Conditions: Paroxysmal Nocturnal Hemoglobinuria
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 50
Healthy volunteers: no

Brief summary:
This is a randomised Phase III, double-blind, multicentre, cross-over study to compare the efficacy, safety, pharmacokinetics, and immunogenicity between SB12 and Soliris® in subjects with PNH.

Detailed description:
Subjects will be randomised in a 1:1 ratio to either treatment sequence. Subjects randomly assigned to treatment with SB12 or Soliris® will receive 600 mg of eculizumab IV every week for first 4 weeks (initial phase) and 900 mg for the fifth week, followed by 900 mg every 2 weeks until Week 52. Subjects who are randomised to initially receive SB12 will be switched to receive Soliris® and subjects who are randomised to initially receive Soliris® will be switched to receive SB12 at Week 26.

Arms:
arm 1: Subjects who are randomised to initially receive SB12 will be switched to receive Soliris® at Week 26 arm 2: Subjects who are randomised to initially receive Soliris® will be switched to receive SB12 at Week 26

Interventions: intervention 1: SB12 (proposed eculizumab biosimilar) intervention 2: Soliris (eculizumab)
Intervention descriptions: intervention 1: 600 mg IV every week for first 4 weeks and 900 mg for the fifth week, followed by 900 mg every 2 weeks thereafter intervention 2: 600 mg IV every week for first 4 weeks and 900 mg for the fifth week, followed by 900 mg every 2 weeks thereafter

Protocol document:
Prot_SAP_000.pdf: 
SB12 (proposed eculizumab biosimilar) 
SB12-3003 
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Samsung Bioepis – Confidential and Proprietary Information 
Page 1 of 173 
 
 
 
Clinical Study Protocol 
A Phase III Randomised, Double-blind, Multicentre Study to Compare the 
Efficacy, Safety, Pharmacokinetics, and Immunogenicity between SB12 
(proposed eculizumab biosimilar) and Soliris® in Subjects with Paroxysmal 
Nocturnal Haemoglobinuria 
 
 
 
 
Product 
SB12 (proposed eculizumab biosimilar) 
EudraCT Number 
2018‐002857‐31 
US pre-IND Number 
PIND 135254 
Protocol Number 
SB12-3003 
Study Phase 
Phase III 
Version and Effective Date 
Version 6.0 
Nov 27, 2020 
Version 5.0 
Aug 21, 2020 
Version 4.0 
Nov 29, 2019 
Version 3.0 
Dec 12, 2018 
Version 2.0 
Oct 08, 2018 
Version 1.0 
Jul 31, 2018 
Sponsor 
Samsung Bioepis Co., Ltd. 
107, Cheomdan-daero, Yeonsu-gu, 
Incheon, 21987 
Republic of Korea 
 
This document contains confidential information belonging to Samsung Bioepis Co., Ltd. Your acceptance or 
review of this document constitutes agreement that you will not copy or disclose the information contained 
herein to others or use it for unauthorised purposes without written authorisation from the Sponsor. 
 
 


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SYNOPSIS 
Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB12 (proposed eculizumab biosimilar) 
Name of Active Ingredient: 
Eculizumab 
Title of Study: A Phase III Randomised, Double-blind, Multicentre Study to Compare the Efficacy, Safety, 
Pharmacokinetics, and Immunogenicity between SB12 (proposed eculizumab biosimilar) and Soliris® in 
Subjects with Paroxysmal Nocturnal Haemoglobinuria 
Protocol No: 
SB12-3003 
Phase: III 
Planned Study Period: After Screening, the duration of study participation will be 58 weeks per subject 
including 50 weeks of treatment and 8 weeks of post-treatment follow-up. After completion of study 
treatment, subjects may be entered into an extended supply of up to 2 years. 
Objectives: 
Primary objective 
The primary objective of this study is to demonstrate comparable clinical efficacy of SB12 and Soliris®, by 
evaluating the lactate dehydrogenase (LDH) in subjects with paroxysmal nocturnal haemoglobinuria (PNH). 
Secondary objectives 
The secondary objectives are: 
• 
To evaluate the efficacy of SB12 compared to Soliris® by 
- 
LDH profile over time  
- 
Number of units of packed red blood cells (pRBCs) transfused 
• 
To evaluate the safety and tolerability of SB12 compared to Soliris® 
• 
To evaluate the pharmacokinetic (PK) of SB12 compared to Soliris® 
• 
To evaluate the immunogenicity of SB12 compared to Soliris® 
• 
To evaluate the pharmacodynamic (PD) of SB12 compared to Soliris® 
Study Design: 
This is a randomised, Phase III, double-blind, multicentre, cross-over study to compare the efficacy, safety, 
pharmacokinetics, and immunogenicity between SB12 and Soliris® in subjects with PNH. 
Subjects will be randomised in a 1:1 ratio to treatment sequence I (SB12 to Soliris®) or treatment sequence II 
(Soliris® to SB12). Subjects who are randomised to initially receive SB12 will be switched to receive Soliris® 
and subjects who are randomised to initially receive Soliris® will be switched to receive SB12 at Week 26. 
In special circumstances of a shortage of the comparator, to ensure continuity of study treatment for the 
duration of study, the Sponsor will provide SB12 instead of Soliris® in a blinded manner. 
After completion of activities at Week 52, an open-label extended supply of SB12 will be provided for up to 
2 calendar years to subjects who have benefited from study treatment and opt to participate in extended 
supply under an ethical basis.  
Number of Subjects: 
A total of approximately 50 subjects (25 subjects per treatment sequence) will be randomised in this study.  


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Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB12 (proposed eculizumab biosimilar) 
Name of Active Ingredient: 
Eculizumab 
Treatment Sequence 
Period 1 
Period 2 
I (n = 25) 
SB12 
Soliris® 
II (n = 25) 
Soliris® 
SB12 
Target Population:  
Eculizumab-naïve patients with PNH 
Eligibility Criteria: 
Inclusion criteria 
Subjects must meet all of the following criteria to be eligible for the study: 
1. Male or female aged 18 or older at the time of signing the informed consent form (ICF), if local 
regulations are different in this regard, follow the local regulations. 
2. Documented diagnosis of PNH.  
3. Presence of the PNH white blood cell (WBC) clone, with a granulocyte or monocyte clone size of ≥ 
10% by high-sensitivity flow cytometry at Screening. 
4. Documented LDH level ≥ 1.5 × upper limit of normal (ULN) at Screening. 
5. History of transfusion for anaemia within 12 months prior to Screening or having PNH-related 
symptoms (e.g., fatigue, haemoglobinuria, abdominal pain, chest pain, shortness of breath 
[dyspnoea], dysphagia, erectile dysfunction) at Screening. 
6. All subjects must be vaccinated against Neisseria meningitidis within 3 years prior to or on Day 1 in 
accordance with current local guidelines or Soliris® Summary of Product Characteristics (SmPC) to 
reduce the risk of meningococcal infection.  
7. Female subjects who are not pregnant or nursing at Screening and on initiation of study drug (Day 
1) and who are not planning to become pregnant from Screening until 5 months after the last dose of 
study drug. 
8. Subjects and their partners of childbearing potential (female or male) who agree to use of a highly 
effective contraceptive method (e.g., established use of oral, injected or implanted hormonal 
contraceptive, placement of an intrauterine device or intrauterine system, male sterilisation, or true 
abstinence [see Section 8.4.1]) from Screening until 5 months after the last dose of study drug. 
9. Subjects must be able to understand the implications of taking part in the study and be willing to 
follow the study instructions and requirements fully. 
10. Subjects must be able to provide informed consent, which must be obtained prior to any study 
related procedures. 
Exclusion criteria 
Subjects meeting any of the following criteria are not eligible for the study: 
1. Previous treatment with a complement pathway inhibitor (including eculizumab). 


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Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB12 (proposed eculizumab biosimilar) 
Name of Active Ingredient: 
Eculizumab 
2. Known hypersensitivity to the investigational product (IP) or any of the ingredients or excipients of 
the IP. 
3. Known contraindication/hypersensitivity for meningococcal vaccine or the antibiotic to be used in 
the study. 
4. Abnormal haematological parameters at Screening defined as the following: 
a. 
Absolute neutrophil count (ANC) ≤ 0.5 × 103/µL 
b. Platelet count < 70 × 103/µL 
5. History of meningococcal disease. 
6. History of haematopoietic stem cell transplantation. 
7. History of serious thrombotic event (e.g., stroke, myocardial infarction, pulmonary embolism, etc.). 
8. Known or suspected active bacterial, virus, fungal infection within 30 days prior to initiation of 
study drug (Day 1). 
9. Known history of human immunodeficiency virus (HIV) infection or have positive results at 
Screening. 
10. Concomitant use of any of the following medications is prohibited if the following conditions apply. 
a. 
Erythropoietin, systemic corticosteroids, low-molecular-weight heparins, iron supplements, 
and androgen therapy that have not been on a stable dose for at least 4 weeks prior to initiation 
of study drug (Day 1). 
b. Warfarin with an unstable international normalised ratio (INR) for at least 4 weeks prior to 
initiation of study drug (Day 1) at the discretion of the Investigator.   
c. 
Cyclosporine that has not been on a stable dose for at least 8 weeks prior to initiation of study 
drug (Day 1). 
11. Subjects who have received or participated in another investigational drug, device, or procedures 
within 30 days or within 5 half-lives of that IP prior to Screening, whichever is greater. 
12. History of malignancy within 5 years prior to Screening, except for curatively treated carcinoma in 
situ of uterine cervix, basal cell carcinoma of the skin, or squamous cell carcinoma of the skin. 
13. Any other cardiac, hepatic, immunologic, pulmonary, rheumatoid disease, other conditions causing 
rise in LDH (e.g., tumours, muscular dystrophies, liver and bile disease, etc.), or the disorder which, 
at the discretion of the Investigator, will put the subjects at risk if they are enrolled. 
14. Other unspecified reasons that, at the discretion of the Investigator or Sponsor, make the subjects 
unsuitable for enrolment. 
Investigational Products: 
• 
Name: SB12 (proposed eculizumab biosimilar) or Soliris® 
• 
Formulation: A vial of 30 mL contains 300 mg of eculizumab (10 mg/mL)  
• 
Route of administration: Intravenous (IV) infusion 35 ± 10 minutes 


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Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB12 (proposed eculizumab biosimilar) 
Name of Active Ingredient: 
Eculizumab 
• 
Dose regimen: 600 mg every 7 days for the first 4 weeks (initial phase) and 900 mg for the fifth 
week, followed by 900 mg every 14 ± 2 days until Week 50 (maintenance phase).  
Main Criteria for Evaluation  
Primary endpoints 
• 
LDH level (U/L) at Week 26  
• 
Time-adjusted area under the effect curve (AUEC) of LDH from Week 14 to Week 26 and from 
Week 40 to Week 52  
Secondary endpoints 
Efficacy endpoints 
• 
LDH profile over time 
• 
Number of units of pRBCs transfused throughout the study period 
Safety endpoints 
• 
Incidence of adverse events (AEs) 
• 
Incidence of serious AEs (SAEs) 
• 
Incidence of infection-related AEs 
- 
Meningococcal infection 
- 
Other systemic infections 
• 
Incidence of infusion-related reactions (IRRs) 
Safety of subjects will be monitored by 12-lead electrocardiogram (ECG), vital sign assessment, and physical 
examination. Haematological, biochemical, and urinalysis laboratory parameters will be also measured. 
PK endpoint 
• 
Concentration prior to infusion (trough serum concentration [Ctrough]) at Weeks 0 (Day 1), 2, 4, 6, 
10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 44, 48, and 52 
Immunogenicity endpoints  
• 
Incidence of anti-drug antibodies (ADAs) at Weeks 0 (Day 1), 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 
36, 40, 44, 48, 52, and early termination (ET) visit 
• 
Incidence of neutralising antibodies (NAbs) at Weeks 0 (Day 1), 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 
32, 36, 40, 44, 48, 52, and ET visit 
PD endpoint  
• 
Terminal complement activity at Weeks 0 (Day 1), 2, 4, 6, 10, 14, 26, 28, 30, 32, 36, 40, and 52 
Statistical Methods 


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Analysis sets for efficacy analyses 
Modified Full Analysis Set (M-FAS) consists of all randomised subjects who do not have positive result of 
pharmacogenetic analysis (C5 gene polymorphism). However, subjects who do not have any efficacy 
assessment result after randomisation and do not receive IP during the study period will be excluded from this 
analysis set. Following the intent-to-treat principle, subjects will be analysed according to the treatment 
sequence they are assigned to at randomisation.  
Per-Protocol Set for AUEC of LDH (PPS-AUEC) consists of all M-FAS subjects who have sufficient LDH 
assessments for AUEC calculation without any major protocol deviations (PDs) that have impact on efficacy 
assessment. Subjects excluded from the primary analysis will be pre-defined on a case-by-case basis prior to 
unblinding the treatment sequence assignment for analyses. In addition, subjects who received different 
treatment from the randomised treatment sequence due to a shortage of the comparator will be excluded from 
this analysis set. 
Per-Protocol Set for LDH at a single time point (PPS-single) consists of all M-FAS subjects who have LDH 
assessment at Week 26 without any major PDs that have impact on efficacy assessment. Subjects excluded 
from the primary analysis will be pre-defined on a case-by-case basis prior to unblinding the treatment 
sequence assignment for analyses. In addition, subjects who received different treatment in Period 1 from the 
randomised treatment sequence due to a shortage of the comparator will be excluded from this analysis set. 
Efficacy analyses 
 
for those who are in favour of the time-adjusted AUEC of LDH, the primary efficacy analysis 
will be performed for the PPS-AUEC using a linear mixed model with treatment, sequence, period, and 
gender as fixed effects, and subject nested within sequence as a random effect. The analysis will be 
performed with loge-transformed time-adjusted AUEC of LDH estimating the difference in least squares 
means and its 90% confidence interval (CI), and back transformation of those values will provide the ratio of 
geometric means and 90% CI. The equivalence will be declared if the two-sided 90% CI of the ratio of 
geometric means in time-adjusted AUEC of LDH between SB12 and Soliris® lies within the pre-defined 
equivalence margin of [0.77, 1.29]. 
 
 for those who are in favour of the LDH level at a single time point, the 
primary efficacy analysis will be performed for the PPS-single using a linear mixed model with treatment, 
and gender as a fixed effect. The analysis will be performed with loge-transformed LDH at Week 26 
estimating the difference in least squares means and its 95% CI, and the delta method will be used to provide 
the mean difference and 95% CI in original scale. The equivalence will be declared if the two-sided 95% CI 
of the mean difference in LDH level at Week 26 between SB12 and Soliris® lies within the pre-defined 
equivalence margin of [−1.2 × ULN, 1.2 × ULN] where ULN of LDH to be specified in the central laboratory 
specification for this study. If normal range of LDH is gender specific, the smaller/smallest ULN will be used 
for the equivalence margin; otherwise ULN is not gender specific, unified ULN will be used for the 
equivalence margin. 
For sensitivity analysis, the primary efficacy analysis will be repeated for the M-FAS. Missing data will be 
imputed using multiple imputation method for subjects who drop out for the study prior to the primary 
analysis time point. Complete case analysis will also be performed. 
As a secondary efficacy endpoint, the number of units of pRBCs transfused will be summarised descriptively 
by treatment sequence and treatment sequence within period and will be analysed using Wilcoxon rank-sum 
test. And mean LDH profile will be presented over time. 
Safety analyses 
Safety analyses will be performed in the Safety Set (SAF). 


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Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB12 (proposed eculizumab biosimilar) 
Name of Active Ingredient: 
Eculizumab 
All reported terms for AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA®). 
AEs will be collected and classified according to National Cancer Institute-Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) v5.0. 
All AE data will be summarised by count and percentage of subjects experiencing events by system organ 
class, preferred term. TEAEs leading to IP discontinuation and treatment-emergent AEs (TEAEs) by causality 
and severity will be summarised similarly. Infection-related AEs including meningococcal infection and other 
systemic infection, and IRRs will also be summarised. 
Changes in vital signs and clinical laboratory parameters will be summarised descriptively by treatment 
sequence and visit. Other safety variables will be summarised unless otherwise specified.  
Additional analyses will be performed for the subjects who received different treatment from the randomised 
treatment sequence due to a shortage of the comparator if needed. For example, AEs and concomitant 
medications will be analysed based on the actual switched treatment. 
PK analyses 
PK analysis will be performed for the PK Analysis Set (PKS). Ctrough will be summarised descriptively by 
treatment sequence and visit. 
Immunogenicity analyses 
The immunogenicity analyses will be performed for the SAF. ADA and NAb results will be summarised with 
count and percentage by treatment sequence and visit. The incidence of overall ADA will be summarised by 
treatment sequence and period. 
PD analyses 
PD analysis will be performed for the PD Analysis Set (PDS). The absolute value and change from baseline 
in terminal complement activities will be summarised by treatment sequence and visit. 
Sample size 
The equivalence margin for the mean difference of LDH at Week 26 is derived from two historical studies 
with Soliris®. In TRIUMPH study, the mean (standard deviation [SD]) of LDH at Week 26 is 327.3 (432.9) 
U/L and 2,418.9 (930.6) U/L for eculizumab and non-eculizumab arms, respectively. PNH registry study 
reported the mean of LDH at 6 months is 352.1 (224.0) U/L and 1,201.0 (815.6) U/L for eculizumab and non-
eculizumab arms, respectively.  
A meta-analysis with fixed-effect model estimates −1,152.5 U/L of LDH mean at Week 26 with a 95% CI 
[−1,303.4, −1,001.7]. The 
 of upper limit of 95% CI was approximately 
 U/L, which implies that at 
least 
 treatment effect is obtained to preserve the treatment effect over placebo if the 
 U/L was 
statistically chosen as the equivalence limit. 
In the clinical study, LDH detection level or normal range of LDH would depend on the specification of 
laboratory parameters chosen for the study. Therefore, it is not likely to be clinically meaningful to propose 
any specific LDH level as the equivalence margin without the consideration of normal range of LDH level. 
 
 
 
 


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Name of Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished Product: 
SB12 (proposed eculizumab biosimilar) 
Name of Active Ingredient: 
Eculizumab 
 
Therefore, the equivalence margin will be [−1.2 × ULN, 1.2 × ULN] for the comparison with the 95% CI of 
the mean difference in LDH at Week 26 where ULN of LDH to be specified in the central laboratory 
specification for this study. For sample size calculation, [−268 U/L, 268 U/L] is chosen to be 23 subjects per 
treatment sequence with the assumptions of no mean difference and common SD of 270 U/L at the overall 
5% significance level. Assuming a 5% loss from randomised subjects after 26 weeks, a sample size of 25 
subjects per treatment sequence (overall sample size of 50) will give 23 completers per treatment sequence 
after 26 weeks, which is estimated to give 80% power to detect the equivalence within the margin of 268 
U/L. 
For calculation of the equivalence margin for time-adjusted AUEC of LDH, mean and coefficient of variation 
(%CV) were referred from TRIUMPH study. The mean (%CV) of AUEC of LDH at Week 26 is 81,140.0 U/L 
× day (142.45%) and 429,874.1 U/L × day (33.49%) for eculizumab and non-eculizumab arms, respectively.  
From the results in the reference study, mean ratio of AUEC of LDH is estimated to be 0.19 with a 90% CI 
[0.1308, 0.2724]. The upper limit of the equivalence margin is calculated as 
 
where it preserves at least 
 of eculizumab treatment effect over the placebo, but 
 
 the equivalence margin will be [0.77, 1.29] for the comparison with the 90% CI of mean 
ratio of time-adjusted AUEC of LDH. 
With the given equivalence margin of [0.77, 1.29], 22 subjects per treatment sequence was calculated with 
the assumptions of the mean ratio of 1, common %CV of 42% at the overall 10% significance level. 
Assuming a 10% loss from randomised subjects after 52 weeks, a sample size of 25 subjects per treatment 
sequence (overall sample size of 50) will give 22 completers per treatment sequence after 52 weeks, which is 
estimated to give 80% power to detect the equivalence within the margin of [0.77, 1.29]. 
Therefore, the sample size of 50 allows enough power to detect the equivalence in both situations.  


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GRAPHICAL STUDY DESIGN AND SCHEDULE OF ACTIVITIES 
 
 
Figure 1. Graphical Study Design 
® = Randomisation; AUEC = Area under the Effect Curve; EOS = End of Study; n = No. of Subjects; PNH = Paroxysmal Nocturnal Haemoglobinuria; W = Week 
a. 
Randomisation will trigger the shipping of study drugs to investigational site. The initiation of study drug should be done within 21 days of randomisation.  
b. 
Week 0 (Day 1) is defined as the day of the initiation of study drug. During Week 0 (Day 1) to Week 3, 600 mg of SB12 or Soliris® every 7 ± 2 days 
c. 
From Week 4, 900 mg of SB12 or Soliris® every 14 ± 2 days up to Week 50. 
d. 
Primary endpoints: 1) LDH level (U/L) at Week 26 and 2) AUEC of LDH from Week 14 to Week 26 and from Week 40 to Week 52 
e. 
Cross-over from SB12 to Soliris® and Soliris® to SB12 at Week 26 
f. 
After completion of activities at Week 52, an open-label extended supply of SB12 will be provided for up to 2 calendar years to subjects who have benefited from study treatment and opt to 
participate in extended supply under an ethical basis. 
g. 
EOS is defined as either completion of safety follow-up at Week 58 or completion of ET visit (8 weeks after the last dose of SB12 or Soliris®), which may be up to Week 56. 
h. 
During the treatment period, in special circumstances of a shortage of the comparator, to ensure continuity of study treatment for the duration of study, the Sponsor will provide SB12 
instead of Soliris® in a blinded manner. 
 
 


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Table 1. Schedule of Activities (Period 1, before Cross-over) 
Assessments 
Study Period 
Study Visit 
Scree 
-ning 
Randomi 
-sation 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Week 
0 
1 
2 
3 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
Day (± Visit Window) 
−63 to 
−22 
−21 to −1 
1 
8 
(±2) 
15 
(±2) 
22 
(±2) 
29 
(±2) 
43 
(±2) 
57 
(±2) 
71 
(±2) 
85 
(±2) 
99 
(±2) 
113 
(±2) 
127 
(±2) 
141 
(±2) 
155 
(±2) 
169 
(±2) 
Obtain informed consent1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic information 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical, transfusion, and thrombosis history 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccination for Neisseria meningitidis2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology (HIV-1 and HIV-2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisation4  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacogenetic sampling5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG6 
 
 
 
 
 
 
 
 
 
 
 
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Pregnancy test7 
 
 
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PNH clone size8 
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Coagulation profile9 
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Ferritin, vitamin B12, folate 
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LDH10 
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Haematology and chemistry tests11 
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Reticulocyte count, haptoglobin, free haemoglobin 
 
 
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Urinalysis 
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Blood sampling for PK analysis12 
 
 
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Blood sampling for PD analysis13 
 
 
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Blood sampling for immunogenicity assay14 
 
 
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PNH symptomatology15 
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Physical examination16 
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Vital sign17 
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IP administration18 
 
 
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Adverse events19 
Continuously 
Previous and concomitant medications20 
Continuously 
Thrombosis record (MAVEs)  
Continuously 
Transfusion record (date and number of pRBCs)21 
Continuously 
HIV = Human Immunodeficiency Virus; FSH = Follicle Stimulating Hormone; ECG = Electrocardiogram; PNH = Paroxysmal Nocturnal Haemoglobinuria; LDH = Lactate Dehydrogenase;  
PK = Pharmacokinetic; PD = Pharmacodynamic; IP = Investigational Product; MAVEs = Major Adverse Vascular Events; pRBCs = Packed Red Blood Cells 


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1.  Informed consent should be obtained prior to any study related procedures. 
2.  Neisseria meningitidis vaccination should be conducted prior to or on Day 1 according to current local guidelines or Soliris® SmPC. In case subjects were vaccinated against meningococcal 
infection within 3 years prior to Day 1, which is properly documented, vaccination could be omitted. Subject who initiates study drug administration less than 14 days after receiving a 
meningococcal vaccine must receive treatment with appropriate prophylactic antibiotics (e.g., ciprofloxacin) until 14 days after vaccination.  
3.  FSH levels will be measured at Screening and Week 26 in order to confirm postmenopausal status only for women who present natural (spontaneous) amenorrhea for at least 12 months prior 
to Screening regardless of the subjects’ age. 
4.  All screening procedures must be completed and reviewed within 42 days prior to randomisation. All eligibility criteria not dependent on Day 1 must be reviewed and confirmed prior to 
randomisation. The initiation of study drug (Day 1) should be done within 21 days of randomisation. Eligibility criteria that are dependent on Day 1 should be checked at Day 1 and if found 
in violation then should be withdrawn according to discontinuation criteria.  
5.  Blood sample for pharmacogenetic analysis (C5 gene polymorphism) will be taken at Day 1. If missing, it would be taken at the next scheduled blood sampling time.  
6.  Twelve-lead ECG will be collected at Screening and pre-dose on Week 14, Week 26, Week 40, and Week 52. 
7.  Females of childbearing potential only. Serum pregnancy test at Screening and 8 weeks after the last dose of study drug in case of early termination (ET); urine pregnancy test at other 
applicable visits before study drug administration. 
8.  Both white blood cell (WBC) and red blood cell (RBC) clone size will be measured by flow cytometry at Screening and prior to dosing at Day 1 and Week 52. At other visits (Week 14, 
Week 26, and Week 40), only RBC clone size will be measured prior to dosing. 
9.  Parameters included in coagulation profile are prothrombin time, partial thromboplastin time, and international normalised ratio (INR). 
10.  LDH will be measured at pre-dose on each visit and will also be measured if the suspected sign or symptom of breakthrough haemolysis occurs.  
11.  Parameters included in haematology test are WBC count, RBC count, haemoglobin, haematocrit, platelet count, differential WBC count, nucleated RBC, mean corpuscular haemoglobin 
(MCH), mean corpuscular haemoglobin concentration (MCHC), mean corpuscular volume (MCV), mean platelet volume (MPV), and red cell distribution width (RDW). Parameters 
included in chemistry tests are sodium, potassium, creatinine, blood urea nitrogen (BUN), glucose, calcium, phosphorus, total bilirubin, direct/indirect bilirubin, albumin, total protein, 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase. All these parameters will be measured at pre-dose on 
each visit. 
12.  Blood sample for PK analysis will be taken prior to dosing at Weeks 0, 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 44, 48, and 52. Blood samples should be collected at the same day of 
study drug administration. If the administration of IPs is delayed for any reasons after pre-dose blood sampling for PK analysis, blood sample should be re-collected on actual dosing day and 
be used for analysis. PK samples will also be collected if the suspected sign or symptom of breakthrough haemolysis occurs. 
13.  Blood sample for PD (terminal complement activity) analysis will be taken prior to dosing at Weeks 0, 2, 4, 6, 10, 14, 26, 28, 30, 32, 36, 40, and 52. Blood samples should be collected at the 
same day of study drug administration. If the administration of IPs is delayed for any reasons after pre-dose blood sampling for PD analysis, blood sample should be re-collected on actual 
dosing day and be used for analysis. PD samples will also be collected if the suspected sign or symptom of breakthrough haemolysis occurs. 
14.  Blood sample for immunogenicity assay will be taken prior to dosing at Weeks 0, 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 44, 48, 52, and ET visit. Blood samples should be collected at 
the same day of study drug administration. If the administration of IPs is delayed for any reasons after pre-dose blood sampling for immunogenicity assay, blood sample should be re-
collected on actual dosing day and be used for analysis. 
15.  Investigator and/or designee will assess the PNH-related symptoms including fatigue, haemoglobinuria (discolouration of urine), chest pain, abdominal pain, dyspnoea, dysphagia, and 
erectile dysfunction.  
16.  Physical examination including height and weight at Screening; physical examination including weight at subsequent visits. Physical examination will be conducted before study drug 
administration. 
17.  Measured in a sitting position after remaining in a sitting or supine position for at least 5 minutes, including blood pressure, heart rate, and body temperature. On dosing days, vital signs will 
be taken before study drug administration.  
18.  Intravenous (IV) infusion will be performed for 35 ± 10 minutes.  


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19.  Adverse events (AEs) will be collected from the time of signing the informed consent until end of study (EOS).  
20.  Previous medications (within 4 weeks prior to Screening except immunosuppressant, 8 weeks prior to Screening for immunosuppressant) will be recorded and concomitant medications will 
be recorded until EOS.  
21.  Transfusion record will be collected from the time of signing the informed consent until EOS. 
 


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Table 2. Schedule of Activities (Period 2 and Safety Follow-up/ET, after Cross-over) 
Assessments 
Study Period 
Study Visit 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
Safety 
Follow-up21 
ET22 
Week 
261 
28 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50 
5220 
58 
8 (±1) weeks 
after the last 
dose of study 
drug 
Day (± Visit Window) 
183 
(±2) 
197 
(±2) 
211 
(±2) 
225 
(±2) 
239 
(±2) 
253 
(±2) 
267 
(±2) 
281 
(±2) 
295 
(±2) 
309 
(±2) 
323 
(±2) 
337 
(±2) 
351 
(±2) 
365 
(±2) 
407 (±7) 
FSH2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PNH clone size5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation profile6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ferritin, vitamin B12, folate 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LDH7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Haematology and chemistry tests8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reticulocyte count, haptoglobin, free 
haemoglobin 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling for PK analysis9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling for PD analysis10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling for immunogenicity assay11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PNH symptomatology12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital sign14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IP administration15 
16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events17 
Continuously 
Previous and concomitant medications18 
Continuously 
Thrombosis record (MAVEs)  
Continuously 
Transfusion record (date and number of pRBCs)19 
Continuously 
ET = Early Termination; FSH = Follicle Stimulating Hormone; ECG = Electrocardiogram; PNH = Paroxysmal Nocturnal Haemoglobinuria; LDH = Lactate Dehydrogenase; PK = 
Pharmacokinetic; PD = Pharmacodynamic; IP = Investigational Product; MAVEs = Major Adverse Vascular Events; pRBCs = Packed Red Blood Cells  
 
1.  All subjects who roll over into Period 2 will be switched to receive the other IP (SB12 or Soliris®) on Week 26 after all assessments have been performed. 
2.  FSH levels will be measured at Screening and Week 26 in order to confirm postmenopausal status only for women who present natural (spontaneous) amenorrhea for at least 12 months prior 
to Screening regardless of the subjects’ age. 
3.  Twelve-lead ECG will be collected at Screening and pre-dose on Week 14, Week 26, Week 40, and Week 52. 


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4.  Females of childbearing potential only. Serum pregnancy test at Screening and 8 weeks after the last dose of study drug in case of ET; urine pregnancy test at other applicable visits before 
study drug administration. 
5.  Both WBC and RBC clone size will be measured by flow cytometry at Screening and prior to dosing at Day 1 and Week 52. At other visits (Week 14, Week 26, and Week 40), only RBC 
clone size will be measured prior to dosing. 
6.  Parameters included in coagulation profile are prothrombin time, partial thromboplastin time, and INR. 
7.  LDH will be measured at pre-dose on each visit and will also be measured if the suspected sign or symptom of breakthrough haemolysis occurs. 
8.  Parameters included in haematology test are WBC count, RBC count, haemoglobin, haematocrit, platelet count, differential WBC count, nucleated RBC, MCH, MCHC, MCV, MPV and 
RDW. Parameters included in chemistry tests are sodium, potassium, creatinine, BUN, glucose, calcium, phosphorus, total bilirubin, direct/indirect bilirubin, albumin, total protein, ALT, 
AST, ALP, and gamma-glutamyl transpeptidase. All these parameters will be measured at pre-dose on each visit. 
9.  Blood sample for PK analysis will be taken prior to dosing at Weeks 0, 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 44, 48, and 52. Blood samples should be collected at the same day of 
study drug administration. If the administration of IPs is delayed for any reasons after pre-dose blood sampling for PK analysis, blood sample should be re-collected on actual dosing day and 
be used for analysis. PK samples will also be collected if the suspected sign or symptom of breakthrough haemolysis occurs. 
10.  Blood sample for PD (terminal complement activity) analysis will be taken prior to dosing at Weeks 0, 2, 4, 6, 10, 14, 26, 28, 30, 32, 36, 40, and 52. Blood samples should be collected at the 
same day of study drug administration. If the administration of IPs is delayed for any reasons after pre-dose blood sampling for PD analysis, blood sample should be re-collected on actual 
dosing day and be used for analysis. PD samples will also be collected if the suspected sign or symptom of breakthrough haemolysis occurs. 
11.  Blood sample for immunogenicity assay will be taken prior to dosing at Weeks 0, 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 44, 48, 52, and ET visit. Blood samples should be collected at 
the same day of study drug administration. If the administration of IPs is delayed for any reasons after pre-dose blood sampling for immunogenicity assay, blood sample should be re-
collected on actual dosing day and be used for analysis. 
12.  Investigator and/or designee will assess the PNH-related symptoms including fatigue, haemoglobinuria (discolouration of urine), chest pain, abdominal pain, dyspnoea, dysphagia, and 
erectile dysfunction. 
13.  Physical examination including height and weight at Screening; physical examination including weight at subsequent visits. Physical examination will be conducted before study drug 
administration. 
14.  Measured in a sitting position after remaining in a sitting or supine position for at least 5 minutes, including blood pressure, heart rate, and body temperature. On dosing days, vital signs will 
be taken before study drug administration. 
15.  IV infusion will be performed for 35 ± 10 minutes. 
16.  The switched IP will be received on Week 26 and dosing on Week 26 is the start of Period 2. 
17.  AEs will be collected from the time of signing the informed consent until EOS. 
18.  Concomitant medications will be recorded until EOS. 
19.  Transfusion record will be collected from the time of signing the informed consent until EOS. 
20.  After completion of activities at Week 52, an open-label extended supply of SB12 will be provided for up to 2 calendar years to subjects who have benefited from study treatment and opt to 
participate in extended supply under an ethical basis. The Week 52 activities must be completed prior to initiation of extended supply. Subjects who are eligible to participate should provide 
separate informed consent prior to enter an extended supply of SB12.  
21.  Safety follow-up will be done at Week 58 for subjects who complete the study treatments until Week 50, regardless whether subject receives extended supply of SB12 or not. These activities 
will be conducted either by visit or by phone call on subjects’ preference. 
22.  ET visit is defined as 8 weeks after the last dose of SB12 or Soliris®, which may be up to Week 56. Subjects who discontinue from the study at any time post-Day 1 (after the initiation of 
study drug) before completion of last study treatment at Week 50 will be required to have an ET visit.  
 
 


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LIST OF ABBREVIATIONS 
ADAs 
Anti-drug antibodies 
ADL 
Activities of daily living 
AEs 
Adverse events 
aHUS 
Atypical haemolytic uremic syndrome 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
ATG 
Anti-thymocyte globulin 
AUEC 
Area under the effect curve 
BUN 
Blood urea nitrogen 
CHO 
Chinese hamster ovary 
CI 
Confidence interval 
COVID-19 
Coronavirus Disease 2019 
CRO 
Contract research organisation 
CSR 
Clinical study report 
Ctrough 
Trough serum concentration 
CV 
Coefficient of variation 
DNA 
Deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board 
DSUR 
Development Safety Update Report 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EMA 
European Medicines Agency 
EOS 
End of study 
ESF 
Eligibility screening form 
ET 
Early termination 
EU 
European Union 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 


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GCP 
Good Clinical Practice 
gMG 
Generalised myasthenia gravis 
GMP 
Good Manufacturing Practice 
GPI 
Glycosylphosphatidylinositol 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
INR 
International normalised ratio 
IP 
Investigational product 
IRB 
Institutional Review Board 
IRRs 
Infusion-related reactions 
IV 
Intravenous 
IWRS 
Interactive web response system 
LDH 
Lactate dehydrogenase 
MAC 
Membrane attack complex 
MAVE 
Major adverse vascular event 
MCH 
Mean corpuscular haemoglobin 
MCHC 
Mean corpuscular haemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA® 
Medical Dictionary for Regulatory Activities 
M-FAS 
Modified Full Analysis Set 
MFDS 
Ministry of Food and Drug Safety 
MPV 
Mean platelet volume 
NAbs 
Neutralising antibodies 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse 
Events 
NMOSD 
Neuromyelitis optica spectrum disorder 
NO 
Nitric oxide 


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PC 
Product Complaints 
PD 
Pharmacodynamic 
PDs 
Protocol deviations 
PDS 
PD Analysis Set 
PIG-A 
Phosphatidylinositol glycan class-A 
PK 
Pharmacokinetic 
PKS 
PK Analysis Set 
PNH 
Paroxysmal nocturnal haemoglobinuria 
PPS-AUEC 
Per-Protocol Set for AUEC of LDH 
PPS-single 
Per-Protocol Set for LDH at a single time point 
pRBCs 
Packed red blood cells 
PSUR 
Periodic Safety Update Report 
RAN 
Randomised Set 
RBC 
Red blood cell 
RDW 
Red cell distribution width 
RSI 
Reference safety information 
SAEs 
Serious adverse events 
SAF 
Safety Set  
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SmPC 
Summary of Product Characteristics 
SOP 
Standard operating procedure 
TEAEs 
Treatment-emergent adverse events 
TOST 
Two one-sided test 
ULN 
Upper limit of normal 
US 
United States of America 
WBC 
White blood cell 
WHO-DDE 
World Health Organization-Drug Dictionary Enhanced 


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TABLE OF CONTENTS 
SYNOPSIS ............................................................................................................................................. 2 
GRAPHICAL STUDY DESIGN AND SCHEDULE OF ACTIVITIES .......................................... 9 
LIST OF ABBREVIATIONS ............................................................................................................ 15 
TABLE OF CONTENTS ................................................................................................................... 18 
LIST OF TABLES .............................................................................................................................. 23 
LIST OF FIGURES ............................................................................................................................ 23 
LIST OF STUDY STAFF ................................................................................................................... 24 
1. INTRODUCTION ........................................................................................................................... 25 
 Paroxysmal Nocturnal Haemoglobinuria ................................................................................... 25 
 Overview of SB12 ...................................................................................................................... 25 
1.2.1. Non-clinical Studies of SB12 .............................................................................................. 26 
1.2.2. Clinical Pharmacology of SB12 .......................................................................................... 26 
 Comparator Investigational Product: Soliris® ............................................................................ 26 
1.3.1. Non-clinical Data of Soliris® ............................................................................................... 26 
1.3.2. Clinical Data of Soliris® ...................................................................................................... 27 
 Study Rationale .......................................................................................................................... 28 
 Risk and Benefit Assessment ..................................................................................................... 28 
1.5.1. Known Potential Risks ........................................................................................................ 28 
1.5.2. Known Potential Benefits .................................................................................................... 29 
1.5.3. Assessment of Potential Risks and Benefits ........................................................................ 29 
2. STUDY OBJECTIVES AND ENDPOINTS ................................................................................. 29 
 Study Objectives......................................................................................................................... 29 
2.1.1. Primary Objective ................................................................................................................ 29 
2.1.2. Secondary Objectives .......................................................................................................... 29 
 Endpoints .................................................................................................................................... 30 
2.2.1. Primary Endpoints ............................................................................................................... 30 
2.2.2. Secondary Endpoints ........................................................................................................... 30 
3. STUDY DESIGN ............................................................................................................................. 31 
 Overview of Study Design ......................................................................................................... 31 
 Rationale for Study Design ........................................................................................................ 31 
3.2.1. Scientific Rationale for Study Design ................................................................................. 31 


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3.2.2. Rationale for Dose Selection ............................................................................................... 32 
3.2.3. Rationale for Pharmacokinetic Assessments ....................................................................... 32 
3.2.4. Rationale for Immunogenicity Assessments ........................................................................ 32 
 Duration of Study Participation .................................................................................................. 32 
 Number of Subjects .................................................................................................................... 33 
 End of Study Definition ............................................................................................................. 33 
4. STUDY POPULATION ................................................................................................................. 33 
 Overview .................................................................................................................................... 33 
 Inclusion Criteria ........................................................................................................................ 33 
 Exclusion Criteria ....................................................................................................................... 34 
 Screen Failures and Re-screening .............................................................................................. 35 
5. TREATMENT AND INVESTIGATIONAL PRODUCT ........................................................... 35 
 Treatment of the Subjects ........................................................................................................... 35 
5.1.1. Dosing and Treatment Schedule .......................................................................................... 35 
5.1.2. Assignment of Subjects to Treatment Sequence .................................................................. 36 
5.1.3. Blinding ............................................................................................................................... 36 
 Investigational Product ............................................................................................................... 36 
5.2.1. Identity of Investigational Product ...................................................................................... 36 
5.2.2. Formulation, Packaging, and Labelling ............................................................................... 37 
5.2.3. Product Storage and Stability .............................................................................................. 37 
5.2.4. Preparation and Administration of Investigational Products ............................................... 37 
5.2.5. Treatment Compliance and Investigational Product Accountability ................................... 38 
 Concomitant Medication or Treatment ...................................................................................... 39 
5.3.1. Permitted Concomitant Medications or Treatment .............................................................. 39 
5.3.2. Prohibited Concomitant Medications or Treatment ............................................................. 39 
6. STUDY ASSESSMENT .................................................................................................................. 39 
 Efficacy Assessment................................................................................................................... 39 
6.1.1. Disease-related Laboratory Parameters ............................................................................... 39 
6.1.2. Breakthrough Haemolysis ................................................................................................... 40 
6.1.3. Transfusions ......................................................................................................................... 40 
6.1.4. Major Adverse Vascular Events ........................................................................................... 40 
6.1.5. Paroxysmal Nocturnal Haemoglobinuria-related Symptoms .............................................. 40 


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 Safety Assessment ...................................................................................................................... 41 
6.2.1. Adverse Events .................................................................................................................... 41 
6.2.2. Clinical Laboratory Evaluations .......................................................................................... 41 
6.2.3. Physical Examinations ......................................................................................................... 43 
6.2.4. Twelve-lead Electrocardiograms ......................................................................................... 43 
6.2.5. Vital Signs ............................................................................................................................ 43 
 Other Assessments ..................................................................................................................... 43 
6.3.1. Pharmacokinetic Assessments ............................................................................................. 43 
6.3.2. Immunogenicity Assessments .............................................................................................. 43 
6.3.3. Pharmacodynamic Assessments .......................................................................................... 44 
6.3.4. Pharmacogenetic Assessments ............................................................................................. 44 
7. STUDY PROCEDURES ................................................................................................................ 45 
 Study Flow and Visit Schedule .................................................................................................. 45 
7.1.1. Screening Period .................................................................................................................. 45 
7.1.2. Randomisation ..................................................................................................................... 47 
7.1.3. Treatment Period .................................................................................................................. 47 
7.1.4. Unscheduled Visits .............................................................................................................. 50 
 Discontinuation .......................................................................................................................... 50 
7.2.1. Subject Discontinuation from Study Treatment ................................................................... 50 
7.2.2. Investigational Site Discontinuation .................................................................................... 52 
 Early Termination of the Study .................................................................................................. 52 
8. SAFETY MONITORING AND REPORTING............................................................................ 52 
 Adverse Events ........................................................................................................................... 52 
8.1.1. Definition of Adverse Event ................................................................................................ 52 
8.1.2. Period of Observation for Adverse Events .......................................................................... 53 
8.1.3. Reporting Adverse Events ................................................................................................... 53 
8.1.4. Severity Assessment ............................................................................................................ 53 
8.1.5. Causality Assessment........................................................................................................... 54 
8.1.6. Expectedness Assessment .................................................................................................... 54 
8.1.7. Withdrawal due to Adverse Events ...................................................................................... 54 
 Serious Adverse Events .............................................................................................................. 54 
8.2.1. Definition of Serious Adverse Event ................................................................................... 54 


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8.2.2. Reporting Serious Adverse Events ...................................................................................... 56 
 Adverse Events of Special Interest ............................................................................................. 56 
8.3.1. Meningococcal Infection ..................................................................................................... 56 
8.3.2. Other Systemic Infections .................................................................................................... 57 
8.3.3. Infusion-related Reactions ................................................................................................... 57 
 Pregnancy ................................................................................................................................... 58 
8.4.1. Pregnancy Prevention .......................................................................................................... 58 
 Emergency Unblinding of Assigned Treatment ......................................................................... 59 
 Independent Data and Safety Monitoring Board ........................................................................ 59 
9. STATISTICAL METHODS AND DATA ANALYSIS ............................................................... 59 
 Statistical Hypotheses................................................................................................................. 59 
 Analysis Sets .............................................................................................................................. 60 
 Subject Demographic and Baseline Characteristics ................................................................... 60 
 Analysis of the Primary Objectives ............................................................................................ 61 
 Analysis of the Secondary Objectives ........................................................................................ 61 
9.5.1. Efficacy Variable Analyses .................................................................................................. 61 
9.5.2. Safety Analyses .................................................................................................................... 62 
9.5.3. Pharmacokinetic Analyses ................................................................................................... 62 
9.5.4. Immunogenicity Analyses ................................................................................................... 62 
9.5.5. Pharmacodynamic Analyses ................................................................................................ 62 
 Sample Size Calculations ........................................................................................................... 62 
10. DATA COLLECTION AND MANAGEMENT ........................................................................ 64 
 Data Confidentiality ................................................................................................................. 64 
 Monitoring ................................................................................................................................ 64 
 Data Handling and Record Keeping ......................................................................................... 65 
 Future Use of Stored Specimens and Data ............................................................................... 65 
 Database Management and Coding .......................................................................................... 65 
 Quality Control and Quality Assurance ................................................................................... 66 
 Protocol Deviation .................................................................................................................... 66 
11. ETHICS CONSIDERATIONS AND ADMINISTRATIVE PROCEDURES ......................... 66 
 Institutional Review Boards and Independent Ethics Committees .......................................... 66 
 Ethical Conduct of the Study .................................................................................................... 67 


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 Written Informed Consent ........................................................................................................ 67 
 Investigator Information ........................................................................................................... 67 
11.4.1. Investigator Obligations ..................................................................................................... 67 
11.4.2. Training of Investigational Site Personnel ......................................................................... 67 
11.4.3. Protocol Signatures ............................................................................................................ 67 
11.4.4. Financing and Insurance .................................................................................................... 68 
12. PUBLICATION POLICY ............................................................................................................ 68 
13. EXTENDED SUPPLY .................................................................................................................. 69 
14. REFERENCES .............................................................................................................................. 70 
APPENDIX A. PAROXYSMAL NOCTURNAL HAEMOGLOBINURIA SYMPTOMS 
SUBJECT QUESTIONNAIRE .......................................................................................................... 72 
PROTOCOL SIGNATURE PAGES ................................................................................................. 73 
CHANGE HISTORY OF PROTOCOL AMENDMENT ............................................................... 76 
Amendment 1: Version 2.0, Oct 08, 2018 ......................................................................................... 76 
Amendment 2: Version 3.0, Dec 12, 2018 ........................................................................................ 82 
Amendment 3: Version 4.0, Nov 29, 2019 ........................................................................................ 91 
Amendment 4: Version 5.0, Aug 21, 2020 ...................................................................................... 138 
Amendment 5: Version 6.0, Nov 27, 2020 ...................................................................................... 166 
 
 


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LIST OF TABLEs 
Table 1. Schedule of Activities (Period 1, before Cross-over) ............................................................. 10 
Table 2. Schedule of Activities (Period 2 and Safety Follow-up/ET, after Cross-over) ....................... 13 
Table 3. Investigational Products Description ...................................................................................... 36 
Table 4. Parameters for Clinical Laboratory Tests ............................................................................... 42 
Table 5. Severity Grade of NCI-CTCAE v5.0 ...................................................................................... 53 
Table 6. LDH Level from Reference Studies........................................................................................ 63 
 
LIST OF FIGUREs 
Figure 1. Graphical Study Design ........................................................................................................... 9 
 
 
 


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LIST OF STUDY STAFF 
 
Sponsor: 
Samsung Bioepis Co., Ltd. 
107, Cheomdan-daero, Yeonsu-gu, 
Incheon, 21987 
Republic of Korea 
Tel: +82 (32) 455 6114 
Clinical Project Manager  
 
 
 
Clinical Development 
Lead  
 
 
 
Clinical Research 
Physician  
 
 
 
Clinical Research 
Scientist 
 
 
Statistician  
 
 
 
Safety Physician 
 
 
 
Project Safety Lead 
 
 
 
 
 


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1. Introduction 
 Paroxysmal Nocturnal Haemoglobinuria 
Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired haematopoietic disorder characterised by 
intravascular haemolysis and manifested by haemoglobinuria, anaemia, and venous thrombosis, which 
in turn produces severe and even potentially fatal clinical consequences. PNH is a very rare disease 
with a prevalence of about 16 per million people, and it can present at any range but mainly occurs in 
young adults, with the usual age at diagnosis being early 30s [1; 2; 3]. 
PNH results from a somatic mutation in the phosphatidylinositol glycan class-A (PIG-A) gene which is 
necessary for the synthesis of glycosylphosphatidylinositol (GPI)-anchors. The mutation leads to a 
deficiency of the GPI-anchored terminal complement inhibitors (e.g., CD55, CD59) on the surface of 
clonal populations of haematopoietic stem cells. Normally CD59 forms a defensive shield for red blood 
cells (RBCs) against complement-mediated lysis and inhibits the assembly of the membrane attack 
complex (MAC). The CD55 prevents formation and augments instability of the C3 convertases, 
attenuating the complement cascade. Without these complement inhibitors on the surface of cells, the 
cells are subjected to complement-mediated haemolysis, which in turn produces the clinical 
manifestations of the disease. The clinical features of the PNH arise as a result of complement-mediated 
haemolysis in unprotected RBCs, leukocytes, and platelets as well as the release of free haemoglobin 
that occurs with RBCs destruction [4].  
Haemolysis contributes significantly to the anaemia and treatment is indicated for the following reasons: 
(1) Patients with chronic haemolysis complain of lethargy, malaise, myalgia, and loss of sense of well-
being that diminishes significantly quality of life; (2) there is evidence that chronic haemolysis has an 
untoward effect on renal function; (3) the dysphagia and male impotence of PNH appear related to 
haemolysis; (4) a correlation between thrombosis and haemolysis may exist [5]. 
Conventional treatment options such as corticosteroids were limited, and the outcome of treatment was 
often unsatisfactory. Bone marrow transplantation is a curative treatment for PNH, but the procedure 
has risks of transplant-related morbidity and mortality and most PNH patients lack a suitable donor [6]. 
Soliris® (eculizumab, Alexion Pharmaceuticals, Inc.) is a humanised monoclonal antibody that blocks 
terminal complement by binding to C5 and is the approved therapy for PNH. The drug is highly effective 
in stopping intravascular haemolysis, eliminating or decreasing the need for RBC transfusions, 
improving quality of life, and reducing the risk of thrombosis, the leading cause of mortality from PNH 
[7; 8; 9]. 
 Overview of SB12 
SB12 has been developed as a similar biological medicinal product to Soliris® (eculizumab, Alexion 
Pharmaceuticals, Inc.). Soliris® is currently indicated for the treatment of patients with PNH, atypical 
haemolytic uremic syndrome (aHUS), refractory generalised myasthenia gravis (gMG), and 
neuromyelitis optica spectrum disorder (NMOSD) [10; 21]. SB12 and Soliris® have identical primary 
structure and the active substance for both products is eculizumab, a humanised monoclonal antibody 
(immunoglobulin G[IgG]2/4 kappa) that binds to the human C5 complement protein with high affinity. 
Binding to this protein blocks its cleavage into C5a and C5b, thereby inhibiting terminal complement-
mediated intravascular haemolysis. 
SB12 is produced by recombinant deoxyribonucleic acid (DNA) technology in a chinese hamster ovary 
(CHO) mammalian cell expression system and purified by various affinity and ion exchange 
chromatography steps that include specific viral inactivation and removal procedures. 


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According to the guideline International Council for Harmonisation (ICH) Q6B, characterisation of a 
biological therapeutic must involve its physicochemical properties, biological activities, purity, 
impurities, and quantity. The characterisation study will employ the ‘state-of-the-art’ analytical methods 
in order to investigate the primary, secondary, higher-order structures, and the post-translational 
modifications associated the structural heterogeneity, the charge variants, the purity, and the biological 
activities. It was demonstrated that SB12 has similar structural, physicochemical, and biological 
characteristics with Soliris®. 
1.2.1. Non-clinical Studies of SB12 
As outlined in the “Guideline on similar biological medicinal products containing monoclonal 
antibodies” [11], a risk-based approach was taken to the non-clinical evaluation of SB12. A series of in 
vitro biologic activity studies was performed in order to demonstrate similarity between SB12 and 
Soliris®. In addition, in vivo non-clinical study may not be necessary to provide non-clinical evidence 
of similarity between the two products, as eculizumab does not inhibit C5 in animal species. Therefore, 
no pharmacology or toxicology studies were conducted with eculizumab in normal rodents or non-
human primates. Also, non-clinical safety pharmacology, reproductive and developmental toxicity, and 
carcinogenicity studies were not performed, as they are not required for non-clinical testing of 
biosimilars as outlined in the “Guideline on similar biological medicinal products containing 
monoclonal antibodies” [11]. There were no significantly different results observed in the in vitro 
studies between SB12 and Soliris®. 
1.2.2. Clinical Pharmacology of SB12 
Based on biosimilarity between SB12 and Soliris®, which was demonstrated through extensive quality 
and non-clinical similarity exercise, a Phase I study was conducted in healthy subjects to compare the 
pharmacokinetic (PK), safety, tolerability, immunogenicity, and pharmacodynamic (PD) profiles and a 
Phase III study will be conducted in subjects with PNH to compare the efficacy, safety, 
pharmacokinetics, and immunogenicity of SB12 to Soliris®. Information on the safety of SB12 based 
on the product information of Soliris®, non-clinical, and clinical exercise is presented in the 
Investigator’s Brochure (IB).  
 Comparator Investigational Product: Soliris® 
1.3.1. Non-clinical Data of Soliris®  
The tissue cross-reactivity of eculizumab was evaluated by assessing binding to a panel of 38 human 
tissues. C5 expression in the human tissue panel examined in this study is consistent with published 
reports of C5 expression, as C5 has been reported in smooth muscle, striated muscle, and renal proximal 
tubular epithelium. No unexpected tissue cross-reactivity was observed.  
Animal reproduction studies have not been conducted with eculizumab due to lack of pharmacologic 
activity in non-human species and no animal studies have been conducted to evaluate the genotoxic and 
carcinogenic potential of eculizumab.  
In a 26-week toxicity study performed in mice with a surrogate antibody directed against murine C5, 
treatment did not affect any of the toxicity parameters examined. Haemolytic activity during the course 
of the study was effectively blocked in both female and male mice.  
No clear treatment-related effects or adverse effects were observed in reproductive toxicology studies 
in mice with a surrogate terminal complement inhibitory antibody, which was utilised to assess the 
reproductive safety of C5 inhibitor. These studies included assessment of fertility and early embryonic 
development, developmental toxicity, and pre and post-natal development.  


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When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasia 
and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the 
higher antibody dose (approximately 4 times the maximum recommended human Soliris® dose, based 
on a body weight comparison); however, the exposure did not increase foetal loss or neonatal death.  
Regarding in vivo non-clinical study, the publicly available information of Soliris® performed a species 
cross-reactivity of eculizumab to the functional complement C5 inhibition activity of eculizumab in 
human serum samples compared to primate and non-primate serum samples including eight-different 
species. The result concluded that there is no cross-reactivity of the eculizumab with non-primate 
species and primate species and that the result suggests that eculizumab effectively inhibits C5 only in 
human serum. In this context, the in vivo study in irrelevant non-primate animal species is unlikely to 
provide any additional meaningful non-clinical evidence. 
1.3.2. Clinical Data of Soliris® 
In 40 patients with PNH, a 1-compartmental model was used to estimate PK parameters after multiple 
doses. Mean clearance was 0.31 ± 0.12 mL/h/kg, mean volume of distribution was 110.3 ± 17.9 mL/kg, 
and mean elimination half-life was 11.3 ± 3.4 days. The steady state is achieved by 4 weeks using the 
PNH adult dosing regimen. 
In PNH patients, PD activity correlates directly with eculizumab serum concentrations and maintenance 
of trough levels above ≥ 35 µg/mL results in essentially complete blockade of haemolytic activity in 
the majority of PNH patients.  
The safety and efficacy of Soliris® in PNH patients were assessed in a randomised, double-blind, 
placebo-controlled 26-week study (C04-001). PNH patients were also treated with Soliris® in a single 
arm 52-week study (C04-002) and in a long term extension study (E05-001). Patients received 
meningococcal vaccination prior to receipt of Soliris®. In all studies, the dose of eculizumab was 600 
mg every 7 ± 2 days for 4 weeks, followed by 900 mg 7 ± 2 days later, then 900 mg every 14 ± 2 days 
for the study duration. Soliris® was administered as an intravenous (IV) infusion over 25-45 minutes. 
An observational non-interventional registry in patients with PNH (M07-001) was also initiated to 
characterise the natural history of PNH in untreated patients and the clinical outcomes during Soliris® 
treatment. 
In study C04-001 (TRIUMPH), PNH patients with at least 4 transfusions in the prior 12 months, flow 
cytometric confirmation of at least 10% PNH cells, and platelet counts of at least 100,000/µL were 
randomised to either Soliris® (n = 43) or placebo (n = 44). Prior to randomisation, all patients underwent 
an initial observation period to confirm the need for RBC transfusion and to identify the haemoglobin 
concentration (the ‘set-point’) which would define each patient’s haemoglobin stabilisation and 
transfusion outcomes. The haemoglobin set-point was less than or equal to 9 g/dL in patients with 
symptoms and was less than or equal to 7 g/dL in patients without symptoms. Primary efficacy 
endpoints were haemoglobin stabilisation (patients who maintained a haemoglobin concentration above 
the haemoglobin set-point and avoid any RBC transfusion for the entire 26-week period) and blood 
transfusion requirement. Fatigue and health-related quality of life were relevant secondary endpoints. 
Haemolysis was monitored mainly by the measurement of serum lactate dehydrogenase (LDH) levels, 
and the proportion of PNH RBCs was monitored by flow cytometry. Patients receiving anticoagulants 
and systemic corticosteroids at baseline continued these medications. Major baseline characteristics 
were balanced. Study patients treated with Soliris® had significantly reduced (p < 0.001) haemolysis 
resulting in improvements in anaemia as indicated by increased haemoglobin stabilisation and reduced 
need for RBC transfusions compared to placebo treated patients. These effects were seen among patients 
within each of the three pre-study RBC transfusion strata (4-14 units; 15-25 units; > 25 units). After 3 
weeks of Soliris® treatment, patients reported less fatigue and improved health-related quality of life. 


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Because of the study sample size and duration, the effects of Soliris® on thrombotic events could not be 
determined. 
In the non-controlled study C04-002 (SHEPHERD), PNH patients with at least one transfusion in the 
prior 24 months and at least 30,000 platelets/µL received Soliris® over 52-week period. Concomitant 
medications included anti-thrombotic agents in 63% of the patients and systemic corticosteroid in 40% 
of the patients. Ninety-six of the 97 enrolled patients completed the study (one patient died following a 
thrombotic event). A reduction in intravascular haemolysis as measured by serum LDH levels was 
sustained for the treatment period and resulted in increased transfusion avoidance, a reduced need for 
RBC transfusion and less fatigue. 
 Study Rationale 
Patients with PNH suffer from severe impaired quality of life arising from haemolysis leading to 
anaemia, thrombosis, renal impairment, and fatigue, which are the most common morbidities for this 
disease, with a significant increase in free haemoglobin levels. Cell-free haemoglobin consumes the 
serum nitric oxide (NO) and reduction in serum NO causes smooth muscle dystonia including 
vasoconstriction and gastrointestinal contractions and these consequences induce abdominal pain, 
dysphagia, pulmonary hypertension, dyspnoea, or erectile dysfunction [12; 13; 14; 15; 16]. Low serum 
NO also results in platelet activation/aggregation and thrombosis which may lead arterial myocardial 
infarction or cerebral vascular accident [12]. 
Thrombosis and renal failure are the leading cause of death in PNH and PNH patients with haemolysis 
whose LDH level is equal to or greater than 1.5 × upper limit of normal (ULN) showed a 4.8-fold 
increase in mortality rate compared with the general population [16].  
Currently there are no approved treatments for PNH except for Soliris® but several types of supportive 
care have no any impact on progression or risk of severe morbidities and mortality. Unfortunately 
eculizumab does not alter the underlying defect of the disease, thus, treatment needs to continue life-
long or until spontaneous remission, however Soliris® is barely affordable for the most of PNH patients 
as it costs 700,000 USD a year [1; 17]. 
Considering all the treatment options available, it is highly expected there are still patient needs for the 
right treatment with reasonable price. SB12 would meet this patient needs in extending the treatment 
opportunity by providing the medicine with lower price than the originator. 
 Risk and Benefit Assessment 
1.5.1. Known Potential Risks 
According to Soliris® Summary of Product Characteristics (SmPC) [10], supportive safety data were 
collected from 31 completed clinical studies that included 1,503 patients exposed to eculizumab in 
complement-mediated disease populations, including PNH, aHUS, refractory gMG and NMOSD. The 
most common adverse reaction was headache (occurred mostly in the initial phase) and the most 
frequently reported serious adverse reaction was meningococcal sepsis.  
Considering the mechanism of action of eculizumab, C5 inhibition is known to increase the 
susceptibility to infection caused by encapsulated bacteria, especially by Neisseria meningitidis. In 
order to minimise the risk of meningococcal infection, all subjects participating in this study will receive 
meningococcal vaccines according to current local guidelines or Soliris® SmPC before investigational 
product (IP) administration. However, vaccination may not be sufficient to prevent meningococcal 
infection. Consideration will be given to current local guidelines and/or the discretion of the Investigator 
on the appropriate use of antibacterial agents. All subjects will be monitored for early signs of 


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meningococcal infection, evaluated immediately if infection is suspected, and treated with appropriate 
antibiotics if necessary. 
According to the study design, the switch of IP (cross-over) occurs during the study. The potential 
negative impact from this IP switch is considered to be minimal given similarity and comparability of 
SB12 to Soliris® and low antibody responses in Soliris® (3.4%) similar to that of placebo (4.8%) in 
placebo controlled studies in subjects with PNH [10]. 
In order to ensure the safety of subjects who participate in the study, the followings will be performed 
during the study. This study will take place at multicentre with accessible medical facilities which will 
allow immediate treatment of medical emergencies. All study related procedures will be conducted by 
medical staff with appropriate level of training and expertise and an understanding of the IPs, its target 
and mechanism of action. Subjects will have a safety follow-up until 8 weeks after the last dose of study 
drug. An independent Data and Safety Monitoring Board (DSMB) will convene at pre-specified 
intervals to conduct interim monitoring of accumulating safety data. Following each data review, the 
DSMB will make recommendations regarding the conduct of the study, including continuation of the 
study without modifications, modification of the protocol, pausing of subject enrolment until the 
resolution of issues, or termination of the study for safety reasons.  
1.5.2. Known Potential Benefits 
Soliris® is the approved therapy for PNH and is indicated for the treatment patients with aHUS, gMG, 
and NMOSD [10; 21]. The drug is highly effective in stopping intravascular haemolysis, eliminating or 
decreasing the need for RBC transfusions, improving quality of life, and reducing the risk of thrombosis, 
the leading cause of mortality from PNH [7; 8; 9].  
Although clinical data is currently unavailable, SB12 is expected to have similar clinical outcome to 
Soliris® based on the physicochemical and biological similarity. 
1.5.3. Assessment of Potential Risks and Benefits 
The available data demonstrate a high degree of physicochemical and biological similarity of SB12 
with the reference medicinal product (Soliris®). The suitability of the methodology employed to 
evaluate the similarity of SB12 and Soliris® in a pharmaceutical setting and these data were confirmed 
by the European Medicines Agency (EMA) and the United States of America (US) Food and Drug 
Administration (FDA). The known and potential risks of receiving SB12 are expected to be similar to 
those seen with Soliris®. In conclusion, sufficient evidence exists for the justification of the 
administration of SB12, as a similar biological medicinal product of Soliris®, to subjects with PNH. 
The study protocol provides adequate instructions for the detection and treatment of adverse events 
(AEs) arising following the administration of the IP.  
2. Study Objectives and Endpoints 
 Study Objectives 
2.1.1. Primary Objective 
The primary objective of this study is to demonstrate comparable clinical efficacy of SB12 and Soliris®, 
by evaluating the LDH in subjects with PNH. 
2.1.2. Secondary Objectives 
The secondary objectives are: 


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• 
To evaluate the efficacy of SB12 compared to Soliris® by 
- 
LDH profile over time  
- 
Number of units of packed red blood cells (pRBCs) transfused 
• 
To evaluate the safety and tolerability of SB12 compared to Soliris® 
• 
To evaluate the PK of SB12 compared to Soliris® 
• 
To evaluate the immunogenicity of SB12 compared to Soliris® 
• 
To evaluate the PD of SB12 compared to Soliris® 
 Endpoints 
2.2.1. Primary Endpoints 
 
LDH level (U/L) at Week 26 
 
Time-adjusted area under the effect curve (AUEC) of LDH from Week 14 to Week 26 and 
from Week 40 to Week 52 
2.2.2. Secondary Endpoints 
Efficacy endpoints 
 
LDH profile over time 
 
Number of units of pRBCs transfused throughout the study period  
Safety endpoints 
 
Incidence of AEs  
 
Incidence of serious AEs (SAEs) 
 
Incidence of infection-related AEs 
- 
Meningococcal infection 
- 
Other systemic infection 
 
Incidence of infusion-related reactions (IRRs) 
Safety of subjects will be monitored by 12-lead electrocardiogram (ECG), vital sign assessment, and 
physical examination. Haematological, biochemical, and urinalysis laboratory parameters will be also 
measured. 
PK endpoint 
 
Concentration prior to infusion (trough serum concentration [Ctrough]) at Weeks 0 (Day 1), 2, 4, 
6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 44, 48, and 52 
Immunogenicity endpoints 
 
Incidence of anti-drug antibodies (ADAs) at Weeks 0 (Day 1), 2, 4, 6, 10, 14, 18, 22, 26, 28, 
30, 32, 36, 40, 44, 48, 52, and early termination (ET) visit  
 
Incidence of neutralising antibodies (NAbs) at Weeks 0 (Day 1), 2, 4, 6, 10, 14, 18, 22, 26, 28, 


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30, 32, 36, 40, 44, 48, 52, and ET visit  
PD endpoint 
 
Terminal complement activity at Weeks 0 (Day 1), 2, 4, 6, 10, 14, 26, 28, 30, 32, 36, 40, and 
52 
3. Study Design 
 Overview of Study Design 
This is a randomised, Phase III, double-blind, multicentre, cross-over study to compare the efficacy, 
safety, pharmacokinetics, and immunogenicity between SB12 and Soliris® in subjects with PNH.  
Subjects will be randomised in a 1:1 ratio to treatment sequence I (SB12 to Soliris®) or treatment 
sequence II (Soliris® to SB12). Subjects randomly assigned to treatment with SB12 or Soliris® will 
receive 600 mg of eculizumab IV every week for first 4 weeks (initial phase) and 900 mg for the fifth 
week, followed by 900 mg every 2 weeks thereafter. Subjects who are randomised to initially receive 
SB12 will be switched to receive Soliris® and subjects who are randomised to initially receive Soliris® 
will be switched to receive SB12 at Week 26. SB12 or Soliris® will be given until Week 50. However, 
in special circumtances of a shortage of the comparator, to ensure continuity of study treatment for the 
duration of study, the Sponsor will provide SB12 instead of Soliris® in a blinded manner. 
Details of assessment that will be conducted and treatment that will be administered are presented in, 
Table 1 and Table 2. The last assessment will be performed at Week 58 or 8 weeks after the last dose of 
SB12 or Soliris® in case of ET.  
After completion of activities at Week 52, an open-label extended supply of SB12 will be provided for 
up to 2 calendar years to subjects who have benefited from study treatment and opt to participate in 
extended supply under an ethical basis. 
 Rationale for Study Design 
3.2.1. Scientific Rationale for Study Design 
It is acknowledged that PNH is a rare disease with an estimated incidence of 0.1-0.2/100,000 
persons/year [18] and executing an adequately powered comparative trial is therefore challenging. The 
guiding principle of a biosimilar development is, however to demonstrate similar clinical efficacy and 
safety compared to the reference medicinal product, not patient benefit per se, which has already been 
shown for the reference medicinal product [11]. In view of this, the two arms design with randomisation 
between SB12 and Soliris® is endorsed. And in view of the very limited sample size (approximately 50 
subjects), the study will be conducted in treatment-naïve patients to allow proper evaluation of safety 
and immunogenicity of the compound, as it reduces heterogeneity of the population. 
LDH has been considered an authentic and useful clinical marker and direct measure of intravascular 
haemolysis in patients with PNH, published data support. And also, LDH is useful in evaluating 
response to treatment, as its level decreases along with the reduction of the haemolytic rate, which has 
been described in PNH following treatment [19; 20]. Results from the eculizumab clinical study showed 
that serum LDH levels continued markedly elevated and unchanged in untreated patients, while 
eculizumab treated patients had an immediate reduction in serum LDH to normal or near normal level 
[10; 21]. The reduction of serum LDH level reflected a rapid, sustained reduction in haemolysis and 
improvement in fatigue as well [9]. 
This study has two different primary endpoints, depending on regulatory agency’s requirements for 


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assessing equivalence in efficacy between SB12 and Soliris®. 
 for analysis of haemolysis reduction as 
measured by time-adjusted AUEC of LDH between two different time points in each period, the primary 
objective is to demonstrate comparable clinical efficacy of SB12 and Soliris® in terms of time-adjusted 
AUEC of LDH from Week 14 to Week 26 and from Week 40 to Week 52. 
, 
for analysis of haemolysis reduction as measured by the LDH level at single time point, the primary 
objective is to demonstrate comparable clinical efficacy of SB12 and Soliris® in terms of the LDH level 
(U/L) at Week 26. 
3.2.2. Rationale for Dose Selection 
The dosing regimen for adult patients (≥ 18 years of age) of Soliris® is approved for the treatment of 
PNH as 4-week initial phase followed by a maintenance phase as below: 
 
Initial phase: 600 mg of Soliris® administered via a 25-45 minutes IV infusion every 7 days 
for the first 4 weeks 
 
Maintenance phase: 900 mg of Soliris® administered via a 25-45 minutes IV infusion for the 
fifth week, followed by 900 mg of Soliris® administered via a 25-45 minutes IV infusion every 
14 ± 2 days 
As SB12 is a proposed biosimilar of Soliris®, an identical dose is selected for both treatments.  
3.2.3. Rationale for Pharmacokinetic Assessments 
A randomised, three-arm, parallel, single-dose Phase I PK study was conducted in healthy subjects to 
demonstrate similarity in PK profiles of SB12, European Union (EU) sourced Soliris®, and US sourced 
Soliris®. However, since target-mediated clearance of eculizumab can be more accurately investigated 
in patients, additional PK assessments will be performed in this Phase III study to provide supportive 
evidence to PK similarity. 
3.2.4. Rationale for Immunogenicity Assessments 
Biological/biotechnology-derived proteins can induce an unwanted immune response that is triggered 
by more than a single factor and the consequence of immunogenicity may vary considerably, ranging 
from irrelevant to therapy to serious and life-threatening. Immune responses may affect both safety and 
effectiveness such as altering PK, inducing anaphylaxis, or promoting development of NAbs that 
neutralise the product as well as its endogenous protein counterpart. 
In all clinical studies of Soliris®, the frequency of ADAs has been reported as 0.0% to 4.8%. In PNH 
placebo controlled studies, low antibody responses have been reported with a frequency (3.4%) similar 
to that of placebo (4.8%). There has been no observed correlation of antibody development to clinical 
response or AEs. 
For subject safety and for demonstrating biosimilarity, immunogenicity will be assessed in this study 
according to the recommended guideline.  
 Duration of Study Participation 
After Screening, the duration of study participation will be 58 weeks per subject including 50 weeks of 
treatment and 8 weeks of post-treatment follow-up . After completion of study treatment, subjects may 
be entered into an extended supply of up to 2 years. 


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 Number of Subjects 
Approximately 50 subjects (25 subjects per treatment sequence) are planned to be randomised in this 
study over a planned recruitment period. 
 End of Study Definition 
A subject is considered to have completed the study if he or she has completed all study treatment and 
the last visit or the last scheduled procedure shown in Table 2. The end of study (EOS) is defined as 
completion of safety follow-up at Week 58 or completion of ET visit (8 weeks after the last dose of 
SB12 or Soliris®). The end of this clinical study is defined as completion of the last subject’s EOS.  
4. Study Population 
 Overview 
The study population for this study is subjects with PNH. 
 Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for the study: 
1. Male or female aged 18 or older at the time of signing the informed consent form (ICF), if 
local regulations are different in this regard, follow the local regulations. 
2. Documented diagnosis of PNH. 
3. Presence of the PNH white blood cell (WBC) clone, with a granulocyte or monocyte clone 
size of ≥ 10% by high-sensitivity flow cytometry at Screening. 
4. Documented LDH level ≥ 1.5 × ULN at Screening. 
5. History of transfusion for anaemia within 12 months prior to Screening or having PNH-related 
symptoms (e.g., fatigue, haemoglobinuria, abdominal pain, chest pain, shortness of breath 
[dyspnoea], dysphagia, erectile dysfunction) at Screening. 
6. All subjects must be vaccinated against Neisseria meningitidis within 3 years prior to or on 
Day 1 in accordance with current local guidelines or Soliris® SmPC to reduce the risk of 
meningococcal infection.  
7. Female subjects who are not pregnant or nursing at Screening and on initiation of study drug 
(Day 1) and who are not planning to become pregnant from Screening until 5 months after the 
last dose of study drug. 
8. Subjects and their partners of childbearing potential (female or male) who agree to use of a 
highly effective contraceptive method (e.g., established use of oral, injected or implanted 
hormonal contraceptive, placement of an intrauterine device or intrauterine system, male 
sterilisation, or true abstinence [see Section 8.4.1]) from Screening until 5 months after the 
last dose of study drug.  
9. Subjects must be able to understand the implications of taking part in the study and be willing 
to follow the study instructions and requirements fully. 


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10. Subjects must be able to provide informed consent, which must be obtained prior to any study 
related procedures. 
 Exclusion Criteria 
Subjects meeting any of the following criteria are not eligible for the study: 
1. Previous treatment with a complement pathway inhibitor (including eculizumab).  
2. Known hypersensitivity to the IP or any of the ingredients or excipients of the IP. 
3. Known contraindication/hypersensitivity for meningococcal vaccine or the antibiotic to be 
used in the study. 
4. Abnormal haematological parameters at Screening defined as the following: 
a. 
Absolute neutrophil count (ANC) ≤ 0.5 × 103/µL  
b. Platelet count < 70 × 103/µL  
5. History of meningococcal disease. 
6. History of haematopoietic stem cell transplantation. 
7. History of serious thrombotic event (e.g., stroke, myocardial infarction, pulmonary embolism, 
etc.). 
8. Known or suspected active bacterial, virus, fungal infection within 30 days prior to initiation 
of study drug (Day 1). 
9. Known history of human immunodeficiency virus (HIV) infection or have positive results at 
Screening. 
10. Concomitant use of any of the following medications is prohibited if the following conditions 
apply.  
a. 
Erythropoietin, 
systemic 
corticosteroids, 
low-molecular-weight 
heparins, 
iron 
supplements, and androgen therapy that have not been on a stable dose for at least 4 weeks 
prior to initiation of study drug (Day 1).  
b. Warfarin with an unstable international normalised ratio (INR) for at least 4 weeks prior 
to initiation of study drug (Day 1) at the discretion of the Investigator. 
c. 
Cyclosporine that has not been on a stable dose for at least 8 weeks prior to initiation of 
study drug (Day 1). 
11. Subjects who have received or participated in another investigational drug, device, or 
procedures within 30 days or within 5 half-lives of that IP prior to Screening, whichever is 
greater. 


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12. History of malignancy within 5 years prior to Screening, except for curatively treated 
carcinoma in situ of uterine cervix, basal cell carcinoma of the skin, or squamous cell 
carcinoma of the skin. 
13. Any other cardiac, hepatic, immunologic, pulmonary, rheumatoid disease, other conditions 
causing rise in LDH (e.g., tumours, muscular dystrophies, liver and bile disease, etc.), or the 
disorder which, at the discretion of the Investigator, will put the subjects at risk if they are 
enrolled. 
14. Other unspecified reasons that, at the discretion of the Investigator or Sponsor, make the 
subjects unsuitable for enrolment. 
 Screen Failures and Re-screening 
Screen failures are defined as subjects who consent to participate in the clinical trial but do not meet 
one or more criteria required for participation in the trial during the screening procedures. A minimal 
set of screen failure information is required.  
Subjects who are screen failure due to technical issue, not medical issue, might be re-screened once 
based on discussion and agreement between the Investigator and the medical monitor. 
During Coronavirus Disease 2019 (COVID-19) pandemic circumstances, eligibility may not be 
confirmed at Screening due to unexpected COVID-19 related restrictions. These cases may fall into 
screen failures due to out of 42 days screening window or consent withdrawal related with COVID-19 
concern, etc. These will be considered as technical issue so that re-screening is applicable after COVID-
19 related restrictions are relieved.  
5. Treatment and Investigational Product 
 Treatment of the Subjects 
5.1.1. Dosing and Treatment Schedule 
SB12 or Soliris® will be administered up to Week 50 (a total of 28 administrations of IP) unless they 
are early discontinued from study treatment. Dosing and treatment schedule should be kept as follows:  
 
600 mg every 7 ± 2 days for the first 4 weeks, followed by 
 
900 mg for the fifth dose (Week 4) 7 ± 2 days later, then 
 
900 mg every 14 ± 2 days thereafter 
The treatment schedule is dependent on the previous treatment date rather than the absolute (i.e., fixed) 
number of days from Day 1. In other words, the next 7 ± 2 days or 14 ± 2 days treatment schedule 
described above is re-scheduled every time based on the date when the previous treatment is given. 
The subject receiving SB12 or Soliris® therapy may require dosing interval adjustment within the 
recommended 14 ± 2 days dosing schedule during the maintenance period (up to every 12 days) when 
it is deemed necessary at the discretion of the Investigator; e.g., two consecutive events of elevated 
LDH ≥ 2 × ULN combined with sign or symptom of intravascular haemolysis after prior LDH reduction 
to < 1.5 × ULN on treatment. If a 12 or 13 day dosing interval conflicts with administrative schedules 
(e.g., holidays or weekends) but a shortened dosing interval is considered necessary for safety of subject, 
consultation with medical monitor (or Sponsor) is recommended. For subjects whose dosing interval is 
adjusted to 12 days in Period 1, it is recommended that the dosing interval be switched back to 14 days 
after switching IP at Week 26. Once the above event has occurred, the Investigator should inform the 


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medical monitor and/or Sponsor immediately.  
In special circumstances of a shortage of the comparator, to ensure continuity of study treatment for the 
duration of study, the Sponsor will provide SB12 instead of Soliris® in a blinded manner. Rules for 
allocation of remaining comparators during the comparator shortage situation will be prespecified prior 
to execution of the potential change of IP assignment from Soliris® to SB12 in a blinded manner. This 
is to avoid the risk of unblinding and potential bias. 
5.1.2. Assignment of Subjects to Treatment Sequence 
Subjects who meet all criteria for enrolment will be randomly assigned to treatment sequence I (SB12 
to Soliris®) or II (Soliris® to SB12). The randomisation numbers will be generated by the interactive 
web response system (IWRS) to ensure that treatment sequence assignment is unbiased and concealed 
from subjects, Investigators, and other study personnel. These randomisation numbers are linked to the 
each treatment sequence, which in turn are linked to IP kit numbers.  
Subjects will not be stratified and the assigned randomisation numbers will not be re-used. 
5.1.3. Blinding 
This study is double-blinded. Subjects, Investigators, and other study personnel will remain blinded to 
the treatment sequence assignment throughout the study period after randomisation. 
To ensure the blinding for the treatment sequence assignment, one carton will contain only one IP vial 
(SB12 or Soliris®). The carton and IP vial will be packed and labelled in identical appearance.  
Emergency unblinding is referred to Section 8.5. 
 Investigational Product 
5.2.1. Identity of Investigational Product 
The IPs will be supplied to investigational site in one carton containing a single vial. These IP vials will 
be packed and labelled in a double-blinded manner for clinical use.  
The Investigator shall take responsibility for all steps to maintain appropriate records and ensure 
appropriate supply, storage, handling, distribution, and usage of IPs in accordance with the protocol and 
any applicable laws and regulations. 
A detailed guidance for IP preparation, administration, storage, and destruction will be provided in the 
pharmacy manual. 
Details of the IPs are provided in Table 3. 
Table 3. Investigational Products Description 
Active Pharmaceutical Ingredient: Eculizumab 
SB12 
Formulation 
Solutions for IV infusion 
Contents 
One vial of 30 mL contains 300 mg of eculizumab (10 mg/mL) 
Storage conditions 
Stored in a refrigerator (2-8°C), do not freeze 
Stored in the original package in order to protect from light 
Soliris® 


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Formulation 
Solutions for IV infusion 
Contents 
One vial of 30 mL contains 300 mg of eculizumab (10 mg/mL) 
Storage conditions 
Stored in a refrigerator (2-8°C), do not freeze 
Stored in the original package in order to protect from light 
5.2.2. Formulation, Packaging, and Labelling 
Eculizumab (SB12 or Soliris®) will be supplied for use as a concentrate for solution for infusion (300 
mg per vial for SB12, Soliris®). 
Packaging and labelling of SB12 or Soliris® will follow standard operating procedure (SOP) of the 
manufacturing site and regulatory requirements in each country, as well as will be in accordance with 
ICH-Good Clinical Practice (GCP). SB12 or Soliris® will be pre-packaged and labelled in a double-
blinded form. The labels will contain the following information: The pharmaceutical dosage form, route 
of administration, identification number, the protocol number, use by date, storage details, and all other 
details required by local regulations and Good Manufacturing Practice (GMP). 
5.2.3. Product Storage and Stability 
SB12 and Soliris® should be stored at 2-8°C (36-46°F) in the original carton in order to protect from 
light. The temperature will be monitored properly during the study period. If continuous monitoring is 
not available then manual temperature logs should be generated and recorded to ensure proper storage 
conditions. If a temperature deviation occurred, responsible person should contact the Sponsor to 
determine if the drug is still appropriate for use. The IPs should be stored in a secure area, clearly 
labelled, and stored away from other IPs or medication to prevent confusion (for example, in a clearly 
marked box on a separate shelf of the refrigerator).  
Do not freeze and do not shake SB12 or Soliris® vials. The IPs must not be used beyond the expiration 
date.  
5.2.4. Preparation and Administration of Investigational Products 
When IPs arrive at investigational sites, responsible site staff should check the IPs for damage, quantity, 
integrity, and temperature conditions during shipment, and report any deviations or product complaints 
(PC) to the Sponsor according to written procedure. 
Dilution should be performed in accordance with good practices rules, particularly for the respect of 
asepsis. Withdraw the total amount of SB12 or Soliris® from the vials using a sterile syringe. Transfer 
the recommended dose to an infusion bag. Dilute SB12 or Soliris® to a final concentration of 5 mg/mL 
by addition to the infusion bag using sodium chloride 9 mg/mL (0.9%) solution for injection, sodium 
chloride 4.5 mg/mL (0.45%) solution for injection, or 5% dextrose in water, as the diluent.  
The final admixed SB12 or Soliris® 5 mg/mL infusion volume is 120 mL for 600 mg doses and 180 mL 
for 900 mg doses. The solution should be clear and colourless. Gently agitate the infusion bag 
containing the diluted solution to ensure thorough mixing of the product and diluent. Although the 
chemical and physical stability of the diluted solution has been demonstrated for 24 hours at 2-8°C (36-
46°F), the medicinal product should be used immediately after dilution. If not used immediately, in-use 
storage times and conditions prior to use are the responsibility of the user and would normally not be 
longer than 24 hours at 2-8°C, unless dilution has taken place in controlled and validated aseptic 
conditions. The diluted solution should be allowed to warm to room temperature (18-25°C, 64-77°F) 
prior to administration by exposure to ambient air and must not be heated in a microwave or with any 


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heat source. 
The pharmacist and/or designee are responsible for preparing infusion setting for IP administration. 
Prior to administration, the IPs should be visually inspected for particulate matter and discolouration 
and checked to ensure match between subject number and assigned treatment. 
IP injection will be performed by the Investigator and/or designee according to delegation of study 
personnel for this study. Do not administer IPs as an IV push or bolus injection. The diluted solution of 
IPs should be administered by IV infusion over 25-45 minutes via gravity feed, a syringe-type pump, 
or an infusion pump. It is not necessary to protect the diluted solution of IPs from light during 
administration to the subject. 
Subjects should be monitored and documented for at least one hour following completion of the infusion 
for signs or symptoms of an infusion reaction. If an adverse reaction occurs during the administration 
of IPs, the infusion may be slowed or stopped at the discretion of the Investigator. If the infusion is 
slowed, the total infusion time may not exceed 2 hours. 
5.2.5. Treatment Compliance and Investigational Product Accountability 
Compliance will be assessed by the subject’s source documents and electronic case report form (eCRF). 
All dosing information including exact date and time of IV infusion should be recorded in the subject’s 
source documents and eCRF.  
Also any reason for non-compliance should be documented. For example, insufficient compliance is 
defined when a subject missing more than one IP for reasons other than toxicity, missed scheduled study 
activities. 
IP accountability and dispensing records must be kept current and contain the following information: 
 
The identification of the subjects to whom the drug was dispensed 
 
The dates and quantity of the drug dispensed to the subject 
 
The dispensing and inventory logs must be available for inspection by the study monitor 
The Investigator and/or designee is responsible for accounting all unused IP and all used IP containers. 
The Investigator uses this information to maintain an accurate and complete dispensing and inventory 
record provided by the Sponsor. 
IP supplies are shipped to the investigational site as needed. The monitor will review drug accounting 
during routine monitoring visits with the documents containing relevant information provided by the 
Sponsor. At the completion or termination of the study, a final drug accountability review and 
reconciliation must be completed; any discrepancies must be investigated and their resolution must be 
documented.  
To avoid accidental unblinding, used drug kits (empty vials, vials with residual materials, and cartons) 
should be promptly discarded after the infusion bag is prepared and in accordance with the local 
destruction SOP/policies for clinical study drugs. All unused IPs should be returned to the Sponsor or 
designated vendor unless local destruction site is approved by the Sponsor. If destruction is authorised 
at the investigational site, the Investigator must ensure that the materials are destroyed in compliance 
with all applicable environmental regulations, institutional policies, and any instructions provided by 
the Sponsor. Destruction of the IPs must be adequately documented. 


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 Concomitant Medication or Treatment 
All medication including both prescription and non-prescription drugs, and any procedures undertaken 
between 4 weeks prior to Screening (except for immunosuppressant) and EOS should be recorded in 
the subject’s source documents and eCRF. This record will include all prescription drugs, herbal 
products, vitamins, minerals, over-the-counter medications, and current medications for PNH. Details 
to be recorded include: Name (generic name preferred), dose number and unit, frequency of 
administration, route of administration, start and stop dates, reason for administration, and the AE it 
relates to (if applicable). 
Medication ended prior to the first IP administration will be reported as a prior medication and 
medication ended on or after IP administration will be reported as a concomitant medication. It is the 
responsibility of the Investigator to ensure that details regarding all medications are recorded in full in 
the subject’s source documents and eCRF. 
5.3.1. Permitted Concomitant Medications or Treatment 
The following concomitant medications are allowed if given on a stable dose (only for chronic 
administration) during the study period. However, for the subject’s welfare, medications can be adjusted 
under discussion between the Investigator and medical monitor and/or Sponsor.  
 
Erythropoietin, systemic corticosteroids, low-molecular-weight heparins, iron supplements, 
and androgen therapy with a stable dose from at least 4 weeks prior to initiation of study drug 
(Day 1). 
 
Warfarin with a stable INR from at least 4 weeks prior to initiation of study drug (Day 1). 
 
Cyclosporine with a stable dose from at least 8 weeks prior to initiation of study drug (Day 1). 
5.3.2. Prohibited Concomitant Medications or Treatment 
Immunosuppressant except for cyclosporine is prohibited during the study period from randomisation 
including but not limited to: 
 
Anti-thymocyte globulin (ATG), cyclophosphamide, etc. 
Investigator should discuss with the medical monitor and/or Sponsor before using any other 
immunosuppressant. 
6. Study Assessment 
 Efficacy Assessment 
6.1.1. Disease-related Laboratory Parameters 
Blood samples will be collected before IP administration at the visits specified in Table 1 and Table 2. 
Blood samples for the parameters will be analysed in central laboratory. Laboratory reports will be 
available to the Investigator in a timely manner. The parameters include PNH clone size of RBC and 
WBC evaluated by high-sensitivity flow cytometry, LDH, reticulocyte count, haptoglobin, and free 
haemoglobin.  
If the LDH level is not changed after the initiation of study drug (lack of efficacy), the Investigator and 
medical monitor and/or Sponsor should discuss to determine how to manage this case including whether 
or not to perform pharmacogenetic analysis (C5 gene polymorphism). 
Detail instructions of collection, processing, labelling, storage, and shipment for blood samples will be 


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provided in the laboratory manual. 
6.1.2. Breakthrough Haemolysis 
The Investigator and/or designee will record the breakthrough haemolysis in the source documents and 
eCRF during the study period.  
The breakthrough haemolysis is defined as ≥ 1 new or worsening sign or symptom of intravascular 
haemolysis (fatigue, haemoglobinuria, abdominal pain, chest pain, shortness of breath, dysphagia, 
erectile dysfunction, anaemia [haemoglobin < 10 g/dL], or major adverse vascular event [MAVE] 
including thrombosis) in the presence of elevated LDH ≥ 2 × ULN after prior LDH reduction to < 1.5 
× ULN on treatment.  
If a suspected sign or symptom of breakthrough haemolysis occurs, blood collection is required for 
evaluation of LDH, PK, and PD parameters by central laboratory. If necessary, an unscheduled visit 
should occur for evaluation of the subject and collection of the required LDH, PK, and PD parameters. 
For purposes of confirming breakthrough haemolysis, assessment of LDH must be based on a central 
laboratory value. 
6.1.3. Transfusions 
The subjects will receive pRBC transfusion in case the Investigator discovers a subject’s haemoglobin 
warrants a transfusion;  
 
Haemoglobin value ≤ 9 g/dL with signs or symptoms, or 
 
Haemoglobin value ≤ 7 g/dL regardless of signs or symptoms 
It is recommended that the transfusion would be performed within 48 hours of the haemoglobin 
assessment. The decision to give a transfusion may be based on either local or central laboratory 
haemoglobin values. 
Transfusion record will be collected from the signing of the informed consent until EOS. Anaemia-
related signs or symptoms, haemoglobin value, number of units of pRBCs will be documented on the 
source documents and eCRF.  
6.1.4. Major Adverse Vascular Events 
The description of MAVEs, anatomical site, method of diagnosis, date of diagnosis, and outcome will 
be recorded in the source documents and eCRF as AEs during the study period.  
The MAVE is defined as following; 
• 
Thrombophlebitis/deep vein thrombosis, pulmonary embolus, cerebral arterial/venous 
occlusion, myocardial infarction, transient ischemic attack, unstable angina, renal vein 
thrombosis, mesenteric vein thrombosis, portal vein thrombosis (Budd-Chiari syndrome), 
acute mesenteric ischaemia, etc. 
6.1.5. Paroxysmal Nocturnal Haemoglobinuria-related Symptoms 
The PNH-related symptom questionnaire will be completed by subjects. The questionnaire should be 
completed by subjects before IP administration at the visits specified in Table 1 and Table 2; at Screening, 
Weeks 0 (Day 1), 4, 14, 26, 30, 40, and 52.  
The symptoms in the past 7 days will be rated by severity. The questionnaire is provided in APPENDIX 
A. Investigator and/or designee will record the presence or absence of the following signs and symptoms 


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of PNH; 
 
Fatigue, haemoglobinuria (discolouration of urine), chest pain, abdominal pain, dyspnoea 
(shortness of breath), dysphagia, and erectile dysfunction  
 Safety Assessment 
6.2.1. Adverse Events 
All AEs will be recorded according to Section 8. 
6.2.2. Clinical Laboratory Evaluations 
Blood and urine sampling for clinical laboratory tests will be collected before IP administration at the 
visits specified in Table 1 and Table 2.  
Blood and urine samples will be analysed in central laboratory except urine pregnancy test which will 
be performed at investigational site using centrally supplied pregnancy kit. A detailed process for 
clinical laboratory sampling, handling, storage, and shipping will be provided in the laboratory manual 
for safety lab testing. Laboratory reports will be available to the Investigator in a timely manner. 
If laboratory tests are performed as per local practice and found to be abnormal, it is recommended that 
the Investigator uses their best clinical judgement to determine if the abnormal values would affect 
subjects’ safety while participating in the study. It is highly recommended to test the abnormal parameter 
by central laboratory as well, if available. 
During COVID-19 pandemic circumstances, it may be unable to get central laboratory values in time 
due to COVID-19 related restrictions. For those cases, local laboratory will be allowed in addition to 
central laboratory for scheduled visit after randomisation until COVID-19 restrictions are relieved under 
discussion with Sponsor.  
The parameters for clinical laboratory tests are listed in the Table 4. 


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Table 4. Parameters for Clinical Laboratory Tests 
Haematology 
 
WBC count 
 
RBC count 
 
Haemoglobin 
 
Haematocrit 
 
Platelet count 
 
Differential WBC count 
 
Nucleated RBC 
 
Mean corpuscular haemoglobin 
(MCH) 
 
Mean corpuscular haemoglobin 
concentration (MCHC) 
 
Mean corpuscular volume (MCV) 
 
Mean platelet volume (MPV) 
 
Red cell distribution width 
(RDW) 
Chemistry 
 
Sodium  
 
Potassium 
 
Creatinine 
 
Blood urea nitrogen (BUN) 
 
Glucose 
 
Calcium 
 
Phosphorus 
 
Total bilirubin 
 
Direct/indirect bilirubin 
 
Albumin 
 
Total protein 
 
Alanine aminotransferase (ALT) 
 
Aspartate aminotransferase (AST) 
 
Alkaline phosphatase (ALP) 
 
Gamma-glutamyl transpeptidase 
Coagulation Profile 
 
Prothrombin time 
 
Partial thromboplastin time 
 
INR 
 
Urinalysis 
 
Protein 
 
Blood 
 
Leukocyte esterase  
 
Nitrate 
 
Ketone 
 
Glucose 
 
pH 
 
Specific gravity 
 
Bilirubin 
 
Urobilinogen 
 
Appearance 
 
Colour 
Others 
 
Ferritin 
 
Vitamin B12 
 
Folate 
 
Serology (HIV-1 and HIV-2) 
 
Pregnancy test (serum or urine)1 
 
Serum follicle stimulating 
hormone (FSH)2 
1 Pregnancy test will be performed for women of childbearing potential (serum or urine). Serum pregnancy test will be 
performed at Screening and 8 weeks after the last dose of study drug in case of ET and urine pregnancy test will be performed 
at other applicable visits before study drug administration. 
2 Serum FSH levels will be measured at Screening and Week 26 in order to confirm postmenopausal status only for women 
who present natural (spontaneous) amenorrhea for at least 12 months prior to Screening regardless of the subjects’ age. 
The Investigator will check any laboratory values which have potential significance in subject’s safety 
during the study period. The Investigator will also evaluate any change in laboratory values. Each out 


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of range result should be assessed as not clinically significant or clinically significant by the Investigator. 
All laboratory abnormalities that require intervention (i.e., IP temporary discontinuation, IP 
discontinuation, concomitant medication, etc.) should be assessed as clinically significant and the 
clinically significant abnormalities should be recorded as AEs (see Section 8.1). 
6.2.3. Physical Examinations 
Physical examination including height and weight will be performed at Screening and physical 
examination including weight before IP administration at the visits specified in Table 1 and Table 2.  
Abnormal findings will be documented on the source documents and eCRF, and any clinically 
significant abnormality or worsening of a previously noted abnormality should be recorded as an AE 
(see Section 8.1). 
6.2.4. Twelve-lead Electrocardiograms 
Twelve-lead ECG measurements will be performed before IP administration at the visits specified in 
Table 1 and Table 2. 
6.2.5. Vital Signs 
Vital signs (blood pressure, heart rate, and body temperature) will be assessed at the visits specified in 
Table 1 and Table 2. When vital signs are scheduled to be assessed at the same time point with blood 
sampling, it is recommended that the vital signs should be measured prior to the blood collection being 
performed. 
The Investigator should assess all vital signs before IP administration on dosing days and any clinically 
significant abnormalities should be recorded as AEs (see Section 8.1). 
 Other Assessments 
6.3.1. Pharmacokinetic Assessments 
Blood sampling for PK analysis will be performed in all randomised subjects before IP administration 
at the visits specified in Table 1 and Table 2. Blood samples should be collected at the same day of study 
drug administration. Subjects’ samples may be used for PK analysis method development and/or 
method validation. 
If the IP administration is delayed for any reasons after blood sample for PK is collected, blood sample 
for PK analysis should be repeated on actual dosing day and be used for analysis.  
In all cases, the exact date and time of the PK sampling and IP administration must be carefully recorded 
in the source documents and eCRF. Detail instructions of handling, storage, and shipment for PK 
samples are described in the laboratory manual. 
The Sponsor or its designated representative will store PK samples after the end of the clinical study 
for maximum 15 years in order to have the possibility to repeat the assay already performed (e.g., re-
analysis requested by regulatory authorities or failure of first analysis [see Section 10.4]). 
6.3.2. Immunogenicity Assessments 
The purpose of immunogenicity assay is to determine whether ADAs and NAbs against SB12 or Soliris® 
occur in similar rate and influence the safety or efficacy. Blood sampling for immunogenicity assay will 
be done before IP administration at the visits specified in Table 1 and Table 2. Blood samples should be 
collected at the same day of study drug administration. Subjects’ samples may be used for 
immunogenicity testing assay method development and/or method validation. 


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If the IP administration is delayed for any reasons after blood sample for immunogenicity is collected, 
blood sample for immunogenicity assay should be repeated on actual dosing day and be used for 
analysis. 
In all cases, the exact date and time of the ADAs and NAbs sampling and IP administration must be 
carefully recorded in the source documents and eCRF. Detail instructions of handling, storage, and 
shipment for immunogenicity samples are described in the laboratory manual. 
The Sponsor or its designated representative will store immunogenicity samples after the end of the 
clinical study for maximum 15 years in order to have the possibility to repeat the assay already 
performed (e.g., re-analysis requested by regulatory authorities or failure of first analysis [see Section 
10.4]). 
6.3.3. Pharmacodynamic Assessments 
Blood samples for PD analysis will be collected at prior to infusion before IP administration at the visits 
specified in Table 1 and Table 2. Blood samples should be collected at the same day of study drug 
administration. Subjects’ samples may be used for PD analysis method development and/or method 
validation. 
Complement activity will be measured within the secured sample stability period by the validated 
method by the Sponsor or its designated representative. 
If the IP administration is delayed for any reasons after blood sample for PD is collected, blood sample 
for PD analysis should be repeated on actual dosing day and be used for analysis. 
In all cases, the exact date and time of the PD sampling and IP administration must be carefully recorded 
in the source documents and eCRF. Detail instructions of handling, storage, and shipment for PD 
samples are described in the laboratory manual. 
The Sponsor or its designated representative will store PD samples after the end of the clinical study 
for maximum 15 years in order to have the possibility to repeat the assay already performed (e.g., re-
analysis requested by regulatory authorities or failure of first analysis [see Section 10.4]). 
6.3.4. Pharmacogenetic Assessments 
Blood sample will be collected for pharmacogenetic analysis, ideally on Day 1 before initiation of study 
drug, or at the next scheduled blood sampling.  
Genetic variants in C5 is associated with poor response to eculizumab since C5 mutation causes the 
structural change in binding site of eculizumab, resulting in less suppression of complement-mediated 
haemolysis. These blood samples can be used for extraction and analysis of DNA in order to investigate 
the mutational status of the subjects including, but not limited to C5. The analysis will be performed 
during or after the study for subjects who present poor response to study drug, or only if scientifically 
appropriate and data required.  
The exact date and time of blood sampling for pharmacogenetic analysis must be recorded in the source 
documents and eCRF. Detail instructions of handling, storage, and shipment for pharmacogenetic 
samples are described in the laboratory manual. 
The Sponsor or its designated representative will store pharmacogenetic samples after the end of the 
clinical study for maximum 15 years in order to have the possibility to repeat the assay already 
performed (e.g., re-analysis requested by regulatory authorities or failure of first analysis [see Section 
10.4]). 


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7. Study Procedures 
 Study Flow and Visit Schedule 
During this study, efficacy, safety, PK, immunogenicity, and PD assessments will be performed. The 
complete schedule of activities is outlined in Table 1 and Table 2. 
7.1.1. Screening Period 
7.1.1.1. Screening Visit (D−63 to D−22) 
Screening should be performed within 42 days before randomisation. All subjects must provide written 
informed consent prior to any study related procedures being performed. 
An eligibility screening form (ESF) documenting the subject’s fulfilment of the entry criteria is to be 
completed by the Investigator or designee for all individuals considered for the study and subsequently 
included or excluded from the study. ESF should be reviewed by study monitor and submitted to 
medical monitor to determine the eligibility. Subjects who are confirmed to meet all criteria for 
enrolment will be randomly assigned in a 1:1 ratio to receive SB12 or Soliris®. Subjects who are 
considered for study entry but fail to meet the eligibility requirements should also have an ESF 
completed with the reason for lack of eligibility included, since this provides information on the selected 
study population. All ESFs should be kept in the study files at the investigational sites. 
The following procedures and assessments should be performed within 42 days before randomisation. 
Retesting or re-evaluation is allowed within the screening period, but the latest result will be used to 
determine the eligibility.  
 
Written informed consent 
 
Demographic data 
 
Review of medical history including clinically significant diseases especially related to 
eligibility criteria (see Section 4.3), surgical procedures, and thrombosis history 
 
Review of transfusion history (anaemia-related signs or symptoms which precipitated 
transfusion, haemoglobin level before transfusion, number of units of pRBCs, date of 
transfusion, if available) within 12 months prior to Screening 
 
Physical examination (including height and body weight) 
 
Vital signs (blood pressure, heart rate, and body temperature) 
 
Twelve-lead ECG 
 
FSH test (serum) for women with at least 12 months natural (spontaneous) amenorrhea prior 
to Screening. 
 
Pregnancy test (serum) for women of childbearing potential. Female subjects of non-
childbearing potential are defined as: 
a. 
At least 12 months natural amenorrhea and FSH > 40 U/L confirmed by serum blood test 
OR 
b. Those with history of hysterectomy, ligation of both fallopian tubes, surgical removal of 
both ovaries, or appropriate sterilisation operation. Documentation of surgical procedure 


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performed at least 90 days prior to Screening or appropriate medical documentation is 
required for confirmation of surgical sterilisation. 
 
Review of laboratory results  
- 
Disease-related laboratory parameters: PNH clone size of RBC and WBC evaluated by 
high-sensitivity flow cytometry, LDH, reticulocyte count, haptoglobin, and free 
haemoglobin  
- 
Haematology: Haemoglobin, haematocrit, RBC count, total WBC count including 
differential count, platelet count, nucleated RBC, MCH, MCHC, MCV, MPV and RDW 
 Note: If concurrent bone marrow failure is suspected, bone marrow examination is 
highly recommended to rule out the combined disease (e.g., myelodysplastic 
syndrome, severe aplastic anaemia, etc.).  
- 
Chemistry: Sodium, potassium, serum creatinine, BUN, glucose, calcium, phosphorus, 
total bilirubin, direct/indirect bilirubin, albumin, total protein, ALT, AST, ALP, and 
gamma-glutamyl transpeptidase 
- 
Coagulation profile: Prothrombin time, partial thromboplastin time, and INR 
- 
Urinalysis: Protein, blood, leukocyte esterase, nitrite, ketone, glucose, pH, specific gravity, 
bilirubin, urobilinogen, appearance, and colour (if urinalysis result is abnormal, urine 
microscopic examination will be performed) 
- 
Serology: HIV-1 and HIV-2  
- 
Others: Ferritin, vitamin B12, and folate 
 
PNH symptomatology will be assessed. 
 
AEs assessment 
 
Review of previous medication (within 4 weeks prior to Screening except immunosuppressant, 
which will be assessed for 8 weeks prior to Screening)  
 
Review of MAVEs 
 
Evaluate subject compliance with all eligibility criteria 
7.1.1.2. Vaccination for Neisseria meningitidis 
Due to its mechanism of action, the use of SB12 or Soliris® increases the subject’s susceptibility to 
meningococcal infection (Neisseria meningitidis). Meningococcal disease due to any serogroup may 
occur.  
To reduce the risk of meningococcal infection, all subjects must be vaccinated against Neisseria 
meningitidis prior to or on Day 1 in accordance with current local guidelines or Soliris® SmPC. Vaccines 
against serogroups A, C, Y, W135, and B where available, are recommended in preventing the 
commonly pathogenic meningococcal serogroups. In case subjects were vaccinated against 
meningococcal infection within 3 years prior to Day 1, which is properly documented, vaccination for 
this study could be omitted. For the information including formulation, preparation, and storage of 
vaccine, refer to the prescribing information in SmPC of vaccine. Subjects must be revaccinated later 
during the study if local guidelines indicate to do so. 


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Subjects who initiate SB12 or Soliris® treatment less than 14 days after receiving a meningococcal 
vaccine must receive treatment with appropriate prophylactic antibiotics until 14 days after vaccination. 
Vaccination for Neisseria meningitidis and the prophylactic antibiotics should be recorded in the source 
documents and eCRF. As vaccination might not be sufficient to prevent meningococcal infection, 
appropriate use of antibiotics may be considered according to the current local guidelines and/or at the 
discretion of the Investigator.  
As vaccination may further activate complement, subjects with PNH may experience increased signs 
and/or symptoms of their underlying disease, such as haemolysis. Therefore, subjects should be closely 
monitored for disease symptoms after vaccination.  
To raise risk awareness of meningococcal infection and its signs and/or symptoms, subjects will be 
given the safety card to carry with them during the study period.  
The safety card will contain following: 
 
Signs and symptoms of infection and sepsis 
 
Warning to seek immediate medical care if signs and/or symptoms of meningococcal infection 
are present 
 
Statement that the patient is receiving eculizumab 
 
Contact details where a health care practitioner can receive further information 
7.1.2. Randomisation 
Investigator should check the whole eligibility criteria of the subjects based on the laboratory report, 
medical history, and subjects’ assessment. After a subject’s eligibility is confirmed by the Investigator 
and medical monitor, subject should be randomised to either treatment sequence through an IWRS. 
Once the subject is confirmed eligible for the study, the subject will be advised on study restrictions 
such as contraception, prohibited medications, and other study requirements if any. 
During COVID-19 pandemic circumstances, Day 1 (1st dosing) may not be started within 21 days of 
randomisation due to unexpected COVID-19 related restrictions. In such cases, the subject will be 
monitored for safety per Investigator’s discretion. Day 1 will be started after the COVID-19 related 
restrictions are relieved. 
7.1.3. Treatment Period 
The Investigator should check if the subject does not meet the discontinuation criteria before the 
initiation of study drug at Day 1. 
All procedures and assessments will be performed at the visits specified in Table 1 and Table 2, and 
before IP administration on same day or up to 2 days prior, unless otherwise specified. 
Laboratory assessments will be performed at central laboratory. Detail instructions of collecting, 
processing, storing, and shipping for blood samples are described in the laboratory manual. Laboratory 
reports will be available to the Investigator in a timely manner for clinical management of subjects 
during treatment period. 
The Investigator will evaluate the assessment results and manage subjects based on the medicinal 
judgement and/or knowledge. 


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In special circumstances of a shortage of the comparator, to ensure continuity of study treatment for 
the duration of study, the Sponsor will provide SB12 instead of Soliris® in a blinded manner. 
Investigators and subjects will be informed prior to the execution of the potential change of IP 
assignment. Subjects willing to continue the study treatment after knowing that they may receive 
SB12 instead of Soliris® in a blinded manner during the study, should have their agreement both 
documented in the source document and an ICF. If the Investigators or subjects do not agree to the 
potential change of IP assignment, then subjects may withdraw from the study and be closely 
monitored for at least 8 weeks after last dose of study drug.  
7.1.3.1. Treatment Period 1 (before Cross-over) 
 
Blood sampling for pharmacogenetic analysis (C5 gene polymorphism) will be performed at 
Week 0 (Day 1). If missing, it would be taken at the next scheduled blood sampling time. 
 
Physical examination (including body weight) will be performed at each scheduled visit. 
 
Vital signs (blood pressure, heart rate, and body temperature) will be checked at each 
scheduled visit. 
 
Twelve-lead ECG will be performed at Week 14. 
 
Pregnancy test (urine) will be performed at the visits specified in Table 1 for women of 
childbearing potential only. 
 
Clinical laboratory tests including haematology, chemistry (includes or does not include 
ferritin, vitamin B12, and folate), coagulation profile, and urinalysis will be performed at the 
visits specified in Table 1.  
 
Blood sample collection for disease-related laboratory parameters will be performed at the 
visits specified in Table 1. 
 
Blood sample collection for PK analysis will be performed at pre-dose of Week 0 (Day 1), 
Week 2, Week 4, Week 6, Week 10, Week 14, Week 18, and Week 22. 
 
Blood sample collection for immunogenicity assay will be performed at pre-dose of Week 0 
(Day 1), Week 2, Week 4, Week 6, Week 10, Week 14, Week 18, and Week 22. 
 
Blood sample collection for PD analysis will be performed at pre-dose of Week 0 (Day 1), 
Week 2, Week 4, Week 6, Week 10, and Week 14. 
 
PNH symptomatology will be assessed at the visits specified in Table 1. 
 
AEs, concomitant medications, MAVEs, and transfusion record will be assessed and recorded. 
IP administration 
 
IP administrations by IV infusion for 35 ± 10 minutes (600 mg every week for first 4 weeks 
and 900 mg for the fifth week, followed by 900 mg every 2 weeks, the visit window allowed 
for each visit is ± 2 days) 
7.1.3.2. Visit 16 (Week 26/Day 183) 
Each subject will cross-over from the treatment initially assigned to another treatment at Visit 16 (Week 
26) and IPs will be given until Visit 28 (Week 50).  
 
Physical examination (including body weight) 
 
Vital signs (blood pressure, heart rate, and body temperature) 


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 
Twelve-lead ECG 
 
FSH test (serum) for women with at least 12 months natural (spontaneous) amenorrhea prior 
to Screening. 
 
Pregnancy test (urine) for women of childbearing potential only. 
 
Clinical laboratory tests including haematology, chemistry (includes ferritin, vitamin B12, and 
folate), coagulation profile, and urinalysis. 
 
Blood sample collection for disease-related laboratory parameters. 
 
Blood sample collection for PK analysis will be performed at pre-dose. 
 
Blood sample collection for immunogenicity assay will be performed at pre-dose. 
 
Blood sample collection for PD analysis will be performed at pre-dose. 
 
PNH symptomatology will be assessed. 
 
AEs, concomitant medications, MAVEs, and transfusion record will be assessed and recorded. 
IP administration 
 
IP administration by IV infusion for 35 ± 10 minutes (900 mg) 
7.1.3.3. Treatment Period 2 (after Cross-over) 
 
Physical examination (including body weight) will be performed at each scheduled visit. 
 
Vital signs (blood pressure, heart rate, and body temperature) will be checked at each 
scheduled visit. 
 
Twelve-lead ECG will be performed at Week 40 and Week 52. 
 
Pregnancy test (urine) will be performed at the visits specified in Table 2 for women of 
childbearing potential only. 
 
Clinical laboratory tests including haematology, chemistry (includes or does not include 
ferritin, vitamin B12, and folate), coagulation profile, and urinalysis will be performed at the 
visits specified in Table 2.  
 
Blood sample collection for disease-related laboratory parameters will be performed at the 
visits specified in Table 2. 
 
Blood sample collection for PK analysis will be performed at pre-dose of Week 28, Week 30, 
Week 32, Week 36, Week 40, Week 44, Week 48, and Week 52. 
 
Blood sample collection for immunogenicity assay will be performed at pre-dose of Week 28, 
Week 30, Week 32, Week 36, Week 40, Week 44, Week 48, and Week 52. 
 
Blood sample collection for PD analysis will be performed at pre-dose of Week 28, Week 30, 
Week 32, Week 36, Week 40, and Week 52. 
 
PNH symptomatology will be assessed at the visits specified in Table 2. 
 
AEs, concomitant medications, MAVEs, and transfusion record will be assessed and recorded. 
IP administration 


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 
IP administrations by IV infusion for 35 ± 10 minutes (900 mg every 14 ± 2 days) 
7.1.3.4. Safety Follow-up (Week 58/Day 407)  
Safety follow-up will be done at Week 58 (± 7 days) which is 8 weeks after the last dose of SB12 or 
Soliris® for subjects who complete the study treatments until Week 50, regardless whether subject 
receives extended supply of SB12 or not to ensure subject’s safety. These activities will be conducted 
either by visit or by phone call based on subjects’ preference.  
 
AEs, concomitant medications, MAVEs, and transfusion record will be assessed and recorded. 
7.1.3.5. Early Termination Visit 
ET visit is defined as 8 weeks (± 7 days) after the last dose of SB12 or Soliris® during the treatment 
period.  
 
Physical examination (including body weight) 
 
Vital signs (blood pressure, heart rate, and body temperature) 
 
Pregnancy test (serum) for women of childbearing potential only. 
 
Clinical laboratory tests including haematology, chemistry, and urinalysis  
 
Blood sample collection for disease-related laboratory parameters 
 
Blood sample collection for immunogenicity assay 
 
AEs, concomitant medications, MAVEs, and transfusion record will be assessed and recorded. 
7.1.4. Unscheduled Visits 
If a sign or symptom of breakthrough haemolysis is suspected, an unscheduled visit should be occurred 
and samples should be collected for LDH, PK, and PD assessment for central laboratory at that time. 
Additionally, other unscheduled visits are permitted at the discretion of the Investigator. Any tests, 
procedures, or assessments performed at the unscheduled visits must be recorded in the source 
documents and eCRF. 
 Discontinuation 
7.2.1. Subject Discontinuation from Study Treatment 
The study treatment must be discontinued for a subject in the event of the following: 
• 
Consent withdrawal by subject 
- 
Subjects may withdraw from the study or study specific procedures at any time for any 
reason during the entire duration of the study without prejudicing future treatment. 
- 
If subjects withdraw his/her consent, the Investigator must inquire the reasons for consent 
withdrawal as to whether it is related to the study (e.g., documented lack of efficacy, AE, 
or pregnancy); however, the subject could refuse to provide such reason. 
- 
If the main reason for consent withdrawal is considered related to the study, the 
Investigator may select appropriate reason among the reasons listed below other than 
consent withdrawal. 
• 
Pregnancy (study treatment should be immediately stopped when a pregnancy is made known 


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and the pregnant woman will be removed from the study) 
• 
Unblinding the study treatment to the Investigator or subject (i.e., breaking the double-blind). 
• 
Other complement inhibitor use   
The Investigator should discuss with the medical monitor prior to discontinuing a subject’s study 
treatment in case of the following criteria, but not limited to: 
• 
Conditions or intercurrent illness that preclude compliance with the protocol in terms of their 
safety or well-being 
• 
Lack of efficacy (e.g., C5 gene polymorphism) 
Note: If the LDH level is not changed after the initiation of study drug (lack of efficacy), the 
Investigator and medical monitor and/or Sponsor should discuss to determine how to manage 
this case including whether or not to perform pharmacogenetic analysis (C5 gene 
polymorphism). 
• 
Unacceptable toxicity including meningococcal infection or anaphylaxis  
• 
Serious protocol deviations (PDs) including lack of subject’s compliance (e.g., repeated delay 
in study treatment and lost to follow-up) that preclude continuation of the study 
Note: Before a subject is deemed lost to follow-up, the Investigator or designee will make 
every effort to regain contact with the subject. 
• 
Investigator discretion or other reasons 
Discontinuation from study treatment does not mean immediate discontinuation from the study, and 
remaining study procedures should be completed as indicated by the study protocol. Subjects who 
discontinue from the study at any time post-Day 1 (after the initiation of study drug) before completion 
of last study treatment at Week 50 will be required to have an ET visit. The data to be collected at the 8 
weeks after the last dose of study drug are described in the Section 7.1.3.5. Every effort will be 
employed to keep subjects who discontinued from study treatment to undertake the scheduled ET visit 
procedures.  
Subjects who discontinue study treatment after being exposed to study treatment will be monitored 
closely for signs of a potentially life-threatening haemolytic breakthrough event. Serious haemolysis is 
identified by serum LDH levels greater than the pre-treatment level, along with any of the following:  
 
Greater than 25% absolute decrease in PNH clone size (in the absence of dilution due to 
transfusion) in 1 week or less 
 
A haemoglobin level of < 5 g/dL or a decrease of > 4 g/dL in 1 week or less 
 
Angina 
 
Change in mental status 
 
A 50% increase in serum creatinine level 
 
Thrombosis as defined by MAVEs 
Any subject who discontinues SB12 or Soliris® should be monitored for at least 8 weeks after last dose 
of study drug to detect serious haemolysis and other reactions. If serious haemolysis occurs after SB12 
or Soliris® discontinuation, consider the following procedures and/or treatments: 


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 
Blood transfusion (pRBCs) or exchange transfusion if the PNH RBCs are > 50% of the total 
RBCs by flow cytometry 
 
Anticoagulation 
 
Corticosteroids 
 
Complement inhibitors 
7.2.2. Investigational Site Discontinuation 
Investigational site participation may be discontinued if the Sponsor, the Investigator, or the Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) of the investigational site judge it necessary 
for any reason. Health authorities and IRB/IEC will be informed about the discontinuation of the study 
in accordance with applicable regulations. 
 Early Termination of the Study 
The study can be terminated at any time for medical or ethical reasons by the Sponsor. If the study is 
terminated or discontinued prematurely, the Sponsor will promptly notify to the Investigator. 
Investigator may be informed of additional procedures to be followed in order to assure that adequate 
consideration is given to the protection of the subject’s interests.  
Health authorities and IRB/IEC will be informed about the discontinuation of the study in accordance 
with applicable regulations. 
8. Safety Monitoring and Reporting 
 Adverse Events 
8.1.1. Definition of Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject administered 
the medicinal (investigational) product or other protocol-imposed intervention and which does not 
necessarily have to have a causal relationship with this treatment or intervention. An AE can therefore 
be an unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of any dose of a medicinal (investigational) product or other 
protocol-imposed intervention regardless of attribution. 
All AEs during the period of observation (as specified in Section 8.1.2) including the events that 
occurred prior to administration of an IP should be reported as an AE. 
Pre-existing conditions and any abnormal findings from assessments during the screening period which 
are not related to protocol-imposed intervention should not be reported as AEs; however, pre-existing 
conditions which worsen (i.e., increase in severity) that meet the definition of an AE during the study 
are to be reported as AEs. 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not be 
reported as AEs. However, the medical condition for which the procedure was performed should be 
reported if it meets the definition of an AE. For example, an acute appendicitis that begins during the 
AE reporting period should be reported as an AE and the resulting appendectomy should be recorded 
as treatment of the AE. 
The AEs that emerge during treatment with an IP (i.e., treatment-emergent AE [TEAE]) will be analysed 
for the purposes of safety analyses. 


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8.1.1.1. Clinically Significant Abnormality 
If there are any abnormalities discovered during the laboratory tests, physical examinations, vital 
signs, and/or other safety assessments and the abnormality is assessed clinically significant by the 
Investigator, it should be reported as an AE. This does not apply to pre-existing conditions which 
have been documented at Screening or if the abnormality is consistent with a current diagnosis 
(underlying disease or other AEs). If it is not specified or defined elsewhere in the protocol, clinically 
significant abnormality may include the events that led to an intervention, including withdrawal of 
the IP treatment, significant additional concomitant medication, and others evaluated as clinically 
significant by the Investigator. 
If the clinically significant laboratory or other abnormality from safety assessment is not a sign of a 
disease or syndrome, the abnormality itself should be reported as an AE. If the abnormality can be 
characterised by a precise clinical term, the clinical term should be reported as the AE. For example, an 
elevated serum potassium level of 7.0 mEq/L should be reported as ‘hyperkalaemia’. Observations of 
the same clinically significant abnormality from visit to visit should not be repeatedly reported as AEs, 
unless their severity, seriousness, or aetiology changes. 
8.1.2. Period of Observation for Adverse Events 
AEs will be reported from the time of signing the ICF until EOS. 
SAEs must be reported to the Sponsor or its designated representative according to Section 8.2.2.  
Unresolved AEs during the study period should be followed up until EOS. The Investigator should 
observe the AEs for appropriate medical care of the subject until AE resolution or stabilisation. 
If the subject has an ongoing SAE at EOS, these cases will be followed until event resolution or 
stabilisation (see Section 8.2.2). 
8.1.3. Reporting Adverse Events 
AEs are to be reported in the eCRF and reviewed by the Investigator. When reporting an AE, a 
diagnosis (when possible and appropriate) rather than each individual sign and symptom should be 
reported. 
Each AE is to be assessed to determine if it meets the criteria of an SAE (see Section 8.2.1 for SAE 
definition). If an AE is classified as a SAE, it must be reported to the Sponsor, or its designated 
representative, promptly according to the timeline specified in Section 8.2.2. For an SAE, a diagnosis 
with a description of signs and symptoms as well as other supporting information that led to the 
diagnosis should be described in the SAE form provided by the Sponsor (see Section 8.2.2). 
8.1.4. Severity Assessment 
The Investigator is responsible for assessing and reporting the severity of AEs in accordance with 
National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0. 
The following general guideline can be used to describe the severity of the AE. A grading (severity) 
scale for each specific AE is provided in NCI-CTCAE v5.0. 
Table 5. Severity Grade of NCI-CTCAE v5.0 
Grade 
Clinical Description of Severity 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated. 


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Grade 
Clinical Description of Severity 
Grade 2 
Moderate; minimal, local or non-invasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL)a. 
Grade 3 
Severe or medically significant but not immediately life-threatening;  
hospitalisation or prolongation of hospitalisation indicated; disabling;  
limiting self-care ADLb. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
a Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
b Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden 
8.1.5. Causality Assessment 
The Investigator is responsible for assigning a causal relationship to each AE. The causal relationship 
between the IP and the AE should be defined as not related (no) or related (yes). 
Events should be classified as ‘related’ if there is a reasonable possibility that the IP caused the AE. 
This means that there are facts (evidence) or arguments to suggest a causal relationship. 
Events should be classified as ‘not related’ if there is no reasonable possibility that the IP caused the 
AE. 
8.1.6. Expectedness Assessment 
Expectedness of AEs will be assessed by reference safety information (RSI) in IB. More detailed 
information on expectedness assessment will be explained in IB. The latest Soliris® SmPC [10] will 
be used to assess the expectedness for the reference product after database lock or emergency 
unblinding. 
8.1.7. Withdrawal due to Adverse Events 
Subject withdrawal from the study due to an AE should be distinguished from withdrawal due to 
personal reasons and recorded in the source documents and appropriate eCRF section. Subjects 
withdrawn due to an AE should be followed up until the time point specified in Section 7.2.1. When 
a subject withdraws from the study due to an SAE, the SAE must be reported and followed in 
accordance with the requirements outlined in Section 8.2.2. 
Subjects who discontinue the administration of IPs because of serious or significant safety issues 
should be followed closely until the events are fully and permanently resolved or stabilised. 
 Serious Adverse Events 
8.2.1. Definition of Serious Adverse Event 
An SAE is any untoward medical occurrence at any dose that: 
• 
Results in death, 
• 
Is life-threatening, 
• 
Requires inpatient hospitalisation or prolongation of existing hospitalisation, 


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• 
Results in persistent or significant disability/incapacity, 
• 
Results in congenital anomaly/birth defects, 
• 
Is medically important.  
Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalisation. However, if it is determined that the event may 
jeopardise the subject and may require intervention to prevent one of the other outcomes listed in the 
definition above, the important medical event should be reported as serious. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias 
or convulsions that do not result in hospitalisation or development of drug dependency or drug abuse. 
The term ‘severe’ is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache). This is not the same as ‘serious,’ which is based on 
subject/event outcome or action criteria usually associated with events that pose a threat to a subject’s 
life or functioning. 
8.2.1.1. Life-threatening 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the subject was at 
risk of death at the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe. 
8.2.1.2. Hospitalisation 
AEs reported from clinical studies associated with inpatient hospitalisation or prolongations of 
hospitalisation are considered serious. Staying at an observation unit in the emergency room for more 
than 24 hours qualifies for hospitalisation. Any events leading to subsequent emergency room visit 
for less than 24 hours should be in the discretion of the Investigator to assess serious as medically 
important. 
Hospitalisation or prolongation of hospitalisation in the absence of a precipitating clinical AE is not 
in itself an SAE. Examples include: 
• 
Admission for treatment of a pre-existing condition not associated with the development of 
a new AE or with a worsening of the pre-existing condition (e.g., for work-up of persistent 
pre-treatment lab abnormality), 
• 
Social admission for convenience (e.g., admission of a subject who does not have a carer), 
• 
Administrative admission (e.g., for a yearly physical exam), 
• 
Protocol-specified admission during a clinical study (e.g., for a procedure required by the 
study protocol), 
• 
Optional admission not associated with a precipitating clinical AE (e.g., for elective 
cosmetic surgery). 
Pre-planned treatments or surgical procedures should be noted in the relevant source document for 
the individual subject. 


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8.2.2. Reporting Serious Adverse Events 
SAEs must be collected until 8 weeks (± 7 days) from the last dose of study drug (five half-lives of 
the study drug). 
SAEs that occurred at or before EOS must be reported to the Sponsor or its designated representative 
via eCRF SAE report form at least within 24 hours of the Investigator becoming aware of the event. 
SAEs that occurred after EOS must be reported to the Sponsor or its designated representative using 
the paper SAE report form at least within 24 hours of the Investigator becoming aware of the event. 
Date and time (wherever possible) of the Investigator becoming aware of the SAE will be recorded 
in the SAE form and source document properly. 
In particular, if the SAE is fatal or life-threatening, the Sponsor must be notified immediately, 
irrespective of the extent of available AE information. This timeframe also applies to additional 
(follow-up) information that becomes available on previously forwarded SAE reports. Sponsor will 
then follow expedited reporting procedures according to local and international regulations as 
appropriate. 
The Investigator is obligated to pursue and provide information to the Sponsor on all SAEs in 
accordance with the timeframes for reporting specified above. In addition, an Investigator may be 
requested by the Sponsor to obtain specific additional follow-up information in an expedited fashion. 
In general, this will include a description of the SAE, which should be provided in sufficient detail 
so as to allow for a complete medical assessment of the case and independent determination of 
possible causality. Information on other possible causes of the event, such as concomitant medications 
and illnesses must be provided. In the case of a subject death, a summary of available autopsy findings 
must be submitted as soon as possible to the Sponsor or its designated representative. 
All SAEs will be followed until event resolution or stabilisation (for chronic events), if possible, even 
when a subject is withdrawn from treatment. For chronic events that do not fully resolve until years 
later, the outcome should be reported as ‘resolved with sequelae’ as soon as the event has stabilised 
or returned to baseline. Follow-up information for the SAE should be actively sought and submitted 
as the information becomes available. 
 Adverse Events of Special Interest 
8.3.1. Meningococcal Infection 
Due to its mechanism of action, the use of SB12 or Soliris® increases the subject’s susceptibility to 
meningococcal infection (Neisseria meningitidis). These subjects might be at risk of disease by 
serogroups (particularly Y, W135, and X), although meningococcal disease due to any serogroup may 
occur. To reduce the risk of infection, all subjects will be vaccinated against Neisseria meningitidis 
prior to or on Day 1. Subjects must be revaccinated later during the study if local guidelines indicate 
to do so. However, vaccination may not be sufficient to prevent meningococcal infection. 
Consideration should be given to current local guidelines and/or the discretion of the Investigator on 
the appropriate use of antibacterial agents. Cases of serious or fatal meningococcal infections have 
been reported in Soliris®-treated patients. All subjects should be monitored for early signs of 
meningococcal infection, evaluated immediately if infection is suspected, and treated with 
appropriate antibiotics if necessary.  
Subjects should immediately call the Investigator or seek emergency medical care, if subjects 
experience any of the following symptoms: 


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• 
Headache with nausea or vomiting 
• 
Headache and a fever 
• 
Headache with a stiff neck or stiff back 
• 
Fever 
• 
Fever and a rash 
• 
Confusion 
• 
Muscle aches with flu-like symptoms 
• 
Eyes sensitive to light 
Subjects should be informed of these signs and symptoms and steps taken to seek medical care 
immediately. Subjects who are undergoing treatment for serious meningococcal infections should 
discontinue SB12 or Soliris® treatment, and the Investigator must discuss the benefits and risks of 
SB12 or Soliris® treatment with subjects and provide them with medical instructions.  
8.3.2. Other Systemic Infections 
SB12 or Soliris® blocks terminal complement activation; therefore subjects may have increased 
susceptibility to infections, especially with encapsulated bacteria. Serious infection with Neisseria 
species (other than Neisseria meningitidis), including disseminated gonococcal infections, have been 
reported after Soliris® treatment. Additionally, Aspergillus infections have occurred in 
immunocompromised and neutropenic patients. Subjects should immediately call the Investigator or 
seek emergency medical care, if subjects experience other systemic infections. 
8.3.3. Infusion-related Reactions 
Administration of SB12 or Soliris® may result in infusion reactions or immunogenicity that could 
cause allergic or hypersensitivity reactions (including anaphylaxis). In clinical trials, 1 (0.9%) gMG 
patient experienced an infusion reaction which required discontinuation of Soliris®. No PNH, aHUS, 
or NMOSD patients experienced an infusion reaction which required discontinuation of Soliris® in 
clinical trials. 
Administration of SB12 or Soliris® should be performed in a setting with emergency equipment and 
site staff who are trained to medical emergencies. 
If an infusion reaction occurs during the administration of IPs, the infusion may be slowed or stopped 
at the discretion of the Investigator. If the infusion is slowed, the total infusion time may not exceed 
2 hours. The subject will be monitored until resolution of any observed symptoms. The majority of 
subjects will be resolved for symptoms and subsequently will receive further infusions. Subjects 
should be warned of the possibility of late onset reactions and should be instructed to contact their 
Investigator if these reactions occur. Subjects who experience infusion-related symptoms may be pre-
medicated with paracetamol and antihistamines for subsequent infusions. 
When a severe hypersensitivity reaction such as anaphylaxis occurs, the infusion should be 
interrupted immediately and supportive care including oxygen, epinephrine, beta-agonists, and 
corticosteroids should be administered with continuous vital sign monitoring by trained site staff until 
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 Pregnancy 
Any pregnancy, including those of female partners of male subjects treated with the IP, should be 
reported to the Sponsor. If the female partner of a male subject becomes pregnant, a written consent 
must be obtained from the female partner before collecting any pregnancy-related information. All 
pregnancies associated with the subject, from the time the subject receives the first dose of study drug 
until 5 months after the last dose of study drug should be reported to the Sponsor. Pregnancy reports 
should be made within 24 hours of the Investigator becoming aware of the pregnancy using the 
“pregnancy notification and outcome report form”. 
Although pregnancy is not an AE, all pregnancies must be followed up until 6-8 weeks after the 
outcome of the pregnancy becomes available, unless the subject is lost to follow-up. The pregnancy 
outcome should be notified to the Sponsor by submitting a follow-up pregnancy notification and 
outcome report form. If the outcome of the pregnancy meets SAE criteria then the Investigator should 
report this case according to the SAE reporting process (Section 8.2.2). 
8.4.1. Pregnancy Prevention  
In order to minimise the risk to a foetus or embryo for including women of childbearing potential in 
this study, female subjects of childbearing potential and male subjects with female partner of 
childbearing potential must agree to use at least one highly effective birth control method. The 
Investigator and/or designee will discuss with the subject the need to use highly effective 
contraception consistently and correctly and document such conversation on the subject’s source 
documents. 
Highly effective birth control method includes the following: 
• 
Combined (oestrogen and progesterone containing) hormonal contraception associated with 
inhibition of ovulation:  
- 
Oral, intravaginal, transdermal 
• 
Progesterone-only hormonal contraception associated with inhibition of ovulation: 
- 
Oral, injectable, implantable 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system 
• 
Bilateral tubal occlusion 
• 
Vasectomised partner 
• 
True abstinence 
Note: True abstinence could be considered sufficient only for subjects who do not have a 
partner. 
Followings are not highly effective birth control method and cannot be used for this study: 
• 
Progesterone-only oral hormonal contraception where inhibition of ovulation is not the 
primary mode of action, male or female condom with or without spermicide, 
cap/diaphragm/sponge with spermicide, periodic abstinence (calendar, symptothermal, post-
ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational 


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amenorrhoea method 
 Emergency Unblinding of Assigned Treatment 
Unblinding should be considered only when knowledge of the treatment assignment is deemed essential 
for the subject’s safety by their Investigator or a regulatory body. Emergency unblinding should be 
decided based on the medical decision by the Investigator considering subjects safety. In general, 
unblinding of subjects during the conduct of the clinical study should only be performed where there 
are compelling medical or safety reasons to do so. The responsibility to break the treatment code in 
emergency situations resides solely with the Investigator. 
The IWRS will be used to break the blind and details on how to do this are provided in the IWRS 
manual. The Sponsor must be notified immediately after a subject and/or the Investigator is unblinded 
during the course of the study along with the reason for breaking the blind. Pertinent information 
regarding the circumstances of unblinding of a subject’s treatment code must be documented on the 
subject’s source documents. This includes who performed the unblinding, the subject(s) affected, the 
reason for the unblinding, the date of the unblinding, and the relevant IP information. 
 Independent Data and Safety Monitoring Board 
An independent DSMB will be assigned for this study. The DSMB will consist of external experts 
(e.g., haematologists, clinical pharmacologists, and biostatisticians) and will review the safety and 
tolerability data from the study at pre-specified intervals. The details of the safety data and time points 
for review will be described in the DSMB charter and in the DSMB statistical analysis plan (SAP). 
In addition, an ongoing blinded review of AEs, including clinical laboratory data will be regularly and 
continuously undertaken by the Sponsor medical monitor and pharmacovigilance team. 
9. Statistical Methods and Data Analysis 
Further information on the statistical methods for this study will be provided in the SAP, which will be 
finalised prior to the database lock for reporting the clinical study report (CSR). 
Statistical analysis and reporting will be performed as follows: 
 
Interim safety analysis for independent DSMB meeting: 
A DSMB SAP, describing the methodology and presentation of results and access to results 
will be prepared as a separate document. The safety reports for the DSMB data review 
meetings will be prepared according to the DSMB SAP.  
The statistical analysis will be performed by an independent statistical reporting team and the 
results will be communicated to the DSMB directly by an independent unblind statistician. 
 
CSR: 
The analysis will take place after the last subject completes the procedures at Week 58 or the 
corresponding visit. All study data will be analysed and reported for CSR. 
 Statistical Hypotheses 
This is a cross-over study to demonstrate equivalence in terms of LDH between SB12 and Soliris®. The 
null hypothesis tested for the primary efficacy analysis is that either (1) SB12 is inferior to Soliris® or 
(2) SB12 is superior to Soliris® based on a pre-specified equivalence margin. 


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 for those who are in favour of the time-adjusted 
AUEC of LDH, the treatment effect will be measured by time-adjusted AUEC of LDH between two 
different time points in each period, from Week 14 to Week 26 and from Week 40 to Week 52. The 
equivalence will be declared if the 90% confidence interval (CI) of the ratio between treatment effects 
is entirely contained within the pre-defined equivalence margin of [0.77, 1.29].  
 for those who are in favour of the LDH level 
at a single time point, equivalence will be declared if the 95% CI of the difference between treatments 
in LDH level at Week 26 is entirely contained within the pre-defined equivalence margin of [−1.2 × 
ULN, 1.2 × ULN] where ULN of LDH to be specified in the central laboratory specification for this 
study.  
If normal range of LDH is gender specific, the smaller/smallest ULN will be used for the equivalence 
margin; otherwise ULN is not gender specific, unified ULN will be used for the equivalence margin. 
 Analysis Sets 
The following sets will be used for the analyses performed in the study: 
 
Randomised Set (RAN) consists of all subjects who have received a randomisation number. 
 
Modified Full Analysis Set (M-FAS) consists of all RAN subjects who do not have positive 
result of pharmacogenetic analysis (C5 gene polymorphism). However, subjects who do not 
have any efficacy assessment result after randomisation and do not receive IP during the study 
period will be excluded from this analysis set. Following the intent-to-treat principle, subjects 
will be analysed according to the treatment sequence they are assigned to at randomisation.  
 
Per-Protocol Set for AUEC of LDH (PPS-AUEC) consists of all M-FAS subjects who have 
sufficient LDH assessments for AUEC calculation without any major PDs that have impact on 
efficacy assessment. Subjects excluded from the primary analysis will be pre-defined on a 
case-by-case basis prior to unblinding the treatment sequence assignment for analyses. In 
addition, subjects who received different treatment from the randomised treatment sequence 
due to a shortage of the comparator will be excluded from this analysis set. 
 
Per-Protocol Set for LDH at a single time point (PPS-single) consists of all M-FAS subjects 
who have LDH assessment at Week 26 without any major PDs that have impact on efficacy 
assessment. Subjects excluded from the primary analysis will be pre-defined on a case-by-case 
basis prior to unblinding the treatment sequence assignment for analyses. In addition, subjects 
who received different treatment in Period 1 from the randomised treatment sequence due to 
a shortage of the comparator will be excluded from this analysis set. 
 
Safety Set (SAF) consists of all subjects who receive at least one IP during the study period. 
Subjects will be analysed according to the treatment received. 
 
PK Analysis Set (PKS) consists of all subjects in the SAF who have at least one PK sample 
analysed. 
 
PD Analysis Set (PDS) consists of all subjects in the SAF who have at least one PD sample 
analysed. 
 Subject Demographic and Baseline Characteristics 
The baseline value will be defined as the last available measurement value prior to or on the date of the 


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initiation of study drug. 
Subject demographics and baseline disease characteristics will be summarised by treatment sequence 
for the RAN. Continuous variables (e.g., age, weight, height) will be summarised with descriptive 
statistics (n, mean, standard deviation [SD], median, minimum, maximum) and categorical variables 
(e.g., gender, race, ethnicity) will be summarised with count and percentage.  
Comparison between treatment sequences in demographics and baseline disease characteristics will be 
performed using the chi-square test or F-test as appropriate. The results of these tests will be provided 
including the p-value only for descriptive purposes and will not be used as a formal basis to determine 
the factors to be included in primary or secondary efficacy analysis models. If baseline imbalances are 
detected for any of the factors, additional analyses may be performed to adjust for these baseline 
differences. 
Relevant medical history, transfusion history, and continuing medical conditions will be summarised 
by treatment sequence for the RAN. 
 Analysis of the Primary Objectives 
 for those who are in favour of the time-adjusted 
AUEC of LDH, the primary efficacy analysis will be performed for the PPS-AUEC using a linear mixed 
model with treatment, sequence, period, and gender as fixed effects, and subject nested within sequence 
as a random effect. The analysis will be performed with loge-transformed time-adjusted AUEC of LDH 
estimating the difference in least squares means and its 90% CI, and back transformation of those values 
will provide the ratio of geometric means and 90% CI. The equivalence will be declared if the two-
sided 90% CI of the ratio of geometric means in time-adjusted AUEC of LDH between SB12 and 
Soliris® lies within the pre-defined equivalence margin of [0.77, 1.29].  
 for those who are in favour of the 
LDH level at a single time point, the primary efficacy analysis will be performed for the PPS-single 
using a linear mixed model with treatment, and gender as a fixed effect. The analysis will be performed 
with loge-transformed LDH at Week 26 estimating the difference in least squares means and its 95% CI, 
and the delta method will be used to provide the mean difference and 95% CI in original scale. The 
equivalence will be declared if the two-sided 95% CI of the mean difference in LDH level at Week 26 
between SB12 and Soliris® lies within the pre-defined equivalence margin of [−1.2 × ULN, 1.2 × ULN] 
where ULN of LDH to be specified in the central laboratory specification for this study. 
No formal adjustment of Type I error rates will be performed. 
For the primary analysis with the M-FAS, missing data will be imputed for subjects who drop out for 
the study prior to the primary analysis time point. A missing-at-random approach will assume that 
subjects who withdraw from a study had similar missing values to peer subjects who completed the 
study in that treatment sequence. This approach ensures that evidence of lack of equivalence is not 
diluted when there are missing data. Multiple imputation method will be used with the assumption of 
monotone missing pattern and regression method. For the sensitivity analyses, complete case analysis 
will be performed. 
 Analysis of the Secondary Objectives 
9.5.1. Efficacy Variable Analyses 
As a secondary efficacy endpoint, number of units of pRBCs transfused will be summarised 
descriptively by treatment sequence and treatment sequence within period and will be analysed using 


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Wilcoxon rank-sum test. And mean LDH profile will be presented over time. 
9.5.2. Safety Analyses  
All reported terms for AEs will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA®). AEs will be collected and classified according to NCI-CTCAE v5.0. For all AE and SAE 
tables, subjects will be counted once for each preferred term and each system organ class.  
A TEAE will be defined as any AE with an onset date on or after the date of the initiation of study drug. 
AEs which are already present before the initiation of study drug and increase in severity after the 
initiation of study drug will be considered as TEAEs. Pre-existing AEs before the initiation of study 
drug with no increase in severity after the initiation of study drug will not be considered as TEAEs. 
All TEAEs and SAEs will be summarised respectively by count and percentage of subjects experiencing 
events by system organ class, preferred term. TEAEs leading to IP discontinuation and TEAEs by 
causality and severity will be summarised similarly. All AEs including those pre-existing before the 
initiation of study drug will be listed by subject. 
In addition, infection-related AEs including meningococcal infection and other systemic infection, and 
IRRs will also be summarised. 
Duration of exposure to IP and number of IV infusion will be summarised by treatment sequence within 
period with descriptive statistics for the SAF. Prior and concomitant medications, and significant non-
drug therapies will be summarised with count and percentage. 
Changes in vital signs and clinical laboratory parameters will be summarised descriptively by treatment 
sequence and visit. Other safety variables will be summarised unless otherwise specified, and all safety 
variables will be listed. 
All safety analyses will be performed using the SAF. Additional analyses will be performed for the 
subjects who received different treatment from the randomised treatment sequence due to a shortage of 
the comparator if needed. For example, AEs and concomitant medications will be analysed based on 
the actual switched treatment. 
9.5.3. Pharmacokinetic Analyses 
PK analysis will be performed for the PKS. Ctrough will be summarised with descriptive statistics by 
treatment sequence, period, and time point. 
9.5.4. Immunogenicity Analyses 
ADA and NAb results (e.g., ‘positive’ or ‘negative’) will be summarised with count and percentage by 
treatment sequence and visit. In addition, incidence of overall ADA will be summarised by treatment 
sequence and period.  
Immunogenicity analyses will be performed using the SAF. 
9.5.5. Pharmacodynamic Analyses 
PD analysis will be performed for the PDS. The absolute values, and change from baseline in terminal 
complement activities will be summarised by treatment sequence and visit. PD data for each subject 
will also be listed.  
 Sample Size Calculations 
The equivalence margin for the mean difference of LDH at Week 26 is derived from two historical 


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studies with Soliris®. In TRIUMPH study, the mean (SD) of LDH at Week 26 is 327.3 (432.9) U/L and 
2,418.9 (930.6) U/L for eculizumab and non-eculizumab arms, respectively. PNH registry study 
reported the mean of LDH at 6 months is 352.1 (224.0) U/L and 1,201.0 (815.6) U/L for eculizumab 
and non-eculizumab arms, respectively. 
Table 6. LDH Level from Reference Studies 
 
Eculizumab 
Non-eculizumab 
Note 
N 
Mean (SD) 
N 
Mean (SD) 
TRIUMPH study (2006)a 
41 
327.3 (432.9) 
44 
2,418.9 (930.6) 
Results at Week 26 
International PNH registry (2016) 
38 
352.1 (224.0) 
102 
1,201.0 (815.6) 
Results at 6 months 
Meta-analysis for mean difference 
with 95% CIs 
−1,152.5 [−1,303.4, −1,001.7] 
a SD for TRIUMPH study was derived from the standard error in the reference paper.  
A meta-analysis with fixed-effect model estimates −1,152.5 U/L of LDH mean at Week 26 with a 95% 
CI [−1,303.4, −1,001.7]. The 
 of upper limit of 95% CI was approximately 
 U/L, which implies 
that at least 
 treatment effect is obtained to preserve the treatment effect over placebo if the 
 
U/L was statistically chosen as the equivalence limit. 
In the clinical study, LDH detection level or normal range of LDH would depend on the specification 
of laboratory parameters chosen for the study. Therefore, it is not likely to be clinically meaningful to 
propose any specific LDH level as the equivalence margin without the consideration of normal range 
of LDH level. 
 
 
 
 
 
 
 
Therefore, the equivalence margin will be [−1.2 × ULN, 1.2 × ULN] for the comparison with the 95% 
CI of the mean difference in LDH at Week 26 where ULN of LDH to be specified in the central 
laboratory specification for this study. For sample size calculation, [−268 U/L, 268 U/L] is chosen to 
be 23 subjects per treatment sequence with the assumptions of no mean difference and common SD of 
270 U/L at the overall 5% significance level. Assuming a 5% loss from randomised subjects after 26 
weeks, a sample size of 25 subjects per treatment sequence (overall sample size of 50) will give 23 
completers per treatment sequence after 26 weeks, which is estimated to give 80% power to detect the 
equivalence within the margin of 268 U/L. 
The nQuery Advisor® option two-group t-tests (two one-sided test [TOST]) of equivalence in means 
(equal n’s) gives the following statement to estimate the n per group to show the equivalence: “When 
the sample size in each group is 23, a two group design will have 80% power to reject both the null 
hypothesis that the test mean minus the standard mean is below −268 and the null hypothesis that the 
test mean minus the standard mean is above 268 i.e., that the test and standard are not equivalent, in 
favor of the alternative hypothesis that the means of the two groups are equivalent, assuming that the 
expected difference in means is 0, the common standard deviation is 270 and that each test is made at 
the 2.5% level.” 
For calculation of the equivalence margin for time-adjusted AUEC of LDH, mean and coefficient of 


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variation (%CV) were referred from TRIUMPH study. The mean (%CV) of AUEC of LDH at Week 26 
is 81,140.0 U/L × day (142.45%) and 429,874.1 U/L × day (33.49%) for eculizumab and non-
eculizumab arms, respectively.  
From the results in the reference study, mean ratio of AUEC of LDH is estimated to be 0.19 with a 90% 
CI [0.1308, 0.2724]. The upper limit of the equivalence margin is calculated as 
 
 where it preserves at least 
 of eculizumab treatment effect over the 
placebo, but 
 the equivalence margin will be [0.77, 1.29] for the 
comparison with the 90% CI of mean ratio of time-adjusted AUEC of LDH. 
With the given equivalence margin of [0.77, 1.29], 22 subjects per treatment sequence was calculated 
with the assumptions of the mean ratio of 1, common %CV of 42% at the overall 10% significance 
level. Assuming a 10% loss from randomised subjects after 52 weeks, a sample size of 25 subjects per 
treatment sequence (overall sample size of 50) will give 22 completers per treatment sequence after 52 
weeks, which is estimated to give 80% power to detect the equivalence within the margin of [0.77, 1.29]. 
The nQuery Advisor® option two-group t-tests (TOST) of equivalence for ratio of means (log-scale) 
gives the following statement to estimate the n per group to show the equivalence: “When the sample 
size in each sequence group is 22 (and the total sample size is 44), a crossover design will have 80% 
power to reject both the null hypothesis that the ratio of the test mean to the standard mean is below 
0.77 and the null hypothesis that the ratio of test mean to the standard mean is above 1.29; i.e., that the 
test and standard are not equivalent, in favor of the alternative hypothesis that the means of the two 
treatments are equivalent, assuming that the expected ratio of means is 1, the Crossover ANOVA, √MSE 
(ln scale) is 
 (the SD differences, σ (ln scale) is 
), that data will be analyzed in the natural log 
scale using t-tests for differences in means, and that each t-test is made at the 5% level.” 
Therefore, the sample size of 50 allows enough power to detect the equivalence in both situations. 
10. Data Collection and Management 
 Data Confidentiality 
Information about study subjects will be kept confidential. Study information will be labelled with a 
code number, and will not include the subject’s name, hospital number or other information that could 
identify them. A list linking the code and the subject’s name will be kept in the site files as required by 
ICH-GCP to protect the subject’s confidentiality. 
The coded information will be sent to the Sponsor (or designee) who will analyse it and report the study 
results both to regulatory and ethical authorities. The Sponsor may also place data on public websites 
or publish journal articles based upon these results. Care will be taken to prevent subjects being 
identified through these publications. In addition, data may be shared with other companies or 
researchers to aid further research into complement inhibitor. Such data sharing practices will be 
covered by confidentiality agreements. No-one outside the investigational site will have access to 
subject-identifiable information. 
 Monitoring 
The Sponsor has engaged the services of a contract research organisation (CRO) to perform all 
monitoring functions within this clinical study. The monitors will work in accordance with the CRO 
SOPs and have the same rights and responsibilities as monitors from the Sponsor. Monitors will 
establish and maintain regular contact between the Investigator and the Sponsor. 
Monitors will evaluate the competence of each investigational site and inform the Sponsor about any 
problems relating to facilities, technical equipment or investigational site staff. During the study, 


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monitors will check that written informed consent has been obtained correctly from all subjects and that 
data are recorded correctly and completely. Monitors will also perform source data verification by 
comparing entries in the eCRF with corresponding source data and informing the Investigator of any 
errors or omissions. Monitors will verify adherence to the protocol at the investigational site. All PDs 
will be reported to the Sponsor via the monitoring visit reports. Monitors will arrange for the supply of 
IP and ensure appropriate storage conditions are maintained. 
Monitoring visits will be conducted at regular intervals according to ICH-GCP. The monitor will 
provide written reports to the Sponsor on each occasion they contact with the Investigator regardless of 
whether it is by phone or in person. 
Further details on the monitoring processes and the level of source data verification to be performed 
will be outlined in the monitoring plan. 
 Data Handling and Record Keeping 
The Investigator must maintain essential study documents (protocol and protocol amendments, 
completed eCRFs, signed ICFs and its revisions, relevant correspondence, and all other supporting 
documentation) until at least 2 years after the last approval of a marketing application in an ICH region 
and until there are no pending or contemplated marketing applications in an ICH region or at least 2 
years after the formal discontinuation of clinical development of the IP or 15 years from completion of 
the study. These documents should be retained for a longer period if required by the applicable 
regulatory requirements or the investigational sites, institution or private practice in which the study is 
being conducted. Subject identification codes (subject names and corresponding study numbers) will 
be retained for the same period of time. These documents may be transferred to another responsible 
party, deemed acceptable by the Sponsor, and who agrees to abide by the retention policies. Written 
notification of transfer must be submitted to the Sponsor. The Investigator must contact the Sponsor 
prior to disposing of any study records and obtain written permission to do so. 
 Future Use of Stored Specimens and Data 
The Sponsor or designated representative can store PK, immunogenicity, PD, and/or pharmacogenetic 
samples for maximum 15 years after the end of the clinical study. The Sponsor or designated 
representative should operate under the same regulations related to and take the same responsibility to 
save personal data. The sample may be used for additional assay to be performed if considered scientific 
relevant or requested by regulatory authorities in order to have the possibility to perform the assay. 
 Database Management and Coding 
Data generated within this clinical study will be handled according to the relevant SOPs of the data 
management and biostatistics departments of the Sponsor (or an appropriate company designated by 
the Sponsor to perform these activities). Subject data will be captured in an eCRF and reviewed by the 
monitor in order to check adherence to the protocol and to detect any data inconsistency or discrepancy.  
The Investigator must ensure that the clinical data required by the study protocol are carefully reported 
in the eCRF. He/she must also check that the data reported in the eCRF correspond to those in the 
medical records. 
Data must be entered into eCRFs in English by the designated investigational site staffs in a timely 
manner. Forms should be available during periodic visits by study monitors to enable review for 
completeness and acceptability. Any correction to the data entered into the eCRF must be carried out 
by the Investigator or a designated investigational site staffs. These changes may be made either on the 
initiative of the investigational site staffs or in response to monitoring or data queries. Any changes to 


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written data must be made using ICH-GCP corrections and any change to electronic data should be 
made in a system which can provide an audit trail. Monitors and clinical data managers will review the 
eCRF for accuracy and can generate queries to the investigational site staffs for resolution. Corrections 
will be recorded in an audit trail that records the original information, the corrected information, and 
identification of the person making the changes, date of correction made and reason for change. The 
Investigator must sign and date the eCRF pages as indicated. 
Medical/surgical history and underlying diseases and AEs will be coded using the MedDRA®. 
Concomitant medications will be coded using the World Health Organization-Drug Dictionary 
Enhanced (WHO-DDE). The versions of coding dictionaries used will be stated in the CSR. 
 Quality Control and Quality Assurance 
During the conduct of the study, the Sponsor or its agent will conduct periodic monitoring visits to 
ensure that the protocol and ICH-GCP are being followed. The monitors may review source documents 
to confirm that the data recorded are accurate. The Investigator and institution will allow the domestic 
and foreign regulatory authorities, the Sponsor’s monitors and auditors’ direct access to source 
documents to perform this verification. The investigational site may be subject to review by the 
IRB/IEC, and/or to quality assurance audits performed by the Sponsor, and/or to inspection by 
appropriate regulatory authorities. It is important that the Investigators and their relevant personnel are 
available during the monitoring visit, possible audits and/or regulatory inspection(s) and that sufficient 
time is devoted to the process. 
 Protocol Deviation 
PDs will be pre-defined prior to subject enrolment and documented separately named as “protocol 
deviation definition list” which includes category (e.g., violation of inclusion/exclusion criteria, use of 
prohibited medication, non-compliance with treatment), deviation description, severity (major or 
minor), time point for PDs. Major PDs are defined as those deviations from the protocol likely to have 
an impact on the perceived efficacy and/or safety of study treatments.  
PDs will be reviewed and confirmed prior to database lock to decide which subjects and/or subject data 
will be excluded from certain analyses. Decisions regarding the exclusion of subjects and/or subject 
data from analyses will be documented and approved prior to database lock . 
11. Ethics Considerations and Administrative Procedures 
 Institutional Review Boards and Independent Ethics Committees 
The Investigator and the Sponsor will follow all local laws and regulations relating to contact with and 
approvals from the IRB/IEC. 
The Investigator must provide the Sponsor with documentation of IRB/IEC approval of the protocol 
and informed consent before the study may begin at the investigational site. The Investigator will supply 
documentation to the Sponsor relating to the annual renewal of the protocol from the IRB/IEC and any 
approvals of revisions to the ICF or amendments to the protocol. 
The Investigator will report promptly to the IRB/IEC any new information that may adversely affect 
the safety of subjects or the conduct of the study. Similarly, the Investigator will submit written 
summaries of the study status to the IRB/IEC on a regular basis and in accordance with the timelines 
required locally. Upon completion of the study, the Investigator will provide the ethics committee with 
a report on the outcome of the study if required by local regulations.  


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 Ethical Conduct of the Study 
This study will be conducted and informed consent will be obtained from each subject according to the 
ethical principles stated in the Declaration of Helsinki (2013), the applicable guidelines for ICH-GCP 
and the applicable drug and data protection laws and regulations of the countries where the study will 
be conducted. 
 Written Informed Consent 
The written informed consent will be used to explain the risks and benefits of study participation to the 
subject in simple terms before the subject enters into the study. The ICF contains a statement that the 
consent is freely given, that the subject is aware of the risks and benefits of entering the study, and that 
the subject is free to withdraw from the study at any time. Written consent must be given by the subject 
and/or legal representative, after the receipt of detailed information on the study. 
The Investigator is responsible for ensuring that informed consent is obtained from each subject or legal 
representative and for obtaining the appropriate signatures and dates on the ICF prior to the performance 
of any protocol procedures and prior to the administration of IP. The Investigator will provide each 
subject with a copy of the signed and dated ICF and this will be documented on the subject’s source 
document. 
 Investigator Information 
11.4.1. Investigator Obligations 
This study will be conducted in accordance with the ICH-GCP, the ethical principles that have their 
origin in the Declaration of Helsinki (2013) and local laws and regulations. 
The Investigator is responsible for ensuring that the study is conducted according to the signed 
Investigator statement, the study protocol and applicable regulations; for protecting the rights, safety, 
and welfare of subjects under the Investigator’s care; and for the control of drugs under investigation. 
The Investigator must obtain the informed consent of each subject to whom IP is administered. 
11.4.2. Training of Investigational Site Personnel 
Before the first subject is enrolled into the study, the Sponsor representative will review and discuss the 
requirements of the clinical study protocol and related documents with the investigational site staff and 
will also train them in any study-specific procedures. 
The Investigator will ensure that appropriate training relevant to the study is given to all investigational 
site staff and that any new information relevant to the performance of this study is forwarded to the 
investigational site staff involved. 
The Investigator will maintain a record of all individuals involved in the study (medical, nursing, and 
other investigational site staff). 
11.4.3. Protocol Signatures 
The Investigator must sign the Investigator signature page of this protocol prior to starting recruitment 
for the study. By signing the protocol, the Investigator confirms in writing that he/she has read, 
understands and will strictly adhere to the study protocol and will conduct the study in accordance with 
ICH-GCP and applicable regulatory requirements. The study will not be able to start at any 
investigational site where the Investigator has not signed the protocol. 


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11.4.4. Financing and Insurance 
Samsung Bioepis is the Sponsor of this study and will be providing the finances to cover the operation 
of the study. Details of financial agreements are provided in the clinical trial agreement with the 
investigational sites and in contracts with other companies involved in the running of the study. 
The Sponsor has obtained suitable insurance for this study. A copy of the insurance details will be 
provided to each Investigator who will be responsible for providing the IRB/IEC with these details 
according to local requirements. 
12. Publication Policy 
The Sponsor supports the efforts of health authorities to increase the transparency of medical research 
conducted in human subjects. The Sponsor will register and maintain the information of clinical studies 
on a public registry program. The Sponsor is committed to the public disclosure of the results from 
clinical studies through posting on public clinical study data banks. The Sponsor will comply with the 
guidelines of regulatory authorities with regards to public registration and disclosure of clinical study 
data. 
 


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13. Extended Supply 
After completion of activities at Week 52, an open-label extended supply of SB12 will be provided for 
up to 2 calendar years starting from Week 52 to subjects who have benefited from study treatment and 
opt to participate in extended supply under an ethical basis. 
Before entering an extended supply, the Investigator will review the subject status including reduction 
of PNH disease activity, such as improvement of symptoms or laboratory parameters, during 
eculizumab treatment to decide if the subject will benefit from participation in extended supply. Once 
subjects are considered to benefit from extended supply, subjects will be asked if he/she would like to 
receive an extended supply. For receiving an extended supply, subjects should agree with signing ICF 
for extended supply and with required activities including refraining from pregnancy, maintaining a 
highly effective contraceptive method, and receiving meningococcal vaccination (if required by local 
regulations) to ensure subject's safety during extended supply. 
During extended supply, Investigators will treat subjects with 900 mg of SB12 every 14 ± 2 days for up 
to 2 years (104 weeks). SB12 will be packaged and labelled using open label and dispensed through the 
IWRS. Investigators should ensure the compliance and accountability of SB12 during the course of 
extended supply. Any PC must be reported to Sponsor.  
SAEs that occur during this phase must be reported to the Sponsor, which will be reported to regulatory 
authorities by the Sponsor according to local/national requirements via expedited reporting and periodic 
reporting such as Development Safety Update Report (DSUR) or Periodic Safety Update Report 
(PSUR). Pregnancy should also be reported until 5 months after the last SB12 treatment. Other 
particular activities will not be imposed and no data collection or reporting will occur for extended 
supply.  
Discontinuation of study treatment can be decided if unacceptable toxicity, pregnancy, other 
complement inhibitor use or lack of efficacy occurs, or at the discretion of the Investigator or by 
subject’s consent withdrawal. Specific study procedures are not required for subjects who have 
discontinued prematurely except for SAEs reporting and pregnancy reporting.   
 
During the period of extended supply, the Investigator and the Sponsor will follow all local laws and 
regulations relating to contact with and approvals from the IRB/IEC. The Investigator is responsible for 
ensuring that the study is conducted according to the signed Investigator statement, the study protocol 
and applicable regulations; for protecting the rights, safety, and welfare of subjects under the 
Investigator’s care; and for the control of drugs under investigation.  
The Investigators must maintain essential study documents until at least 2 years after the last approval 
of a marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years after the formal discontinuation of clinical development 
of the IP or 15 years from completion of the extended supply, if applicable. 
Investigational sites participation may be discontinued if the Sponsor, Investigator or IRB/IEC consider 
necessary. Extended supply may be terminated by the Sponsor if medically or ethically indicated, and 
in such cases will be promptly notified to the Investigator. In any case, health authorities and IRB/IEC 
will be informed for the action in accordance with applicable regulations.  
 
 
 


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14. References 
[1] Hillmen P, Lewis S, Bessler M, et al. Natural history of paroxysmal nocturnal hemoglobinuria. N 
Engl J Med. 1995; 333 (19): 1253-8. 
[2] Moyo V, Mukhina G, Garrett E, et al. Natural history of paroxysmal nocturnal haemoglobinuria 
using modern diagnostic assays. Br J Haematol. 2004; 126 (1): 133-8. 
[3] Nishimura J, Kanakura Y, Ware R, et al. Clinical course and flow cytometric analysis of paroxysmal 
nocturnal hemoglobinuria in the United States and Japan. Medicine (Baltimore). 2004; 83 (3): 193-207. 
[4] Sharma V. Paroxysmal nocturnal hemoglobinuria: pathogenesis, testing, and diagnosis. Clin Adv 
Hematol Oncol. 2013; 11 Suppl 13 (9): 2-8. 
[5] Parker C, Omine M, Richards S, et al. Diagnosis and management of paroxysmal nocturnal 
hemoglobinuria. Blood. 2005; 106 (12): 3699-709. 
[6] Hartmann R, Jenkins D, Mckee L, et al. Paroxysmal nocturnal hemoglobinuria: clinical and 
laboratory studies relating to iron metabolism and therapy with androgen and iron. Medicine 
(Baltimore). 1966; 45 (5): 331-63. 
[7] Hill A, Hillmen P, Richards S, et al. Sustained response and long-term safety of eculizumab in 
paroxysmal nocturnal hemoglobinuria. Blood. 2005; 106 (7): 2559-65. 
[8] Hillmen P, Young N, Schubert J, et al. The complement inhibitor eculizumab in paroxysmal 
nocturnal hemoglobinuria. N Engl J Med. 2006; 355 (12): 1233-43. 
[9] Brodsky R, Young N, Antonioli E, et al. Multicenter phase 3 study of the complement inhibitor 
eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood. 2008; 111 
(4): 1840-7. 
[10] Soliris® EPAR – Product Information. EMA (Jul 01, 2020). Retrieved Jul 13, 2020 from  
https://www.ema.europa.eu/en/documents/product-information/soliris-epar-product-
information_en.pdf 
[11] Guideline on similar biological medicinal products monoclonal antibodies. EMA. (May 2012). 
EMA/CHMP/BMWP/403543/2010. Retrieved Jun 04, 2018 from 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC50012868
6.pdf 
[12] Rother RP, Bell L, Hillmen P, et al. The clinical sequelae of intravascular hemolysis and 
extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA. 2005; 293 (13): 1653-
62. 
[13] Hill A, Rother R, Wang X, et al. Effect of eculizumab on haemolysis‐associated nitric oxide 
depletion, dyspnoea, and measures of pulmonary hypertension in patients with paroxysmal nocturnal 
haemoglobinuria. Br J Haematol. 2010; 149 (3): 414-25. 
[14] Weitz I. Thrombosis in Paroxysmal Nocturnal Hemoglobinuria – insights into the role of 
complement in thrombosis. Thromb Res. 2010; 125 Suppl 2: S106-7.  
[15] Helley D, de Latour R, Porcher R, et al. Evaluation of hemostasis and endothelial function in 
patients with paroxysmal nocturnal hemoglobinuria receiving eculizumab. Haematologica. 2010; 95 
(4): 574-81.  
[16] Hillmen P, Muus P, Dührsen U, et al. Effect of the complement inhibitor eculizumab on 


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thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2007; 110 (12): 4123-8.  
[17] The Most Expensive Prescription Drugs in the World. Kathlyn Stone. (Updated Aug 26, 2018/Dec 
11, 2017/Apr 24, 2017). Retrieved Oct 04, 2018 from 
https://www.thebalance.com/the-8-most-expensive-prescription-drugs-in-the-world-2663232 
[18] Devalet B, Mullier F, Chatelain B, et al. Pathophysiology, diagnosis, and treatment of paroxysmal 
nocturnal hemoglobinuria: a review. Eur J Haematol. 2015; 95 (3): 190-8. 
[19] de Latour R, Mary J, Salanoubat C, et al. Paroxysmal nocturnal hemoglobinuria: natural history of 
disease subcategories. Blood. 2008; 112 (8): 3099-106. 
[20] Kato G, McGowan V, Machado R, et al. Lactate dehydrogenase as a biomarker of hemolysis-
associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in 
patients with sickle cell disease. Blood. 2006; 107 (6): 2279-85. 
[21] Soliris® Prescribing Information. FDA (Nov 20, 2020). Retrieved Nov 26, 2020 from  
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125166s434lbl.pdf 
 
 


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APPENDIX A. Paroxysmal Nocturnal Haemoglobinuria Symptoms Subject 
Questionnaire 
Following signs and symptoms are associated with PNH.  
If you have had the symptom in the past 7 days, please circle the number below that describe your 
severity for each sign or symptom.  
1) Fatigue 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
Severe 
2) Haemoglobinuria (discolouration of urine) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
Severe 
3) Chest pain 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
Severe 
4) Abdominal pain 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
Severe 
5) Dyspnoea (shortness of breath) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
Severe 
6) Dysphagia 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
Severe 
7) Erectile dysfunction (if applicable) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
 
 
 
 
 
 
 
 
 
Severe 
 
 






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SIGNATURE PAGE 
Declaration of the Principal Investigator 
Protocol Title: A Phase III Randomised, Double-blind, Multicentre Study to Compare the Efficacy, 
Safety, Pharmacokinetics, and Immunogenicity between SB12 (proposed eculizumab biosimilar) and 
Soliris® in Subjects with Paroxysmal Nocturnal Haemoglobinuria 
This clinical study protocol was subjected to critical review. The information it contains is consistent 
with current knowledge of the risks and benefits of the investigational medicinal product, as well as 
with the moral, ethical, and scientific principles governing clinical research as set out in the Declaration 
of Helsinki, 2013 and the guidelines on Good Clinical Practice applicable to this clinical study. 
 
Principal Investigator 
Name: 
 
Institution: 
 
Signature: 
 
Date: 
 
 
 
 
(MMM DD, YYYY) 
 
 


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CHANGE HISTORY OF PROTOCOL AMENDMENT 
Amendment 1: Version 2.0, Oct 08, 2018 
Section 
Affected 
Original Content 
Amended/New Content 
Rationale 
SYNOPSIS 
Exclusion 
Criteria 
4. Abnormal haematological parameters at Screening defined as 
the following: 
a. 
Absolute neutrophil count (ANC) ≤ 500/mm3 
b. Platelet count < 80,000/mm3 
4. Abnormal haematological parameters at Screening defined as 
the following: 
a. 
Absolute neutrophil count (ANC) ≤ 500/mm3 
b. Platelet count < 80,000 70,000/mm3 
To change platelet 
count criteria 
Figure 1 
 
To extend the 
period from 
randomisation to 
initiation of study 
drug taking 
account of IP 
shipment 
Figure 1 
Footnote 
a. 
Randomisation will trigger the shipping of study drugs to 
investigational site. The initiation of study drug should be 
done within 14 days of randomisation.  
a. 
Randomisation will trigger the shipping of study drugs to 
investigational site. The initiation of study drug should be 
done within 14 21 days of randomisation.  
To extend the 
period from 
randomisation to 
initiation of study 
drug taking 
account of IP 
shipment 
Table 1 
Assessments 
Study Period 
Study Visit 
Scree 
-ning 
Randomi 
-sation 
… 
Week 
… 
Day (± Visit Window) 
−56 to −15 
−14 to −1 
… 
 
Assessments 
Study Period 
Study Visit 
Scree 
-ning 
Randomi 
-sation 
… 
Week 
… 
Day (± Visit Window) 
−56 to −15 
−63 to −22 
−14 to −1 
−21 to −1 
… 
 
To extend the 
period from 
randomisation to 
initiation of study 
drug taking 
account of IP 


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Section 
Affected 
Original Content 
Amended/New Content 
Rationale 
shipment 
Table 1 
Footnote 
4.  All screening procedures must be completed and reviewed 
within 42 days prior to randomisation. All eligibility 
criteria must be reviewed and confirmed prior to 
randomisation. The initiation of study drug (Day 1) should 
be done within 14 days of randomisation. 
4.  All screening procedures must be completed and reviewed 
within 42 days prior to randomisation. All eligibility 
criteria must be reviewed and confirmed prior to 
randomisation. The initiation of study drug (Day 1) should 
be done within 14 21 days of randomisation. 
To extend the 
period from 
randomisation to 
initiation of study 
drug taking 
account of IP 
shipment 
Table 1 
Footnote 
8.  Both white blood cell (WBC) and red blood 
cell (RBC) clone size will be measured by 
flow cytometry prior to dosing at Screening, 
Day 1, and Week 52. (…) 
8.  Both white blood cell (WBC) and red blood 
cell (RBC) clone size will be measured by 
flow cytometry prior to dosing at 
Screening, and prior to dosing at Day 1, 
and Week 52. (…) 
To clarify the 
meaning because 
no dosing will be 
done at Screening 
Table 1 
Footnote 
11.  Parameters included in haematology test are 
WBC count, RBC count, haemoglobin, 
haematocrit, platelet count, differential WBC 
count, nucleated RBC, mean corpuscular 
haemoglobin (MCH), mean corpuscular 
haemoglobin concentration (MCHC), mean 
corpuscular volume (MCV), mean platelet 
volume (MPV), and red cell distribution 
width (RDW). (…) 
11.  Parameters included in haematology test are 
WBC count, RBC count, haemoglobin, 
haematocrit, platelet count, differential WBC 
count, and nucleated RBC, mean 
corpuscular haemoglobin (MCH), mean 
corpuscular haemoglobin concentration 
(MCHC), mean corpuscular volume 
(MCV), mean platelet volume (MPV), and 
red cell distribution width (RDW). (…) 
To remove several 
haematology test 
parameters 
Table 2 
Footnote 
5.  Both WBC and RBC clone size will be measured by flow 
cytometry prior to dosing at Screening, Day 1, and Week 
52. (…) 
5.  Both WBC and RBC clone size will be measured by flow 
cytometry prior to dosing at Screening, and prior to 
dosing at Day 1, and Week 52. (…) 
To clarify the 
meaning because 
no dosing will be 
done at Screening 
Table 2 
Footnote 
8.  Parameters included in haematology test are 
WBC count, RBC count, haemoglobin, 
haematocrit, platelet count, differential WBC 
8.  Parameters included in haematology test are 
WBC count, RBC count, haemoglobin, 
haematocrit, platelet count, differential WBC 
To remove several 
haematology test 
parameters 


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Section 
Affected 
Original Content 
Amended/New Content 
Rationale 
count, nucleated RBC, MCH, MCHC, MCV, 
MPV, and RDW. (…) 
count, and nucleated RBC, MCH, MCHC, 
MCV, MPV, and RDW. (…) 
LIST OF 
ABBREVIA
-TIONS 
MCH 
Mean corpuscular haemoglobin 
MCHC 
Mean corpuscular haemoglobin concentration 
MCV 
Mean corpuscular volume 
MPV 
Mean platelet volume 
RDW 
Red cell distribution width 
MCH 
Mean corpuscular haemoglobin 
MCHC 
Mean 
corpuscular 
haemoglobin 
concentration 
MCV 
Mean corpuscular volume 
MPV 
Mean platelet volume 
RDW 
Red cell distribution width 
To remove several 
haematology test 
parameters 
LIST OF 
STUDY 
STAFF 
Clinical 
Research 
Scientist 
 
 
Safety 
Physician 
 
 
 
 
Clinical 
Research 
Scientist 
 
 
 
 
Safety 
Physician 
 
 
 
 
Administrative 
change due to 
study staff change 
4.3. 
Exclusion 
Criteria 
4. Abnormal haematological parameters at Screening defined as 
the following: 
a. 
Absolute neutrophil count (ANC) ≤ 500/mm3 
b. Platelet count < 80,000/mm3 
4. Abnormal haematological parameters at Screening defined as 
the following: 
a. 
Absolute neutrophil count (ANC) ≤ 500/mm3 
b. Platelet count < 80,000 70,000/mm3 
To change platelet 
count criteria 
Table 4. 
Parameters 
for Clinical 
Laboratory 
Haematology 
WBC count 
RBC count 
Mean corpuscular 
haemoglobin 
(MCH) 
Haematology 
 
WBC count 
 
RBC count 
 
Mean 
corpuscular 
haemoglobin 
To remove several 
haematology test 
parameters 


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Section 
Affected 
Original Content 
Amended/New Content 
Rationale 
Tests 
Haemoglobin 
Haematocrit 
Platelet count 
Differential WBC 
count 
Nucleated RBC 
Mean corpuscular 
haemoglobin 
concentration 
(MCHC) 
Mean corpuscular 
volume (MCV) 
Mean platelet 
volume (MPV) 
Red cell distribution 
width (RDW) 
 
 
Haemoglobin 
 
Haematocrit 
 
Platelet count 
 
Differential 
WBC count 
 
Nucleated 
RBC 
(MCH) 
 
Mean 
corpuscular 
haemoglobin 
concentration 
(MCHC) 
 
Mean 
corpuscular 
volume (MCV) 
 
Mean platelet 
volume (MPV) 
 
Red cell 
distribution 
width (RDW) 
6.2.3. 
Physical 
Examination
s 
Physical examination including height and weight will be 
performed before IP administration at Screening and physical 
examination including weight at the visits specified in  
Table 1 and Table 2. (…) 
Physical examination including height and weight will be 
performed before IP administration at Screening and physical 
examination including weight before IP administration at the 
visits specified in  
Table 1 and Table 2. (…) 
To clarify the 
meaning because 
no dosing will be 
done at Screening 
7.1.1.1. 
Screening 
Visit (D−63 
to D−22) 
7.1.1.1.  Screening Visit (D−56 to D−15) 
7.1.1.1.  Screening Visit (D−56 D−63 to D−15 D−22) 
To extend the 
period from 
randomisation to 
initiation of study 
drug taking 
account of IP 
shipment 


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Section 
Affected 
Original Content 
Amended/New Content 
Rationale 
7.1.1.1. 
Screening 
Visit (D−63 
to D−22) 
 
Review of laboratory results  
- 
Haematology: Haemoglobin, haematocrit, RBC count, 
total WBC count including differential count, platelet 
count, nucleated RBC, MCH, MCHC, MCV, MPV, and 
RDW 
 
Review of laboratory results  
- 
Haematology: Haemoglobin, haematocrit, RBC count, 
total WBC count including differential count, platelet 
count, and nucleated RBC, MCH, MCHC, MCV, 
MPV, and RDW 
To remove several 
haematology test 
parameters 
7.1.1.1. 
Screening 
Visit (D−63 
to D−22) 
 
Review of laboratory results  
- 
Urinalysis: Protein, blood, leukocytes, nitrite, ketone, 
glucose, pH, specific gravity, bilirubin, urobilinogen, 
appearance, and colour (if urinalysis result is abnormal, 
urine microscopic examination will be performed) 
 
Review of laboratory results  
- 
Urinalysis: Protein, blood, leukocytes esterase, nitrite, 
ketone, glucose, pH, specific gravity, bilirubin, 
urobilinogen, appearance, and colour (if urinalysis result 
is abnormal, urine microscopic examination will be 
performed) 
To change 
urinalysis 
parameter to be 
consistent with 
Table 4 
7.1.1.1. 
Screening 
Visit (D−63 
to D−22) 
 
Review of laboratory results  
 
Review of laboratory results  
- 
Others: Ferritin, vitamin B12, and folate 
To add laboratory 
tests to be 
consistent with 
Table 1 
8.3.2. Other 
Systemic 
Infections 
SB12 or Soliris® blocks terminal complement activation; 
therefore subjects may have increased susceptibility to 
infections, especially with encapsulated bacteria. Additionally, 
aspergillus infections have occurred in immunocompromised 
and neutropenic patients. Subjects should immediately call the 
Investigator or seek emergency medical care, if subjects 
experience other systemic infections. 
SB12 or Soliris® blocks terminal complement activation; 
therefore subjects may have increased susceptibility to 
infections, especially with encapsulated bacteria. Serious 
infection with Neisseria species (other than Neisseria 
meningitidis), 
including 
disseminated 
gonococcal 
infections, have been reported after Soliris® treatment. 
Additionally, aspergillus infections have occurred in 
immunocompromised and neutropenic patients. Subjects 
should immediately call the Investigator or seek emergency 
medical care, if subjects experience other systemic infections. 
To add the updated 
safety information 
according to the 
latest version of 
regulatory 
document 
13. 
[17] The Most Expensive Prescription Drugs in the World. 
Kathlyn Stone. (Updated Dec 11, 2017/Apr 24, 2017). Retrieved 
[17] The Most Expensive Prescription Drugs in the World. 
Kathlyn Stone. (Updated Aug 26, 2018/Dec 11, 2017/Apr 24, 
To refer the latest 


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Original Content 
Amended/New Content 
Rationale 
References 
Mar 09, 2018 from 
https://www.thebalance.com/the-8-most-expensive-prescription-
drugs-in-the-world-2663232 
2017). Retrieved Mar 09, 2018 Oct 04, 2018 from 
https://www.thebalance.com/the-8-most-expensive-prescription-
drugs-in-the-world-2663232 
information 
13. 
References 
[21] Soliris® Prescribing Information. FDA (Feb 28, 2018). 
Retrieved Apr 25, 2018 from  
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125
166s426lbl.pdf 
[21] Soliris® Prescribing Information. FDA (Feb 28 Jul 25, 
2018). Retrieved Apr 25 Oct 04, 2018 from  
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/
125166s426lbl.pdf 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/
125166s047s048lbl.pdf 
To refer the latest 
version of 
regulatory 
document 
 
 


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Amendment 2: Version 3.0, Dec 12, 2018 
Section 
Affected 
Original Content 
Amended/New Content 
Rationale 
SYNOPSIS 
Exclusion 
Criteria 
N/A 
7. History of serious thrombotic event (e.g., stroke, 
myocardial infarction, pulmonary embolism, etc.) 
To add exclusion 
criteria 
SYNOPSIS 
Secondary 
Endpoints 
Immunogenicity endpoints  
• 
Incidence of anti-drug antibodies (ADAs) at Weeks 0 
(Day 1), 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 
44, 48, 52, and end of study (EOS) 
• 
Incidence of neutralising antibodies (NAbs) at Weeks 0 
(Day 1), 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 
44, 48, 52, and EOS 
Immunogenicity endpoints  
• 
Incidence of anti-drug antibodies (ADAs) at Weeks 0 
(Day 1), 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 
44, 48, 52, and end of study (EOS)/early termination 
(ET) 
• 
Incidence of neutralising antibodies (NAbs) at Weeks 0 
(Day 1), 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 
44, 48, 52, and EOS/ET 
To add time point 
to be consistent 
with Table 2 
SYNOPSIS 
Statistical 
Methods 
PK analyses 
PK analysis will be performed for the PK Analysis Set (PKS). 
Serum trough concentration will be summarised descriptively 
by treatment sequence, period, and time point. 
PK analyses 
PK analysis will be performed for the PK Analysis Set (PKS). 
Serum trough concentration Ctrough will be summarised 
descriptively by treatment sequence, period, and time point. 
To apply 
abbreviation 
Figure 1 
Footnote 
® = Randomisation; AUEC = Area under the Effect Curve; EOS 
= End of Study 
® = Randomisation; AUEC = Area under the Effect Curve; EOS 
= End of Study; PNH = Paroxysmal Nocturnal 
Haemoglobinuria; W = Week 
To add 
abbreviations 
2.2.2. 
Secondary 
Endpoints 
Immunogenicity endpoints  
• 
Incidence of anti-drug antibodies (ADAs) at Weeks 0 
(Day 1), 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 
44, 48, 52, and end of study (EOS) 
Immunogenicity endpoints  
• 
Incidence of anti-drug antibodies (ADAs) at Weeks 0 
(Day 1), 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 
44, 48, 52, and end of study (EOS)/early termination 
(ET) 
To add time point 
to be consistent 
with Table 2 


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• 
Incidence of neutralising antibodies (NAbs) at Weeks 0 
(Day 1), 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 
44, 48, 52, and EOS 
• 
Incidence of neutralising antibodies (NAbs) at Weeks 0 
(Day 1), 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 
44, 48, 52, and EOS/ET 
3.2.1. 
Scientific 
Rationale for 
Study 
Design 
(…) 
 for analysis of haemolysis reduction as 
measured by AUEC of LDH between two different time points in 
each period, the primary objective is to demonstrate comparable 
clinical efficacy of SB12 and Soliris® in terms of AUEC of LDH 
from Week 14 to Week 26 and from Week 40 to Week 52. 
, for analysis of haemolysis reduction as measured by 
the LDH level at single time point, the primary objective is to 
demonstrate comparable clinical efficacy of SB12 and Soliris® in 
terms of the LDH level (U/L) at Week 26. 
(…) 
, for 
analysis of haemolysis reduction as measured by AUEC of LDH 
between two different time points in each period, the primary 
objective is to demonstrate comparable clinical efficacy of SB12 
and Soliris® in terms of AUEC of LDH from Week 14 to Week 
26 and from Week 40 to Week 52. 
, for 
analysis of haemolysis reduction as measured by the LDH level 
at single time point, the primary objective is to demonstrate 
comparable clinical efficacy of SB12 and Soliris® in terms of 
the LDH level (U/L) at Week 26 
To add phrase to be 
consistent within 
the document 
4.3. 
Exclusion 
Criteria 
N/A 
7.  History of serious thrombotic event (e.g., stroke, 
myocardial infarction, pulmonary embolism, etc.) 
To add exclusion 
criteria 
5.1.1. 
Dosing and 
Treatment 
Schedule 
SB12 or Soliris® will be administered up to Week 52 (a total of 
29 administrations of IP) unless they are early discontinued 
from study treatment.  
 
600 mg every 7 ± 2 days for the first 4 weeks, followed 
by 
 
900 mg for the fifth dose 7 ± 2 days later, then 
 
900 mg every 14 ± 2 days thereafter 
SB12 or Soliris® will be administered up to Week 52 (a total of 
29 administrations of IP) unless they are early discontinued 
from study treatment.  
 
600 mg every 7 ± 2 days for the first 4 weeks, followed 
by 
 
900 mg for the fifth dose 7 ± 2 days later, then 
 
900 mg every 14 ± 2 days thereafter 
To clarify dosing 
and treatment 
schedule 


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In case a dosing is delayed, next dosing visit date should not be 
altered. 
The subject receiving SB12 or Soliris® therapy may require 
dose adjustment within the recommended 14 ± 2 days dosing 
schedule during the maintenance period (up to every 12 days) 
when it is deemed necessary at the discretion of the 
Investigator; e.g., two consecutive events of elevated LDH ≥ 2 
× ULN after prior LDH reduction to < 1.5 × ULN on treatment. 
(…) 
In case a dosing is delayed, next dosing visit date should not 
be altered.  
In case previous IP administration was out of window, next 
visit schedule should be adjusted to keep intervals of IP 
administration as indicated above.  
The subject receiving SB12 or Soliris® therapy may require 
dose adjustment within the recommended 14 ± 2 days dosing 
schedule during the maintenance period (up to every 12 days) 
when it is deemed necessary at the discretion of the 
Investigator; e.g., two consecutive events of elevated LDH ≥ 2 
× ULN combined with sign or symptom of intravascular 
haemolysis after prior LDH reduction to < 1.5 × ULN on 
treatment. 
(…) 
5.2.5. 
Treatment 
Compliance 
and 
Investigation
-al Product 
Accountabili
-ty 
(…) 
Unless otherwise notified, empty vials and vials with residual 
materials should be kept for inspection and accountability by the 
study monitor prior to their destruction or handled per local 
pharmacy SOP for clinical study drugs. All unused IPs should be 
returned to the Sponsor or designated vendor unless local 
destruction site is approved by the Sponsor. If destruction is 
authorised at the investigational site, the Investigator must ensure 
that the materials are destroyed in compliance with all applicable 
environmental regulations, institutional policies, and any 
instructions provided by the Sponsor. Destruction of the IPs must 
be adequately documented. 
(…) 
Unless otherwise notified, empty vials and vials with residual 
materials should be kept for inspection and accountability by the 
study monitor prior to their destruction or handled per local 
pharmacy SOP for clinical study drugs. All unused IPs should be 
returned to the Sponsor or designated vendor unless local 
destruction site is approved by the Sponsor. If destruction is 
authorised at the investigational site, the Investigator must ensure 
that the materials are destroyed in compliance with all applicable 
environmental regulations, institutional policies, and any 
instructions provided by the Sponsor. Destruction of the IPs must 
be adequately documented. 
In case of expanded access of SB12 to subjects, the 
To add IP 
accountability 
during additional 
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Investigator is responsible for maintaining the SB12 records 
which include information on amounts delivered, dispensed, 
and returned/destroyed; for ensuring proper storage 
conditions are maintained and documented including details 
of dates, quantities, batch numbers, expiry dates; ensuring 
the SB12 is only used as specified by the expanded access; for 
reconciling all SB12 received from the Sponsor. Further 
details will be provided in a guideline for expanded access. 
5.3. 
Concomitant 
Medication 
or Treatment 
All medication including both prescription and non-prescription 
drugs, and any procedures undertaken during the study period 
(from the study informed consent has been signed to EOS/early 
termination [ET] visit) should be recorded in the subject’s source 
documents and eCRF. (…) 
All medication including both prescription and non-prescription 
drugs, and any procedures undertaken during the study period 
(from the study informed consent has been signed to EOS/ early 
termination [ET] visit) should be recorded in the subject’s 
source documents and eCRF. (…) 
To apply 
abbreviation 
7.1.3. 
Treatment 
Period 
All procedures and assessments will be performed at the visits 
specified in  
Table 1 and Table 2. Samples for laboratory assessments will be 
collected before IP administration.  
(…) 
All procedures and assessments will be performed at the visits 
specified in  
Table 1 and Table 2. Samples for laboratory assessments will be 
collected before IP administration on same day or up to 2 days 
prior, unless otherwise specified.  
(…) 
To clarify the 
window for sample 
collection 
7.2.1. 
Subject 
Discontinuat
ion from 
Study 
Treatment 
(…) 
The Investigator should discuss with the medical monitor prior to 
discontinuing a subject’s study treatment in case of the following 
criteria, but not limited to: 
• 
Conditions or intercurrent illness that preclude 
compliance with the protocol in terms of their safety or 
well-being 
(…) 
The Investigator should discuss with the medical monitor prior to 
discontinuing a subject’s study treatment in case of the following 
criteria, but not limited to: 
• 
Conditions or intercurrent illness that preclude 
compliance with the protocol in terms of their safety or 
well-being 
To clarify the 
meaning of lack of 
subject’s 
compliance 


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• 
Lack of efficacy (e.g., C5 gene polymorphism) 
Note: If the LDH level is not changed after the initiation 
of study drug (lack of efficacy), the Investigator and 
medical monitor and/or Sponsor should discuss to 
determine how to manage this case including whether or 
not to perform pharmacogenetic analysis (C5 gene 
polymorphism). 
• 
Unacceptable toxicity 
• 
Lack of subject’s compliance (e.g., a subject who missed 
two consecutive doses, lost to follow-up) 
Note: Before a subject is deemed lost to follow-up, the 
Investigator or designee will make every effort to regain 
contact with the subject. 
• 
Investigator discretion or other reasons 
(…) 
• 
Lack of efficacy (e.g., C5 gene polymorphism) 
Note: If the LDH level is not changed after the initiation 
of study drug (lack of efficacy), the Investigator and 
medical monitor and/or Sponsor should discuss to 
determine how to manage this case including whether or 
not to perform pharmacogenetic analysis (C5 gene 
polymorphism). 
• 
Unacceptable toxicity 
• 
Lack of subject’s compliance (e.g., a subject who 
missed two consecutive doses, repeated delay in study 
treatment and lost to follow-up) 
Note: Before a subject is deemed lost to follow-up, the 
Investigator or designee will make every effort to regain 
contact with the subject. 
• 
Investigator discretion or other reasons 
(…) 
7.2.1. 
Subject 
Discontinuat
ion from 
Study 
Treatment 
Any subject who discontinues SB12 or Soliris® should be 
monitored for at least 8 weeks after last study drug to detect 
serious haemolysis and other reactions. If serious haemolysis 
occurs after SB12 or Soliris® discontinuation, consider the 
following procedures and/or treatments: 
• 
Blood transfusion (pRBCs) or exchange transfusion if 
the PNH RBCs are > 50% of the total RBCs by flow 
cytometry 
Any subject who discontinues SB12 or Soliris® should be 
monitored for at least 8 weeks after last study drug to detect 
serious haemolysis and other reactions. If serious haemolysis 
occurs after SB12 or Soliris® discontinuation, consider the 
following procedures and/or treatments: 
• 
Blood transfusion (pRBCs) or exchange transfusion if 
the PNH RBCs are > 50% of the total RBCs by flow 
cytometry 
To add the 
additional 
information for 
SB12 provision  


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Rationale 
• 
Anticoagulation 
• 
Corticosteroids 
• 
Complement inhibitors 
• 
Anticoagulation 
• 
Corticosteroids 
• 
Complement inhibitors 
According to the Investigator’s medical judgement, if 
complement inhibitor should be administered again due to 
serious haemolysis and other reactions which occur within 8 
weeks after completion of the study treatment with SB12 or 
Soliris®, the Investigator should discuss with Sponsor for an 
expanded access of SB12 to such subjects. Accordingly, the 
Sponsor will provide SB12 to those subjects as an expanded 
access up to 1 year period, where applicable, in accordance 
with relevant local regulations and/or law.  
8.1.2. Period 
of 
Observation 
for Adverse 
Events 
(…) 
However, SAEs that are considered to be related to the IP can 
be collected until 10.5 weeks from the last dose of study drug 
(five half-lives of the study drug). SAEs that occurred after 
EOS visit or ET visit and that are considered to be related to 
the IP must be reported to the Sponsor or its designated 
representative using the paper SAE report form at least within 
24 hours of the Investigator becoming aware of the event (see 
Section 8.2.2). Unresolved AEs during the study period should 
be followed up until the EOS and recorded in the eCRF. The 
Investigator should observe the AEs for appropriate medical 
care of the subject until AE resolution or stabilisation. 
(…) 
(…) 
However, SAEs must that are considered to be related to 
the IP can be collected until 10.5 weeks from the last dose of 
study drug (five half-lives of the study drug). SAEs that 
occurred after EOS visit or ET visit and that are considered 
to be related to the IP must be reported to the Sponsor or its 
designated representative using the paper SAE report form at 
least within 24 hours of the Investigator becoming aware of the 
event (see Section 8.2.2).  
Unresolved AEs during the study period should be followed up 
until the EOS and recorded in the eCRF. The Investigator 
should observe the AEs for appropriate medical care of the 
subject until AE resolution or stabilisation. 
(…) 
To expand the 
collection scope of 
SAE from serious 
adverse reaction to 
serious adverse 
event. 


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Section 
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8.1.3. 
Reporting 
Adverse 
Events 
(…) 
Each AE is to be assessed to determine if it meets the criteria of 
an SAE (see Section 8.2.1 for SAE definition). If an AE is 
classified as an SAE, it must be reported to the Sponsor, or its 
designated representative, promptly according to the timeline 
specified in Section 8.2.2. For an SAE, a diagnosis with a 
description of signs and symptoms as well as other supporting 
information that led to the diagnosis should be described in the 
SAE form provided by the Sponsor (see Section 8.2.2). 
Each AE is to be assessed to determine if it meets the criteria of 
an SAE (see Section 8.2.1 for SAE definition). If an AE is 
classified as an SAE, it must be reported to the Sponsor, or its 
designated representative, promptly according to the timeline 
specified in Section 8.2.2. For an SAE, a diagnosis with a 
description of signs and symptoms as well as other supporting 
information that led to the diagnosis should be described in the 
SAE form provided by the Sponsor (see Section 8.2.2). 
If the subject who received the additional SB12 provision 
according to Section 7.2.1 has an AE, it must be reported 
to the Sponsor or its designated representative using the 
paper AE report form. If the AE is classified as a SAE, it 
must be reported to Sponsor or its designated 
representative using the paper SAE report form at least 
within 24 hours of the Investigator becoming aware of the 
event (see Section 8.2.2). 
To add the safety 
reporting during 
additional SB12 
provision 
8.2.2. 
Reporting 
Serious 
Adverse 
Events 
SAEs that occurred at or before EOS visit or ET visit must be 
reported to the Sponsor or its designated representative via 
eCRF SAE report form at least within 24 hours of the 
Investigator becoming aware of the event. 
SAEs that occurred after EOS visit or ET visit and that are 
considered to be related to the IP must be reported to the 
Sponsor or its designated representative using the paper SAE 
report form at least within 24 hours of the Investigator 
becoming aware of the event. 
(…) 
SAEs must be collected until 10.5 weeks from the last dose 
of study drug (five half-lives of the study drug). 
SAEs that occurred at or before EOS visit or ET visit must be 
reported to the Sponsor or its designated representative via 
eCRF SAE report form at least within 24 hours of the 
Investigator becoming aware of the event. 
SAEs that occurred after EOS visit or ET visit and that are 
considered to be related to the IP must be reported to the 
Sponsor or its designated representative using the paper SAE 
report form at least within 24 hours of the Investigator 
becoming aware of the event. 
SAEs that occurred from the subject who received the 
To clarify the 
reporting period 
for SAEs and add 
the safety reporting 
during additional 
SB12 provision 


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Amended/New Content 
Rationale 
additional SB12 must be reported to the Sponsor or its 
designated representative using the paper SAE report form 
at least within 24 hours of the Investigator becoming aware 
of the event. 
(…) 
9.1. 
Statistical 
Hypotheses 
(…) 
, the treatment effect will be measured by 
AUEC of LDH between two different time points in each 
period, from Week 14 to Week 26 and from Week 40 to Week 
52. The equivalence will be declared if the 90% confidence 
interval (CI) of the ratio between treatment effects is entirely 
contained within the pre-defined equivalence margin of [0.77, 
1.29].  
, equivalence will be declared if the 95% 
CI of the difference between treatments in LDH level at Week 
26 is entirely contained within the pre-defined equivalence 
margin of [−1.2 × ULN, 1.2 × ULN] where ULN of LDH to be 
specified in the central laboratory specification for this study. 
(…) 
 
 for those who are in favour of the AUEC of 
LDH, the treatment effect will be measured by AUEC of LDH 
between two different time points in each period, from Week 14 
to Week 26 and from Week 40 to Week 52. The equivalence 
will be declared if the 90% confidence interval (CI) of the ratio 
between treatment effects is entirely contained within the pre-
defined equivalence margin of [0.77, 1.29].  
 for 
those who are in favour of the LDH level at a single time 
point, equivalence will be declared if the 95% CI of the 
difference between treatments in LDH level at Week 26 is 
entirely contained within the pre-defined equivalence margin of 
[−1.2 × ULN, 1.2 × ULN] where ULN of LDH to be specified 
in the central laboratory specification for this study.  
To add phrase to be 
consistent within 
the document 
9.5.3. 
Pharmacokin
-etic 
Analyses 
PK analysis will be performed for the PKS. Serum trough 
concentration will be summarised with descriptive statistics by 
treatment sequence, period, and time point. 
PK analysis will be performed for the PKS. Serum trough 
concentration Ctrough will be summarised descriptively by 
treatment sequence, period, and time point. 
To apply 
abbreviation 
13. 
[10] Soliris® EPAR – Product Information. EMA (Jan 18, 2018). 
Retrieved Apr 25, 2018 from  
[10] Soliris® EPAR – Product Information. EMA (Jan 18 Oct 24, 
2018). Retrieved Apr 25 Dec 11, 2018 from  
To refer the latest 
version of 


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Section 
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Original Content 
Amended/New Content 
Rationale 
References 
http://www.ema.europa.eu/docs/en_GB/document_library/EPA
R_-_Product_Information/human/000791/WC500054208.pdf 
 
http://www.ema.europa.eu/docs/en_GB/document_library/E
PAR_-
_Product_Information/human/000791/WC500054208.pdf 
https://www.ema.europa.eu/documents/product-
information/soliris-epar-product-information_en.pdf 
regulatory 
document 
All Sections 
N/A 
All sections were updated to follow consistent usage of 
punctuation. 
Administrative 
update irrelevant to 
study design and/or 
procedures 
 
 
 


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Amendment 3: Version 4.0, Nov 29, 2019 
Section 
Affected 
Original Content 
Amended/New Content 
Rationale 
SYNOPSIS 
Planned 
Study Period 
After Screening, the duration of study participation will be 60 
weeks per subject including 52-week treatment period and 8-
week post-treatment follow-up period. 
After Screening, the duration of study participation will be 60 
weeks per subject including 52-week randomised treatment 
period and 8-week post-treatment follow-up an extension 
period of up to 2 years. 
To reflect the 
changes due to 2-
year extension 
period 
SYNOPSIS 
Study 
Design 
This is a randomised Phase III, double-blind, multicentre, cross-
over study to compare the efficacy, safety, pharmacokinetics, and 
immunogenicity between SB12 and Soliris® in subjects with 
PNH. Subjects will be randomised in a 1:1 ratio to treatment 
sequence I (SB12 to Soliris®) or treatment sequence II (Soliris® 
to SB12). Subjects who are randomised to initially receive SB12 
will be switched to receive Soliris® and subjects who are 
randomised to initially receive Soliris® will be switched to 
receive SB12 at Week 26. 
This multicentre Phase III study is composed of the Main 
Part and Extension Part. 
The Main Part is a randomised Phase III, double-blind 
period, multicentre, cross-over study to compare the efficacy, 
safety, pharmacokinetics, and immunogenicity between SB12 
and Soliris® in subjects with PNH. The Extension Part is an 
open-label, single-arm, 2-year extension period to provide 
SB12 in subjects with PNH for an extended duration under 
an ethical basis. 
For the Main Part, subjects Subjects will be randomised in a 
1:1 ratio to treatment sequence I (SB12 to Soliris®) or treatment 
sequence II (Soliris® to SB12). Subjects who are randomised to 
initially receive SB12 will be switched to receive Soliris® and 
subjects who are randomised to initially receive Soliris® will be 
switched to receive SB12 at Week 26. End of the Main Part is 
defined as completion of pre-dose activities at Week 52. 
Subjects who complete the Main Part will enter the 
Extension Part. For the Extension Part, all subjects will 
receive SB12 for 2 years. 
To reflect the 
changes due to 2-
year extension 
period 
SYNOPSIS 
Inclusion 
Criteria 
3. 
Presence of the PNH white blood cell (WBC) clone ≥ 10% 
by high-sensitivity flow cytometry at Screening. 
3. 
Presence of the PNH white blood cell (WBC) clone, with a 
granulocyte or monocyte clone size of ≥ 10% by high-
sensitivity flow cytometry at Screening. 
To clarify the 
inclusion criteria 


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Rationale 
SYNOPSIS 
Exclusion 
Criteria 
4. Abnormal haematological parameters at Screening defined 
as the following: 
a. 
Absolute neutrophil count (ANC) ≤ 500/mm3 
b. Platelet count < 70,000/mm3 
4. Abnormal haematological parameters at Screening defined 
as the following: 
a. 
Absolute neutrophil count (ANC) ≤ 500/mm3 0.5 × 
103/µL 
b. 
Platelet count < 70,000/mm3 70 × 103/µL 
To change the unit 
of haematology 
parameters 
SYNOPSIS 
Exclusion 
Criteria 
6. History of bone marrow transplantation. 
6. History of bone marrow haematopoietic stem cell 
transplantation. 
To clarify the 
exculsion criteria 
SYNOPSIS 
Exclusion 
Criteria 
10. Concomitant use of any of the following medications is 
prohibited if the following conditions apply. 
b. Warfarin with an unstable international normalized ratio 
(INR) for at least 4 weeks prior to initiation of study 
drug (Day 1). 
10. Concomitant use of any of the following medications is 
prohibited if the following conditions apply. 
b. 
Warfarin with an unstable international normalized 
normalised ratio (INR) for at least 4 weeks prior to 
initiation of study drug (Day 1) at the discretion of the 
Investigator. 
To clarify the 
exculsion criteria 
SYNOPSIS 
Investigation
-al Products 
• 
Dose regimen: 600 mg every 7 days for the first 4 weeks 
(initial phase) and 900 mg for the fifth week, followed by 
900 mg every 14 ± 2 days until Week 52 (maintenance 
phase). 
• 
Dose regimen: 600 mg every 7 days for the first 4 weeks 
(initial phase) and 900 mg for the fifth week, followed by 
900 mg every 14 ± 2 days until Week 52, thereafter 
(maintenance phase).  
To reflect the 
changes due to 2-
year extension 
period 
SYNOPSIS 
Main 
Criteria for 
Evaluation 
Primary endpoints 
• 
LDH level (U/L) at Week 26  
• 
Area under the effect curve (AUEC) of LDH from Week 
14 to Week 26 and from Week 40 to Week 52 
Primary endpoints 
• 
LDH level (U/L) at Week 26  
• 
Area Time-adjusted area under the effect curve (AUEC) 
of LDH from Week 14 to Week 26 and from Week 40 to 
Week 52  
To clarify the 
primary endpoint 


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SYNOPSIS 
Main 
Criteria for 
Evaluation 
Secondary endpoints 
Efficacy endpoints 
• 
LDH profile over time 
• 
Number of units of pRBCs transfused throughout the 
study duration for each period 
Safety endpoints 
• 
Incidence of adverse events (AEs) and serious AEs 
(SAEs) 
• 
Incidence of infection-related AEs 
- 
Meningococcal infection 
- 
Other systemic infections 
• 
Incidence of infusion-related reactions (IRRs) 
(…) 
Immunogenicity endpoints  
• 
Incidence of anti-drug antibodies (ADAs) at Weeks 0 
(Day 1), 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 
44, 48, 52, and end of study (EOS)/early termination 
(ET) 
• 
Incidence of neutralising antibodies (NAbs) at Weeks 0 
(Day 1), 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 
44, 48, 52, and EOS/ET 
Secondary endpoints 
Efficacy endpoints 
• 
LDH profile over time during the Main Part 
• 
Number of units of pRBCs transfused throughout the 
study duration for each period during the Main 
Part 
Safety endpoints 
• 
Incidence of adverse events (AEs) and serious AEs 
(SAEs) 
• 
Incidence of serious AEs (SAEs) 
• 
Incidence of infection-related AEs 
- 
Meningococcal infection 
- 
Other systemic infections 
• 
Incidence of infusion-related reactions (IRRs) 
(…) 
During the Extension Part, only SAEs will be collected. 
Immunogenicity endpoints  
• 
Incidence of anti-drug antibodies (ADAs) at Weeks 0 
(Day 1), 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 
44, 48, 52, and end of study (EOS)/early termination 
(ET) 
• 
Incidence of neutralising antibodies (NAbs) at Weeks 0 
(Day 1), 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 
44, 48, 52, and EOS/ET 
To reflect the 
changes in 
secondary 
endpoints due to 2-
year extension 
period 


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SYNOPSIS 
Statistical 
Methods 
Efficacy analyses 
 
 
for those who are in favour of the AUEC of LDH, the primary 
efficacy analysis will be performed for the PPS-AUEC using a 
linear mixed model with treatment, subject, sequence, and 
period as fixed effects and, subject nested within sequence as a 
random effect. The analysis will be performed with loge-
transformed AUEC of LDH estimating the difference in least 
squares means and its 90% confidence interval (CI), and back 
transformation of those values will provide the ratio of 
geometric means and 90% CI. The equivalence will be declared 
if the two-sided 90% CI of the ratio of geometric means in 
AUEC of LDH between SB12 and Soliris® lies within the pre-
defined equivalence margin of [0.77, 1.29]. 
 
for those who are in favour of the LDH level 
at a single time point, the primary efficacy analysis will be 
performed for the PPS-single using a linear mixed model with 
treatment as a fixed effect. (…) 
(…) 
As a secondary efficacy endpoint, the number of units of 
pRBCs transfused will be analysed using Wilcoxon rank-sum 
test for each period. And mean LDH profile will be presented 
over time. 
Safety analyses 
Safety analyses will be performed for the Safety Set (SAF). 
Efficacy analyses 
 
 
for those who are in favour of the time-adjusted AUEC of 
LDH, the primary efficacy analysis will be performed for the 
PPS-AUEC using a linear mixed model with treatment, subject, 
sequence, and period, and gender as fixed effects, and subject 
nested within sequence as a random effect. The analysis will be 
performed with loge-transformed time-adjusted AUEC of LDH 
estimating the difference in least squares means and its 90% 
confidence interval (CI), and back transformation of those 
values will provide the ratio of geometric means and 90% CI. 
The equivalence will be declared if the two-sided 90% CI of the 
ratio of geometric means in time-adjusted AUEC of LDH 
between SB12 and Soliris® lies within the pre-defined 
equivalence margin of [0.77, 1.29]. 
 
 
or those who are in favour of the LDH level at a 
single time point, the primary efficacy analysis will be performed 
for the PPS-single using a linear mixed model with treatment, 
and gender as a fixed effect. (…) 
If normal range of LDH is gender specific, the 
smaller/smallest ULN will be used for the equivalence 
margin; otherwise ULN is not gender specific, unified ULN 
will be used for the equivalence margin. 
(…) 
To clarify the 
primary endpoint 
and efficacy/safety 
analysis 
To reflect the local 
amendment 
To reflect changes 
in the statistical 
methods due to 2-
year extension 
period 


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All reported terms for AEs will be coded using the latest version 
of Medical Dictionary for Regulatory Activities (MedDRA®). 
AEs will be collected and classified according to National 
Cancer Institute (NCI)-Common Terminology Criteria for 
Adverse Events (CTCAE) v5.0. 
All AE data will be summarised by count and percentage of 
subjects experiencing events by system organ class, preferred 
term, treatment sequence, and period. (…) 
Changes in vital signs and clinical laboratory parameters will be 
summarised descriptively by treatment sequence, period, and 
time point. (…) 
Immunogenicity analyses 
The immunogenicity analyses will be performed for the SAF. 
ADA and NAb results will be summarised with count and 
percentage by treatment sequence, period, and time point. The 
incidence of overall ADA will be summarised by treatment 
sequence and period. 
Sample size 
(…) 
For calculation of the equivalence margin for AUEC of LDH, 
mean and coefficient of variation (%CV) were referred from 
TRIUMPH study. The mean (%CV) of AUEC of LDH at Week 
26 is 81140.0 U/L × day (142.45%) and 429874.1 U/L × day 
(33.49%) for eculizumab and non-eculizumab arms, 
respectively.  
As a secondary efficacy endpoint, the number of units of 
pRBCs transfused during the Main Part will be analysed using 
Wilcoxon rank-sum test for each period. And mean LDH profile 
during the Main Part will be presented over time. 
Safety analyses 
Safety analyses will be performed for in the Safety Set (SAF) 
for the Main Part (SAF1) and Safety Set for the Extension 
Part (SAF2). 
All reported terms for AEs will be coded using the latest 
version of Medical Dictionary for Regulatory Activities 
(MedDRA®). AEs will be collected and classified according to 
National Cancer Institute (NCI)-Common Terminology Criteria 
for Adverse Events (CTCAE) v5.0.  
All AE data reported during the Main Part will be 
summarised by count and percentage of subjects experiencing 
events by system organ class, preferred term, treatment 
sequence, and period for the SAF1. (…) 
Changes in vital signs and clinical laboratory parameters will be 
summarised descriptively by treatment sequence, period, and 
time point for the SAF1. (…)  
All SAEs reported during the Extension Part will be 
summarised by count and percentage of subjects 
experiencing events by system organ class and preferred 
term for the SAF2. 
Immunogenicity analyses 


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From the results in the reference study, mean ratio of AUEC of 
LDH is estimated to be 0.19 with a 90% CI [0.1308, 0.2724]. 
The upper limit of the equivalence margin is calculated as 
 
 where it preserves at least 
 of 
eculizumab treatment effect over the placebo, but 
 
 the equivalence margin will be [0.77, 
1.29] for the comparison with the 90% CI of mean ratio of 
AUEC of LDH. 
(…) 
The immunogenicity analyses will be performed for the SAF 
SAF1. ADA and NAb results will be summarised with count 
and percentage by treatment sequence, period, and time point. 
The incidence of overall ADA will be summarised by treatment 
sequence and period. 
Sample size 
(…) 
For calculation of the equivalence margin for time-adjusted 
AUEC of LDH, mean and coefficient of variation (%CV) were 
referred from TRIUMPH study. The mean (%CV) of AUEC of 
LDH at Week 26 is 81140.0 U/L × day (142.45%) and 429874.1 
U/L × day (33.49%) for eculizumab and non-eculizumab arms, 
respectively.  
From the results in the reference study, mean ratio of AUEC of 
LDH is estimated to be 0.19 with a 90% CI [0.1308, 0.2724]. 
The upper limit of the equivalence margin is calculated as 
 
where it preserves at least 
 of 
eculizumab treatment effect over the placebo, but 
 
 the equivalence margin will be [0.77, 
1.29] for the comparison with the 90% CI of mean ratio of 
time-adjusted AUEC of LDH. 
(…) 


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Figure 1 
 
 
To reflect the 
changes due to 2-
year extension 
period 
Figure 1 
Footnote 
® = Randomisation; AUEC = Area under the Effect Curve; EOS 
= End of Study; PNH = Paroxysmal Nocturnal 
Haemoglobinuria; W = Week 
 
c. 
From Week 4, 900 mg of SB12 or Soliris® every 14 ± 2 
days up to Week 52 
(…) 
f. 
EOS visit is defined as 8 weeks after the last dose of SB12 
or Soliris®. 
® = Randomisation; AUEC = Area under the Effect Curve; EOS 
= End of Study; n = No. of Subjects; PNH = Paroxysmal 
Nocturnal Haemoglobinuria; W = Week 
 
c. 
From Week 4, 900 mg of SB12 or Soliris® every 14 ± 2 
days up to Week 52 50. During the Extension Part, SB12 
will be given to all subjects. 
(…) 
f. 
EOS visit Completion of pre-dose activities at Week 52 
is defined as end of the Main Part 8 weeks after the last 
dose of SB12 or Soliris®. 
g. 
EOS is defined as the date of last subject’s last visit in 
the Extension Part. 
To add 
abbreviations 
To reflect the 
changes due to 2-
year extension 
period 
Table 1 
Table 1. Schedule of Activities (Period 1, before Cross-over) 
Table 1. Schedule of Activities (Main Part: Period 1, before 
Cross-over) 
To reflect the 
changes due to 2-
year extension 
period 
Table 1 
Footnote 
4.  All screening procedures must be completed 
and reviewed within 42 days prior to 
randomisation. All eligibility criteria must be 
reviewed and confirmed prior to 
randomisation. The initiation of study drug 
(Day 1) should be done within 21 days of 
randomisation.  
4.  All screening procedures must be completed 
and reviewed within 42 days prior to 
randomisation. All eligibility criteria not 
dependent on Day 1 must be reviewed and 
confirmed prior to randomisation. The 
initiation of study drug (Day 1) should be 
done within 21 days of randomisation. 
Eligibility criteria that are dependent on 
To clarify the 
randomisation 
process including 
eligibility 
confirmation 
process 


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Day 1 should be checked at Day 1 and if 
found in violation then should be 
withdrawn according to discontinuation 
criteria.  
Table 1 
Footnote 
7.  Females of childbearing potential only. 
Serum pregnancy test at Screening and EOS 
(or 8 weeks after the last dose of study drug 
in case of early termination [ET]); urine 
pregnancy test at other applicable visits. 
7.  Females of childbearing potential only. 
Serum pregnancy test at Screening and EOS 
(or 8 weeks after the last dose of study drug 
in case of early termination [ET]) (ET) 
during the Main Part; urine pregnancy test 
at other applicable visits before study drug 
administration. 
To reflect the 
changes due to 2-
year extension 
period and clarify 
the timeframe 
Table 1 
Footnote 
10.  LDH will be measured at pre-dose on each 
visit and will also be measured throughout 
the study period if the suspected sign or 
symptom of breakthrough haemolysis 
occurs .  
10.  LDH will be measured at pre-dose on each 
visit and will also be measured throughout 
the study period if the suspected sign or 
symptom of breakthrough haemolysis 
occurs.  
To reflect the 
changes due to 2-
year extension 
period 
Table 1 
Footnote 
11.  Parameters included in haematology test are WBC count, 
RBC count, haemoglobin, haematocrit, platelet count, 
differential WBC count, and nucleated RBC. (…) 
11.  Parameters included in haematology test are 
WBC count, RBC count, haemoglobin, 
haematocrit, platelet count, differential WBC 
count, and nucleated RBC, mean 
corpuscular haemoglobin (MCH), mean 
corpuscular haemoglobin concentration 
(MCHC), mean corpuscular volume 
(MCV), mean platelet volume (MPV), and 
red cell distribution width (RDW). (…) 
To add several 
haematology 
parameters 
Table 1 
Footnote 
12.  Blood sample for PK analysis will be taken prior to dosing 
at Weeks 0, 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 
44, 48, and 52. Blood samples should be collected at the 
same day of study drug administration. If the 
administration of IPs is delayed for any reasons after pre-
dose blood sampling for PK analysis, blood sample should 
be re-collected on actual dosing day and be used for 
analysis. PK samples will also be collected throughout the 
12.  Blood sample for PK analysis will be taken 
prior to dosing at Weeks 0, 2, 4, 6, 10, 14, 
18, 22, 26, 28, 30, 32, 36, 40, 44, 48, and 52. 
Blood samples should be collected at the 
same day of study drug administration. If the 
administration of IPs is delayed for any 
reasons after pre-dose blood sampling for 
PK analysis, blood sample should be re-
collected on actual dosing day and be used 
To reflect the 
changes due to 2-
year extension 
period 


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study period if the suspected sign or symptom of 
breakthrough haemolysis occurs. 
for analysis. PK samples will also be 
collected throughout the study period if 
the suspected sign or symptom of 
breakthrough haemolysis occurs. 
Table 1 
Footnote 
13.  Blood sample for PD (terminal complement activity) 
analysis will be taken prior to dosing at Weeks 0, 2, 4, 6, 
10, 14, 26, 28, 30, 32, 36, 40, and 52. Blood samples 
should be collected at the same day of study drug 
administration. If the administration of IPs is delayed for 
any reasons after pre-dose blood sampling for PD analysis, 
blood sample should be re-collected on actual dosing day 
and be used for analysis. PD samples will also be collected 
throughout the study period if the suspected sign or 
symptom of breakthrough haemolysis occurs. 
13.  Blood sample for PD (terminal complement 
activity) analysis will be taken prior to 
dosing at Weeks 0, 2, 4, 6, 10, 14, 26, 28, 30, 
32, 36, 40, and 52. Blood samples should be 
collected at the same day of study drug 
administration. If the administration of IPs is 
delayed for any reasons after pre-dose blood 
sampling for PD analysis, blood sample 
should be re-collected on actual dosing day 
and be used for analysis. PD samples will 
also be collected throughout the study 
period if the suspected sign or symptom of 
breakthrough haemolysis occurs. 
To reflect the 
changes due to 2-
year extension 
period 
Table 1 
Footnote 
14.  Blood sample for immunogenicity assay will be taken prior 
to dosing at Weeks 0, 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 
36, 40, 44, 48, 52, and EOS/ET. Blood samples should be 
collected at the same day of study drug administration 
except for EOS/ET. If the administration of IPs is delayed 
for any reasons after pre-dose blood sampling for 
immunogenicity assay, blood sample should be re-
collected on actual dosing day and be used for analysis. 
14.  Blood sample for immunogenicity assay will 
be taken prior to dosing at Weeks 0, 2, 4, 6, 
10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 44, 48, 
52, and EOS/ET. Blood samples should be 
collected at the same day of study drug 
administration except for EOS/ET visit. If 
the administration of IPs is delayed for any 
reasons after pre-dose blood sampling for 
immunogenicity assay, blood sample should 
be re-collected on actual dosing day and be 
used for analysis. 
To reflect the 
changes due to 2-
year extension 
period 
Table 1 
Footnote 
19.  Adverse events (AEs) will be collected from 
the time of signing the informed consent 
until EOS (or 8 weeks after the last dose of 
study drug in case of ET). 
19.  Adverse events (AEs) will be collected from 
the time of signing the informed consent 
until EOS end of the Main Part (or 8 weeks 
after the last dose of study drug in case of 
ET during the Main Part). 
To reflect the 
changes due to 2-
year extension 
period 


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Table 1 
Footnote 
20.  Previous medications (within 4 weeks prior to Screening 
except immunosuppressant, 8 weeks prior to Screening for 
immunosuppressant) will be recorded and concomitant 
medications will be recorded throughout the study period.  
20.  Previous medications (within 4 weeks prior 
to Screening except immunosuppressant, 8 
weeks prior to Screening for 
immunosuppressant) will be recorded and 
concomitant medications will be recorded 
throughout the study period until end of 
the Main Part (or 8 weeks after the last 
dose of study drug in case of ET during 
the Main Part).  
To reflect the 
changes due to 2-
year extension 
period 
Table 1 
Footnote 
21.  Transfusion record will be collected from the time of 
signing the informed consent until EOS (or 8 weeks after 
the last dose of study drug in case of ET). 
21.  Transfusion record will be collected from the time of 
signing the informed consent until EOS end of the Main 
Part (or 8 weeks after the last dose of study drug in case of 
ET during the Main Part). 
To reflect the 
changes due to 2-
year extension 
period 
Table 2 
Table 2. Schedule of Activities (Period 2 and EOS/ET, after 
Cross-over) 
Table 2. Schedule of Activities (Main Part: Period 2 and 
EOS/ET, after Cross-over) 
To reflect the 
changes due to 2-
year extension 
period 
Table 2 
Assessments 
Study Period 
Study Visit 
29 
EOS/ET20 
Week 
52 
60 
Day (± Visit Window) 
365 
(±2) 
421 (±7) 
IP administration15 
 
 
 
Assessments 
Study Period 
Study Visit 
29 
EOS/ET20 ET21 
Week 
5220 
60 
8 (±1) weeks after the 
last dose of study drug 
Day (± Visit Window) 
365 
(±2) 
421 (±7) 
IP administration15 
 
 
To reflect the 
changes due to 2-
year extension 
period 
Table 2 
Footnote 
EOS = End of Study; 
EOS = End of Study; 
To reflect the 
changes due to 2-
year extension 
period 


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Table 2 
Footnote 
4.  Females of childbearing potential only. 
Serum pregnancy test at Screening and EOS 
(or 8 weeks after the last dose of study drug 
in case of ET); urine pregnancy test at other 
applicable visits. 
4.  Females of childbearing potential only. 
Serum pregnancy test at Screening and EOS 
(or 8 weeks after the last dose of study drug 
in case of ET) during the Main Part; urine 
pregnancy test at other applicable visits 
before study drug administration. 
To reflect the 
changes due to 2-
year extension 
period and clarify 
the timeframe 
Table 2 
Footnote 
7.  LDH will be measured at pre-dose on each 
visit and will also be measured throughout 
the study period if the suspected sign or 
symptom of breakthrough haemolysis 
occurs .  
7.  LDH will be measured at pre-dose on each 
visit and will also be measured throughout 
the study period if the suspected sign or 
symptom of breakthrough haemolysis 
occurs.  
To reflect the 
changes due to 2-
year extension 
period 
Table 2 
Footnote 
8.  Parameters included in haematology test are WBC count, 
RBC count, haemoglobin, haematocrit, platelet count, 
differential WBC count, and nucleated RBC. (…) 
8.  Parameters included in haematology test are 
WBC count, RBC count, haemoglobin, 
haematocrit, platelet count, differential WBC 
count, and nucleated RBC, MCH, MCHC, 
MCV, MPV, and RDW. (…) 
To add several 
haematology 
parameters 
Table 2 
Footnote 
9.  Blood sample for PK analysis will be taken prior to dosing 
at Weeks 0, 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 
44, 48, and 52. Blood samples should be collected at the 
same day of study drug administration. If the 
administration of IPs is delayed for any reasons after pre-
dose blood sampling for PK analysis, blood sample should 
be re-collected on actual dosing day and be used for 
analysis. PK samples will also be collected throughout the 
study period if the suspected sign or symptom of 
breakthrough haemolysis occurs. 
9.  Blood sample for PK analysis will be taken 
prior to dosing at Weeks 0, 2, 4, 6, 10, 14, 
18, 22, 26, 28, 30, 32, 36, 40, 44, 48, and 52. 
Blood samples should be collected at the 
same day of study drug administration. If the 
administration of IPs is delayed for any 
reasons after pre-dose blood sampling for 
PK analysis, blood sample should be re-
collected on actual dosing day and be used 
for analysis. PK samples will also be 
collected throughout the study period if 
the suspected sign or symptom of 
breakthrough haemolysis occurs. 
To reflect the 
changes due to 2-
year extension 
period 
 
Table 2 
Footnote 
10.  Blood sample for PD (terminal complement activity) 
analysis will be taken prior to dosing at Weeks 0, 2, 4, 6, 
10, 14, 26, 28, 30, 32, 36, 40, and 52. Blood samples 
should be collected at the same day of study drug 
administration. If the administration of IPs is delayed for 
10.  Blood sample for PD (terminal complement 
activity) analysis will be taken prior to 
dosing at Weeks 0, 2, 4, 6, 10, 14, 26, 28, 30, 
32, 36, 40, and 52. Blood samples should be 
collected at the same day of study drug 
To reflect the 
changes due to 2-
year extension 
period 


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any reasons after pre-dose blood sampling for PD analysis, 
blood sample should be re-collected on actual dosing day 
and be used for analysis. PD samples will also be collected 
throughout the study period if the suspected sign or 
symptom of breakthrough haemolysis occurs. 
administration. If the administration of IPs is 
delayed for any reasons after pre-dose blood 
sampling for PD analysis, blood sample 
should be re-collected on actual dosing day 
and be used for analysis. PD samples will 
also be collected throughout the study 
period if the suspected sign or symptom of 
breakthrough haemolysis occurs. 
Table 2 
Footnote 
11.  Blood sample for immunogenicity assay will be taken prior 
to dosing at Weeks 0, 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 
36, 40, 44, 48, 52, and EOS/ET. Blood samples should be 
collected at the same day of study drug administration 
except for EOS/ET. If the administration of IPs is delayed 
for any reasons after pre-dose blood sampling for 
immunogenicity assay, blood sample should be re-
collected on actual dosing day and be used for analysis. 
11.  Blood sample for immunogenicity assay will 
be taken prior to dosing at Weeks 0, 2, 4, 6, 
10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 44, 48, 
52, and EOS/ET. Blood samples should be 
collected at the same day of study drug 
administration except for EOS/ET visit. If 
the administration of IPs is delayed for any 
reasons after pre-dose blood sampling for 
immunogenicity assay, blood sample should 
be re-collected on actual dosing day and be 
used for analysis. 
To reflect the 
changes due to 2-
year extension 
period 
Table 2 
Footnote 
17.  Adverse events (AEs) will be collected from 
the time of signing the informed consent 
until EOS (or 8 weeks after the last dose of 
study drug in case of ET). 
17.  Adverse events (AEs) will be collected from 
the time of signing the informed consent 
until EOS end of the Main Part (or 8 weeks 
after the last dose of study drug in case of 
ET during the Main Part). 
To reflect the 
changes due to 2-
year extension 
period 
Table 2 
Footnote 
18.  Concomitant medications will be recorded throughout the 
study period.  
18.  Concomitant medications will be recorded 
throughout the study period until end of 
the Main Part (or 8 weeks after the last 
dose of study drug in case of ET during 
the Main Part).  
To reflect the 
changes due to 2-
year extension 
period 
Table 2 
Footnote 
19.  Transfusion record will be collected from the time of 
signing the informed consent until EOS (or 8 weeks after 
the last dose of study drug in case of ET). 
19.  Transfusion record will be collected from the time of 
signing the informed consent until EOS end of the Main 
Part (or 8 weeks after the last dose of study drug in case of 
ET during the Main Part). 
To reflect the 
changes due to 2-
year extension 
period 


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Table 2 
Footnote 
20.  EOS visit or ET visit is defined as 8 weeks after the last 
dose of SB12 or Soliris®. 
20.  EOS visit or ET visit is defined as 8 weeks 
after the last dose of SB12 or Soliris® 
End of the Main Part is defined as 
completion of pre-dose activities at Week 
52. 
To reflect the 
changes due to 2-
year extension 
period 
Table 2 
Footnote 
N/A 
21.  ET visit is defined as 8 weeks after the last dose of SB12 
or Soliris®, which may be up to Week 58. 
To reflect the 
changes due to 2-
year extension 
period 
Table 3 
N/A 
 
To reflect the 
changes due to 2-
year extension 
period  
Table 3 
Footnote 
N/A 
1.  From Week 52, SB12 will be administered bi-weekly via 
IV infusion for 35 ± 10 minutes for all subjects. 
2.  Only SAEs will be collected during the Extension Part 
from start of study treatment at Week 52. 
3.  End of the Extension Part is defined as 8 weeks after 
the last dose of SB12. Prematurely discontinued 
subjects do not require any specific study procedures as 
done in the Main Part.  
To reflect the 
changes due to 2-
year extension 
period 
LIST OF 
ABBREVIA
-TIONS 
IB 
Investigators’ Brochure 
INR 
International normalized ratio 
N/A 
N/A 
SAF 
Safety Set 
IB 
Investigators’ Investigator’s Brochure 
INR 
International normalized normalised ratio 
MCH 
Mean corpuscular haemoglobin 
MCHC 
Mean 
corpuscular 
haemoglobin 
concentration 
MCV 
Mean corpuscular volume 
To revise/add 
abbreviations 
according to 
updated contents 


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MFDS 
Ministry of Food and Drug Safety 
MPV 
Mean platelet volume 
NMOSD 
Neuromyelitis optica spectrum disorder 
RDW 
Red cell distribution width 
SAF1 
Safety Set for the Main Part 
SAF2 
Safety Set for the Extension Part 
LIST OF 
STUDY 
STAFF 
Sponsor: 
Samsung Bioepis Co., Ltd. 
107, Cheomdan-daero, Yeonsu-gu, 
Incheon, 21987 
Republic of Korea 
Tel: +82 (32) 455 3114 
Fax: +82 (32) 455 6799 
Clinical 
Development 
Lead 
 
 
 
Statistician 
 
 
 
 
Sponsor: 
Samsung Bioepis Co., Ltd. 
107, Cheomdan-daero, Yeonsu-gu, 
Incheon, 21987 
Republic of Korea 
Tel: +82 (32) 455 6114 3114 
Fax: +82 (32) 455 6799 
Clinical 
Development 
Lead 
 
  
 
 
Statistician 
 
 
 
 
Administrative 
change  
1.1. 
Paroxysmal 
Nocturnal 
Haemoglobi-
(…)  
Soliris® (eculizumab, Alexion Pharmaceuticals, Inc.) is a 
humanised monoclonal antibody that blocks terminal 
(…)  
Soliris® (eculizumab, Alexion Pharmaceuticals, Inc.) is a 
humanised monoclonal antibody that blocks terminal 
To refer the latest 
information 


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nuria 
complement by binding to C5 and is the only approved therapy 
for PNH. 
complement by binding to C5 and is the only approved therapy 
for PNH. 
1.2. 
Overview of 
SB12 
SB12 has been developed as a similar biological medicinal 
product to Soliris® (eculizumab, Alexion Pharmaceuticals, Inc.). 
Soliris® is currently indicated for the treatment of patients with 
PNH, atypical haemolytic uremic syndrome (aHUS), and 
refractory generalised myasthenia gravis (gMG) [10]. (…) 
SB12 has been developed as a similar biological medicinal 
product to Soliris® (eculizumab, Alexion Pharmaceuticals, Inc.). 
Soliris® is currently indicated for the treatment of patients with 
PNH, atypical haemolytic uremic syndrome (aHUS), and 
refractory generalised myasthenia gravis (gMG), and 
neuromyelitis optica spectrum disorder (NMOSD) [10; 21]. 
(…) 
To refer the latest 
version of 
regulatory 
document 
1.2.2. 
Clinical 
Pharmacolog
-y of SB12 
As clinical studies using SB12 have not been conducted up to 
date, clinical data is currently not available. Based on 
biosimilarity between SB12 and Soliris®, which was 
demonstrated through extensive quality and non-clinical 
similarity exercise, a Phase I study will be conducted in healthy 
subjects to compare the pharmacokinetic (PK), safety, 
tolerability, immunogenicity, and pharmacodynamic (PD) 
profiles and a Phase III study will be conducted in subjects with 
PNH to compare the efficacy, safety, pharmacokinetics, and 
immunogenicity of SB12 to Soliris®. Information on the safety 
of SB12 based on the product information of Soliris® and non-
clinical exercise is presented in the Investigators’ Brochure (IB). 
The safety results of the Phase I study will be updated when the 
results become available. 
As clinical studies using SB12 have not been conducted up 
to date, clinical data is currently not available. Based on 
biosimilarity between SB12 and Soliris®, which was 
demonstrated through extensive quality and non-clinical 
similarity exercise, a Phase I study will be was conducted in 
healthy subjects to compare the pharmacokinetic (PK), safety, 
tolerability, immunogenicity, and pharmacodynamic (PD) 
profiles and a Phase III study will be conducted in subjects with 
PNH to compare the efficacy, safety, pharmacokinetics, and 
immunogenicity of SB12 to Soliris®. Information on the safety 
of SB12 based on the product information of Soliris® and , non-
clinical, and clinical exercise is presented in the Investigators’ 
Investigator’s Brochure (IB). The safety results of the Phase I 
study will be updated when the results become available. 
To reflect updated 
study progress 
(Phase I study 
completion) 
1.3.2. 
Clinical Data 
of Soliris® 
In 40 patients with PNH, a 1-compartmental model was used to 
estimate PK parameters after multiple doses. Mean clearance was 
0.31 ± 0.12 mL/hr/kg, mean volume of distribution was 110.3 ± 
17.9 mL/kg, and mean elimination half-life was 11.3 ± 3.4 days. 
Based on these data, the onset of steady state is predicted to be 
approximately 49-56 days. 
In 40 patients with PNH, a 1-compartmental model was used to 
estimate PK parameters after multiple doses. Mean clearance was 
0.31 ± 0.12 mL/hr/kg, mean volume of distribution was 110.3 ± 
17.9 mL/kg, and mean elimination half-life was 11.3 ± 3.4 days. 
Based on these data, the onset of The steady state is predicted 
to be approximately 49-56 days achieved by 4 weeks using the 
To refer the latest 
version of 
regulatory 
document 


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(…) 
PNH adult dosing regimen. 
(…) 
1.5.1. 
Known 
Potential 
Risks 
According to Soliris® Summary of Product Characteristics 
(SmPC) [10], supportive safety data were collected from 29 
completed and one ongoing clinical studies that included 1,407 
patients exposed to eculizumab in ten disease populations, 
including PNH, aHUS, and refractory gMG. (…) 
(…) 
(…) Subjects will have a safety follow-up at the end of study 
(EOS) visit 8 weeks after the last dose of study drug. An 
independent Data and Safety Monitoring Board (DSMB) will 
convene at pre-specified intervals to conduct interim monitoring 
of accumulating safety data. Following each data review, the 
DSMB will make recommendations regarding the conduct of 
the study, including continuation of the study without 
modifications, termination of the study for safety reasons, or 
modification of the study design for safety reasons. 
According to Soliris® Summary of Product Characteristics 
(SmPC) [10], supportive safety data were collected from 29 30 
completed and one ongoing clinical studies that included 1,407 
1,503 patients exposed to eculizumab in ten complement-
medicated disease populations, including PNH, aHUS, and 
refractory gMG, and NMOSD. (…) 
(…) 
(…) Subjects will have a safety follow-up at the end of study 
(EOS) visit until 8 weeks after the last dose of study drug. An 
independent Data and Safety Monitoring Board (DSMB) will 
convene at pre-specified intervals to conduct interim monitoring 
of accumulating safety data. Following each data review, the 
DSMB will make recommendations regarding the conduct of 
the study, including continuation of the study without 
modifications, modification of the protocol, pausing of 
subject enrolment until the resolution of issues, or 
termination of the study for safety reasons, or modification of 
the study design for safety reasons. 
To refer the latest 
version of 
regulatory 
document 
To reflect the 
changes due to 2-
year extension 
period  
To further clarify 
the DSMB actions  
1.5.2. 
Known 
Potential 
Benefits 
Soliris® is the only approved therapy for PNH and is indicated 
for the treatment patients with aHUS and gMG [10]. The drug is 
highly 
effective 
in 
stopping 
intravascular 
haemolysis, 
eliminating or decreasing the need for RBC transfusions, 
improving quality of life, and reducing the risk of thrombosis, the 
leading cause of mortality from PNH [7; 8; 9].  
(…) 
Soliris® is the only approved therapy for PNH and is indicated 
for the treatment patients with aHUS, and gMG, and NMOSD 
[10; 21]. The drug is highly effective in stopping intravascular 
haemolysis, eliminating or decreasing the need for RBC 
transfusions, improving quality of life, and reducing the risk of 
thrombosis, the leading cause of mortality from PNH [7; 8; 9].  
(…) 
To refer the latest 
version of 
regulatory 
document 


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2.2.1. 
Primary 
Endpoints 
Primary endpoints 
• 
LDH level (U/L) at Week 26  
• 
Area under the effect curve (AUEC) of LDH from Week 
14 to Week 26 and from Week 40 to Week 52 
Primary endpoints 
• 
LDH level (U/L) at Week 26  
• 
Area Time-adjusted area under the effect curve (AUEC) 
of LDH from Week 14 to Week 26 and from Week 40 to 
Week 52  
To clarify the 
primary endpoint 
2.2.2. 
Secondary 
Endpoints 
Secondary endpoints 
Efficacy endpoints 
• 
LDH profile over time 
• 
Number of units of pRBCs transfused throughout the 
study duration for each period 
Safety endpoints 
• 
Incidence of AEs and serious AEs (SAEs) 
• 
Incidence of infection-related AEs 
- 
Meningococcal infection 
- 
Other systemic infections 
• 
Incidence of infusion-related reactions (IRRs) 
(…) 
Immunogenicity endpoints  
• 
Incidence of anti-drug antibodies (ADAs) at Weeks 0 
(Day 1), 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 
44, 48, 52, and EOS/early termination (ET) 
• 
Incidence of neutralising antibodies (NAbs) at Weeks 0 
(Day 1), 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 
44, 48, 52, and EOS/ET 
Secondary endpoints 
Efficacy endpoints 
• 
LDH profile over time during the Main Part 
• 
Number of units of pRBCs transfused throughout the 
study duration for each period during the Main 
Part 
Safety endpoints 
• 
Incidence of AEs and serious AEs (SAEs) 
• 
Incidence of serious AEs (SAEs) 
• 
Incidence of infection-related AEs 
- 
Meningococcal infection 
- 
Other systemic infections 
• 
Incidence of infusion-related reactions (IRRs) 
(…) 
During the Extension Part, only SAEs will be collected. 
Immunogenicity endpoints  
• 
Incidence of anti-drug antibodies (ADAs) at Weeks 0 
(Day 1), 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 
44, 48, 52, and EOS/early termination (ET) 
To reflect the 
changes in 
secondary 
endpoints due to 2-
year extension 
period 


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• 
Incidence of neutralising antibodies (NAbs) at Weeks 0 
(Day 1), 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 
44, 48, 52, and EOS/ET 
3.1. 
Overview of 
Study 
Design 
This is a randomised Phase III, double-blind, multicentre, cross-
over study to compare the efficacy, safety, pharmacokinetics, and 
immunogenicity between SB12 and Soliris® in subjects with 
PNH.  
(…) IPs will be given until Week 52.  
Details of assessment that will be conducted and treatment that 
will be administered are presented in  
Table 1 and Table 2. The last assessment will be done at Week 
60 or 8 weeks after the last dose of study drug. 
This multicentre Phase III study is composed of the Main Part 
and Extension Part. 
The Main Part is a randomised Phase III, double-blind period, 
multicentre, cross-over study to compare the efficacy, safety, 
pharmacokinetics, and immunogenicity between SB12 and 
Soliris® in subjects with PNH. The Extension Part is an open-
label, single-arm, 2-year extension period to provide SB12 in 
subjects with PNH for an extended duration under an ethical 
basis. 
(…) IPs SB12 or Soliris® will be given until Week 52 50. End 
of the Main Part is defined as completion of pre-dose 
activities at Week 52. Subjects who complete the Main Part 
will enter the Extension Part. 
For the Extension Part, all subjects will receive SB12 for 2 
years. 
Details of assessment that will be conducted and treatment that 
will be administered are presented in Table 1, and Table 2, and 
Table 3. The last assessment for the Main Part will be done 
performed at pre-dose of Week 60 52 or 8 weeks after the last 
dose of study drug in case of ET during the Main Part . The 
last assessment for the Extension Part will be performed at 8 
weeks after the last dose of SB12. 
To reflect the 
changes due to 2-
year extension 
period 
3.2.1. 
Scientific 
Rationale for 
(…) 
, for 
(…) 
, for 
To clarify the 
primary endpoint 
and reflect the 


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Study 
Design 
analysis of haemolysis reduction as measured by AUEC of LDH 
between two different time points in each period, the primary 
objective is to demonstrate comparable clinical efficacy of SB12 
and Soliris® in terms of AUEC of LDH from Week 14 to Week 
26 and from Week 40 to Week 52. 
, for analysis 
of haemolysis reduction as measured by the LDH level at single 
time point, the primary objective is to demonstrate comparable 
clinical efficacy of SB12 and Soliris® in terms of the LDH level 
(U/L) at Week 26. 
analysis of haemolysis reduction as measured by time-adjusted 
AUEC of LDH between two different time points in each period, 
the primary objective is to demonstrate comparable clinical 
efficacy of SB12 and Soliris® in terms of time-adjusted AUEC 
of LDH from Week 14 to Week 26 and from Week 40 to Week 
52. 
 
s, for analysis of 
haemolysis reduction as measured by the LDH level at single 
time point, the primary objective is to demonstrate comparable 
clinical efficacy of SB12 and Soliris® in terms of the LDH level 
(U/L) at Week 26. 
local amendment 
3.2.3. 
Rationale for 
Pharmacokin
-etic 
Assessments 
A randomised, three-arm, parallel, single-dose Phase I PK study 
will be conducted in healthy subjects to demonstrate similarity 
in PK profiles of SB12, European Union (EU) sourced Soliris®, 
and US sourced Soliris®. However, since target-mediated 
clearance of eculizumab can be more accurately investigated in 
patients, additional PK assessments will be performed in this 
Phase III study to provide supportive evidence to PK similarity. 
A randomised, three-arm, parallel, single-dose Phase I PK study 
will be was conducted in healthy subjects to demonstrate 
similarity in PK profiles of SB12, European Union (EU) 
sourced Soliris®, and US sourced Soliris®. However, since 
target-mediated clearance of eculizumab can be more accurately 
investigated in patients, additional PK assessments will be 
performed in this Phase III study to provide supportive evidence 
to PK similarity. 
To reflect updated 
study progress 
(Phase I study 
completion) 
3.3. Duration 
of Study 
Participation 
After Screening, the duration of study participation will be 60 
weeks per subject including 52-week treatment period and 8-
week post-treatment follow-up period 
After Screening, the duration of study participation will be 60 
weeks per subject including 52-week randomised treatment 
period and 8-week post-treatment follow-up an extension 
period of up to 2 years. 
To reflect the 
changes due to 2-
year extension 
period 
3.5. End of 
Study 
Definition 
A subject is considered to have completed the study if he or she 
has completed all study treatment including the last visit or the 
last scheduled procedure shown in Table 2. The EOS is defined 
as completion of the last scheduled visit shown in Table 2. The 
A subject is considered to have completed the each part of 
study if he or she has completed all study treatment including 
the last visit or the last scheduled procedure shown in Table 2 
and Table 3. The EOS is defined as completion of the last 
To reflect the 
changes due to 2-
year extension 
period 


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end of this clinical study is defined as completion of the last 
subject’s EOS. 
scheduled visit shown in Table 2. The end of this clinical 
study the Main Part is defined as completion of the last 
subject’s EOS pre-dose activities at Week 52 for subjects. 
The end of the Extension Part is defined as 8 weeks after the 
last dose of SB12. 
The end of study (EOS) is defined as the date of last 
subject’s last visit in the Extension Part. 
4.2. 
Inclusion 
Criteria 
3. 
Presence of the PNH white blood cell (WBC) clone ≥ 10% 
by high-sensitivity flow cytometry at Screening. 
3. 
Presence of the PNH white blood cell (WBC) clone, with a 
granulocyte or monocyte clone size of ≥ 10% by high-
sensitivity flow cytometry at Screening. 
To clarify the 
inclusion criteria 
4.3. 
Exclusion 
Criteria 
4. Abnormal haematological parameters at Screening defined 
as the following: 
a. 
Absolute neutrophil count (ANC) ≤ 500/mm3 
b. Platelet count < 70,000/mm3 
4. Abnormal haematological parameters at Screening defined 
as the following: 
a. 
Absolute neutrophil count (ANC) ≤ 500/mm3 0.5 × 
103/µL 
b. 
Platelet count < 70,000/mm3 70 × 103/µL 
To change the unit 
of haematology 
parameters 
4.3. 
Exclusion 
Criteria 
6. History of bone marrow transplantation. 
6. History of bone marrow haematopoietic stem cell 
transplantation. 
To clarify the 
exculsion criteria 
4.3. 
Exclusion 
Criteria 
10. Concomitant use of any of the following medications is 
prohibited if the following conditions apply. 
b. Warfarin with an unstable international normalized ratio 
(INR) for at least 4 weeks prior to initiation of study 
drug (Day 1). 
10. Concomitant use of any of the following medications is 
prohibited if the following conditions apply. 
b. 
Warfarin with an unstable international normalized 
normalised ratio (INR) for at least 4 weeks prior to 
initiation of study drug (Day 1) at the discretion of the 
Investigator. 
To clarify the 
exculsion criteria 


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5.1.1. 
Dosing and 
Treatment 
Schedule 
SB12 or Soliris® will be administered up to Week 52 (a total of 
29 administrations of IP) unless they are early discontinued 
from study treatment.  
 
600 mg every 7 ± 2 days for the first 4 weeks, 
followed by 
 
900 mg for the fifth dose 7 ± 2 days later, then 
 
900 mg every 14 ± 2 days thereafter 
In case previous IP administration was out of visit window, next 
visit schedule should be adjusted to keep intervals of IP 
administration as indicated above. 
The subject receiving SB12 or Soliris® therapy may require 
dose adjustment within the recommended 14 ± 2 days dosing 
schedule during the maintenance period (up to every 12 days) 
when it is deemed necessary at the discretion of the 
Investigator; e.g., two consecutive events of elevated LDH ≥ 2 
× ULN combined with sign or symptom of intravascular 
haemolysis after prior LDH reduction to < 1.5 × ULN on 
treatment. Once the above event has occurred, the Investigator 
should inform the medical monitor and/or Sponsor immediately. 
SB12 or Soliris® will be administered up to Week 52 (a total 
of 29 administrations of IP) unless they are early 
discontinued from study treatment.  
Dosing and treatment schedule of SB12 or Soliris® should be 
kept as follows: 
 
600 mg every 7 ± 2 days for the first 4 weeks, 
followed by 
 
900 mg for the fifth dose (Week 4) 7 ± 2 days later, 
then 
 
900 mg every 14 ± 2 days thereafter 
In case previous IP administration was out of visit window, 
next visit schedule should be adjusted to keep intervals of IP 
administration as indicated above. 
The treatment schedule is dependent on the previous 
treatment date rather than the absolute (i.e., fixed) number 
of days from Day 1. In other words, the next 7 ± 2 days or 14 
± 2 days treatment schedule described above is re-scheduled 
every time based on the date when the previous treatment is 
given. 
The subject receiving SB12 or Soliris® therapy may require 
dose dosing interval adjustment within the recommended 14 ± 
2 days dosing schedule during the maintenance period (up to 
every 12 days) when it is deemed necessary at the discretion of 
the Investigator; e.g., two consecutive events of elevated LDH ≥ 
2 × ULN combined with sign or symptom of intravascular 
haemolysis after prior LDH reduction to < 1.5 × ULN on 
treatment. For subjects whose dosing interval is adjusted to 
To clarify dosing 
and treatment 
schedule 
To reflect the 
changes due to 2-
year extension 
period 


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12 days in Period 1 of the Main Part, it is recommended that 
the dosing interval be switched back to 14 days after 
switching IP at Week 26. Once the above event has occurred, 
the Investigator should inform the medical monitor and/or 
Sponsor immediately during the Main Part, but in the 
Extension Part, the event can be managed at the discretion 
of the Investigator. 
5.1.3. 
Blinding 
This study is double-blinded. Subjects, Investigators, and other 
study personnel will remain blinded to the treatment sequence 
assignment throughout the study period after randomisation. 
(…) 
This The Main Part of this study is double-blinded. Subjects, 
Investigators, and other study personnel will remain blinded to 
the treatment sequence assignment throughout the study period 
until end of the Main Part after randomisation. 
(…) 
To reflect the 
changes due to 2-
year extension 
period 
5.2.1. 
Identify of 
Investigation
-al Product 
The IPs will be supplied to investigational site in one carton 
containing a single vial. These IP vials will be packed and 
labelled in a double-blinded manner for clinical use. 
(…) 
The IPs will be supplied to investigational site in one carton 
containing a single vial. These IP vials will be packed and 
labelled in a double-blinded manner for clinical use the Main 
Part. For the Extension Part, SB12 will also be supplied to 
investigational site in one carton containing a single vial. These 
SB12 vials will be packed and labelled using open label for the 
Extension Part. 
(…) 
To reflect the 
changes due to 2-
year extension 
period 
5.2.2. 
Formulation, 
Packaging, 
and 
Labelling 
Eculizumab (SB12 or Soliris®) will be supplied for use as a 
concentrate for solution for infusion (300 mg per vial for SB12, 
EU sourced Soliris®). 
(…). SB12 or Soliris® will be pre-packaged and labelled in a 
double-blinded form. (…) 
Eculizumab (SB12 or Soliris®) will be supplied for use as a 
concentrate for solution for infusion (300 mg per vial for SB12, 
EU sourced Soliris®). 
(…). SB12 or Soliris® will be pre-packaged and labelled in a 
double-blinded form for the Main Part. For the Extension 
Part, SB12 will be packaged and labelled using open label. 
(…) 
To reflect the 
changes due to 2-
year extension 
period 


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5.2.4. 
Preparation 
and 
Administrati
-on of 
Investigation
-al Products 
(…) 
Dilution should be performed in accordance with good particles 
rules, particularly for the respect of asepsis. Withdraw the total 
amount of SB12 or Soliris® from the vials using a sterile syringe. 
Transfer the recommended dose to an infusion bag. Dilute SB12 
or Soliris® to a final concentration of 5 mg/mL by addition to the 
infusion bag using sodium chloride 9 mg/mL (0.9%) solution for 
injection, sodium chloride 4.5 mg/mL (0.45%) solution for 
injection, or 5% dextrose in water, as the diluent. 
(…) 
(…) 
Dilution should be performed in accordance with good particles 
practices rules, particularly for the respect of asepsis. Withdraw 
the total amount of SB12 or Soliris® from the vials using a sterile 
syringe. Transfer the recommended dose to an infusion bag. 
Dilute SB12 or Soliris® to a final concentration of 5 mg/mL by 
addition to the infusion bag using sodium chloride 9 mg/mL 
(0.9%) solution for injection, sodium chloride 4.5 mg/mL 
(0.45%) solution for injection, or 5% dextrose in water, as the 
diluent. 
(…) 
To correct editorial 
error 
5.2.5. 
Treatment 
Compliance 
and 
Investigation
-al Product 
Accountabili
-ty 
(…) 
(…) At the completion or termination of the study, a final drug 
accountability review and reconciliation must be completed; any 
discrepancies must be investigated and their resolution must be 
documented.  
Unless otherwise notified, empty vials and vials with residual 
materials should be kept for inspection and accountability by the 
study monitor prior to their destruction or handled per local 
pharmacy SOP for clinical study drugs. (…) 
In case of expanded access of SB12 to subjects, the Investigator 
is responsible for maintaining the SB12 records which include 
information 
on 
amounts 
delivered, 
dispensed, 
and 
returned/destroyed; for ensuring proper storage conditions are 
maintained and documented including details of dates, quantities, 
batch numbers, expiry dates; ensuring the SB12 is only used as 
specified by the expanded access; for reconciling all SB12 
(…) 
(…) At the completion or termination of each part of the study, 
a final drug accountability review and reconciliation must be 
completed; any discrepancies must be investigated and their 
resolution must be documented.  
Unless otherwise notified, To avoid accidental unblinding, 
used drug kits (empty vials and, vials with residual materials, 
and cartons) should be kept for inspection promptly 
discarded after the infusion bag is prepared 
and 
accountability by the study monitor prior to their in 
accordance with the local destruction or handled per local 
pharmacy SOP/policies for clinical study drugs. (…) 
In case of expanded access of SB12 to subjects, the 
Investigator is responsible for maintaining the SB12 records 
which include information on amounts delivered, dispensed, 
and returned/destroyed; for ensuring proper storage 
To reflect the 
changes due to 2-
year extension 
period  
To revise 
according to latest 
pharmacy manual 


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received from the Sponsor. Further details will be provided in a 
guideline for expanded access. 
conditions are maintained and documented including details 
of dates, quantities, batch numbers, expiry dates; ensuring 
the SB12 is only used as specified by the expanded access; for 
reconciling all SB12 received from the Sponsor. Further 
details will be provided in a guideline for expanded access. 
For the Extension Part, compliance will be assessed by the 
subject’s source documents. All dosing information should be 
recorded in the subject’s source documents. 
5.3. 
Concomitant 
Medication 
or Treatment 
All medication including both prescription and non-prescription 
drugs, and any procedures undertaken during the study period 
(from the study informed consent has been signed to EOS/ET 
visit) should be recorded in the subject’s source documents and 
eCRF. (…) 
(…) 
All medication including both prescription and non-prescription 
drugs, and any procedures undertaken during the study period 
(from the study informed consent has been signed to 
EOS/ET visit) between 4 weeks prior to Screening (except 
for immunosuppressant) and end of the Main Part should be 
recorded in the subject’s source documents and eCRF. (…) 
(…) 
To reflect the 
changes due to 2-
year extension 
period  
5.3.1. 
Permitted 
Concomitant 
Medications 
or Treatment 
The following concomitant medications are allowed if on a 
stable dose (only for chronic administration) during the study 
treatment period (up to Week 52). However, for the subject’s 
welfare, medications can be adjusted after discussion between 
the Investigator and medical monitor and/or Sponsor. 
(…) 
The following concomitant medications are allowed if given on 
a stable dose (only for chronic administration) during the study 
treatment period (up to Week 52) Main Part. However, for 
the subject’s welfare, medications can be adjusted after 
discussion between the Investigator and medical monitor and/or 
Sponsor. 
(…) 
To reflect the 
changes due to 2-
year extension 
period 
5.3.2. 
Prohibited 
Concomitant 
Medications 
Immunosuppressant except for cyclosporine is prohibited 
including but not limited to: 
(…) 
Immunosuppressant except for cyclosporine is prohibited during 
the Main Part including but not limited to: 
(…) 
To reflect the 
changes due to 2-
year extension 
period 


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or Treatment 
6.1.2. 
Breakthroug
-h 
Haemolysis 
The Investigator and/or designee will record the breakthrough 
haemolysis in the source documents and eCRF during the study 
period. 
The Investigator and/or designee will record the breakthrough 
haemolysis in the source documents and eCRF during the study 
period Main Part. 
To reflect the 
changes due to 2-
year extension 
period 
6.1.3. 
Transfusions 
(…) 
It is recommended that the transfusion would be performed 
within 48 hours of the haemoglobin assessment. 
Transfusion record will be collected from the signing of the 
informed consent until EOS (or 8 weeks after the last dose of 
study drug in case of ET). Anaemia-related signs or symptoms, 
haemoglobin value, number of units of pRBCs will be 
documented on the source documents and eCRF. 
(…) 
It is recommended that the transfusion would be performed 
within 48 hours of the haemoglobin assessment. The decision to 
give a transfusion may be based on either local or central 
laboratory haemoglobin values. 
Transfusion record will be collected from the signing of the 
informed consent until EOS end of the Main Part (or 8 weeks 
after the last dose of study drug in case of ET during the Main 
Part). Anaemia-related signs or symptoms, haemoglobin value, 
number of units of pRBCs will be documented on the source 
documents and eCRF. 
To clarify the 
guide for 
transfusion 
To reflect the 
changes due to 2-
year extension 
period  
6.1.4. Major 
Adverse 
Vascular 
Events 
The description of MAVEs, anatomical site, method of diagnosis, 
date of diagnosis, and outcome will be recorded in the source 
documents and eCRF as medical history and AEs throughout the 
study period.  
The MAVE is defined as following; 
• 
Thrombophlebitis/deep vein thrombosis, pulmonary 
embolus, 
cerebrovascular 
accident, 
myocardial 
infarction, transient ischemic attack, unstable angina, 
renal vein thrombosis, mesenteric vein thrombosis, 
The description of MAVEs, anatomical site, method of diagnosis, 
date of diagnosis, and outcome will be recorded in the source 
documents and eCRF as medical history and AEs throughout 
the study period during the Main Part.  
The MAVE is defined as following; 
Thrombophlebitis/deep vein thrombosis, pulmonary embolus, 
cerebrovascular accident cerebral arterial/venous occlusion, 
myocardial infarction, transient ischemic attack, unstable angina, 
renal vein thrombosis, mesenteric vein thrombosis, portal vein 
To reflect the 
changes due to 2-
year extension 
period  
To update MAVE 
definition 


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portal vein thrombosis (Budd-Chiari syndrome), acute 
mesenteric ischaemia, etc. 
thrombosis 
(Budd-Chiari 
syndrome), 
acute 
mesenteric 
ischaemia, etc. 
6.1.5. 
Paroxysmal 
Nocturnal 
Haemolgobi-
nuria-related 
Symptoms 
The PNH-related symptom questionnaire will be completed by 
subjects. The questionnaire will be provided to subjects before 
IP administration at the visits specified in  
Table 1 and Table 2; at Screening, Weeks 0 (Day 1), 4, 14, 26, 
30, 40, and 52. 
(…) 
The PNH-related symptom questionnaire will be completed by 
subjects. The questionnaire will be provided to should be 
completed by subjects before IP administration at the visits 
specified in  
Table 1 and Table 2; at Screening, Weeks 0 (Day 1), 4, 14, 26, 
30, 40, and 52. 
(…) 
To clarify the study 
procedure 
6.2.1. 
Adverse 
Events 
All AEs will be recorded from the timing of the signed informed 
consent until EOS or 8 weeks after the last dose of study drug in 
case of ET. Further description on monitoring and reporting of 
AEs is presented in Section 8. 
All AEs will be recorded from the timing of the signed 
informed consent until EOS or 8 weeks after the last dose of 
study drug in case of ET. Further description on monitoring 
and reporting of AEs is presented in according to Section 8. 
To reduce 
redundant wording 
and simplify the 
paragraph 
6.2.2. 
Clinical 
Laboratory 
Evaluations 
(…) 
If other laboratory tests not listed below are performed as per 
local practice and found to be abnormal, it is recommended that 
the Investigator uses their best clinical judgement to determine 
if the abnormal values would affect subjects’ safety while 
participating in the study. It is highly recommended to test the 
abnormal parameter by central laboratory as well, if available. 
(…) 
(…) 
If other laboratory tests not listed below are performed as per 
local practice and found to be abnormal, it is recommended that 
the Investigator uses their best clinical judgement to determine 
if the abnormal values would affect subjects’ safety while 
participating in the study. It is highly recommended to test the 
abnormal parameter by central laboratory as well, if available. 
(…) 
To clarify the study 
procedure 
Table 5 
Haematology 
• 
WBC count 
• 
RBC count 
• 
Haemoglobi
 
Haematology 
 
WBC count 
 
RBC count 
 
Mean 
corpuscular 
haemoglobin 
To add several 
haematology 
parameters 


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n 
• 
Haematocrit 
• 
Platelet 
count 
• 
Differential 
WBC count 
• 
Nucleated 
RBC 
 
 
Haemoglobin 
 
Haematocrit 
 
Platelet count 
 
Differential 
WBC count 
 
Nucleated 
RBC 
(MCH) 
 
Mean 
corpuscular 
haemoglobin 
concentration 
(MCHC) 
 
Mean 
corpuscular 
volume (MCV) 
 
Mean platelet 
volume (MPV) 
 
Red cell 
distribution 
width (RDW) 
Table 5 
Footnote 
1 Pregnancy test will performed for women of childbearing 
potential (serum or urine). Serum pregnancy test will be 
performed at Screening and EOS and urine pregnancy test will 
be performed at other applicable visits. 
1 Pregnancy test will be performed for women of childbearing 
potential (serum or urine). Serum pregnancy test will be 
performed at Screening and EOS 8 weeks after the last dose of 
study drug in case of ET during the Main Part and urine 
pregnancy test will be performed at other applicable visits 
before study drug administration. 
To reflect the 
changes due to 2-
year extension 
period and clarify 
the timeframe 
6.3.1. 
Pharmacokin
-etic 
Assessments 
(…) 
The Sponsor or its designated representative will store PK 
samples after the end of the clinical study for several years in 
order to have the possibility to repeat the assay already 
performed (e.g., re-analysis requested by regulatory authorities 
or failure of first analysis [see Section 10.4]). 
(…) 
The Sponsor or its designated representative will store PK 
samples after the end of the clinical study for several 
maximum 15 years in order to have the possibility to repeat the 
assay already performed (e.g., re-analysis requested by 
To clarify the 
sample storage 
period 


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regulatory authorities or failure of first analysis [see Section 
10.4]). 
6.3.2. 
Immunogeni
-city 
assessments 
(…) Blood samples should be collected at the same day of study 
drug administration except for EOS/ET. Subjects’ samples may 
be used for immunogenicity testing assay method development 
and/or method validation. 
(…) 
The Sponsor or its designated representative will store 
immunogenicity samples after the end of clinical study for 
several years in order to have the possibility to repeat the assay 
already performed (e.g., re-analysis requested by regulatory 
authorities or failure of first analysis [see Section 10.4]). 
(…) Blood samples should be collected at the same day of study 
drug administration except for EOS/ET visit. Subjects’ samples 
may be used for immunogenicity testing assay method 
development and/or method validation. 
(…) 
The Sponsor or its designated representative will store 
immunogenicity samples after the end of the clinical study for 
several maximum 15 years in order to have the possibility to 
repeat the assay already performed (e.g., re-analysis requested 
by regulatory authorities or failure of first analysis [see Section 
10.4]). 
To reflect the 
changes due to 2-
year extension 
period  
To clarify the 
sample storage 
period 
6.3.3. 
Pharmacody
-namic 
Assessments 
(…) 
Complement activity will be measured by the validated method 
by the Sponsor or its designated representative. 
If the IP administration is delayed for any reasons after blood 
sample for PD is collected, blood sample for PD analysis should 
be repeated on actual dosing day and be used for anlaysis. 
In all cases, the exact date and time of the PD sampling and IP 
administration must be carefully recorded in the source 
documents and eCRF. Detail instructions of handling, storage, 
and shipment for PD samples are described in the laboratory 
manual. 
The Sponsor or its designated representative will store PD 
samples after the end of the clinical study for several years in 
order to have the possibility to repeat the assay already performed 
(e.g., re-analysis requested by regulatory authorities or failure of 
first analysis [see Section 10.4]). 
(…) 
Complement activity will be measured within the secured 
sample stability period by the validated method by the Sponsor 
or its designated representative. 
If the IP administration is delayed for any reasons after blood 
sample for PD is collected, blood sample for PD analysis should 
be repeated on actual dosing day and be used for anlaysis 
analysis. 
In all cases, the exact date and time of the PD sampling and IP 
administration must be carefully recorded in the source 
documents and eCRF. Detail instructions of handling, storage, 
and shipment for PD samples are described in the laboratory 
manual. 
The Sponsor or its designated representative will store PD 
samples after the end of the clinical study for several 
maximum 15 years in order to have the possibility to repeat the 
To reflect agency 
comments 
To clarify the 
sample storage 
period 


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assay already performed (e.g., re-analysis requested by 
regulatory authorities or failure of first analysis [see Section 
10.4]). 
6.3.4. 
Pharmacoge-
netic 
Assessments 
(…) 
Genetic variants in C5 is associated with poor response to 
eculizumab since C5 mutation causes the structural change in 
binding site of eculizumab, resulting in less suppression of 
complement-mediated haemolysis. These blood samples can be 
used for extraction and analysis of DNA in order to investigate 
the mutational status of the subjects including, but not limited to 
C5 protein. The analysis will be performed during or after the 
study for subjects who present poor response to study drug, or 
only if scientifically appropriate and data required.  
(…) 
(…) 
Genetic variants in C5 is associated with poor response to 
eculizumab since C5 mutation causes the structural change in 
binding site of eculizumab, resulting in less suppression of 
complement-mediated haemolysis. These blood samples can be 
used for extraction and analysis of DNA in order to investigate 
the mutational status of the subjects including, but not limited to 
C5 protein. The analysis will be performed during or after the 
study for subjects who present poor response to study drug, or 
only if scientifically appropriate and data required.  
(…) 
The Sponsor or its designated representative will store 
pharmacogenetic samples after the end of the clinical study 
for maximum 15 years in order to have the possibility to 
repeat the assay already performed (e.g., re-analysis 
requested by regulatory authorities or failure of first 
analysis [see Section 10.4]). 
To add the sample 
storage period and 
clarify the meaning 
7.1. Study 
Flow and 
Visit 
Schedule 
During this study, efficacy, safety, PK, immunogenicity, and PD 
assessments will be performed. The complete schedule of 
activities is outlined in  
Table 1 and Table 2. 
During this study, efficacy, safety, PK, immunogenicity, and PD 
assessments will be performed. The complete schedule of 
activities is outlined in Table 1, and Table 2, and Table 3.. 
To reflect the 
changes due to 2-
year extension 
period 
7.1.1.1. 
Screening 
Visit (D−63 
to D−22) 
 
Review of laboratory results  
- 
Haematology: Haemoglobin, haematocrit, RBC count, 
total WBC count including differential count, platelet 
count, and nucleated RBC 
 
Review of laboratory results  
- 
Haematology: Haemoglobin, haematocrit, RBC count, 
total WBC count including differential count, platelet 
count, and nucleated RBC, MCH, MCHC, MCV, 
MPV, and RDW 
To add several 
haematology 
parameters 


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7.1.1.2. 
Vaccination 
for Neisseria 
meningitidis 
(…) 
To reduce the risk of meningococcal infection, all subjects must 
be vaccinated against Neisseria meningitidis prior to or on Day 1 
in accordance with current local guidelines or Soliris® SmPC. 
Vaccines against serogroups A, C, Y, W135, and B where 
available, are recommended in preventing the commonly 
pathogenic meningococcal serogroups. In case subjects were 
vaccinated against meningococcal infection within 3 years prior 
to Day 1, which is properly documented, vaccination for this 
study could be omitted. For the information including 
formulation, preparation, and storage of vaccine, refer to the 
prescribing information in SmPC of vaccine. 
(…) 
(…) 
To reduce the risk of meningococcal infection, all subjects must 
be vaccinated against Neisseria meningitidis prior to or on Day 1 
in accordance with current local guidelines or Soliris® SmPC. 
Vaccines against serogroups A, C, Y, W135, and B where 
available, are recommended in preventing the commonly 
pathogenic meningococcal serogroups. In case subjects were 
vaccinated against meningococcal infection within 3 years prior 
to Day 1, which is properly documented, vaccination for this 
study could be omitted. For the information including 
formulation, preparation, and storage of vaccine, refer to the 
prescribing information in SmPC of vaccine. Subjects must be 
revaccinated later during the study if local guidelines indicate 
to do so . 
(…) 
To add guide for 
re-vaccination  
7.1.3. 
Randomised 
Treatment 
Period 
7.1.3. 
Treatment Period 
All procedures and assessments will be performed at the visits 
specified in  
Table 1 and Table 2. Samples for laboratory assessments will be 
collected before IP administration on same day or up to 2 days 
prior, unless otherwise specified. 
Laboratory assessments will be performed at central laboratory. 
Detail instructions of collecting, processing, storing, and 
shipping for blood samples are described in the laboratory 
manual. Laboratory reports will be available to the Investigator 
in a timely manner for clinical management of subjects during 
treatment period. 
7.1.3. Randomised Treatment Period 
The Investigator should check if the subject does not meet the 
discontinuation criteria before the initiation of study drug at 
Day 1. 
All procedures and assessments will be performed at the visits 
specified in  
Table 1 and Table 2, Samples for laboratory assessments will 
be collected and before IP administration on same day or up to 
2 days prior, unless otherwise specified. 
Laboratory assessments will be performed at central laboratory. 
Detail instructions of collecting, processing, storing, and 
shipping for blood samples are described in the laboratory 
To reflect the 
changes due to 2-
year extension 
period and clarify 
the eligibility re-
confirmation 
process 


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(…) 
manual. Laboratory reports will be available to the Investigator 
in a timely manner for clinical management of subjects during 
randomised treatment period. 
(…) 
7.1.3.1. 
Randomised 
Treatment 
Period 1 
(before 
Cross-over) 
7.1.3.1. Treatment Period 1 (before Cross-over) 
• 
AEs, concomitant medications, MAVEs, and 
transfusion record will be assessed and recorded 
throughout the study period. 
7.1.3.1. Randomised Treatment Period 1 (before Cross-over) 
• 
AEs, 
concomitant 
medications, 
MAVEs, 
and 
transfusion record will be assessed and recorded 
throughout the study period. 
To reflect the 
changes due to 2-
year extension 
period 
7.1.3.2. Visit 
16 (Week 
26/Day 183) 
Each subject will cross-over from the treatment initially 
assigned to another treatment at Visit 16 (Week 26) and IPs 
will be given until Visit 29 (Week 52). 
(…) 
Each subject will cross-over from the treatment initially 
assigned to another treatment at Visit 16 (Week 26) and IPs 
will be given until Visit 29 28 (Week 52 50). 
(…) 
To reflect the 
changes due to 2-
year extension 
period 
7.1.3.3. 
Randomised 
Treatment 
Period 2 
(after Cross-
over) 
7.1.3.3.  Treatment Period 2 (after Cross-over) 
• 
AEs, concomitant medications, MAVEs, and 
transfusion record will be assessed and recorded 
throughout the study period. 
7.1.3.3.  Randomised Treatment Period 2 (after Cross-over) 
• 
AEs, 
concomitant 
medications, 
MAVEs, 
and 
transfusion record will be assessed and recorded 
throughout the study period. 
To reflect the 
changes due to 2-
year extension 
period 
7.1.3.4. 
Early 
Termination 
Visit 
7.1.3.4. End of Study/Early Termination Visit (Week 
60/Day 421) 
EOS visit and ET visit is defined as 8 weeks (± 7 days) after 
the last dose of study drug. 
7.1.3.4.  End of Study/Early Termination Visit (Week 
60/Day 421) 
EOS visit and ET visit is defined as 8 weeks (± 7 days) after the 
last dose of study drug during the randomised treatment 
period. This includes when the subject does not enroll into the 
extension period (i.e., discontinue at Week 52 without study 
drug administration). 
To reflect the 
changes due to 2-
year extension 
period 


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7.1.4. 
Unscheduled 
Visits 
If a sign or symptom of breakthrough haemolysis is suspected, 
an unscheduled visit should be occurred and samples should be 
collected for LDH, PK, and PD assessment for central 
laboratory at that time. Additionally, other unscheduled visits 
are permitted at the discretion of the Investigator. Any tests, 
procedures, or assessments performed at the unscheduled visits 
must be recorded in the source documents and eCRF. 
If a sign or symptom of breakthrough haemolysis is suspected 
during randomised treatment period, an unscheduled visit 
should be occurred and samples should be collected for LDH, 
PK, and PD assessment for central laboratory at that time. 
Additionally, other unscheduled visits are permitted at the 
discretion of the Investigator. Any tests, procedures, or 
assessments performed at the unscheduled visits must be 
recorded in the source documents and eCRF. 
To reflect the 
changes due to 2-
year extension 
period 
7.1.5. 
Extension 
Period 
N/A 
After the randomised treatment period, all subjects who have 
completed the Main Part will enter the extension period and 
receive SB12 from Week 52 for 2 years.  
 
SB12 administrations by IV infusion for 35 ± 10 
minutes (900 mg every 14 ± 2 days) 
 
SAEs will be assessed and recorded. 
Discontinuation of study treatment can be decided at the 
discretion of the Investigator or by subject’s consent 
withdrawal. Specific study procedures are not required for 
subjects who have discontinued prematurely. SAEs must be 
collected until 8 weeks (± 7 days) from the last dose of study 
drug (Section 8.2.2). 
To reflect the 
changes due to 2-
year extension 
period 
7.2.1. 
Subject 
Discontinuat
ion from 
Study 
Treatment 
The study treatment must be discontinued for a subject in the 
event of the following: 
• 
Consent withdrawal by subject 
- 
(...) 
• 
Pregnancy (…) 
• 
Other complement inhibitor use 
The Investigator should discuss with the medical monitor prior to 
The study treatment must be discontinued for a subject in the 
event of the following: 
• 
Consent withdrawal by subject 
- 
(...) 
• 
Pregnancy (…) 
• 
Unblinding the study treatment to the Investigator 
or subject (i.e., breaking the double-blind). 
To add/revise the 
discontinuation 
criteria 


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discontinuing a subject’s study treatment in case of the following 
criteria, but not limited to: 
• 
Conditions or intercurrent illness that preclude 
compliance with the protocol in terms of their safety or 
well-being 
• 
Lack of efficacy (e.g., C5 gene polymorphism) 
Note: (…) 
• 
Unacceptable toxicity  
• 
Lack of subject’s compliance (e.g., repeated delay in 
study treatment and lost to follow-up) 
Note: (…) 
• 
Investigator discretion or other reasons 
• 
Other complement inhibitor use 
The During the Main Part, the Investigator should discuss with 
the medical monitor prior to discontinuing a subject’s study 
treatment in case of the following criteria, but not limited to: 
• 
Conditions or intercurrent illness that preclude 
compliance with the protocol in terms of their safety or 
well-being 
• 
Lack of efficacy (e.g., C5 gene polymorphism) 
Note: (…) 
• 
Unacceptable toxicity including meningococcal 
infection or anaphylaxis 
• 
Serious protocol deviations including lLack of 
subject’s compliance (e.g., repeated delay in study 
treatment and lost to follow-up) that preclude 
continuation fot the study 
Note: (…) 
• 
Investigator discretion or other reasons 
7.2.1. 
Subject 
Discontinuat
ion from 
Study 
Treatment 
Discontinuation from study treatment does not mean 
discontinuation from the study, and remaining study procedures 
should be completed as indicated by the study protocol. Only 
subjects who discontinue from the study at any time post-Day 1 
(after the initiation of study drug) will be required to have an ET 
visit. The data to be collected at the 8 weeks after the last dose 
of study drug are described in the Section 7.1.3.4. Every effort 
will be employed to keep subjects who discontinued from study 
treatment to undertake the scheduled ET visit procedures. 
For the Extension Part, discontinuation of study treatment 
can be decided at the discretion of the Investigator or by 
subject’s consent withdrawal. 
Discontinuation from study treatment does not mean immediate 
discontinuation from the study, and remaining study procedures 
should be completed as indicated by the study protocol. Only 
subjects Subjects who discontinue from the study at any time 
post-Day 1 (after the initiation of study drug) will be required to 
have an ET visit. The data to be collected at the 8 weeks after 
To reflect the 
changes due to 2-
year extension 
period 


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(…) 
Any subject who discontinues SB12 or Soliris® should be 
monitored for at least 8 weeks after last study drug to detect 
serious haemolysis and other reactions. If serious haemolysis 
occurs after SB12 or Soliris® discontinuation, consider the 
following procedures and/or treatments: 
 
Blood transfusion (pRBCs) or exchange transfusion if 
the PNH RBCs are > 50% of the total RBCs by flow 
cytometry 
 
Anticoagulation 
 
Corticosteroids 
 
Complement inhibitors 
According to the Investigator’s medical judgement, if 
complement inhibitor should be administered again due to 
serious haemolysis and other reactions which occur within 8 
weeks after completion of the study treatment with SB12 or 
Soliris®, the Investigator should discuss with Sponsor for an 
expanded access of SB12 to such subjects. Accordingly, the 
Sponsor will provide SB12 to those subjects as an expanded 
access up to 1 year period, where applicable, in accordance with 
relevant local regulations and/or law.   
the last dose of study drug are described in the Section 7.1.3.4. 
Every effort will be employed to keep subjects who 
discontinued from study treatment to undertake the scheduled 
ET visit procedures. For the Extension Part, specific study 
procedures are not required for subjects who have 
discontinued the study treatment prematurely and the 
subject will discontinue from the study once the study 
treatment is permanently discontinued. SAEs must be 
collected until 8 weeks (± 7 days) from the last dose of study 
drug in such cases (Section 8.2.2). Once study treatment is 
discontinued during the Extension Part, it is recommended 
to inform the Sponsor, if occurs. 
(…) 
Any subject who discontinues SB12 or Soliris® should be 
monitored for at least 8 weeks after last dose of study drug to 
detect serious haemolysis and other reactions. If serious 
haemolysis occurs after SB12 or Soliris® discontinuation, 
consider the following procedures and/or treatments: 
 
Blood transfusion (pRBCs) or exchange transfusion if 
the PNH RBCs are > 50% of the total RBCs by flow 
cytometry 
 
Anticoagulation 
 
Corticosteroids 
 
Complement inhibitors 
According to the Investigator’s medical judgement, if 
complement inhibitor should be administered again due to 
serious haemolysis and other reactions which occur within 8 
weeks after completion of the study treatment with SB12 or 


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Soliris®, the Investigator should discuss with Sponsor for an 
expanded access of SB12 to such subjects. Accordingly, the 
Sponsor will provide SB12 to those subjects as an expanded 
access up to 1 year period, where applicable, in accordance 
with relevant local regulations and/or law. 
8.1.1. 
Definition of 
Adverse 
Event 
(…) 
All AEs during the period of observation (as specified in Section 
8.1.2) including the events that occurred prior to administration 
of an IP should be reported as an AE in the AE section of the 
eCRF. 
(…) 
(…) 
All AEs during the period of observation (as specified in Section 
8.1.2) including the events that occurred prior to administration 
of an IP should be reported as an AE in the AE section of the 
eCRF. 
(…) 
To reflect the 
changes due to 2-
year extension 
period 
8.1.1.1. 
Clinically 
Significant 
Abnormality 
(…) 
If the clinically significant laboratory or other abnormality from 
safety assessment is not a sign of a disease or syndrome, the 
abnormality itself should be reported as an AE in the eCRF. If 
the abnormality can be characterised by a precise clinical term, 
the clinical term should be reported as the AE. For example, an 
elevated serum potassium level of 7.0 mEq/L should be reported 
as ‘hyperkalaemia.’ Observations of the same clinically 
significant abnormality from visit to visit should not be 
repeatedly reported as AEs in the eCRF, unless their severity, 
seriousness, or aetiology changes. 
(…) 
If the clinically significant laboratory or other abnormality from 
safety assessment is not a sign of a disease or syndrome, the 
abnormality itself should be reported as an AE in the eCRF. If 
the abnormality can be characterised by a precise clinical term, 
the clinical term should be reported as the AE. For example, an 
elevated serum potassium level of 7.0 mEq/L should be reported 
as ‘hyperkalaemia.’. Observations of the same clinically 
significant abnormality from visit to visit should not be 
repeatedly reported as AEs in the eCRF, unless their severity, 
seriousness, or aetiology changes. 
To reflect the 
changes due to 2-
year extension 
period 
8.1.2. Period 
of 
Observation 
for Adverse 
Events 
AEs will be reported from the time of signing the ICF until 
EOS visit or ET visit. 
However, SAEs must be collected until 10.5 weeks from the 
last dose of study drug (five half-lives of the study drug). SAEs 
that occurred after EOS visit or ET visit must be reported to 
the Sponsor or its designated representative using the paper 
SAE report form at least within 24 hours of the Investigator 
AEs will be reported from the time of signing the ICF until 
EOS visit end of the Main Part (or ET visit of the Main 
Part). Only SAEs will be collected during the Extension 
Part from start of study treatment at Week 52. 
However, SAEs must be collected until 10.5 weeks from the 
last dose of study drug (five half-lives of the study drug). 
SAEs that occurred after EOS visit or ET visit must be 
To reflect the 
changes in 
AE/SAE reporting 
period due to 2-
year extension 
period 


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becoming aware of the event (see Section 8.2.2).  
Unresolved AEs during the study period should be followed up 
until the EOS and recorded in the eCRF. The Investigator 
should observe the AEs for appropriate medical care of the 
subject until AE resolution or stabilisation. 
If the subject has an ongoing SAE at the EOS, these cases will 
be followed until event resolution or stabilisation (see Section 
8.2.2). 
reported to the Sponsor or its designated representative using 
the paper SAE report form at least within 24 hours of the 
Investigator becoming aware of the event (see according to 
Section 8.2.2).  
Unresolved AEs during the study period Main Part should be 
followed up until end of the EOS Main Part and recorded in 
the eCRF. The Investigator should observe the AEs for 
appropriate medical care of the subject until AE resolution or 
stabilisation. 
If the subject has an ongoing SAE at 8 weeks after the last 
dose of study drug EOS, these cases will be followed until 
event resolution or stabilisation (see Section 8.2.2). 
8.1.3. 
Reporting 
Adverse 
Events 
(…) 
If the subject who received the additional SB12 provision 
according to Section 7.2.1 has an AE, it must be reported to the 
Sponsor or its designated representative using the paper AE 
report form. If the AE is classified as an SAE, it must be 
reported to Sponsor or its designated representative using the 
paper SAE report form at least within 24 hours of the 
Investigator becoming aware of the event (see Section 8.2.2). 
(…) 
If the subject who received the additional SB12 provision 
according to Section 7.2.1 has an AE, it must be reported to 
the Sponsor or its designated representative using the paper 
AE report form. If the AE is classified as an SAE, it must be 
reported to Sponsor or its designated representative using the 
paper SAE report form at least within 24 hours of the 
Investigator becoming aware of the event (see Section 8.2.2). 
To reflect the 
changes in AE 
reporting due to 2-
year extension 
period 
8.1.7. 
Withdrawal 
due to 
Adverse 
Events 
Subject withdrawal from the study due to an AE should be 
distinguished from withdrawal due to personal reasons and 
recorded in the source documents and appropriate eCRF 
section. Subjects withdrawn due to an AE should be followed 
up until the time point specified in the protocol. When a subject 
withdraws from the study due to an SAE, the SAE must be 
reported and followed in accordance with the requirements 
outlined in Section 8.2.2. 
Subject withdrawal from the study due to an AE should be 
distinguished from withdrawal due to personal reasons and 
recorded in the source documents and appropriate eCRF 
section. Subjects withdrawn due to an AE should be followed 
up until the time point specified in the protocol Section 7.2.1. 
When a subject withdraws from the study due to an SAE, the 
SAE must be reported and followed in accordance with the 
requirements outlined in Section 8.2.2. 
To specify the 
reference section 


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(…) 
(…) 
8.2.2. 
Reporting 
Serious 
Adverse 
Events 
SAEs must be collected until 10.5 weeks from the last dose of 
study drug (five half-lives of the study drug). 
SAEs that occurred at or before EOS visit or ET visit must be 
reported to the Sponsor or its designated representative via 
eCRF SAE report form at least within 24 hours of the 
Investigator becoming aware of the event. 
SAEs that occurred after EOS visit or ET visit must be reported 
to the Sponsor or its designated representative using the paper 
SAE report form at least within 24 hours of the Investigator 
becoming aware of the event. 
SAEs that occurred from the subject who received the 
additional SB12 must be reported to the Sponsor or its 
designated representative using the paper SAE report form at 
least within 24 hours of the Investigator becoming aware of the 
event. 
(…) 
The Investigator is obligated to pursue and provide 
information to the Sponsor on all SAEs in accordance with the 
timeframes for reporting specified above. In addition, an 
Investigator may be requested by the Sponsor to obtain 
specific additional follow-up information in an expedited 
fashion. This information may be more detailed than that 
captured on eCRF. In general, this will include a description of 
the SAE, which should be provided in sufficient detail so as to 
allow for a complete medical assessment of the case and 
SAEs must be collected until 10.5 8 weeks (± 7 days) from the 
last dose of study drug (five half-lives of the study drug). 
SAEs that occurred at or before EOS visit until end of the 
Main Part (or ET visit of the Main Part) must be reported to 
the Sponsor or its designated representative via eCRF SAE 
report form at least within 24 hours of the Investigator 
becoming aware of the event. 
SAEs that occurred after EOS visit or ET visit end of the 
Main Part must be reported to the Sponsor or its designated 
representative using the paper SAE report form at least within 
24 hours of the Investigator becoming aware of the event. 
SAEs that occurred from the subject who received the 
additional SB12 must be reported to the Sponsor or its 
designated representative using the paper SAE report form 
at least within 24 hours of the Investigator becoming aware 
of the event. 
(…) 
The Investigator is obligated to pursue and provide 
information to the Sponsor on all SAEs in accordance with the 
timeframes for reporting specified above. In addition, an 
Investigator may be requested by the Sponsor to obtain 
specific additional follow-up information in an expedited 
fashion. This information may be more detailed than that 
captured on eCRF. In general, this will include a description 
of the SAE, which should be provided in sufficient detail so as 
To align the SAE 
reporting period 
with the safety 
follow-up oeriod (8 
weeks)  
To reflect the 
changes in SAE 
reporting due to 2-
year extension 
period 


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independent determination of possible causality. Information 
on other possible causes of the event, such as concomitant 
medications and illnesses must be provided. In the case of a 
subject death, a summary of available autopsy findings must 
be submitted as soon as possible to the Sponsor or its 
designated representative. 
(…) 
to allow for a complete medical assessment of the case and 
independent determination of possible causality. Information 
on other possible causes of the event, such as concomitant 
medications and illnesses must be provided. In the case of a 
subject death, a summary of available autopsy findings must 
be submitted as soon as possible to the Sponsor or its 
designated representative. 
(…) 
8.3.1. 
Meningococ
-cal 
Infection 
Due to its mechanism of action, the use of SB12 or Soliris® 
increases the subject’s susceptibility to meningococcal 
infection (Neisseria meningitidis). These subjects might be at 
risk of disease by serogroups (particularly Y, W135, and X), 
although meningococcal disease due to any serogroup may 
occur. To reduce the risk of infection, all subjects will be 
vaccinated against Neisseria meningitidis prior to or on Day 1. 
However, vaccination may not be sufficient to prevent 
meningococcal infection. Consideration should be given to 
current local guidelines and/or the discretion of the 
Investigator on the appropriate use of antibacterial agents. 
Cases of serious or fatal meningococcal infections have been 
reported in Soliris®-treated patients. All subjects should be 
monitored for early signs of meningococcal infection, 
evaluated immediately if infection is suspected, and treated 
with appropriate antibiotics if necessary.  
(…) 
Subjects should be informed of these signs and symptoms and 
steps taken to seek medical care immediately. The Investigator 
must discuss the benefits and risks of SB12 or Soliris® 
treatment with subjects and provide them with medical 
Due to its mechanism of action, the use of SB12 or Soliris® 
increases the subject’s susceptibility to meningococcal 
infection (Neisseria meningitidis). These subjects might be at 
risk of disease by serogroups (particularly Y, W135, and X), 
although meningococcal disease due to any serogroup may 
occur. To reduce the risk of infection, all subjects will be 
vaccinated against Neisseria meningitidis prior to or on Day 1. 
Subjects must be revaccinated later during the study if 
local guidelines indicate to do so. However, vaccination may 
not be sufficient to prevent meningococcal infection. 
Consideration should be given to current local guidelines 
and/or the discretion of the Investigator on the appropriate use 
of antibacterial agents. Cases of serious or fatal meningococcal 
infections have been reported in Soliris®-treated patients. All 
subjects should be monitored for early signs of meningococcal 
infection, evaluated immediately if infection is suspected, and 
treated with appropriate antibiotics if necessary.  
(…) 
Subjects should be informed of these signs and symptoms and 
steps taken to seek medical care immediately. Subjects who 
are undergoing treatment for serious meningococcal 
To add guide for 
re-vaccination 
To clarify the 
paragraph based on 
the regulatory 
document 


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instructions. 
infections should discontinue SB12 or Soliris® treatment, 
and the The Investigator must discuss the benefits and risks 
of SB12 or Soliris® treatment with subjects and provide them 
with medical instructions. 
8.3.3. 
Infusion-
related 
Reaction 
Administration of SB12 or Soliris® may result in infusion 
reactions or immunogenicity that could cause allergic or 
hypersensitivity reactions (including anaphylaxis), though 
immune reactions within 48 hours of Soliris® administration 
did not differ from placebo arm in PNH, aHUS, refractory 
gMG, and other studies conducted with Soliris®. In clinical 
trials no PNH, aHUS, or refractory gMG patients experienced 
an infusion reaction which required discontinuation of 
Soliris®. 
(…) 
Administration of SB12 or Soliris® may result in infusion 
reactions or immunogenicity that could cause allergic or 
hypersensitivity reactions (including anaphylaxis), though 
immune reactions within 48 hours of Soliris® administration 
did not differ from placebo arm in PNH, aHUS, refractory 
gMG, NMOSD, and other studies conducted with Soliris®. In 
clinical trials no PNH, aHUS, or refractory gMG, or NMOSD 
patients experienced an infusion reaction which required 
discontinuation of Soliris®. 
(…) 
To refer the latest 
version of 
regulatory 
document 
8.5. 
Emergency 
Unblinding 
of Assigned 
Treatment 
(…) 
If IWRS is not working at emergency situation, Investigator can 
contact the Sponsor representative to unblind the treatment. Still, 
the Sponsor representative is not entitled to stall or reject 
unblinding and provides treatment code to the Investigator in a 
manual way. 
(…) 
If IWRS is not working at emergency situation, Investigator 
can contact the Sponsor representative to unblind the 
treatment. Still, the Sponsor representative is not entitled to 
stall or reject unblinding and provides treatment code to the 
Investigator in a manual way. 
Deleted as the 
process is no 
longer applicable. 
IWRS problems 
can be solved 
within IWRS 
framework. 
8.6. 
Independent 
Data and 
Safety 
Monitoring 
Board 
An independent DSMB will be assigned for this study. The 
DSMB will consist of external experts (i.e., haematologists, 
clinical pharmacologists, and biostatisticians) and will review 
the safety and tolerability data from the study at pre-specified 
intervals. The details of the safety data and time points for 
review will be described in the DSMB charter and in the 
DSMB statistical analysis plan (SAP). 
An independent DSMB will be assigned for this study. The 
DSMB will consist of external experts (i.e., e.g., 
haematologists, clinical pharmacologists, and biostatisticians) 
and will review the safety and tolerability data from the study 
at pre-specified intervals. The details of the safety data and 
time points for review will be described in the DSMB charter 
and in the DSMB statistical analysis plan (SAP). 
To clarify the 
DSMB activities 
and safety 
monitoring process 


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In addition, an ongoing blinded review of AEs, including 
clinical laboratory data will be regularly and continuously 
undertaken by the Sponsor medical monitor. 
In addition, an ongoing blinded review of AEs, including 
clinical laboratory data will be regularly and continuously 
undertaken by the Sponsor medical monitor and 
pharmacovigilance team. 
9. Statistical 
Methods and 
Data 
Analysis 
Further information on the statistical methods for this study will 
be provided in the SAP, which will be finalised prior to the 
database lock for reporting the final clinical study report (CSR). 
Statistical analysis and reporting will be performed as follows: 
 
Interim safety analysis for independent DSMB meeting: 
A DSMB SAP, describing the methodology and presentation 
of results and access to results will be prepared as a separate 
document and included in the DSMB charter. The safety 
reports for the DSMB data review meetings will be prepared 
according to the DSMB SAP.  
The statistical analysis will be performed by an independent 
statistical reporting team and the results 
will be 
communicated to the DSMB directly by an independent 
unblind statistician. 
 
Final CSR: 
The final analysis will take place after the last subject 
completes the procedures at Week 60 or the corresponding 
visit. All study data will be analysed and reported for final 
CSR. 
Further information on the statistical methods for this study will 
be provided in the SAP, which will be finalised prior to the 
database lock for reporting the final clinical study report (CSR). 
Statistical analysis and reporting will be performed as follows: 
 
Interim safety analysis for independent DSMB meeting: 
A DSMB SAP, describing the methodology and presentation 
of results and access to results will be prepared as a separate 
document and included in the DSMB charter. The safety 
reports for the DSMB data review meetings will be prepared 
according to the DSMB SAP.  
The statistical analysis will be performed by an independent 
statistical reporting team and the results 
will be 
communicated to the DSMB directly by an independent 
unblind statistician. 
 
Final Main Part CSR: 
The final analysis will take place after the last subject 
completes the procedures at Week 60 52 or the 
corresponding visit. All study data will be analysed and 
reported for final the Main Part CSR. 
 
Extension Part CSR: 
A separate SAP for analyses of 2-year extension period 
will be prepared describing the methodology and 
To reflect the 
changes due to 2-
year extension 
period 


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presentation of results. The analysis will take place after 
the last subject completes the procedures of 2-year 
extension period. 
9.1. 
Statistical 
Hypotheses 
(…) 
 
or those who are in favour of the AUEC of LDH, 
the treatment effect will be measured by AUEC of LDH 
between two different time points in each period, from Week 14 
to Week 26 and from Week 40 to Week 52. The equivalence 
will be declared if the 90% confidence interval (CI) of the ratio 
between treatment effects is entirely contained within the pre-
defined equivalence margin of [0.77, 1.29].  
 for those 
who are in favour of the LDH level at a single time point, 
equivalence will be declared if the 95% CI of the difference 
between treatments in LDH level at Week 26 is entirely contained 
within the pre-defined equivalence margin of [−1.2 × ULN, 1.2 
× ULN] where ULN of LDH to be specified in the central 
laboratory specification for this study. 
(…) 
 
 for those who are in favour of the time-adjusted 
AUEC of LDH, the treatment effect will be measured by time-
adjusted AUEC of LDH between two different time points in 
each period, from Week 14 to Week 26 and from Week 40 to 
Week 52. The equivalence will be declared if the 90% 
confidence interval (CI) of the ratio between treatment effects is 
entirely contained within the pre-defined equivalence margin of 
[0.77, 1.29].  
 
 for those who are in favour of the LDH level at a 
single time point, equivalence will be declared if the 95% CI of 
the difference between treatments in LDH level at Week 26 is 
entirely contained within the pre-defined equivalence margin of 
[−1.2 × ULN, 1.2 × ULN] where ULN of LDH to be specified in 
the central laboratory specification for this study. 
If normal range of LDH is gender specific, the 
smaller/smallest ULN will be used for the equivalence 
margin; otherwise ULN is not gender specific, unified ULN 
will be used for the equivalence margin. 
To clarify the 
primary endpoint 
and reflect the 
local amendment 
9.2. Analysis 
Sets 
The following sets will be used for the analyses performed in the 
study: 
The following sets will be used for the analyses performed in the 
study: 
To reflect the 
changes in analysis 
set due to 2-year 


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• 
(…) 
• 
Safety Set (SAF) consists of all subjects who receive at least 
one IP during the study period. Subjects will be analysed 
according to the treatment received. 
• 
PK Analysis Set (PKS) consists of all subjects in the SAF 
who have at least one PK sample analysed. 
• 
PD Analysis Set (PDS) consists of all subjects in the SAF 
who have at least one PD sample analysed. 
• 
(…) 
• 
Safety Set for the Main Part (SAF1) consists of all subjects 
who receive at least one IP during the study randomised 
treatment period. Subjects will be analysed according to 
the treatment received. 
• 
Safety Set for the Extension Part (SAF2) consists of all 
subjects who receive at least one IP during the extension 
period 
• 
PK Analysis Set (PKS) consists of all subjects in the SAF1 
who have at least one PK sample analysed. 
• 
PD Analysis Set (PDS) consists of all subjects in the SAF1 
who have at least one PD sample analysed. 
extension period 
9.4. Analysis 
of the 
Primary 
Objectives 
 for those 
who are in favour of the AUEC of LDH, the primary efficacy 
analysis will be performed for the PPS-AUEC using a linear 
mixed model with treatment, subject, sequence, and period as 
fixed effects and subject nested within sequence as a random 
effect. The analysis will be performed with loge-transformed 
AUEC of LDH estimating the difference in least squares means 
and its 90% CI, and back transformation of those values will 
provide the ratio of geometric means and 90% CI. The 
equivalence will be declared if the two-sided 90% CI of the ratio 
of geometric means in AUEC of LDH between SB12 and Soliris® 
lies within the pre-defined equivalence margin of [0.77, 1.29].  
 for those who 
are in favour of the LDH level at a single time point, the primary 
 for those 
who are in favour of the time-adjusted AUEC of LDH, the 
primary efficacy analysis will be performed for the PPS-AUEC 
using a linear mixed model with treatment, subject, sequence, 
period, and period gender as fixed effects, and subject nested 
within sequence as a random effect. The analysis will be 
performed with loge-transformed time-adjusted AUEC of LDH 
estimating the difference in least squares means and its 90% CI, 
and back transformation of those values will provide the ratio of 
geometric means and 90% CI. The equivalence will be declared 
if the two-sided 90% CI of the ratio of geometric means in time-
adjusted AUEC of LDH between SB12 and Soliris® lies within 
the pre-defined equivalence margin of [0.77, 1.29].  
 
To clarify the 
efficacy analysis 
and reflect the 
local amendment 


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efficacy analysis will be performed for the PPS-single using a 
linear mixed model with treatment as a fixed effect. The analysis 
will be performed with loge-transformed LDH at Week 26 
estimating the difference in least squares means and its 95% CI, 
and the delta method will be used to provide the mean difference 
and 95% CI in original scale. The equivalence will be declared if 
the two-sided 95% CI of the mean difference in LDH level at 
Week 26 between SB12 and Soliris® lies within the pre-defined 
equivalence margin of [−1.2 × ULN, 1.2 × ULN] where ULN of 
LDH to be specified in the central laboratory specification for this 
study. 
(…) 
for those who are in favour of the LDH level at a single time 
point, the primary efficacy analysis will be performed for the 
PPS-single using a linear mixed model with treatment, and 
gender as a fixed effect. The analysis will be performed with 
loge-transformed LDH at Week 26 estimating the difference in 
least squares means and its 95% CI, and the delta method will be 
used to provide the mean difference and 95% CI in original scale. 
The equivalence will be declared if the two-sided 95% CI of the 
mean difference in LDH level at Week 26 between SB12 and 
Soliris® lies within the pre-defined equivalence margin of [−1.2 
× ULN, 1.2 × ULN] where ULN of LDH to be specified in the 
central laboratory specification for this study. 
(…) 
9.5.1. 
Efficacy 
Variable 
Analyses 
As a secondary efficacy endpoint, number of units of pRBCs 
transfused will be analysed using Wilcoxon rank-sum test for 
each period. And mean LDH profile will be presented over time. 
As a secondary efficacy endpoint, number of units of pRBCs 
transfused during the Main Part will be analysed using 
Wilcoxon rank-sum test for each period. And mean LDH profile 
during the Main Part will be presented over time. 
To reflect the 
changes due to 2-
year extension 
period 
9.5.2. Safety 
Analyses for 
the Main 
Part 
9.5.2. 
Safety Analyses 
(…) 
All TEAEs and SAEs will be summarised respectively by count 
and percentage of subjects experiencing events by system organ 
class, preferred term, treatment sequence, and period. SAEs 
leading to IP discontinuation and TEAEs by causality and 
severity will be summarised similarly. All AEs including those 
pre-existing before the initiation of study drug will be listed by 
subject. 
In addition, infection-related AEs including meningococcal 
9.5.2. 
Safety Analyses for the Main Part 
(…) 
All TEAEs and SAEs reported during the randomised 
treatment period will be summarised respectively by count and 
percentage of subjects experiencing events by system organ 
class, preferred term, treatment sequence, and period. SAEs 
leading to IP discontinuation and TEAEs by causality and 
severity will be summarised similarly. All AEs including those 
pre-existing before the initiation of study drug will be listed by 
subject. 
To reflect the 
changes due to 2-
year extension 
period 


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infection and other systemic infection, and IRRs will also be 
summarised. 
Duration of exposure to IP and number of IV infusion will be 
summarised by treatment sequence and period with descriptive 
statistics for the SAF. Prior and concomitant medications, and 
significant non-drug therapies will be summarised by treatment 
sequence and period with count and percentage. 
(…) 
All safety analyses will be performed using the SAF. 
In addition, infection-related AEs including meningococcal 
infection and other systemic infection, and IRRs reported 
during the randomised treatment period will also be 
summarised. 
Duration of exposure to IP and number of IV infusion during the 
randomised treatment period will be summarised by treatment 
sequence and period with descriptive statistics for the SAF1. 
Prior and concomitant medications, and significant non-drug 
therapies will be summarised by treatment sequence and period 
with count and percentage. 
(…) 
All safety analyses will be performed using the SAF1. 
9.5.3. Safety 
Analyses for 
the 
Extension 
Part 
N/A 
9.5.3. 
Safety Analyses for the Extension Part 
All reported terms for SAEs will be coded using MedDRA®. 
SAEs reported during the Extension Part will be summarised 
and listed for the SAF2.  
Duration of exposure to IP and number of IV infusion during 
the Extension Part will be summarised with descriptive 
statistics for the SAF2.  
To reflect the 
changes due to 2-
year extension 
period 
9.5.5. 
Immunogeni
city 
Analyses 
(…) 
Immunogenicity analyses will be performed using the SAF. 
(…) 
Immunogenicity analyses will be performed using the SAF1. 
To reflect the 
changes due to 2-
year extension 
period 
9.6. Sample 
Size 
(…) 
For calculation of the equivalence margin for AUEC of LDH, 
(…) 
For calculation of the equivalence margin for time-adjusted 
To clarify the 
primary endpoint 


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Calculation 
mean and coefficient of variation (%CV) were referred from 
TRIUMPH study. The mean (%CV) of AUEC of LDH at Week 
26 is 81140.0 U/L × day (142.45%) and 429874.1 U/L × day 
(33.49%) for eculizumab and non-eculizumab arms, respectively. 
From the results in the reference study, mean ratio of AUEC of 
LDH is estimated to be 0.19 with a 90% CI [0.1308, 0.2724]. 
The upper limit of the equivalence margin is calculated as 
 
 where it preserves at least 
 of 
eculizumab treatment effect over the placebo, but 
 
 the equivalence margin will be [0.77, 
1.29] for the comparison with the 90% CI of mean ratio of 
AUEC of LDH. 
(…) 
AUEC of LDH, mean and coefficient of variation (%CV) were 
referred from TRIUMPH study. The mean (%CV) of AUEC of 
LDH at Week 26 is 81140.0 U/L × day (142.45%) and 429874.1 
U/L × day (33.49%) for eculizumab and non-eculizumab arms, 
respectively.  
From the results in the reference study, mean ratio of time-
adjusted AUEC of LDH is estimated to be 0.19 with a 90% CI 
[0.1308, 0.2724]. The upper limit of the equivalence margin is 
calculated as 
 where it preserves 
at least 
 of eculizumab treatment effect over the placebo, 
but 
 the equivalence margin 
will be [0.77, 1.29] for the comparison with the 90% CI of mean 
ratio of AUEC of LDH. 
(…) 
10.2 
Monitoring 
(…) 
(…) Monitors will also perform source data verification by 
comparing entries in the eCRF with corresponding source data 
and informing the Investigator of any errors or omissions. 
Monitors will verify adherence to the protocol at the 
investigational site. All PDs will be reported to the Sponsor via 
the monitoring visit reports. Monitors will arrange for the supply 
of IP and ensure appropriate storage conditions are maintained. 
Monitoring visits will be conducted at regular intervals according 
to ICH-GCP. The monitor will provide written reports to the 
Sponsor on each occasion they make contact with the 
Investigator regardless of whether it is by phone or in person. 
(…) 
(…) 
(…) Monitors will also perform source data verification by 
comparing entries in the eCRF with corresponding source data 
and informing the Investigator of any errors or omissions for the 
Main Part and IP infusion date/time at Week 52. Monitors will 
verify adherence to the protocol at the investigational site. All 
PDs will be reported to the Sponsor via the monitoring visit 
reports. Monitors will arrange for the supply of IP and ensure 
appropriate storage conditions are maintained. 
Monitoring visits will be conducted at regular intervals according 
to ICH-GCP. The monitor will provide written reports to the 
Sponsor on each occasion they make contact with the 
Investigator regardless of whether it is by phone or in person 
(…) 
To reflect the 
changes due to 2-
year extension 
period 


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Section 
Affected 
Original Content 
Amended/New Content 
Rationale 
10.5. 
Database 
Management 
and Coding 
Data generated within this clinical study will be handled 
according to the relevant SOPs of the data management and 
biostatistics departments of the Sponsor (or an appropriate 
company designated by the Sponsor to perform these activities). 
Subject data will be captured in an eCRF and reviewed by the 
monitor in order to check adherence to the protocol and to 
detect any data inconsistency or discrepancy. 
(…) 
Data generated within this clinical study will be handled 
according to the relevant SOPs of the data management and 
biostatistics departments of the Sponsor (or an appropriate 
company designated by the Sponsor to perform these activities). 
Subject data will be captured in an eCRF and reviewed by the 
monitor in order to check adherence to the protocol and to 
detect any data inconsistency or discrepancy. The eCRF will be 
used only during the Main Part and IP infusion date/time at 
Week 52. 
(…) 
To reflect the 
changes due to 2-
year extension 
period 
10.6. Quality 
Control and 
Quality 
Assurance 
During the conduct of the study, the Sponsor or its agent will 
conduct periodic monitoring visits to ensure that the protocol 
and ICH-GCP are being followed. The monitors may review 
source documents to confirm that the data recorded in the eCRF 
are accurate. The Investigator and institution will allow the 
domestic and foreign regulatory authorities, the Sponsor’s 
monitors and auditors’ direct access to source documents to 
perform this verification. The investigational site may be 
subject to review by the IRB/IEC, and/or to quality assurance 
audits performed by the Sponsor, and/or to inspection by 
appropriate regulatory authorities. It is important that the 
Investigators and their relevant personnel are available during 
the monitoring visit and possible audits or inspections and that 
sufficient time is devoted to the process. 
During the conduct of the study, the Sponsor or its agent will 
conduct periodic monitoring visits to ensure that the protocol 
and ICH-GCP are being followed. The monitors may review 
source documents to confirm that the data recorded in the 
eCRF are accurate. The Investigator and institution will allow 
the domestic and foreign regulatory authorities, the Sponsor’s 
monitors and auditors’ direct access to source documents to 
perform this verification. The investigational site may be 
subject to review by the IRB/IEC, and/or to quality assurance 
audits performed by the Sponsor, and/or to inspection by 
appropriate regulatory authorities. It is important that the 
Investigators and their relevant personnel are available during 
the monitoring visit, and possible audits and/or inspections 
regulatory inspection(s) and that sufficient time is devoted to 
the process. 
To reflect the 
changes due to 2-
year extension 
period 
10.7. 
Protocol 
Deviation 
(…) 
PDs will be reviewed and confirmed prior to database lock to 
decide which subjects and/or subject data will be excluded from 
certain analyses. Decisions regarding the exclusion of subjects 
and/or subject data from analyses will be documented and 
approved prior to database lock. 
(…) 
PDs will be reviewed and confirmed prior to database lock for 
the Main Part to decide which subjects and/or subject data will 
be excluded from certain analyses. Decisions regarding the 
exclusion of subjects and/or subject data from analyses will be 
documented and approved prior to database lock for the Main 
Part. 
To reflect the 
changes due to 2-
year extension 
period 


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Section 
Affected 
Original Content 
Amended/New Content 
Rationale 
13. 
References 
[10] Soliris® EPAR – Product Information. EMA (Oct 24, 2018). 
Retrieved Dec 11, 2018 from  
https://www.ema.europa.eu/documents/product-
information/soliris-epar-product-information_en.pdf 
[10] Soliris® EPAR – Product Information. EMA (Oct 24, 2018 
Sep 04, 2019). Retrieved Dec 11, 2018 Sep 09, 2019 from  
https://www.ema.europa.eu/documents/product-
information/soliris-epar-product-information_en.pdf 
To refer the latest 
version of 
regulatory 
document 
13. 
References 
[21] Soliris® Prescribing Information. FDA (Jul 25, 2018). 
Retrieved Oct 04, 2018 from  
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/
125166s047s048lbl.pdf 
[21] Soliris® Prescribing Information. FDA (Jul 25, 2018 Jun 
27, 2019). Retrieved Oct 04, 2018 Jul 09, 2019 from  
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/
125166s047s048lbl.pdf 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/
125166s431lbledt.pdf 
To refer the latest 
version of 
regulatory 
document 
Protocol 
Signature 
Pages 
Sponsor Representative 
Name: 
 
 
Sponsor Representative 
Name: 
 
 
Administrative 
change 
Protocol 
Signature 
Pages 
Declaration 
of 
the 
Global 
Principal/Coordinating 
Investigator 
(…) 
Global Principal/Coordinating Investigator 
Declaration 
of 
the 
Global 
Principal/Coordinating 
Investigator 
(…) 
Global Principal/Coordinating Investigator 
To use the 
terminology as 
defined by GCP 
 
 
 


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Amendment 4: Version 5.0, Aug 21, 2020 
Section 
Affected 
Original Content 
Amended/New Content 
Rationale 
SYNOPSIS 
Planned 
Study Period 
After Screening, the duration of study participation will be 52-
week randomised treatment period and an extension period of up 
to 2 years. 
After Screening, the duration of study participation will be 58 
weeks per subject including 52-week randomised treatment 
period and an extension period of up to 2 years. 50 weeks of 
treatment and 8 weeks of post-treatment follow-up. After 
completion of study treatment, subjects may be entered into 
an extended supply of up to 2 years.  
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 
SYNOPSIS 
Study 
Design 
This multicentre Phase III study is composed of the Main Part 
and Extension Part. 
The Main Part is a randomised, double-blind period to compare 
the efficacy, safety, pharmacokinetics, and immunogenicity 
between SB12 and Soliris® in subjects with PNH. The 
Extension Part is an open-label, single-arm, 2-year extension 
period to provide SB12 in subjects with PNH for an extended 
duration under an ethical basis. 
For the Main Part, subjects will be randomised in a 1:1 ratio to 
treatment sequence I (SB12 to Soliris®) or treatment sequence II 
(Soliris® to SB12). Subjects who are randomised to initially 
receive SB12 will be switched to receive Soliris® and subjects 
who are randomised to initially receive Soliris® will be switched 
to receive SB12 at Week 26. End of the Main Part is defined as 
completion of pre-dose activities at Week 52. Subjects who 
complete the Main Part will enter the Extension Part. For the 
Extension Part, all subjects will receive SB12 for 2 years. 
This multicentre Phase III study is composed of the Main 
Part and Extension Part. 
The Main Part is a randomised, Phase III, double-blind 
period, multicentre, cross-over study to compare the efficacy, 
safety, pharmacokinetics, and immunogenicity between SB12 
and Soliris® in subjects with PNH. The Extension Part is an 
open-label, single-arm, 2-year extension period to provide 
SB12 in subjects with PNH for an extended duration under 
an ethical basis. 
For the Main Part, sSubjects will be randomised in a 1:1 ratio 
to treatment sequence I (SB12 to Soliris®) or treatment 
sequence II (Soliris® to SB12). Subjects who are randomised to 
initially receive SB12 will be switched to receive Soliris® and 
subjects who are randomised to initially receive Soliris® will be 
switched to receive SB12 at Week 26. End of the Main Part is 
defined as completion of pre-dose activities at Week 52. 
Subjects who complete the Main Part will enter the 
Extension Part. For the Extension Part, all subjects will 
receive SB12 for 2 years. 
After completion of activities at Week 52, an open-label 
extended supply of SB12 will be provided for up to 2 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 


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calendar years to subjects who have benefited from study 
treatment and opt to participate in extended supply under 
an ethical basis.  
SYNOPSIS 
Eligibiltiy 
Criteria 
Main Eligibility Criteria: 
Main Eligibility Criteria: 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 
SYNOPSIS 
Investigation
-al Products 
• 
Dose regimen: 600 mg every 7 days for the first 4 weeks 
(initial phase) and 900 mg for the fifth week, followed by 
900 mg every 14 ± 2 days, thereafter (maintenance phase). 
• 
Dose regimen: 600 mg every 7 days for the first 4 weeks 
(initial phase) and 900 mg for the fifth week, followed by 
900 mg every 14 ± 2 days, thereafter until Week 50 
(maintenance phase).  
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 
SYNOPSIS 
Main 
Criteria for 
Evaluation 
Secondary endpoints 
Efficacy endpoints 
• 
LDH profile during the Main Part 
• 
Number of units of pRBCs transfused during the Main 
Part 
Safety endpoints 
(…) 
During the Extension Part, only SAEs will be collected. 
Immunogenicity endpoints  
• 
Incidence of anti-drug antibodies (ADAs) at Weeks 0 
(Day 1), 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 
44, 48, 52, and early termination (ET) 
• 
Incidence of neutralising antibodies (NAbs) at Weeks 0 
(Day 1), 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 
44, 48, 52, and ET 
Secondary endpoints 
Efficacy endpoints 
• 
LDH profile during the Main Part over time 
• 
Number of units of pRBCs transfused during the Main 
Part throughout the study period 
Safety endpoints 
(…) 
During the Extension Part, only SAEs will be collected. 
Immunogenicity endpoints  
• 
Incidence of anti-drug antibodies (ADAs) at Weeks 0 
(Day 1), 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 
44, 48, 52, and early termination (ET) visit 
• 
Incidence of neutralising antibodies (NAbs) at Weeks 0 
(Day 1), 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 
44, 48, 52, and ET visit 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 


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SYNOPSIS 
Statistical 
Methods 
Efficacy analyses 
(…) 
As a secondary efficacy endpoint, the number of units of 
pRBCs transfused during the Main Part will be analysed using 
Wilcoxon rank-sum test for each period. And mean LDH profile 
during the Main Part will be presented over time. 
Safety analyses 
Safety analyses will be performed in the Safety Set for the Main 
Part (SAF1) and Safety Set for the Extension Part (SAF2). 
(…) 
All AE data reported during the Main Part will be summarised 
by count and percentage of subjects experiencing events by 
system organ class, preferred term, treatment sequence, and 
period for the SAF1. SAEs leading to IP discontinuation and 
treatment-emergent AEs (TEAEs) by causality and severity will 
be summarised similarly. (…) 
Changes in vital signs and clinical laboratory parameters will be 
summarised descriptively by treatment sequence, period, and 
time point for the SAF1. (…)  
All SAEs reported during the Extension Part will be 
summarised by count and percentage of subjects experiencing 
events by system organ class and preferred term for the SAF2. 
PK analyses 
PK analysis will be performed for the PK Analysis Set (PKS). 
Ctrough will be summarised descriptively by treatment sequence, 
period, and time point. 
Efficacy analyses 
(…) 
As a secondary efficacy endpoint, the number of units of 
pRBCs transfused during the Main Part will be summarised 
descriptively by treatment sequence and treatment sequence 
within period and will be analysed using Wilcoxon rank-sum 
test for each period. And mean LDH profile during the Main 
Part will be presented over time. 
Safety analyses 
Safety analyses will be performed in the Safety Set (SAF). for 
the Main Part (SAF1) and Safety Set for the Extension Part 
(SAF2). 
All AE data reported during the Main Part will be 
summarised by count and percentage of subjects experiencing 
events by system organ class, preferred term, treatment 
sequence, and period for the SAF1. SAEs TEAEs leading to 
IP discontinuation and treatment-emergent AEs (TEAEs) by 
causality and severity will be summarised similarly. (…) 
Changes in vital signs and clinical laboratory parameters will be 
summarised descriptively by treatment sequence, period, and 
time point for the SAF1 visit. (…)  
All SAEs reported during the Extension Part will be 
summarised by count and percentage of subjects 
experiencing events by system organ class and preferred 
term for the SAF2. 
PK analyses 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 
To clarify the 
efficacy/safety 
analysis 


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Immunogenicity analyses 
The immunogenicity analyses will be performed for the SAF1. 
ADA and NAb results will be summarised with count and 
percentage by treatment sequence, period, and time point. The 
incidence of overall ADA will be summarised by treatment 
sequence and period. 
PD analyses 
PD analysis will be performed for the PD Analysis Set (PDS). 
The absolute value and change from baseline in terminal 
complement activities will be summarised by treatment 
sequence, period, and time point. 
PK analysis will be performed for the PK Analysis Set (PKS). 
Ctrough will be summarised descriptively by treatment sequence, 
period, and time point visit. 
Immunogenicity analyses 
The immunogenicity analyses will be performed for the SAF1. 
ADA and NAb results will be summarised with count and 
percentage by treatment sequence, period, and time point visit. 
The incidence of overall ADA will be summarised by treatment 
sequence and period. 
PD analyses 
PD analysis will be performed for the PD Analysis Set (PDS). 
The absolute value and change from baseline in terminal 
complement activities will be summarised by treatment 
sequence, period, and time point visit. 
Figure 1 
 
 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 
Figure 1 
Footnote 
d. From Week 4, 900 mg of SB12 or Soliris® every 14 ± 2 
days up to Week 50. During the Extension Part, SB12 will 
be given to all subjects. 
(…) 
f. 
Completion of pre-dose activities at Week 52 is defined as 
end of the Main Part. 
g. EOS is defined as the date of last subject’s last visit in the 
Extension Part. 
d. From Week 4, 900 mg of SB12 or Soliris® every 14 ± 2 
days up to Week 50. During the Extension Part, SB12 
will be given to all subjects. 
(…) 
f. 
Completion of pre-dose activities at Week 52 is defined 
as end of the Main Part. 
After completion of activities at Week 52, an open-label 
extended supply of SB12 will be provided for up to 2 
calendar years to subjects who have benefited from 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 


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study treatment and opt to participate in extended 
supply under an ethical basis. 
g. EOS is defined as the date of last subject’s last visit in 
the Extension Part. either completion of safety follow-
up at Week 58 or completion of ET visit (8 weeks after 
the last dose of SB12 or Soliris®), which may be up to 
Week 56. 
Table 1 
Table 1. Schedule of Activities (Main Part: Period 1, before 
Cross-over) 
Table 1. Schedule of Activities (Main Part: Period 1, before 
Cross-over) 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 
Table 1 
Footnote 
7. Females of childbearing potential only. Serum pregnancy 
test at Screening and 8 weeks after the last dose of study 
drug in case of early termination (ET) during the Main Part; 
urine pregnancy test at other applicable visits before study 
drug administration. 
(…) 
14. Blood sample for immunogenicity assay will be taken prior 
to dosing at Weeks 0, 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 
36, 40, 44, 48, 52, and ET. Blood samples should be 
collected at the same day of study drug administration 
except for ET visit. If the administration of IPs is delayed 
for any reasons after pre-dose blood sampling for 
immunogenicity assay, blood sample should be re-collected 
on actual dosing day and be used for analysis. 
(…) 
19. Adverse events (AEs) will be collected from the time of 
signing the informed consent until end of the Main Part (or 
7. Females of childbearing potential only. Serum pregnancy 
test at Screening and 8 weeks after the last dose of study 
drug in case of early termination (ET) during the Main 
Part; urine pregnancy test at other applicable visits before 
study drug administration. 
(…) 
14. Blood sample for immunogenicity assay will be taken prior 
to dosing at Weeks 0, 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 
36, 40, 44, 48, 52, and ET visit. Blood samples should be 
collected at the same day of study drug administration 
except for ET visit. If the administration of IPs is delayed 
for any reasons after pre-dose blood sampling for 
immunogenicity assay, blood sample should be re-collected 
on actual dosing day and be used for analysis. 
(…) 
19. Adverse events (AEs) will be collected from the time of 
signing the informed consent until end of the Main Part 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 


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8 weeks after the last dose of study drug in case of ET 
during the Main Part). 
20. Previous medications (within 4 weeks prior to Screening 
except immunosuppressant, 8 weeks prior to Screening for 
immunosuppressant) will be recorded and concomitant 
medications will be recorded until end of the Main Part (or 
8 weeks after the last dose of study drug in case of ET 
during the Main Part). 
21. Transfusion record will be collected from the time of 
signing the informed consent until end of the Main Part (or 
8 weeks after the last dose of study drug in case of ET 
during the Main Part). 
(or 8 weeks after the last dose of study drug in case of 
ET during the Main Part) end of study (EOS). 
20. Previous medications (within 4 weeks prior to Screening 
except immunosuppressant, 8 weeks prior to Screening for 
immunosuppressant) will be recorded and concomitant 
medications will be recorded until end of the Main Part 
(or 8 weeks after the last dose of study drug in case of 
ET during the Main Part) EOS. 
21. Transfusion record will be collected from the time of 
signing the informed consent until end of the Main Part 
(or 8 weeks after the last dose of study drug in case of 
ET during the Main Part) EOS. 
Table 2 
Table 2. Schedule of Activities (Main Part: Period 2, after 
Cross-over) 
Table 2. Schedule of Activities (Main Part: Period 2 and Safety 
Follow-up/ET, after Cross-over) 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 
Table 2 
Assessments 
Study Period 
Study Visit 
ET21 
Week 
8 (±1) weeks after the last 
dose of study d 
rug 
Day (± Visit Window) 
 
Assessments 
Study Period 
Study Visit 
Safety 
Follow-up21 
ET22 
Week 
58 
8 (±1) weeks 
after the last 
dose of study 
drug 
Day (± Visit Window) 
407 (±7) 
Adverse events17 
Continuously 
Previous and 
concomitant 
medications18 
Continuously 
Thrombosis record 
(MAVEs) 
Continuously 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 


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Transfusion record (date 
and number of 
pRBCs)19 
Continuously 
 
Table 2 
Footnote 
ET = Early Termination; (…) 
4. Females of childbearing potential only. Serum pregnancy 
test at Screening and 8 weeks after the last dose of study 
drug in case of ET during the Main Part; urine pregnancy 
test at other applicable visits before study drug 
administration. 
(…) 
11. Blood sample for immunogenicity assay will be taken prior 
to dosing at Weeks 0, 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 
36, 40, 44, 48, 52, and ET. Blood samples should be 
collected at the same day of study drug administration 
except for ET visit. If the administration of IPs is delayed 
for any reasons after pre-dose blood sampling for 
immunogenicity assay, blood sample should be re-collected 
on actual dosing day and be used for analysis. 
(…) 
17. AEs will be collected from the time of signing the informed 
consent until end of the Main Part (or 8 weeks after the last 
dose of study drug in case of ET during the Main Part). 
18. Concomitant medications will be recorded until end of the 
Main Part (or 8 weeks after the last dose of study drug in 
case of ET during the Main Part). 
19. Transfusion record will be collected from the time of 
signing the informed consent until end of the Main Part (or 
ET = Early Termination; (…) 
4. Females of childbearing potential only. Serum pregnancy 
test at Screening and 8 weeks after the last dose of study 
drug in case of ET during the Main Part; urine pregnancy 
test at other applicable visits before study drug 
administration. 
(…) 
11. Blood sample for immunogenicity assay will be taken prior 
to dosing at Weeks 0, 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 
36, 40, 44, 48, 52, and ET visit. Blood samples should be 
collected at the same day of study drug administration 
except for ET visit. If the administration of IPs is delayed 
for any reasons after pre-dose blood sampling for 
immunogenicity assay, blood sample should be re-collected 
on actual dosing day and be used for analysis. 
(…) 
17. AEs will be collected from the time of signing the informed 
consent until end of the Main Part (or 8 weeks after the 
last dose of study drug in case of ET during the Main 
Part) EOS. 
18. Concomitant medications will be recorded until end of the 
Main Part (or 8 weeks after the last dose of study drug 
in case of ET during the Main Part) EOS. 
19. Transfusion record will be collected from the time of 
signing the informed consent until end of the Main Part 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 


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8 weeks after the last dose of study drug in case of ET 
during the Main Part). 
20. End of the Main Part is defined as completion of pre-dose 
activities at Week 52. 
21. ET visit is defined as 8 weeks after the last dose of SB12 or 
Soliris®, which may be up to Week 58. 
(or 8 weeks after the last dose of study drug in case of 
ET during the Main Part) EOS. 
20. End of the Main Part is defined as completion of pre-
dose activities at Week 52. 
After completion of activities at Week 52, an open-label 
extended supply of SB12 will be provided for up to 2 
calendar years to subjects who have benefited from 
study treatment and opt to participate in extended 
supply under an ethical basis. The Week 52 activities 
must be completed prior to initiation of extended 
supply. Subjects who are eligible to participate should 
provide separate informed consent prior to enter an 
extended supply of SB12. 
21. ET visit is defined as 8 weeks after the last dose of SB12 
or Soliris®, which may be up to Week 58. 
Safety follow-up will be done at Week 58 for subjects 
who complete the study treatments until Week 50, 
regardless whether subject receives extended supply of 
SB12 or not. These activities will be conducted either by 
visit or by phone call on subjects’ preference. 
22. ET visit is defined as 8 weeks after the last dose of SB12 
or Soliris®, which may be up to Week 56. Subjects who 
discontinue from the study at any time post-Day 1 (after 
the initiation of study drug) before completion of last 
study treatment at Week 50 will be required to have an 
ET visit. 
Table 3 
Table 7. Schedule of Activities (Extension Part: 2-year 
Extension Period) 
Table 8. Schedule of Activities (Extension Part: 2-year 
Extension Period) 
To update study 
design/process in 
order to minimize 
the risk of COVID-


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Assessment
s 
Study Period 
Week 
52 
54 
… 
152 
154 
End 
of 
the 
Exte
nsio
n 
Part
3 
SB12 
administrati
on1 
 
 
… 
 
 
 
Serious 
adverse 
events2 
Continuously 
 
1.  From Week 52, SB12 will be administered bi-weekly via 
IV infusion for 35 ± 10 minutes for all subjects. 
2.  Only SAEs will be collected during the Extension Part 
from start of study treatment at Week 52. 
3.  End of the Extension Part is defined as 8 weeks after the 
last dose of SB12. Prematurely discontinued subjects do 
not require any specific study procedures as done in the 
Main Part.  
Assessment
s 
Study Period 
Week 
52 
54 
… 
152 
154 
End 
of 
the 
Exte
nsio
n 
Part
3 
SB12 
administrati
on1 
 
 
… 
 
 
 
Serious 
adverse 
events2 
Continuously 
 
1.  From Week 52, SB12 will be administered bi-weekly via 
IV infusion for 35 ± 10 minutes for all subjects. 
2.  Only SAEs will be collected during the Extension Part 
from start of study treatment at Week 52. 
3.  End of the Extension Part is defined as 8 weeks after the 
last dose of SB12. Prematurely discontinued subjects do 
not require any specific study procedures as done in the 
Main Part.  
19 pandemic 
LIST OF 
ABBREVIA
-TIONS 
N/A 
N/A 
SAF1 
Safety Set for the Main Part 
SAF2 
Safety Set for the Extension Part 
COVID-19 
Coronavirus Disease 2019 
DSUR 
Development Safety Update Report 
IgG 
Immunoglobulin G 
PC 
Product Complaints 
PSUR 
Periodic Safety Update Report 
To revise/add 
abbreviations 
according to 
updated contents 


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SAF1 
Safety Set for the Main Part 
SAF2 
Safety Set for the Extension Part 
LIST OF 
STUDY 
STAFF 
Clinical Project 
Manager  
  
  
  
Clinical 
Development 
Assistant  
  
  
  
Statistician  
  
  
  
Project Safety 
Lead 
 
 
 
 
Clinical Project 
Manager  
  
 
 
  
 
Clinical Research 
Physician  
 
 
 
Clinical 
Development 
Assistant 
Research 
Scientist 
 
 
Statistician  
 
 
 
Project Safety 
Lead 
 
 
 
Administrative 
change  
1.2. 
Overview of 
SB12 
(…) SB12 and Soliris® have identical primary structure and the 
active substance for both products is eculizumab, a humanised 
monoclonal antibody (IgG2/4 kappa immunoglobulin) that 
binds to the human C5 complement protein with high affinity. 
Binding to this protein blocks its cleavage into C5a and C5b, 
thereby inhibiting terminal complement-mediated intravascular 
haemolysis. 
(…) SB12 and Soliris® have identical primary structure and the 
active substance for both products is eculizumab, a humanised 
monoclonal antibody (immunoglobulin G[IgG]2/4 kappa 
immunoglobulin) that binds to the human C5 complement 
protein with high affinity. Binding to this protein blocks its 
cleavage into C5a and C5b, thereby inhibiting terminal 
complement-mediated intravascular haemolysis. 
To refer the latest 
information 


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(…) 
According to the guideline International Conference on 
Harmonisation Q6B, characterisation of a biological therapeutic 
must involve its physicochemical properties, biological 
activities, purity, impurities, and quantity. (…) 
(…) 
According to the guideline International Conference on 
Council for Harmonisation (ICH) Q6B, characterisation of a 
biological therapeutic must involve its physicochemical 
properties, biological activities, purity, impurities, and quantity. 
(…) 
1.5.1. 
Known 
Potential 
Risks 
According to Soliris® Summary of Product Characteristics 
(SmPC) [10], supportive safety data were collected from 30 
completed and one ongoing clinical studies that included 1,503 
patients exposed to eculizumab in complement-mediated 
disease populations, including PNH, aHUS, refractory gMG and 
NMOSD. The most common adverse reaction was headache 
(occurred mostly in the initial phase) and of all meningococcal 
infections the most frequently reported serious adverse reaction 
was meningococcal sepsis. 
According to Soliris® Summary of Product Characteristics 
(SmPC) [10], supportive safety data were collected from 30 31 
completed and one ongoing clinical studies that included 1,503 
patients exposed to eculizumab in complement-mediated 
disease populations, including PNH, aHUS, refractory gMG and 
NMOSD. The most common adverse reaction was headache 
(occurred mostly in the initial phase) and of all meningococcal 
infections the most frequently reported serious adverse reaction 
was meningococcal sepsis.  
(…) 
To refer the latest 
version of 
regulatory 
document  
2.2.2. 
Secondary 
Endpoints 
Secondary endpoints 
Efficacy endpoints 
• 
LDH profile during the Main Part 
• 
Number of units of pRBCs transfused during the Main 
Part 
Safety endpoints 
(…) 
During the Extension Part, only SAEs will be collected. 
Immunogenicity endpoints  
• 
Incidence of anti-drug antibodies (ADAs) at Weeks 0 
(Day 1), 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 
44, 48, 52, and early termination (ET) 
Secondary endpoints 
Efficacy endpoints 
• 
LDH profile during the Main Part over time 
• 
Number of units of pRBCs transfused during the Main 
Part throughout the study period 
Safety endpoints 
(…) 
During the Extension Part, only SAEs will be collected. 
Immunogenicity endpoints  
• 
Incidence of anti-drug antibodies (ADAs) at Weeks 0 
(Day 1), 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 
44, 48, 52, and early termination (ET) visit 
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the risk of COVID-
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• 
Incidence of neutralising antibodies (NAbs) at Weeks 0 
(Day 1), 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 
44, 48, 52, and ET 
• 
Incidence of neutralising antibodies (NAbs) at Weeks 0 
(Day 1), 2, 4, 6, 10, 14, 18, 22, 26, 28, 30, 32, 36, 40, 
44, 48, 52, and ET visit 
3.1. 
Overview of 
Study 
Design 
This multicentre Phase III study is composed of the Main Part 
and Extension Part. 
The Main Part is a randomised, double-blind period to compare 
the efficacy, safety, pharmacokinetics, and immunogenicity 
between SB12 and Soliris® in subjects with PNH. The Extension 
Part is an open-label, single-arm, 2-year extension period to 
provide SB12 in subjects with PNH for an extended duration 
under an ethical basis. 
Subjects will be randomised in a 1:1 ratio to treatment sequence 
I (SB12 to Soliris®) or treatment sequence II (Soliris® to SB12). 
Subjects randomly assigned to treatment with SB12 or Soliris® 
will receive 600 mg of eculizumab IV every week for first 4 
weeks (initial phase) and 900 mg for the fifth week, followed by 
900 mg every 2 weeks thereafter. Subjects who are randomised 
to initially receive SB12 will be switched to receive Soliris® and 
subjects who are randomised to initially receive Soliris® will be 
switched to receive SB12 at Week 26. SB12 or Soliris® will be 
given until Week 50. End of the Main Part is defined as 
completion of pre-dose activities at Week 52. Subjects who 
complete the Main Part will enter the Extension Part. 
For the Extension Part, all subjects will receive SB12 for 2 years. 
Details of assessment that will be conducted and treatment that 
will be administered are presented in, Table 1, Table 2, and Table 
3. The last assessment for the Main Part will be performed at pre-
dose of Week 52 or 8 weeks after the last dose of SB12 or Soliris® 
in case of ET during the Main Part. The last assessment for the 
Extension Part will be performed at 8 weeks after the last dose of 
This multicentre Phase III study is composed of the Main Part 
and Extension Part. 
The Main Part is a randomised, Phase III, double-blind period , 
multicentre, cross-over study to compare the efficacy, safety, 
pharmacokinetics, and immunogenicity between SB12 and 
Soliris® in subjects with PNH. The Extension Part is an open-
label, single-arm, 2-year extension period to provide SB12 in 
subjects with PNH for an extended duration under an ethical 
basis. 
Subjects will be randomised in a 1:1 ratio to treatment sequence 
I (SB12 to Soliris®) or treatment sequence II (Soliris® to SB12). 
Subjects randomly assigned to treatment with SB12 or Soliris® 
will receive 600 mg of eculizumab IV every week for first 4 
weeks (initial phase) and 900 mg for the fifth week, followed by 
900 mg every 2 weeks thereafter. Subjects who are randomised 
to initially receive SB12 will be switched to receive Soliris® and 
subjects who are randomised to initially receive Soliris® will be 
switched to receive SB12 at Week 26. SB12 or Soliris® will be 
given until Week 50. End of the Main Part is defined as 
completion of pre-dose activities at Week 52. Subjects who 
complete the Main Part will enter the Extension Part. 
For the Extension Part, all subjects will receive SB12 for 2 
years. 
Details of assessment that will be conducted and treatment that 
will be administered are presented in, Table 1 and Table 2, and 
Table 3. The last assessment for the Main Part will be 
performed at pre-dose of Week 52 58 or 8 weeks after the last 
To update study 
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SB12. 
dose of SB12 or Soliris® in case of ET during the Main Part. 
The last assessment for the Extension Part will be 
performed at 8 weeks after the last dose of SB12. 
After completion of activities at Week 52, an open-label 
extended supply of SB12 will be provided for up to 2 calendar 
years to subjects who have benefited from study treatment and 
opt to participate in extended supply under an ethical basis. 
3.3. Duration 
of Study 
Participation 
After Screening, the duration of study participation will be 52-
week randomised treatment period and an extension period of up 
to 2 years. 
After Screening, the duration of study participation will be 58 
weeks per subject including 52-week randomised treatment 
period and an extension period of up to 2 years. 50 weeks of 
treatment and 8 weeks of post-treatment follow-up. After 
completion of study treatment, subjects may be entered into 
an extended supply of up to 2 years.  
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 
3.5. End of 
Study 
Definition 
A subject is considered to have completed the each part of study 
if he or she has completed all study treatment including the last 
visit or the last scheduled procedure shown in Table 2 and Table 
3. The end of the Main Part is defined as completion of pre-dose 
activities at Week 52 for subjects. The end of the Extension Part 
is defined as 8 weeks after the last dose of SB12.  
The end of study (EOS) is defined as the date of last subject’s last 
visit in the Extension Part. 
A subject is considered to have completed the each part of study 
if he or she has completed all study treatment including and the 
last visit or the last scheduled procedure shown in Table 2 and 
Table 3. The end of the Main Part end of study (EOS) is 
defined as completion of pre-dose activities safety follow-up at 
Week 52 for subjects. The end of the Extension Part is defined 
as 58 or completion of ET visit (8 weeks after the last dose of 
SB12 or Soliris®). The end of this clinical study is defined as 
completion of the last subject’s EOS.  
The end of study (EOS) is defined as the date of last 
subject’s last visit in the Extension Part. 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 
4.4. Screen 
Failures and 
Re-screening  
N/A 
During Coronavirus Disease 2019 (COVID-19) pandemic 
circumstances, eligibility may not be confirmed at Screening 
due to unexpected COVID-19 related restrictions. These 
cases may fall into screen failures due to out of 42 days 
screening window or consent withdrawal related with 
COVID-19 concern, etc. These will be considered as 
To implement 
recommendations 
belonging to DDLs 
issued to address 
COVID-19 
pandemic 


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technical issue so that re-screening is applicable after 
COVID-19 related restrictions are relieved. 
5.1.1. 
Dosing and 
Treatment 
Schedule 
Dosing and treatment schedule of SB12 or Soliris® should be kept 
as follows:  
 
600 mg every 7 ± 2 days for the first 4 weeks, 
followed by 
 
900 mg for the fifth dose 7 ± 2 days later, then 
 
900 mg every 14 ± 2 days thereafter 
(…) 
The subject receiving SB12 or Soliris® therapy may require 
dosing interval adjustment within the recommended 14 ± 2 days 
dosing schedule during the maintenance period (up to every 12 
days) when it is deemed necessary at the discretion of the 
Investigator; e.g., two consecutive events of elevated LDH ≥ 2 
× ULN combined with sign or symptom of intravascular 
haemolysis after prior LDH reduction to < 1.5 × ULN on 
treatment. For subjects whose dosing interval is adjusted to 12 
days in Period 1 of the Main Part, it is recommended that the 
dosing interval be switched back to 14 days after switching IP at 
Week 26. Once the above event has occurred, the Investigator 
should inform the medical monitor and/or Sponsor immediately 
during the Main Part, but in the Extension Part, the event can be 
managed at the discretion of the Investigator. 
SB12 or Soliris® will be administered up to Week 50 (a total 
of 28 administrations of IP) unless they are early 
discontinued from study treatment. Dosing and treatment 
schedule of SB12 or Soliris® should be kept as follows:  
 
600 mg every 7 ± 2 days for the first 4 weeks, 
followed by 
 
900 mg for the fifth dose 7 ± 2 days later, then 
 
900 mg every 14 ± 2 days thereafter 
(…) 
The subject receiving SB12 or Soliris® therapy may require 
dosing interval adjustment within the recommended 14 ± 2 days 
dosing schedule during the maintenance period (up to every 12 
days) when it is deemed necessary at the discretion of the 
Investigator; e.g., two consecutive events of elevated LDH ≥ 2 
× ULN combined with sign or symptom of intravascular 
haemolysis after prior LDH reduction to < 1.5 × ULN on 
treatment. If a 12 or 13 day dosing interval conflicts with 
administrative schedules (e.g., holidays or weekends) but a 
shortened dosing interval is considered necessary for safety 
of subject, consultation with medical monitor (or Sponsor) is 
recommended. For subjects whose dosing interval is adjusted 
to 12 days in Period 1 of the Main Part, it is recommended that 
the dosing interval be switched back to 14 days after switching 
IP at Week 26. Once the above event has occurred, the 
Investigator should inform the medical monitor and/or Sponsor 
immediately during the Main Part, but in the Extension 
To update study 
design/process in 
order to minimize 
the risk of COVID-
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To add clarification 
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adjustement to 
address DSMB 
feedback  


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Part, the event can be managed at the discretion of the 
Investigator. 
5.1.3. 
Blinding 
The Main Part of this study is double-blinded. Subjects, 
Investigators, and other study personnel will remain blinded to 
the treatment sequence assignment until end of the Main Part 
after randomisation. 
(…) 
The Main Part of tThis study is double-blinded. Subjects, 
Investigators, and other study personnel will remain blinded to 
the treatment sequence assignment until end of the Main Part 
throughout the study period after randomisation. 
(…) 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 
5.2.1. 
Identify of 
Investigation
-al Product 
The IPs will be supplied to investigational site in one carton 
containing a single vial. These IP vials will be packed and 
labelled in a double-blinded manner for the Main Part. For the 
Extension Part, SB12 will also be supplied to investigational site 
in one carton containing a single vial. These SB12 vials will be 
packed and labelled using open label for the Extension Part.  
(…) 
The IPs will be supplied to investigational site in one carton 
containing a single vial. These IP vials will be packed and 
labelled in a double-blinded manner for the Main Part. For the 
Extension Part, SB12 will also be supplied to investigational 
site in one carton containing a single vial. These SB12 vials 
will be packed and labelled using open label for the Extension 
Part clinical use.  
(…) 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 
5.2.2. 
Formulation, 
Packaging, 
and 
Labelling 
(…) 
Packaging and labelling of SB12 or Soliris® will follow 
standard operating procedure (SOP) of the manufacturing site 
and regulatory requirements in each country, as well as will be 
in accordance with International Council for Harmonisation 
(ICH)-Good Clinical Practice (GCP). SB12 or Soliris® will be 
pre-packaged and labelled in a double-blinded form for the 
Main Part. For the Extension Part, SB12 will be packaged and 
labelled using open label. (…) 
(…) 
Packaging and labelling of SB12 or Soliris® will follow 
standard operating procedure (SOP) of the manufacturing site 
and regulatory requirements in each country, as well as will be 
in accordance with International Council for Harmonisation 
(ICH)-Good Clinical Practice (GCP). SB12 or Soliris® will be 
pre-packaged and labelled in a double-blinded form for the 
Main Part. For the Extension Part, SB12 will be packaged 
and labelled using open label. (…) 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 
5.2.5. 
Treatment 
Compliance 
and 
Investigation
-al Product 
(…) 
(…) At the completion or termination of each part of the study, a 
final drug accountability review and reconciliation must be 
completed; any discrepancies must be investigated and their 
(…) 
(…) At the completion or termination of each part of the study, 
a final drug accountability review and reconciliation must be 
completed; any discrepancies must be investigated and their 
To update study 
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Accountabili
-ty 
resolution must be documented.  
(…) 
For the Extension Part, compliance will be assessed by the 
subject’s source documents. All dosing information should be 
recorded in the subject’s source documents. 
resolution must be documented.  
(…) 
For the Extension Part, compliance will be assessed by the 
subject’s source documents. All dosing information should 
be recorded in the subject’s source documents. 
5.3. 
Concomitant 
Medication 
or Treatment 
All medication including both prescription and non-prescription 
drugs, and any procedures undertaken between 4 weeks prior to 
Screening (except for immunosuppressant) and end of the Main 
Part should be recorded in the subject’s source documents and 
eCRF. (…) 
(…) 
All medication including both prescription and non-prescription 
drugs, and any procedures undertaken between 4 weeks prior to 
Screening (except for immunosuppressant) and end of the Main 
Part EOS should be recorded in the subject’s source documents 
and eCRF. (…) 
(…) 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 
5.3.1. 
Permitted 
Concomitant 
Medications 
or Treatment 
The following concomitant medications are allowed if given on 
a stable dose (only for chronic administration) during the Main 
Part. However, for the subject’s welfare, medications can be 
adjusted after discussion between the Investigator and medical 
monitor and/or Sponsor.  
(…) 
The following concomitant medications are allowed if given on 
a stable dose (only for chronic administration) during the Main 
Part study period. However, for the subject’s welfare, 
medications can be adjusted after under discussion between the 
Investigator and medical monitor and/or Sponsor.  
(…) 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 
To clarify the 
meaning regarding 
permitted 
medications dose 
adjustement for 
subjects’ welfare 
5.3.2. 
Prohibited 
Concomitant 
Medications 
or Treatment 
Immunosuppressant except for cyclosporine is prohibited during 
the Main Part including but not limited to: 
(…) 
Immunosuppressant except for cyclosporine is prohibited during 
the Main Part study period from randomisation including but 
not limited to: 
(…) 
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6.1.2. 
Breakthroug
-h 
Haemolysis 
The Investigator and/or designee will record the breakthrough 
haemolysis in the source documents and eCRF during the Main 
Part.  
(…) 
The Investigator and/or designee will record the breakthrough 
haemolysis in the source documents and eCRF during the Main 
Part study period.  
(…) 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 
6.1.3. 
Transfusions 
(…) 
Transfusion record will be collected from the signing of the 
informed consent until end of the Main Part (or 8 weeks after the 
last dose of study drug in case of ET during the Main Part). 
Anaemia-related signs or symptoms, haemoglobin value, number 
of units of pRBCs will be documented on the source documents 
and eCRF.  
(…) 
Transfusion record will be collected from the signing of the 
informed consent until end of the Main Part (or 8 weeks after 
the last dose of study drug in case of ET during the Main 
Part) EOS. Anaemia-related signs or symptoms, haemoglobin 
value, number of units of pRBCs will be documented on the 
source documents and eCRF.  
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 
6.1.4. Major 
Adverse 
Vascular 
Events 
The description of MAVEs, anatomical site, method of diagnosis, 
date of diagnosis, and outcome will be recorded in the source 
documents and eCRF as AEs during the Main Part.  
(…) 
The description of MAVEs, anatomical site, method of diagnosis, 
date of diagnosis, and outcome will be recorded in the source 
documents and eCRF as AEs during the Main Part study 
period.  
(…) 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 
6.2.2. 
Clinical 
Laboratory 
Evaluations 
N/A 
During COVID-19 pandemic circumstances, it may be unable 
to get central laboratory values in time due to COVID-19 
related restrictions. For those cases, local laboratory will be 
allowed in addition to central laboratory for scheduled visit 
after randomisation until COVID-19 restrictions are relieved 
under discussion with Sponsor.  
To implement 
recommendations 
belonging to DDLs 
issued to address 
COVID-19 
pandemic 
Table 4 
Footnote 
1 Pregnancy test will be performed for women of childbearing 
potential (serum or urine). Serum pregnancy test will be 
performed at Screening and 8 weeks after the last dose of study 
drug in case of ET during the Main Part and urine pregnancy 
test will be performed at other applicable visits before study 
drug administration. 
1 Pregnancy test will be performed for women of childbearing 
potential (serum or urine). Serum pregnancy test will be 
performed at Screening and 8 weeks after the last dose of study 
drug in case of ET during the Main Part and urine pregnancy 
test will be performed at other applicable visits before study 
drug administration. 
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6.3.2. 
Immunogeni
-city 
assessments 
(…) Blood samples should be collected at the same day of study 
drug administration except for ET visit. (…) 
(…) 
(…) Blood samples should be collected at the same day of study 
drug administration except for ET visit. (…) 
(…) 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 
7.1. Study 
Flow and 
Visit 
Schedule 
During this study, efficacy, safety, PK, immunogenicity, and PD 
assessments will be performed. The complete schedule of 
activities is outlined in Table 1, Table 2, and Table 3. 
During this study, efficacy, safety, PK, immunogenicity, and PD 
assessments will be performed. The complete schedule of 
activities is outlined in Table 1, and Table 2, and Table 3. 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 
7.1.2. 
Randomisati
-on 
N/A 
During COVID-19 pandemic circumstances, Day 1 (1st 
dosing) may not be started within 21 days of randomisation 
due to unexpected COVID-19 related restrictions. In such 
cases, the subject will be monitored for safety per 
Investigator’s discretion. Day 1 will be started after the 
COVID-19 related restrictions are relieved. 
To implement 
recommendations 
belonging to DDLs 
issued to address 
COVID-19 
pandemic 
7.1.3. 
Treatment 
Period 
7.1.3. 
Randomised Treatment Period 
(…) 
Laboratory assessments will be performed at central laboratory. 
Detail instructions of collecting, processing, storing, and 
shipping for blood samples are described in the laboratory 
manual. Laboratory reports will be available to the Investigator 
in a timely manner for clinical management of subjects during 
randomised treatment period. 
(…) 
7.1.3. Randomised Treatment Period 
(…) 
Laboratory assessments will be performed at central laboratory. 
Detail instructions of collecting, processing, storing, and 
shipping for blood samples are described in the laboratory 
manual. Laboratory reports will be available to the Investigator 
in a timely manner for clinical management of subjects during 
randomised treatment period. 
(…) 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 
7.1.3.1. 
Randomised 
Treatment 
Period 1 
(before 
7.1.3.1. Randomised Treatment Period 1 (before Cross-over) 
7.1.3.1. Randomised Treatment Period 1 (before Cross-over) 
To update study 
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Cross-over) 
19 pandemic 
7.1.3.3. 
Randomised 
Treatment 
Period 2 
(after Cross-
over) 
7.1.3.3. Randomised Treatment Period 2 (after Cross-over) 
7.1.3.3.  Randomised Treatment Period 2 (after Cross-over) 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 
7.1.3.4. 
Early 
Termination 
Visit 
N/A 
7.1.3.4. Safety Follow-up (Week 58/Day 407)  
Safety follow-up will be done at Week 58 (± 7 days) which is 
8 weeks after the last dose of SB12 or Soliris® for subjects who 
complete the study treatments until Week 50, regardless 
whether subject receives extended supply of SB12 or not to 
ensure subject’s safety. These activities will be conducted 
either by visit or by phone call based on subjects’ preference.  
 
AEs, concomitant medications, MAVEs, and 
transfusion record will be assessed and recorded. 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 
7.1.3.5. 
Early 
Termination 
Visit 
7.1.3.4. Early Termination Visit  
ET visit is defined as 8 weeks (± 7 days) after the last dose of 
study drug during the randomised treatment period. This includes 
when the subject does not enroll into the extension period (i.e., 
discontinue at Week 52 without study drug administration). 
(…) 
7.1.3.4. 7.1.3.5.  Early Termination Visit 
ET visit is defined as 8 weeks (± 7 days) after the last dose of 
study drug SB12 or Soliris® during the randomised treatment 
period. This includes when the subject does not enroll into the 
extension period (i.e., discontinue at Week 52 without study 
drug administration). 
(…) 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 
7.1.4. 
Unscheduled 
Visits 
If a sign or symptom of breakthrough haemolysis is suspected 
during randomised treatment period, an unscheduled visit should 
be occurred and samples should be collected for LDH, PK, and 
If a sign or symptom of breakthrough haemolysis is suspected 
during randomised treatment period, an unscheduled visit 
To update study 
design/process in 
order to minimize 
the risk of COVID-


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PD assessment for central laboratory at that time. (…) 
should be occurred and samples should be collected for LDH, 
PK, and PD assessment for central laboratory at that time. (…) 
19 pandemic 
7.1.5. 
Extension 
Period 
7.1.5. Extension Period  
After the randomised treatment period, all subjects who have 
completed the Main Part will enter the extension period and 
receive SB12 from Week 52 for 2 years.  
 
SB12 administrations by IV infusion for 35 ± 10 
minutes (900 mg every 14 ± 2 days) 
 
SAEs will be assessed and recorded. 
Discontinuation of study treatment can be decided at the 
discretion of the Investigator or by subject’s consent 
withdrawal. Specific study procedures are not required for 
subjects who have discontinued prematurely. SAEs must be 
collected until 8 weeks (± 7 days) from the last dose of study 
drug (Section 8.2.2). 
7.1.5. Extension Period  
After the randomised treatment period, all subjects who 
have completed the Main Part will enter the extension 
period and receive SB12 from Week 52 for 2 years.  
 
SB12 administrations by IV infusion for 35 ± 10 
minutes (900 mg every 14 ± 2 days) 
 
SAEs will be assessed and recorded. 
Discontinuation of study treatment can be decided at the 
discretion of the Investigator or by subject’s consent 
withdrawal. Specific study procedures are not required for 
subjects who have discontinued prematurely. SAEs must be 
collected until 8 weeks (± 7 days) from the last dose of study 
drug (Section 8.2.2). 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 
7.2.1. 
Subject 
Discontinuat
ion from 
Study 
Treatment 
(…) 
During the Main Part, the Investigator should discuss with the 
medical monitor prior to discontinuing a subject’s study 
treatment in case of the following criteria, but not limited to: 
(…) 
For the Extension Part, discontinuation of study treatment can be 
decided at the discretion of the Investigator or by subject’s 
consent withdrawal. 
Discontinuation from study treatment does not mean immediate 
discontinuation from the study, and remaining study procedures 
should be completed as indicated by the study protocol. Subjects 
(…) 
During the Main Part, tThe Investigator should discuss with the 
medical monitor prior to discontinuing a subject’s study 
treatment in case of the following criteria, but not limited to: 
(…) 
For the Extension Part, discontinuation of study treatment 
can be decided at the discretion of the Investigator or by 
subject’s consent withdrawal. 
Discontinuation from study treatment does not mean immediate 
discontinuation from the study, and remaining study procedures 
should be completed as indicated by the study protocol. Subjects 
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who discontinue from the study at any time post-Day 1 (after the 
initiation of study drug) will be required to have an ET visit. The 
data to be collected at the 8 weeks after the last dose of study drug 
are described in the Section 7.1.3.4. Every effort will be 
employed to keep subjects who discontinued from study 
treatment to undertake the scheduled ET visit procedures. For the 
Extension Part, specific study procedures are not required for 
subjects who have discontinued the study treatment prematurely 
and the subject will discontinue from the study once the study 
treatment is permanently discontinued. SAEs must be collected 
until 8 weeks (± 7 days) from the last dose of study drug in such 
cases (Section 8.2.2). Once study treatment is discontinued 
during the Extension Part, it is recommended to inform the 
Sponsor, if occurs.   
(…) 
who discontinue from the study at any time post-Day 1 (after the 
initiation of study drug) before completion of last study 
treatment at Week 50 will be required to have an ET visit. The 
data to be collected at the 8 weeks after the last dose of study drug 
are described in the Section 7.1.3.4 7.1.3.5. Every effort will be 
employed to keep subjects who discontinued from study 
treatment to undertake the scheduled ET visit procedures. For 
the Extension Part, specific study procedures are not 
required for subjects who have discontinued the study 
treatment prematurely and the subject will discontinue from 
the study once the study treatment is permanently 
discontinued. SAEs must be collected until 8 weeks (± 7 days) 
from the last dose of study drug in such cases (Section 8.2.2). 
Once study treatment is discontinued during the Extension 
Part, it is recommended to inform the Sponsor, if occurs.   
(…) 
8.1.2. Period 
of 
Observation 
for Adverse 
Events 
AEs will be reported from the time of signing the ICF until end 
of the Main Part (or ET visit of the Main Part). Only SAEs will 
be collected during the Extension Part from start of study 
treatment at Week 52. 
(…) 
Unresolved AEs during the Main Part should be followed up 
until end of the Main Part and recorded. The Investigator 
should observe the AEs for appropriate medical care of the 
subject until AE resolution or stabilisation. 
If the subject has an ongoing SAE at 8 weeks after the last dose 
of study drug, these cases will be followed until event 
resolution or stabilisation (see Section 8.2.2). 
AEs will be reported from the time of signing the ICF until end 
of the Main Part (or ET visit of the Main Part). Only SAEs 
will be collected during the Extension Part from start of 
study treatment at Week 52 EOS. 
(…) 
Unresolved AEs during the Main Part study period should be 
followed up until end of the Main Part and recorded EOS. 
The Investigator should observe the AEs for appropriate 
medical care of the subject until AE resolution or stabilisation. 
If the subject has an ongoing SAE at 8 weeks after the last dose 
of study drug EOS, these cases will be followed until event 
resolution or stabilisation (see Section 8.2.2). 
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8.2.2. 
Reporting 
Serious 
Adverse 
Events 
(…) 
SAEs that occurred until end of the Main Part (or ET visit of 
the Main Part) must be reported to the Sponsor or its 
designated representative via eCRF SAE report form at least 
within 24 hours of the Investigator becoming aware of the 
event. 
SAEs that occurred after end of the Main Part must be reported 
to the Sponsor or its designated representative using the paper 
SAE report form at least within 24 hours of the Investigator 
becoming aware of the event. 
(…) 
(…) 
SAEs that occurred until end of the Main Part ( at or ET visit 
of the Main Part) before EOS must be reported to the 
Sponsor or its designated representative via eCRF SAE report 
form at least within 24 hours of the Investigator becoming 
aware of the event. 
SAEs that occurred after end of the Main Part EOS must be 
reported to the Sponsor or its designated representative using 
the paper SAE report form at least within 24 hours of the 
Investigator becoming aware of the event. 
(…) 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 
9. Statistical 
Methods and 
Data 
Analysis 
Statistical analysis and reporting will be performed as follows: 
(…) 
 
Main Part CSR: 
The analysis will take place after the last subject completes 
the procedures at Week 52 or the corresponding visit. All 
study data will be analysed and reported for the Main Part 
CSR. 
 
Extension Part CSR: 
A separate SAP for analyses of 2-year extension period will 
be prepared describing the methodology and presentation of 
results. The analysis will take place after the last subject 
completes the procedures of 2-year extension period. 
Statistical analysis and reporting will be performed as follows: 
(…) 
 
Main Part CSR: 
The analysis will take place after the last subject completes 
the procedures at Week 52 58 or the corresponding visit. All 
study data will be analysed and reported for the Main Part 
CSR. 
 
Extension Part CSR: 
A separate SAP for analyses of 2-year extension period 
will be prepared describing the methodology and 
presentation of results. The analysis will take place after 
the last subject completes the procedures of 2-year 
extension period. 
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9.2. Analysis 
Sets 
The following sets will be used for the analyses performed in the 
study: 
• 
(…) 
• 
Safety Set for the Main Part (SAF1) consists of all subjects 
who receive at least one IP during the randomised treatment 
period. Subjects will be analysed according to the treatment 
received. 
• 
Safety Set for the Extension Part (SAF2) consists of all 
subjects who receive at least one IP during the extension 
period. 
• 
PK Analysis Set (PKS) consists of all subjects in the SAF1 
who have at least one PK sample analysed. 
• 
PD Analysis Set (PDS) consists of all subjects in the SAF1 
who have at least one PD sample analysed. 
The following sets will be used for the analyses performed in the 
study: 
• 
(…) 
• 
Safety Set for the Main Part (SAF1) consists of all subjects 
who receive at least one IP during the randomised 
treatment study period. Subjects will be analysed 
according to the treatment received. 
• 
Safety Set for the Extension Part (SAF2) consists of all 
subjects who receive at least one IP during the extension 
period. 
• 
PK Analysis Set (PKS) consists of all subjects in the SAF1 
who have at least one PK sample analysed. 
• 
PD Analysis Set (PDS) consists of all subjects in the SAF1 
who have at least one PD sample analysed. 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 
9.5.1. 
Efficacy 
Variable 
Analyses 
As a secondary efficacy endpoint, number of units of pRBCs 
transfused during the Main Part will be analysed using Wilcoxon 
rank-sum test for each period. And mean LDH profile during the 
Main Part will be presented over time. 
As a secondary efficacy endpoint, number of units of pRBCs 
transfused during the Main Part will be summarised 
descriptively by treatment sequence and treatment sequence 
within period and will be analysed using Wilcoxon rank-sum 
test for each period. And mean LDH profile during the Main 
Part will be presented over time. 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 
To clarify the 
efficacy/safety 
analysis 
9.5.2. Safety 
Analyses 
9.5.2. 
Safety Analyses for the Main Part 
(…) 
All TEAEs and SAEs reported during the randomised treatment 
9.5.2. 
Safety Analyses for the Main Part 
(…) 
All TEAEs and SAEs reported during the randomised 
To update study 
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the risk of COVID-


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period will be summarised respectively by count and percentage 
of subjects experiencing events by system organ class, preferred 
term, treatment sequence, and period. SAEs leading to IP 
discontinuation and TEAEs by causality and severity will be 
summarised similarly. All AEs including those pre-existing 
before the initiation of study drug will be listed by subject. 
In addition, infection-related AEs including meningococcal 
infection and other systemic infection, and IRRs reported during 
the randomised treatment period will also be summarised. 
Duration of exposure to IP and number of IV infusion during the 
randomised treatment period will be summarised by treatment 
sequence and period with descriptive statistics for the SAF1. 
Prior and concomitant medications, and significant non-drug 
therapies will be summarised by treatment sequence and period 
with count and percentage. 
Changes in vital signs and clinical laboratory parameters will be 
summarised descriptively by treatment sequence, period, and 
time point. Other safety variables will be summarised unless 
otherwise specified, and all safety variables will be listed. 
All safety analyses will be performed using the SAF1. 
treatment period will be summarised respectively by count and 
percentage of subjects experiencing events by system organ 
class, preferred term, treatment sequence, and period. SAEs 
TEAEs leading to IP discontinuation and TEAEs by causality 
and severity will be summarised similarly. All AEs including 
those pre-existing before the initiation of study drug will be listed 
by subject. 
In addition, infection-related AEs including meningococcal 
infection and other systemic infection, and IRRs reported 
during the randomised treatment period will also be 
summarised. 
Duration of exposure to IP and number of IV infusion during the 
randomised treatment period will be summarised by treatment 
sequence and within period with descriptive statistics for the 
SAF1. Prior and concomitant medications, and significant non-
drug therapies will be summarised by treatment sequence and 
period with count and percentage. 
Changes in vital signs and clinical laboratory parameters will be 
summarised descriptively by treatment sequence, period, and 
time point visit. Other safety variables will be summarised 
unless otherwise specified, and all safety variables will be listed. 
All safety analyses will be performed using the SAF1. 
19 pandemic 
To clarify the 
efficacy/safety 
analysis 
9.5.3. Safety 
Analyses for 
the 
Extension 
Part 
9.5.3. 
Safety Analyses for the Extension Part 
All reported terms for SAEs will be coded using MedDRA®. 
SAEs reported during the Extension Part will be summarised and 
listed for the SAF2.  
Duration of exposure to IP and number of IV infusion during 
the Extension Part will be summarised with descriptive statistics 
for the SAF2. 
9.5.3. 
Safety Analyses for the Extension Part 
All reported terms for SAEs will be coded using MedDRA®. 
SAEs reported during the Extension Part will be summarised 
and listed for the SAF2.  
Duration of exposure to IP and number of IV infusion 
during the Extension Part will be summarised with 
descriptive statistics for the SAF2. 
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design/process in 
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the risk of COVID-
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9.5.4. 
Immunogeni
-city 
Analyses 
ADA and NAb results (e.g., ‘positive’ or ‘negative’) will be 
summarised with count and percentage by treatment sequence, 
period, and time point. In addition, incidence of overall ADA will 
be summarised by treatment sequence and period.  
Immunogenicity analyses will be performed using the SAF1. 
ADA and NAb results (e.g., ‘positive’ or ‘negative’) will be 
summarised with count and percentage by treatment sequence, 
period, and time point visit. In addition, incidence of overall 
ADA will be summarised by treatment sequence and period.  
Immunogenicity analyses will be performed using the SAF1. 
To clarify the 
efficacy/safety 
analysis 
9.5.5. 
Pharmacody
-namic 
Analyses 
PD analysis will be performed for the PDS. The absolute values, 
and change from baseline in terminal complement activities will 
be summarised by treatment sequence, period, and time point. 
(…) 
PD analysis will be performed for the PDS. The absolute values, 
and change from baseline in terminal complement activities will 
be summarised by treatment sequence, period, and time point 
visit. (…) 
To clarify the 
efficacy/safety 
analysis 
10.2 
Monitoring 
(…) 
(…) Monitors will also perform source data verification by 
comparing entries in the eCRF with corresponding source data 
and informing the Investigator of any errors or omissions for the 
Main Part and IP infusion date/time at Week 52. (…) 
(…) 
(…) 
(…) Monitors will also perform source data verification by 
comparing entries in the eCRF with corresponding source data 
and informing the Investigator of any errors or omissions for the 
Main Part and IP infusion date/time at Week 52. (…) 
(…) 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 
10.5. 
Database 
Management 
and Coding 
(…) The eCRF will be used only during the Main Part and IP 
infusion date/time at Week 52. 
(…) 
(…) The eCRF will be used only during the Main Part and IP 
infusion date/time at Week 52. 
(…) 
To update study 
design/process in 
order to minimize 
the risk of COVID-
19 pandemic 
10.7. 
Protocol 
Deviation 
(…) 
PDs will be reviewed and confirmed prior to database lock for 
the Main Part to decide which subjects and/or subject data will 
be excluded from certain analyses. Decisions regarding the 
exclusion of subjects and/or subject data from analyses will be 
documented and approved prior to database lock for the Main 
Part. 
(…) 
PDs will be reviewed and confirmed prior to database lock for 
the Main Part to decide which subjects and/or subject data will 
be excluded from certain analyses. Decisions regarding the 
exclusion of subjects and/or subject data from analyses will be 
documented and approved prior to database lock for the Main 
Part. 
To update study 
design/process in 
order to minimize 
the risk of COVID-
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13. Extended 
Supply 
N/A 
After completion of activities at Week 52, an open-label 
extended supply of SB12 will be provided for up to 2 calendar 
years starting from Week 52 to subjects who have benefited 
from study treatment and opt to participate in extended 
supply under an ethical basis. 
Before entering an extended supply, the Investigator will 
review the subject status including reduction of PNH disease 
activity, such as improvement of symptoms or laboratory 
parameters, during eculizumab treatment to decide if the 
subject will benefit from participation in extended supply. 
Once subjects are considered to benefit from extended 
supply, subjects will be asked if he/she would like to receive 
an extended supply. For receiving an extended supply, 
subjects should agree with signing ICF for extended supply 
and with required activities including refraining from 
pregnancy, maintaining a highly effective contraceptive 
method, and receiving meningococcal vaccination (if 
required by local regulations) to ensure subject's safety 
during extended supply. 
During extended supply, Investigators will treat subjects with 
900 mg of SB12 every 14 ± 2 days for up to 2 years (104 
weeks). SB12 will be packaged and labelled using open label 
and dispensed through the IWRS. Investigators should 
ensure the compliance and accountability of SB12 during the 
course of extended supply. Any PC must be reported to 
Sponsor.  
SAEs that occur during this phase must be reported to the 
Sponsor, which will be reported to regulatory authorities by 
the Sponsor according to local/national requirements via 
expedited reporting and periodic reporting such as 
Development Safety Update Report (DSUR) or Periodic 
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Safety Update Report (PSUR). Pregnancy should also be 
reported until 5 months after the last SB12 treatment. Other 
particular activities will not be imposed and no data 
collection or reporting will occur for extended supply.  
Discontinuation of study treatment can be decided if 
unacceptable toxicity, pregnancy, other complement inhibitor 
use or lack of efficacy occurs, or at the discretion of the 
Investigator or by subject’s consent withdrawal. Specific 
study procedures are not required for subjects who have 
discontinued prematurely except for SAEs reporting and 
pregnancy reporting.   
 
During the period of extended supply, the Investigator and 
the Sponsor will follow all local laws and regulations relating 
to contact with and approvals from the IRB/IEC. The 
Investigator is responsible for ensuring that the study is 
conducted according to the signed Investigator statement, the 
study protocol and applicable regulations; for protecting the 
rights, safety, and welfare of subjects under the Investigator’s 
care; and for the control of drugs under investigation.  
The Investigators must maintain essential study documents 
until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region or 
at least 2 years after the formal discontinuation of clinical 
development of the IP or 15 years from completion of the 
extended supply, if applicable. 
Investigational sites participation may be discontinued if the 
Sponsor, Investigator or IRB/IEC consider necessary. 
Extended supply may be terminated by the Sponsor if 
medically or ethically indicated, and in such cases will be 


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promptly notified to the Investigator. In any case, health 
authorities and IRB/IEC will be informed for the action in 
accordance with applicable regulations.. 
14. 
References 
[10] Soliris® EPAR – Product Information. EMA (Sep 04, 
2019). Retrieved Sep 09, 2019 from  
https://www.ema.europa.eu/documents/product-
information/soliris-epar-product-information_en.pdf 
[10] Soliris® EPAR – Product Information. EMA (Sep 04, 2019 
Jul 01, 2020). Retrieved Sep 09, 2019 Jul 13, 2020 from  
https://www.ema.europa.eu/documents/product-
information/soliris-epar-product-information_en.pdf 
To refer the latest 
version of 
regulatory 
document 


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Amendment 5: Version 6.0, Nov 27, 2020 
Section 
Affected 
Original Content 
Amended/New Content 
Rationale 
SYNOPSIS 
Study 
Design 
This is a randomised, Phase III, double-blind, multicentre, 
cross-over study to compare the efficacy, safety, 
pharmacokinetics, and immunogenicity between SB12 and 
Soliris® in subjects with PNH. 
Subjects will be randomised in a 1:1 ratio to treatment sequence 
I (SB12 to Soliris®) or treatment sequence II (Soliris® to SB12). 
Subjects who are randomised to initially receive SB12 will be 
switched to receive Soliris® and subjects who are randomised to 
initially receive Soliris® will be switched to receive SB12 at 
Week 26. 
After completion of activities at Week 52, an open-label 
extended supply of SB12 will be provided for up to 2 calendar 
years to subjects who have benefited from study treatment and 
opt to participate in extended supply under an ethical basis. 
This is a randomised, Phase III, double-blind, multicentre, 
cross-over study to compare the efficacy, safety, 
pharmacokinetics, and immunogenicity between SB12 and 
Soliris® in subjects with PNH. 
Subjects will be randomised in a 1:1 ratio to treatment sequence 
I (SB12 to Soliris®) or treatment sequence II (Soliris® to SB12). 
Subjects who are randomised to initially receive SB12 will be 
switched to receive Soliris® and subjects who are randomised to 
initially receive Soliris® will be switched to receive SB12 at 
Week 26. 
In special circumstances of a shortage of the comparator, to 
ensure continuity of study treatment for the duration of 
study, the Sponsor will provide SB12 instead of Soliris® in a 
blinded manner. 
After completion of activities at Week 52, an open-label 
extended supply of SB12 will be provided for up to 2 calendar 
years to subjects who have benefited from study treatment and 
opt to participate in extended supply under an ethical basis. 
To update study 
design/process in 
order to address a 
special 
circumstances of a 
shortage of the 
comparator 
SYNOPSIS 
Statistical 
Methods 
Analysis sets for efficacy analyses 
Modified Full Analysis Set (M-FAS) consists of all randomised 
subjects who do not have positive result of pharmacogenetic 
analysis (C5 gene polymorphism). However, subjects who do 
not have any efficacy assessment result after randomisation and 
do not receive IP during the study period will be excluded from 
this analysis set. Following the intent-to-treat principle, subjects 
Analysis sets for efficacy analyses 
Modified Full Analysis Set (M-FAS) consists of all randomised 
subjects who do not have positive result of pharmacogenetic 
analysis (C5 gene polymorphism). However, subjects who do 
not have any efficacy assessment result after randomisation and 
do not receive IP during the study period will be excluded from 
this analysis set. Following the intent-to-treat principle, subjects 
To update study 
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special 
circumstances of a 
shortage of the 
comparator 


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will be analysed according to the treatment sequence they are 
assigned to at randomisation.  
Per-Protocol Set for AUEC of LDH (PPS-AUEC) consists of all 
M-FAS subjects who have sufficient LDH assessments for 
AUEC calculation without any major protocol deviations (PDs) 
that have impact on efficacy assessment. Subjects excluded 
from the primary analysis will be pre-defined on a case-by-case 
basis prior to unblinding the treatment sequence assignment for 
analyses. 
Per-Protocol Set for LDH at a single time point (PPS-single) 
consists of all M-FAS subjects who have LDH assessment at 
Week 26 without any major PDs that have impact on efficacy 
assessment. Subjects excluded from the primary analysis will be 
pre-defined on a case-by-case basis prior to unblinding the 
treatment sequence assignment for analyses.  
(…) 
Safety analyses 
Safety analyses will be performed in the Safety Set (SAF). 
All reported terms for AEs will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA®). AEs will be 
collected and classified according to National Cancer Institute-
Common Terminology Criteria for Adverse Events (NCI-
CTCAE) v5.0. 
All AE data will be summarised by count and percentage of 
subjects experiencing events by system organ class, preferred 
term. TEAEs leading to IP discontinuation and treatment-
emergent AEs (TEAEs) by causality and severity will be 
summarised similarly. Infection-related AEs including 
will be analysed according to the treatment sequence they are 
assigned to at randomisation.  
Per-Protocol Set for AUEC of LDH (PPS-AUEC) consists of all 
M-FAS subjects who have sufficient LDH assessments for 
AUEC calculation without any major protocol deviations (PDs) 
that have impact on efficacy assessment. Subjects excluded 
from the primary analysis will be pre-defined on a case-by-case 
basis prior to unblinding the treatment sequence assignment for 
analyses. In addition, subjects who received different 
treatment from the randomised treatment sequence due to a 
shortage of the comparator will be excluded from this 
analysis set. 
Per-Protocol Set for LDH at a single time point (PPS-single) 
consists of all M-FAS subjects who have LDH assessment at 
Week 26 without any major PDs that have impact on efficacy 
assessment. Subjects excluded from the primary analysis will be 
pre-defined on a case-by-case basis prior to unblinding the 
treatment sequence assignment for analyses. In addition, 
subjects who received different treatment in Period 1 from 
the randomised treatment sequence due to a shortage of the 
comparator will be excluded from this analysis set. 
(…) 
Safety analyses 
Safety analyses will be performed in the Safety Set (SAF). 
All reported terms for AEs will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA®). AEs will be 
collected and classified according to National Cancer Institute-
Common Terminology Criteria for Adverse Events (NCI-
CTCAE) v5.0. 


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meningococcal infection and other systemic infection, and IRRs 
will also be summarised. 
Changes in vital signs and clinical laboratory parameters will be 
summarised descriptively by treatment sequence and visit. 
Other safety variables will be summarised unless otherwise 
specified.  
All AE data will be summarised by count and percentage of 
subjects experiencing events by system organ class, preferred 
term. TEAEs leading to IP discontinuation and treatment-
emergent AEs (TEAEs) by causality and severity will be 
summarised similarly. Infection-related AEs including 
meningococcal infection and other systemic infection, and IRRs 
will also be summarised. 
Changes in vital signs and clinical laboratory parameters will be 
summarised descriptively by treatment sequence and visit. 
Other safety variables will be summarised unless otherwise 
specified.  
Additional analyses will be performed for the subjects who 
received different treatment from the randomised treatment 
sequence due to a shortage of the comparator if needed. For 
example, AEs and concomitant medications will be analysed 
based on the actual switched treatment. 
Figure 1 
 
 
To update study 
design/process in 
order to address a 
special 
circumstances of a 
shortage of the 
comparator 
Figure 1 
Footnote 
N/A 
During the treatment period, in special circumstances of a 
shortage of the comparator, to ensure continuity of study 
treatment for the duration of study, the Sponsor will provide 
SB12 instead of Soliris® in a blinded manner. 
To update study 
design/process in 
order to address a 
special 
circumstances of a 
shortage of the 
comparator 


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LIST OF 
STUDY 
STAFF 
Clinical Project 
Manager  
 
 
 
Clinical 
Development 
Lead  
 
 
 
Clinical Research 
Physician  
 
 
 
Clinical Research 
Scientist 
 
 
 
Clinical Project 
Manager  
 
 
 
 
Clinical 
Development 
Lead  
 
 
 
 
Clinical Research 
Physician  
 
 
 
 
Clinical Research 
Scientist 
 
 
Administrative 
change  
1.5.1. 
Known 
Potential 
Risks 
Considering the mechanism of action of eculizumab, (…) All 
subjects will be monitored for early signs of meningococcal 
infection, evaluated immediately if infection is suspected, and 
treated with appropriate antibiotics if necessary. 
In order to ensure the safety of subjects who participate in the 
study, (…)  
Considering the mechanism of action of eculizumab, (…) All 
subjects will be monitored for early signs of meningococcal 
infection, evaluated immediately if infection is suspected, and 
treated with appropriate antibiotics if necessary. 
According to the study design, the switch of IP (cross-over) 
occurs during the study. The potential negative impact from 
this IP switch is considered to be minimal given similarity and 
comparability of SB12 to Soliris® and low antibody responses 
in Soliris® (3.4%) similar to that of placebo (4.8%) in placebo 
controlled studies in subjects with PNH [10]. 
In order to ensure the safety of subjects who participate in the 
study, (…) 
To update risk 
assessment in order 
to address a special 
circumstances of a 
shortage of the 
comparator 


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3.1. 
Overview of 
Study 
Design 
This is a randomised, Phase III, double-blind, multicentre, cross-
over study to compare the efficacy, safety, pharmacokinetics, and 
immunogenicity between SB12 and Soliris® in subjects with 
PNH.  
Subjects will be randomised in a 1:1 ratio to treatment sequence 
I (SB12 to Soliris®) or treatment sequence II (Soliris® to SB12). 
Subjects randomly assigned to treatment with SB12 or Soliris® 
will receive 600 mg of eculizumab IV every week for first 4 
weeks (initial phase) and 900 mg for the fifth week, followed by 
900 mg every 2 weeks thereafter. Subjects who are randomised 
to initially receive SB12 will be switched to receive Soliris® and 
subjects who are randomised to initially receive Soliris® will be 
switched to receive SB12 at Week 26. SB12 or Soliris® will be 
given until Week 50.  
This is a randomised, Phase III, double-blind, multicentre, cross-
over study to compare the efficacy, safety, pharmacokinetics, and 
immunogenicity between SB12 and Soliris® in subjects with 
PNH.  
Subjects will be randomised in a 1:1 ratio to treatment sequence 
I (SB12 to Soliris®) or treatment sequence II (Soliris® to SB12). 
Subjects randomly assigned to treatment with SB12 or Soliris® 
will receive 600 mg of eculizumab IV every week for first 4 
weeks (initial phase) and 900 mg for the fifth week, followed by 
900 mg every 2 weeks thereafter. Subjects who are randomised 
to initially receive SB12 will be switched to receive Soliris® and 
subjects who are randomised to initially receive Soliris® will be 
switched to receive SB12 at Week 26. SB12 or Soliris® will be 
given until Week 50. However, in special circumtances of a 
shortage of the comparator, to ensure continuity of study 
treatment for the duration of study, the Sponsor will provide 
SB12 instead of Soliris® in a blinded manner. 
To update study 
design/process in 
order to address a 
special 
circumstances of a 
shortage of the 
comparator 
5.1.1. 
Dosing and 
Treatment 
Schedule 
(…) 
The subject receiving SB12 or Soliris® therapy may require 
dosing interval adjustment within the recommended 14 ± 2 days 
dosing schedule during the maintenance period (up to every 12 
days) when it is deemed necessary at the discretion of the 
Investigator; e.g., two consecutive events of elevated LDH ≥ 2 × 
ULN combined with sign or symptom of intravascular 
haemolysis after prior LDH reduction to < 1.5 × ULN on 
treatment. If a 12 or 13 day dosing interval conflicts with 
administrative schedules (e.g., holidays or weekends) but a 
shortened dosing interval is considered necessary for safety of 
subject, consultation with medical monitor (or Sponsor) is 
recommended. For subjects whose dosing interval is adjusted to 
12 days in Period 1, it is recommended that the dosing interval be 
(…) 
The subject receiving SB12 or Soliris® therapy may require 
dosing interval adjustment within the recommended 14 ± 2 days 
dosing schedule during the maintenance period (up to every 12 
days) when it is deemed necessary at the discretion of the 
Investigator; e.g., two consecutive events of elevated LDH ≥ 2 × 
ULN combined with sign or symptom of intravascular 
haemolysis after prior LDH reduction to < 1.5 × ULN on 
treatment. If a 12 or 13 day dosing interval conflicts with 
administrative schedules (e.g., holidays or weekends) but a 
shortened dosing interval is considered necessary for safety of 
subject, consultation with medical monitor (or Sponsor) is 
recommended. For subjects whose dosing interval is adjusted to 
12 days in Period 1, it is recommended that the dosing interval be 
To update study 
design/process in 
order to address a 
special 
circumstances of a 
shortage of the 
comparator 


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switched back to 14 days after switching IP at Week 26. Once the 
above event has occurred, the Investigator should inform the 
medical monitor and/or Sponsor immediately.  
switched back to 14 days after switching IP at Week 26. Once the 
above event has occurred, the Investigator should inform the 
medical monitor and/or Sponsor immediately.  
In special circumstances of a shortage of the comparator, to 
ensure continuity of study treatment for the duration of 
study, the Sponsor will provide SB12 instead of Soliris® in a 
blinded manner. Rules for allocation of remaining 
comparators during the comparator shortage situation will 
be prespecified prior to execution of the potential change of 
IP assignment from Soliris® to SB12 in a blinded manner. 
This is to avoid the risk of unblinding and potential bias. 
7.1.3. 
Treatment 
Period 
The Investigator will evaluate the assessment results and 
manage subjects based on the medicinal judgement and/or 
knowledge.  
The Investigator will evaluate the assessment results and manage 
subjects based on the medicinal judgement and/or knowledge. 
In special circumstances of a shortage of the comparator, to 
ensure continuity of study treatment for the duration of 
study, the Sponsor will provide SB12 instead of Soliris® in a 
blinded manner. Investigators and subjects will be informed 
prior to the execution of the potential change of IP 
assignment. Subjects willing to continue the study treatment 
after knowing that they may receive SB12 instead of Soliris® 
in a blinded manner during the study, should have their 
agreement both documented in the source document and an 
ICF. If the Investigators or subjects do not agree to the 
potential change of IP assignment, then subjects may 
withdraw from the study and be closely monitored for at 
least 8 weeks after last dose of study drug.  
To update study 
design/process in 
order to address a 
special 
circumstances of a 
shortage of the 
comparator 
8.3.3. 
Infusion-
related 
Reactions 
Administration of SB12 or Soliris® may result in infusion 
reactions or immunogenicity that could cause allergic or 
hypersensitivity reactions (including anaphylaxis), though 
immune reactions within 48 hours of Soliris® administration 
did not differ from placebo arm in PNH, aHUS, refractory 
Administration of SB12 or Soliris® may result in infusion 
reactions or immunogenicity that could cause allergic or 
hypersensitivity reactions (including anaphylaxis), though 
immune 
reactions 
within 
48 
hours 
of 
Soliris® 
administration did not differ from placebo arm in PNH, 
To refer the latest 
version of 
regulatory 
document  


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gMG, NMOSD, and other studies conducted with Soliris®. In 
clinical trials no PNH, aHUS, refractory gMG, or NMOSD 
patients experienced an infusion reaction which required 
discontinuation of Soliris®. 
(…) 
aHUS, refractory gMG, NMOSD, and other studies 
conducted with Soliris®. In clinical trials, 1 (0.9%) gMG 
patient experienced an infusion reaction which required 
discontinuation of Soliris®. nNo PNH, aHUS, refractory 
gMG, or NMOSD patients experienced an infusion reaction 
which required discontinuation of Soliris® in clinical trials. 
(…) 
9.2. Analysis 
Sets 
The following sets will be used for the analyses performed in the 
study: 
• 
(…) 
• 
Per-Protocol Set for AUEC of LDH (PPS-AUEC) consists 
of all M-FAS subjects who have sufficient LDH assessments 
for AUEC calculation without any major PDs that have 
impact on efficacy assessment. Subjects excluded from the 
primary analysis will be pre-defined on a case-by-case basis 
prior to unblinding the treatment sequence assignment for 
analyses. 
• 
Per-Protocol Set for LDH at a single time point (PPS-single) 
consists of all M-FAS subjects who have LDH assessment 
at Week 26 without any major PDs that have impact on 
efficacy assessment. Subjects excluded from the primary 
analysis will be pre-defined on a case-by-case basis prior to 
unblinding the treatment sequence assignment for analyses.  
(…) 
The following sets will be used for the analyses performed in the 
study: 
• 
(…) 
• 
Per-Protocol Set for AUEC of LDH (PPS-AUEC) consists 
of all M-FAS subjects who have sufficient LDH assessments 
for AUEC calculation without any major PDs that have 
impact on efficacy assessment. Subjects excluded from the 
primary analysis will be pre-defined on a case-by-case basis 
prior to unblinding the treatment sequence assignment for 
analyses. In addition, subjects who received different 
treatment from the randomised treatment sequence due 
to a shortage of the comparator will be excluded from 
this analysis set. 
• 
Per-Protocol Set for LDH at a single time point (PPS-single) 
consists of all M-FAS subjects who have LDH assessment 
at Week 26 without any major PDs that have impact on 
efficacy assessment. Subjects excluded from the primary 
analysis will be pre-defined on a case-by-case basis prior to 
unblinding the treatment sequence assignment for analyses. 
In addition, subjects who received different treatment in 
Period 1 from the randomised treatment sequence due 
to a shortage of the comparator will be excluded from 
To update study 
design/process in 
order to address a 
special 
circumstances of a 
shortage of the 
comparator 


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this analysis set. 
(…) 
9.5.2. Safety 
Analyses 
(…) 
All safety analyses will be performed using the SAF. 
(…) 
All safety analyses will be performed using the SAF. Additional 
analyses will be performed for the subjects who received 
different treatment from the randomised treatment sequence 
due to a shortage of the comparator if needed. For example, 
AEs and concomitant medications will be analysed based on 
the actual switched treatment. 
To update study 
design/process in 
order to address a 
special 
circumstances of a 
shortage of the 
comparator 
14. 
References 
[21] Soliris® Prescribing Information. FDA (Jun 27, 2019). 
Retrieved Jul 09, 2019 from 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125
166s431lbledt.pdf 
[21] Soliris® Prescribing Information. FDA (Jun 27, 2019 Nov 
20, 2020). Retrieved Jul 09, 2019 Nov 26, 2020 from  
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125
166s434lbl.pdf 
To refer the latest 
version of 
regulatory 
document