwegian Competent Authority will be notified promptly of 
discontinuation of the entire clinical study. Respective protocol modifications will be submitted 
prospectively to the IRB/EC and to the FDA/Norwegian Competent Authority for discontinuation 
or modification of parts of the clinical study. Enrolled subjects, investigators, and sub-investigators 
will be notified immediately of discontinuation of parts of the clinical study or if the study ends or 
the discontinuation of a subject is necessary. 
If there are changes to the protocol and a new informed consent has been approved, subjects should 
be informed of the changes and of any changes to the risks/benefits of participation. Subjects will 
need to go through the informed consent process and sign a new approved ICF to be eligible to 
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If a subject decides she or he does not want to continue with the treatment portion of the study, a 
subject can give consent to be followed for safety only and can continue to allow access to 
Protected Health Information (PHI) even after withdrawal. However, the amended and approved 
ICF will need to be signed, and discontinuing treatment only should be clearly documented in a 
progress note in the subject’s source documents. A subject still retains the right to withdraw 
participation in the study at any time and to discontinue further access to PHI. However, all data 
collected to that point will be made available to the sponsor and CRO. 
10.3 
Informed Consent and Assent 
 
The investigator must explain to each subject the nature of the study, the purpose, the procedures 
involved, the expected duration, the potential risks and benefits involved, and any discomfort it 
may entail. The investigational product(s) should be identified as “experimental” and that its side 
effects are not completely known. This information must be provided in language that the subject 
understands. Each subject must be informed that participation in the study is voluntary and that 
they may withdraw from the study at any time, and that withdrawal of consent/assent will not 
affect their subsequent medical treatment or relationship with the treating physician. The subject 
should be given sufficient time to read the informed consent/assent form and the opportunity to 
ask questions and consider the statement before signing and dating it, and should be given a copy 
of the signed document(s). 
Informed consent will be obtained from each subject (or subject’s legally authorized 
representative) before the subject is admitted to the study. Assents will be obtained from each 
child. The assent will be presented to the child at an appropriate level of understanding for the 
particular child. The assent consists of the same components as the consent and requires discussion 
between the child and the parent or guardian and the investigator. The child will provide verbal 
assent and provide their signature or mark on the assent form (the parent or guardian may fill out 
the time and date, if necessary). No subject can enter the study before informed consent/assent has 
been obtained. 
The sponsor or its designee will supply a model informed consent/assent form that complies with 
regulatory requirements and is considered appropriate for the study, as well as a model informed 
consent/assent form for optional genetic testing for plasminogen. Any changes to the sample 
consent form suggested by the investigator must be agreed to by the sponsor or its designee before 
submission to the IRB/EC, and a copy of the approved version must be provided to the sponsor or 
the designated medical monitor after IRB/EC approval. 
During the study, subjects will be given any new information that may affect their decision to 
continue participation. Should a protocol amendment be required, the consent/assent may be 
revised to reflect the changes of the protocol. If the consent/assent form is revised, it is the 

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investigator’s responsibility to ensure that an amended consent/assent form is reviewed and 
approved by the IRB or ethics committee, and this amended form is signed by all subjects 
subsequently entered in the study as well as those currently in the study. 
10.4 
Changes in the Conduct of the Study 
 
The investigator may change the protocol without IRB/EC or sponsor approval only if it is 
necessary in order to safeguard the safety or rights of the subjects (i.e., in emergent situations). 
Any protocol amendment must be submitted for information or consideration to the applicable 
regulatory agencies. 
IRB approval will be requested for any change to this protocol, which could affect the safety of 
subjects, the scope or design of the study. Minor procedural changes will be implemented by Study 
Notes to File, with supporting documentation at each site, if appropriate. A non-substantial 
amendment of a study protocol includes minor correction or clarification that have no significant 
impact on the way the clinical study is to be conducted and no effect on subject safety (i.e., 
administrative changes like change of telephone number(s), logistical changes, etc.). Any changes 
of the protocol (substantial amendments and non-substantial amendments) will be integrated into 
an updated study protocol, with a listing of all changes and reasoning for them. 
11 
Confidentiality 
The collection and processing of personal data from subjects enrolled in this study will be limited 
to those data that are necessary to investigate the efficacy, safety, quality, and utility of the IMP 
used in this study. 
The investigator will ensure that the subjects’ anonymity will be maintained. The privacy rules of 
the US HIPAA will be followed to obtain authorization for most uses and disclosures of Protected 
Health Information. On eCRFs or other documents submitted to the sponsor or its designee, 
subjects will not be identified by their names, but by an identification code, consisting of the 
combination of subject’s initials and study number. Documents not for submission to sponsor or 
its designee (e.g., the site confidential subject enrollment log and original subjects’ consent forms) 
will be maintained by the investigator in strict confidence. Appropriate technical and 
organizational measures to protect the personal data against unauthorized disclosures or access, 
accidental or unlawful destruction, or accidental loss, or alteration must be put in place. Sponsor 
personnel whose responsibilities require access to personal data agree to keep the identity of study 
subjects confidential. 
The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator to allow direct access to his or her original medical records 

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for study-related monitoring, audit, IRB, and regulatory inspection. This consent also addresses 
the transfer of the data to other entities and to other countries. 
The subject has the right to request through the investigator access to his/her personal data and the 
right to request rectification of any data that are not correct or complete. Reasonable steps should 
be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations. 
12 
Publication Policy 
In collaboration with the sponsor, the CRO will prepare a draft study report after the completion 
of the study. The final draft study report will be submitted to the selected investigators for 
information, review, and comments. 
Publication of data generated in the study is governed by the Investigator Clinical Trial Agreement. 
13 
Liabilities and Insurance 
The sponsor will pay for all study related costs. A separate financial agreement will be made (as 
appropriate) with the investigator and/or institutions. 
The sponsor also carries insurance coverage for incidents of damage or injury to study subjects 
while participating in the study or taking IMP. 
14 
References 
Bateman JB, Pettit TH, Isenberg SJ, Simons KB. (1986) Ligneous conjunctivitis: an autosomal 
recessive disorder. J Pediatr Ophthalmol Strabismus. 23(3):137-40. 
Bugge TH, Flick MJ, Daugherty CC, Degen JL. (1995) Plasminogen deficiency causes severe 
thrombosis but is compatible with development and reproduction. Genes Dev. 9(7):794-807. 
Bugge TH, Kombrinck KW, Flick MJ, Daugherty CC, Danton MJ, Degen JL. (1996) Loss of 
fibrinogen rescues mice from the pleiotropic effects of plasminogen deficiency. Cell. 87(4):709- 
19. 
Castellino FJ, Ploplis VA. (2005) Structure and function of the plasminogen/plasmin system. 
Thromb Haemost. 93(4):647-54. 
Claeys H, Molla A, Verstraete M. (1973) Conversion of NH2-Terminal Glutamic Acid to NH2- 
Terminal Lysine Human Plasminogen by Plasmin. Thrombosis Research, 3:515. 
Collen D, Ong EB, Johnson AJ. (1991) Human Plasminogen: In Vitro and In Vivo Evidence for 
the Biological Integrity of NH2-Terminal Glutamic Acid Plasminogen. Thrombosis Research, 
7:515. 

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De Cock R, Ficker LA, Dart JG, Garner A, Wright P. (1995) Topical heparin in the treatment of 
ligneous conjunctivitis. Ophthalmology. 102(11):1654-9. 
Heidemann DG, Williams GA, Hartzer M, Ohanian A, Citron ME. (2003) Treatment of ligneous 
conjunctivitis with topical plasmin and topical plasminogen. Cornea. 22(8):760-2. 
Kraft J, Lieb W, Zeitler P, Schuster V. (2000) Ligneous conjunctivitis in a girl with severe type I 
plasminogen deficiency. Graefe’s Arch Clin Exp Ophthalmol. 238(9):797-800. 
Lijnen HR, Carmeliet P, Bouché A, Moons L, Ploplis VA, Plow EF, et al. (1996) Restoration of 
thrombolytic potential in plasminogen-deficient mice by bolus administration of plasminogen. 
Blood. 88(3):870-6. 
Mehta R, Shapiro AD. (2008) Plasminogen deficiency. Haemophilia.,14(6):1261-8. 
Pergantou H, Likaki D, Fotopoulou M, Katsarou O, Xafaki P, Platokouki H. (2011) Management 
of ligneous conjunctivitis in a child with plasminogen deficiency. Eur J Pediatr. 170(10):1333-6. 
Ploplis VA, Carmeliet P, Vazirzadeh S, Van Vlaenderen I, Moons L, Plow EF, et al. (1995) Effects 
of disruption of the plasminogen gene on thrombosis, growth, and health in mice. Circulation. 
92(9):2585-93. 
Rubin BI, Holland EJ, de Smet MD, Belfort R Jr, Nussenblatt RB. (1991) Response of reactivated 
ligneous conjunctivitis to topical cyclosporine. Am J Ophthalmol. 112(1):95-6. 
Schott D, et al. (1998) Therapy with a Purified Plasminogen Concentrate in an Infant with 
Ligneous Conjunctivitis and Homozygous Plasminogen Deficiency. New Engl J Med. 339:1679. 
Schuster V, Hügle B, Tefs K. (2007) Plasminogen deficiency. J Thromb Haemost. 5(12):2305-22. 
Schuster V, Seregard S. (2003) Ligneous conjunctivitis. Surv Ophthalmol. 48(4):369-88. 
Silva GB, Bariani C, Mendonça EF, Batista AC. (2006) Clinical manifestations due to severe 
plasminogen deficiency: a case report. J Dent Child (Chic). 73(3):179-82. 
Tabbara KF. (2004) Prevention of ligneous conjunctivitis by topical and subconjunctival fresh 
frozen plasma. Am J Ophthalmol. 138(2):299-300. 
Tefs K, Gueorguieva M, Klammt J, Allen CM, Aktas D, Anlar FY, et al. (2006) Molecular and 
clinical spectrum of type I plasminogen deficiency: A series of 50 patients. Blood. 108(9):3021- 
Watts P, Suresh P, Mezer E, Ells A, Albisetti M, Bajzar L, et al. (2002) Effective treatment of 
ligneous conjunctivitis with topical plasminogen. Am J Ophthalmol. 133(4):451-5. 

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15 
Appendices 
15.1 
Declaration of Helsinki 
 
WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human 
Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and amended by 
the: 29th WMA General Assembly, Tokyo, Japan, October 1975 35th WMA General Assembly, 
Venice, Italy, October 1983 41st WMA General Assembly, Hong Kong, September 1989 48th 
WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 53rd WMA General 
Assembly, Washington DC, USA, October 2002 (Note of Clarification added) 55th WMA 
General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 59th WMA 
General Assembly, Seoul, Republic of Korea, October 2008 64th WMA General Assembly, 
Fortaleza, Brazil, October 2013 
Preamble 
1. 
The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including research 
on identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should be applied with consideration of all other relevant paragraphs. 
2. 
Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving human 
subjects to adopt these principles. 
General Principles 
3. 
The Declaration of Geneva of the WMA binds the physician with the words, 
“The health of my patient will be my first consideration,” and the International Code of Medical 
Ethics declares that, “A physician shall act in the patient's best interest when providing medical 
care.” 
4. 
It is the duty of the physician to promote and safeguard the health, well-being and rights of 
patients, including those who are involved in medical research. The physician's knowledge and 
conscience are dedicated to the fulfillment of this duty. 
5. 
Medical progress is based on research that ultimately must include studies involving human 
subjects. 
6. 
The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and therapeutic 
interventions (methods, procedures and treatments). Even the best proven interventions must be 

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evaluated continually through research for their safety, effectiveness, efficiency, accessibility and 
quality. 
7. 
Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 
8. 
While the primary purpose of medical research is to generate new knowledge, this goal can 
never take precedence over the rights and interests of individual research subjects. 
9. 
It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal information 
of research subjects. The responsibility for the protection of research subjects must always rest 
with the physician or other health care professionals and never with the research subjects, even 
though they have given consent. 
10. 
Physicians must consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms and 
standards. No national or international ethical, legal or regulatory requirement should reduce or 
eliminate any of the protections for research subjects set forth in this Declaration. 
11. 
Medical research should be conducted in a manner that minimizes possible harm to the 
environment. 
12. 
Medical research involving human subjects must be conducted only by individuals with 
the appropriate ethics and scientific education, training and qualifications. Research on patients or 
healthy volunteers requires the supervision of a competent and appropriately qualified physician 
or other health care professional. 
13. 
Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research. 
14. 
Physicians who combine medical research with medical care should involve their patients 
in research only to the extent that this is justified by its potential preventive, diagnostic or 
therapeutic value and if the physician has good reason to believe that participation in the research 
study will not adversely affect the health of the patients who serve as research subjects. 
15. 
Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
Risks, Burdens and Benefits 
16. 
In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the risks and burdens to the research subjects. 
17. 
All medical research involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in comparison 
with foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation. 

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Measures to minimize the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher. 
18. 
Physicians may not be involved in a research study involving human subjects unless they 
are confident that the risks have been adequately assessed and can be satisfactorily managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive 
proof of definitive outcomes, physicians must assess whether to continue, modify or immediately 
stop the study. 
Vulnerable Groups and Individuals 
19. 
Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
20. 
Medical research with a vulnerable group is only justified if the research is responsive to 
the health needs or priorities of this group and the research cannot be carried out in a non- 
vulnerable group. In addition, this group should stand to benefit from the knowledge, practices or 
interventions that result from the research. 
Scientific Requirements and Research Protocols 
21. 
Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources of 
information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of 
animals used for research must be respected. 
22. 
The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should include 
information regarding funding, sponsors, institutional affiliations, potential conflicts of interest, 
incentives for subjects and information regarding provisions for treating and/or compensating 
subjects who are harmed as a consequence of participation in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions. 
Research Ethics Committees 
23. 
The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This committee must 
be transparent in its functioning, must be independent of the researcher, the sponsor and any other 
undue influence and must be duly qualified. It must take into consideration the laws and regulations 
of the country or countries in which the research is to be performed as well as applicable 
international norms and standards but these must not be allowed to reduce or eliminate any of the 
protections for research subjects set forth in this Declaration. 

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The committee must have the right to monitor ongoing studies. The researcher must 
provide monitoring information to the committee, especially information about any serious 
adverse events. No amendment to the protocol may be made without consideration and approval 
by the committee. After the end of the study, the researchers must submit a final report to the 
committee containing a summary of the study’s findings and conclusions. 
Privacy and Confidentiality 
24. 
Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
Informed Consent 
25. 
Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members or 
community leaders, no individual capable of giving informed consent may be enrolled in a research 
study unless he or she freely agrees. 
26. 
In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, any 
possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and 
potential risks of the study and the discomfort it may entail, post-study provisions and any other 
relevant aspects of the study. The potential subject must be informed of the right to refuse to 
participate in the study or to withdraw consent to participate at any time without reprisal. Special 
attention should be given to the specific information needs of individual potential subjects as well 
as to the methods used to deliver the information. 
After ensuring that the potential subject has understood the information, the physician or 
another appropriately qualified individual must then seek the potential subject’s freely-given 
informed consent, preferably in writing. If the consent cannot be expressed in writing, the non- 
written consent must be formally documented and witnessed. 
All medical research subjects should be given the option of being informed about the 
general outcome and results of the study. 
27. 
When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician or 
may consent under duress. In such situations the informed consent must be sought by an 
appropriately qualified individual who is completely independent of this relationship. 
28. 
For a potential research subject who is incapable of giving informed consent, the physician 
must seek informed consent from the legally authorized representative. These individuals must not 
be included in a research study that has no likelihood of benefit for them unless it is intended to 
promote the health of the group represented by the potential subject, the research cannot instead 
be performed with persons capable of providing informed consent, and the research entails only 
minimal risk and minimal burden. 

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29. 
When a potential research subject who is deemed incapable of giving informed consent is 
able to give assent to decisions about participation in research, the physician must seek that assent 
in addition to the consent of the legally authorized representative. The potential subject’s dissent 
should be respected. 
30. 
Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition that 
prevents giving informed consent is a necessary characteristic of the research group. In such 
circumstances the physician must seek informed consent from the legally authorized 
representative. If no such representative is available and if the research cannot be delayed, the 
study may proceed without informed consent provided that the specific reasons for involving 
subjects with a condition that renders them unable to give informed consent have been stated in 
the research protocol and the study has been approved by a research ethics committee. Consent to 
remain in the research must be obtained as soon as possible from the subject or a legally authorized 
representative. 
30. The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to withdraw 
from the study must never adversely affect the patient- physician relationship. 
32. 
For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek informed 
consent for its collection, storage and/or reuse. There may be exceptional situations where consent 
would be impossible or impracticable to obtain for such research. In such situations the research 
may be done only after consideration and approval of a research ethics committee. 
Use of Placebo 
33. 
The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; 
or 
Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention is 
necessary to determine the efficacy or safety of an intervention 
and the patients who receive any intervention less effective than the best proven one, 
placebo, or no intervention will not be subject to additional risks of serious or irreversible harm as 
a result of not receiving the best proven intervention. 
Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34. 
In advance of a clinical trial, sponsors, researchers and host country governments should 
make provisions for post-trial access for all participants who still need an intervention identified 

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as beneficial in the trial. This information must also be disclosed to participants during the 
informed consent process. 
Research Registration and Publication and Dissemination of Results 
35. 
Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
36. 
Researchers, authors, sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research. Researchers have a duty to 
make publicly available the results of their research on human subjects and are accountable for the 
completeness and accuracy of their reports. All parties should adhere to accepted guidelines for 
ethical reporting. Negative and inconclusive as well as positive results must be published or 
otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of 
interest must be declared in the publication. Reports of research not in accordance with the 
principles of this Declaration should not be accepted for publication. 
Unproven Interventions in Clinical Practice 
37. 
In the treatment of an individual patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, with 
informed consent from the patient or a legally authorized representative, may use an unproven 
intervention if in the physician's judgement it offers hope of saving life, re-establishing health or 
alleviating suffering. This intervention should subsequently be made the object of research, 
designed to evaluate its safety and efficacy. In all cases, new information must be recorded and, 
where appropriate, made publicly available. 
 
© World Medical Association, Inc. - All Rights reserved. 

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15.2 
Clinical Laboratory Tests 
 
Hematology 
red blood cell count (RBC), white blood cell count (WBC), platelets, 
hemoglobin, and hematocrit 
Biochemistry 
albumin, AST, ALT, ALP, creatinine, blood urea nitrogen (BUN), lactate 
dehydrogenase (LDH), and bilirubin 
Urinalysis 
protein, albumin, and RBC; pregnancy test (female of child-bearing potential 
only) 
Fibrinolysis/ 
coagulation 
Fibrinolysis panel: 
• D-dimer* 
• Alpha 2-antiplasmin (chromogenic assay) 
• Fibrin monomer (hemagglutination) 
• Alpha-1-antitrypsin 
Coagulation panel: 
• Prothrombin time (PT) 
• Partial thromboplastin time (PTT) 
• International normalization ratio (INR) 
Immunogenicity 
anti-plasminogen antibody 
Pharmacokinetic 
and trough level 
sampling* 
• Plasminogen antigen and activity levels 
• D-dimer* 
Virology 
• At screening, serology for HIV-1, HIV-2, HCV, HBV, parvovirus B19, 
and HAV. 
• At the End-of-Treatment visit, serology and PCR for HIV-1, HIV-2, 
HCV, HBV; PCR for B19 and HAV. 
• 30 days after last IMP dose (in Segment 2 or 3): serology and PCR for 
HIV-1, HIV-2, HCV, HBV; PCR for B19 and HAV. 
*D-dimer is measured as part of the fibrinolysis panel and along with plasminogen trough level or PK level. 

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15.3 
Clinical Global Impression – Global Improvement (CGI-I) 
 
Patient Name: 
Date: 
 
 
Clinician Name: 
 
 
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Clinical Global Impression – Global Improvement (CGI –I) Scale 
Rate total improvement whether or not, in your clinical judgment, it is due entirely to drug treatment. 
 
 
Compared to his/her condition at baseline, how much has he/she changed? 
 
 
□ 0 = Not assessed 
□ 1 = Very much improved 
□ 2 = Much improved 
□ 3 = Minimally improved 
□ 4 = No change 
□ 5 = Minimally worse 
□ 6 = Much worse 
□ 7 = Very much worse 

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15.4 
Quality of life assessment