Clinical trial NCT04170023
Conditions: Paroxysmal Nocturnal Hemoglobinuria (PNH)
Keywords: paroxysmal nocturnal hemoglobinuria PNH extravascular hemolysis EVH factor D inhibitor complement C5 inhibitor danicopan
Sponsor: Alexion Pharmaceuticals, Inc.
Start date: 2019-12-16; Completion date: 2024-03-20
Enrollment: 29 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The study will evaluate the efficacy and safety of the oral Factor D (FD) inhibitor ALXN2050 (ACH-0145228) monotherapy in patients with PNH that are treatment naïve, or patients currently treated with eculizumab who still experience anemia and reticulocytosis, or patients currently treated with ALXN2040 (danicopan) as monotherapy. After signing consent, participants will have periodic visits through Week 12, at which time the primary endpoint and key secondary assessments will be analyzed. Participants will continue on treatment past 12 weeks into a long-term extension portion of the trial.

Detailed description:
Experimental: Open-label ALXN2050 Monotherapy orally

Group 1: Patients with PNH who are treatment naïve

Group 2: Patients with PNH who have received complement component 5 (C5) inhibition with eculizumab for at least 6 months, who continue to experience anemia and reticulocytes above the upper limit of normal (ULN) who will switch to ALXN2050 monotherapy

Group 3: Patients with PNH receiving danicopan monotherapy in study ACH471-103 will switch to ALXN2050 monotherapy

After signing the informed consent form, participants will enter the screening period. During the Screening Period, eligibility and screening assessments will be performed. Screening assessments may be spread over more than one visit if necessary. At the baseline visit, screened participants who continue to meet eligibility criteria will enter the Treatment Period.

The treatment phase will be followed by a long-term extension phase, where ALXN2050 will continue to be administered.

Blood will be collected to assess the efficacy endpoints, such as, change in hemoglobin (Hgb), lactate dehydrogenase (LDH), and other measures of hemolysis. Safety and transfusion requirements will also be assessed.

Participants will continue on treatment past 12 weeks in a long-term extension portion of the trial.

Arms: arm 1: Experimental: Open-label ALXN2050 Monotherapy ALXN2050 orally administered

Group 1: Patients with PNH who are treatment naïve

Group 2: Patient with PNH who have received complement component 5 (C5) inhibition with eculizumab for at least 6 months, who continue to experience anemia and reticulocytes above the upper limit of normal (ULN)

Group 3: Patients with PNH who have received danicopan monotherapy during study ACH471-103
Interventions: intervention 1: ALXN2050
Intervention descriptions: intervention 1: Oral FD inhibitor

Protocol documents:
Prot_002.pdf: 
Protocol Amendment 4.0
07 Oct 2021
ACH228-110
TITLE PAGE
Protocol Titlel A Phase 2 Open-Label Proof of Concept Study to Assess the Efficacy, Safety,
and Pharmacokinetics of the Oral Factor D (FD) Inhibitor ADC{2050 (ACH-0145228) in
Paroxysmal Nocturnal Hanoglobinuria (PNH) Patients as Monotherapy
Protocol Number: ACH228- 1 I 0
Amendment Number: 4.0
Compound: AL)O.{2050 (ACH-O 14 5228)
Study Phase:2
Short Tifle: Study of the Oral Factor D (FD) Inhibitor AD0{2050 in PNH Patients as
Monotherapy
Sponsor Name: Alexion Pharmaceuticals Inc.
Legal Registered Address: 121 Seaport Blvd, Boston, MA 02210 USA
Regulatory Agency ldentifier Number(s)
Registry 
II)
EudraCT 
2019-003830-17
wHo UTN 
uttlt-1241-2441
ClinicalTrials.gov NCT04I70023
Release Date: 07 Oct202I
Sponsor Signatory:
Date
Medical Monitor Name and Contact Information can be found in study contact list.
Page I of97
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Protocol Amendment 4.0   
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INVESTIGATOR’S AGREEMENT 
I have read the study protocol and agree to conduct the study in accordance with this protocol, all 
applicable government regulations, the principles of the ICH E6 Guidelines for Good Clinical 
Practice, and the principles of the World Medical Association Declaration of Helsinki. I also 
agree to maintain the confidentiality of all information received or developed in connection with 
this protocol.  
 
 
 
 
 
____________________________________ 
Printed Name of Investigator 
 
_____________________________________ 
Signature of Investigator 
 
_______________ 
Date 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
 
Document 
Date 
Original Protocol 
01 October 2019 
Global Amendment 1.0 
06 April 2020 
Local Amendment 1.1 (UK) 
20 July 2020 
Global Amendment 2.0 
07 January 2021 
Global Amendment 2.1 
12 April 2021 
Global Amendment 3.0 
03 May 2021 
Local Amendment 3.1 (France) 
09 Sep 2021 
Local Amendment 3.2 (Germany) 
10 Sep 2021 
Global Amendment 4.0 
07 Oct 2021 
Amendment 4.0 (Global) 07 Oct 2021 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment:  
This global amendment was initiated to extend the Long-Term Extension period for an additional 
52 weeks to collect safety and efficacy data for longer term. 
This amendment also includes:  
• Clarification of exclusion criteria and additional prohibited medications to align with 
exclusion criteria. 
• Changes implemented in response to questions from the regulatory body in Germany 
(Protocol Amendment 3.2). 
Section # and Name 
Description of Change 
Brief Rationale 
Throughout the protocol 
Change in version number and document 
date; updated to summarize changes. 
Administrative change. 
Synopsis, Overall 
Design 
Section 4.1 Overall 
Design 
Enrollment text has been revised. 
New text: 
Group 1 will be enrolled in all countries 
except the US. Group 2 will be enrolled in all 
countries. Group 3 will be enrolled in 
countries where Study ACH471-103 is being 
conducted. 
Updated to provide clarity on the 
countries where the different groups 
will be enrolled. 
Section 1.1 Synopsis 
Section 3.0 Objectives 
and Endpoints 
Changed the timepoint Week 108 to Week 
160 for all endpoints 
Updated to reflect extension of the 
LTE period by 52 weeks 
Section 1.2 Schema 
Updated Figure 1. Study Design Schematic + 
footnotes 
Updated to reflect extension of the 
LTE period by 52 weeks 
Section 1.3 Schedule of 
Activities 
Table 3 Visit weeks were updated 
Footnotes were updated to define visit 
intervals 
Updated to reflect extension of the 
LTE period by 52 weeks 
Throughout the protocol 
Updated LTE period duration to 148 weeks 
and total study duration to 173 weeks 
Updated end of treatment as Week 160 and 
End of study as Week 165 
Updated to reflect extension of the 
LTE period by 52 weeks 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 5.1.2 Exclusion 
Criteria 
Exclusion #2 
Updated exclusion criterion 2 to remove 
“cyclosporine, tacrolimus, mycophenolate, 
or others” as example medications 
To remove unnecessary list of 
examples of immunosuppressive 
agents and be consistent with Section 
6.5.1 Concomitant Medications 
exclusion criterion # 2 did not 
change 
Section 6.1 Study 
Intervention 
Administered 
Removed 40 mg tablet from study 
intervention table 
This dose strength is no longer 
available and was not necessary for 
this study 
Section 6.5.2 Prohibited 
Medications 
Added the following: 
Medications known to significantly prolong 
the corrected QT interval (QTc) 
To align with exclusion criterion #9; 
change does not impact patient 
population 
Section 9.4.5 
Pharmacokinetic 
Analysis 
Updated PK parameters table to remove 
“AUC” 
To remove redundant term and align 
with the statistical analysis plan 
Section 10.2 
Appendix  2: Clinical 
Laboratory Tests 
Updated Table 5 to correct HbsAg to HbcAb  
To clarify the test done at Screening 
as part of the exclusion #16 
Section 10.3.5. 
Timeframe for 
Collection of Adverse 
Events 
Deleted the following text: 
(ie, within 24 hours of the Investigator 
becoming aware of the event). Such events 
are not entered into the CRF. 
To align with Section 8.5.1 and 
PA 3.2. 
 
Amendment 3.2 (Germany) 10 Sep 2021 
This local amendment is considered to be non-substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment:  
This local amendment was initiated to address a question from the German Federal Institute for 
Drugs and Medical Devices (BfArM). 
Section # and Name 
Description of Change 
Brief Rationale 
Throughout the 
protocol 
Change in version number and document date; updated 
to summarize changes. 
Change in title of protocol signatory 
Administrative changes. 
Section 8.4.1 Time 
Period and Frequency 
for Collecting AE and 
SAE Information 
Deleted the following text: 
(ie, within 24 hours of the Investigator becoming aware 
of the event). Such events are not entered into the CRF. 
To address BfArM query and 
this timeframe is not 
applicable in relation to 
reporting after study is 
concluded. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 10.6  
Updated Appendix 6. Seizure Management Plan as 
follows. 
Revised text: 
If the seizure is confirmed, ALXN2050 will be 
withdrawn, and the patient will be discontinued from 
the study. 
Deleted text: 
If an alternative cause for the seizure is determined, 
dosing with ALXN2050 may resume as deemed 
appropriate by the Investigator in consultation with the 
Sponsor. 
To address BfArM query on 
patient management after 
confirmed seizures. 
 
Amendment 3.1 (France) 09 Sep 2021 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment:  
This local amendment was initiated to respond to questions from Regulatory Bodies in France. 
Section # and Name 
Description of Change 
Brief Rationale 
Throughout the protocol 
Change in version number and document date; 
updated to summarize changes. 
Change in title of protocol signatory 
Administrative changes 
Synopsis and 
4.1.Overall Design 
 
The following text was revised: 
Group 2 will be enrolled in all countries. Groups 
1 and 3 will be enrolled in all countries except in 
the US. 
 
New text reads as follows: 
Group 1 will be enrolled in all countries except 
the US and France. Group 2 will be enrolled in 
all countries. Group 3 will be enrolled in 
countries where Study ACH471-103 is being 
conducted. 
To clarify the countries where 
the different groups will be 
enrolled.  
 
1.2 Schema 
Figure 1: Study Design Schematic updated and 
the footnotes about countries involved added 
 
Amendment 3.0 (Global) 03 May 2021 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment:  
This global amendment was initiated to remove the following language from the dose-escalation 
instructions: “Dose escalation to 180 mg bid will be allowed once additional safety data from the 
currently ongoing Study ALXN2050-HV-107 is available. The Sponsor will inform study sites 
when dose escalation can be implemented.” Preliminary data from Study ALXN2050-HV-107 
are now available to support for the dose escalation to proceed. 


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This amendment also includes additional information regarding prohibited medications (ie, list of 
inhibitors, inducers, and substrates of CYP3A, and list of medications known to lower seizure 
threshold). 
Section # and Name 
Description of Change 
Brief Rationale 
Throughout the protocol 
Change in version number and document 
date; updated to summarize changes. 
Administrative change. 
Throughout the protocol 
Removed dose escalation instructions. 
Data from Study 
ALXN2050-HV-107 support the 
dose escalation to proceed, hence 
these instructions are no longer 
necessary. 
Section 1.1 Synopsis 
Section 3 Objectives and 
Endpoints 
Updated definition of transfusion avoidance 
in the secondary endpoint: 
“Number of patients who have transfusion 
avoidance (defined as patients remaining 
transfusion-free and not requiring 
transfusion as per protocol-specified 
guidelines).” 
Updated definition to align with 
Section 9.4.3.2 that defines the 
statistical consideration of efficacy 
endpoints. 
The endpoint remains unchanged. 
Section 1.1 Synopsis 
 
Section 4.2 Scientific 
Rationale 
Updated study duration to include taper and 
safety follow-up. The total duration will be 
approximately 121 weeks. 
 
Updated to clarify total study 
duration. 
Section 1.2 Schema 
Updated Figure 1: Study Design Schematic. 
Updated to clearly show the taper, 
safety follow-up, and overall study 
duration. 
Section 1.3 Schedule of 
Activities 
 
Section 6.7.5 PK/PD 
Sampling During Dose 
Modification 
 
Section 8.6 
Pharmacokinetics 
 
 
Added PK sample collections on Day 1 
(Table 1), during Week 108/ET (Table 3), 
and on Day 196 (Week 28) (Table 2). 
 
Table footnotes were also updated to align 
with the changes. 
 
Removed PD sampling points (6h and 10h) 
from Table 2. 
 
Updated corresponding sections on PK and 
PD sampling (Section 6.7.5 and Section 8.6). 
 
PK sampling on Day 1 and during 
Week 108/ET was inadvertently 
missed in the previous version of the 
protocol. 
In order to collect steady-state PK 
data on the new tablet formulation 
being introduced in this study, an 
additional day of intensive PK 
sample collection was added at Week 
28 (for comparison to the intensive 
PK at Week 4). 
 
PD sampling points were minimized 
to reduce patient burden 
Section 1.3 Schedule of 
Activities 
Removed physical examination from taper 1 
and taper 2 columns in SoA in Table 3. 
The taper visits are done by visiting 
healthcare services who will not 
perform physical examination. 
Section 2.3.1. Risk 
Assessment 
Headings of the risks were updated: 
Hepatic Injury was replaced with Liver 
Enzyme Elevation 
Central Nervous System was replaced with 
Seizures 
Text on seizures was updated. 
Replaced headings with clearer 
terminology: no injuries to th e liver 
or CNS were seen in non-clinical and 
healthy volunteer studies. Text 
updated for clarity. 
The updated Investigators’ Brochure 
provides details. 
Section 2.3.2. Benefit 
Assessment 
New text on the benefit of treatment- naive 
PNH patients who have IVH and EVH 
added. 
Added to indicate benefit of 
ALXN2050 for treatment-naïve 
patients. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 4.2 Scientific 
Rationale 
Text added to define patient groups. 
Added for clarity. 
Section 4.3. Justification 
for Dose 
Updated text on dose justification and 
supporting data. 
Updated to align with recent data in 
the updated Investigators’ Brochure. 
Section 4.4 End of Study 
Definition 
Updated text of the time point of early 
termination. 
Updated for clarity and alignment 
with the time point of study 
completion. The actual timing does 
not change. 
Section 5.1.2 Exclusion 
Criteria 
 
Updated exclusion criterion 11 on the use of 
CYP3A substrates, inducers, and inhibitors. 
 
Added cross-reference to Section 10.9 with a 
list of these substances. 
Provided additional information on 
potential interaction with CYP3A 
substrates, inducers, and inhibitors 
per US FDA source. 
Section 5.1.2 Exclusion 
Criteria 
 
Updated exclusion criterion 13 on the use of 
selected medications known to lower the 
seizure threshold and/or cause seizure. 
 
Added cross-reference to Section 10.10 with 
a list of these medications. 
Provided additional information on 
medications related to seizures as 
part of risk assessment in Section 
2.3.1. 
Section 5.1.2 Exclusion 
Criteria 
Seizure 
Updated exclusion criterion 16 on serology 
tests for different viral infections. 
Text aligned with current Alexion 
protocol standard text.  
Section 5.2 Eligibility 
Criteria Specific for 
Group 1 
Criterion 2 split into 2 criteria: 2 and 3. 
Updated for clarity. 
Section 5.5. Lifestyle 
Considerations 
Added new section describing restriction on 
consumption of foods and beverages known 
to be CYP3A inhibitors. 
Added text to support requirements 
on the use of CYP3A substrates, 
inducers, and inhibitors.  
Section 6 Study 
Intervention 
Defined the term “bid” in Section 6.1, text 
updated 
Updated for clarity. 
Section 6.5 Concomitant 
Therapy 
 
 
Concomitant therapy text updated. 
 
Added 2 subsections and texts in the 
appropriate subsections: 
 
6.5.1 Concomitant Medications 
• 
Added “Prophylactic antibiotics...” in 
this section 
• 
Moved “gastric acid reducing 
agents...” to this section 
6.5.2 Prohibited Medications 
• 
Updated text on prohibition of known 
CYP3A substrates, inducers, and 
inhibitors  
• 
Added text on prohibition of selected 
medications known to lower the 
seizure threshold and/or cause seizure 
 
Added cross-references to Section 10.9 and 
Section 10.10 for detailed list of prohibited 
medications. 
Provided additional information on 
concomitant and prohibited 
medications 
 
Texts rearranged for clarity 
 
 
 
 
 
 
Provided additional information on 
potential interaction with CYP3A 
substrates, inducers, and inhibitors 
per US FDA source. 
 
Provided additional information on 
medications related to seizures as 
part of risk assessment in 
Section 2.3.1. 
 
 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.9. Intervention 
After the End of the 
Study 
Text streamlined. 
Updated for clarity. 
Section 7.2 Dose Taper 
Text on taper streamlined. 
Updated for clarity. 
Section 8.3.1 Physical 
Examinations 
Added text on symptoms-based neurologic 
examination; updated footnotes in SoA tables 
referring to this examination 
Updated for clarity and  consistency 
Section 9.4.7. Population 
PK/PD Analysis 
Updated text  
To clarify population PK/PD 
sampling 
Section 9.5 Interim 
Analyses 
Added text on additional interim analyses. 
Updated to clarify the possibility of 
additional interim analyses as 
needed. 
Section 10 Appendices 
Added the following Appendices: 
• 
Appendix 9: List of Inhibitors, 
Inducers, and Substrates of CYP3A 
• 
Appendix 10: Selected Medications 
Known to Lower the Seizure 
Threshold and/or Cause Seizure 
These appendices are provided to 
clarify concomitant therapies 
(Section 6.5) 
Section 10.2. Appendix 
2: Clinical Laboratory 
Tests 
Removed erythropoietin from Table 5 
Erythropoietin is not part of routine 
laboratory panel 
Section 10.3 
Appendix 3: Adverse 
Events: Definitions and 
Procedures for 
Recording, Evaluating, 
Follow-up, and 
Reporting  
Section 10.3 updated to remove redundancies 
and inconsistencies with respect to 
pregnancy. 
 
Section 10.3.8 Pregnancy is now 
consolidated in Section 10.4 Contraceptive 
Guidance and Collection of Pregnancy 
Information 
Updated for clarity. 
Section 10.3.8 was deleted as this 
section is a duplication of Section 
10.4.2.3. 
The text and the pregnancy 
guidelines did not change. 
 
Amendment 2.1 (Global) 12 April 2021 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment:  
This global amendment was initiated to add back an exclusion criterion regarding history or 
presence of any risk factors for Torsades de Pointes, a screening QT interval corrected using 
Fridericia's formula (QTcF) > 450 msec for males and > 470 msec for females, or receiving 
medications known to significantly increase the corrected QT interval (QTc), which was 
inadvertently removed from Protocol Amendment (PA) 2.0.  
Section # and Name 
Description of Change 
Brief Rationale 
Throughout the protocol 
Change in version number and document date 
Administrative change 
Summary of Changes  
p. 7 
Added: 
Removed inclusion and exclusion criteria that 
were not applicable 
Added text to describe 
change not previously 
captured in prior Summary of 
Changes 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 2.3.1 Risk 
Assessment 
Coronavirus Disease 
2019 
Added cross-reference to Section 10.8 COVID-19 
Vaccine Risk Assessment 
 
To point to the location of 
COVID-19 vaccination 
information in a specific 
section of the protocol 
Section 5.1.2. Exclusion 
Criteria  
The following exclusion criterion was added back 
into the protocol:  
9. History or presence of any risk factors for 
Torsades 
de 
Pointes 
(eg, 
heart 
failure/cardiomyopathy or family history of Long 
QT Syndrome), a screening QT interval corrected 
using Fridericia's formula (QTcF) > 450 msec for 
males and > 470 msec for females, or receiving 
medications known to significantly increase the 
corrected QT interval (QTc). 
 
Numbering of exclusion criteria duly updated because 
of this addition 
Criterion 9 was inadvertently 
removed from protocol 
amendment 2.0 
Section 6.5 Concomitant 
Therapy 
Medications that are known to significantly prolong 
the QTc interval will be reviewed by the site with the 
Medical Monitor prior to enrollment. 
Sentence removed as this is 
not aligned with exclusion 
criterion 9  
Section 10.8 Appendix 8 
COVID-19 Vaccine Risk 
Assessment 
Table 7 
Added this section on potential risks and mitigation 
strategies related to COVID-19 vaccination 
 
Numbering of Appendices duly updated because of 
this addition 
To provide guidance on 
COVID-19 vaccine risk 
assessment   
 
Amendment 2.0 (Global) 07 Jan 2021  
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.  
Overall Rationale for the Amendment:   
This global amendment was initiated to align the patient population of this Phase 2 study with 
the expected Phase 3 populations and to explore the efficacy and safety of ALXN2050 as a 
monotherapy option for patients with PNH. The changes include updates to the study design, 
eligibility criteria and clarification of the endpoints. 
Changes were also made to further align the protocol with Alexion standards in all applicable 
sections, including SAE reporting, list of protocol-specific laboratory assessments, vaccination 
requirements and other safety monitoring and the statistical sections. The Schedule of Activities 
was updated to reflect these changes. 
Section # and Name 
Description of Change 
Brief Rationale 
Throughout protocol 
Protocol content transferred to Alexion template 
Administrative change 
Throughout protocol 
Updated the compound name from “ACH-0145228” 
to “ALXN2050.” 
Administrative change 
Title Page, Section 1.1 
Synopsis 
Revised the study title 
Updated Sponsor name and address. 
Administrative change 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis, 
Section 1.2 Schema; 
Section 2 Introduction, 
Section 4.1 Overall 
Design, Section 4.2 
Scientific Rationale for 
Study Design, and 
throughout the protocol 
where applicable 
Changed the study design with the following 
3 patient groups:  
• Group 1: PNH patients who are treatment naïve 
• Group 2: PNH patients who have received 
complement component 5 (C5) inhibition with 
eculizumab for at least 6 months, who continue 
to experience anemia (hemoglobin 
[Hgb] < 10 g/dL) and reticulocytes above the 
upper limit of normal (ULN), and who will 
switch to ALXN2050 in this study 
• Group 3: PNH patients who have received 
danicopan monotherapy during Study ACH471-
103, and who will switch to ALXN2050 in this 
study 
 
Added Study Schema 
To clearly define the 3 
patient groups 
Section 1.1 Synopsis, 
Section 2.1 
Revised the study rationale. 
To clarify the rationale for 
the 3 patient groups 
Section 1.1 Synopsis, 
Section 3 Objectives and 
Endpoints 
Removed the co-primary endpoint “Hgb levels and 
changes from baseline in Hgb levels at 
protocol-specified time points, including Week 12.” 
To clarify the endpoints and 
correct typographical errors 
Section 1.1 Synopsis, 
Section 3 Objectives and 
Endpoints 
Revised a secondary endpoint to include the 
following 2 endpoints: change in absolute 
reticulocyte count and direct and total bilirubin from 
baseline at Week 12 and change in PNH RBC clone 
size and C3 fragment deposition on PNH RBCs from 
baseline at Week 12. 
Aligned endpoints in Section 1.1 and Section 3. 
To clarify the endpoints, 
correct typographical errors 
and ensure consistency 
across the document 
Section 1.1 Synopsis, 
Section 3 Objectives and 
Endpoints, Section 
9.4.3.2 Analyses of 
Secondary Efficacy 
Endpoints, Section 
9.4.8.1 FACIT-Fatigue 
(Version 4) 
Added secondary objective to evaluate the effect of 
ALXN2050 on FACIT scores and added secondary 
endpoint of change in FACIT scores from baseline to 
Week 12 and EOT. 
To clarify objective and 
endpoint for FACIT 
Section 1.1 Synopsis, 
Section 3 Objectives and 
Endpoints 
Replaced secondary endpoint, “number of patients 
who are RBC transfusion-independent during the 
LTE Period” with secondary endpoint, “number of 
patients who have transfusion-avoidance during 
12 weeks of treatment with ALXN2050.” 
Added definition of transfusion avoidance in the 
endpoint and all throughout the document, where 
applicable 
To clarify the endpoints and 
correct typographical errors 
Section 1.1 Synopsis, 
Section 3 Objectives and 
Endpoints, Section 9.4.6. 
Pharmacodynamic 
Analysis, Section 9.4.7 
PK/PD Analysis 
Added exploratory objective to characterize PK and 
PD of ALXN2050 and endpoints: plasma 
concentrations of ALXN2050 over time and changes 
from baseline in PD biomarkers. 
Described the analyses for these endpoints. 
To clarify objective and 
endpoint for PK and PD 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis, 
Section 3 Objectives and 
Endpoints, Section 
9.4.8.3 EORTC 
Added health-related QoL exploratory endpoint, 
“change in the European Organisation for Research 
and Treatment of Cancer (EORTC) QoL 
Questionnaire-Core 30 scale (QLQ-C30), Version 
3.0 at Week 12 and EOT.” 
To clarify objective and 
endpoint for PROs 
Section 1.1 Synopsis 
(Overall Design), 
Section 4.1 Overall 
Design, Section 4.2 
Scientific Rationale for 
Study Design, Section 
4.3 Justification for 
Dose, Section 6.7 Dose 
Modification of 
ALXN2050 
Revised the criteria for dose escalation to 180 mg bid 
to be based on clinical response and tolerability as 
defined for each patient group in the dose 
modification section (Section 6.7). 
To clarify dose escalation 
process 
Section 1.1 Synopsis 
(Overall Design), 
Section 1.3 Schedule of 
Activities (SoA) Table 3, 
Section 4.1 Overall 
Design, Section 6.8 
Intervention After the 
End of the Study, 
Section 7.1 
Discontinuation of Study 
Medication, Section 7.3 
Follow-up Period, 
Section 8.4.1 Time 
Period and Frequency 
for Collecting AE and 
SAE Information 
Removed 1 of 2 safety Follow-up Visits and 
established a single Follow-up Visit at approximately 
30 (+ 7) days after the last dose of study drug. 
To consolidate follow up to 1 
visit with the aim to reduce 
patient and site burden. 
Section 1.1 Synopsis 
(Overall Design), 
Section 4.1 Overall 
Design 
Corrected the total study duration from 108 weeks to 
116 weeks, which includes a 60-day Screening 
Period, 12-week Treatment Period, and 96-week 
LTE Period. 
To correct error in study 
duration 
Section 1.3 Schedule of 
Activities (SoA) Table 1 
and Table 2 
Updated SoA with the following key changes: 
• Added screening requirements for the 3 patient 
groups 
• Added review of the Patient Safety Card. 
• Added study drug accountability. 
• Streamlined PK/PD sampling, vital signs, 
laboratory assessments, PROs, and Follow up Visit 
• Updated footnotes and revised for clarity. 
 
To streamline SoA with the 
aim to reduce patient and site 
burden. 
Section 1.3 Schedule of 
Activities (SoA) Table 2, 
Section 6.7.5 PK/PD 
Sampling During Dose 
Modification 
Clarified that intensive PK/PD sampling may be 
performed without food restrictions and at the next 
clinic visit > 4 days after dose escalation. For sites 
that are unable to perform intensive PK/PD 
sampling, pre-dose and 2.5-hour postdose samples 
obtained at the next clinic visit, but no less than 
4 days after dose escalation, will be acceptable. 
To streamline PK/PD 
sampling to reduce patient 
and site burden. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 2.3.1 Risk 
Assessment, Section 4.2 
Scientific Rationale for 
Study Design, Section 
8.3.7 Patient Safety Card 
Removed Fever Management Plan. 
Added the Patient Safety Card. 
To remove redundancy as the 
safety card addresses fever 
monitoring and management. 
Section 2.3.1 Risk 
Assessment 
Updated information on CNS risk. 
To provide risk update on 
data from a preclinical 
toxicity study 
Section 2.3.1 Risk 
Assessment, Section 
8.10 Changes in 
Schedule of Assessment 
due to COVID-19 
Pandemic, Section 10.7 
Appendix 7 
Added COVID-19 risk assessment. 
To provide guidance on 
potential risks and mitigation 
measures in light of the 
COVID-19 pandemic. These 
changes are being included in 
all Alexion protocols. 
Section 2.3.3 Overall 
Benefit: Risk Conclusion 
Revised the overall benefit risk conclusion. 
To clarify benefit-risk 
assessments based on 
changes in above sections 
Section 4.4 End of Study 
Definition 
Clarified early termination and end of study 
definitions. 
To provide clarity for these 
definitions 
Section 5.0 Study 
Population (Sections 5.1, 
5.2, 5.3, 5.4) 
• Revised inclusion and exclusion criteria for all 
patients. 
• Added eligibility criteria for Groups 1, 2 and 3 
• Removed inclusion and exclusion criteria that 
were not applicable  
To clarify eligibility criteria 
for the different patient 
groups 
 
Section 6 Study 
Intervention, Section 6.1 
Study Intervention 
Administered, Section 
6.2 Preparation/ 
Handling/ Storage/ 
Accountability 
Added language describing the tablet formulation of 
the study drug that will be introduced in this study 
once the tablet formulation becomes available. 
To incorporate tablet form 
Section 6.4 Study 
Medication Compliance 
Removed use of the electronic dose reminder system. 
The system is not being used. 
Section 6.6 Switching to 
ALXN2050 
Added guidance for dosing patients in Groups 2 and 
3 who are switching from eculizumab to ALXN2050 
or from danicopan to ALXN2050. 
To clarify dosing 
requirements 
Section 6.8 Transfusion 
Guidelines Before and 
During the Study 
Added this section 
To clarify transfusion 
guidelines in relation to 
transfusion avoidance 
Section 7.1 
Discontinuation of Study 
Medication 
Added the following to the list of reasons for 
withdrawing patients from the study: patient request, 
pregnancy or planned pregnancy, lack of efficacy, 
development of seizures, and participation in other 
clinical studies with investigational products. 
To clarify early 
discontinuation criteria 
Section 7.1 
Discontinuation of Study 
Medication, Section 
8.3.1 Physical 
Examinations, Section 
10.6 Appendix 6 
Revised the Seizure Management Plan to require 
treatment according to local protocols for seizures 
that are not self-limiting and to require reporting of 
seizure to the Sponsor within 24 hours of the 
Investigator’s awareness. 
To provide clarity on seizure 
based on new preclinical 
CNS data 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.1 Screening 
Visit 
Revised screening requirements based on patient 
groups 
To clarify the screening 
process for the 3 patient 
groups 
Section 9.0  
• Revised language for sample size determination. 
• Revised analyses and presentation of efficacy and 
safety data based on the 3 patient groups 
• Updated Patient-Reported Outcome Measures 
Assessment 
• Added an interim analysis. 
• To clarify statistical 
methods and justify the 
interim analysis 
• Where applicable, 
statistical methods were 
updated to reflect the 
patient groups and updated 
endpoints 
Section 10.3 Appendix 3 
Revised text on documentation, reporting, severity, 
and grading of AEs, SAEs, and pregnancies. 
To align with Alexion 
standards and processes 
Section 10 
• Removed Section 10.6 Appendix 6 Fever 
Management Plan 
• Updated Seizure Management Plan (new 
numbering is Section 10.6 Appendix 6) 
• Added Section 10.7 Appendix 7 COVID-19 risk 
assessment 
• Information on fever 
management is already 
covered on the safety card. 
• The seizure management 
plan was updated to 
include guidance to 
investigators on actions 
patients should take should 
they experience a seizure.  
• COVID-19 risk assessment 
is being added to all 
Alexion protocols 
General/All Sections 
Editorial and formatting changes throughout the 
document, including minor spelling corrections and 
updating the list of abbreviations and table of 
contents. 
For clarity and completeness. 
Abbreviations: AE = adverse event; C3 = complement component 3; C5 = complement component 5; CNS = central nervous 
system; COVID-19 = coronavirus disease 2019; ECG = electrocardiogram; ET = early termination; EOT = end of treatment; 
FACIT = Functional Assessment of Chronic Illness Therapy-Fatigue scale; Hgb = hemoglobin; LTE = long-term extension; 
PD = pharmacodynamic; PK = pharmacokinetic; PNH = paroxysmal nocturnal hemoglobinuria; PRO = patient reported 
outcomes; QoL = quality of life; RBC = red blood cell; SAE = serious adverse event; ULN = upper limit of normal. 
 
Amendment 1.1 (Local) 20 Jul 2020 
Overall Rationale for the Amendment: 
This local amendment was initiated to address questions from the UK’s MHRA. 
Section # and Name 
Description of Change 
Brief Rationale 
Header (all Pages), Title 
Page, Contact 
Information, 
Investigator’s signature 
page 
Updated the amendment version and date for 
Amendment 1.1, 20 Jul 2020. 
To reflect the new amendment 
version and date. 
Title Page, Compound 
Number 
Included the Alexion compound number, revising 
text to “ACH-0145228 (ALXN2050).” 
Included the Alexion 
compound number. 
Title Page, Regulatory 
Agency Identifier 
Number(s) 
Added the ClinicalTrials.gov identification number, 
NCT04170023. 
Added ClinicalTrails.gov 
number. 


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Section # and Name 
Description of Change 
Brief Rationale 
Sponsor’s Signature 
page 
Updated the name of the medical monitor from 
 
Updated the amendment 
version and date. Updated the 
name of the medical monitor. 
Synopsis and Section 3 
Objectives and 
Endpoints 
Added secondary endpoints for the LTE evaluating 
safety and tolerability of study drug as monotherapy 
and as add-on therapy to an approved C5 inhibitor 
and to evaluate the maintenance of response as 
monotherapy and as add-on therapy. 
Updated secondary endpoints 
to include LTE objectives 
evaluating safety and 
tolerability of study drug as a 
monotherapy and as an add-on 
therapy to an approved C5 
inhibitor and to evaluate the 
maintenance of response as a 
monotherapy and as an add-on 
therapy. 
Synopsis ‘Overall 
Design’ and Section 4.1 
Overall Design 
Clarified that the LTE period was through 
Week 108. 
Clarified duration of the LTE 
period. 
Section 6.6 Dose 
Modification 
Added text clarifying that dose escalation is 
allowed during the 12-week Treatment Period and 
during the LTE. 
 
Updated to confirm that dose 
escalation is allowed during 
the initial 12-week treatment 
period and during the LTE 
period. 
Section 6.7 Study 
Medication after the End 
of the Study 
Clarified that study drug will not be provided to 
patients after the last scheduled dosing. 
Updated to clarify that the no 
study drug will be provided to 
the patients after the last 
scheduled dosing. 
Section 7 
Discontinuation of Study 
Medication and Patients 
Discontinuation or 
Withdrawal 
Removed references to the Safety Management 
Plan and specified that the Sponsor’s medical 
monitor should be notified before dosing is 
terminated. 
Updated to remove references 
to the Safety Management 
plan and added guidance 
regarding the Principal 
Investigator’s notification of 
the Sponsor before dosing is 
terminated. 
General/All Sections 
Minor editorial and formatting changes throughout 
the document, including minor spelling corrections 
and updating the list of abbreviations and table of 
contents. 
For clarity and completeness. 
Abbreviations: C5 = complement component 5; LTE = long-term extension. 
 
Amendment 1.0 (Global) 06 Apr 2020 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
This global amendment was initiated to allow females of childbearing potential to participate in 
the study and to align the protocol with Alexion standards in all applicable sections. The changes 
include updates to the eligibility criteria, SAE reporting, list of protocol-specific laboratory 
assessments, vaccination requirements and the statistical sections. The Schedule of Activities 
was updated to reflect these changes. 


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Section # and Name 
Description of Change 
Brief Rationale 
Header (all Pages), Title 
Page, Contact Information, 
Sponsor’s Signature page 
Investigator’s signature page 
• Updated the amendment version and date for 
Amendment 1.0, 06 Apr 2020. 
• Updated Sponsor name to Achillion 
Pharmaceuticals, Inc., a wholly owned 
subsidiary of Alexion Pharmaceuticals Inc. 
• Added confidentiality statement. 
• Updated Sponsor signatory. 
Administrative changes  
 
To reflect the new 
amendment version and 
date. 
 
Synopsis (Overall Design), 
Section 4.1 Overall Design 
• Clarified that patients enrolled in studies 
ACH471-101 and ACH471-103, who were 
eligible to participate in this study, received 
danicopan in those studies. 
• Removed the term “sub-optimal response” 
when referring to response to treatment with C5 
inhibitor. 
• Clarified the start of study drug dosing, 
including for patients rolling over from studies 
ACH471-101 and ACH471-103. 
• Clarified visits for the Taper and Follow-up 
Periods. 
To clarify the start of 
treatment. 
To clarify the conditions for 
patients rolling over from 
Studies ACH471-101 or 
ACH471-103. 
To clarify how the taper 
and Follow-up Period will 
be conducted. 
Synopsis (Inclusion Criteria 
and Exclusion Criteria), 
Section 5 Study Population 
• Updated study entry criteria to allow females of 
childbearing potential 
• Revised entry criteria specific to patients rolling 
over from studies ACH471-101 and ACH471-
103 and for patients not currently receiving 
danicopan. 
To allow enrollment of 
women of childbearing 
potential and to include 
patients enrolled in the 
ACH471-101 and 
ACH471-103 studies. 
Synopsis (Sample Size and 
Statistical Methods), Section 
9.2 Sample Size 
Determination, and 
throughout the protocol, 
where applicable 
For PNH patients already receiving treatment 
with an approved C5 inhibitor who may be 
eligible to enroll in this study, removed the term 
“sub-optimal response” when referring to 
response to treatment with the C5 inhibitor. 
Minor editorial updates for 
consistency and to remove 
the term “sub-optimal 
response.” 
Synopsis (Efficacy 
Parameters), Section 9.4.3 
Efficacy Analyses 
• Updated safety endpoints to specify the 
incidence of TEAEs, SAEs, and events leading 
to discontinuation of study medication and to 
remove laboratory abnormalities by toxicity 
grade. 
• Specified separate PK, PD, and complement 
biomarker endpoints to include change in 
circulating complement biomarkers including 
Bb concentrations at Week 12 relative to 
baseline; change from baseline in serum AP 
activity at Week 12; correlation between PK 
and complement biomarkers; correlation 
between PK and selected chemistry and 
hematology measures; correlation among 
different complement biomarkers; and 
correlation between complement biomarkers, 
selected chemistry and hematology measures. 
• Removed endpoints for PK concentration at 
various time points and PK parameters on 
intensive PK sampling days. 
• Added change in PRO (FACIT and EQ-5D-3L) 
relative to baseline at Week 12. 
Updated endpoints 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.2 Schedule of 
Assessments, Table 1 
The following major changes were made to the 
Schedule of Assessments Table 1: 
• Replaced visit numbers with study day numbers. 
• Added HCV RNA and HIV RNA to viral 
serology during screening and the treatment 
periods. 
• Added coagulation to clarify PT/PTT/INR. 
• Added details for iron studies: iron, transferrin, 
ferritin serum. 
• For Bb, AP activity (APH), deleted the tests 
performed at Days 7, 42, and 70, and added test 
at post escalation. 
• For FD, C3, CP activity, added CH50 and tests 
at post escalation. 
• Added row for UGT1A1 test to be performed at 
any time for patients with a history or family 
history suggestive of Gilbert’s syndrome. 
• Clarified tests to be performed for patients 
rolling over from studies ACH471-101 and 
ACH471-103. 
• Clarified tests to be conducted in case of early 
withdrawal. 
• Clarified that dose escalation must be approved 
by the Sponsor’s Medical Monitor and removed 
the requirement for measurement of ALT, AST, 
GGT, and ALP by the visiting healthcare service 
or at the clinic 72 to 96 hours after a dose 
escalation. 
• Clarified the timing of assessments. 
• Updated footnotes. 
To reflect changes with this 
protocol amendment. 
Section 1.2 Schedule of 
Assessments, Table 2 
Clarified the timing of PK/PD assessments. 
To clarify when PK/PD 
tests should be conducted. 
Section 1.2 Schedule of 
Assessments, Table 3 
The following major changes were made to the 
Schedule of Assessments Table 3: 
• 
Changed Week 112 to Week 104. 
• 
Added clinic visit added for post escalation. 
• 
Added study drug dispensing at T2. 
• 
Added abbreviated physical examination at T1 
and T2. 
• 
Added row for chemistry, performed at post 
escalation. 
• 
Added coagulation to clarify PT/PTT/INR. 
• 
Added row for intensive PK samples to be 
performed at post escalation. 
• 
Added test for AP activity (APH); added Bb at 
post escalation. 
• 
Added CH50 at post escalation for FD, C3, CP 
activity. 
• 
Changed “Genetic biomarker testing” to 
“Plasma/Serum samples for additional 
nongenetic biomarker testing” with test added 
at post escalation and F/U2. 
To clarify when tests should 
be conducted. 


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Section # and Name 
Description of Change 
Brief Rationale 
• 
Clarified that dose escalation must be 
approved by the Sponsor’s Medical Monitor 
and removed the requirement for measurement 
of ALT, AST, GGT, and ALP by the visiting 
healthcare service or at the clinic 72 to 96 
hours after a dose escalation. 
• 
Clarified assessments during study drug taper. 
• 
Updated footnotes. 
Section 2.3.1 Infection, 
Section 6.5.2 Vaccines, 
Section 8.4 Safety 
Assessments and Procedures 
• 
Updated vaccine requirements to specify the 
timing for vaccinations against meningococcal 
infections and treatment with appropriate 
prophylactic antibiotics for patients who 
initiate study drug treatment less than 2 weeks 
after receiving a meningococcal vaccine. 
• 
Recommended vaccines against serotypes A, 
C, Y, W135, and B, where available. 
• 
Specified that patient must be vaccinated or 
revaccinated according to current national 
vaccination guidelines or local practice for 
vaccination use with complement inhibitors. 
To clarify vaccination 
requirements 
Section 5.3 Screen Failures 
Clarified that patients rolling over from studies 
ACH471-100 and ACH471-103 will start the 
study at the baseline visit and are not required to 
go through screening. 
To clarify the process for 
patients rolling over from 
studies ACH471-101 and 
ACH471-103. 
Section 6.2 
Preparation/Handling/Storage 
Revised language to omit patient initials and 
initials of the person dispensing study drug in 
dispensing records. 
To keep consistency with 
the amended protocol. 
Section 6.6 Dose 
Modification 
Clarified the timing of dose modification and 
intensive PK/PD sampling. 
To clarify PK/PD sampling 
description. 
Section 7.1 Dose Taper 
Clarified dose taper for patients who withdraw 
prior to and after Week 12. 
To clarify how the taper 
should be conducted for 
patients withdrawing prior 
to Week 12. 
Section 7.2 Follow-up Period 
Described assessments for the Follow-up Period. 
To clarify the conduct of 
the Follow-up Period. 
Section 8.1 Screening Visit 
• Clarified baseline assessments for patients 
rolling over from studies ACH471-101 and 
ACH471-103. 
• Clarified the vaccination assessment at 
screening. 
To clarify the criteria for 
inclusion of patients rolling 
over from studies 
ACH471-101 and 
ACH471-103. 
Section 8.4.2 Physical 
Examination 
Clarified the timing of neurological examination. 
To update details on timing 
of neurological 
examination. 
Section 8.4.4 
Electrocardiogram 
Added ECG parameters PR and RR and removed 
respiratory rate. 
To remove respiratory rate 
(not an ECG parameter) and 
add additional ECG 
parameters. 
Section 8.5.1 Time Period 
and Frequency for Collecting 
Adverse Events and Serious 
Adverse Event Information, 
Section 10.3.5 Timeframe for 
Collection of Adverse Events 
Clarified that Investigators must report SAEs for 
patients discharged from the study within 24 
hours of becoming aware of the event. 
To clarify the acceptable 
timeframe for transmission 
of information regarding an 
SAE reported after a patient 
has been discharged from 
the study. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.6 Treatment of 
Overdose 
Revised and clarified the process to be followed 
in case of study drug overdose. 
To clarify the process to be 
followed in case of 
overdose. 
Section 8.9 Genetic Samples, 
Section 10.5 Appendix 5: 
Genetics 
Clarified that the consent form for genetic testing 
is a separate form and that genetic testing is 
optional. 
To clarify that genetic 
testing is optional. 
Section 8.10 Changes in 
Schedule of Assessment due 
to COVID-19 Pandemic 
Added text regarding changes to assessments due 
to the COVID-19 pandemic. 
To clarify assessments 
affected by the COVID-19 
pandemic. 
Section 9.6 
Pharmacodynamic Analysis 
Added details of the analyses for PD biomarkers. 
Updated details on PD 
biomarkers. 
Section 9.7 Patient-Reported 
Outcome Measures 
Assessment 
Added details of the analyses for PRO 
assessments. 
Updates details of PRO 
analyses. 
Section 10.2 Appendix 2: 
Clinical Laboratory Tests 
Updated table on Protocol-Required Laboratory 
Assessments1 
Added clinical laboratory 
tests to ensure patient 
safety. 
Section 10.3.9 Reporting 
Serious Adverse Events 
Clarified the process for reporting SAEs and 
pregnancies. 
To clarify the process for 
reporting SAEs and 
pregnancies. 
Section 10.3.10 Investigator 
Reporting Requirements for 
Serious Adverse Events 
Added section for suspected unexpected serious 
adverse reactions. 
Reassignment of the section 
specifically for SUSARs. 
General/All Sections 
Minor editorial changes and updates to section 
numbers, table numbers, list of abbreviations, and 
table of contents. 
For correctness 
Abbreviations: AB = antibody; AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; 
AP = alternative pathway; APH = alternative pathway hemolysis; AST = aspartate aminotransferase; Bb = Bb fragment of 
complement factor B; C3 = complement component 3; C5 = complement component 5; COVID-19 = coronavirus disease 
2019; CP = classical pathway; ECG = electrocardiogram; FACIT = Functional Assessment of Chronic Illness Therapy-Fatigue 
scale; FD = (complement) factor D; FSH = follicle stimulation hormone; F/U = Follow-up (visit); GGT = gamma-glutamyl 
transferase; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; 
INR = international normalized ratio; PD = pharmacodynamic; PK = pharmacokinetic; PNH = paroxysmal nocturnal 
hemoglobinuria; PRO = patient-reported outcome; PT = prothrombin time; PTT = partial thromboplastin time; 
RNA = ribonucleic acid; SAE = serious adverse event; SUSAR = suspected unexpected serious adverse reaction; 
TEAE = treatment-emergent adverse event; UGT1A1 = uridine diphosphate glucuronosyltransferase 1 family, member A1 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
INVESTIGATOR’S AGREEMENT ...............................................................................................2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................3 
TABLE OF CONTENTS ...............................................................................................................19 
LIST OF TABLES .........................................................................................................................24 
LIST OF FIGURES .......................................................................................................................24 
1. 
PROTOCOL SUMMARY ..........................................................................................25 
1.1. 
Synopsis ......................................................................................................................25 
1.2. 
Schema ........................................................................................................................29 
1.3. 
Schedule of Activities .................................................................................................30 
2. 
INTRODUCTION ......................................................................................................37 
2.1. 
Study Rationale ...........................................................................................................37 
2.2. 
Background .................................................................................................................38 
2.2.1. 
Complement Factor D .................................................................................................38 
2.2.2. 
Paroxysmal Nocturnal Hemoglobinuria .....................................................................38 
2.3. 
Benefit/Risk Assessment ............................................................................................39 
2.3.1. 
Risk Assessment .........................................................................................................39 
2.3.2. 
Benefit Assessment .....................................................................................................41 
2.3.3. 
Overall Benefit: Risk Conclusion ...............................................................................41 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................42 
4. 
STUDY DESIGN .......................................................................................................44 
4.1. 
Overall Design ............................................................................................................44 
4.2. 
Scientific Rationale for Study Design ........................................................................44 
4.3. 
Justification for Dose ..................................................................................................46 
4.4. 
End of Study Definition ..............................................................................................46 
5. 
STUDY POPULATION .............................................................................................47 
5.1. 
Eligibility Criteria for All Patients .............................................................................47 
5.1.1. 
Inclusion Criteria ........................................................................................................47 
5.1.2. 
Exclusion Criteria .......................................................................................................48 
5.2. 
Eligibility Criteria Specific for Group 1 .....................................................................49 
5.3. 
Eligibility Criteria Specific for Group 2 .....................................................................49 


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5.4. 
Eligibility Criteria Specific for Group 3 .....................................................................49 
5.5. 
Lifestyle Considerations .............................................................................................50 
5.6. 
Screen Failures ............................................................................................................50 
6. 
STUDY INTERVENTION ........................................................................................51 
6.1. 
Study Intervention Administered ................................................................................51 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................51 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................52 
6.4. 
Study Medication Compliance ...................................................................................52 
6.5. 
Concomitant Therapy .................................................................................................52 
6.5.1. 
Concomitant Medications ...........................................................................................52 
6.5.2. 
Prohibited Medications ...............................................................................................53 
6.5.3. 
Vaccines ......................................................................................................................53 
6.6. 
Switching to ALXN2050 ............................................................................................53 
6.6.1. 
Switching from Eculizumab to ALXN2050 ...............................................................53 
6.6.2. 
Switching from Danicopan to ALXN2050 .................................................................53 
6.7. 
Dose Modification of ALXN2050 ..............................................................................54 
6.7.1. 
Dose Escalation for Treatment Naïve Patients (Group 1) ..........................................54 
6.7.2. 
Dose Escalation for Patients Switched from Eculizumab (Group 2) .........................54 
6.7.3. 
Dose Escalation for Patients Switched from Danicopan (Group 3) ...........................54 
6.7.4. 
Dose Escalation or Modification at Other Time Points for All Patient Groups .........54 
6.7.5. 
PK/PD Sampling During Dose Modification .............................................................54 
6.8. 
Transfusion Guidelines Before and During the Study ................................................55 
6.9. 
Intervention After the End of the Study .....................................................................55 
7. 
DISCONTINUATION OF STUDY MEDICATION AND PATIENT 
DISCONTINUATION/WITHDRAWAL ..................................................................56 
7.1. 
Discontinuation of Study Medication .........................................................................56 
7.2. 
Dose Taper ..................................................................................................................57 
7.3. 
Follow-up Period ........................................................................................................57 
7.4. 
Lost to Follow-up .......................................................................................................57 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................58 
8.1. 
Screening Visit ............................................................................................................58 
8.1.1. 
Screening for All Patients ...........................................................................................58 
8.1.2. 
Screening for Groups 1 and 2: ....................................................................................58 


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8.1.3. 
Screening for Group 3: ...............................................................................................59 
8.2. 
Efficacy Assessments .................................................................................................59 
8.3. 
Safety Assessments .....................................................................................................59 
8.3.1. 
Physical Examinations ................................................................................................59 
8.3.2. 
Vital Signs ..................................................................................................................60 
8.3.3. 
Electrocardiograms .....................................................................................................60 
8.3.4. 
Clinical Safety Laboratory Assessments ....................................................................60 
8.3.5. 
Blood Collection .........................................................................................................60 
8.3.6. 
Pregnancy ...................................................................................................................61 
8.3.7. 
Patient Safety Card .....................................................................................................61 
8.4. 
Adverse Events and Serious Adverse Events .............................................................61 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................61 
8.4.2. 
Method of Detecting AEs and SAEs ..........................................................................62 
8.4.3. 
Follow-up of AEs and SAEs .......................................................................................62 
8.4.4. 
Regulatory Reporting Requirements for SAEs ...........................................................62 
8.5. 
Treatment of Overdose ...............................................................................................62 
8.6. 
Pharmacokinetics ........................................................................................................63 
8.7. 
Pharmacodynamics .....................................................................................................63 
8.8. 
Genetic Samples .........................................................................................................63 
8.9. 
Patient-Reported Outcomes ........................................................................................63 
8.9.1. 
FACIT-Fatigue ...........................................................................................................64 
8.9.2. 
EQ-5D-3L ...................................................................................................................64 
8.9.3. 
EORTC .......................................................................................................................64 
9. 
STATISTICAL CONSIDERATIONS .......................................................................65 
9.1. 
Statistical Hypotheses .................................................................................................65 
9.2. 
Sample Size Determination ........................................................................................65 
9.3. 
Populations for Analyses ............................................................................................65 
9.4. 
Statistical Analyses .....................................................................................................65 
9.4.1. 
General Considerations ...............................................................................................65 
9.4.2. 
Demographics and Baseline Characteristics ...............................................................65 
9.4.3. 
Efficacy Analyses .......................................................................................................66 
9.4.3.1. 
Analyses of Primary Efficacy Endpoints ....................................................................66 
9.4.3.2. 
Analyses of Secondary Efficacy Endpoints ................................................................66 


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9.4.4. 
Safety Analyses ..........................................................................................................66 
9.4.5. 
Pharmacokinetic Analysis ..........................................................................................67 
9.4.6. 
Pharmacodynamic Analysis........................................................................................67 
9.4.7. 
Population PK/PD Analysis ........................................................................................67 
9.4.8. 
Patient-Reported Outcome Measures Assessment .....................................................67 
9.4.8.1. 
FACIT-Fatigue (Version 4) ........................................................................................67 
9.4.8.2. 
EQ-5D-3L ...................................................................................................................67 
9.4.8.3. 
EORTC .......................................................................................................................68 
9.5. 
Interim Analyses .........................................................................................................68 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................69 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................69 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................69 
10.1.2. 
Financial Disclosure ...................................................................................................69 
10.1.3. 
Informed Consent Process ..........................................................................................69 
10.1.4. 
Data Protection ...........................................................................................................70 
10.1.5. 
Dissemination of Clinical Study Data ........................................................................70 
10.1.6. 
Data Quality Assurance ..............................................................................................71 
10.1.7. 
Source Documents ......................................................................................................71 
10.1.8. 
Study and Site Start and Closure ................................................................................72 
10.1.9. 
Publication Policy .......................................................................................................72 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................74 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................76 
10.3.1. 
Definition of Adverse Event .......................................................................................76 
10.3.2. 
Criteria for Assessing Seriousness ..............................................................................77 
10.3.3. 
Documentation and Reporting of Adverse Events .....................................................78 
10.3.4. 
Treatment and Follow-Up of Adverse Events ............................................................78 
10.3.5. 
Timeframe for Collection of Adverse Events .............................................................79 
10.3.6. 
Severity and Grading of Adverse Events ....................................................................79 
10.3.7. 
Assessment of Causality .............................................................................................80 
10.3.8. 
Reporting Serious Adverse Events and Pregnancies ..................................................80 


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10.3.9. 
Investigator Reporting Requirements for Suspected Unexpected Serious 
Adverse Reactions ......................................................................................................81 
10.3.10. 
Concomitant Medication Assessments .......................................................................82 
10.3.11. 
Monitoring Patient Safety ...........................................................................................82 
10.3.12. 
Removal of Patients from the Trial or Study Medication ...........................................82 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................................83 
10.4.1. 
Definition: Woman of Childbearing Potential (WOCBP) ..........................................83 
10.4.2. 
Contraception Guidance .............................................................................................83 
10.4.2.1. 
Contraception for Male Patients .................................................................................83 
10.4.2.2. 
Contraception for Female Patients ..............................................................................84 
10.4.2.3. 
Collection of Pregnancy Information .........................................................................85 
10.5. 
Appendix 5: Genetics .................................................................................................85 
10.6. 
Appendix 6: Seizure Management Plan .....................................................................87 
10.7. 
Appendix 7: COVID-19 Risk Assessment .................................................................89 
10.8. 
Appendix 8: COVID-19 Vaccine Risk Assessment ...................................................90 
10.9. 
Appendix 9: List of Inhibitors, Inducers, and Substrates of CYP3A .........................91 
10.10. 
Appendix 10: Selected Medications Known to Lower the Seizure Threshold 
and/or Cause Seizure ..................................................................................................92 
10.11. 
Appendix 11: Abbreviations .......................................................................................93 
11. 
REFERENCES ...........................................................................................................96 


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LIST OF TABLES 
Table 1: 
Schedule of Activities: Screening and Treatment Periods .........................................30 
Table 2: 
Intensive Pharmacokinetic and Pharmacodynamic Blood Sampling .........................33 
Table 3: 
Schedule of Activities: Long-term Extension Period, Taper, and Follow-up 
Periods ........................................................................................................................34 
Table 4: 
ALXN2050 Taper Schedule .......................................................................................57 
Table 5: 
Protocol-Required Laboratory Assessments1 .............................................................74 
Table 6: 
Potential Risks and Mitigation Measures due to COVID-19 .....................................89 
Table 7: 
Potential Risks and Mitigation Measures due to COVID19 Vaccine.........................90 
Table 8: 
List of Prohibited Inducers, Inhibitors, and Substrates of CYP3A.............................91 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................29 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Phase 2 Open-Label Proof of Concept Study to Assess the Efficacy, Safety, 
and Pharmacokinetics of the Oral Factor D (FD) Inhibitor ALXN2050 (ACH-0145228) in 
Paroxysmal Nocturnal Hemoglobinuria (PNH) Patients as Monotherapy  
Short Title: Study of the Oral Factor D (FD) Inhibitor ALXN2050 in PNH Patients as 
Monotherapy 
Rationale: This is a study to evaluate the efficacy and safety of ALXN2050 monotherapy in 
treatment naïve PNH patients, in PNH patients currently treated with eculizumab who still 
experience anemia and reticulocytosis, and in PNH patients currently treated with ALXN2040 
(danicopan) as monotherapy.  
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To evaluate the efficacy of ALXN2050 based on 
improvement in hemoglobin (Hgb)  
• 
Change in Hgb relative to baseline at Week 12 
Secondary 
 
• 
To evaluate the efficacy of ALXN2050 based on 
reduction in transfusion requirements 
• 
To evaluate the efficacy of ALXN2050 based on 
lactate dehydrogenase (LDH)  
• 
To assess laboratory markers of hemolysis and 
other markers relevant in patients with paroxysmal 
nocturnal hemoglobinuria (PNH)  
• 
Number of patients who have transfusion 
avoidance (defined as patients remaining 
transfusion-free and not requiring transfusion as 
per protocol-specified guidelines) during 12 weeks 
of treatment with ALXN2050 
• 
Number of RBC units transfused and transfusion 
instances during 12 weeks of treatment as 
compared with transfusion data prior to screening 
• 
Change in LDH relative to baseline at Week 12 
• 
Change in absolute reticulocyte count and direct 
and total bilirubin from baseline at Week 12 
• 
Change in PNH RBC clone size and C3 fragment 
deposition on PNH RBCs from baseline at Week 
12 
• 
To evaluate the safety and tolerability of 
ALXN2050  
• 
Incidence of TEAEs, SAEs, and events leading to 
discontinuation of study medication 
• 
To evaluate maintenance of response of 
ALXN2050 during the LTE period. 
• 
Change in Hgb relative to baseline 
• 
Change in LDH relative to baseline  


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Objectives 
Endpoints 
• 
To evaluate the effect of ALXN2050 on 
Functional Assessment of Chronic Illness 
Therapy-Fatigue scale (FACIT) scores 
• 
Change in FACIT Fatigue scale (Version 4) scores 
from baseline at Week 12 and at Week 160. 
Exploratory 
 
• 
To characterize the pharmacokinetics (PK) and 
pharmacodynamics (PD) of ALXN2050 
• 
Change in circulating complement biomarkers, 
including Bb fragment of complement factor B 
(Bb) concentrations at Week 12 relative to baseline 
• 
Change in serum alternative pathway (AP) activity 
at Week 12 relative to baseline 
• 
Plasma concentrations of ALXN2050 over time 
• 
To evaluate other health-related quality of life 
(QOL) in patients with PNH based on 
patient-reported outcome instruments and their 
evolution over the course of ALXN2050 treatment 
• 
Change in the European Organisation for Research 
and Treatment of Cancer (EORTC) QoL 
Questionnaire-Core 30 scale (QLQ-C30), Version 
3.0 from baseline at Week 12 and at Week 160 
• 
Change in EuroQoL-5-Dimensions, 3-level version 
(EQ-5D-3L) scores from baseline at Week 12 and 
at Week 160. 
 
 


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Overall Design 
This is a multiple-center, open-label multiple dose study to assess the efficacy, safety, 
pharmacokinetics (PK), and pharmacodynamics (PD) of the oral factor D (FD) inhibitor 
ALXN2050 (previously ACH-0145228) monotherapy in patients with PNH. 
This study will assess ALXN2050 as monotherapy in the following three different patient 
groups: 
• Group 1: PNH patients who are treatment naïve 
• Group 2: PNH patients who have received complement component 5 (C5) inhibition 
with eculizumab for at least 6 months, who continue to experience anemia 
(hemoglobin [Hgb] < 10 g/dL) and reticulocytes above the upper limit of normal 
(ULN), and who will switch to ALXN2050 in this study 
• Group 3: PNH patients who have received danicopan monotherapy during 
Study ACH471-103, and who will switch to ALXN2050 in this study 
Group 1 will be enrolled in all countries except the US. Group 2 will be enrolled in all countries. 
Group 3 will be enrolled in countries where Study ACH471-103 is being conducted. 
To mitigate the potential risk of meningococcal infection, all patients must be vaccinated against 
meningococcal infections within 3 years prior to, or at the time of, initiating the study 
medication.  
After signing the informed consent form (ICF), patients will enter the Screening Period. During 
the Screening Period, eligibility and screening assessments will be performed. Screened patients 
who continue to meet eligibility criteria will enter the Treatment Period and will receive their 
first dose of the study medication during the Baseline Visit (Day 1) in this study. Eligible 
patients will be enrolled in the study and will receive ALXN2050 at a dose of 120 mg twice daily 
(bid) for 12 weeks, with potential escalation to 180 mg bid based on clinical response and 
tolerability as defined in the dose escalation section (Section 6.7).At the end of Week 12, patients 
will enter the 148-week Long-term Extension (LTE) Period. During the course of the study, all 
patients will return to the clinic for safety and other assessments as shown in Table 1 to Table 3.  
For Group 1: PNH treatment naïve study patients will receive their first dose of ALXN2050 on 
Day 1 (Baseline Visit).  
For Group 2: Patients switching from eculizumab to ALXN2050 monotherapy will receive their 
first dose of ALXN2050 (Day 1) 7 (± 1) days after the last dose of eculizumab.  
For Group 3: Patients who are rolling over from Study ACH471-103 will receive their last 
danicopan dose the evening prior (Day -1) to the first dose (approximately 8 hours) of 
ALXN2050 (Day 1) in this study.  
Patients will have the option to have selected visits performed via the visiting healthcare service 
provided by Sponsor. With this service, the patient does not physically visit the investigative site. 
Instead, a healthcare provider visits the patient at the patient’s residence to perform 
protocol-specified assessments with appropriate documentations.  


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Withdrawals and Discontinuation 
If the patient withdraws from the study prior to Week 12, the patient will be encouraged to 
complete the Week 12/Early Termination (ET) Visit as soon as possible and should take the 
study medication per protocol until that time. After the ET Visit is completed, ALXN2050 will 
be tapered over 6 days. Additionally, a safety Follow-up visit will be conducted 30 (+ 7) days 
after the last dose of ALXN2050. 
If the patient has entered the LTE Period and discontinues from the study, the patient will be 
encouraged to complete the ET Visit, and the dose of ALXN2050 will be tapered over a 6-day 
period. The patient will attend a Follow-up visit as described above. 
Disclosure Statement: This is a multiple-center, open-label, multiple-dose study with 3 patient 
groups.  
Number of Patients: Approximately 26 patients which will include approximately 10 patients in 
Group 1, approximately 10 patients in Group 2, and approximately 6 patients in Group 3. 
Intervention Groups and Duration: ALXN2050 will be administered orally, 120 mg bid, with 
the option for dose escalation to 180 mg bid according to the protocol specified dose escalation 
guidance for the 3 planned patient groups. 
The study consists of a 60-day Screening Period, a 12-week Treatment Period, and a 148-week 
LTE Period, followed by a 6-day taper and a 30-day safety follow-up after the last dose. The 
total duration of the study will be approximately 173 weeks. 
Data Monitoring Committee: No 
 


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1.2. 
Schema 
Figure 1: 
Study Design Schematic 
 
Group 1 will be enrolled in all countries except the US. Group 2 will be enrolled in all countries. Group 3 will be 
enrolled in countries where Study ACH471-103 is being conducted. 
Abbreviations: PNH = paroxysmal nocturnal hemoglobinuria. 
 


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1.3. 
Schedule of Activities  
Table 1: 
Schedule of Activities: Screening and Treatment Periods 
 
Screening1 
Treatment 
Visit 
Day -60  
to -1 
Baseline1  
(1st Day 
Dosed) 
Wk 1 
(± 1 day) 
Wk 2 
(± 1 
day) 
Wk 3 
(± 1 
day) 
Wk 4 
(± 1 
day) 
Wk 6 
(± 3 
days) 
Wk 8 
(± 3 
days) 
Wk 10 
(± 3 
days) 
Wk 
12/ET2 
(± 3 
days) 
Post-
escalation3 
Day Number 
7 
14 
21 
28 
42 
56 
70 
84 
 
Clinic visit days 
X 
X 
 
X 
 
X 
 
X 
 
X 
X  
Visiting healthcare visit4 
 
 
X 
 
X 
 
X 
 
X 
 
 
Last eculizumab/danicopan dose5 
X 
 
 
 
 
 
 
 
 
 
 
General assessments 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Medical history6  
X 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Review patient safety card7 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vaccination history 
X 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Neisseria meningitidis 
vaccinations 
X 
 
Administer according local/national guidelines 
ALXN2050 dispensing8  
 
X 
 
X 
 
X 
 
X 
 
X 
 
Study medication accountability 
 
 
 
X  
 
X  
 
X  
 
X 
 
Clinical assessments 
 
 
 
 
 
 
 
 
 
 
 
Physical examination9 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Vital signs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight10 
X 
X 
 
 
 
X 
 
X 
 
X 
 
Single 12-lead ECG  
X 
X 
 
 
 
 
 
 
 
X 
X 
PRO assessments11 
 
X 
 
X  
 
X 
 
X  
 
X 
 
RBC transfusion review6 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
AE/SAE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Table 1: 
Screening and Treatment Periods (Continued) 
 
Screening1 
Treatment 
Visit 
Day -60  
to -1 
Baseline1  
(1st Day 
Dosed) 
Wk 1 
(± 1 day) 
Wk 2 
(± 1 
day) 
Wk 3 
(± 1 
day) 
Wk 4 
(± 1 
day) 
Wk 6 
(± 3 
days) 
Wk 8 
(± 3 
days) 
Wk 10 
(± 3 
days) 
Wk 
12/ET2 
(± 3 
days) 
Post-
escalation3 
Day Number 
7 
14 
21 
28 
42 
56 
70 
84 
 
Laboratory assessments12 
 
 
 
 
 
 
 
 
 
 
 
FSH13 
X 
 
 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
 
 
 
 
 
 
 
 
 
 
Serology for hepatitis C, B and 
HIV  
X 
 
 
 
 
 
 
 
 
 
 
Genetic biomarker testing 
(optional) 
  
X 
 
 
 
 
 
 
 
 
 
Direct Coombs 
X 
X 
 
 
 
X 
 
 
 
X 
 
Hematology and chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Pregnancy test14 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Coagulation (PT/PTT/INR), 
D-dimer 
X 
X 
 
 
 
X 
 
X 
 
X 
 
Free Hgb, haptoglobin 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Iron studies (Iron, Transferrin, 
Ferritin Serum)15 
X 
 
 
 
 
  
 
 
 
  
 
Trough PK samples16 
 
X 
 
X 
 
 
 
X 
 
X 
 
PK samples17 
 
X 
 
 
 
X 
 
 
 
 
X 
Bb, AP activity (APH)17 
 
X 
 
X 
 
X 
 
X 
 
X 
X  
FD, C3, CH5017 
 
X 
 
 
 
X 
 
 
 
X 
  
Plasma/Serum samples for 
additional nongenetic biomarker 
testing17 
 
X 
 
 
 
X 
 
X 
 
X 
X 
Flow cytometry: clone size 
X 
X 
 
 
 
X 
 
 
 
X 
 
Flow cytometry: C3 fragment 
deposition 
 
X 
 
 
 
X 
 
 
 
X 
 
UGT1A1 (Gilbert’s) 
At any time – Test only if history or family history suggestive of Gilbert’s syndrome 


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1. Screening will be performed for Group 1 and Group 2 patients. For Group 3 patients rolling over from Study ACH471-103 study, a Screening visit is not 
required but informed consent and documentation of eligibility to participate in this study must be obtained and documented. Group 3 patients will begin study 
participation at the Baseline visit. The Baseline visit should be delayed if the patient has active bacterial or viral infection, a body temperature > 38°C on 2 
consecutive days, or other evidence of infection at Baseline, or history of febrile illness within 14 days prior to first study medication administration. 
2. If the patient withdraws from the study prior to Week 12, the patient should complete the Week 12/ET visit as soon as possible prior to tapering. Patients 
should take study medication per protocol until the tapering period begins. ALXN2050 will be tapered over 6 days and a Follow-up visit will be conducted 30 + 
7 days after the last dose. Patients must return any left-over ALXN2050 medication on the follow-up visit. Refer to Table 3 and Table 4 for details regarding 
Taper and Follow-up visits.  
3. Intensive PK/PD sampling (refer to Table 2) should be obtained at the next clinic visit after dose escalation as feasible, but no sooner than 4 days after the dose 
escalation has occurred. For sites that cannot perform the intensive PK/PD sampling, a pre-dose and a 2.5-hour postdose sample obtained at the next clinic visit, 
but no less than 4 days after dose escalation occurred will be acceptable. 
4. Laboratory samples will be collected by a visiting healthcare service provided by the Sponsor or site clinic for hematology, chemistry, and urinalysis 
assessments. If the visiting healthcare service is used, the site will call patient within 1 to 3 days to confirm that the visiting healthcare visit occurred and assess 
AEs, SAEs, and concomitant medications. If needed, site may ask about AEs, SAEs, and concomitant medications over the phone. 
5. For Group 2, patients will receive their first dose of ALXN2050 (Day 1) 7 (± 1) days after last dose of eculizumab. For Group 3, patients will receive their last 
danicopan dose the evening prior (Day -1) to the first dose (approximately 8 hours) of ALXN2050 (Day 1). All patients will receive their first dose of 
ALXN2050 on Day 1. 
6. Medical history must include at least 24 weeks and up to 52 weeks (if available) of RBC transfusion history. See Section 6.8 for transfusion guidelines before 
and during the study. 
7. Patients are instructed to carry patient safety card at all times and bring to scheduled visits. Review signs and symptoms of infections using the safety card. 
8. Patients will be provided with sufficient study medication to last until their next appointment. Depending on when dose is escalated, patients may need to return 
to the clinic in between visits or a visiting healthcare visit could be made into a clinic visit to be dispensed ALXN2050 and new dosing instructions. 
9 A full physical examination will be performed at Screening, at Baseline and at Week 12 and will include an assessment of general appearance, a review of body 
systems, and a neurologic examination (refer to Section 8.3.1 ). Height will be recorded at Screening only. Abbreviated physical examination will be collected 
at all other timepoints. A symptoms-based neurologic examination will be performed if the patient has any complaints or clinical findings attributable to the 
central nervous system and if positive for findings, full neurologic examination will need to be performed at each assessment timepoint. 
10 .Weight will be measured and should be taken in light clothing or underwear and without shoes.  
11.PROs will include the FACIT-Fatigue, the EORTC QLQ-C30 and the EQ-5D-3L as described in Section 8.9. PROs should be performed as early as possible 
during the clinic visits. On Day 1, PROs must be obtained before the first dose of study medication. 
12.Patients should refrain from heavy exercise 24 hours before blood collection for laboratory assessments. Walking and light exercise are acceptable. 
13.Follicle stimulating hormone assessment for postmenopausal women only. 
14.Serum pregnancy test at Screening. Urine pregnancy test for women of childbearing potential only at all other clinic visit days. At Baseline, the predose urine 
pregnancy test must be negative to continue study participation. Any positive urine pregnancy test will be confirmed by a follow-up serum pregnancy test. 
15.If there is evidence of iron deficiency at Screening, patients will be enrolled if on a stable iron supplementation for at least 30 days.  
16.Trough PK samples should be collected predose 
17.On Day 1, for all sites, one predose and one 2.5 hour post dose PK sample will be collected. In addition, one predose PD sample (for all biomarkers) will be 
collected. On Day 28 (Week 4) or if patient's dose is escalated after Week 4, refer to Table 2 for intensive PK/PD sampling. Sites should collect as many 
samples as possible during the 12-hour period. For those sites that cannot perform the intensive PK/PD sampling, a pre-dose and a 2.5-hour postdose sample 
obtained at the next clinic visit, but no less than 4 days after dose escalation occurred, will be acceptable. 


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Abbreviations: AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; APH = hemolytic alternative pathway activity; 
AST = aspartate aminotransferase; Bb = Bb fragment of complement factor B; C = complement component 3; CBC = complete blood count; CH50 = hemolytic 
classical pathway activity; ECG = electrocardiogram; ET = Early Termination; FD = factor D; FSH = follicle stimulating hormone; GGT = gamma 
glutamyltransferase; Hgb = hemoglobin; HIV = human immunodeficiency virus; INR = international normalized ratio; PD = pharmacodynamic(s); 
PI = Principal Investigator; PK = pharmacokinetic(s); PT = prothrombin time; PTT = partial thromboplastin time; QoL = quality of life; RBC = red blood cell; 
SAE = serious adverse event; UGT1A1 = uridine diphosphate glucuronosyltransferase 1 family, member A1;Wk = week. 
 
Table 2: 
Intensive Pharmacokinetic and Pharmacodynamic Blood Sampling 
 
Predose 
Week 4 (Day 28),  Week 28 (Day 196) and Postdose Escalation1 
Time After Dosing (Hour ± 10 min) 
Hour 
0 
1 
1.5 
2 
2.5 
3 
6 
8 
10 
12 
PK plasma samples 
X2 
X 
X 
X 
X2 
X 
X 
X 
X 
X 
APH, Bb 
X 
 
 
 
X 
 
 
 
 
X 
Plasma/serum samples for additional nongenetic biomarker testing 
X 
 
 
  
 
 
 
 
  
X 
1. Intensive PK/PD sampling may be performed, if feasible, without food restrictions. Samples should be obtained at the next clinic visit but not before 4 days 
after dose escalation has occurred. All patients will have a (Week 4) Day 28 and Week 28 (Day 196) intensive PK sampling regardless of whether their dose 
has been escalated. If an escalation occurs less than 4 days prior to the Week 4 and Week 28 visits, intensive PK sampling collection should be shifted 
accordingly so at least 4 days have lapsed since the dose escalation. Blood volumes are provided in the Study Laboratory Manual.  
2. Sites should collect as many samples as possible during the 12-hour period, with the last sample collected being a PK/PD sample before the patient leaves the 
site. For those sites that cannot perform the intensive PK/PD sampling, a pre-dose and a 2.5hour postdose sample, obtained at the next clinic visit, but no less 
than 4 days after dose escalation occurred will be acceptable.  
Abbreviations: APH = hemolytic alternative pathway activity; Bb = Bb fragment of complement factor B; ECG = electrocardiogram; PD = pharmacodynamic(s); 
PK = pharmacokinetic(s). 


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Table 3: 
Schedule of Activities: Long-term Extension Period, Taper, and Follow-up Periods 
 
Long-term Extension (LTE) Period 
Taper 
Follow-up  
(+ 7 days) 
Interim Visits1 
Clinic 
Visits2 
 
 
 
Weeks  
16 – 152 
(± 3 days) 
Weeks  
20 - 144 
(± 3 days) 
Postdose 
escalation4 
ET /  
Week 160 
T111 
T211 
F/U12 
Clinic Visit  
 
X 
X4 
X 
  
  
X 
Visiting healthcare service 
X 
 
 
 
X 
X 
 
ALXN2050 dispensing3 
 
X 
 
X 
 
 
 
Study medication 
accountability 
X 
X 
 
X 
X 
X 
X 
Review patient safety card5 
X 
X 
X 
X 
X 
X 
X 
Neisseria meningitidis 
vaccinations 
Administer according to local/national guidelines 
Physical examination6 
 
X 
 
X 
  
  
X 
Vital signs 
 
X 
 
X 
X 
X 
X 
ECG 
 
 
X 
X 
 
 
X 
Weight 
 
X 
X 
X 
 
 
X 
PRO questionnaires7 
 
X 
 
X 
 
X 
X 
RBC transfusion review 
 
X 
 
X 
X 
X 
X 
AE/SAE 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications/ 
protocol restrictions 
X 
X 
X 
X 
X 
X 
X 
Hematology and chemistry, and 
urinalysis8 
X 
X 
X 
X 
  
  
  
Pregnancy test9 
X 
X 
 
X 
 
 
X 
Coagulation (PT/PTT/INR), 
D-dimer 
 
X 
 
X 
 
 
  
Free Hgb, haptoglobin 
 
X 
 
X 
 
 
  
Direct Coombs 
 
X 
 
 
 
 
 
PK samples10 
 
X10 
X4 
X 
 
 
 
AP activity (APH); Bb10 
 
X 
X4 
X 
 
 
  


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Table 3: 
Schedule of Assessments: Long-term Extension Period, Taper, and Follow-up Periods (Continued) 
 
Long-term Extension (LTE) Period 
Taper 
Follow-up  
(+ 7 days) 
Interim Visits1 
Clinic 
Visits2 
 
 
 
Weeks  
16 – 152 
(± 3 days) 
Weeks  
20 - 144 
(± 3 days) 
Postdose 
escalation4 
ET /  
Week 160 
T111 
T211 
F/U12 
FD, C3, CP activity (CH50)10 
 
X 
  
X 
 
 
  
Plasma/Serum samples for 
additional nongenetic 
biomarker testing10 
 
X 
X4 
X 
 
 
  
Flow cytometry: clone size 
 
X 
 
X 
 
 
  
Flow cytometry: C3 fragment 
deposition 
 
X 
 
X 
 
 
  
1. Visiting healthcare service visits will occur every other visit, starting at Week 16 (ie, W16, W24, W32, W40, W48, W56, W64, W72, W80, W88, W96, W104, 
W112, W120, W136, and W152). A visiting homecare service will collect samples for hematology, chemistry, and urinalysis. The site will call the patient 
within 1 to 3 days to confirm that samples were collected and to assess AEs, SAEs, and concomitant medications. If needed, site may ask about AEs, SAEs, 
and concomitant medications over the phone. 
2. Clinic visits will occur every other visit starting at Week 20 (ie, W20, W28, W36, W44, W52, W60, W68, W76, W84, W92, W100, W108, W116, W128, and 
W144).  
3. Patients will be provided with sufficient study medication to last until their next appointment. 
4. The postdose escalation visit is only applicable for patients that escalated from 120 mg to 180 mg. This visit ideally should occur at the next in-clinic visit but 
no less than 4 days after the beginning of the new dose. Depending on when dose is escalated, patients may need to return to the clinic in between visits to be 
dispensed ALXN2050 and new dosing instructions. Intensive PK/PD sampling, (refer to Table 2), is required to be obtained at the next clinic visit after the 
dose escalation, but no sooner than 4 days after the start of the new dose. For sites that cannot perform the intensive PK/PD sampling, a predose and a 
2.5-hour postdose sample, obtained at the next clinic visit, but no less than 4 days after dose escalation occurred will be acceptable. Refer to Table 2 for 
intensive PK/PD sampling requirements. 
5. Review signs and symptoms of infections using the patient safety card. 
6. A full physical examination is required at the ET/WK 160 visit; At other clinic visits, an abbreviated physical examination is required, including a 
symptoms-based neurologic examination if the patient has any complaints or clinical findings attributable to the central nervous system and if positive for 
findings, full neurologic examination will need to be performed.  
7. PROs will include the FACIT-Fatigue, the EORTC QLQ-C30 and the EQ-5D-3L as described in Section 8.9.These will be administered approximately every 
6 months within the LTE (ie, W36, W60, W84, W108, W128, and W160) Period. PROs should be performed as early as possible during the clinic visits. 
8. Patients should refrain from heavy exercise 24 hours before blood collection. Walking and light exercise are acceptable. 
9. Urine pregnancy test for women of childbearing potential at all clinic visit days. Any positive urine pregnancy test will be confirmed by a follow-up serum 
pregnancy test. 


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10. Predose PK and PD samples are to be collected within the LTE Period at W44, W60, W76, W92, and W108. Intensive PK/PD sampling will be collected at 
Week 28 (Refer to Table 2 for details).  
11. Any patient who discontinues study medication will need to have an ET visit completed, followed by a 6-day Tapering Period and a Follow-up visit 30 (+ 7 
days) after the last dose of ALXN2050. T1 and T2 may be done through VHA or via phone call on Day 3 and Day 6 of the taper period. 
12. Follow-up visit (F/U) takes place 30 (+7) days after the last dose of study medication (ie, post Taper Period 2 completion). Patients will be instructed to 
bring back all unused study medication on this visit. 
Abbreviations: AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AP = alternative pathway; APH = AP hemolysis; Bb = Bb 
fragment of complement factor B; C3 = complement component 3;CP = classical pathway; ECG = electrocardiogram; ET = Early Termination; FD = factor D; 
F/U = follow-up; GGT = gamma glutamyltransferase; Hgb = hemoglobin; INR = international normalized ratio; LTE = Long-term Extension; 
PD = pharmacodynamic(s); PK = pharmacokinetic(s); PT = prothrombin time; PTT = partial thromboplastin time; QoL = quality of life; RBC = red blood cell; 
SAE = serious adverse event; T = taper; W = week. 
 


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2. 
INTRODUCTION 
ALXN2050 is a small molecule, orally administered FD inhibitor being developed for the 
treatment of complement-mediated diseases, such as PNH. A serine protease, FD catalyzes the 
cleavage of factor B (FB), a rate-limiting step in the alternative pathway (AP) of the complement 
cascade. By inhibiting FD, ALXN2050 potently and specifically inhibits AP activity. 
ALXN2050 is a second-generation molecule. It has an identical mechanism of action (FD 
inhibition) as danicopan (ALXN2040), the first-generation molecule, but with increased potency, 
improved PK/PD profile, and associated incremental potential benefits in terms of monotherapy 
dosing and clinical efficacy. 
The Sponsor has conducted a Phase 2 proof-of-concept Study ACH471-100 to evaluate 
danicopan monotherapy in patients with PNH with an ongoing LTE Study ACH471-103. Results 
from these studies demonstrate that danicopan at doses of 100 to 200 mg taken orally 3 times a 
day provides AP suppression, clinically significant improvements in Hgb and lactate 
dehydrogenase (LDH), increases in PNH red blood cell (RBC) Type III clone size, and patient-
reported well-being. 
This study will assess the efficacy and safety of ALXN2050 as monotherapy in the following 
patient groups: 
• Group 1: PNH patients who are treatment naïve 
• Group 2: PNH patients who have received C5 inhibition with eculizumab for at least 
6 months, who continue to experience anemia (Hgb < 10 g/dL) and reticulocytes 
above the ULN, and who will switch to ALXN2050 in this study 
• Group 3: PNH patients who have received danicopan monotherapy during 
Study ACH471-103, and who will switch to ALXN2050 in this study 
A detailed description of the chemistry, pharmacology, efficacy, and safety of ALXN2050 is 
provided in the Investigator’s Brochure. 
2.1. 
Study Rationale 
The purpose of this study is to establish safety and efficacy of ALXN2050 in PNH as 
monotherapy. 
The C5 inhibitor monoclonal antibody, eculizumab, has been proven effective for the treatment 
of PNH, resulting in a sustained control of complement-mediated intravascular hemolysis (IVH). 
Although eculizumab treatment brings patients with PNH a significant clinical benefit, a 
low-level hemolysis still occurs in many eculizumab-treated patients, leaving approximately 
one-third of treated patients transfusion-dependent. The blockade of the complement cascade at 
C5 by eculizumab allows complement component 3 (C3) fragment deposition to proceed without 
hemolysis on PNH RBCs during C5 inhibitor treatment and is a likely cause for suboptimal 
response in the subset of patients with PNH who experience extravascular clearance of PNH 
RBCs coated by C3 fragments (Risitano, 2009). 
By inhibiting the cleavage of FB, danicopan, the first-generation FD inhibitor, targets the control 
point for the amplification loop of the complement cascade, blocking C3 convertase formation 
and, therefore, significantly reduces the production of C3 cleavage fragments and downstream 


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membrane attack complex (MAC) formation ex vivo (Yuan, 2017). In addition, although FD 
inhibition does not inhibit components specific to the classical or lectin complement pathways, 
nor does it inhibit components of the terminal complement pathway, it will inhibit the 
AP-mediated amplification of complement activity initiated via the classical and lectin pathways. 
By inhibiting FD with danicopan, both IVH, mediated by the activation of the complement 
terminal pathway, and extravascular hemolysis (EVH), mediated by C3 fragment opsonization in 
eculizumab-treated patients, can be blocked or significantly attenuated. 
Danicopan has been studied in patients with PNH as monotherapy (Study ACH471-100) with 
proof of concept established as evidenced by improvement in Hgb and decrease in LDH. 
Danicopan has also been studied in patients with PNH on background therapy with a C5 
inhibitor, with proof of concept established (Study ACH471-101). Interim results from this study 
demonstrate clinically significant improvements in Hgb, a dramatic reduction in transfusion 
needs, and improvements in other clinical parameters of interest in PNH. 
ALXN2050 is derived through optimization of danicopan for potency and for PK properties. 
ALXN2050 displays approximately 3-fold greater potency compared to danicopan and is able to 
achieve sustained potent inhibition of complement AP activity at bid dosing as opposed to 
danicopan’s tid dosing. Given its optimized PK profile and its mechanistic advantage targeting 
the control point for the amplification loop of the complement cascade, ALXN2050 has the 
potential to provide a superior oral alternative for the treatment of patients with PNH by 
controlling IVH and EVH. 
2.2. 
Background 
2.2.1. 
Complement Factor D 
One of 9 serine proteases in the complement system, FD is a highly specific enzyme with only 
one known substrate, FB. Of all the complement proteins, it is among the lowest abundance in 
serum with a concentration of approximately 2 µg/mL (Schnabolk, 2015), and it catalyzes the 
rate-limiting step of the AP activation (Figueroa, 1991, Volanakis, 1996). The FD is a low 
molecular weight protein (24 kDa) that is primarily produced by adipocytes, but can also be 
produced and secreted by monocytes/macrophages and astrocytes in humans (Figueroa, 1991, 
Schnabolk, 2015). Due to its small size, it is freely filtered at the glomerulus, and then taken up 
by the proximal tubule cell where it is catabolized with an estimated fractional catabolic rate of 
60% per hour. It is this rapid catabolism that is responsible for maintaining low circulating FD 
levels. As a result, renal dysfunction is associated with elevated FD levels, which may lead to 
increased AP activity and inflammation (Kobayakawa, 1992, Miyata, 1991). The biochemical, 
physiological, and functional features of FD make it an attractive target for pharmacological 
inhibition, as this may prove useful in the treatment of a wide spectrum of complement-mediated 
diseases. 
2.2.2. 
Paroxysmal Nocturnal Hemoglobinuria 
Paroxysmal nocturnal hemoglobinuria is a rare disease that has a reported prevalence of 
approximately 16 per million people (Szer, 2012). Paroxysmal nocturnal hemoglobinuria may 
occur at any age; it has been reported in children as young as 2 years to adults as old as 83 years, 


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but is most frequently diagnosed in adults, with a median age at diagnosis of approximately 
40 years. Men and women are affected equally, and no familial tendencies exist.  
Paroxysmal nocturnal hemoglobinuria is caused by a somatic mutation in the 
phosphatidylinositol N acetylglucosaminyltransferase subunit A gene in one or more 
hematopoietic stem cells, resulting in the loss of glycosylphosphatidylinositol-anchored proteins, 
including the complement regulatory proteins CD55 and CD59, from the surface of mutant 
RBCs. This leaves these mutant RBCs vulnerable to MAC mediated IVH and to EVH, 
presumably mediated by C3 fragment opsonization, primarily due to constitutive activation of 
the complement AP via tickover mechanism (Schubert, 2015). In addition to anemia that can 
require frequent RBC transfusions, patients with PNH are at high risk for thrombotic events, 
which can be life-threatening and are the major cause of morbidity and mortality in untreated 
patients. Patients with PNH also experience smooth muscle dysfunction (eg, dysphagia, erectile 
dysfunction, and abdominal pain), presumably related to the liberation of intracellular Hgb and 
its consequent derangement of nitric oxide levels in the vasculature. 
The only curative treatment for PNH is hematopoietic stem cell transplantation (HSCT) using 
allogeneic donors. Given the high transplant-related mortality, especially when using unrelated 
or mismatched donors, HSCT is generally not offered as initial therapy for most patients with 
classic PNH. Other supportive therapies include recombinant erythropoietin, corticosteroids, and 
androgens to stimulate erythropoiesis, anticoagulants to treat thrombotic complications, and 
immunosuppressive agents to stimulate hematopoiesis in the aplastic phase. 
The only currently approved drugs to treat PNH are eculizumab or ravulizumab (in some 
countries), closely related monoclonal antibodies directed against complement C5, which prevent 
IVH by inhibiting formation of the terminal complement complex. However, approximately 30% 
of patients on eculizumab continue to have ongoing EVH (Hill, 2010).  
Inhibition of FD with ALXN2050 is expected to prevent EVH and control IVH, given its 
potential mechanistic advantage over C5 inhibition. By inhibiting the cleavage of FB, 
ALXN2050 targets the control point for the amplification loop of the complement cascade, 
blocking C3 convertase formation and the production of C3 cleavage fragments, blocking 
opsonization in addition to significantly reducing the downstream terminal pathway which leads 
to MAC formation. As a result, ALXN2050 can prevent EVH (via C3 fragment opsonization) 
while also being able to control IVH (mediated by the terminal pathway). 
2.3. 
Benefit/Risk Assessment 
2.3.1. 
Risk Assessment 
Neisseria meningitidis 
Since a primary function of the complement system is to fight infections, pharmacologic 
inhibition of the complement system could result in an increased risk of infections. As suggested 
by individual case reports of patients with complement system deficiencies, including FD, 
inhibition of the complement system may result in increased risk of infection, notably with N 
meningitidis (Biesma, 2001, Hiemstra, 1989, Sprong, 2006). However, this remains a theoretical 
risk since FD inhibition does not block the classical and lectin pathways of complement and 


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appears to have little impact on opsonophagocytic killing or serum bactericidal activity in 
samples obtained from vaccinated or previously exposed patients (Konar, 2017). 
To mitigate the potential risk of meningococcal infection, all patients must be vaccinated against 
meningococcal infections within 3 years prior to, or at the time of, initiating study medication. 
Patients who initiate study medication treatment less than 2 weeks after receiving a 
meningococcal vaccine must receive treatment with appropriate prophylactic antibiotics until 
2 weeks after vaccination. Vaccines against serotypes A, C, Y, W135, and B, where available, 
are recommended to prevent common pathogenic meningococcal serotypes. 
Patients must be vaccinated or revaccinated according to current national vaccination guidelines 
or local practice (eg, Advisory Committee on Immunization Practices [ACIP]) for vaccination 
use with complement inhibitors (eg, eculizumab, ravulizumab).  
Vaccination may not be sufficient to prevent meningococcal infection. All patients should be 
monitored for early signs of meningococcal infection, evaluated immediately if infection is 
suspected, and treated with appropriate antibiotics, if necessary. 
To increase risk awareness and promote quick disclosure of any potential signs or symptoms of 
infection experienced by patients during the course of the study, patients will be provided a 
Patient Safety Card to carry with them at all times. Additional discussion and explanation of the 
potential risks, signs, and symptoms will occur at specific time points as part of the review of the 
Patient Safety Card (Section 8.3.7) and throughout the study as described in the Schedule of 
Activities (SoA) (Section 1.3). 
Liver Enzyme Elevation 
In animal toxicology studies, reversible, non-adverse elevations in hepatic transaminases and 
total bilirubin, suggestive of a possible hepatobiliary effect (without histopathologic correlates), 
were seen in rats and dogs (see Investigator Brochure for Studies ACH-17-138, ACH-17-109, 
and ACH-17-157). 
No clinically significant abnormalities occurred in any of these parameters in the single 
ascending dose (SAD) or multiple ascending dose (MAD) studies. However, these parameters 
will be routinely monitored as part of safety laboratory testing in this study. 
Seizures 
Convulsions and/or electroencephalogram (EEG) abnormalities have been observed in the dog 
toxicity studies at doses of 75 mg/kg/day and higher, and the no observed adverse effect level 
(NOAEL) based on the dog 13-week toxicology study is 62.5 mg/kg/day. Convulsions were also 
observed in WT TgRasH2 mice at doses of ≥ 500 mg/kg/day, at approximately 5x higher 
systemic exposures than in Beagle dogs. The Beagle dog is the most sensitive species with a 
NOAEL of 62.5 mg/kg/day. A 24-hour EEG monitoring of the 2 highest dose cohorts in the 
MAD study (120 mg and 200 mg orally (PO) bid) was conducted; no EEG abnormalities were 
identified with dosing. Physical examinations and adverse event (AE) monitoring will be 
performed with special attention to any neurologic AEs. 
The safety margins based on the nonclinical toxicity profile of ALXN2050 are specified in the 
Investigators Brochure. 


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Physical examinations (including neurologic examination) will be performed during this study 
(see SoA). In the event of a seizure, assessment recommendations are provided in Section 10.6, 
Appendix 6; Seizure Management Plan. Patients with a seizure history will be excluded from the 
study. 
Coronavirus Disease 2019 
The coronavirus disease 2019 (COVID-19) pandemic is active in many countries at the time of 
this protocol amendment. Given this unique circumstance, specific consideration has been given 
to the risks and benefits of the study as they relate to COVID-19, and the global and local 
changes that exist as a result of the pandemic. This assessment is described in Section 10.7, 
Appendix 7. The risk assessment for COVID-19 vaccination is described in Section 10.8 
Appendix 8. 
2.3.2. 
Benefit Assessment 
Currently, no oral medicines for the treatment of PNH are available. Unmet needs in patients 
with PNH, not addressed by a C5 inhibitor, can be addressed by an oral FD inhibitor. Three 
groups of patients, whose disease cannot be adequately addressed with a C5 inhibitor, have been 
identified: 
• Patients who have a suboptimal response to an approved C5 inhibitor, presumably largely 
due to EVH that is a result of C3-mediated opsonization. Eculizumab/ravulizumab 
treatment blocks the hemolytic destruction of PNH erythrocytes by the MAC (terminal 
stage of the complement pathway); however, neither of these C5 inhibitors prevents 
deposition of C3 fragments on PNH erythrocyte membranes, which results in 
opsonization of these red cells and subsequent destruction of these red cells in the spleen 
and liver (Hill, 2010). ALXN2050 has a potential mechanistic advantage since it acts 
upstream of C3 cleavage and has been shown to block C3 fragment deposition. 
• Patients who only respond partially to eculizumab due to a genetic polymorphism in 
complement receptor 1 (CR1; eg, HindIII H/L and L/L genotypes [Rondelli, 2014]), 
which has been postulated to result in an increased proportion of C3-opsonized RBCs, 
may have an improved treatment response with FD inhibition. 
• Rare patients (~1%) with no response to eculizumab due to mutations in C5 (eg, 
Arg885His) could also benefit from FD inhibition because it acts at a different target in 
the complement cascade and should be unaffected by a mutation in C5 (Harder, 2019). 
• For treatment of treatment-naïve PNH patients, given that ALXN2050 has the potential to 
control IVH and prevent the development of EVH (Yuan, 2017). 
2.3.3. 
Overall Benefit: Risk Conclusion 
Considering the severity of the disease, the continuing anemia and reticulocytosis in some 
patients on C5 inhibitors, and the lack of an effective oral therapy alternative for PNH patients, 
there is a clear need for new therapies to improve PNH management. ALXN2050 is expected to 
provide improved efficacy based on its mechanism of action and optimized PK profile. Based on 
the preclinical and clinical data available to date, the benefit-risk profile remains favorable for 
advancing the development of ALXN2050 for the treatment of patients with PNH. 


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3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
• 
To evaluate the efficacy of ALXN2050 based on 
improvement in hemoglobin (Hgb)  
• 
Change in Hgb relative to baseline at Week 12 
Secondary 
 
• 
To evaluate the efficacy of ALXN2050 based on 
reduction in transfusion requirements 
• 
To evaluate the efficacy of ALXN2050 based on 
lactate dehydrogenase (LDH)  
• 
To assess laboratory markers of hemolysis and 
other markers relevant in patients with paroxysmal 
nocturnal hemoglobinuria (PNH)  
• 
Number of patients who have transfusion 
avoidance (defined as patients remaining 
transfusion-free and not requiring transfusion as 
per protocol-specified guidelines) during 12 weeks 
of treatment with ALXN2050 
• 
Number of RBC units transfused and transfusion 
instances during 12 weeks of treatment as 
compared with transfusion data prior to screening 
• 
Change in LDH relative to baseline at Week 12 
• 
Change in absolute reticulocyte count and direct 
and total bilirubin from baseline at Week 12 
• 
Change in PNH RBC clone size and C3 fragment 
deposition on PNH RBCs from baseline at 
Week 12 
• 
To evaluate the safety and tolerability of 
ALXN2050  
• 
Incidence of TEAEs, SAEs, and events leading to 
discontinuation of study medication 
• 
To evaluate maintenance of response of 
ALXN2050 during the LTE period. 
• 
Change in Hgb relative to baseline 
• 
Change in LDH relative to baseline  
• 
To evaluate the effect of ALXN2050 on 
Functional Assessment of Chronic Illness 
Therapy-Fatigue scale (FACIT) scores 
• 
Change in FACIT Fatigue scale (Version 4) scores 
from baseline at Week 12 and at Week 160 
Exploratory 
 
• 
To characterize the pharmacokinetics (PK) and 
pharmacodynamics (PD) of ALXN2050 
• 
Change in circulating complement biomarkers, 
including Bb fragment of complement factor B 
(Bb) concentrations at Week 12 relative to baseline 
• 
Change in serum alternative pathway (AP) activity 
at Week 12 relative to baseline 
• 
Plasma concentrations of ALXN2050 over time 
• 
To evaluate other health-related quality of life 
(QOL) in patients with PNH based on patient-
• 
Change in the European Organisation for Research 
and Treatment of Cancer (EORTC) QoL 


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Objectives 
Endpoints 
reported outcome instruments and their evolution 
over the course of ALXN2050 treatment 
Questionnaire-Core 30 scale (QLQ-C30), Version 
3.0 from baseline at Week 12 and at Week 160. 
• 
Change in EuroQoL-5-Dimensions, 3-level version 
(EQ-5D-3L) scores from baseline at Week 12 and 
at Week 160. 
 


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a multiple-center, open-label multiple-dose study to assess the efficacy, safety, PK, and 
PD of the oral FD inhibitor ALXN2050 (previously ACH-0145228) monotherapy in patients 
with PNH. 
This study will assess ALXN2050 as monotherapy in the following patient groups: 
• Group 1: PNH patients who are treatment naïve 
• Group 2: PNH patients who have received C5 inhibition with eculizumab for at least 
6 months, who continue to experience anemia (Hgb < 10 g/dL) and reticulocytes 
above the ULN, and who will switch to ALXN2050 in this study 
• Group 3: PNH patients who have received danicopan monotherapy during Study 
ACH471-103, and who will switch to ALXN2050 in this study 
Group 1 will be enrolled in all countries except the US. Group 2 will be enrolled in all countries. 
Group 3 will be enrolled in countries where Study ACH471-103 is being conducted. 
4.2. 
Scientific Rationale for Study Design 
This is a multiple-center, open-label, multiple-dose study to assess the efficacy, safety, PK, and 
PD of the oral FD inhibitor ALXN2050 (previously ACH-0145228) monotherapy in patients 
with PNH.  
The first-generation FD inhibitor, danicopan, has been studied in patients with PNH, both as 
monotherapy and on top of background therapy with a C5 inhibitor, with proof of concept 
established (Studies ACH471-100 and ACH471-101, respectively). ALXN2050 is a 
second-generation FD inhibitor with increased potency and the improved convenience of an oral, 
bid dosing regimen. Therefore, FD inhibition should be an effective therapy for PNH. This study 
aims to establish both the safety and efficacy of ALXN2050 as monotherapy for PNH patients.  
ALXN2050 is expected to address both intravascular and EVH in all PNH patients. The study 
will include patients who are PNH treatment naïve and patients who, despite treatment with 
eculizumab for a minimum of 6 months, continue to have anemia and reticulocytosis. The study 
design schematic is shown in Figure 1. 
The study will enroll approximately 26 patients with PNH distributed across the 3 patient groups 
as follows: 
• Group 1 (patients who are treatment naïve): approximately 10 patients 
• Group 2 (patients switching from eculizumab to ALXN2050): approximately 10 patients 
• Group 3 (patients rolling over from Study ACH471-103, switching from danicopan to 
ALXN2050): approximately 6 patients 
The study consists of 3 periods: A 60-day Screening Period, a 12-week Treatment Period, and a 
148-week LTE Period (up to Week 160) This is followed by a 6-day taper and 30-day safety 
follow-up giving a total duration of approximately 173 weeks.  


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Patients will be evaluated for history of vaccination. All patients must be vaccinated against 
meningococcal infections within 3 years prior to, or at the time of, initiating study medication. 
See Section 6.5.3 for details.  
To increase risk awareness and promote quick disclosure of any potential signs or symptoms of 
infection experienced by the patients during the course of the study, patients will be provided a 
Patient Safety Card to carry with them at all times (Section 8.3.7) and throughout the study as 
described in the SoA (Section 1.3). 
The starting dose of ALXN2050 will be 120 mg bid. The dose may be escalated to 180 mg bid 
based clinical response according to the protocol dose escalation guidance in Section 6.7. 
For Group 1: PNH treatment naïve study patients will receive their first dose of ALXN2050 on 
Day 1 (Baseline Visit).  
For Group 2: Patients switching from eculizumab to ALXN2050 monotherapy will receive their 
first dose of ALXN2050 (Day 1) 7 (± 1) days after the last dose of eculizumab.  
For Group 3: Patients who are rolling over from Study ACH471-103 will receive their last 
danicopan dose the evening prior (Day -1) to the first dose (approximately 8 hours) of 
ALXN2050 (Day 1) on this study.  
After signing the informed consent form (ICF), patients will enter the Screening Period. During 
the Screening Period, eligibility and screening assessments will be performed. Screened patients 
who continue to meet eligibility criteria will enter the Treatment Period and will receive their 
first dose of study medication during the Baseline Visit (Day 1) in this study. Eligible patients 
will be enrolled in the study and will receive ALXN2050 at a dose of 120 mg twice daily (bid), 
daily for 12 weeks, with potential escalation to 180 mg bid based on clinical response and 
tolerability as defined in the dose escalation section (Section 6.7). At the end of Week 12, 
patients will enter the 148-week Long-term Extension (LTE) Period. During the course of the 
study, all patients will return to the clinic for safety and other assessments as shown in Table 1 to 
Table 3.  
Patients will have the option to have selected visits performed via the visiting healthcare service 
provided by Sponsor. With this service, the patient does not physically visit the investigative site. 
Instead, a healthcare provider visits the patient at the patient’s residence to perform 
protocol-specified assessments with appropriate documentations.  
If the patient withdraws from the study prior to Week 12, the patient will be encouraged to 
complete the Week 12/Early Termination (ET) Visit as soon as possible and should take the 
study medication per protocol until that time. After the ET Visit is completed, ALXN2050 will 
be tapered over 6 days. Additionally, a safety Follow-up visit will be conducted 30 (+ 7) days 
after the last dose of ALXN2050. 
If the patient has entered the LTE Period and discontinues from the study, the patient will be 
encouraged to complete the ET Visit, and the dose of ALXN2050 will be tapered over a 6-day 
period. The patient will attend a Follow-up visit as described above. 
During the course of the study, all patients will return to the clinic for safety and other 
assessments as shown in Table 1 to Table 3. 


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4.3. 
Justification for Dose 
Clinical PK and PD data have been generated for ALXN2050 in single ascending and multiple 
ascending doses in healthy volunteers (Studies ACH228-001 and ACH228-002, respectively). In 
these Phase 1 healthy volunteer studies, ALXN2050 PK exposures increased dose-proportionally 
following a single dose administration, and in a greater-than-dose-proportional manner following 
multiple doses at steady state over the dose range of 40 mg bid to 200 mg bid. Corresponding PD 
activity as determined by AP inhibition increased with increasing exposure. 
In the multiple-dose Study ACH228-002, the dosage regimens of both 120 mg bid and 200 mg 
bid were safe and effective, showing approximately 10-fold or greater safety margin in both 
maximum plasma concentration (Cmax) and the area under the concentration-time curve from 
time zero to 24 hours (AUC0-24) over the exposures achieved at the no observed adverse effect 
level (NOAEL) from nonclinical chronic toxicology studies (see Investigator’s Brochure). In 
addition, both dosage regimens provided complete (> 90%) and sustained inhibition of AP 
activity throughout the 12-hour dosing interval.  
However, large variabilities were observed in the PK and PD data and in the established PK/PD 
relationship. Intersubject variability in PK and the PK/PD relationship indicated that a dosage 
higher than 120 mg bid, such as 180 mg bid, may be required to ensure more participants reach 
and maintain an ALXN2050 concentration above the threshold for 90% AP inhibition. 
Based on the favorable clinical safety and tolerability data from these studies and the PK and PD 
characterization of ALXN2050, these results indicate that 120 mg bid of ALXN2050 would be a 
safe and efficacious starting dose for proposed human studies in patients with PNH. Based on 
data from the Phase 1 studies, the starting dose regimen will be 120 mg bid, with a dose titration 
option available (if additional efficacy is anticipated) to 180 mg bid. 
4.4. 
End of Study Definition 
A patient is considered to have completed the study if he/she has completed all periods of the 
study including the last scheduled procedure shown in the SoA. 
A patient is considered to early terminate from the study if the patient is discontinued from the 
study before completing all scheduled visits as per SoA. 
The end of the study is defined as the date the last patient completes the last visit (including 
follow up) as shown in the SoA. 
 


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5. 
STUDY POPULATION 
5.1. 
Eligibility Criteria for All Patients 
5.1.1. 
Inclusion Criteria 
All patients must meet all of the following conditions: 
1. Diagnosis of PNH. 
2. Male or female, ≥ 18 years of age (or minimum adult age in accordance with local legal 
requirements). 
3. Documentation of vaccination for N meningitidis: all patients must be vaccinated against 
meningococcal infections within 3 years prior to, or at the time of, initiating study 
medication. Patients who initiate study medication treatment less than 2 weeks after 
receiving a meningococcal vaccine must receive treatment with appropriate prophylactic 
antibiotics until 2 weeks after vaccination. 
4. Female patients of childbearing potential must agree to use a highly effective method of 
contraception from the date of signing the ICF to 30 days after their last dose of study 
medication.  
− Female patients of childbearing potential must also have a negative serum 
pregnancy test during Screening and a negative urine pregnancy test at baseline 
prior to administration of the first dose.  
− Female patients of non-childbearing potential, as defined in Section 10.4, need not 
employ a method of contraception. 
5. Non-sterile male patients must agree to use a highly effective method of contraception 
with their partner(s) of childbearing potential from the first day of dosing through 90 days 
after their last dose of study medication.  
− Males who are surgically sterile need not employ additional contraception. 
− Males must agree not to donate sperm while enrolled in this study and for 90 days 
after their last dose of study medication. 
6. Capable of providing written informed consent which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol. 
7. Patients who are on iron, folic acid, and/or vitamin B12 supplementation are eligible for 
the study. If patients are on iron, patients must be on stable iron supplementation for at 
least 30 days prior to Day 1. 
8.  Patients with aplastic anemia or bone marrow failure who meet the rest of the eligibility 
criteria and are currently treated with immunosuppressants may be eligible, only if on a 
stable regimen for at least 3 months prior to enrollment. The regimen of these 
medications must remain unchanged during the 12-week Treatment Period.  


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5.1.2. 
Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply: 
1. History of a major organ transplant (eg, heart, lung, kidney, liver) or hematopoietic stem 
cell/marrow transplant (unless HSCT engraftment has failed). 
2. Known aplastic anemia or other bone marrow failure that requires HSCT, or if these 
patients are on immunosuppressive agents for less than 24 weeks prior to enrollment. 
3. Received another investigational agent other than danicopan within 30 days or 
5 half-lives of the investigational agent prior to study entry, whichever is greater.  
4. Known or suspected complement deficiency. 
5. Known underlying bleeding disorders (eg, coagulation factor deficiencies, idiopathic 
thrombocytopenic purpura, Von Willebrand disease) or any other conditions leading to 
anemia not primarily associated with PNH. 
6. Active bacterial or viral infection, a body temperature > 38°C on 2 consecutive daily 
measures, evidence of other infection, or history of any febrile illness within 14 days 
prior to first study medication administration. 
7. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 and/or are on dialysis. 
8. Laboratory abnormalities at screening, including: 
− Alanine aminotransferase (ALT) > 2 × ULN. 
− Direct bilirubin > 2 × ULN (unless due to EVH, in the opinion of the 
investigator). 
9. History or presence of any risk factors for Torsades de Pointes (eg, heart 
failure/cardiomyopathy or family history of Long QT Syndrome), a screening QT interval 
corrected using Fridericia's formula (QTcF) > 450 msec for males and > 470 msec for 
females, or receiving medications known to significantly increase the corrected QT interval 
(QTc) 
10. Any other clinically significant laboratory abnormality that, in the opinion of the 
Principal Investigator (PI), would make the patient inappropriate for the study or put the 
patient at undue risk. 
11. Use of known cytochrome P450, family 3, subfamily A (CYP3A) sensitive substrates, 
moderate or strong CYP3A inducers, and/or moderate or strong CYP3A inhibitors, from 
2 weeks or 5 half-lives, whichever is longer, prior to the first administration of study 
intervention on Day 1 (full list provided in Section 10.9). 
12. History or presence of any clinically relevant co-morbidities that would make the patient 
inappropriate for the study (for example, is likely to result in deterioration of the patient’s 
condition, affect the patient’s safety during the study, or confound the results of the 
study). 
13. History of seizures and/or current use of selected medications known to lower the seizure 
threshold and/or cause seizure (See Section 10.10). 


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14. Females who are pregnant, nursing, or planning to become pregnant during the study. 
15. Patients with a female partner who is either pregnant, nursing, or planning to become 
pregnant during the study. 
16. Evidence of hepatitis B (positive hepatitis surface antigen [HBsAg] or positive core 
antibody [anti-HBc] with negative surface antibody [anti-HBs]) or hepatitis C viral 
infection (hepatitis C virus [HCV] antibody positive, except for patients with documented 
successful treatment and documented sustained virologic response [SVR]) at Screening. 
17. Evidence of human immunodeficiency virus (antibody positive) infection at Screening. 
18. Hypersensitivity to the investigational drug or any of its excipients. 
In addition, specific eligibility criteria for the different patient groups are provided in the 
following sections. 
5.2. 
Eligibility Criteria Specific for Group 1 
In addition to the eligibility criteria in Section 5.1, this patient group must meet the following 
additional eligibility requirements: 
1. PNH patients who have no history of treatment with any complement inhibitor at any 
dose  
2. PNH Type III erythrocyte or granulocyte clone size ≥ 10% 
3. Absolute reticulocyte count ≥ 100 × 109/L 
4. Anemia (Hgb < 10.5 g/dL) 
5. LDH ≥ 1.5 × ULN 
6. Platelet count ≥ 30,000/µL without platelet transfusion 
7. Absolute neutrophil count (ANC) ≥ 750/µL  
5.3. 
Eligibility Criteria Specific for Group 2 
In addition to the eligibility criteria in Section 5.1, PNH patients on stable eculizumab switching 
to ALXN2050 (Group 2) must meet the following criteria: 
1. Stable background regimen of at least 24 weeks for eculizumab, without change in dose 
or interval for at least the past 8 weeks 
2. Anemia (Hgb < 10 g/dL) 
3. Absolute reticulocyte count ≥ 100 × 109/L 
4. Platelet count ≥ 30,000/μL without the need for platelet transfusions 
5. Absolute neutrophil count ≥ 750/μL 
5.4. 
Eligibility Criteria Specific for Group 3 
In addition to meeting the criteria listed in Section 5.1, patients in Group 3 need to fulfill the 
following criterion:  


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1. Patient received danicopan during Study ACH471-103. 
5.5. 
Lifestyle Considerations 
Certain foods such as grapefruit have been shown to be inhibitors of CYP3A4 enzyme activity. 
Participants should refrain from consuming these foods and beverages from 2 weeks prior to the 
first administration of study intervention on Day 1 until 2 weeks after the final dose of study 
intervention. 
5.6. 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently entered in the study. The Investigator must maintain a log of screen failure patients 
that includes, at a minimum, demography, screen failure details, eligibility criteria, and any 
serious adverse events (SAEs) occurring after providing informed consent. 
If the patient is unable to receive study medication within 60 days of screening, the patient may 
be rescreened once. 
See details for rescreening in Section 8.1. 
 


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6. 
STUDY INTERVENTION 
“Study medication” in this protocol refers to ALXN2050. All patients will receive the study 
medication.  
In most countries, patients will take the capsule formulation of the study medication during the 
first 12 weeks of the study. A tablet formulation (described in Section 6.1 below) is being 
developed by the Sponsor. Once this tablet formulation is available, it will be introduced in this 
study, and the capsule formulation will be discontinued.  
The study medication should be taken at approximately the same time each day and as close as 
possible to 12 hours apart with or without food. If a dose is missed, it should be taken within 
4 hours of the originally scheduled time. After 4 hours, the missed dose should be skipped. In 
either case, the next dose should be taken according to the original dosing schedule. 
6.1. 
Study Intervention Administered 
Intervention Name 
ALXN2050 (formerly ACH-0145228) 
ALXN2050 (formerly ACH-0145228) 
Type  
Drug  
Drug 
Dose Formulation 
Capsule  
Tablet 
Unit Dose 
Strength(s) 
60 mg 
60 mg 
Dosage Level(s) 
120 mg or 180 mg 
120 mg or 180 mg 
Route of 
Administration 
Oral twice daily (bid) 
Oral twice daily (bid) 
Use 
Experimental 
Experimental 
IMP/NIMP  
IMP 
IMP 
Sourcing 
Provided by Sponsor 
Provided by Sponsor 
Packaging and 
Labeling 
Study medication will be provided in 
bottles. Each bottle will be labeled as 
required per country requirement. 
Study medication will be provided in bottles. 
Each bottle will be labeled as required per 
country requirement. 
Abbreviations: IMP = investigational medicinal product; NIMP = non-investigational medicinal product 
Details on the formulation of the study medication are provided in the Investigators’ Brochure 
and Pharmacy Manual. 
6.2. 
Preparation/Handling/Storage/Accountability 
At the pharmacy, ALXN2050 capsules and tablets must be stored as provided in containers at 
controlled room temperature (20°C to 25°C). Patients should be instructed to keep their study 
medications in the original container at room temperature.  
The PI or designee (eg, pharmacist) is responsible for ensuring storage as per the label on the 
drug product at the site and adequate accountability of all used and unused study medication. 
This includes acknowledgment of receipt of each shipment of study medication (quantity and 
condition), patient dispensing records, and returned or destroyed drug. Dispensing records will 
document quantities received from the Sponsor and quantities dispensed to patients, including lot 
number, date dispensed, and patient identifier number. All drug supplies and associated 
documentation will be periodically reviewed and verified by the study monitor over the course of 
the study. 
Storage condition details for the drug product are described in the Pharmacy Manual provided by 
the Sponsor. Handling and storage conditions of capsules and tablets are identical. 


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6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is a single-arm, open-label study. 
6.4. 
Study Medication Compliance 
An interactive web response system will be used to monitor drug accountability. Patients will be 
required to bring their supply of study medication to each visit so that study site personnel may 
perform drug accountability. Site personnel will keep a record of all drug dispensed and returned 
at each visit. Drug dispensing records will be updated at each visit. 
6.5. 
Concomitant Therapy 
6.5.1. 
Concomitant Medications 
Any medications that the patient is using during the study, including vitamins and/or 
supplements are considered concomitant medications.  
New concomitant medications that need to be added to the patient’s regimen during the study 
should be discussed between the PI and Sponsor before implementing, if possible. If this is not 
possible, the PI should evaluate the potential medication for interactions, taking into 
consideration the list of prohibited medications provided in this protocol, before implementing 
and inform the Sponsor as soon as feasible. If a new concomitant medication is started by 
another physician that is not associated with the study site without discussion with the PI, the PI 
should evaluate for interaction potential and inform the Sponsor. 
Details of all concomitant medication use, including all medications administered for the 
treatment of AEs, must be recorded in the patient’s case report form (CRF).  
The use of concomitant medications during the study will be assessed at every visit, as indicated 
in Table 1. 
The following are some general guidelines for concomitant medication use based on currently 
available data: 
• Concomitant administration of folic acid and/or erythropoiesis-stimulating agents is 
permitted if on stable doses for at least 4 weeks prior to Baseline.  
• Concomitant administration of steroids or other immunosuppressants is permitted if 
the dosage regimen is stable for at least 3 months before enrollment. 
• Prophylactic antibiotics may be administered if deemed appropriate by local clinical 
practice and/or guidelines for treatment with a complement inhibitor. Because 
commercially available products will be used, information about any specific 
antibiotics administered can be found on the package inserts/product labels for those 
products. 
• Gastric acid reducing agents should be avoided whenever possible. 
 


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6.5.2. 
Prohibited Medications 
The use of the following medications is prohibited during the study: 
• Known CYP3A sensitive substrates, moderate or strong CYP3A inducers, and/or 
moderate or strong CYP3A inhibitors are prohibited throughout the study, until 
1 week after the final administration of study intervention (See Section 10.9 for a full 
list of these medications). 
• Selected medications known to lower the seizure threshold and/or cause seizure 
(see Section 10.10 for a full list of these medications). 
• Medications known to significantly prolong the corrected QT interval (QTc) 
6.5.3. 
Vaccines 
To mitigate the potential risk of meningococcal infection, all patients must be vaccinated against 
meningococcal infections within 3 years prior to, or at the time of, initiating study medication. 
Patients who initiate study medication treatment less than 2 weeks after receiving a 
meningococcal vaccine must receive treatment with appropriate prophylactic antibiotics until 2 
weeks after vaccination. Vaccines against serotypes A, C, Y, W135, and B, where available, are 
recommended to prevent common pathogenic meningococcal serotypes. 
Patients must be vaccinated or revaccinated according to current national vaccination guidelines 
or local practice for vaccination use with complement inhibitors (eg, ACIP). Vaccination may 
not be sufficient to prevent meningococcal infection. All patients should be monitored for early 
signs of meningococcal infection, evaluated immediately if infection is suspected, and treated 
with appropriate antibiotics, if necessary. 
Any patient without sufficient history of these vaccines may be vaccinated or provided boosters, 
as appropriate. Vaccinations and/or boosters may be administered either during the Screening 
Period, after all other screening assessments have been completed, or once study medication 
treatment has commenced, according to national or local guidelines. For patients who will 
receive vaccinations, all other screening procedures must be completed, and patients must 
qualify for the study prior to vaccinations being administered. Female patients of childbearing 
potential who require vaccinations must also have a negative urine pregnancy test on the days of 
vaccination before any vaccine or booster is administered. 
For any vaccines or boosters given as part of this study, full identifying information, including 
the brand, should be recorded in the patient’s CRF. 
6.6. 
Switching to ALXN2050 
6.6.1. 
Switching from Eculizumab to ALXN2050 
Patients switching from eculizumab to ALXN2050 monotherapy will receive their first dose of 
ALXN2050 (Day 1) 7 (± 1) days after last dose of eculizumab. 
6.6.2. 
Switching from Danicopan to ALXN2050 
Patients will receive the last dose of danicopan the evening before (approximately 8 hours) 
Day 1. On Day 1, patients will receive the first dose of ALXN2050 120 mg.  


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6.7. 
Dose Modification of ALXN2050 
Dose escalation to 180 mg bid will be allowed in this study. 
The decisions to dose escalate patients will be made by the site PI based on each patient’s 
individual data and guided by the dose escalation guidelines below. The PI should notify the 
Medical Monitor of any decision to proceed with dose escalation. 
6.7.1. 
Dose Escalation for Treatment Naïve Patients (Group 1) 
Patients in this group will be escalated if 
• Hgb has not increased at least 1 g/dL by Week 4 relative to baseline, or  
• Patient has received a blood transfusion, or 
• LDH > 1.5 × ULN by Day 14 in 2 consecutive assessments 
6.7.2. 
Dose Escalation for Patients Switched from Eculizumab (Group 2) 
Patients in this group may be dose escalated if:  
• Hgb by Week 4 has not increased at least by 1 g/dL relative to baseline, or  
• Patient has received a blood transfusion, or 
• LDH > 1.5 × ULN by Day 14 in 2 consecutive assessments  
6.7.3. 
Dose Escalation for Patients Switched from Danicopan (Group 3) 
Patients in this group will be escalated if 
• Hgb by Day 14 has dropped by 1 g/dL or more, relative to baseline, and it is below 
the lower limit of normal, or  
• Patient has received a blood transfusion, or 
• LDH > 1.5 × ULN by Day 14 in 2 consecutive assessments  
6.7.4. 
Dose Escalation or Modification at Other Time Points for All Patient Groups 
Dose modification decisions can be made at any point in the study after Day 14, including during 
the LTE Period (through Week 160). The PI should notify the Medical Monitor of any decision 
to proceed with dose escalation. 
Patients who have been dose-escalated may be dose reduced to a lower dose for safety or 
tolerability reasons based on the Investigator’s judgement. 
6.7.5. 
PK/PD Sampling During Dose Modification 
Intensive PK/PD sampling may be performed, if feasible, without food restrictions. All patients 
will have a Week 4 (Day 28) and a Week 28 (Day 196) intensive PK sampling regardless of 
whether their dose has been escalated (see Table 2). Sites should collect as many samples as 
possible during the 12-hour period, with the last sample collected being a PK/PD sample before 
the patient leaves the site.  


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For sites that cannot perform the intensive PK/PD sampling, a predose and a 2.5-hour postdose 
sample will be acceptable. Samples for PK/PD and safety laboratory assessments should be 
performed at the next in-clinic visit and not sooner than 4 days after the dose escalation (refer to 
Table 2) since it will take at least 4 days to achieve steady-state conditions.  
Patients who have been dose escalated may be dose reduced to a lower dose for safety or 
tolerability reasons following consultation between the Investigator and the Sponsor’s Medical 
Monitor. 
6.8. 
Transfusion Guidelines Before and During the Study 
It is recommended to administer RBC transfusion when a patient has a: 
1. Hemoglobin value of less than 7 g/dL regardless of presence of clinical signs or 
symptoms, or 
2. Hemoglobin value of less than 9 g/dL with signs or symptoms of sufficient severity to 
warrant a transfusion. 
In the event of life-threatening anemia, transfusion of ABO- and RhD-matched blood is 
appropriate. Further matching for Kell and JK Antigens can be conducted if this does not delay 
availability of blood for emergent transfusion. The reason for transfusion as well as signs or 
symptoms associated with the subject’s need for transfusion will be documented on the 
electronic case report form (eCRF) for each individual subject. Typical anemia-related symptoms 
warranting transfusions include angina, change in mental status, syncope, light headedness, 
confusion, shortness of breath, and fatigue. 
The Investigator will determine the appropriate number of units of RBCs to be transfused. In the 
event a transfusion is required, a blood sample for central lab is to be collected for assessments 
prior to transfusion. Administration of transfusion including the reason for transfusion 
(hemoglobin result, signs, and symptoms) and the number of units transfused, will be 
documented in the eCRF. 
6.9. 
Intervention After the End of the Study 
Study medication will not be provided to patients after the last scheduled dosing.  


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7. 
DISCONTINUATION OF STUDY MEDICATION AND PATIENT 
DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Medication 
In rare instances, it may be necessary for a patient to permanently discontinue (definitive 
discontinuation) the study medication. If study medication is permanently discontinued, the dose 
of the patient will be tapered as described in Section 7.2, and the patient will remain in the study 
for 30 days after last dose of ALXN2050 to be evaluated for AEs. 
A patient is free to withdraw from the study at any time without jeopardizing future medical 
care. In addition, the PI (or designee) may decide, for reasons of medical prudence or patient 
noncompliance or if C5 inhibitor is deemed necessary, to discontinue dosing of ALXN2050 for 
an individual patient. The Sponsor’s Medical Monitor will be notified immediately, and if 
possible, before dosing is terminated.  
Reasons for patient withdrawal include: 
• Intercurrent illness that would, in the judgment of the Investigator, affect assessment 
of clinical status to a significant degree 
• Unacceptable toxicity (including a clinically significant laboratory abnormality) 
necessitating discontinuation of study participation or that, in the judgment of the 
Investigator, compromises the ability to continue study-specific procedures, or it is 
considered not to be in the patient’s best interest to continue the study 
• Patient request to discontinue for any reason 
• Pregnancy or planned pregnancy 
• Patient noncompliance 
• Lack of efficacy 
• Development of seizures (see Section 10.6 Seizure Management Plan) 
• Discontinuation of the study at the request of the Sponsor, Regulatory Agency, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) 
• Any other condition or circumstance that that would jeopardize the welfare of the 
patient if s/he were to continue in the study 
• Participation in other clinical studies with investigational products during this study 
The reason for any patient’s discontinuation and the date of withdrawal will be recorded in the 
patient’s CRF. The patient’s CRF, which will be completed up to the point of withdrawal, will be 
retained for the Sponsor. If a patient discontinues from the study for any reason, all protocol 
procedures as defined in Table 1 for treatment Week 12 should be performed as an ET visit if the 
patient discontinues prior to Week 12. 
If the patient withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. If a patient withdraws 
from the study, he/she may request destruction of any samples taken and not tested, and the 
Investigator must document this in the site study records. 


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7.2. 
Dose Taper 
If ALXN2050 is discontinued for any reason, the dose will be tapered over a 6-day period. The 
dosing taper regimen is described in Table 4. The taper schedule may be adjusted to allow for 
slower taper in a patient who is not tolerating discontinuation of the drug.  
If dosing needs to be terminated for safety reasons (eg, development of a seizure), it may be done 
so immediately (without tapering), if it is considered to be in the best interest of the patient. 
If the patient withdraws from the study, an ET visit must be completed, and the tapering schedule 
below should be followed. 
 Table 4: 
ALXN2050 Taper Schedule 
Dose at Termination 
Taper Period 1 (T1) 
(Taper Days 1 - 3) 
Taper Period 2 (T2) 
(Taper Days 4 - 6) 
120 mg bid 
60 mg bid 
60 mg qd 
180 mg bid 
120 mg bid 
60 mg bid 
T1 and T2 visits may done by visiting health care assessment or by phone call on Day 3 and Day 6, respectively. 
T1 visit can be combined with the Early Termination visit if the patient discontinues prior to Week 12. 
T1 should assess safety and give instructions to taper dosing. T2 should give instructions to terminate dosing. 
Abbreviations: qd = once daily; bid = twice daily. 
7.3. 
Follow-up Period 
After completion of the Taper Period, patients will enter the Follow-up Period. Patients will be 
evaluated at the clinical site 30 days (+ 7 days) after the last dose of study medication. At this 
Follow-up Visit, physical examination and assessment of vital signs, AEs, and SAEs will be 
performed as specified in the SoA (Table 3). 
7.4. 
Lost to Follow-up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the patient wishes to and/or should continue in 
the study. 
• Before a patient is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the patient (where possible, 3 telephone calls and, 
if necessary, a certified letter to the patient’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the patient’s 
medical record. 
• Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
Discontinuation of specific sites or of the study as a whole are handled as part of Section 10.1.8. 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
The required study assessments procedures are described in this section. The timeline for all 
procedures may be found in Section 1.3. 
8.1. 
Screening Visit  
8.1.1. 
Screening for All Patients 
The PI or designee is responsible for administering and obtaining freely given consent, in 
writing, before the patient enters the study and before any study-related procedures are 
performed. Each patient will sign an ICF (see Section 10.1.3). 
A window of up to 60 days is permitted for screening. Screening procedures may be spread over 
more than one visit. The screening clinic and laboratory procedures listed in Table 1 must be 
performed and documented. This will include a review of the inclusion and exclusion criteria. 
The patient’s medical history will be reviewed, and a complete physical examination will be 
conducted. The medical history must include at least 24 weeks and up to 52 weeks (if available) 
of RBC transfusion history. A urine drug screen will be performed during screening. The PI, in 
consultation with the Sponsor, will use professional judgment in allowing the patient to continue 
participation in the study when evaluating the results of the drug screen, if any positive results 
are obtained. 
Iron studies must be performed as early as possible in the Screening Period to identify and 
initiate iron supplementation, if clinically indicated, in patients with iron deficiency. Patients on 
iron, folic acid, and/or vitamin B12 supplementation are eligible for the study. If patients are on 
iron, the dose should be stable for at least 30 days prior to Day 1. 
All patients must meet all the overall as well as group-specific eligibility requirements listed in 
Section 5. It will be required that all female patients of childbearing potential have a negative 
serum pregnancy test to be eligible for the study. 
If the patient is unable to receive study medication within 60 days of screening, they may be 
rescreened once.  
For patients screened more than 60 days prior to the first dose of study medication, all screening 
assessments must be repeated to confirm eligibility. Patients will also be required to sign a new 
ICF and should be assigned the same patient number from the initial screening visit. 
Repeating any screening laboratory test(s) may be permitted on a case-by-case basis with the 
approval of the Sponsor’s Medical Monitor (or designee). In these instances, repeating a single 
laboratory test or a subset of the full panel may be acceptable. 
As part of the screening process, patients will be evaluated to determine whether and which 
vaccinations are required (see Section 2.3). 
8.1.2. 
Screening for Groups 1 and 2: 
For newly identified patients with PNH (PNH treatment naïve; Group 1) and for patients 
switching from eculizumab (Group 2), prospective patients should be screened within 60 days 
prior to first administration of study medication. All evaluations must be completed before the 


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patient is enrolled into the study. If the patient is unable to receive study medication within 60 
days of screening, the patient may be rescreened once. 
8.1.3. 
Screening for Group 3: 
If a patient is rolling over from Study ACH471-103, the patient enters the study at the Baseline 
Visit, ie, the Screening Visit is not needed, but informed consent and documentation of eligibility 
are required. Available laboratory data from Study ACH471-103 may be used to determine 
eligibility if they were performed within the 60-day screening window. 
8.2. 
Efficacy Assessments 
Blood will be collected according to the SoA (see Section 1.3) to assess the efficacy endpoints of 
change in Hgb, transfusion requirements, LDH, and other measures of hemolysis. Blood 
collection procedures are described in Section 8.3.5. 
Transfusion data, including number of RBC units transfused during screening to the end of 
follow-up will be collected (from study site records and any other location where the patient 
receives any transfusions) and recorded in each patient’s CRF. 
Transfusion avoidance is defined as patients remaining transfusion-free and not requiring a 
transfusion through Week 12 as per protocol-specified guidelines in Section 6.8. 
8.3. 
Safety Assessments 
Safety will be evaluated by monitoring and assessment of AEs, clinical laboratory tests, physical 
examination findings, and vital signs measurements. Timepoints for all safety assessments are 
provided in Section 1.3. All findings must be recorded in the patient’s source documents and 
CRF. Details on mandatory and recommended vaccinations are provided in Section 2.3. 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.3.1. 
Physical Examinations 
A complete physical examination will be performed at Screening, Baseline, at Week 12, the LTE 
(as needed) and at the ET/Week 160 Visit and will include an assessment of general appearance 
and a review of systems. A symptoms-based neurologic examination will be performed if the 
patient has any complaints or physical findings attributable to the CNS. An abbreviated physical 
examination will be conducted at other time points, as indicated in Section 1.3. Additional brief, 
complete, or symptom-driven physical examinations may be conducted at the discretion of the 
Investigator or designee and/or when patients present with AEs. Height will be collected at 
Screening only. 
Weight will be measured and should be taken in light clothing or underwear and without shoes. 
A neurologic examination will be performed as part of the full physical examination at 
Screening, Baseline, at Week 12, and at ET/Week 160 Visit and will include: 
• Mental status (orientation to person, place, and time), 
• Cranial nerve examination (extraocular movements, facial muscles [raise eyebrows, 
eye closure, and smile]), 


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• Upper and lower proximal and distal extremity strength, 
• Gait stability, 
• Coordination: finger to nose (looking for tremor) and arms outstretched looking for 
drift  
• Sensory examination if patient presents relevant symptoms 
A symptoms-based neurologic examination will be performed if the patient has any complaints 
or clinical findings attributable to the CNS and if positive for findings, full neurologic 
examination will need to be performed at each assessment timepoint. 
Consideration for neurologic consultation and/or EEG testing is at the discretion of the 
Investigator in consultation with the Sponsor. See Section 10.6 (Appendix 6) for Seizure 
Management Plan. 
8.3.2. 
Vital Signs 
Vital signs will include blood pressure, heart rate, and respiration rate at the visits indicated in 
Section 1.3. Vital signs will be measured in the supine position following a 5-minute rest.  
Body temperature will be measured and collected using an oral or temporal thermometer at the 
visits indicated in Section 1.3. 
8.3.3. 
Electrocardiograms 
Electrocardiogram (ECG) measurements will be conducted at the times indicated in Section 1.3. 
All ECG recordings will be 12-lead and will be performed after the patient has rested quietly for 
at least 5 minutes in a supine position and before blood is drawn (whenever possible). The 
following parameters and intervals will be assessed: heart rate, PR, RR, QRS, QT, and QTcF. 
The occurrence of depolarization or repolarization disorders, arrhythmic disorders, or other 
abnormalities will be noted. 
In some cases, it may be appropriate to repeat an abnormal ECG to rule out improper lead 
placement that could contribute to ECG abnormality. It is important that the leads are placed in 
approximately the same positions each time in order to achieve precise ECG recordings. 
All ECGs must be read by the PI or designee. All ECG parameters and assessments must be 
recorded or stored in the patient’s source documents and CRF. Any clinically significant finding 
must be reported as an AE. 
8.3.4. 
Clinical Safety Laboratory Assessments 
See Section 10.2 for the list of clinical laboratory tests to be performed and to the SoA 
(Section 1.3) for the timing and frequency.  
8.3.5. 
Blood Collection 
Patients will be in a seated or supine position during the blood collection. Specific instructions 
for sample collection, processing, and shipping will be provided in a separate laboratory manual. 
If central laboratory tests results are not obtainable in a timely manner, samples may be collected 


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at an unscheduled visit and analyzed locally. See the laboratory manual for additional 
information. 
8.3.6. 
Pregnancy 
Details of any pregnancy in patients and/or partners of male patients that occurs or is confirmed 
within the timelines listed in Section 8.4.1 will be collected. If a pregnancy is reported, the 
Investigator should inform the Sponsor within 24 hours of learning of the pregnancy and should 
follow the procedures outlined in Section 10.3, Appendix 3. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.7. 
Patient Safety Card 
A Patient Safety Card will be provided to patients to carry with them at all times. The card is 
provided to increase patient awareness of the risk of meningococcal infection and promote quick 
recognition and disclosure of any potential signs or symptoms of infection experienced during 
the course of the study and to inform patients on what actions must be taken if they are 
experiencing signs or symptoms of infection. 
At each visit throughout the study, the study staff will ensure that the patient has the Patient 
Safety Card and will review it with the patient at each visit as described in the SoA (Section 1.3).  
8.4. 
Adverse Events and Serious Adverse Events 
The definitions of AEs and SAEs can be found in Section 10.3. All AEs will be reported to the 
Investigator or qualified designee by the patient (or, when appropriate, by a caregiver, surrogate, 
or the patient’s legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study medication or study procedures, or that 
caused the patient to discontinue the study medication. (see Section 7). 
Procedures for recording, evaluating, follow-up, and reporting AEs and SAEs are outlined in 
Section 10.3 (Appendix 3).  
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the signing of the ICF until 30 days after the last dose 
of study medication, at the time points specified in Section 1.3.  
Medical occurrences that begin before the start of study medication but after obtaining informed 
consent will be recorded as pretreatment AEs. This does not include pretreatment or 
post-treatment complications that occur as a result of protocol-mandated procedures (eg, invasive 
procedures, such as venipuncture or biopsy), which should be reported as AEs. Pregnancy is not 
an AE. A pregnancy occurring after the start of study medication should be reported on the 
pregnancy forms, as described in Section 10.3, Appendix 3. 
All SAEs will be recorded and reported to the Sponsor or the designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 10.3 (Appendix 3). The 


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Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being 
available. 
Investigators are not obliged to actively seek AE or SAE data after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a patient has been discharged from the study, and he/she considers the event to be reasonably 
related to the study medication or study participation, the Investigator must promptly notify the 
Sponsor. 
8.4.2. 
Method of Detecting AEs and SAEs  
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3, 
Appendix 3. 
8.4.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow-up on each 
patient at subsequent visits/contacts. All SAEs will be followed-up until resolution, stabilization, 
the event is otherwise explained, or the patient is lost to follow-up (as defined in Section 7.3). 
Further information on follow-up procedures is provided in Section 10.3. 
8.4.4. 
Regulatory Reporting Requirements for SAEs  
Prompt notification of an SAE by the Investigator to the Sponsor is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of a study 
medication under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study medication under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRBs/ IECs, and Investigators. 
Suspected unexpected serious adverse reactions (SUSARs) must be reported according to local 
regulatory requirements and Sponsor policy and forwarded to Investigators as necessary. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then file it 
along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to 
local requirements. 
8.5. 
Treatment of Overdose 
For this study, any dose of ALXN2050 greater than that specified in the protocol will be 
considered an overdose.  
Sponsor does not recommend specific treatment for an overdose; general supportive measures 
are recommended. 
In the event of an overdose or suspected overdose, the Investigator should: 
1. Contact the Medical Monitor immediately. 


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2. Assess the patient and determine the need for any monitoring in a medical setting; if the 
Investigator cannot see the patient or the patient cannot reach the Investigator, the patient 
should go to the emergency room. 
3. Closely monitor the patient for any AE/SAE. 
4. If necessary, based on consultation with the sponsor’s medical monitor, obtain a plasma 
sample for PK analysis or safety labs. 
5. Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the patient. 
8.6. 
Pharmacokinetics 
Blood samples will be collected at the times outline in the SoA (Section 1.3) to determine plasma 
concentrations of ALXN2050.  
ALXN2050 concentrations will be determined using validated bioanalytical methods. Single 
trough PK samples will be taken at other time points as outlined in Section 1.3. 
The logistics of obtaining any intensive PK profile in this study will be discussed between the 
Sponsor and the PI. Sites should collect as many samples as possible during the 12-hour period. 
For those sites that cannot perform the intensive PK/PD sampling, a pre-dose and a 2.5-hour 
postdose sample obtained at the next clinic visit, but no less than 4 days after dose escalation 
occurred, will be acceptable. See also PK sampling during dose modification in Section 6.7.5. 
Additional information on sample collection and shipping instructions will be provided in a 
separate laboratory manual. 
8.7. 
Pharmacodynamics 
Pharmacodynamics (Bb, APH, FD, C3, CH50) will be evaluated using serum or plasma collected 
during the study as outlined in Section 1.3. Additional information on sample collection and 
shipping instructions will be provided in a separate laboratory manual. Sponsor may store 
samples for other biomarker tests for future research. 
8.8. 
Genetic Samples 
If a patient provides separate informed consent via the optional genetic consent form, samples 
will be collected and retained for potential future genetic testing. Genetic analyses may be 
conducted: 1) if a patient does not respond to the study medication; 2) if a patient experiences 
drug-related toxicity; or 3) to further characterize PNH. Refer to Section 10.5, Appendix 5 for 
details. 
8.9. 
Patient-Reported Outcomes 
Patient reported outcomes will be captured using an electronic device. All patients enrolled in the 
study will complete the self-administered questionnaires for the FACIT-Fatigue (Version 4), 
EuroQoL 5 Dimensions, 3-Level version (EQ-5D-3L) scales and European Organisation for 


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Research and Treatment of Cancer (EORTC) QoL Questionnaire-Core 30 scale (QLQ-C30), 
Version 3.0, as indicated in Section 1.3. PROs should be administered as early as possible during 
clinic visits. 
8.9.1. 
FACIT-Fatigue 
The FACIT-Fatigue scale, Version 4.0, is a collection of QoL questionnaires pertaining to the 
management of fatigue symptoms due to a chronic illness. The FACIT-Fatigue is a 13-item 
questionnaire that assesses self-reported fatigue and its impact upon daily activities and function 
over the preceding 7 days. Patients will score each item on a 5-point scale: 0 (not at all) to 4 
(very much). Total scores range from 0 to 52, with higher score indicating better QoL. 
8.9.2. 
EQ-5D-3L 
The EQ-5D-3L is defined by 5 dimensions: mobility, usual activities, self-care, pain/discomfort, 
and anxiety/depression. Each of the EQ-5D dimensions may be summarized and analyzed as 
categorical variables. The visual analog scale results and EQ-5D-3L index may be summarized 
and analyzed as continuous variable. The EQ-5D index score (time trade off [TTO]) to determine 
the health state value will be based on the US population-based preference weights. 
8.9.3. 
EORTC 
The EORTC QLQ-C30, Version 3.0, is a questionnaire developed to assess the QoL of cancer 
patients. The questionnaire includes the following subscales: global health status, functional 
scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and 
social activity), symptom scales (fatigue, nausea and vomiting, and pain), and single items 
(dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Thirty 
questions related to QoL, with the first 28 questions scored on a 4-point scale (1 = not at all to 4 
= very much) and the final 2 questions that probe the patient’s overall health and QoL scored on 
a scale of 1 (very poor) to 7 (excellent). Each subscale has a range of 0 to 100%, with a high 
score representing a higher response level. Thus, a high score for a functional scale represents a 
high level of functioning but a high score for a symptom scale represents a high level of 
symptomatology/problem. 


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
No hypotheses will be formally tested in this study. 
9.2. 
Sample Size Determination 
The sample sizes are based on a pragmatic approach to study patients with PNH who are 
treatment-naïve, and patients with PNH who have received C5 inhibition treatment with 
eculizumab. Based on the results from the PNH monotherapy Studies ACH471-100 and 
ACH471-103, and the PNH combination therapy Study ACH471-101, it is anticipated that 
10 patients in the treatment naïve group and 10 patients in C5 inhibitor switch group will be 
adequate to demonstrate the effectiveness of ALXN2050 as monotherapy in treating patients 
with PNH. For the primary endpoint of change from baseline to Week 12 in Hgb, the group of 10 
patients each in treatment naïve cohort and eculizumab switch cohort will provide 87% power to 
detect the mean increase from baseline of 2 g/dL, assuming standard deviation of 1.8 g/dL and 
two-sided 0.05 significance level. The patients who switch from danicopan monotherapy in 
Study ACH471-103 will provide additional efficacy and safety data for ALXN2050 
monotherapy. 
9.3. 
Populations for Analyses 
All patients who receive at least 1 dose of ALXN2050 will be included in the safety and efficacy 
analyses. 
9.4. 
Statistical Analyses 
Statistical methods described in this section will be further elaborated in a separate Statistical 
Analysis Plan (SAP).  
9.4.1. 
General Considerations 
Descriptive and exploratory statistical methods will be utilized to present results from data 
collected during 12 weeks of ALXN2050 Treatment Period and LTE period. 
Unless otherwise specified, all efficacy and safety data will be analyzed and presented separately 
by the three patient Groups 1 to 3 as specified in study design Section 4.  
Patient listings will be provided for all efficacy, PK and PD, and safety parameters, including 
data from the LTE Period. Summary statistics will be computed for selected efficacy and safety 
parameters so that meaningful clinical interpretations can be made. Graphic presentations will 
also be produced for selected efficacy and safety parameters. 
An SAP will be developed to describe the data analysis procedures and data presentations in 
detail. 
9.4.2. 
Demographics and Baseline Characteristics 
Demographic parameters (age, gender, race, weight, body mass index) and baseline PNH disease 
characteristics, including RBC transfusion history and baseline laboratory measurements, will be 


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summarized to provide an overall description of the study populations. Data will be presented by 
group and by total patients receiving ALXN2050. For the group switching from eculizumab or 
danicopan to ALXN2050, a summary of usage prior to screening will also be provided. 
9.4.3. 
Efficacy Analyses 
9.4.3.1. 
Analyses of Primary Efficacy Endpoints 
The primary efficacy endpoint will be: 
• Change in Hgb level from baseline measurement to Week 12 
9.4.3.2. 
Analyses of Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
• Number of patients who have RBC transfusion avoidance during 12 weeks of treatment 
with ALXN2050. Transfusion avoidance is defined as patients remaining transfusion-free 
and not requiring a transfusion through Week 12 as per protocol-specified guidelines 
(Section 6.8). 
• Number of RBC units transfused and transfusion instances during 12 weeks of treatment 
as compared with transfusion data prior to screening  
• Change in LDH level from baseline measurement at Week 12 
• Change in absolute reticulocyte count and direct and total bilirubin from baseline 
measurement at Week 12 
• Change in PNH RBC clone size and C3 fragment deposition on PNH RBCs from 
baseline measurement at Week 12. 
• Change in FACIT-Fatigue score from baseline to Week 12 and Week 160. 
Similar to Hgb measurements, descriptive statistics and graphic presentations for the numeric 
secondary endpoints listed above will also be provided. Summary statistics for RBC transfusion 
units received during 12 weeks of dosing will also be provided. 
9.4.4. 
Safety Analyses 
The evaluation of safety during the 12 weeks of ALXN2050 Treatment Period and during the 
LTE Period will be based primarily on the frequency of AEs, clinical laboratory assessments, 
vital signs, and 12-lead ECG. Other safety data will be summarized as appropriate. 
Descriptive statistics using summary statistics will be calculated for quantitative safety data, as 
well as for the difference to baseline measurement by visit, when appropriate. 
Adverse events will be coded using the latest version of MedDRA. Treatment-emergent adverse 
events (TEAEs) (ie, those AEs that newly occur or worsen in severity during treatment) will be 
summarized by system organ class and preferred term. Tabulated listing of patients with SAEs 
and those who discontinue from the treatment due to an AE will be provided. 
Shift tables may be provided for selected graded laboratory parameters, if clinically deemed 
meaningful. 


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Data on vital signs and ECGs will be examined through patient listings, and by summary 
statistics of selected parameters. 
9.4.5. 
Pharmacokinetic Analysis 
Pharmacokinetic analysis will be done using a validated computer program. The PK 
characteristics of ALXN2050 from patients, including, but not limited to, the standard PK 
parameters outlined in the table below, will be derived from the individual plasma concentration 
time data on study day(s) with intensive PK sampling. Descriptive statistics (number of patients, 
mean/geometric mean, SD, median, minimum, and maximum) will be used to summarize the 
calculated PK parameters. 
AUC0-12 
Area under the curve 
Cmax 
Maximum plasma concentration 
tmax 
Time after administration of a drug when the maximum plasma concentration is 
reached 
C(0) 
Trough concentration at start of steady-state dose interval 
C(12) 
Trough concentration at end of steady-state dose interval 
9.4.6. 
Pharmacodynamic Analysis 
Pharmacodynamic analyses will be performed for all patients who receive at least 1 dose of 
ALXN2050 and who have evaluable baseline and postdose PD data. Descriptive statistics will be 
presented for all PD endpoints at each sampling time. The PD effects of ALXN2050 
administered orally will be evaluated by assessing the absolute values and changes and 
percentage changes from baseline in serum or plasma concentrations over time, as appropriate. 
Assessments of ALXN2050 PK-PD relationships may be explored using data from this study or 
in combination with data from other studies. 
9.4.7. 
Population PK/PD Analysis 
Population PK modeling will be conducted using data from this study alone and/or in 
combination with data from other studies. In addition, the exposure response (PD markers and 
other clinical endpoints) relationship may be explored. Population PK/PD analysis results may 
be presented in a separate report. 
9.4.8. 
Patient-Reported Outcome Measures Assessment 
9.4.8.1. 
FACIT-Fatigue (Version 4) 
The change in FACIT-Fatigue scores from baseline to Week 12 and end of LTE will be analyzed 
as a secondary outcome. FACIT-Fatigue data will be summarized at baseline and each 
postbaseline time point using descriptive statistics for continuous variables for the observed 
value as well as the change from baseline.  
9.4.8.2. 
EQ-5D-3L 
Both EQ-5D-3L Visual Analogue scale (VAS) and index score (TTO) will be calculated. The 
EQ-5D-3L TTO to determine the health state value will be based on the US population-based 
preference weights. The EQ-5D-3L data will be summarized at baseline and each postbaseline 


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time point using descriptive statistics for continuous variables for the observed value as well as 
the change from baseline.  
9.4.8.3. 
EORTC 
Changes from baseline in EORTC-QLQ-C30 will be summarized by treatment group at baseline 
and at the study visits where this assessment is collected. Descriptive statistics for continuous 
variables for the observed value as well as the change from baseline will be presented.  
9.5. 
Interim Analyses  
Interim analyses are planned when either 6 patients in Group 1 or Group 2 complete the 12-week 
Treatment Period. The primary endpoint of change in Hgb levels at Week 12, as well as the 
secondary efficacy endpoints, will be evaluated. The interim analyses data will not be used to 
modify the design of the study. Results from the interim analyses may be used to inform design 
of next phase clinical studies. Additional interim analyses may be conducted and described in 
detail in the SAP. 
 


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
− Applicable ICH Good Clinical Practice (GCP) Guidelines 
− Applicable laws and regulations 
• The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator 
and reviewed and approved by the IRB/IEC before the study is initiated.  
• Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study patients.  
• The Investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
− Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
10.1.2. 
Financial Disclosure 
Investigators and Sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3. 
Informed Consent Process 
The Investigator, or his/her representative, will explain the nature of the study to the patient or 
his/her legally authorized representative, and will review the informed consent and answer any 


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questions regarding the study. No study assessments or procedures will be performed until all the 
patient’s questions have been answered and the patient has signed the ICF. 
Patients must be informed that their participation is voluntary. Patients or their legally authorized 
representative will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained before 
the patient was enrolled in the study, and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
If the ICF is revised, patients must be reconsented to the most current version of the ICF during 
their active participation in the study. 
A copy of the ICF must be provided to the patient or the patient’s legally authorized 
representative. 
A patient who is rescreened is required to sign another ICF. 
10.1.4. 
Data Protection 
Patients will be assigned a unique identifier by the sponsor. Any patient records or datasets that 
are transferred to the Sponsor will contain the identifier only; patient names or any information 
which would make the patient identifiable will not be transferred. 
The patient must be informed that his/her personal study-related data will be used by the Sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the patient. 
The patient must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
The Sponsor as a data controller has implemented privacy and security controls designed to help 
protect patient personal data, including information security controls, firewalls, incident 
detection, and secure transfer measures. 
In the event of any accidental or unlawful destruction, loss, alteration, unauthorized disclosure 
of, or access to, personal data (“breach”), the controller has implemented procedures and 
measures to promptly address and mitigate any risk to the data subject. In the event of a breach, 
the controller will notify the appropriate regulatory authorities and/or the data subject in 
accordance with applicable data protection law. 
10.1.5. 
Dissemination of Clinical Study Data 
Study-related information and study results may be posted on publicly accessible clinical study 
databases (eg, the US website www.clinicaltrials.gov or the EU website 
www.clinicaltrialsregister.eu), as appropriate, and in accordance with national, regional, and 
local regulations. 
All information contained in this protocol and the study results are considered to be confidential. 
The Investigator agrees to use this information for purposes of conducting this study. It is 


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understood that the Sponsor may use data derived from this study for the purpose of research and 
development. The data may be disclosed by the Sponsor to other Investigators, the US FDA, 
other government agencies, or foreign drug regulatory authorities, or to the public. No 
publication of study design or results is permitted without specific Sponsor’s approval. To gain 
approval, a copy of the manuscript for review must, therefore, be sent to the Sponsor 60 days 
before submission for publication. 
10.1.6. 
Data Quality Assurance 
All patient data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the CRF.  
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.  
Monitoring details describing strategy, methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Medical Monitoring, Safety Monitoring and Global Monitoring 
Plans. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data.  
The Sponsor assumes accountability for actions delegated to other individuals (eg, Contract 
Research Organizations [CRO]). 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements.  
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 2 years after the last marketing application approval, or if not 
approved, 2 years following the discontinuance of the study medication, unless local regulations 
or institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be transferred to 
another location or party without written notification to the Sponsor.  
10.1.7. 
Source Documents 
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the Investigator’s site. 
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 


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request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available.  
10.1.8. 
Study and Site Start and Closure 
The Sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the Sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines 
• Inadequate recruitment of patients by the Investigator 
• Discontinuation of further study medication development 
10.1.9. 
Publication Policy 
All information contained in this protocol and the study results will be considered confidential. 
The Investigator agrees to use this information for purposes of conducting this study. It is 
understood that the Sponsor may use data derived from this study for the purpose of research and 
development. The data may be disclosed by the Sponsor to other Investigators, the FDA, other 
government agencies, or foreign drug regulatory authorities, or to the public. No publication of 
study design or results is permitted without specific Sponsor approval.  
• Where possible, primary manuscripts reporting results of the primary efficacy 
endpoint or the final results will be submitted for publication within 12 to 18 months 
of the primary evaluation date or end of study, whichever is earlier.  
• Investigators who participate as authors in manuscripts derived from 
Alexion-sponsored studies will agree to the prerequisites as outlined in the Sponsor 
author engagement agreement prior to engaging in manuscript development.  
• The Investigator agrees to submit proposals for new manuscripts (whether or not the 
proposed analyses are derived from protocol-specified endpoints) to the Sponsor for 
review and consideration. All manuscripts or abstracts emanating from approved 
proposals are to be submitted to the Sponsor for review before submission to the 
journal/society. This allows the Sponsor to protect proprietary information and to 
provide comments.  
− The proprietary nature of some development work may preclude publication. In 
some cases, it may be necessary to delay a publication to allow the Sponsor to 
ensure protection of intellectual property.  
• In general, primary publications, including congress and journal publications, 
containing the protocol-specified results of a study should occur prior to the 


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publication of individual study site results or case reports. Alexion’s policy prohibits 
duplicate publication, whereby the same results must not be published in multiple 
peer-reviewed journal manuscripts.  
− Encore congress publications may be appropriate to allow communication of 
research findings to relevant audience and geographical regions. 
• Alexion will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, Alexion will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a Coordinating Investigator will be designated by mutual 
agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements and per the Alexion 
Publication Policy. 


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10.2. 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 5 will be performed by the central and/or local laboratory. Protocol-
specific requirements for inclusion or exclusion of patients are detailed in Section 5 of the 
protocol. 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations. Investigators must document their review of each 
laboratory report. 
Table 5: 
Protocol-Required Laboratory Assessments1 
Hematology 
Chemistry 
Urine 
Other Assessments 
Complete blood count 
(CBC), including: 
- 
RBC count 
- 
White blood cell 
(WBC) count 
- 
WBC differential 
(absolute and 
percent): 
- neutrophils 
- lymphocytes 
- monocytes 
- eosinophils 
- basophils 
- 
Hematocrit (Hct) 
- 
Hemoglobin (Hgb) 
- 
Mean corpuscular 
volume (MCV)  
- 
Mean corpuscular 
hemoglobin (MCH) 
- 
Mean corpuscular 
hemoglobin 
concentration 
(MCHC)  
- 
Mean platelet volume 
(MPV) 
- 
Platelet count 
- 
Red cell distribution 
width (RDW) 
- 
Reticulocyte count 
(absolute and 
percent) 
Alanine aminotransferase 
(ALT) 
Albumin 
Alkaline phosphatase 
Aspartate 
aminotransferase (AST) 
Bicarbonate (HCO3) 
Bilirubin (fractionated)2 
Blood urea nitrogen 
(BUN) 
Calcium 
Calculated eGFR3 
Chloride 
C-reactive protein (CRP) 
Creatine kinase4 
Creatinine 
Gamma-glutamyl 
transferase  
Glucose5 
LDH 
Lipid profile including: 
- 
Cholesterol/HDL 
ratio 
- 
High-density 
lipoprotein 
cholesterol (HDL-C) 
- 
Low-density 
lipoprotein 
cholesterol (LDL-C) 
- 
Non-HDL-C 
- 
Total cholesterol 
- 
Triglycerides 
- 
Very low-density 
lipoprotein 
cholesterol 
(VLDL-C) 
Potassium 
Sodium 
Total protein 
Uric acid 
Urinalysis and 
microscopy: 
- 
Bilirubin 
- 
Color 
- 
Glucose 
- 
Hgb 
- 
Ketones 
- 
Leukocytes 
- 
Nitrite 
- 
Occult blood 
- 
pH 
- 
Protein 
- 
Specific gravity 
- 
Urobilinogen 
Microscopic 
examination of 
sediment 
Urine pregnancy test6 
Urine drug screens:  
- 
Cocaine 
- 
Amphetamines, 
- 
Barbiturates 
- 
Benzodiazepines 
- 
Cannabinoids 
- 
Opiates 
- 
Phencyclidine 
- 
Propoxyphene 
- 
methadone 
Hemolytic alternative 
pathway activity (APH) 
Bb 
C3 
C3 fragment deposition 
Hemolytic classical 
pathway activity (CH50) 
D-dimer 
Direct Coombs 
Factor D  
Free hemoglobin 
Follicle stimulating 
hormone (FSH) 
Haptoglobin 
Plasma/serum samples for 
additional nongenetic 
biomarker testing 
PNH clone size 
Coagulation 
(PT/PTT/INR)  
Pregnancy (serum)6 
Iron studies: 
- 
Serum ferritin 
- 
Serum iron 
- 
Serum transferrin  
- 
Transferrin 
saturation 
(TSAT) 
- 
Total iron binding 
capacity (TIBC) 
Serology: 
- 
HCV Ab 
- 
HbsAg 
- 
HbcAb 
- 
HIV Ab 
- 
UGT1A1 
(Gilbert’s)7 
Genetic biomarkers 
(optional) 
PK 


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1. 
Check the Schedule of Activities for specific times when these tests should be done. 
2. 
Fractionate and obtain measurements of direct and indirect bilirubin for all patients.  
3. 
Provide eGFR based on Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) creatinine equation 
(2009) for patients ≥ 19 years of age and based on the “bedside Schwartz” equation (2009) for patients 
< 19 years of age. 
4. 
Perform at baseline, and then subsequently only as a reflex if AST > ULN.  
5. 
If glucose is > ULN, reflexively test HbA1c.  
6. 
Any positive urine pregnancy test will be confirmed by a serum pregnancy test. 
7. 
Test only if history or family history suggestive of Gilbert’s Syndrome. 
Abbreviations: APH = alternative pathway activity; AST = aspartate aminotransferase; Bb = Bb fragment of 
complement factor B; CH50 = classical pathway activity; eGFR = Estimated glomerular filtration rate; 
HbsAg = hepatitis B surface antigen; HCV Ab = hepatitis C virus antibody; HIV Ab = human immunodeficiency 
virus antibody; INR = international normalized ratio; PT = prothrombin time; PTT = partial thromboplastin time; 
RBC = red blood cell; ULN = upper limit of normal. 


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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of Adverse Event 
Adverse events must be assessed for the investigational product(s) in this study. An 
investigational product is defined as a pharmaceutical form of an active ingredient or placebo 
being tested or used as a reference in the study, whether blinded or unblinded. The term “adverse 
event” is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not it is considered to be drug related. An AE can arise with any use of the 
drug (eg, off-label use, use in combination with another drug) and with any route of 
administration, formulation, or dose, including an overdose. 
Medical occurrences that begin before the start of study medication but after obtaining informed 
consent will be recorded as pretreatment AEs. This includes pre- or posttreatment complications 
that occur as a result of protocol-mandated procedures (eg, invasive procedures, such as 
venipuncture or biopsy).While pregnancy itself is not considered an AE, for the purposes of 
safety, a pregnancy occurring after the start of study medication should be reported on the 
pregnancy forms. 
A TEAE is defined as an AE that emerges during treatment, having been absent prior to 
treatment, or worsens relative to the pretreatment state. In this study, any AE first assessed after 
receipt of the first dose of investigational product until 30 days after the last dose of study 
medication will be considered treatment-emergent, as defined in Section 10.3.5. All TEAEs will 
be recorded and reported. 
An AE (including a TEAE) can be one or more of the following: 
• Any unfavorable and unintended sign (eg, an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a drug and does not imply any 
judgment about causality. 
• Any new disease or exacerbation of an existing disease. 
• Recurrence of an intermittent medical condition (eg, headache) not present at 
baseline. 
• Any case of abuse of alcohol, illicit drugs, or prescription drugs; abuse of study 
medication(s) or protocol-specified drug(s); addiction. 
• Laboratory test or other clinical test (eg, ECG or X-ray) with a clinically significant 
abnormality (as defined below). 
• An effect of the study medication, including comparator. 
• Any dose of medication (study medication or other concomitant medication) that is 
taken at a dose higher than the prescribed dose (ie, an overdose). Overdose should be 
reported as an AE, only if it is associated with any symptoms or signs. 
The following are not considered to be AEs: 
• Medical or surgical procedures (eg, surgery, endoscopies, tooth extraction, 
transfusion) – the condition which leads to the procedure is the AE. 


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• Preexisting diseases or conditions or laboratory abnormalities present or detected 
prior to the screening evaluation that do not worsen. 
• Situations where an untoward medical occurrence has not occurred (eg, 
hospitalization for elective surgery, social and/or convenience admissions). 
Clinically significant changes in objective findings (eg, laboratory, ECG, physical examination) 
should be considered AEs only if they meet one or more of the following criteria: 
• Associated with accompanying symptoms 
• Require medical/surgical intervention 
• Lead to a change in study medication dosing or discontinuation from the study  
• Lead to significant additional concomitant drug treatment, or other therapy 
• Lead to any of the outcomes included in the definition of a serious adverse event  
• Are considered clinically significant by the Investigator 
Whenever possible, the etiology of the abnormal finding (rather than the abnormal finding itself) 
should be documented as the adverse event. Repeated additional tests and/or other evaluations 
required to establish the significance and etiology of an abnormal result should be obtained when 
clinically indicated. 
Any abnormal test result that is determined to be an error does not require reporting as an AE. 
Surgical procedures themselves are not AEs but are therapeutic measures for conditions that 
require surgery. The condition for which the surgery is required may be an adverse event, if it 
occurs, or is detected during the study period. Planned surgical measures permitted by the 
clinical study protocol (if any) and the condition(s) leading to these measures are not AEs, if the 
condition(s) was (were) known before the start of the study treatment and documented in the 
patient’s medical record. In the latter case, the condition should be reported as medical history. 
All patients who have AEs, whether considered to be associated with the use of the 
Investigational product or not, must be monitored to determine the outcome of the event(s). The 
clinical course of the AE will be followed according to accepted standards of medical practice, 
even after the end of the period of observation, until a satisfactory explanation is found, or the 
Investigator considers it medically justifiable to terminate follow-up. 
10.3.2. 
Criteria for Assessing Seriousness 
All AEs must be evaluated as potential SAEs. If an event is not an AE per definition above, then 
it cannot be an SAE even if serious conditions are met. An SAE is any untoward medical 
occurrence that occurs at any dose and meets at least one of the following criteria: 
• Results in death 
• Is life-threatening ie, the patient was at immediate risk of death from the AE as it 
occurred.  (This does not include an event that, had it occurred in a more severe form, 
or was allowed to continue, might have caused death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization for the 
AE 


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• The following types of hospitalizations are not considered SAEs for regulatory 
reporting purposes: 
− Hospitalization(s) for planned (pre-scheduled) medical procedures known at the 
time of screening 
− Protocol-specific hospital admission 
− Respite care 
− Admission for the treatment of pre-existing condition (known at the time of 
screening) not associated with the development of a new AE or with the 
worsening of the pre-existing condition 
− Observation/same day/ambulatory procedure 
• Is a persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions 
• Is a congenital anomaly/birth defect (in the child of a patient who was exposed to the 
study medication) 
• Is an important medical event or reaction 
10.3.3. 
Documentation and Reporting of Adverse Events 
Adverse events, including TEAEs, may be spontaneously reported to the Investigator by a 
patient or his/her representative, or elicited during questioning and examination of a patient. All 
AEs will be assessed by the Investigator and documented regardless of apparent causality from 
use of the study treatment(s). For each AE, the Investigator will evaluate and report the date of 
onset and resolution, outcome, severity, relationship to study treatment(s), action taken, 
additional treatments required to manage the event, and determination of seriousness. All 
identified AEs occurring during the trial and follow-up period must be fully recorded and 
described on the appropriate CRF page. The AE will be reported in standard medical 
terminology. Whenever possible, the AE should be evaluated and reported as a diagnosis, rather 
than as individual signs or symptoms. A cluster of signs and symptoms that results from a single 
cause will be reported as a single diagnosis (eg, fever, elevated WBC, cough, and abnormal chest 
X-ray can all be reported as “pneumonia”). 
If a definitive diagnosis is not possible, the individual symptoms and signs will be individually 
recorded. Documentation must be supported by an entry in the patient’s medical record. The 
relationship to study medication or study procedures will be assessed using the definitions in 
Section 10.3.7. 
10.3.4. 
Treatment and Follow-Up of Adverse Events 
All AEs will be followed up (including obtaining relevant laboratory tests) until they have 
returned to baseline status or stabilized. If a clear explanation is established, it should be 
recorded. Follow-up of AEs will continue through the last day on study (including the follow-up 
period) or until the events have resolved or stabilized to the satisfaction of the PI and the sponsor 
Medical Monitor (or designee). The Sponsor may request that certain AEs be followed until 
resolution or stabilization. 


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10.3.5. 
Timeframe for Collection of Adverse Events 
Adverse events include events that appeared or worsened during the course of the clinical trial. 
AEs may also include pre- or post-treatment complications that occur as a result of 
protocol-mandated procedures (eg, invasive procedures, such as venipuncture or biopsy). 
Any AE (ie, a new event or an exacerbation of a preexisting condition) with an onset date after 
the patient provides informed consent through the 30 days following the patient’s last study 
medication dose will be recorded as an AE on the appropriate CRF page(s). 
All SAEs, regardless of cause or relationship, occurring within 30 days of last study medication 
dose will be documented and reported. Follow-up of SAEs will continue through the last day on 
study or until the event has resolved or stabilized to the satisfaction of the PI and the Sponsor’s 
Medical Monitor (or designee). 
Investigators are not obligated to actively seek out SAEs beyond the follow-up period. However, 
if the PI (or designee) learns of an SAE occurring after completion of the final follow-up visit, 
and the SAE is deemed by the PI (or designee) to be related to the study medication(s), the PI (or 
designee) will promptly document and report the event to the Sponsor. 
10.3.6. 
Severity and Grading of Adverse Events 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to one of the following categories from National Cancer Institute 
CTCAE v5.0, published 27 Nov 2017:  
• Grade 1: Mild (awareness of sign or symptom, but easily tolerated) 
• Grade 2: Moderate (discomfort sufficient to cause interference with normal activities) 
• Grade 3: Severe (incapacitating, with inability to perform normal activities) 
• Grade 4: Life-threatening 
• Grade 5: Fatal 
 
An event is defined as “serious” when it meets at least one of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe. 
The PI (or designee) should determine the severity of the AE based on the overall clinical 
importance or significance of the finding for that individual patient. If a lab abnormality is 
deemed to be clinically significant, according to the criteria described in Section 10.3.1, it will be 
reported as an AE, and the AE grade reported should correspond to the grade of the laboratory 
abnormality on the CTCAE grading scale. 
If an AE that was reported during the study increases or decreases in severity, then that AE is 
given a resolution date and time and a new record initiated with the new severity. If the severity 
of an AE remains the same, the AE will be kept open through to resolution. 
An event is defined as “serious” when it meets at least 1 of the pre-defined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 


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10.3.7. 
Assessment of Causality 
Assessment of Causality 
• The Investigator is obligated to assess the relationship between the study intervention 
and each occurrence of each AE or SAE. An Investigator causality assessment must be 
provided for all AEs (both nonserious and serious). This assessment must be recorded 
in the CRF and on any additional forms, as appropriate. The definitions for the 
causality assessments are as follows: 
− Not related: There is no reasonable possibility the study intervention caused the 
AE.  
 The AE has a more likely alternative etiology; it may be due to 
underlying or concurrent illness, complications, concurrent treatments, 
or effects of another concurrent drug.  
 The event does not follow a reasonable temporal relationship to 
administration of the study intervention. 
− Related: There is a reasonable possibility the study intervention caused the AE. 
 The AE has a temporal relationship to the administration of the study 
intervention. 
 The event does not have a likely alternative etiology.  
 The event corresponds with the known pharmaceutical profile of the 
study intervention. 
 There is improvement on discontinuation and/or reappearance on 
rechallenge. 
• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The Investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred, and the Investigator has 
minimal information to include in the initial report to Alexion. However, it is very 
important that the Investigator always makes an assessment of causality for every 
event before the initial transmission of the SAE data to Alexion. 
• The Investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
10.3.8. 
Reporting Serious Adverse Events and Pregnancies 
Alexion has requirements for the expedited reporting of safety events meeting specific 
requirements to worldwide regulatory authorities; therefore, Alexion must be notified 


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immediately regarding the occurrence of any SAE and/or pregnancy that occurs during the study 
(time frames outlined in Section 10.3.5). 
The procedures for reporting all SAEs and/or pregnancies, regardless of causal relationship, are 
as follows: 
• SAE 
o Record the SAE within 24 hours of becoming aware of the event by logging into 
the EDC system (Fusion) and completing an initial SAE report. 
o This will trigger an email notification to the Axiom and Alexion Pharmaceuticals 
distribution lists. 
• Pregnancy 
o Record the pregnancy within 24 hours of becoming aware of the event into the 
EDC system (Fusion) and complete the pregnancy form. 
This will trigger an email notification to the Axiom and Alexion Pharmaceuticals distribution 
lists. 
Contact information is provided below. 
SAE CONTACT 
Report all SAEs and/or pregnancy events into Axiom Fusion EDC 
In the event of system failure, or for questions about completing the forms in EDC: 
SAE Telephone Number and email:  
Axiom Real-Time Metrics 
1-866-91-AXIOM (1-866-912-9466) 
ACH-SAEHelp@axiom.cc 
For fatal or life-threatening events, provide redacted copies of hospital discharge reports, autopsy 
reports, and other documents, as applicable. The Sponsor may request additional information 
from the PI to ensure the timely completion of accurate safety reports. 
Any follow-up information collected on any report of an SAE and/or pregnancy must be reported 
by the Investigator within 24 hours of becoming aware of information. 
In the case of a medical emergency, the Medical Monitor should be contacted. 
10.3.9. 
Investigator Reporting Requirements for Suspected Unexpected Serious Adverse 
Reactions 
Alexion is responsible for ensuring that Investigators and central IECs/IRBs are notified of all 
AEs that are serious, unexpected, and considered related, probably related, or possibly related to 
the Investigational product. A CRO may be designated to perform this notification. This 
notification will be in the form of a MedWatch/CIOMS report. The PI will notify the local IECs 
or IRBs as per IEC or IRB requirements. Upon receiving such notices, the PI must review and 
retain the notice. The Sponsor, Investigator, and EC or IRB will determine if the informed 


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consent requires revision. The PI should also comply with IEC or IRB procedures for reporting 
any other safety information. 
10.3.10. 
Concomitant Medication Assessments 
Details of all prior (within 90 days of the screening evaluation) and concomitant medication use, 
including all medications administered for the treatment of AEs as well as prior administration of 
danicopan from previous Sponsor studies, will be recorded in the patient’s CRF at each study 
visit. 
10.3.11. 
Monitoring Patient Safety 
The safety of patients will be monitored by Investigators and by a Medical Monitor (or designee) 
at the Sponsor on an ongoing basis while patients are receiving investigational product.  
10.3.12. 
Removal of Patients from the Trial or Study Medication 
A patient is free to withdraw from the study at any time without jeopardizing future medical 
care. The PI (or designee) may decide, for reasons of medical prudence or patient 
noncompliance, to discontinue dosing in a patient. The Sponsor’s Medical Monitor should be 
notified immediately, and if possible, before dosing is terminated. 
If dosing is to be terminated, it may be done so immediately, or a taper can be implemented as 
described in Section 7.2, whichever is considered to be in the best interest of the patient. When 
dosing is terminated, study participation is not necessarily immediately terminated. Instead, 
whenever possible, the patient should complete all activities in the Taper and Follow-up Periods 
(if tapered) or in the Follow-up Period (if discontinued immediately), as described in Section 7. 
The criteria for patient withdrawal are listed in Section 7.1. 
The reason for any patient’s discontinuation and the date of withdrawal will be recorded in the 
patient’s CRF. The patient’s CRF, which will be completed up to the point of withdrawal, will be 
retained for the Sponsor. 
 


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10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
10.4.1. 
Definition: Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study medication, additional evaluation should be considered. 
Women in the Following Categories Are Not Considered WOCBP 
1. Premenarchal 
2. Premenopausal female with one of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(eg, Mullerian agenesis, androgen insensitivity), Investigator discretion should be applied to 
determining study entry. 
Note: Documentation can come from the site personnel’s review of the patient’s medical records, 
medical examination, or medical history interview. 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
• A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state. 
Females on hormonal replacement therapy (HRT) and whose menopausal status is in doubt will 
be required to use one of the non-estrogen hormonal highly effective contraception methods if 
they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 
10.4.2. 
Contraception Guidance 
10.4.2.1. Contraception for Male Patients  
All non-sterile male patients must use highly effective contraception with their partner(s) of 
childbearing potential from the first day of dosing (baseline) through 90 days (a spermatogenesis 
cycle) after their last dose of study medication. 
Sterile is defined as having bilateral orchiectomy. 
Highly effective contraception for males is defined as any of the following: 
• Vasectomy with confirmed medical assessment of surgical success 


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• Condom plus use of one of the following by partner(s) of child-bearing potential: 
− Oral, intravaginal, or transdermal combined (estrogen and progestogen 
containing) hormonal contraception associated with inhibition of ovulation 
− Oral, injectable, or implantable progestogen-only hormonal contraception 
associated with inhibition of ovulation 
− Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) 
− Bilateral tubal occlusion 
• Sexual abstinence, defined as completely refraining from heterosexual intercourse 
during the entire period. Periodic abstinence (eg, calendar, symptothermal, 
postovulation methods) is not an acceptable method of contraception. The reliability 
of sexual abstinence needs to be evaluated in relation to the duration of the clinical 
study and the preferred and usual lifestyle of the patient. If a patient is usually not 
sexually active but becomes active, they, with their partner(s), will comply with the 
contraceptive requirements described in this section. 
Male patients will agree to refrain from sperm donation while enrolled in this study and for 
90 days (a spermatogenesis cycle) after their last dose of study medication. 
10.4.2.2. Contraception for Female Patients 
Female patients of childbearing potential must use a highly effective method of contraception 
from the moment of ICF signature through 30 days after their last dose of study medication. 
Highly effective contraception for females is defined as any of the following: 
• Oral, intravaginal, or transdermal combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of ovulation 
• Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation 
• Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized partner(s) with confirmed medical assessment of surgical success 
• Sterile partner(s) (bi-lateral orchiectomy) 
• Sexual abstinence, defined as completely refraining from heterosexual intercourse 
during the entire period. Periodic abstinence (eg, calendar, symptothermal, 
postovulation methods) is not an acceptable method of contraception. The reliability 
of sexual abstinence needs to be evaluated in relation to the duration of the clinical 
study and the preferred and usual lifestyle of the patient. If a patient is usually not 
sexually active but becomes active, they, with their partner(s), must comply with the 
contraceptive requirements described in this section. 


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Female patients of childbearing potential must have a negative serum pregnancy test in order to 
enter the study and must have urine pregnancy tests throughout the study at the intervals defined 
in the SoA. 
Female patients of nonchildbearing potential need not employ a method of contraception. 
10.4.2.3. Collection of Pregnancy Information 
Any pregnancy, including female partner pregnancies of male patients, that occurs or becomes 
confirmed during a clinical study will be reported to the Sponsor (or designee) within 24 hours of 
first knowledge of the pregnancy, as described in Section 8.3.6. The report will be provided on 
the pregnancy form. While pregnancy itself is not considered an AE, for the purposes of 
tracking, it should be reported on the pregnancy forms. 
All pregnancies temporally related to taking study medication should be followed and discussed 
with the Medical Monitor as follows: 
• The Investigator will follow up with the patient approximately every 3 months 
throughout the pregnancy to collect information on the status of the pregnancy. 
Generally, follow up will not be required for longer than 3 months beyond the 
estimated delivery date. 
• The Investigator will report any information on the status of the pregnancy to the 
Sponsor (or designee) using the pregnancy forms. 
The final outcome of the pregnancy will be reported to the Sponsor (or designee) using the 
pregnancy forms. Any termination of pregnancy will be reported, regardless of fetal status (ie, 
presence or absence of anomalies) or indication for the procedure. 
Any SAEs related to the pregnancy (see below), or occurring during the pregnancy, or after 
delivery, must be documented and reported to the Sponsor (or designee) on both the SAE form 
and the pregnancy forms. Serious adverse events occurring in the child (eg, congenital anomalies 
or other conditions present at birth, whether genetically inherited or occurring in utero) must also 
be documented on both the SAE form and the pregnancy forms. 
Reportable SAEs associated with pregnancy include, but are not limited to: 
• Pregnancy losses (eg, spontaneous abortion, late fetal death) 
• Life-threatening developments (eg, placental abruption, fetal distress) 
• Congenital anomalies 
• Neonatal or maternal death 
• Any event resulting in maternal or neonatal hospitalization/prolonged hospitalization 
10.5. 
Appendix 5: Genetics  
Provision of genetic sampling is optional. If a patient provides separate informed consent via the 
optional genetic consent form, samples will be collected and retained for potential future genetic 
testing. Genetic analyses may be conducted if a patient does not respond to the Investigative 
drug, to better understand a potential drug-related toxicity, or to further characterize the 
underlying disease. Genes which may be sequenced include (but are not limited to): 


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• Complement component C3 
• Complement factor H-related proteins (CFHR1, CFHR3, CFHR4, CFHR5) 
• Complement factor B  
• Complement factor D 
• Complement factor H 
• Complement factor I 
• Membrane co-factor protein/cluster of differentiation 46 (MCP/CD46) 
• Thrombomodulin (THBD) 
• CR1 
All genetic samples will be stored for a maximum of 3 years after completion of the clinical 
study report. During that time, samples may be retested if other mutations are discovered that 
may be associated with PNH or a drug safety signal. Patients may withdraw their consent for 
genetic testing and withdraw their samples from further genetic testing at any time by notifying 
the study Investigator verbally and in writing. After the 3-year storage period defined above, or 
once the Sponsor is informed of withdrawal of consent for further analysis, the sample will be 
destroyed consistent with accepted laboratory standards, and no further testing or analysis will be 
completed. Any data already generated from the sample may continue to be used for the 
purposes of this study and future research. 
 


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10.6. 
Appendix 6: Seizure Management Plan 
Convulsions and/or EEG abnormalities have been observed in dog and mouse repeated dose 
toxicology studies. The dog is the most sensitive species studied, and the NOAEL based on the 
dog 13-week toxicology study is 62.5 mg/kg/day.  
Seizures are considered a potential risk that is to be closely monitored in patients. Seizures are 
defined as a transient occurrence of clinical signs and/or symptoms that are due to abnormal 
excessive or synchronous neuronal activity in the brain. 
Should a suspected seizure occur during the study, the following procedures should be 
performed: 
• Patients and family members should be instructed to call an ambulance or report to a 
medical facility if the patient experiences a seizure. In general, most seizures are self-
limiting and do not require acute intervention  
• For seizures that are not self-limiting, the patient should be treated medically 
according to local protocols for ongoing seizure. 
• Patients and family members should be instructed to call the investigator to inform 
them of the seizure 
• Treatment with ALXN2050 should be suspended until a complete work up is 
performed  
• The following assessments are recommended for all patients with suspected seizure:  
o Blood samples should be taken to evaluate electrolytes (including calcium and 
magnesium), glucose, complete blood count, renal function tests, liver function 
tests, creatine kinase, toxicology screen, ethanol level, serum lactate, and any 
other tests or investigations determined to be pertinent (eg. brain imaging, blood 
and urine cultures). 
o An EEG should be performed. 
o Blood samples should be taken to evaluate ALXN2050 PK levels. 
• If the seizure is confirmed, ALXN2050 will be withdrawn, and the patient will be 
discontinued from the study. 
Any event of seizure or suspected seizure must be reported to Alexion within 24 hours of the 
Investigator’s awareness as an SAE. The following clinical information in addition to the above 
recommended assessments should also be collected: 
• Seizure start date and time 
• Description of the seizure 
− The type of seizure (eg, generalized tonic-clonic seizure, partial seizure, etc) 
− A detailed description of what the patient was doing before, during, and after each 
seizure. If possible, describe all aspects from start to end 
− What was the earliest sign of seizure onset? 


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− Duration of seizure(s) 
− Was the patient unconscious, unaware, or confused?  
− Evidence of bowel or bladder dysfunction? 
− Post-ictal period duration and signs.  
− Abnormal findings on neurologic examination?  
− Evidence of injury from the seizure (eg, tongue bites, bruises, or other injuries) 
− How did the patient recover after the seizure? 
• Document identifiable seizure triggers 
− Was there any recognizable trigger that may have provoked the seizures for this 
person? Please include any recent medication changes, illness, or sleep 
deprivation. 
• Past medical and surgical history review 
− Relevant medical history? 
• Document concomitant medications 
 


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10.7. 
Appendix 7: COVID-19 Risk Assessment 
PNH can cause irreversible morbidity and even mortality, if untreated. As such, and due to the 
limited number of available treatment options, the benefit a patient may receive from joining an 
investigational study with a therapeutic treatment is potentially significant. Given that treatment 
for PNH does involve immunosuppression, there is a theoretical concern that the risk for 
infection may be higher than in participants not receiving immunosuppressants. However, there 
is no specific data to further inform this risk. The site Investigator will therefore balance the 
risk/benefit considerations in the study participant taking these factors into account.  
The potential risks identified and mitigation measures put in place in light of the COVID-19 
pandemic are provided in Table 6. 
Table 6: 
Potential Risks and Mitigation Measures due to COVID-19 
Risks category 
Summary of Data/ 
Rationale for Risk 
Mitigation Strategy 
Potential risks 
Healthcare institution 
availability for 
non-COVID-19 
related activities  
COVID-19 pandemic may impact the workload of 
healthcare institutions globally and may reduce staff 
availability to perform non-urgent activities and 
non-COVID-19 related activities. 
 
During the time that the COVID-
19 pandemic is active, Alexion 
will not open study sites or enroll 
new participants at sites unless 
the sites have the resources and 
capabilities to implement the 
study per protocol. 
Data quality and 
integrity 
Lack of availability of site personnel to perform 
study assessments and capture study specific data in 
a timely manner and to maintain adequate quality 
standards. 
Lack of availability of site personnel to ensure 
adequate and continuous chain of custody, storage 
conditions, and monitoring for investigational 
product and biological samples. 
Inability of study monitors and quality personnel to 
conduct in-person visits to exercise adequate 
oversight of study execution at investigational sites. 
Missing data (COVID-19 pandemic may impact 
study visit schedules and increase missed visits 
and/or participant study discontinuations 
inadvertently resulting in missing data [eg, for 
protocol-specified procedures]). 
During the time that the COVID-
19 pandemic is active, Alexion 
will only open study sites that 
report enough personnel capacity 
to sufficiently conduct clinical 
study-related activities.  
During this timeframe, 
participants eligibility as well as 
site capacity will be reviewed by 
the site Investigator and the study 
Medical Monitor prior to 
Screening. Each site is also 
evaluated for the capacity to 
perform remote monitoring visits 
and remote source data 
verification. 
During the time that the COVID-
19 pandemic is active, it will be 
important to capture specific 
information in the electronic case 
report form that explains the 
reason the data is missing (eg, 
missed study visits or participant 
study discontinuations due to 
COVID-19). 
Abbreviation: COVID-19 = SARS-CoV-2 coronavirus disease 2019. 


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10.8. 
Appendix 8: COVID-19 Vaccine Risk Assessment 
Following a review of the available COVID-19 vaccine data (eg, Pfizer/BioNTech, Moderna, 
AstraZeneca, Johnson & Johnson), it is unlikely that the immune response to a COVID-19 
vaccine (and therefore the efficacy of the vaccination) would be diminished with concomitant 
ALXN2050 administration, based on ALXN2050’s mechanism of action. There is currently no 
information available evaluating the safety and efficacy of COVID-19 vaccines in participants 
treated with ALXN2050. Same precautions should be taken as described in Section 6.5.3. 
Vaccination may further activate complement. As a result, patients with complement-mediated 
diseases may experience increased signs and symptoms of their underlying disease. Therefore, 
patients should be closely monitored for disease symptoms after recommended vaccination 
Because vaccines may activate complement, if possible, consider vaccination when the 
underlying complement mediated disease is clinically controlled and subsequent complement 
blockade is relatively high, shortly after administration. 
Local and national guidelines should be consulted for recommendations related to COVID-19 
vaccination.  
The potential risks identified and mitigation measures put in place in light of the COVID-19 
vaccination rollout are provided in Table 7. 
Table 7: 
Potential Risks and Mitigation Measures due to COVID19 Vaccine 
Risks category 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Potential risks 
Data quality and 
integrity 
Missing data due to appointments for COVID-19 
vaccination or side effects of COVID-19 vaccine 
may impact study visit schedules and increase 
missed visits and/or participant study 
discontinuations, inadvertently resulting in 
missing data (eg, for protocol-specified 
procedures). 
Capture specific information in the 
eCRF that explains the reason the 
data is missing (eg, missed study 
visits due to appointments for 
COVID-19 vaccination or side 
effects of COVID-19 vaccine)  
Abbreviation: COVID-19 = coronavirus disease 2019. 
 


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10.9. 
Appendix 9: List of Inhibitors, Inducers, and Substrates of CYP3A 
Table 8: 
List of Prohibited Inducers, Inhibitors, and Substrates of CYP3A 
Classification 
Medication 
Table Numbera 
Strong CYP3A inhibitors 
boceprevir, cobicistat, danoprevir and ritonavir, elvitegravir 
and ritonavir, grapefruit juice, indinavir and ritonavir, 
itraconazole, ketoconazole, lopinavir and ritonavir, 
paritaprevir and ritonavir and (ombitasvir and/or dasabuvir), 
posaconazole, ritonavir, saquinavir and ritonavir, telaprevir, 
tipranavir and ritonavir, telithromycin, troleandomycin, 
voriconazole, clarithromycin, idelalisib, nefazodone, and 
nelfinavir 
3-2 
Moderate CYP3A 
inhibitors 
aprepitant, ciprofloxacin, conivaptan, crizotinib, cyclosporine, 
diltiazem, dronedarone, erythromycin, fluconazole, 
fluvoxamine, imatinib, tofisopam, and verapamil 
3-2 
Strong inducers of 
CYP3A 
apalutamide, carbamazepine, enzalutamide, mitotane, 
phenytoin, rifampin, and St. John’s wort 
3-3 
Moderate inducers of 
CYP3A 
bosentan, efavirenz, etravirine, phenobarbital, and primidone 
3-3 
Sensitive substrates of 
CYP3A 
alfentanil, avanafil, buspirone, conivaptan, darifenacin, 
darunavir, ebastine, everolimus, ibrutinib, lomitapide, 
lovastatin, midazolam, naloxegol, nisoldipine, saquinavir, 
simvastatin, sirolimus, tacrolimus, tipranavir, triazolam, 
vardenafil, budesonide, dasatinib, dronedarone, eletriptan, 
eplerenone, felodipine, indinavir, lurasidone, maraviroc, 
quetiapine, sildenafil, ticagrelor, tolvaptan 
3-1 
Note: This list is complete as of 25 Jan 2021. Please visit the link below for the most up-to-date information. 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm09
3664.htm. 
 a Table number from FDA Table of Clinical CYP Inhibitors and Inducers. 
Abbreviation: CYP3A = cytochrome P450, family 3, subfamily A. 
 
Source: FDA Drug Development and Drug Interactions 
 
 


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10.10. 
Appendix 10: Selected Medications Known to Lower the Seizure 
Threshold and/or Cause Seizure 
The following medications are PROHIBITED while on the study: 
• Meperidine/pethidine 
• Tramadol 
• Typical (first generation) antipsychotics 
• Clozapine 
• Olanzapine 
• Lithium 
• Tricyclic antidepressants 
• Bupropion 
• Aminophylline/theophylline 
 


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10.11. 
Appendix 11: Abbreviations 
Abbreviation 
Definition 
ACH-0144471 
ALXN2040; danicopan 
ACH-0145228 
ALXN2050, study medication for this study 
ACIP 
Advisory Committee on Immunization Practices 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AP 
alternative pathway  
APH 
alternative pathway hemolysis’ 
AST 
aspartate aminotransferase 
Bb 
Bb fragment of complement factor B 
bid 
twice daily 
C3 
complement component 3 
C5 
complement component 5 
CFHR 
complement factor H-related protein  
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
maximum plasma concentration 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
CP 
classical pathway 
CRF 
case report form 
CR1 
complement receptor 1 
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP3A 
cytochrome P450, family 3, subfamily A 
ECG 
electrocardiogram 
EDC 
electronic data capture 
eCRF 
electronic case report form 
EEG 
electroencephalogram 
eGFR 
estimated glomerular filtration rate 
EORTC 
European Organisation for Research and Treatment of Cancer 
EQ-5D-3L 
EuroQoL 5 Dimensions, 3-Level version 
ET 
early termination (visit) 
EVH 
extravascular hemolysis 
FACIT-Fatigue 
Functional Assessment of Chronic Illness Therapy-Fatigue scale (Version 4.0) 
FB 
(complement) factor B 
FD 
(complement) factor D 
FSH  
follicle stimulating hormone 


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Abbreviation 
Definition 
F/U 
follow-up (visit) 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation  
GDS 
Global Drug Safety 
Hgb 
hemoglobin  
HRT 
hormonal replacement therapy 
HIPAA 
Health Insurance Portability and Accountability Act 
HSCT 
hematopoietic stem cell transplantation 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use 
IEC  
Independent Ethics Committee 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IVH 
intravascular hemolysis  
LDH 
lactate dehydrogenase 
LTE 
long-term extension (period) 
MAC 
membrane attack complex 
MAD 
multiple ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOAEL 
no observed adverse effect level 
PD 
pharmacodynamic(s) 
PI 
Principal Investigator 
PK 
pharmacokinetic(s) 
PNH 
paroxysmal nocturnal hemoglobinuria 
QLQ-C30 
QoL Questionnaire-Core 30 scale 
QOL 
quality of life 
QT 
interval between the start of the Q wave and the end of the T wave in an ECG 
QTc 
corrected QT interval 
QTcF 
QT interval corrected using Fridericia's formula 
RBC  
red blood cell 
SAD 
single ascending dose 
SAE  
serious adverse event 
SAP 
statistical analysis plan 
SMS 
short message service 
SoA 
schedule of activities 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 


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Abbreviation 
Definition 
TTO 
time trade off 
UGT1A1 
uridine diphosphate glucuronosyltransferase 1 family, member A1  
ULN 
upper limit of normal 
WOCBP 
woman of childbearing potential 
 


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11. 
REFERENCES 
1. 
Biesma DH, Hannema AJ, van Velzen-Blad H, Mulder L, van Zwieten R, Kluijt I, et al. 
A family with complement factor D deficiency. J Clin Invest. 2001;108(2):233-40. doi: 
10.1172/jci12023. 
2. 
Figueroa JE, Densen P. Infectious diseases associated with complement deficiencies. Clin 
Microbiol Rev. 1991;4(3):359-95. doi: 10.1128/cmr.4.3.359. 
3. 
Harder MJ, Höchsmann B, Dopler A, Anliker M, Weinstock C, Skerra A, et al. Different 
levels of incomplete terminal pathway inhibition by eculizumab and the clinical response 
of PNH patients. Front Immunol. 2019;10:1639. doi: 10.3389/fimmu.2019.01639. 
4. 
Hiemstra PS, Langeler E, Compier B, Keepers Y, Leijh PC, van den Barselaar MT, et al. 
Complete and partial deficiencies of complement factor D in a Dutch family. J Clin 
Invest. 1989;84(6):1957-61. doi: 10.1172/jci114384. 
5. 
Hill A, Rother RP, Arnold L, Kelly R, Cullen MJ, Richards SJ, et al. Eculizumab 
prevents intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria 
and unmasks low-level extravascular hemolysis occurring through C3 opsonization. 
Haematologica. 2010;95(4):567-73. doi: 10.3324/haematol.2009.007229. 
6. 
Kobayakawa H, Miyata T, Inagi R, Shinzato T, Maeda K. Effects of excess factor D on 
early- and late-phase activation of the complement cascade. Nihon Jinzo Gakkai Shi. 
1992;34(1):103-6. 
7. 
Konar M, Granoff DM. Eculizumab treatment and impaired opsonophagocytic killing of 
meningococci by whole blood from immunized adults. Blood. 2017;130(7):891-9. doi: 
10.1182/blood-2017-05-781450. 
8. 
Miyata T, Inagi R, Oda O, Inoue I, Okada H, Miyama A, et al. Deterioration of immune 
complex solubilization activity of serum by increased concentration of factor D. 
Nephron. 1991;59(3):409-15. doi: 10.1159/000186600. 
9. 
Risitano AM, Notaro R, Marando L, Serio B, Ranaldi D, Seneca E, et al. Complement 
fraction 3 binding on erythrocytes as additional mechanism of disease in paroxysmal 
nocturnal hemoglobinuria patients treated by eculizumab. Blood. 2009;113(17):4094-
100. doi: 10.1182/blood-2008-11-189944. 
10. 
Rondelli T, Risitano AM, Peffault de Latour R, Sica M, Peruzzi B, Ricci P, et al. 
Polymorphism of the complement receptor 1 gene correlates with the hematologic 
response to eculizumab in patients with paroxysmal nocturnal hemoglobinuria. 
Haematologica. 2014;99(2):262-6. doi: 10.3324/haematol.2013.090001. 
11. 
Schnabolk G, Coughlin B, Joseph K, Kunchithapautham K, Bandyopadhyay M, O'Quinn 
EC, et al. Local production of the alternative pathway component factor B is sufficient to 
promote laser-induced choroidal neovascularization. Invest Ophthalmol Vis Sci. 
2015;56(3):1850-63. doi: 10.1167/iovs.14-15910. 
12. 
Schubert J, Röth A. Update on paroxysmal nocturnal haemoglobinuria: on the long way 
to understand the principles of the disease. Eur J Haematol. 2015;94(6):464-73. doi: 
10.1111/ejh.12520. 
13. 
Sprong T, Roos D, Weemaes C, Neeleman C, Geesing CL, Mollnes TE, et al. Deficient 
alternative complement pathway activation due to factor D deficiency by 2 novel 


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mutations in the complement factor D gene in a family with meningococcal infections. 
Blood. 2006;107(12):4865-70. doi: 10.1182/blood-2005-07-2820. 
14. 
Szer J, Hill A, Weitz IC. Clinical roundtable monograph: Paroxysmal nocturnal 
hemoglobinuria: a case-based discussion. Clin Adv Hematol Oncol. 2012;10(11 Suppl 
21):1-16. 
15. 
Volanakis JE, Narayana SV. Complement factor D, a novel serine protease. Protein Sci. 
1996;5(4):553-64. doi: 10.1002/pro.5560050401. 
16. 
Yuan X, Gavriilaki E, Thanassi JA, Yang G, Baines AC, Podos SD, et al. Small-molecule 
factor D inhibitors selectively block the alternative pathway of complement in 
paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. 
Haematologica. 2017;102(3):466-75. doi: 10.3324/haematol.2016.153312. 
 

SAP_001.pdf: 
Alexion Pharmaceuticals 
Statistical Analysis Plan 
ACH228-110 03May 2021 (Amendment 3) 
29 Jun 2021, Version 1.0 
Proprietary and Confidential 
  Page 1 of 31 
STATISTICAL ANALYSIS PLAN 
PROTOCOL NUMBER: ACH228-110 
A Phase 2 Open-Label Proof of Concept Study to Assess the 
Efficacy, Safety, and Pharmacokinetics of the Oral Factor D 
(FD) Inhibitor ALXN2050 (ACH-0145228) in 
Paroxysmal Nocturnal Hemoglobinuria (PNH) Subjects as 
Monotherapy 
Author:  
 
Date:   
29 Jun 2021 
Version:  1.0 Final 
NCT #: NCT04170023


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1. 
APPROVAL SIGNATURES 
 
 
 
 
 
Date dd Mmm yyyy 
 
 
 
 
Date dd Mmm yyyy 
 
 
 
 
 
 
 
 
Date dd Mmm yyyy 
 
29-Jun-2021 | 12:35:25 EDT
07-Jul-2021 | 08:52:44 EDT
29-Jun-2021 | 11:21:28 EDT


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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
APPROVAL SIGNATURES .......................................................................................2 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .................3 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................6 
LIST OF FIGURES .........................................................................................................................6 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS...............................7 
4. 
DESCRIPTION OF THE PROTOCOL .......................................................................9 
4.1. 
Changes from Analyses Specified in the Protocol .....................................................10 
4.2. 
Changes from Analyses Specified in the Previous Version of the Statistic 
Analysis Plan ..............................................................................................................10 
5. 
DEFINITIONS ...........................................................................................................11 
5.1. 
Efficacy .......................................................................................................................11 
5.1.1. 
Primary Endpoints ......................................................................................................11 
5.1.2. 
Secondary Endpoints ..................................................................................................11 
5.1.3. 
Exploratory Efficacy Endpoints .................................................................................11 
5.2. 
Pharmacokinetics/Pharmacodynamics .......................................................................12 
5.3. 
Safety ..........................................................................................................................12 
5.3.1. 
Adverse Events (AEs) .................................................................................................12 
5.3.2. 
Laboratory Assessments .............................................................................................13 
5.3.3. 
Vital Signs ..................................................................................................................13 
5.3.4. 
Electrocardiogram .......................................................................................................13 
5.3.5. 
Physical Examination .................................................................................................13 
6. 
DATA SETS ANALYZED (STUDY POPULATIONS) ...........................................15 
6.1. 
Full Analysis (FA) Set ................................................................................................15 
6.2. 
Per Protocol (PP) Set ..................................................................................................15 
6.3. 
Safety Set ....................................................................................................................15 
6.4. 
Other Sets ....................................................................................................................15 
7. 
STATISTICAL ANALYSIS ......................................................................................16 
7.1. 
Study Subjects ............................................................................................................16 
7.1.1. 
Disposition of Subjects ...............................................................................................16 


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7.1.2. 
Protocol Deviations ....................................................................................................16 
7.1.3. 
Demographics, Disease Characteristics, and Medical History ...................................17 
7.1.3.1. 
Demographics .............................................................................................................17 
7.1.3.2. 
Disease Characteristics ...............................................................................................17 
7.1.3.3. 
Medical / Surgical History ..........................................................................................17 
7.1.4. 
Prior and Concomitant Medications / Therapies ........................................................17 
7.2. 
Efficacy Analyses .......................................................................................................18 
7.2.1. 
Primary Endpoint Analysis .........................................................................................18 
7.2.1.1. 
Handling of Dropouts or Missing Data ......................................................................19 
7.2.1.2. 
Subgroup Analysis ......................................................................................................19 
7.2.1.3. 
Multicenter Studies .....................................................................................................19 
7.2.1.4. 
Hypothesis Testing and Significance Level ...............................................................19 
7.2.1.5. 
Sensitivity Analyses ....................................................................................................19 
7.2.2. 
Secondary Endpoint Analyses ....................................................................................19 
7.2.2.1. 
FACIT Fatigue Scale (Version 4) ...............................................................................20 
7.2.3. 
Other Efficacy Analyses .............................................................................................20 
7.2.3.1. 
EORTC-QLQ-C30 (Version 3) ..................................................................................20 
7.2.3.2. 
EQ-5D-3L ...................................................................................................................21 
7.2.4. 
Pharmacokinetic and Pharmacodynamic Analyses ....................................................21 
7.2.5. 
Adverse Events ...........................................................................................................22 
7.2.5.1. 
Overall Summary of Adverse Events .........................................................................23 
7.2.5.2. 
AEs and SAEs by System Organ Class (SOC) and Preferred Term (PT) ..................23 
7.2.5.3. 
AEs and SAEs by SOC, PT, and Relationship ...........................................................23 
7.2.5.4. 
AEs and SAEs by SOC, PT, and Severity ..................................................................23 
7.2.5.5. 
Deaths, Other SAEs, and Other Significant Adverse Events .....................................23 
7.2.6. 
Other Safety ................................................................................................................24 
7.2.6.1. 
Analyses for Laboratory Tests ....................................................................................24 
7.2.6.2. 
Vital Signs ..................................................................................................................24 
7.2.6.3. 
Electrocardiogram .......................................................................................................24 
7.2.6.4. 
Physical Examination .................................................................................................25 
7.3. 
COVID-19 Related Analyses .....................................................................................25 
8. 
INTERIM ANALYSES ..............................................................................................26 
9. 
REFERENCES ...........................................................................................................27 


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10. 
APPENDICES ............................................................................................................28 
10.1. 
Protocol Schedule of Assessments .............................................................................28 
10.2. 
Changes from Analyses Specified in the Previous Version of the SAP .....................28 
10.3. 
Scoring the EORTC QLQ-C30 version 3.0 ................................................................28 
10.4. 
Scoring EQ-5Q-3L Health State Index .......................................................................29 
10.5. 
Technical Specifications for Derived Variables .........................................................30 
 


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LIST OF TABLES 
Table 1. 
Abbreviations and acronyms ........................................................................................7 
Table 2  
Scoring of EORTC QLQ-C30 version 3.0 .................................................................28 
Table 3  
Definition for variables used in calculating health state index using US 
population estimates ...................................................................................................29 
Table 4 
Definition for variables used in calculating health state index using UK 
population estimates ...................................................................................................30 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................10 
 
 
 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table 1. 
Abbreviations and acronyms 
Abbreviation or 
acronym 
Explanation 
AE 
Adverse event 
ALT 
Alanine aminotransferase (SGPT) 
AST 
Aspartate aminotransferase (SGOT) 
ATC 
Anatomical Therapeutic Chemical  
AP 
Alternative Pathway 
APH 
Alternative pathway hemolysis  
Bb 
Bb fragment of complement factor B 
bid 
twice daily 
BMI 
Body mass index 
C3 
Complement C3 
C5 
Complement C5 
CH50 
Classical pathway activity 
CI 
Confidence interval 
cm 
Centimeters  
CRF 
Case Report Form 
CTCAE  
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
ECG 
Electrocardiogram 
eGFR 
Estimated glomerular filtration rate 
EORTC 
European Organiztion for Research and Treatment of Cancer 
FA 
Full analysis 
GGT 
Gamma-Glutamyltransferase (GGT) 
Hgb  
Hemoglobin 
HR  
Heart rate 
kg 
Kilogram 
LDH 
Lactate dehydrogenase 
LTE 
Long-term extension 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
PD  
Pharmacodynamic(s) 
PIC 
Powder in capsule 
PK  
Pharmacokinetic(s) 
PNH  
Paroxysmal nocturnal hemoglobinuria 
PR interval  
Period that extends from the beginning of the P wave until the 
beginning of the QRS complex 
PT 
Preferred term (MedDRA) 
pRBC 
Packed red blood cell 
QoL  
Quality of life 
QRS 
Group of electrocardiogram waves comprising the Q, R, and S waves 


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Abbreviation or 
acronym 
Explanation 
QT interval 
Period from deflection of QRS complex to end of T wave  
QTcF 
QT interval Fridericia correction formula 
RBC 
Red blood cells 
RR  
Respiration rate 
RR interval 
Period between QRS complexes 
SAE  
Serious adverse event 
SD 
Standard deviation 
SAS® 
Statistical Analysis Software® 
SOC 
System organ class (MedDRA) 
TEAEs 
Treatment-emergent adverse events 
WHO 
World Health Organization 


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4. 
DESCRIPTION OF THE PROTOCOL 
This is a multiple-center, open-label multiple dose study to evaluate the efficacy, safety, 
pharmacokinetics (PK), and pharmacodynamics (PD) of the oral factor D (FD) inhibitor 
ALXN2050 monotherapy in PNH subjects. 
ALXN2050 (formerly ACH-0145228) is a small molecule, orally administered FD inhibitor 
being developed for the treatment of complement-mediated diseases, such as PNH. A serine 
protease, FD catalyzes the cleavage of factor B (FB), a rate-limiting step in the alternative 
pathway (AP) of the complement cascade. By inhibiting FD, ALXN2050 potently and 
specifically inhibits AP activity. 
ALXN2050 is a second-generation molecule. It has an identical mechanism of action (FD 
inhibition) as danicopan (ALXN2040), the first-generation molecule, but with increased potency, 
improved PK/PD profile, and associated incremental potential benefits in terms of monotherapy 
dosing and clinical efficacy. 
This study will assess ALXN2050 as monotherapy in the following three different subject 
groups: 
 Group 1: PNH subjects who are treatment naïve 
 Group 2: PNH subjects who have received complement component 5 (C5) inhibition 
with eculizumab for at least 6 months, who continue to experience anemia 
(hemoglobin [Hgb] < 10 g/dL) and reticulocytes above the upper limit of normal 
(ULN), and who will switch to ALXN2050 in this study 
 Group 3: PNH subjects who have received danicopan monotherapy during 
Study ACH471-103, and who will switch to ALXN2050 in this study 
After signing the informed consent form (ICF), subjects will enter the Screening Period. During 
the Screening Period, eligibility and screening assessments will be performed. Eligible subjects 
will enter the Treatment Period and will receive their first dose of the study medication during 
the Baseline Visit (Day 1) in this study. At the end of Week 12, subjects will enter the 96-week 
Long-term Extension (LTE) Period. Figure 1 displays the study design schema. 
Approximately 26 patients will be enrolled including approximately 10 patients in Group 1, 
approximately 10 patients in Group 2, and approximately 6 patients in Group 3. 
ALXN2050 will be administered orally, 120 mg bid, with the option for dose escalation to 180 
mg bid according to the protocol specified dose escalation guidance for the 3 planned patient 
groups. 
The primary objective is:  
 To evaluate the efficacy of ALXN2050 based on improvement in hemoglobin (Hgb). 
The secondary objectives include: 
 To evaluate the efficacy of ALXN2050 based on reduction in transfusion 
requirements 
 To evaluate the efficacy of ALXN2050 based on lactate dehydrogenase (LDH)  
 To assess laboratory markers of hemolysis and other markers relevant in subjects with 
PNH 
 To evaluate the safety and tolerability of ALXN2050 


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 To evaluate maintenance of response of ALXN2050 during the LTE period 
 To evaluate the effect of ALXN2050 on Functional Assessment of Chronic Illness 
Therapy-Fatigue scale (FACIT) scores 
 The exploratory objectives include: 
 To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of 
ALXN2050 
 To evaluate other health-related quality of life (QoL) in subjects with PNH based on 
subject-reported outcome instruments and their evolution over the course of 
ALXN2050 treatment 
 
Figure 1: 
Study Design Schematic 
 
4.1. 
Changes from Analyses Specified in the Protocol 
Not applicable. 
4.2. 
Changes from Analyses Specified in the Previous Version of the 
Statistic Analysis Plan  
Not applicable. 
 


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5. 
DEFINITIONS 
5.1. 
Efficacy  
5.1.1. 
Primary Endpoints 
The primary efficacy endpoint is: 
 Change in Hgb level from baseline at Week 12 
5.1.2. 
Secondary Endpoints 
The secondary safety endpoints will be included in Section 5.3. 
The secondary efficacy endpoints are: 
 Number of subjects with RBC transfusion avoidance (TA) during 12 weeks of treatment 
with ALXN2050 
 Number of RBC units transfused and transfusion instances during 12 weeks of treatment 
as compared with transfusion data prior to screening  
 Change in LDH level from baseline measurement at Week 12 
 Change in absolute reticulocyte count and direct and total bilirubin from baseline 
measurement at Week 12 
 Change in PNH RBC clone size and C3 fragment deposition on PNH RBCs from 
baseline measurement at Week 12. 
 Change in FACIT-Fatigue score from baseline to Week 12 and Week 108. 
 Change in Hgb relative to baseline at Week 108 
 Change in LDH relative to baseline at Week 108 
Transfusion avoidance is defined as subjects remaining transfusion-free and not requiring 
transfusion as per protocol-specified guidelines through the specified analysis period. For the 
analysis for this protocol, patients who meet the protocol-specified guidelines for a transfusion 
will be counted as having received a transfusion, regardless of whether a transfusion was 
administered. The following are the protocol specified transfusion guidelines: 
It is recommended to administer packed red blood cells (pRBC) transfusion when a subject has 
a: 
 hemoglobin value of less than 7 g/dL regardless of presence of clinical signs or 
symptoms, or 
 hemoglobin value of less than 9 g/dL with signs or symptoms of sufficient severity to 
warrant a transfusion 
 
5.1.3. 
Exploratory Efficacy Endpoints 
Other efficacy endpoints include 


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 Change from baseline for the following biomarkers: 
o Free Hgb 
o Haptoglobin 
o D-dimer 
o Direct Coombs  
 Change in the European Organization for Research and Treatment of Cancer (EORTC) 
QoL Questionnaire-Core 30 scale (QLQ-C30), Version 3.0 from baseline at Week 12 and 
at Week 108. 
 Change in EuroQoL-5-Dimensions, 3-level version (EQ-5D-3L) scores from baseline at 
Week 12 and at Week 108. 
5.2. 
Pharmacokinetics/Pharmacodynamics 
Assessments for PK/PD are as follows: 
 Change from baseline in circulating complement biomarkers, including Bb fragment 
of complement factor B (Bb) concentrations at Week 12  
 Change from baseline in serum alternative pathway (AP) activity at Week 12  
 Plasma concentrations of ALXN2050 over time  
5.3. 
Safety 
The safety and tolerability of ALXN2050 will be evaluated by incidence of adverse events 
(AEs), serious adverse events (SAEs) and events leading to discontinuation of study medication , 
laboratory assessments, vital signs, electrocardiograms (ECGs), and physical examinations. 
5.3.1. 
Adverse Events (AEs) 
The definitions of AEs and SAEs can be found in protocol Section 10.3. All AEs and SAEs will 
be collected from the signing of the ICF until 30 days after the last dose of study medication. A 
treatment-emergent adverse event (TEAE) is defined as an AE that emerges during treatment, 
having been absent prior to treatment, or worsens relative to the pretreatment state. In this study, 
any AE first assessed after receipt of the first dose of ALXN2050 until 30 days after the last dose 
of study medication will be considered treatment-emergent. If the start date of an AE is partially 
or completely missing and the end (stop) date and time of the AE does not indicate that it 
occurred prior to first dose, then the determination of treatment-emergent status will be based on 
the following: 
 If the start year is after the year of the first study drug dose, then the AE is treatment-
emergent; else, 
 If the start year is the same as the year of the first study drug dose and  
o the start month is missing, then the AE is treatment-emergent, else if 
o the start month is present and is the same or after the month of the first study drug dose, 
then the AE is treatment-emergent; else, 
 If the start date is completely missing, then the AE is treatment-emergent. 
All other AEs are considered Pre-Treatment Adverse Events (PTAEs).  


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Each AE will be assessed regarding its seriousness, severity, and causal relationship (related, not 
related) with the study drug. The severity of an adverse event will be graded according to the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.03 or higher. 
5.3.2. 
Laboratory Assessments 
Blood and urine samples will be collected at protocol-specified visits for safety evaluation. The 
laboratory tests performed as hematology, chemistry, urinalysis, and other assessments are listed 
in the protocol Section 10.2. 
5.3.3. 
Vital Signs 
Vital sign measurements include blood pressure (BP), heart rate (HR), respiration rate (RR), 
body temperature, and weight at protocol-specified visits. Vital signs will be measured in the 
supine position on the dominant arm (if possible) following a 5-minute rest. Body temperature 
will be measured using an oral or temporal thermometer.  
5.3.4. 
Electrocardiogram 
Electrocardiogram (ECG) measurements will be conducted at the protocol specified time points. 
The following parameters and intervals will be assessed: heart rate, PR, RR, QRS, QT, and 
QTcF. The occurrence of depolarization or repolarization disorders, arrhythmic disorders, or 
other abnormalities will be noted. All ECG parameters and assessments must be recorded or 
stored in the subject’s source documents and CRF. Any clinically significant finding must be 
reported as an AE. 
5.3.5. 
Physical Examination 
A complete physical examination will be performed at Screening, Baseline, at Week 12 and at 
the ET/Week108 Visits and will include an assessment of general appearance and a review of 
systems. An abbreviated physical examination will be conducted at other time points. Additional 
brief, complete, or symptom-driven physical examinations may be conducted at the discretion of 
the Investigator or designee and/or when subjects present with AEs.  
A neurologic examination will be performed as part of the full physical examination at 
Screening, Baseline, at Week 12, and at ET/Week 108 Visit and will include: 
 Mental status (orientation to person, place, and time) 
 Cranial nerve examination (extraocular movements, facial muscles [raise eyebrows, 
eye closure, and smile]) 
 Upper and lower proximal and distal extremity strength 
 Gait stability 
 Coordination: finger to nose (looking for tremor) and arms outstretched looking for 
drift 
 Sensory examination if subject presents relevant symptoms 


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A symptoms-based neurologic examination will be performed if the subject has any complaints 
or clinical findings attributable to the CNS and if positive for findings, full neurologic 
examination will need to be performed at each assessment timepoint. 
 
 


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6. 
DATA SETS ANALYZED (STUDY POPULATIONS) 
6.1. 
Full Analysis (FA) Set 
All subjects who receive at least one dose of ALXN2050 in this study will be included in the full 
analysis set (FAS). Efficacy analyses will be performed using the FAS. 
6.2. 
Per Protocol (PP) Set 
Not Applicable 
6.3. 
Safety Set 
All subjects who receive at least one dose of ALXN2050 in this study will be included in the 
safety set (SS). Safety analyses will be performed using the safety set. 
Per the definitions, FAS and SS are identical in this study. 
6.4. 
Other Sets 
PK Analysis Set: 
All subjects who receive at least one dose of ALXN2050 in this study and have evaluable PK 
data will be included in the PK analysis set. 
 
PD Analysis Set: 
All subjects who receive at least one dose of ALXN2050 in this study and have evaluable 
baseline and post-dose PD data will be included in the PD analysis set. 
 
 


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7. 
STATISTICAL ANALYSIS 
Descriptive and exploratory statistical methods will be utilized to present results from data 
collected during 12 weeks of ALXN2050 Treatment Period and LTE period separately. Unless 
otherwise specified, all efficacy and safety data will be analyzed and presented separately by the 
three patient Groups 1 to 3 as specified in SAP Section 4 and overall.  
In general, descriptive statistics for continuous variables will minimally include the number of 
participants, mean, median, standard deviation (SD), minimum, and maximum.  
For categorical variables, frequencies and percentages will be presented. Summary statistics will 
be computed for selected efficacy and safety parameters so that meaningful clinical 
interpretations can be made.  
Graphical displays will be provided as appropriate. For continuous endpoints, mean values over 
time will be plotted with standard deviation unless specified otherwise. 
In general, baseline is defined as the last non-missing assessment value prior to first dose of 
study drug unless otherwise specified. For the analysis of numeric changes from baseline in 
laboratory parameters, only values from the central laboratory will be considered for baseline 
definition. For the analysis of change in Hgb, baseline is defined as the lowest Hgb value 
observed between and including screening and first dose date. Baseline for LDH is defined as the 
average of all available assessments prior to the first dose of study drug. 
All data collected in this study will be presented in listings. Assessments from unscheduled visits 
will not be included in table summaries but be included in listings.  
Analyses will be performed using the SAS® (Statistical Analysis Software®) software Version 
9.4 or higher. 
7.1. 
Study Subjects 
7.1.1. 
Disposition of Subjects 
A summary for the number of the screened patients (patients who signed informed consent of the 
study), screen failures, and treated patients (received at least one dose of study drug) will be 
tabulated. The number and percent of treated subjects who completed the week 12 and LTE and 
who discontinued the study will be summarized. For subjects who discontinued the study, the 
reason for discontinuation will be summarized.  
The number and percentage of patients in each analysis set will be tabulated. 
By-patient data listings with disposition will be provided as well as a listing of patients who did 
not meet the inclusion/exclusion criteria. 
7.1.2. 
Protocol Deviations 
All protocol deviations will be appropriately categorized, and the severity determined (major or 
minor) prior to the planned interim analysis or database lock. The number and percentage of 
subjects with major protocol deviations will be summarized overall, by protocol deviation 
category, and a listing with all protocol deviations will also be provided based on the FAS.  


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7.1.3. 
Demographics, Disease Characteristics, and Medical History 
All demographic, baseline disease characteristics, physical exam findings, and medical history 
data will be summarized using descriptive statistics for the FAS. Listings will also be provided. 
Data will be presented by group and by total patients receiving ALXN2050.  
7.1.3.1. 
Demographics 
The following demographic variables will be summarized: 
 Age (in years) at Informed Consent 
 Age category: <65, ≥65 years (65-74, 75-84, 85+) 
 Gender  
 Race  
 Ethnicity 
 Baseline Weight (kg)  
 Baseline Height (cm) 
 Baseline Body mass index (BMI, kg/m2) 
7.1.3.2. 
Disease Characteristics 
Baseline disease characteristics will be summarized using descriptive statistics for the following 
parameters: 
 Age (years) at PNH diagnosis  
 Duration of PNH (Years from PNH diagnosis to informed consent) 
 pRBC transfusion history including number of transfusion instances and units transfused   
during 24-week and 52-week prior to receiving study drug 
 Packed RBCs transfused within 24 weeks and within 52 weeks prior to first dose of study 
drug (units) 
 PNH clone sizes (RBC Type II and III, granulocyte)  
 Absolute reticulocyte count (10^3/uL) 
 Hemoglobin (g/dL) 
 LDH 
 FACIT-fatigue score at baseline 
7.1.3.3. 
Medical / Surgical History  
Medical history will be coded using the latest version of Medical Dictionary for Regulatory 
Activities (MedDRA) available. Number and percentage of subjects with medical history 
findings will be summarized by system organ class (SOC) and preferred term (PT). Additionally, 
the MedDRA preferred term and verbatim text describing each diagnosis will be presented in a 
listing. 
7.1.4. 
Prior and Concomitant Medications / Therapies 
Concomitant medication/therapies are defined as medications/therapies received on or after the 
date of the first dose of the study drug (Day 1) through 30 days after the patient’s last dose of study 
drug unless the patient transitions to an alternate treatment for PNH. If the start date of a 


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medication/therapy is partially or completely missing and the end date of the medication/therapy 
does not indicate that it ended prior to the first dose, then the determination of the concomitant 
status will be based on the following: 
 If the start year is after the year of the first dose of study drug, then the 
medication/therapy is concomitant; else, 
 If the start year is the same as the year of the first dose of study drug and 
o the start month is missing, then the medication/therapy is concomitant, else if 
o the start month is present and is the same or after the month of the first dose of 
study drug, then the medication/therapy is concomitant; else, 
 If the start date is completely missing, then the medication/therapy is concomitant. 
Medications/therapies received prior to Day 1 are considered Prior Medications/Therapies. The 
latest version of World Health Organization (WHO) Drug Dictionary available will be used to 
code the medications. Medications will be summarized by Anatomical Therapeutic Chemical 
(ATC) level 2 class and generic drug name.  
Concomitant medications will be summarized for the Safety Set. The number and percentage of 
subjects receiving any medication will be summarized, as well as the number and percentage 
receiving any medication by ATC drug class and generic drug name. Subjects reporting use of 
more than one medication at each level of summarization (any medication received, ATC class, 
and generic drug name) will be counted only once. ATC class will be presented alphabetically 
followed by decreasing frequency of generic name. Concomitant medications will be presented 
in listings.  
For the group switching from eculizumab or danicopan to ALXN2050, a summary of usage prior 
to the first dose of study drug will also be provided. 
A separate by-subject listing of N meningitidis vaccinations during the study will be produced 
showing the date(s) and brand of vaccinations for each subject. 
7.2. 
Efficacy Analyses 
All efficacy analyses will be performed on the FAS.  In general, when evaluating mean change 
from baseline in numeric laboratory parameters, only values reported by the central laboratory 
will be included in analysis. 
In addition to the analyses described below, the observed values and changes from baseline of 
efficacy endpoints at each study visit will also be summarized by group using descriptive 
statistics. 
For primary and continuous secondary endpoints during 12 weeks of treatment period, 2-sided 
95% confidence interval (CI) will be provided based on the Student’s t-statistics. 
All endpoints (including the derived ones) will be presented in listings. 
7.2.1. 
Primary Endpoint Analysis 
The primary efficacy endpoint is: 
 Change in Hgb level from baseline at Week 12 


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The primary objective is to evaluate the efficacy of ALXN2050 based on improvement in Hgb 
after 12 weeks of treatment. Transfusion is an intercurrent event that can occur during the 
treatment period and impact patient Hgb values. To address the impact of transfusion, Hgb 
values collected within 4 weeks after transfusion will not be included in the primary efficacy 
analysis. 
Descriptive statistics and graphic presentations for Hgb level and change from baseline at Week 
12 and other planned visits will be provided. Two-sided 95% CI will be provided based on the 
Student’s t-statistics. 
7.2.1.1. 
Handling of Dropouts or Missing Data 
Analysis will be on observed values and no imputation will be applied. 
7.2.1.2. 
Subgroup Analysis 
No subgroup analysis is planned. 
7.2.1.3. 
Multicenter Studies 
Sample size is too small to warrant meaningful analysis to assess study site effect. 
7.2.1.4. 
Hypothesis Testing and Significance Level 
None 
7.2.1.5. 
Sensitivity Analyses 
Sensitivity analysis will be performed for the primary endpoint Hgb with exclusion of measures 
collected after major Protocol Deviations that affect efficacy. The analysis method is the same as 
described in Section 7.2.1. 
7.2.2. 
Secondary Endpoint Analyses 
Similar to Hgb measurement, other laboratory measurements (including LDH, absolute 
reticulocyte count, direct and total bilirubin, PNH RBC clone size, and C3 fragment deposition 
on PNH RBCs) and their changes from baseline (including LDH percentage of change from 
baseline) will be summarized using descriptive statistics and graphic presentations for each 
planned visit. Summary statistics for RBC transfusion units received and transfusion instances 
during 12 weeks of treatment and during 12 weeks prior to screening will also be provided.  
Sensitivity analysis as described in Section 7.2.1.5 will be performed for LDH. 
Transfusion avoidance is defined as patients who remained transfusion free and did not require a 
transfusion after the first dose of study drug.  
 
Patients are included in the denominator for a visit only if they have data for that visit. For the 
12- week duration of treatment, patients having at least one data for a visit will be included in the 
denominator and only visits with data will be used to assess transfusion avoidance. Those 
patients who withdraw due to a lack of efficacy will be counted as needing transfusion.  
The number and proportion of patients who do not require a transfusion will be summarized over 
time by presenting the number and proportion of patients who remained transfusion free after the 


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first dose of study drug along with a 2-sided 95% CI for each applicable postbaseline time point. 
Additionally, this proportion will be summarized during 12 weeks of treatment, during the 12 
weeks prior to screening, during the LTE and during the entire study. The above analyses of 
transfusion avoidance will be repeated only to count patients who didn’t receive a transfusion. 
7.2.2.1. 
FACIT Fatigue Scale (Version 4) 
The FACIT-Fatigue scale is a collection of QoL questionnaires pertaining to the management of 
fatigue symptoms due to a chronic illness. The FACIT-Fatigue is a 13-item questionnaire that 
assesses self-reported fatigue and its impact upon daily activities and function over the preceding 
7 days. Patients will score each item on a 5-point scale: 0 (not at all) to 4 (very much).  A total 
score will be calculated as below: 
All negatively stated items (ie, all items except An5 and An7 from the CRF) are to be reversed 
by subtracting the response from 4. After reversing the proper items, all items are summed to 
obtain a score. The fatigue subscale score is then calculated by multiplying the sum of the item 
scores by 13, then dividing by the number of items answered. When there are missing data, 
prorating by subscale in this way is acceptable if more than 50% of the items were answered.  
The score has a range of 0-52 and the higher the score, the better the QoL. 
FACIT total score and change from baseline will be summarized by study visit using descriptive 
statistics and graphic presentations.  
7.2.3. 
Other Efficacy Analyses 
Other efficacy endpoints to monitor and evaluate the long-term effects of ALXN2050 on PNH 
cells and complement AP components and function include the following: 
 Free Hgb 
 Haptoglobin 
 D-dimer 
 Direct Coombs  
These measures and change from baseline will be summarized by study visit using descriptive 
statistics and graphic presentations. 
7.2.3.1. 
EORTC-QLQ-C30 (Version 3) 
There are 30 items in the EORTC-QLQ-C30 questionnaire. The 2 global health status items have 
7 possible responses, with 1 being poor and 7 being excellent.  All the other 28 items have 4 
possible responses, with 1 being “Not at All” and 4 being “Very Much”. These 30 items are 
composed of both multi-item scales and single-item measures, which include five functional 
scales, nine symptom scales/items, and one global health status/QoL scale as the following: 
 Functional scales: 
 Physical functioning  
 Role functioning  
 Emotional functioning  
 Cognitive functioning  
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 Symptom scales/items: 
 Fatigue  
 Nausea and vomiting  
 Pain  
 Dyspnoea  
 Insomnia  
 Appetite loss  
 Constipation 
 Diarrhoea  
 Financial difficulties 
 Global health status/QoL scale 
All scales and single-item measures will be transformed into scores from 0 to 100. Details for 
transforming raw scores into scale scores for the scales and single-item measures are provided in 
SAP Section 10.3.  
A high scale score represents a higher response level. A high score for a functional scale 
represents a high/healthy level of functioning, and a high score for the global health status/QoL 
represents a high QoL, while a high score for a symptom scale/item represents a high level of 
symptomatology/problems. 
Scale scores and change from baseline for each QLQ-C30 scale/single-item measure will be 
summarized by study visit using descriptive statistics and graphic presentations.  
7.2.3.2. 
EQ-5D-3L 
The EQ-5D-3L essentially consists of 2 pages - the EQ-5D descriptive system (page 2) and the 
EQ visual analogue scale (EQ VAS; page 3).  
The EQ-5D descriptive system uses 5 domains (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression), each with 3 response options (no problems, moderate 
problems, severe problems), defining a total of 243 unique health states (Rabin, 2001). For health 
state index, scoring algorithms derived for the U.S. general population will be applied using 
individual health profiles. Details for scoring algorithms are provided in SAP Section 10.4. 
The EQ VAS records the respondent’s self-rated health on a vertical, visual analogue scale 
where the endpoints are labelled ‘The best health you can imagine’ for 100 and ‘The worst health 
you can imagine’ for 0.  Missing values will be coded as ‘999’. If there is a discrepancy between 
where the respondent has placed the X and the number written in the box, number in the box will 
be used for VAS. 
The EQ-5D-3L scores (US index and VAS) and changes from baseline will be summarized by 
study visit using descriptive statistics and graphic presentations. 
7.2.4. 
Pharmacokinetic and Pharmacodynamic Analyses 
Pre-dose and post-dose PK and PD samples will be taken at the time points specified in the 
protocol schedule of assessments. Individual ALXN2050 plasma concentrations will be listed 
and summarized at each sampling time point. Descriptive statistics (number of non-missing 
observations (N), arithmetic mean, SD, median, coefficient of variation (CV%), minimum, 
maximum, geometric mean and geometric CV%) will be used to summarize ALXN2050 


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concentrations by dose level (120 mg and 180 mg) and formulation (PIC and tablet). Individual 
plasma concentration-time data on study day(s) with intensive PK sampling will be used to 
generate individual and mean concentration-time PK profiles. Mean concentration-time PK 
profiles will be presented for each dose level (120 mg and 180 mg) and formulation (PIC and 
tablet). 
Pharmacokinetic analysis will be performed using Phoenix WinNonlin® Version 8.1 or higher. 
ALXN2050 PK parameters, including, but not limited to, the standard PK parameters outlined in 
the table below, will be derived from the individual plasma concentration-time data on study 
day(s) with intensive PK sampling. Descriptive statistics (number of non-missing observations 
(N), arithmetic mean, SD, median, coefficient of variation (CV%), minimum, maximum, 
geometric mean and geometric CV%) will be used to summarize the calculated PK parameters 
by dose level (120 mg and 180 mg) and formulation (PIC and tablet). 
For the calculation of PK parameters, concentrations that are below the lower limit of 
quantification (BLQ) prior to the Tmax will be set to 0 and those thereafter as missing. AUC 
values will be estimated using the linear trapezoidal rule and will require at least 3 post-dose 
concentration values that occur after and do not include Tmax. Actual sampling times relative to 
dosing will be used in the calculation of PK parameters. 
 
AUC(0-12) 
Area under the concentration-time curve from time zero to the end of steady-state dose 
interval 
Cmax 
Maximum plasma concentration 
tmax 
Time after administration of a drug when the maximum plasma concentration is 
reached 
C(0) 
Trough concentration at start of steady-state dose interval 
C(12) 
Trough concentration at end of steady-state dose interval 
PD analyses of Bb, FD, C3, APH and CH50 will be performed for the PD Analysis Set. 
Descriptive statistics (number of patients, mean/geometric mean, coefficient of variation (CV%), 
SD, median, minimum, and maximum) and graphical presentations will be presented for all PD 
endpoints at each sampling time point, stratified by dose level (120 mg and 180 mg) and 
formulation (PIC and tablet). The PD effects of ALXN2050 administered orally will be 
evaluated by assessing the absolute values and changes and percentage changes from baseline in 
APH, CH50 and Bb concentrations over time (using descriptive statistics and graphical 
presentations), as appropriate.  
7.2.5. 
Adverse Events 
TEAEs will be summarized with number and percentage of subjects with AEs and event counts.   
 Patients having multiple TEAEs within a category (eg, overall, SOC, PT) will be counted once 
in that category. For severity/relationship tables, the patient’s highest grade/most related event 
within a category will be counted. Percentages will be based on the number of treated patients in 
the Safety Set within a group and overall. Tables will be sorted by alphabetical order of SOC and 
by descending frequency of PT within SOC within the overall group. PTs with same frequency 
will be sorted in alphabetical order. Any TEAEs lasted across treatment periods will be only 
counted once in the treatment period the event started. 


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TEAE and Pre-Treatment Adverse Events (PTAEs) will be listed separately. 
7.2.5.1. 
Overall Summary of Adverse Events 
An overall summary of TEAEs for all subjects will summarize number of events and the 
number/percentage of subjects experiencing TEAEs in the following categories: 
 Any TEAEs  
 TEAEs related and not related to study drug 
 TEAEs by CTCAE severity grade 
 Serious adverse events 
 TEAE leading to study drug withdrawal 
 TEAE resulting in death if any 
The above summary will also be performed to only include subjects with dose escalation to 180 
mg bid, separately for the before-escalation and after-escalation periods. 
A listing of all TEAEs by subject will be presented. Separate listings will be produced for SAEs, 
AEs leading to study drug withdrawal, and AEs resulting in death when applicable.  
7.2.5.2. 
AEs and SAEs by System Organ Class (SOC) and Preferred Term (PT) 
The number of TEAEs and the number and percentage of subjects with TEAEs will be presented 
by SOC and PT. Subjects will be counted once in each SOC and PT. Percentages will be based 
on the total number of subjects in the Safety set. SOC will be listed in alphabetical order, and 
PTs within a SOC will be listed in order of decreasing frequency, with ties broken alphabetically. 
7.2.5.3. 
AEs and SAEs by SOC, PT, and Relationship 
The number of TEAEs and the number and percentage of subjects with TEAEs will be presented 
by SOC, PT and relationship to study drug (related, not related). If a subject has more than one 
occurrence of an AE, the most related event to study treatment within one category will be 
counted in the summary table. Missing relationship to study drug will be assumed to be related.  
7.2.5.4. 
AEs and SAEs by SOC, PT, and Severity 
The number of TEAEs and the number and percentage of subjects with events will be presented 
by SOC, PT and CTCAE toxicity grade. If a subject has more than one occurrence of an AE, the 
highest toxicity reported will be used. If toxicity is missing, the AE will be treated as 
‘Unknown’.  
7.2.5.5. 
Deaths, Other SAEs, and Other Significant Adverse Events 
A listing of subject deaths will be produced. 
Events of interest in this study include TEAEs of meningococcal infections and seizures. These 
events of interest will be summarized by group in tabular form. The AE MedDRA terms that will 
be considered for these summaries is listed below: 
 Meningococcal infections: MedDRA preferred terms of Meningococcal bacteraemia, 
Meningitis meningococcal, Meningococcal infection, Meningococcal sepsis, 
Meningococcal carditis, Encephalitis meningococcal, Endocarditis meningococcal, 


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Myocarditis meningococcal, Optic neuritis meningococcal, and Pericarditis 
meningococcal.  
 Seizures: MedDRA high level group term (HLGT) of seizures 
In addition, a medical review will be performed to ensure that no relevant events were missed. 
The event of breakthrough hemolysis will be summarized by group in tabular form. 
7.2.6. 
Other Safety 
7.2.6.1. 
Analyses for Laboratory Tests 
Descriptive statistics for observed values and the change from baseline by study visit will be 
presented for each laboratory parameter by the scheduled visits, except those described in the 
efficacy analysis. Missing laboratory data will not be imputed, and only scheduled assessments 
at central laboratory will be included in by-visit summaries. Unscheduled assessments and local 
laboratory values will not be included in the by visit summary tables.  
Shift tables over time will be presented for all central laboratory values, where applicable, using 
normal, low, or high based on normal range values. For purposes of analyses, laboratory results 
based upon standardized units will be used. 
For laboratory tests with CTCAE toxicity grades available, laboratory abnormalities will be 
summarized by worst treatment-emergent grade [treatment emergent (TE) lab abnormalities].  
Note that the post-baseline laboratory value with the highest treatment-emergent toxicity grade 
will be reported for each test.  
Box plots will be presented for the following central lab parameters by visit: Hemoglobin, 
absolute reticulocytes count, LDH, bilirubin (total and direct), haptoglobin, free hemoglobin, 
eGFR, AST, ALT, GGT, and D-dimer. Additionally, scatter plots of the worst value post first 
study drug versus baseline will be provided for the above-mentioned parameters. 
All laboratory results as well as the associated normal ranges and high/low indicators of 
abnormal results will be presented in listings. Worst treatment emergent toxicity grade laboratory 
results will also be presented in a listing. 
7.2.6.2. 
Vital Signs 
Observed values and the change from baseline in vital signs (blood pressure, heart rate, 
respiratory rate, body temperature, and weight) at each visit will be summarized descriptively. 
Missing vital signs data will not be imputed and only scheduled assessments will be summarized 
in tables; unscheduled assessments will be presented in by-subject data listings. A listing of vital 
signs will be presented by subject, vital sign, and visit. 
7.2.6.3. 
Electrocardiogram 
All observed ECG data and changes from baseline in ECG data (heart rate, PR interval, RR 
interval, QRS duration, QT interval and QTcF) will be summarized descriptively by study visit. 
At each planned visit with ECG, the number and percentage of subjects falling into the following 
treatment emergent ECG abnormality categories will be presented:  


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 PR interval:  > 200 ms 
 QTcF actual values: 450 ms, >450 to 480 ms, >480 to 500 ms, and >500 ms 
 QTcF increases from baseline of >30 ms and >60 ms 
All ECG data will be presented in a listing. 
7.2.6.4. 
Physical Examination 
Results of the abnormal physical examination results will be summarized and listed by scheduled 
visit.  
7.3. 
COVID-19 Related Analyses 
The following COVID-19 related data will be collected in this study: 
 Modified and missed study visits (and COVID-19 related reasons) 
 Discontinuation (impacted by COVID-19) 
 COVID-19 Exposure  
 TEAEs related to COVID-19 
 Protocol deviations related to COVID-19 
The number of subjects with modified study visits and the reasons for modified study visits 
(COVID related or other) will be summarized by groups and overall. Similarly, the number of 
subjects with missed study visits and the reasons for missed study visits (COVID-related or 
other) will be summarized by groups and overall.  
The number of subjects with discontinuation status impacted by COVID-19 will be summarized 
by groups and overall.  
Treatment compliance percentage will be summarized for subjects with COVID-19 exposure 
during the study by groups and overall.  
An overall summary table of TEAEs related to COVID-19 will be presented. The number of 
TEAEs related to COVID-19 and the number and percentage of patients with TEAEs related to 
COVID-19 will be presented by SOC and PT. 
Protocol deviations related to COVID-19 will be summarized as the overall protocol deviations 
specified in SAP Section 7.1.2. 
 


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8. 
INTERIM ANALYSES 
Three interim analyses are planned: when 6 patients in Group 1, 6 patients in Group 2 and all 
patients complete the 12-week Treatment Period. All analyses in Section 7 will be performed. 
 


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9. 
REFERENCES 
1. Dolan P. Modeling valuations for EuroQol health states. Med Care. 1997;35(11):1095-
108. doi: 10.1097/00005650-199711000-00002. 
2. Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf 
of the EORTC Quality of Life Group; The EORTC QLQ-C30 Scoring Manual (3rd 
Edition); European Organisation for Research and Treatment of Cancer, Brussels 2001. 
3. Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Group. Ann 
Med. 2001;33(5):337-43. doi: 10.3109/07853890109002087. 
4. Shaw JW, Johnson JA, Coons SJ. US valuation of the EQ-5D health states: development 
and testing of the D1 valuation model. Med Care. 2005;43(3):203-20. doi: 
10.1097/00005650-200503000-00003. 
 
 
 


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10. 
APPENDICES 
10.1. 
Protocol Schedule of Assessments 
Refer to the protocol for a schedule of activities. 
10.2. 
Changes from Analyses Specified in the Previous Version of the SAP 
Not applicable. 
10.3. 
Scoring the EORTC QLQ-C30 version 3.0 
The following Table 2. shows the component questions of QLQ-C30 included in each of the 
scales and single-item measures and their ranges (Fayers, 2001). 
Table 2  
Scoring of EORTC QLQ-C30 version 3.0 
 
* Item range is the difference between the possible maximum and the minimum response to individual 
items; most items take values from 1 to 4, giving range = 3.  
† Scales are those that have been changed since version 1.0, and their short names are indicated in this 
manual by a suffix “2” – for example, PF2.  
 
Transforming responses to scale scores for each of the scales and single-item measures are as follows: 
For all scales, the RawScore, is the mean responses of the component items: 
RawScore= ( I1 + I2 +…+ In)/n  


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Once the raw scores are calculated, a linear transformation to 0-100 is applied to obtain the 
particular score as follows:  
For functional scales: Score = {1-(Raw score-1)/Range}*100 
For all other scales/items: Score = {(Raw score-1)/Range}*100 
Each scale has a range of 0% - 100%. A high scale score represents a higher response level. Thus 
a high score for a functional scale represents a high level of functioning but a high score for a 
symptom scale represents a high level of symptomatology/problem. 
Missing data: In the case of multi-item scales missing one of the items, raw scores can still be 
calculated using the completed items as long as more than 50% of the items were answered. So, 
for example, if the fatigue scale is missing Q10, the average of Q12 and Q18 would be used to 
calculate the raw score. For single-item measures, the score will be set to missing. 
10.4. 
Scoring EQ-5Q-3L Health State Index 
The EQ-5D descriptive system uses 5 domains (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression), each with 3 response options (no problems, moderate 
problems, severe problems), defining a total of 243 unique health states (Rabin, 2001). 
For health state index, scoring algorithms derived for the U.S. general population will be applied 
using individual health profiles. This scoring algorithm was derived from time tradeoff 
assessments of EQ-5D health states made by a population sample of some 4,000 U.S. adults in 
face-to-face household interviews (Shaw, 2005). Health state index is to be calculated using the 
below equation with the US population-based sample estimates (Shaw, 2005).  Variable 
definition is provided in Table 3. 
Y=1 − 0.146*M2 − 0.558*M3 − 0.175*S2 − 0.471*S3 − 0.140*U2 − 0.374*U3 – 0.173*P2 
− 0.537*P3 − 0.156*A2 − 0.450*A3 + 0.140*D1− 0.011*I22 + 0.122*I3 + 0.015*I32 
 
Table 3  
Definition for variables used in calculating health state index using US 
population estimates 
Variable 
Definition 
M2 
1 if mobility is level 2; 0 otherwise 
M3 
1 if mobility is level 3; 0 otherwise 
S2 
1 if self-care is level 2; 0 otherwise 
S3 
1 if self-care is level 3; 0 otherwise 
U2 
1 if usual activities is level 2; 0 otherwise 
U3 
1 if usual activities is level 3; 0 otherwise 
P2 
1 if pain/discomfort is level 2; 0 otherwise 
P3 
1 if pain/discomfort is level 3; 0 otherwise 


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A2 
1 if anxiety/depression is level 2; 0 otherwise 
A3 
1 if anxiety/depression is level 3; 0 otherwise 
D1 
The number of dimensions at level 2 or 3 beyond the first 
I2 
The number of dimensions at level 2 beyond the first 
I3 
The number of dimensions at level 3 beyond the first 
In addition, the scoring algorithms derived from the UK population will also be applied to obtain 
the health state index, using the equation below (Dolan, 1997). Variable definition is provided in 
Table 4. 
Y = 1 − 0.081*a − 0.069*MO − 0.104*SC − 0.036*UA − 0.123*PD − 0.071*AD − 
0.176*M2 − 0.006*S2 − 0.022*U2 − 0.140*P2 − 0.094*A2 − 0.269*N3 
 
Table 4 
Definition for variables used in calculating health state index using UK 
population estimates 
 
10.5. 
Technical Specifications for Derived Variables 
Missing and Partial Dates 
In cases where only the month and year are provided for a date, the day for the date will be 
imputed as 15. Missing months will be imputed as June. In cases where the day is observed but 
the month is missing, the date will be imputed as June 15. Should the date created with these 
imputation rules place it outside the possible range of values established by complete, known 
dates (such as the birth date, death date, or the ICF date for study procedures), the closest known 
date will be used. For example, a subject with a partial AE start date of June 2011 and a death 
date of June 5th 2011 would have the AE date imputed as June 5th 2011 instead of the 15th. 


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Analysis Relative Day 
Analysis relative day is the day relative to the first dosing day.  It will be calculated as: analysis 
date – first dose date + 1 if analysis date is after the first dose date, or else as: analysis date first -
dose date.  
Disease Duration 
PNH disease duration will be presented as the number of years between the date of first infusion 
and the date of PNH diagnosis (i.e., INT [(Date of first infusion – Date of PNH diagnosis + 
1)/365.25] or a similar formula using months and years or years only in the event of partial dates 
for PNH diagnosis).