Conditions: Paroxysmal Nocturnal Hemoglobinuria
Keywords: Paroxysmal Nocturnal Hemoglobinuria (PNH) Extravascular Hemolysis (EVH) Factor D inhibitor Complement Danicopan C5 inhibitor
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 86
Healthy volunteers: no

Brief summary:
The main objective of this study is to evaluate the efficacy of danicopan as add-on therapy to a complement component 5 (C5) inhibitor (eculizumab or ravulizumab) in participants with PNH who have clinically evident EVH.

Detailed description:
This is a multiple-region, randomized, double-blind, placebo controlled, multiple-dose, study in participants with PNH who have clinically evident EVH on a C5 inhibitor (eculizumab or ravulizumab).

Participants will be randomized to receive danicopan or placebo, in a 2:1 ratio for 12 weeks (Treatment Period 1) in addition to their C5 inhibitor (eculizumab or ravulizumab) therapy. At Week 12, participants randomized to receive placebo will be switched to danicopan in addition to their C5 inhibitor for an additional 12 weeks (Treatment Period 2) and participants randomized to danicopan will continue on danicopan for an additional 12 weeks, while remaining on their ongoing C5 inhibitor therapy.

At the end of the 2 treatment periods (Week 24), participants may enter a Long-Term Extension (LTE) Period and continue to receive danicopan in addition to their C5 inhibitor therapy. The Long-Term Extension period will consist of a first year of LTE(Year1) and a second year of optional LTE(Year2).All patients will complete 72 weeks of LTE(Year 1) assessments. After Week 72 (at the end of the first year of LTE), patients have the choice to complete participation in this study or continue to the optional second year (Year2) of LTE.

Arms:
arm 1: Participants will receive danicopan, in addition to their C5 inhibitor therapy, for 24 weeks (12 weeks in Treatment Period 1, followed by 12 weeks in Treatment Period 2). arm 2: Participants will receive placebo, in addition to their C5 inhibitor therapy, for 12 weeks during Treatment Period 1. At Week 12, participants randomized to receive placebo will be switched to danicopan for an additional 12 weeks (Treatment Period 2).

Interventions: intervention 1: Danicopan intervention 2: Placebo intervention 3: C5 Inhibitor
Intervention descriptions: intervention 1: Oral tablet intervention 2: Oral tablet intervention 3: Participants will continue to receive their ongoing C5 inhibitor (eculizumab or ravulizumab) therapy according to their usual dose and schedule.

Protocol document:
Prot_000.pdf: 
ALXN2040  
Alexion Pharmaceuticals, Inc. 
Protocol ALXN2040-PNH-301 Amendment 6.3 (US) 08 Aug 2022 
Page 1 of 85 
Alexion Confidential 
Title Page 
Protocol Title: A Phase 3 Study of Danicopan (ALXN2040) as Add-on Therapy to a C5 
Inhibitor (Eculizumab or Ravulizumab) in Patients with Paroxysmal Nocturnal Hemoglobinuria 
Who Have Clinically Evident Extravascular Hemolysis (EVH)  
Protocol Number: ALXN2040-PNH-301 
Compound Number: ALXN2040 (previously ACH-0144471) 
Study Phase: 3 
Short Title: Pivotal study of danicopan as add-on therapy to a C5 inhibitor (eculizumab or 
ravulizumab) in patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) who have Clinically 
Evident EVH  
Sponsor Name: Alexion Pharmaceuticals Inc. 
Legal Registered Address: 121 Seaport Blvd, Boston, MA 02210 USA 
Regulatory Agency Identifier Number(s) 
Registry 
ID 
IND 
127,367 
EudraCT  
2019-003829-18 
ClinicalTrials.gov
NCT04469465 
Approval Date:  
Original Version: 18 November 2019 
Amendment 1.0: 17 April 2020 
Amendment 2.0: 10 June 2020 
Amendment 3.0: 11 August 2020 
Amendment 4.0: 21 October 2020 
Amendment 5.0: 16 July 2021 
Amendment 6.0: 25 February 2022 
Amendment 6.3 (US): 08 Aug 2022 
Sponsor Signatory:  
 
 
 
Alexion Pharmaceuticals, Inc.
121 Seaport Boulevard 
Boston MA, 02210 USA 
Date
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ALXN2040  
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Protocol ALXN2040-PNH-301 Amendment 6.3 (US) 08 Aug 2022 
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Investigator’s Signature(s) 
 
 
Study Title: 
A Phase 3 Study of Danicopan (ALXN2040) as Add-on Therapy to a C5 
Inhibitor (Eculizumab or Ravulizumab) in Patients with Paroxysmal 
Nocturnal Hemoglobinuria Who Have Clinically Evident Extravascular 
Hemolysis (EVH) 
 
Study Number: 
ALXN2040-PNH-301  
Version and Date Global Amendment 6.3 (US) 08 Aug 2022 
I have read the protocol described above. I agree to comply with all applicable regulations and to 
conduct the study as described in the protocol. 
 
 
 
 
 
<Name and Credentials/Title> 
<Affiliation/Company> 
<Address> 
<Address> 
<Phone Number> 
Date 
 
 
 


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Protocol ALXN2040-PNH-301 Amendment 6.3 (US) 08 Aug 2022 
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Table of Contents 
Title Page .........................................................................................................................................1 
Investigator’s Signature(s) ...............................................................................................................2 
Table of Contents .............................................................................................................................3 
List of Tables ...................................................................................................................................6 
1. 
Protocol Summary ....................................................................................................................7 
1.1. 
Synopsis ...........................................................................................................................7 
1.2. 
Schedule of Assessments ...............................................................................................17 
2. 
Introduction ............................................................................................................................25 
2.1. 
Study Rationale ..............................................................................................................25 
2.2. 
Background ....................................................................................................................26 
2.2.1. Complement Factor D ................................................................................................26 
2.2.2. Paroxysmal Nocturnal Hemoglobinuria .....................................................................26 
2.3. 
Benefit/Risk Assessment ...............................................................................................27 
2.3.1. Meningococcal Infection ............................................................................................27 
2.3.2. Liver Enzyme Elevations ...........................................................................................27 
2.3.3. Coronavirus Disease 2019 ..........................................................................................28 
2.3.4. Benefits .......................................................................................................................28 
3. 
Objectives and Endpoints .......................................................................................................29 
4. 
Study Design ..........................................................................................................................32 
4.1. 
Overall Design ...............................................................................................................32 
4.2. 
Scientific Rationale for Study Design ...........................................................................33 
4.3. 
Justification for Dose .....................................................................................................34 
4.4. 
End of Study Definition .................................................................................................35 
4.5. 
Data Monitoring Committee ..........................................................................................35 
5. 
Study Population ....................................................................................................................36 
5.1. 
Inclusion Criteria ...........................................................................................................36 
5.2. 
Exclusion Criteria ..........................................................................................................37 
5.3. 
Screen Failures ...............................................................................................................38 
6. 
Study Drug .............................................................................................................................39 
6.1. 
Study Intervention Administered ...................................................................................39 
6.2. 
Preparation/Handling/Storage ........................................................................................39 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ...........................................39 


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6.4. 
Assessments of Study Drug Compliance .......................................................................40 
6.5. 
Background and Concomitant Therapies .......................................................................40 
6.5.1. Background C5 Inhibitor Therapy: Eculizumab and Ravulizumab ...........................41 
6.5.2. Vaccines .....................................................................................................................41 
6.6. 
Study Drug Dose Modification ......................................................................................42 
6.6.1. Dose Escalation During Treatment Period 1 ..............................................................42 
6.6.2. Dose Escalation During Treatment Period 2 ..............................................................42 
6.6.3. Dose Escalation During the LTE Period ....................................................................42 
6.6.4. Monitoring After Drug Escalation .............................................................................42 
6.7. 
Dose Interruptions ..........................................................................................................43 
6.8. 
Transfusion Guidelines Before and During the Study ...................................................43 
6.9. 
Intervention After the End of the Study .........................................................................44 
7. 
Discontinuation of Study Drug and Patient Discontinuation or Withdrawal .........................45 
7.1. 
Study Stopping Criteria .................................................................................................46 
7.2. 
Dose Taper .....................................................................................................................47 
7.2.1. Follow-up Period ........................................................................................................47 
7.3. 
Lost to Follow up ...........................................................................................................47 
8. 
Study Assessments and Procedures ........................................................................................49 
8.1. 
Screening Period ............................................................................................................49 
8.2. 
Efficacy Assessments ....................................................................................................50 
8.3. 
Patient-Reported Outcomes ...........................................................................................50 
8.4. 
Safety Assessments and Procedures ..............................................................................50 
8.4.1. Clinical Laboratory Tests ...........................................................................................50 
8.4.1.1. Blood Collection ................................................................................................51 
8.4.2. Physical Examinations ...............................................................................................51 
8.4.3. Vital Signs ..................................................................................................................51 
8.4.4. Electrocardiograms .....................................................................................................51 
8.5. 
Adverse Events and Serious Adverse Events ................................................................52 
8.5.1. Time Period and Frequency for Collecting AE and SAE Information ......................52 
8.5.2. Method of Detecting AEs and SAEs ..........................................................................52 
8.5.3. Follow-up of AEs and SAEs ......................................................................................52 
8.5.4. Regulatory Reporting Requirements for SAEs ..........................................................52 
8.5.5. Pregnancy ...................................................................................................................53 


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8.6. 
Treatment of Overdose ..................................................................................................53 
8.7. 
Pharmacokinetics ...........................................................................................................54 
8.8. 
Pharmacodynamics ........................................................................................................54 
8.9. 
Genetic Samples ............................................................................................................54 
9. 
Statistical Considerations .......................................................................................................55 
9.1. 
Statistical Hypotheses ....................................................................................................55 
9.2. 
Sample Size Determination ...........................................................................................55 
9.3. 
Populations for Analyses ...............................................................................................55 
9.4. 
Statistical Analyses ........................................................................................................56 
9.4.1. Patient Disposition and Demographic/Baseline Characteristics ................................56 
9.4.2. Study Drug Exposure, Compliance, and Concomitant and Background Therapies ..56 
9.4.3. Efficacy Analyses .......................................................................................................57 
9.4.3.1. Primary Efficacy Analysis .................................................................................57 
9.4.3.2. Secondary Efficacy Analysis .............................................................................58 
9.4.4. Analyses of Safety ......................................................................................................59 
9.4.5. Analyses of Pharmacokinetics (PK) and Pharmacodynamics (PD) ...........................60 
9.5. 
Interim Analyses ............................................................................................................60 
9.6. 
Staged Population PK/PD Analysis ...............................................................................61 
10. Supporting Documentation and Operational Considerations .................................................62 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........................62 
10.1.1. Regulatory and Ethical Considerations ......................................................................62 
10.1.2. Financial Disclosure ...................................................................................................62 
10.1.3. Informed Consent Process ..........................................................................................62 
10.1.4. Data Protection ...........................................................................................................63 
10.1.5. Dissemination of Clinical Study Data ........................................................................63 
10.1.6. Data Quality Assurance ..............................................................................................64 
10.1.7. Source Documents ......................................................................................................64 
10.1.8. Study and Site Closure ...............................................................................................65 
10.1.9. Publication Policy .......................................................................................................65 
10.2. Appendix 2: Clinical Laboratory Tests ..........................................................................65 
10.3. Appendix 3: Adverse Events: Definitions and Procedures  for Recording, Evaluating, 
Follow-up, and Reporting ..............................................................................................67 
10.3.1. Definitions ..................................................................................................................67 


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10.3.2. Criteria for Assessing Seriousness .............................................................................68 
10.3.3. Documentation and Reporting of Adverse Events .....................................................69 
10.3.4. Treatment and Follow-Up of Adverse Events ............................................................70 
10.3.5. Timeframe for Collection of Adverse Events ............................................................70 
10.3.6. Severity and Grading of Adverse Events ...................................................................70 
10.3.7. Assessment of Causality .............................................................................................70 
10.3.8. Pregnancy ...................................................................................................................71 
10.3.9. Reporting Serious Adverse Events and Pregnancies ..................................................72 
10.3.10. 
Investigator Reporting Requirements for SUSARs ...........................................72 
10.3.11. 
Concomitant/Background Medication Assessments .........................................72 
10.3.12. 
Monitoring Participant Safety ...........................................................................73 
10.3.13. 
Removal of Participants from the Study or Study Drug ...................................73 
10.4. Appendix 4: Contraception Guidance and Collection of Pregnancy Information .........74 
10.5. Appendix 5: Genetics .....................................................................................................77 
10.6. Appendix 6: COVID-19 Risk Assessment ....................................................................78 
10.7. Appendix 7: COVID-19 Vaccine Risk Assessment ......................................................80 
10.8. Appendix 8: Abbreviations ............................................................................................81 
11. References ..............................................................................................................................83 
 
List of Tables 
Table 1: 
Schedule of Assessments Treatment Period 1: All Patients ..................................17 
Table 2: 
Schedule of Assessments Treatment Period 2: All Patients ..................................20 
Table 3: 
Schedule of Assessments: Long-term Extension, Taper, and Follow-up Periods .22 
Table 4: 
PK and PD Blood Sampling Schedule and Approximate Volumes ......................24 
Table 5: 
Study Interventions Administered .........................................................................39 
Table 6: 
Study Drug Taper Schedule ...................................................................................47 
Table 7: 
Protocol-Required Laboratory Assessments ..........................................................66 
Table 8: 
Potential Risks and Mitigation Measures due to COVID-19.................................78 
Table 9: 
Potential Risk and Mitigation Measures due to COVID-19 Vaccination ..............80 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
 Synopsis 
Protocol Title: A Phase 3 Study of Danicopan (ALXN2040) as Add-on Therapy to a C5 
Inhibitor (Eculizumab or Ravulizumab) in Patients with Paroxysmal Nocturnal Hemoglobinuria 
Who Have Clinically Evident Extravascular Hemolysis (EVH)  
Short Title: Pivotal study of danicopan as add-on therapy to a C5 inhibitor (eculizumab or 
ravulizumab) in patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) who have Clinically 
Evident EVH  
Rationale: This is a registration study to evaluate the efficacy of danicopan as an add-on therapy 
to a C5 inhibitor (eculizumab or ravulizumab) to treat clinically-evident EVH. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
• To evaluate the efficacy of danicopan as 
compared to placebo as add-on therapy to 
a C5 inhibitor at 12 weeks  
• Change in hemoglobin (Hgb) relative to 
baseline after 12 weeks of treatment 
with danicopan compared to placebo 
Secondary 
Key Secondary  
 
• To evaluate the efficacy of danicopan on 
Hgb improvement in absence of 
transfusion as compared to placebo as 
add-on therapy to a C5 inhibitor at 12 
weeks 
• Proportion of patients with Hgb increase 
of ≥ 2 g/dL at Week 12 in the absence of 
transfusion 
• To evaluate the efficacy of danicopan as 
compared to placebo as add-on therapy to 
a C5 inhibitor on transfusion avoidance at 
12 weeks  
• Proportion of patients with transfusion 
avoidance (TA), defined as patients who 
remain transfusion-free and do not require 
a transfusion as per protocol-specified 
guidelines through Week 12 
• To evaluate the effect of danicopan as 
compared to placebo as add-on therapy to 
a C5 inhibitor on Functional Assessment 
of Chronic Illness Therapy (FACIT) 
Fatigue scores at 12 weeks of treatment 
• Change from baseline in FACIT Fatigue 
scores at Week 12  
• To evaluate the effect of danicopan as 
compared to placebo as add-on therapy to 
a C5 inhibitor on absolute reticulocyte 
count  
• Change from baseline in absolute 
reticulocyte count at Week 12 


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Objectives 
Endpoints 
Other Secondary  
• To evaluate the efficacy of danicopan as 
add-on therapy to a C5 inhibitor on 
transfusion requirements at 24 weeks for 
those patients receiving 24 weeks of 
danicopan  
• Change in the number of red blood cell 
(RBC) units transfused and transfusion 
instances during the 24 weeks of treatment 
with danicopan compared to the 24 weeks 
prior to initiation of treatment with 
danicopan 
• Percentage of patients who have 
transfusion avoidance through 24 weeks of 
treatment 
• To evaluate the efficacy of danicopan as 
compared to placebo as add-on therapy to 
a C5 inhibitor on transfusion 
requirements at 12 weeks  
• Change in the number of RBC units 
transfused and transfusion instances 
during the 12 weeks of treatment with 
danicopan compared to the 12 weeks 
while receiving placebo  
• To evaluate the effect of danicopan as 
add-on therapy to a C5 inhibitor on 
Functional Assessment of Chronic Illness 
Therapy (FACIT) Fatigue scores for 
24 weeks of treatment 
• Change from baseline in FACIT Fatigue 
scores at Week 24 in all patients 
• To assess the efficacy of danicopan as 
add-on therapy to a C5 inhibitor on Hgb 
stabilization 
• Percentage of patients with Hgb 
stabilization during the last 12 weeks of 
treatment in patients receiving 24 weeks of 
danicopan 
• To evaluate the efficacy of danicopan on 
Hgb improvement in absence of 
transfusion as add-on therapy to a C5 
inhibitor at 24 weeks 
• Proportion of patients with Hgb increase 
of ≥ 2 g/dL at Week 24 in the absence of 
transfusion 
• To assess additional laboratory markers 
relevant in PNH patients 
• Change from baseline of danicopan treated 
patients compared to placebo in total and 
direct bilirubin at 12 weeks 
• Changes in PNH RBC clone size and C3 
fragment deposition on PNH RBCs at 
12 weeks of treatment with danicopan 
compared to placebo 
• Changes in lactate dehydrogenase (LDH) 
at 12 weeks  
• Percentage of patients with Hgb 
normalization at 12 weeks and 24 weeks 


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Objectives 
Endpoints 
Exploratory  
• To assess Patient-Reported Outcomes 
(PRO) and other health-related quality of 
life (QoL) measures during 24 weeks of 
treatment 
• Change from baseline relative to placebo 
in Three-level EuroQoL 5 dimensions 
(EQ-5D-3L) scores at Week 12 
• Change from baseline in EQ-5D-3L scores 
at Week 24 
• Change from baseline relative to placebo 
in European Organization for Research 
and Treatment of Cancer (EORTC) 
Quality of Life Questionnaire-Core 30 
Scale (QLQ-C30) at Week 12 
• Change from baseline in EORTC-QLQ-
C30 scale at Week 24 
• Change from baseline relative to placebo 
in Work Productivity and Activity 
Impairment Questionnaire: Anemic 
Symptoms (WPAI:ANS) at Week 12 
• Change from baseline in WPAI:ANS 
scores at Week 24 
• Change from baseline relative to placebo 
in Healthcare Resource Utilization (HRU) 
at Week 12 
• Change from baseline in HRU scores at 
Week 24 
• To characterize pharmacokinetics (PK) 
and pharmacodynamics (PD) of 
danicopan 
• Plasma concentrations of danicopan over 
time 
• Changes from baseline in PD biomarkers  
Safety 
• To evaluate the safety and tolerability of 
24 weeks of treatment with danicopan as 
add-on therapy to a C5 inhibitor  
• Incidence of treatment-emergent adverse 
events (TEAEs), serious adverse events 
(SAEs), laboratory abnormalities, and 
events leading to discontinuation of study 
drug during Treatment Periods 1 and 2. 
• To evaluate the safety and tolerability of 
danicopan as add-on therapy to a C5 
inhibitor during the long-term extension 
(LTE) Period 
• Incidence of treatment-emergent adverse 
events (TEAEs), serious adverse events 
(SAEs), laboratory abnormalities, and 
events leading to discontinuation of study 
drug 
 


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Overall Design: This is a multiple-region, randomized, double-blind, placebo controlled, 
multiple-dose, Phase 3 study in patients with PNH who have clinically evident EVH on a C5 
inhibitor (eculizumab or ravulizumab). This study will include approximately 84 patients who 
are receiving C5 inhibitor therapy according to the usual dose and schedule and continue to 
experience anemia with or without the need of transfusion support. At randomization, patients 
will be stratified by transfusion history (ie, > 2 or ≤ 2 transfusions within 6 months of Screening) 
and Hgb (ie, < 8.5 g/dL and ≥ 8.5 g/dL) at Screening, and Japanese patients (defined as patients 
enrolled from Japan)/non-Japanese patients.  
Patients will be randomized to danicopan tid or placebo tid in a 2:1 ratio for 12 weeks 
(Treatment Period 1) in addition to their C5 inhibitor therapy (eculizumab or ravulizumab). At 
Week 12, patients randomized to receive placebo will be switched to danicopan for an additional 
12 weeks (Treatment Period 2) and patients randomized to danicopan will continue on danicopan 
for an additional 12 weeks, while remaining on the ongoing C5 inhibitor therapy. At the end of 
the treatment periods (Week 24), patients may enter the Long-Term Extension (LTE) Period and 
continue to receive danicopan + their C5 inhibitor therapy. 
In this study, patients will have been on a C5 inhibitor therapy for a time period sufficient to 
receive the full benefit of the therapy but still remain anemic. Prolonged therapy with a C5 
inhibitor alone is not projected to have additional impact on their clinical response. Historical 
transfusion needs and pretransfusion hemoglobin levels will be captured for the 52 weeks prior 
to the Screening Visit. These historical data will be used to assess the efficacy and safety of 
combination therapy in this study. 
The Screening Visit should occur no earlier than 4 weeks after a transfusion in order to minimize 
the effect of the transfusion on the screening Hgb level, which will be used for stratification 
purposes. 
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 drug. Patients 
who initiate study drug treatment less than 2 weeks after receiving a meningococcal vaccine 
must receive treatment with appropriate prophylactic antibiotics until 2 weeks after vaccination. 
The starting dose of danicopan or placebo is 150 mg tid. The dose may be escalated to 
200 mg tid based on safety and clinical effect at any of the protocol-specified time points (Weeks 
6, 12, and 18). All dose escalations will be made on a patient-by-patient basis at the discretion of 
the Principal Investigator, in consultation with the Sponsor based on the protocol dose escalation 
guidelines (see Section 6.6). Patients may not switch from their Day 1 C5 inhibitor to any other 
C5 inhibitor during the first 24 weeks of the study but may do so during the LTE Period. The 
only authorized switch is from eculizumab to ravulizumab. 
The C5 inhibitor + placebo group will be dose-escalated in the same manner as the C5 inhibitor 
+ danicopan group during the study to maintain the blind.  
After Week 12, the C5 inhibitor + placebo group will switch from placebo to receive danicopan 
during Treatment Period 2. 
All patients will return to the clinic for protocol specified assessments during the treatment 
periods and during the LTE Period as shown in Table 1 to Table 3. 


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Patients will have the option to have some selected visits in-clinic or via the home healthcare 
service provided by the 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.  
Upon completion of Treatment Period 2 (Week 24), patients may enter the LTE Period at the 
same danicopan dose they were receiving at Week 24, plus their C5 inhibitor therapy. During the 
LTE Period, patients may be dose escalated, to a maximum of 200 mg tid, at the discretion of the 
Principal Investigator and in consultation with the Sponsor.  
The LTE period will consist of a first year of LTE (Year 1) and a second year of optional LTE 
(Year 2). All patients will complete 72 weeks of LTE (Year 1) assessments as shown in Table 3. 
After Week 72 (at the end of the first year of LTE), patients have the choice to complete 
participation in this study or continue to the optional second year of LTE. Once Study 
ALXN2040PNH-303 opens for enrolment, all patients participating in the second optional year 
of LTE must transition without treatment interruption to Alexion study ALXN2040-PNH-303, 
completing the End of Treatment Period Visit as soon as possible (no taper or follow up visits 
are required), or complete participation in the current study by completing the End of Treatment 
Period Visit, plus Taper and Follow Up Visits as soon as possible. See Section 4.4 for definition 
of study completion. 
If a patient discontinues from the study, dosing of danicopan or placebo should be tapered over 
6 days (Taper Visit 1 and 2), and a Follow-up Visit will be conducted approximately 30 days 
after the last dose of study drug. Patients will continue to receive their C5 inhibitor therapy at the 
same dose and interval that they were receiving during the taper and follow-up visits. 
Number of Patients: Approximately 84 patients on a C5 inhibitor will be enrolled and treated 
with danicopan or placebo (2:1 ratio).  
Intervention Groups and Duration: Patients will be randomized to danicopan or placebo, in a 
2:1 ratio, for 12 weeks (Treatment Period 1) in addition to their C5 inhibitor therapy. At 
Week 12, patients randomized to receive placebo will be switched to danicopan for an additional 
12 weeks (Treatment Period 2), and patients randomized to danicopan will continue for an 
additional 12 weeks. At the end of the treatment periods (24 weeks), patients may enter the LTE 
Period at the same dose plus their C5 inhibitor therapy. Any patient discontinuing from the study 
at any time point should undergo a 6-day taper and will have a Follow-Up Visit approximately 
30 days after the last dose during the Tapering Period. 
The C5 inhibitor (eculizumab or ravulizumab) used in this study will be considered a background 
therapy. If patients switch from eculizumab to ravulizumab after completion of 24 weeks of 
treatment, the new medication used in this manner will also be considered a background therapy. 
Inclusion Criteria: 
1. Diagnosis of PNH 
2. Clinically evident extravascular hemolysis (EVH) defined by: 
• Anemia (Hgb ≤ 9.5 g/dL) with absolute reticulocyte count ≥ 120 × 109/L. 
3. Receiving an approved C5 inhibitor for at least 6 months prior to Day 1 in this study at 
an approved dose (or higher) and with no change in the prescribed dose or interval for 


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at least 24 weeks preceding Day 1. For those patients who recently switched from 
eculizumab to ravulizumab, they must have received at least the loading dose and 3 
maintenance doses (minimum of 24 weeks) of ravulizumab preceding Day 1. Infusions 
outside the prescribed interval due to logistical reasons/patient convenience are not 
considered a change in the prescribed frequency and should be discussed with the 
Medical Monitor prior to randomization. 
4. Platelet count ≥ 30,000/µL without the need for platelet transfusions. 
5. Absolute neutrophil counts ≥ 500/μL. 
6. Documentation of vaccination for Neisseria meningitidis: All patients must be 
vaccinated against meningococcal infections within 3 years prior to, or at the time of 
initiating study drug. Patients who initiate study drug treatment less than 2 weeks after 
receiving a meningococcal vaccine must receive treatment with appropriate 
prophylactic antibiotics until 2 weeks after vaccination. 
7. Age 18 years or older (or greater than or equal to minimum adult age in accordance 
with local legal requirements).  
8. Female patients of childbearing potential must agree to use a highly effective or 
acceptable method of contraception from the date of signing the informed consent until 
the specified duration after the last dose of their background C5 inhibitor as per the 
product labelling. Female patients of childbearing potential must also have a negative 
serum pregnancy test during Screening and negative urine pregnancy test on Day 1. 
9. Female patients with documented evidence of non-childbearing potential need not 
employ a method of contraception. 
10. Nonsterile male patients must agree to use a highly effective or acceptable method of 
contraception with their partner(s) of childbearing potential from the first day of dosing 
to 90 days after their last dose of study drug. 
• 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 drug. 
11. Capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the informed consent form and in this protocol. 
12. Must have access to emergency medical care. 
13. Patients who are on iron, folic acid, and vitamin B12 supplementation are eligible for 
the study if on a stable dose for at least 30 days prior to Day 1. See Section 6.5.  
Exclusion Criteria: 
1. History of a major organ transplant (eg, heart, lung, kidney, liver) or hematopoietic stem 
cell transplantation (HSCT).  
2. Known aplastic anemia or other bone marrow failure that requires HSCT or other 
therapies including anti-thymocyte globulin and/or immunosuppressants, unless the 


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Alexion Pharmaceuticals, Inc. 
Protocol ALXN2040-PNH-301 Amendment 6.3 (US) 08 Aug 2022 
Page 13 of 85 
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dosage regimen of immunosuppressant has been stable for at least 12 weeks before Day 1 
and patient is expected to remain on stable doses through Week 24 (see Section 6.5).  
3. Received another investigational agent other than C5 inhibitors (eculizumab or 
ravulizumab) 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, etc.) or any conditions leading to 
anemia that are not primarily due to PNH.  
6. Active bacterial or viral infection, a body temperature >38°C on two consecutive daily 
measures, evidence of other infection, or history of any febrile illness within 14 days 
prior to first study drug administration. 
7. History or presence of any clinically relevant co-morbidities that would make the patient 
inappropriate for the study (e.g., 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). 
8. Laboratory abnormalities at screening, including: 
• Alanine aminotransferase (ALT) > 2 × ULN (> 3 × ULN in the case of patients with 
documented liver iron overload defined by serum ferritin values ≥ 500 ng/mL). The 
inclusion of patients with documented iron overload and ALT > 2 × ULN will be 
done in a case by case basis, with prior discussion with the Medical Monitor. 
• Direct bilirubin > 2 × ULN, with the exception of: 
o patients who, in the opinion of investigator, have direct bilirubin 
> 2 × ULN due to EVH and/or  
o patients with documented Gilbert’s syndrome (if Gilbert's syndrome is 
suspected, the patient will be tested for this condition at screening).  
9. Any other clinically significant laboratory abnormality as judged by the Investigator that, 
in the opinion of the Principal Investigator, would make the patient inappropriate for the 
study or put the patient at undue risk. 
10. Females who are pregnant, nursing, or planning to become pregnant during the study or 
within 90 days of study drug administration. 
11. Current evidence of biliary cholestasis. 
12.  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 (HCV antibody positive), except for patients with documented successful 
treatment and documented sustained virologic response (SVR) at Screening. 
13.  Evidence of human immunodeficiency virus (HIV antibody positive) infection at 
Screening. 
14. Estimated glomerular filtration rate < 30 mL/min/1.73 m2 and/or are on dialysis. 


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Alexion Pharmaceuticals, Inc. 
Protocol ALXN2040-PNH-301 Amendment 6.3 (US) 08 Aug 2022 
Page 14 of 85 
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15. Hypersensitivity to the investigational drug (danicopan) or any of its excipients 
Data Monitoring Committee (DMC):  
An independent DMC comprising experts in relevant biomedical fields and one external 
statistician who have no direct relationship with the study will be appointed by the sponsor. The 
DMC will review and evaluate the accumulated study data for patient safety and make 
recommendations on continuing study drug administration. The DMC will review study 
information on a regular basis as outlined in the DMC charter, which is maintained separately 
from the study protocol. Final decisions regarding the conduct of the study will be made by the 
Sponsor after consultation with the DMC. All appropriate regulatory authorities and IRBs/IECs 
will be notified of any significant action.  
Statistical Methods:  
The null statistical hypothesis is the improvement in hemoglobin levels from baseline at 
Week 12 for danicopan treatment being similar to the improvement for placebo treatment; that is, 
the difference in mean changes from baseline between danicopan and placebo at Week 12 is 
zero. 
Sample Size Determination: 
The PNH literature indicates that patients with PNH who have received a C5 inhibitor 
(eculizumab or ravulizumab) but are still anemic have hemoglobin levels, on the average, of 
10.5 g/dL. All patients entering this study will have a hemoglobin level of ≤ 9.5 g/dL. A 
minimum of 2 g/dL in difference between danicopan and placebo treatments in terms of mean 
improvement from baseline after 12 weeks of treatment is considered clinically meaningful. 
A total of approximately 84 patients will be enrolled into this study to ensure an evaluable 
number of patients in each study arm. It is anticipated that approximately 10% of patients will 
discontinue prior to the primary endpoint. For the primary endpoint of change from baseline to 
Week 12 in hemoglobin level, the statistical power using a two-sample t-test is 99% to detect the 
difference in mean change from baseline of 2 g/dL (alternative hypothesis), assuming the 
statistical significance level of 0.05 (two-sided) and the standard deviation of 1.6 g/dL which is 
estimated from study ACH471-101. For the key secondary endpoint of patients with Hgb 
increase of ≥ 2 g/dL at Week 12 in the absence of transfusions, the study has >95% power 
assuming at least 35% of patients in the danicopan arm and 5% of patients in the placebo arm 
can meet the criterion.  
For the key secondary endpoint of patients with transfusion avoidance (TA), the study has70% 
power for the TA endpoint, assuming 90% of patients in the danicopan arm and 64% of patients 
in the placebo arm will have TA. For the key secondary endpoint of change from baseline to 
Week 12 in FACIT-Fatigue score, the study has 91% power with two-sample t-test to detect a 9-
point difference between treatment arms in mean change from baseline, which is considered 
clinically meaningful. The power calculation is based on the assumption of a standard deviation 
of 11 for the FACIT-Fatigue change, which was observed in Study ALXN1210-PNH-301 in 
PNH patients. The power is 80% based on the standard deviation assumption of 13, which was 
observed in Study ACH471-101. 


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Alexion Pharmaceuticals, Inc. 
Protocol ALXN2040-PNH-301 Amendment 6.3 (US) 08 Aug 2022 
Page 15 of 85 
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Analysis populations are as follows: 
• Intent-to-treat (ITT) population: All randomized patients; data will be analyzed by the 
treatment groups to which patients are randomly assigned, even if the patient does not 
take the assigned treatment, does not receive the correct treatment, or does not 
comply with the protocol.  
• Per Protocol population: Intent-to-treat (ITT) patients who do not have protocol 
deviations expected to affect the primary efficacy endpoint (Week 12). Such protocol 
deviations will be prespecified in the statistical analysis plan prior to database lock. 
• Safety population: All patients who take at least one dose of study drug. 
If the ITT population and Per Protocol population have a similar number of patients (<5% 
difference), analyses will not be performed using the Per Protocol population. 
Efficacy Analyses: Summary statistics for the baseline and post-baseline measurements, and 
changes from baseline will be presented by visit for all continuous efficacy variables to be 
analyzed. 
The primary efficacy endpoint is the change in hemoglobin at Week 12 relative to baseline 
(defined as the lowest Hgb value, between and including screening and Day 1) between 
danicopan and placebo. The longitudinal changes from baseline in hemoglobin will be analyzed 
using a mixed model for repeated measures (MMRM) (Mallinckrodt, 2001,  
Mallinckrodt, 2004) which includes the fixed, categorical effects of treatment, study visit, and 
study visit by treatment group interaction as well as the continuous, fixed covariate of baseline 
hemoglobin value and the stratification randomization indicator of transfusion history in the 
model. The Kenward-Roger approximation will be used to estimate denominator degrees of 
freedom. The primary test for statistical significance of the treatment group difference between 
the danicopan and placebo arms at Week 12 will be conducted via a re-randomization test at a 
2-sided 0.05 significance level. 
Longitudinal graphic presentations will also be provided to examine the hemoglobin profile 
throughout 12 weeks of treatment with danicopan or placebo, plus C5 inhibitor.  
The primary efficacy analysis will be based on the ITT population. A supportive analysis will be 
carried out for the primary efficacy endpoint, changes in hemoglobin measurement, based on the 
Per Protocol population to examine the impact due to major protocol deviations. 
Secondary efficacy analyses will be conducted on the ITT population. Key secondary efficacy 
endpoints will be analyzed using a hierarchical fixed sequence test procedure to determine the 
statistical significance at a level of 0.05 for each endpoint sequentially. 
Safety Analyses: All safety analyses will be conducted on the Safety population. The evaluation 
of safety will be performed separately for the 12-week blinded Treatment Period 1, subsequent 
12-week Treatment Period 2, and the LTE Period. The safety analysis will be based primarily on 
the frequency of adverse events, clinical laboratory assessments, vital signs, and 12-lead 
electrocardiogram (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 by visit, when appropriate. No inferential statistical analysis 
of safety data is planned. 


ALXN2040  
Alexion Pharmaceuticals, Inc. 
Protocol ALXN2040-PNH-301 Amendment 6.3 (US) 08 Aug 2022 
Page 16 of 85 
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Interim Analysis: An interim analysis may be conducted at the discretion of the study sponsor 
(based on enrollment progression) when approximately 75% of patients have been randomly 
assigned to study treatment and have had the opportunity to complete the 12-week Treatment 
Period 1 (information fraction = 0.75). The purpose of the interim analysis is to evaluate the 
study for stopping early for efficacy. If conducted, the primary endpoint of change in Hgb levels 
at Week 12, as well as the key secondary endpoints will be evaluated using the alpha-spending 
methods specified below to control family-wise error rate. 
• The evaluation of primary endpoint at interim analysis will be using the gamma 
family alpha-spending function (Hwang, 1990) with parameter -4.  
• The evaluation of key secondary endpoints at interim analysis will be using the 
gamma family alpha-spending function with parameter 1. 
Due to the hierarchical nature of primary and key secondary endpoint, and proper alpha-spending 
function used to control error rate at one-sided 0.025 level for each endpoint, the overall family-
wise error rate is controlled at one-sided 0.025 level across primary and key secondary endpoints 
among interim and final analyses (Glimm, 2010, Tamhane, 2010). The recommendation of 
stopping study enrollment and placebo-controlled Treatment Period 1 for efficacy can be made 
only if, at a minimum, the primary endpoint and the key secondary endpoints of proportion of 
patients with Hgb increase ≥ 2g/dL in the absence of transfusion and proportion of patients with 
transfusion avoidance through the 12week Treatment Period 1 meet the prespecified significance 
level. . 
The interim analysis will be conducted under the auspices of an independent DMC. The final 
decision to stop the study enrolment and placebo-controlled Treatment Period 1 for efficacy will 
be done by the Sponsor based on the DMC recommendation. The DMC review of the data will 
be independent of the Sponsor as the Sponsor will remain blinded. Details of the DMC’s 
responsibilities and logistics will be outlined in the charter before the dosing of the first patient. 
 


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Alexion Pharmaceuticals, Inc. 
Protocol ALXN2040-PNH-301 Amendment 6.3 (US) 08 Aug 2022 
Page 17 of 85 
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1.2. 
Schedule of Assessments 
Table 1: 
Schedule of Assessments Treatment Period 1: All Patients 
 
Screening 
Treatment Period 1 
 
Day -45  
to -1 
Day 1 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 6 
Wk 76 
Wk 8 
Wk 10 
Wk 12 
Clinic visit days1 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
Visiting healthcare assessment2 
 
 
X 
 
X 
 
 
X 
 
X 
 
N. meningitidis vaccinations3 
X 
Administer according to local/national guidelines 
Study drug dispensing4 
 
X 
 
 
 
X 
X 
 
X 
 
X 
Drug accountability 
 
 
 
X 
 
X 
X 
 
X 
 
X 
Dose escalation decision day5 
 
 
 
 
 
 
X 
 
 
 
X 
CLINICAL ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Review safety card 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history  
X 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Vaccination history 
X 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Physical exam7 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
Vital signs 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
Weight 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
12-lead ECG (single) 
 
X 
 
 
 
 
 
 
 
 
X 
PRO and QoL questionnaires8 
 
X 
 
X 
 
X 
 
 
X 
 
X 
RBC transfusion review 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
AE/SAE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications/ protocol 
restrictions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FSH9 
X 
 
 
 
 
 
 
 
 
 
 
HCV, HBs Ag, HIV 
X 
 
 
 
 
 
 
 
 
 
 
Erythropoietin 
X 
 
 
 
 
 
 
 
 
 
 
Sample for genetic testing (optional, 
white blood cells) 
 
X 
 
 
 
 
 
 
 
 
 
Hematology, chemistry, and urinalysis10 
X 
X 
X 
X 
X 
X5 
X 
X 
X 
X 
X14 


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Alexion Pharmaceuticals, Inc. 
Protocol ALXN2040-PNH-301 Amendment 6.3 (US) 08 Aug 2022 
Page 18 of 85 
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Table 1: 
Schedule of Assessments Treatment Period 1: All Patients 
 
Screening 
Treatment Period 1 
 
Day -45  
to -1 
Day 1 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 6 
Wk 76 
Wk 8 
Wk 10 
Wk 12 
Pregnancy test11 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
PT/PTT/INR, D-dimer 
X 
 
 
 
 
X 
 
 
 
 
X 
Free hemoglobin, haptoglobin 
 
X 
 
X 
 
X 
 
 
X 
 
X 
Iron studies12 
X 
 
 
 
 
 
 
 
 
 
X 
Direct Coombs 
X 
X 
 
 
 
X 
 
 
 
 
X 
Flow cytometry: clone size 
 
X 
 
 
 
X 
 
 
 
 
X 
Flow cytometry: C3 fragment 
deposition 
 
X 
 
 
 
X 
 
 
 
 
X 
Bb, AP activity, FD, C3, CP activity, 
free C513 
 
X 
 
 
 
X 
 
 
 
 
X 
PK samples13 
 
X 
 
 
 
X 
 
 
 
 
X 
Abbreviations: AE = adverse event; AP = alternative pathway; Bb = Bb fragment of complement factor B; C3 = complement protein 3; C5 = complement protein 
5; CP = classical pathway; ECG = electrocardiogram; ET = early termination; FD = factor D; FSH = follicle-stimulating hormone; Hgb = hemoglobin; Hbs Ag 
= hepatitis B surface antigen; HCV = hepatitis C virus; HIV= human immunodeficiency virus; HRU = Healthcare Resource Utilization; INR = international 
normalized ratio; PD = pharmacodynamics; PK= pharmacokinetics; PRO = patient-reported outcome; PT = prothrombin time; PTT = partial thromboplastin 
time; QoL = quality of life; RBC = red blood cell; SAE = serious adverse event.; Wk = week. 
1 Visit window is ± 1 day for Weeks 1 through 12. A patient can discontinue from the study at any time and should complete all Week 24/ET assessments at final 
visit. 
2 Due to the time required to assign visiting nurses via the home healthcare provider, visiting healthcare assessments may not be available to patients. If not 
available, patients will need to get these assessments performed onsite. Availability of home healthcare visits will be patient- and location-specific and will be 
discussed with each site at the time of patient enrollment. The site will call the patient within 1 to 3 days to confirm that visiting healthcare assessment has 
occurred and AEs, SAEs, and concomitant medications have been assessed. If needed, site may ask about AEs, SAEs, and concomitant medications over the 
phone. 
3 Female patients of childbearing potential receiving vaccinations or boosters must have a negative urine pregnancy test on the days of vaccination before any 
vaccine or booster is administered.  
4 Patients will be provided with sufficient study drug to last until their next appointment. On the visits where PK/PD sampling will be done, the site will instruct 
the patient to take their study drug dose at the clinic. For in-clinic dosing, the kit dispensed at the corresponding visit (not the kit being returned from the 
previous visit) should be used. At dose escalation visits, patients will return to the clinic to be dispensed study drug and receive new dosing instructions. 
5 Weeks 6 and 12 are potential dose escalation time points. Hgb at Weeks 4 and 10 are to be used for dose escalation decisions at Weeks 6 and 12, respectively 


ALXN2040  
Alexion Pharmaceuticals, Inc. 
Protocol ALXN2040-PNH-301 Amendment 6.3 (US) 08 Aug 2022 
Page 19 of 85 
Alexion Confidential 
 
Table 1: 
Schedule of Assessments Treatment Period 1: All Patients 
6 Week 7 visit is applicable only for patients who are dose escalated. If a dose escalation occurs, blood will be drawn for safety laboratory assessments by the 
visiting healthcare service or at the clinic 1 week after escalation. 
7 Full physical exam at Screening and Day 1. Brief physical exam at all other time points. 
8 PROs and QoLs should be performed as early as possible during the clinic visits. On Day 1, PROs must be obtained before the first dose of study drug. Refer to 
PRO and QoL questionnaires in Section 8.3. HRU will be administered at Day 1 and Week 12. If patient is to receive infusion of their C5 inhibitor agent on a 
clinic visit where PROs and QoLs will be obtained, it is recommended that patients fill out the PRO and QoL instruments before the C5 inhibitor infusion. 
9 FSH for postmenopausal women. 
10 Patients should refrain from heavy exercise 24 hours before blood collection. Walking and light exercise are acceptable. The screening hematology assessments 
should occur no earlier than 4 weeks if possible, after the occurrence of a transfusion in patients who require transfusion support in order to minimize the effect 
of transfusion on the screening Hgb level.  
11 Serum pregnancy test at screening. Urine pregnancy test for women of childbearing potential only. On Day 1, the pre-dose urine pregnancy test must be 
negative to continue. Any positive urine pregnancy test will be confirmed by a follow-up serum pregnancy test. 
12 If there is evidence of iron deficiency at Screening, patients will be enrolled if on stable iron supplementation for at least 30 days. See Section 6.5. 
13 Patients should have a snack and take their dose of study drug in the clinic 15 to 30 minutes post snack. Site should collect accurate information on the timing 
when patient takes the last 2 doses prior to the in-clinic dose, and the missing doses (morning, noon, or evening) in the last 2 days. Site will obtain a predose 
sample and a 2 ± 0.5 hours post dose PK sample. Samples for AP activity, Bb, FD, C3, CP activity, and free C5 should be taken at the same time as the PK 
samples (pre and post dose, as needed). Actual sampling time and the most recent dose time prior to sample collection should be recorded. See Table 4 for 
sample collection timing. 
14 A backup central hematology sample must be obtained at the Week 12 visit for all patients. 
 


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Alexion Pharmaceuticals, Inc. 
Protocol ALXN2040-PNH-301 Amendment 6.3 (US) 08 Aug 2022 
Page 20 of 85 
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Table 2: 
Schedule of Assessments Treatment Period 2: All Patients 
 
Wk 13 
Wk 14 
Wk 15 
Wk 16 
Wk 18 
Wk 196 
Wk 20 
Wk 22 
Wk 24/ET11 
Clinic visit days1 
 
X 
 
X 
X 
 
X 
 
X 
Visiting healthcare assessement2 
X 
 
X 
 
 
X 
 
X 
 
N. meningitidis vaccinations3 
Administer according to local/national guidelines 
Study drug dispensing4 
 
 
 
X 
X 
 
X 
 
X 
Drug accountability 
 
X 
 
X 
X 
 
X 
 
X 
Dose escalation decision5 
 
 
 
 
X 
 
 
 
 
Review safety card 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Brief Physical exam 
 
X 
 
X 
 
 
X 
 
X 
Vital signs  
 
X 
 
X 
 
 
X 
 
X 
Weight 
 
X 
 
X 
 
 
X 
 
X 
12-lead ECG (single) 
 
 
 
 
 
 
 
 
X 
PRO and QoL questionnaires7 
 
X 
 
X 
 
 
X 
 
X 
RBC transfusion review 
 
X 
 
X 
 
 
X 
 
X 
AE/SAE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications/ protocol 
restrictions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology, chemistry, and 
urinalysis8 
X 
X 
X 
X 
X 
X 
X 
X 
X12 
Pregnancy test9 
 
X 
 
 
 
 
X 
 
X 
PT/PTT/INR, D-dimer 
 
 
 
X 
 
 
 
 
X 
Free hemoglobin, haptoglobin 
 
X 
 
X 
 
 
X 
 
X 
Iron studies 
 
 
 
 
 
 
 
 
X 
Direct Coombs 
 
 
 
X 
 
 
 
 
X 
Flow cytometry: clone size 
 
 
 
X 
 
 
 
 
X 
Flow cytometry: C3 fragment 
deposition 
 
 
 
X 
 
 
 
 
X 
Bb, AP activity, FD, C3, CP 
activity, free C510 
 
 
 
X 
 
 
 
 
X 
PK samples10 
 
 
 
X 
 
 
 
 
X 


ALXN2040  
Alexion Pharmaceuticals, Inc. 
Protocol ALXN2040-PNH-301 Amendment 6.3 (US) 08 Aug 2022 
Page 21 of 85 
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Table 2: 
Schedule of Assessments Treatment Period 2: All Patients 
Abbreviations: AE = adverse event; AP = alternative pathway; Bb = Bb fragment of complement factor B; C3 = complement protein 3; C5 = complement protein 
5; CP = classical pathway; ECG = electrocardiogram; EORTC QLQ30 = European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30 Scale; ET= early termination; FD = factor D; Hgb = hemoglobin; HRU = Healthcare Resource Utilization; INR = international 
normalized ratio; PK= pharmacokinetics; PRO = patient-reported outcome; PT = prothrombin time; PTT = partial thromboplastin time; QoL = quality of life; 
RBC = red blood cell; SAE = serious adverse event; Wk = week; WPAI:ANS = Work Productivity and Activity Impairment Questionnaire: Anemic 
Symptoms. 
1 Visit window is ± 1 day for Weeks 13 through 24. 
2 The site will call patient within 1 to 3 days to confirm that visiting healthcare assessment has occurred and AEs, SAEs, and concomitant medications have been 
assessed. If needed, site may ask about AEs, SAEs, and concomitant medications over the phone. 
3 Female patients of childbearing potential receiving vaccinations or boosters must have a negative urine pregnancy test on the days of vaccination before any 
vaccine or booster is administered. 
4 Patients will be provided with sufficient study drug to last until their next appointment. At dose escalation visits, patients will return to the clinic to be 
dispensed study drug and receive new dosing instructions. 
5 Week 18 is a potential dose escalation time point. Hgb at Week 16 is to be used for dose escalation decision at Week 18. 
6 Week 19 is applicable only for patients who are dose escalated. If a dose escalation occurs, blood will be drawn for safety laboratory assessments by the 
visiting healthcare service or at the clinic 1 week after escalation. 
7 PROs and QoLs should be performed as early as possible during clinic visits. If patient is to receive infusion of their C5 inhibitor agent on a clinic visit where 
PROs and QoLs will be obtained, it is recommended that patients fill the PROs and QoL instruments before the C5 inhibitor infusion. Refer to PRO and QoL 
questionnaires in Section 8.3. Healthcare Resource Utilization (HRU), EORTC-QLQ30, and WPAI:ANS will be collected only at Week 24. 
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 only. 
10 Patients should have a snack and take their dose of study drug in the clinic 15 to 30 minutes post snack. Site should collect accurate information on the timing 
when patient takes the last 2 doses prior to the in-clinic dose, and the missing doses (morning, noon, or evening) in the last 2 days. Site will obtain a predose 
sample and a 2 ± 0.5 hours post dose PK sample. Samples for AP activity, Bb, FD, C3, CP activity, and free C5 should be taken at the same time as the PK 
samples (pre-and postdose, as needed). Actual sampling time and the most recent dose time prior to sample collection should be recorded. See Table 4 for 
sample collection timing. 
11 Patients will be instructed to bring back all remaining study drugs on this visit. 
12 A backup central hematology sample must be obtained at the Week 24 visit for all patients. 
 


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Alexion Pharmaceuticals, Inc. 
Protocol ALXN2040-PNH-301 Amendment 6.3 (US) 08 Aug 2022 
Page 22 of 85 
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Table 3: 
Schedule of Assessments: Long-term Extension, Taper, and Follow-up Periods 
 
Long-term Extension 
Year 11 
Optional Long-term 
Extension Year 21 
Post-
escalation 
Visit2 
End of 
Treatment 
Period Visit / 
Wk 72 or 1201 
/ ET 
Taper4 
Follow Up 
 
VHA Visits2 
Clinic 
Visits3 
VHA 
Visits2 
Clinic 
Visits2 
 
Weeks 28, 
36, 44, 52, 
60, 68 
Weeks 
32,40, 48, 
56, 64 
Weeks 80, 
96, 112 
Weeks 88, 
104 
 
 
T1 
Taper 
Days 1-3 
T2 
Taper Days 
4-6 
F/U10 
Clinic visit days 
 
X 
 
X 
 
X 
 
 
X 
Visiting healthcare 
assessment 
X 
 
X 
 
 
 
X 
X 
 
N. meningitidis 
vaccinations 
Administer according to local/national guidelines 
Study drug dispensing5 
 
X 
 
X 
 
X 
 
 
 
Drug accountability 
 
X 
 
X 
 
X 
X 
X 
X 
Review safety card 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Brief physical exam 
 
X 
 
X 
 
X 
 
 
X 
Vital signs  
 
X 
 
X 
 
X 
 
 
X 
Weight 
 
X 
 
X 
 
X 
 
 
X 
PRO and QoL 
questionnaires6 
 
X 
 
X 
 
X 
 
 
 
RBC transfusion review 
 
X 
 
X 
 
X 
 
 
X 
AE/SAE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications/ 
protocol restrictions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology, chemistry, 
and urinalysis7 
X 
X 
X 
X 
X 
X 
 
 
 
Pregnancy test8 
X 
X 
X 
X 
 
X 
 
 
X 
PT/PTT/INR, D-dimer 
 
X 
 
X 
 
X 
 
 
 
Free hemoglobin, 
haptoglobin 
 
X 
 
 
 
X 
 
 
 
Direct Coombs 
 
X 
 
 
 
X 
 
 
 
Flow cytometry: clone 
size9 
 
X 
 
 
 
X 
 
 
 
Flow cytometry: 
C3 fragment deposition9 
 
X 
 
 
 
X 
 
 
 


ALXN2040  
Alexion Pharmaceuticals, Inc. 
Protocol ALXN2040-PNH-301 Amendment 6.3 (US) 08 Aug 2022 
Page 23 of 85 
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Table 3: 
Schedule of Assessments: Long-term Extension, Taper, and Follow-up Periods 
Abbreviations: AE = adverse event; C3 = complement protein 3; EOS = end of study; ET = early termination; F/U = follow-up; INR = international normalized 
ratio; LTE = long term extension; PRO = patient-reported outcome; PT= prothrombin time; PTT = partial thromboplastin time; QoL = quality of life; RBC = 
red blood cell; SAE = serious adverse event; T = taper; VHA = visiting healthcare assessment. 
1 Week 72 and Week 120 visit window is ± 4 days. The LTE period will consist of a first year of LTE (Year 1) and a second year of optional LTE (Year 2). All 
patients will complete 72 weeks of LTE (Year 1) assessments. After Week 72 (at the end of the first year of LTE), patients have the choice to complete 
participation in this study or continue to the optional second year of LTE. Once Study ALXN2040PNH-303 opens for enrolment, all patients participating in 
the second optional year of LTE must transition without treatment interruption to Alexion study ALXN2040-PNH-303, completing the end of treatment period 
visit as soon as possible (no taper or follow up visits are required), or complete participation in the current study by completing the end of treatment period 
visit, plus taper and follow up visits as soon as possible. See Section 4.4 for definition of study completion. 
2 VHA visit window is ± 7 days. The site will call the patient within 1 to 3 days to confirm that samples were collected and AEs, SAEs, and concomitant 
medications have been assessed. If needed, site may ask about AEs, SAEs, and concomitant medications over the phone. 
3  Visit window is ± 4 days. If a dose escalation occurs, blood should be drawn for safety laboratory assessments by the visiting healthcare service or at the clinic 
72 to 96 hours after escalation. 
4 Any patient who discontinues study drug will complete Taper and Follow-up Periods. T1 and T2 may be done through VHA or via phone call on Day 3 and 
Day 6 of the Taper Period. If a patient discontinues from the study for any reason, all early termination patients should follow Week 24/ET Visit assessments. 
See Section 7.2 for tapering instructions. 
5 Patients will be provided with sufficient study drug to last until their next appointment. At dose escalation visits, patients will return to the clinic to be 
dispensed study drug and receive new dosing instructions. 
6 PROs and QoLs should be performed as early as possible during clinic visits. If patient is to receive infusion of their C5 inhibitor agent on a clinic visit where 
PROs and QoLs will be obtained, it is recommended that patients fill the PROs and QoL instruments before the C5 inhibitor infusion. PRO and QoL 
questionnaires will be administered at Weeks 40, 56, and 72, and Weeks 88, 104, and 120, if applicable.  
7 Patients should refrain from heavy exercise 24 hours before blood collection. Walking and light exercise are acceptable.  
8 Any positive test will be confirmed by a follow-up serum pregnancy test. 
9 Tests will be performed at Weeks 40, 56, 72 and Weeks 88, 104, and 120, if applicable. 
10 F/U: Clinic visit 30 (+ 7) days after the last dose of the study drug. Patients will be instructed to bring back all remaining study drugs on this visit. See 
Section 7.2. 
 
 


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Table 4: 
PK and PD Blood Sampling Schedule and Approximate Volumes 
Test 
Blood Collection on  
Day 1 
Volume (mL)1 
Blood Collection on Other 
Scheduled Visits Week 4, 
Week 12, Week 16, Week 24 
(mL)1 
Matrix Types 
PK 
2 mL predose 
2 mL postdose 
2 mL predose 
2 mL postdose 
Plasma 
AP activity 
1 mL predose 
1 mL postdose 
1 mL predose 
1 mL postdose 
Serum 
FD 
2 mL predose 
2 mL predose 
Plasma 
Bb 
2 mL predose 
2 mL postdose 
2 mL predose 
Plasma 
C3 
1 mL predose 
1 mL predose 
Serum 
CP activity 
1 mL predose 
1 mL predose 
Serum 
Free C5 
1 mL predose 
1 mL predose 
Serum 
Volume 
15 mL 
13 mL * 4 visits = 52 mL 
 
Total volume 
67 mL2 
Predose = immediately prior to in-clinic dose administration; postdose = 2 ± 0.5 h after in-clinic dose administration  
Abbreviations: AP = alternative pathway; Bb = Bb fragment of complement factor B; C3 = complement protein 3; 
C5 = complement protein 5; CP= classical pathway; FD = factor D; PD = pharmacodynamics; PK = 
pharmacokinetics.  
1 During PK/PD sampling visits, patients are instructed to bring their study drug to the clinic. Patients should have a 
snack and take their dose of study drug in the clinic 15 to 30 minutes post snack. Site should collect accurate 
information on the timing when patient takes the last 2 doses prior to the in-clinic dose, and the missing doses 
(morning, noon, or evening) in the last 2 days. Site will obtain a predose sample and a 2 ± 0.5 hours postdose PK 
sample. PD samples should be taken at the same time as the PK samples (pre- and postdose). Actual sampling time 
and the most recent dose time prior to sample collection should be recorded. 
2 Volumes may slightly vary depending on site and laboratory specifications. Details are provided in the study 
laboratory manual.  


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2. 
INTRODUCTION 
Danicopan (ALXN2040, previously ACH-0144471), a small molecule, orally administered, 
factor D (FD) inhibitor, is being developed for the treatment of complement-mediated diseases, 
such as paroxysmal nocturnal hemoglobinuria (PNH) and C3 glomerulopathy (C3G). Factor D is 
a serine protease that catalyzes the cleavage of factor B (FB), a rate-limiting step in the 
alternative pathway (AP) of complement. By inhibiting FD, danicopan potently and specifically 
inhibits AP activity. 
Interim data from a Phase 2 proof-of-concept study (ACH471-101) has demonstrated the 
efficacy of danicopan, in addition to eculizumab, a C5 inhibitor, at stable dose and regimen, to 
increase hemoglobin levels after 24 weeks of treatment in PNH patients. Results from this 
ongoing Phase 2 combination study demonstrates clinically significant improvements in both the 
primary and secondary endpoints. A mean increase in hemoglobin ≥ 2 g/dL was demonstrated, 
from a baseline mean of 7.9 g/dL. The efficacy was observed as early as Week 2 of treatment 
with danicopan for most patients. 
This pivotal study will assess the efficacy and safety of danicopan in patients who have clinically 
evident extravascular hemolysis (EVH) on a C5 inhibitor (eculizumab or ravulizumab). 
A detailed description of the chemistry, pharmacology, efficacy, and safety of danicopan is 
provided in the Investigator’s Brochure. 
2.1. 
Study Rationale 
This study is a pivotal study designed to demonstrate that danicopan can increase hemoglobin 
relative to baseline in patients being treated simultaneously with an approved C5 inhibitor. 
C3 fragment deposition on PNH red blood cells (RBCs) during C5 inhibitor treatment is a likely 
cause for suboptimal response due to extravascular clearance of PNH RBCs coated by C3 
fragments (Risitano, 2009). Danicopan inhibits the complement cascade upstream of C3 and also 
blocks the complement amplification loop. Danicopan has been shown to prevent deposition of 
C3 fragments on PNH erythrocytes ex vivo (Yuan, 2017). As a result, both intravascular 
hemolysis (mediated by the activation of the complement terminal pathway) and extravascular 
hemolysis (EVH, likely via C3 fragment opsonization) could be blocked or significantly 
attenuated by danicopan. In addition, although danicopan 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. Lastly, FD is among the lowest plasma 
concentrations of all complement plasma proteins, making it a more druggable target. 
Currently approved treatments for PNH are the humanized monoclonal antibodies C5 inhibitors 
eculizumab (Soliris®) and ravulizumab (Ultomiris®). In countries where these products are 
authorized, eculizumab and ravulizumab will be used in this study as commercial background 
therapies. However, the ultimate intent and scope of this study is to evaluate the benefit/risk of 
danicopan as add-on therapy to C5 inhibitors in PNH patients. 


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2.2. 
Background 
2.2.1. 
Complement Factor D 
Factor D is one of nine serine proteases in the complement system. It 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 is 
the rate-limiting step of AP activation (Figueroa, 1991, Volanakis, 1996). It 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,  
Volanakis, 1996). 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 (PNH) is a rare disease that has a reported prevalence of 
approximately 16 per million people (Hill, 2007). PNH may occur at any age; it has been 
reported in children as young as 2 years to adults as old as 83 years, but it is most frequently 
diagnosed in adults, with a median age at diagnosis of approximately 40 years (Curran, 2012, 
Hillmen, 1995). Men and women are affected equally, and no familial tendencies exist.  
PNH is caused by a somatic mutation in the phosphatidylinositol N-acetylglucosaminyl 
transferase subunit A (PIG-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 intravascular hemolysis mediated by the membrane attack complex of complement and to 
extravascular hemolysis, presumably mediated by C3 fragment opsonization, primarily due to 
constitutive activation of the complement AP via the tick over mechanism (Schubert, 2015). In 
addition to anemia that can require frequent RBC transfusions, PNH patients are at high risk for 
thrombotic events, which can be life-threatening and is the major cause of morbidity and 
mortality in untreated patients. PNH patients also experience smooth muscle dysfunction (e.g., 
dysphagia, erectile dysfunction, abdominal pain), presumably related to the liberation of 
intracellular hemoglobin (Hgb) and 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 morbidity and 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. 


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Currently approved treatments for PNH are the humanized monoclonal antibody C5 inhibitors 
eculizumab and ravulizumab and the C3 inhibitor pegcetacoplan. Although C5 inhibitors prevent 
intravascular hemolysis by inhibiting formation of the membrane attack complex, approximately 
30% of patients on eculizumab continue to have ongoing extravascular hemolysis (Debureaux, 
2019). 
2.3. 
Benefit/Risk Assessment 
2.3.1. 
Meningococcal Infection 
Since a primary function of the complement system is to fight infections, pharmacologic 
inhibition of the complement system could theoretically result in an increased rate or severity of 
infections. As suggested by individual case reports with complement system deficiencies, 
including FD, inhibition of the complement system may result in a lifetime increased risk of 
infection, notably with Neisseria meningitidis (Biesma, 2001, Hiemstra, 1989, Sprong, 2006) . 
Patients receiving complement inhibitor therapy such as C5 inhibitors, in general, may have 
increased susceptibility to increased risk of bacterial infections, particularly Neisseria 
meningitidis (Socié, 2019). However, this risk remains theoretical for FD inhibition as the 
classical pathway of complement is not inhibited by FD blockade and FD inhibition appears to 
have little impact on serum bactericidal activity in vaccinated or previously exposed patients 
(Konar, 2017). 
To reduce the risk of meningococcal infection, all patients must be vaccinated against 
meningococcal infections within 3 years prior to, or at the time of, initiating study drug. Patients 
who initiate study drug 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 (e.g., Advisory Committee on 
Immunization Practices ([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. 
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. 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 and throughout the study as described in the Schedule of Assessments in 
Section 1.2. 
2.3.2. 
Liver Enzyme Elevations 
In human healthy volunteers, elevations in alanine aminotransferase (ALT) levels have been 
observed in the multiple ascending dose study (ACH471-002) with the high doses of 500 mg 
twice daily and 800 mg twice daily for 14 days (Investigators Brochure). These ALT elevations 
were not associated with signs or symptoms of hepatic failure, occurred after completion of 
dosing, and were self-limited. 


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Transient elevations in transaminases have occurred in the Phase 2 PNH studies, some in 
association with breakthrough hemolysis. These transient elevations were not associated with 
evidence of hepatic decompensation and resolved within a short time period. Liver function tests 
including, ALT, aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ-glutamyl 
transferase (GGT), and total, direct, and indirect bilirubin are being closely monitored in all 
clinical studies to ensure early identification of any potential cases of drug-induced liver toxicity. 
Rigorous stopping criteria are included ensuring prompt discontinuation of any patient with 
evidence of liver injury (see Section 7). 
2.3.3. 
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 10.6. Risk 
assessment for COVID-19 vaccination is described in Section 10.7. 
2.3.4. 
Benefits 
PNH is a serious, life-threatening disease, and there are unmet needs in this population that are 
not addressed by an approved C5 inhibitor that could potentially be addressed by an effective 
oral FD inhibitor. Three groups of patients whose PNH is not adequately controlled have been 
identified: 
• In patients who have a suboptimal response to eculizumab or ravulizumab, C5 
inhibitors have been used to control intravascular hemolysis, leading to reduction of 
thrombo-embolic events and improved survival. However, 20%-50% of patients 
remain transfusion-dependent due to persistent extravascular hemolysis (EVH), and 
20%-40% of patients exhibit different degrees of residual anemia (Risitano, 2020). 
Danicopan 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 or ravulizumab due to a genetic 
polymorphism in 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 danicopan. 
• Rare patients (~1%) with no response to eculizumab or ravulizumab due to mutations 
in C5 (e.g., Arg885His) (Nishimura, 2014) could also benefit from danicopan because 
it acts at a different target in the complement cascade and should be unaffected by a 
mutation in C5. 


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3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
• To evaluate the efficacy of danicopan as 
compared to placebo as add-on therapy to 
a C5 inhibitor at 12 weeks  
• Change in hemoglobin (Hgb) relative to 
baseline after 12 weeks of treatment 
with danicopan compared to placebo 
Secondary 
Key Secondary  
 
• To evaluate the efficacy of danicopan on 
Hgb improvement in absence of 
transfusion as compared to placebo as 
add-on therapy to a C5 inhibitor at 12 
weeks 
• Proportion of patients with Hgb increase 
of ≥ 2 g/dL at Week 12 in the absence of 
transfusion 
• To evaluate the efficacy of danicopan as 
compared to placebo as add-on therapy to 
a C5 inhibitor on transfusion avoidance at 
12 weeks  
• Proportion of patients with transfusion 
avoidance (TA), defined as patients who 
remain transfusion-free and do not require 
a transfusion as per protocol-specified 
guidelines through Week 12 
• To evaluate the effect of danicopan as 
compared to placebo as add-on therapy to 
a C5 inhibitor on Functional Assessment 
of Chronic Illness Therapy (FACIT) 
Fatigue scores for 12 weeks of treatment 
• Change from baseline in FACIT Fatigue 
scores at Week 12  
• To evaluate the effect of danicopan as 
compared to placebo as add-on therapy to 
a C5 inhibitor on absolute reticulocyte 
count 
• Change from baseline in absolute 
reticulocyte count at Week 12 
Other Secondary  
• To evaluate the efficacy of danicopan as 
add-on therapy to a C5 inhibitor on 
transfusion requirements at 24 weeks for 
those patients receiving 24 weeks of 
danicopan  
• Change in the number of red blood cell 
(RBC) units transfused and transfusion 
instances during the 24 weeks of treatment 
with danicopan compared to the 24 weeks 
prior to initiation of treatment with 
danicopan 
• Percentage of patients who have 
transfusion avoidance through 24 weeks of 
treatment 


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Objectives 
Endpoints 
• To evaluate the efficacy of danicopan as 
compared to placebo as add-on therapy to 
a C5 inhibitor on transfusion 
requirements at 12 weeks  
• Change in the number of RBC units 
transfused and transfusion instances 
during the 12 weeks of treatment with 
danicopan compared to the 12 weeks 
while receiving placebo  
• To evaluate the effect of danicopan as 
add-on therapy to a C5 inhibitor on 
Functional Assessment of Chronic Illness 
Therapy (FACIT) Fatigue scores for 
24 weeks of treatment 
• Change from baseline in FACIT Fatigue 
scores at Week 24 in all patients 
• To assess the efficacy of danicopan as 
add-on therapy to a C5 inhibitor on Hgb 
stabilization  
• Percentage of patients with Hgb 
stabilization during the last 12 weeks of 
treatment in patients receiving 24 weeks of 
danicopan 
• To evaluate the efficacy of danicopan on 
Hgb improvement in absence of 
transfusion as add-on therapy to a C5 
inhibitor at 24 weeks 
• Proportion of patients with Hgb increase 
of ≥ 2 g/dL at Week 24 in the absence of 
transfusion 
• To assess additional laboratory markers 
relevant in PNH patients 
• Change from baseline of danicopan treated 
patients compared to placebo in total and 
direct bilirubin at 12 weeks 
• Changes in PNH RBC clone size and C3 
fragment deposition on PNH RBCs at 
12 weeks of treatment with danicopan 
compared to placebo 
• Changes in lactate dehydrogenase (LDH) 
at 12 weeks  
• Percentage of patients with Hgb 
normalization at 12 weeks and 24 weeks 


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Objectives 
Endpoints 
Exploratory 
• To assess Patient-Reported Outcomes 
(PRO) and other health-related quality of 
life (QoL) measures during 24 weeks of 
treatment 
• Change from baseline relative to placebo 
in Three-level EuroQoL 5 dimensions 
(EQ-5D-3L) scores at Week 12 
• Change from baseline in EQ-5D-3L scores 
at Week 24 
• Change from baseline relative to placebo 
in European Organization for Research 
and Treatment of Cancer (EORTC) 
Quality of Life Questionnaire-Core 30 
Scale (QLQ-C30) at Week 12 
• Change from baseline in EORTC-QLQ-
C30 scale at Week 24 
• Change from baseline relative to placebo 
in Work Productivity and Activity 
Impairment Questionnaire: Anemic 
Symptoms (WPAI: ANS) at Week 12 
• Change from baseline in WPAI:ANS 
scores at Week 24 
• Change from baseline relative to placebo 
in Healthcare Resource Utilization (HRU) 
at Week 12 
• Change from baseline in HRU scores at 
Week 24 
• To characterize PK and PD of danicopan 
• Plasma concentrations of danicopan over 
time 
• Changes from baseline in PD biomarkers  
Safety 
• To evaluate the safety and tolerability of 
24 weeks of treatment with danicopan as 
add-on therapy to a C5 inhibitor  
• Incidence of treatment-emergent adverse 
events (TEAEs), serious adverse events 
(SAEs), laboratory abnormalities, and 
events leading to discontinuation of study 
drug during Treatment Periods 1 and 2 
• To evaluate the safety and tolerability of 
danicopan as add-on therapy to a C5 
inhibitor during the LTE Period 
• Incidence of treatment-emergent adverse 
events (TEAEs), serious adverse events 
(SAEs), laboratory abnormalities, and 
events leading to discontinuation of study 
drug 


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a multiple-region, randomized, double-blind, placebo-controlled, multiple-dose, Phase 3 
study in patients with PNH who have clinically evident EVH on a C5 inhibitor (eculizumab or 
ravulizumab). This study will include approximately 84 patients who are receiving a background 
therapy with an C5 inhibitor according to the usual dose and schedule and continue to experience 
anemia with or without the need of transfusion. Randomization will be stratified by transfusion 
history (ie, > 2 or ≤ 2 transfusions within 6 months of Screening) and Hgb (ie, < 8.5 g/dL and 
≥ 8.5 g/dL) at Screening, and Japanese patients (defined as patients enrolled from 
Japan)/non-Japanese patients. 
Patients will be randomized to danicopan tid or placebo tid, in a 2:1 ratio for 12 weeks 
(Treatment Period 1) in addition to their background C5 inhibitor (eculizumab or ravulizumab). 
At Week 12, patients randomized to receive placebo will be switched to danicopan for an 
additional 12 weeks (Treatment Period 2) and patients randomized to danicopan will continue on 
danicopan for an additional 12 weeks while remaining on the ongoing C5 inhibitor therapy. 
This is followed by a 2-year long-term extension (LTE Period), period in which patients will 
continue to receive danicopan + C5 inhibitor therapy.  
In this study, patients will have been on an approved C5 inhibitor for a time period sufficient to 
receive the full benefit of the therapy but remain anemic. Prolonged therapy with a C5 inhibitor 
alone is not projected to have additional impact on their clinical response. Historical transfusion 
needs and pretransfusion Hgb levels will be captured for 52 weeks prior to the Screening visit. 
These historical data will be used to assess the efficacy and safety of combination therapy in this 
study. 
The screening hematology assessments should occur no earlier than 4 weeks after a transfusion, 
if possible in order to minimize the effect of the transfusion on the screening Hgb level, which 
will be used for stratification purposes. If patient’s transfusion needs do not allow for this 4-week 
interval, the patient may still be screened. 
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 drug. Patients 
who initiate study drug treatment less than 2 weeks after receiving a meningococcal vaccine 
must receive treatment with appropriate prophylactic antibiotics until 2 weeks after vaccination. 
(see Section 6.5.2). 
The starting dose of danicopan or placebo is 150 mg tid. A minimum of 4 weeks of treatment 
will be required at each dose level before any subsequent escalation to the next dose level. Doses 
may be escalated to a maximum of 200 mg tid based on safety and clinical effect at protocol-
specified time points (Week 6, Week 12, and Week 18) (See Section 6.6 dose escalation 
guidelines). All dose escalations will be made on a patient-by-patient basis at the discretion of 
the Principal Investigator to a maximum of 200 mg tid, in consultation with the Sponsor. The 
maximum dose is 200 mg tid. Patients may not switch from their Day 1 C5 inhibitor to any other 
approved C5 inhibitor during the first 24 weeks of the study but may do so during the LTE 
Period (see Section 6.5.1). 


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The C5 inhibitor + placebo Group will be dose escalated in the same manner as the 
C5 inhibitor + danicopan Group during the study to maintain the blind to the patient. After all 
patients have completed Week 12, the C5 inhibitor + placebo group will switch from placebo to 
danicopan, starting at the 150 mg tid dose with opportunity to be escalated to 200 mg tid during 
Treatment Period 2.  
All patients will return to the clinic for safety and other protocol-specified assessments during 
Treatment Period 1, Treatment Period 2 and during the LTE Period as shown in Table 1,Table 2, 
and Table 3, respectively. Patients will have the option to have some designated visits performed 
either in-clinic or via the home healthcare service provided by the 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.  
Upon completion of the Treatment Period 2 (Week 24), patients may enter the LTE Period at the 
same danicopan dose they were receiving at Week 24, in addition to their background C5 
inhibitor therapy. During the LTE Period, patients may be dose escalated to a maximum of 200 
mg tid, at the discretion of the Principal Investigator and in consultation with the sponsor.  
The LTE period will consist of a first year of LTE (Year 1) and a second year of optional LTE 
(Year 2). All patients will complete 72 weeks of LTE (Year 1) assessments as shown in Table 3. 
After Week 72 (at the end of the first year of LTE), patients have the choice to complete 
participation in this study or continue to the optional second year of LTE. Once Study 
ALXN2040-PNH-303 opens for enrolment, all patients participating in the second optional year 
of LTE must transition without treatment interruption to Alexion Study ALXN2040-PNH-303, 
completing the End of Treatment Period Visit as soon as possible (no taper or follow up visits 
are required), or complete participation in the current study by completing the End of Treatment 
Period Visit, plus Taper and Follow Up Visits as soon as possible. See Section 4.4 for definition 
of study completion. 
If a patient discontinues from the study, dosing of study drug should be tapered over 6 days 
(Taper Visit 1 and 2), and a Follow-up Visit will be conducted approximately 30 days after the 
last dose of study drug during the Tapering Period. Patients will continue to receive C5 inhibitor 
therapy at the same dose and interval that they were receiving during the taper and follow-up 
visits. 
4.2. 
Scientific Rationale for Study Design 
The purpose of this study is to evaluate whether patients with clinically evident EVH on a 
C5 inhibitor therapy (when administered a therapeutic dose), may benefit from the addition of 
danicopan. 
A recent report showed that eculizumab failed to completely block terminal pathway activity in 
several clinically relevant situations ex vivo (Harder, 2017). Terminal pathway inhibition by 
eculizumab became less effective as more complement was activated. The degree of residual 
terminal pathway activity in the presence of eculizumab correlated with the number of 
surface-deposited C3b molecules. Addition of danicopan to reduce the density of C3b is 
expected to convert the incomplete terminal pathway inhibition by eculizumab into complete 
inhibition, leading to a synergistic effect. To test this, an in vitro study was conducted to assess 
the synergy of danicopan combined with eculizumab. The study was performed in an AP-


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dependent hemolytic assay using RBCs from a PNH patient and 20% normal human serum in the 
presence of 10 mM Mg2++EGTA. A strong synergy in protection of PNH RBCs from hemolysis 
was observed, suggesting the potential for a similar synergistic effect in the clinical setting. This 
experiment indicates that danicopan doses of ≤ 200 mg tid could contribute meaningfully in a 
combination regimen with eculizumab. 
Enrollment in the Phase 2 dose-finding, open-label study of danicopan in patients with PNH who 
have been treated with eculizumab has been completed. The study allowed for dose escalation at 
4-week intervals through Week 12, with additional escalations permitted after Week 12, based 
on biochemical and clinical response. Results from this ongoing Phase 2 combination study 
continue to demonstrate clinically significant improvements in both the primary and secondary 
endpoints. In addition to the rise in Hgb that has been observed in patients receiving danicopan 
and improvements in reticulocyte counts and bilirubin levels, near elimination of RBC 
transfusion needs over the 24-week treatment/study period has also been demonstrated. 
Both eculizumab and ravulizumab patients will be included as the C5 inhibitor therapy. Both 
agents are utilized in the real-world setting as a standard of care, those patients who have 
clinically evident EVH on either eculizumab or ravulizumab will be enrolled in this study. The 
study will enroll at least 35% of the patients with ravulizumab as the C5 inhibitor therapy. 
4.3. 
Justification for Dose 
Details regarding healthy volunteer dose-ranging studies can be found in the Investigator’s 
Brochure. To date, doses up to 200 mg tid as monotherapy in the ACH471-100 study have 
demonstrated clinically significant improvements in Hgb, LDH, and patient reported well-being. 
Treatment has been generally well tolerated.  
The dose range used in the proof of concept study (ACH471-101) was 100 to 200 mg tid. This 
range was clinically effective and generally well tolerated in patients with PNH on a C5 
inhibitor. In this prior study, 150 mg tid was a reasonable effective starting dose in a subset of 
patients, with upward titration based on clinical response to 200 mg tid. Approximately 25% of 
patients in this study were escalated to the 200 mg dose during the 24-week treatment period. 
Patients with abnormalities of ALT and/or direct bilirubin at baseline received a starting dose of 
100 mg tid and were cautiously escalated based on clinical response, up to the maximum of 
200 mg tid. No hepatic safety signals have been identified at starting doses of either 100 or 
150 mg in the danicopan clinical studies. Based on the safety data of all patients treated with 
danicopan in studies ACH471-101, ACH471-103, ACH471-204, and ACH471-205, along with 
the efficacy data observed in study ACH471-101 (danicopan + C5 inhibitor) and PK/PD 
modeling and simulation, the 150 mg dose is considered to be the adequate starting dose for 
PNH patients. Therefore, in study ALXN2040-PNH-301, the starting dose of danicopan will be 
150 mg tid. Dose increase will be made based on safety monitoring and Hgb levels and will not 
exceed 200 mg tid. Patients will continue to receive C5 inhibitor according to their usual dose 
and schedule. 
The etiology of clinically significant, persistent anemia in the setting of C5 inhibition is 
extravascular hemolysis, which is mechanism based. C5 inhibition with eculizumab, or 
ravulizumab still allows for C3 cleavage and these cleavage fragments are then deposited on 
PNH RBCs, marking them for extravascular destruction. This process occurs independent of the 
half-life of the C5 inhibitor. 


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4.4. 
End of Study Definition 
A patient is considered to have completed this study if at the end of the first year of LTE, they 
decide not to participate in the optional second year of LTE and completed the Week 72 Visit, 
plus the taper and follow up visits.  
For those who enter the optional second year of LTE, a patient is considered to have completed 
this study if they:  
• transition to ALXN2040PNH-303, after completing the end of treatment period visit at 
any time during the second year of LTE; no taper or follow up visits are needed for the 
transition 
OR 
• decide not to transition to ALXN2040-PNH-303, and complete the end of treatment 
period visit at any time during the second year of LTE, plus the taper and follow up visits  
OR 
• complete Week 120 visit, plus the taper and follow up visits. 
The end of the study is defined as the date of the last follow up visit of the last patient in the 
study. 
4.5. 
Data Monitoring Committee 
An independent DMC comprising experts in relevant biomedical fields and one external 
statistician who have no direct relationship with the study will be appointed by the sponsor. The 
DMC will review and evaluate the accumulated study data for patient safety and make 
recommendations on continuing study drug administration. The DMC will review study 
information on a regular basis as outlined in the DMC charter, which is maintained separately 
from the study protocol.   
Final decisions regarding the conduct of the study will be made by the sponsor after consultation 
with the DMC. All appropriate regulatory authorities and IRBs/IECs will be notified of any 
significant action.  
Each member of the DMC will be required to sign a contract agreement, which includes a 
confidentiality and financial disclosure statement, assuring no conflicts of interest as a condition 
for membership on the committee.  
The specific responsibilities of the DMC are described in the DMC Charter, which is maintained 
as a separate document. 


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5. 
STUDY POPULATION 
5.1. 
Inclusion Criteria 
Patients are eligible to be included in the study only if all of the following criteria apply: 
1. Diagnosis of PNH.  
2. Clinically evident extravascular hemolysis (EVH) defined by: 
• Anemia (Hgb ≤ 9.5 g/dL) with absolute reticulocyte count ≥ 120 × 109/L. 
3. Receiving an approved C5 inhibitor for at least 6 months prior to Day 1 in this study at an 
approved dose (or higher) and with no change in the prescribed dose or interval for at 
least 24 weeks preceding Day 1. For those patients who recently switched from 
eculizumab to ravulizumab, they must have received at least the loading dose and 3 
maintenance doses (minimum of 24 weeks) of ravulizumab preceding Day 1. Infusions 
outside the prescribed interval due to a logistical reasons/patient convenience are not 
considered a change in the prescribed interval and should be discussed with the Medical 
Monitor prior to randomization. 
4. Platelet count ≥ 30,000/µL without the need for platelet transfusions. 
5. Absolute neutrophil counts (ANC) ≥ 500/μL. 
6. 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 
drug. Patients who initiate study drug treatment less than 2 weeks after receiving a 
meningococcal vaccine must receive treatment with appropriate prophylactic antibiotics 
until 2 weeks after vaccination. 
7. Age 18 years or older (or greater than or equal to minimum adult age in accordance with 
local legal requirements). 
8. Female patients of childbearing potential must agree to use a highly effective or 
acceptable method of contraception from the date of signing the informed consent until 
the specified duration after the last dose of their background C5 inhibitor as per the 
product labelling. Female patients of childbearing potential must also have a negative 
serum pregnancy test during Screening and negative urine pregnancy test on Day 1. 
9. Female patients with documented evidence of non-childbearing potential need not 
employ a method of contraception. 
10. Nonsterile male patients must agree to use a highly effective or acceptable method of 
contraception with their partner(s) of childbearing potential from the first day of dosing 
to 90 days after their last dose of study drug. 
• 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 drug. 


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11. Capable of giving signed informed consent as described in Appendix 1 which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol. 
12. Must have access to emergency medical care.  
13. Patients who are on iron, folic acid, and vitamin B12 supplementation are eligible for the 
study if on a stable dose for at least 30 days prior to Day 1. See Section 6.5.  
5.2. 
Exclusion Criteria  
Patients are excluded from the study if any of the following criteria apply: 
1. History of a major organ transplant (e.g., heart, lung, kidney, liver) or HSCT.  
2. Known aplastic anemia or other bone marrow failure that requires HSCT or other 
therapies including anti-thymocyte globulin and/or immunosuppressants, unless the 
dosage regimen of immunosuppressant has been stable for at least 12 weeks before Day 1 
and patient is expected to remain on stable doses through Week 24 (see Section 6.5). 
3. Received another investigational agent other than C5 inhibitors (eculizumab or 
ravulizumab) 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, etc.) or any conditions leading to 
anemia that are not primarily due to PNH. 
6. Active bacterial or viral infection, a body temperature >38°C on two consecutive daily 
measures, evidence of other infection, or history of any febrile illness within 14 days 
prior to first study drug administration. 
7. History or presence of any clinically relevant co-morbidities that would make the patient 
inappropriate for the study (eg, 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). 
8. Laboratory abnormalities at screening, including: 
• ALT > 2 × ULN (> 3 × ULN in the case of patients with documented liver iron 
overload defined by serum ferritin values ≥ 500 ng/mL). The inclusion of patients 
with documented iron overload and ALT > 2 × ULN will be done in a case by case 
basis, with prior discussion with the Medical Monitor. 
• Direct bilirubin > 2 × ULN, with the exception of: 
o patients who, in the opinion of investigator, have direct bilirubin 
> 2 × ULN due to EVH and/or  
o patients with documented Gilbert’s syndrome (if Gilbert's syndrome is 
suspected, the patient will be tested for this condition at screening). 
See Section 8.1 for details. 


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9. Any other clinically significant laboratory abnormality as judged by the Investigator that, 
in the opinion of the Principal Investigator, would make the patient inappropriate for the 
study or put the patient at undue risk. 
10. Females who are pregnant, nursing, or planning to become pregnant during the study or 
within 90 days of study drug administration. 
11. Current evidence of biliary cholestasis. 
12. 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 (HCV antibody positive), except for patients with documented successful 
treatment and documented sustained virologic response (SVR) at Screening 
13. Evidence of human immunodeficiency virus (HIV antibody positive) infection at 
Screening 
14. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 and/or are on dialysis. 
15. Hypersensitivity to the investigational drug (danicopan) or any of its excipients 
5.3. 
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. 
Prospective patients should be screened within 45 days of first administration of study drug. All 
evaluations must be completed before the patient is accepted into the study. If the patient is 
unable to receive study drug within 45 days of screening, the patient may be rescreened once. 
Repeating any screening laboratory result(s) may be permitted on a case-by-case basis with the 
approval of the Medical Monitor (or designee). In these instances, repeating of a single 
laboratory test or a subset of the full panel may be acceptable. 
For patients screened more than 45 days prior to the first administration of study drug, all 
screening procedures must be reassessed to confirm eligibility. In this case, patients must sign a 
new ICF but should be assigned the same patient number as for the initial screening. 


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6. 
STUDY DRUG 
“Study Drug” in this protocol refers to danicopan or matching placebo. 
Patients should take all doses of study drug approximately 15 to 30 minutes after eating a meal 
or snack. Water intake is not restricted. 
6.1. 
Study Intervention Administered 
 
Table 5: 
Study Interventions Administered 
Compound Name 
Danicopan (ALXN2040)  
Placebo 
Type  
Drug 
Placebo 
Dose Formulation 
Tablet 
Tablet 
Unit Dose Strengths 
50 mg; 100 mg 
50 mg; 100 mg 
Dosage Levels 
150 mg; 200 mg 
150 mg; 200 mg 
Route of Administration 
Oral 
Oral 
Sourcing 
Provided by sponsor 
Provided by sponsor 
The container closure system used to package danicopan film coated tablet is white high-density 
polyethylene bottle with white child resistant polypropylene screw cap, fitted with induction-
sealed aluminum-faced liner. 
Most doses will be taken outside of the clinic. Patients will be provided with sufficient study 
drug to last until their next study visit. On visits when PK/PD sampling is scheduled, the patients 
will be instructed to take their dose at the clinic to enable predose sampling. At dose escalation 
decision visits, patients will return to the clinic to be dispensed study drug and receive new 
dosing instructions. See time points in Section 1.2. 
6.2. 
Preparation/Handling/Storage 
At the pharmacy, study drug must be stored as provided at controlled room temperature (20°C to 
25°C), with allowed excursion of 15°C to 30°C. Patients should be instructed to keep their study 
drugs in the original container at room temperature. 
The Principal Investigator or designee (e.g., 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 drug. This includes acknowledgment of receipt of each shipment of study drug (quantity 
and condition) and patient dispensing records and returned or destroyed drug. Dispensing records 
will document quantities received from the Sponsor. (or designee) 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. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is a double-blind, placebo-controlled Study with 2:1 randomization. The randomization 
scheme will be stratified by transfusion history (ie, > 2 or ≤ 2 transfusions within 6 months of 
Screening), Hgb (ie, < 8.5 g/dL and ≥ 8.5 g/dL) at Screening, and Japanese patients (defined as 
patients enrolled from Japan)/non-Japanese patients. The stochastic dynamic allocation rules on 


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the stratification factor will be used to assign patients to either danicopan or placebo treatment 
group at a 2:1 ratio through an interactive response technology (IRT) system on Study Day 1.  
Although all patients will receive active drug during Treatment Period 2 and LTE Period, the 
treatment arm assignment during Treatment Period 1 will not be unblinded until after database 
lock occurs. 
The IRT will be programmed with blind-breaking instructions. In the event that emergency 
unblinding is necessary, the IRT will provide clear step-by-step instructions for the investigator 
to follow. Details are also provided in the IRT Site User Guide.  
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a participants’ intervention assignment is warranted. Participant safety must always be the first 
consideration in making such a determination. If the investigator decides that unblinding is 
warranted, the investigator should make efforts to contact Alexion prior to unblinding a 
participant’s intervention assignment unless this could delay emergency treatment of the 
participant. If a participant’s intervention assignment is unblinded, Alexion must be notified 
within 24 hours after breaking the blind. The date and reason that the blind was broken must be 
recorded in the source documentation and case report form, as applicable. 
6.4. 
Assessments of Study Drug Compliance  
Patients will be required to bring their supply of study drug to each scheduled in-clinic 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 in-
clinic dispensing visit. 
6.5. 
Background and Concomitant Therapies 
Use of specific concomitant medications other than a C5 inhibitor will be considered on a 
case-by-case basis with decisions made jointly between the Principal Investigator and sponsor, 
based on available knowledge of danicopan as well as the characteristics of the potential 
concomitant medication. 
Details of all concomitant medication use, including all medications administered for the 
treatment of AEs, must be recorded in the patient’s electronic case report form (eCRF). 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 30 days prior to Day 1; patients should be 
maintained on stable doses (without any modifications of quantity or frequency) of 
these agents through Week 24. 
• Concomitant administration of steroids or other immunosuppressants is permitted if 
the dosage regimen is stable for at least 12 weeks before Day 1 and remain on stable 
doses through Week 24. 
• Oral, injectable, implantable, transdermal, or intravaginal hormonal therapies are 
allowed for either contraception or hormonal replacement therapy. 


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• 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. 
The use of concomitant medications during the study will be assessed at the time points indicated 
in Table 1. 
6.5.1. 
Background C5 Inhibitor Therapy: Eculizumab and Ravulizumab 
All patients are to be treated with study drug in combination with a C5 inhibitor therapy (i.e., 
eculizumab or ravulizumab) at the approved dosages for the purpose of data collection and 
analysis. C5 inhibitor used in this manner will be considered a background therapy. If patients 
switch to a different approved C5 inhibitor after completion of the study at Week 24, the new 
medication used in this manner will be also considered a background therapy. 
Approved C5 inhibitor dose may not be increased, nor interval shortened, during this study (with 
the exception of ravulizumab weight-based dosing based on changes in weight). The dose of the 
C5 inhibitor may be decreased, if indicated, with a dose re-escalation to the prior dose if the dose 
reduction was not tolerated. 
Changes in frequency of C5 inhibitor administration that are due to patient convenience or 
logistical reasons, but do not result in a change of the prescribed dosage and frequency are 
considered stable and should be discussed with the Medical Monitor prior to randomization. 
Patients may not switch from their Day 1 C5 inhibitor to any other C5 inhibitor during the first 
24 weeks of the study but may do so during the LTE period. The only authorized switch is from 
eculizumab to ravulizumab (possible only in those countries where ravulizumab is commercially 
available). 
C5 inhibitor therapy will be provided according to local regulations and approvals. 
6.5.2. 
Vaccines 
To reduce the risk of meningococcal infection, all patients must be vaccinated against 
meningococcal infections within 3 years prior to, or at the time of, initiating study drug. Patients 
who initiate study drug 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, Advisory Committee on 
Immunization Practices ([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 on once study drug 


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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 eCRF. 
6.6. 
Study Drug Dose Modification 
Doses of study drug (danicopan or placebo) may be escalated to a maximum of 200 mg tid, 
based on safety and clinical effect, at specified time points during the initial treatment period and 
during the LTE Period using the criteria below. All dose escalations decisions will be made 
based on central laboratory data and at the discretion of the Principal Investigator, in consultation 
with the sponsor. This applies to both Treatment Periods 1 and 2. The C5 Inhibitor + Placebo 
Treatment Group will be escalated in the same manner as the C5 Inhibitor + Danicopan 
Treatment Group during the study to maintain the blind. 
6.6.1. 
Dose Escalation During Treatment Period 1 
If the starting dose is well tolerated and the available safety data are satisfactory, a patient may 
be escalated to the next highest dose at the following time points: 
• At the Week 6 Visit, if the patient’s Hgb level at Week 4 has not increased by 
≥2 g/dL from their baseline value (Day 1), or the patient received a transfusion during 
the previous 4 weeks.  
• At the Week 12 Visit, if the patient’s Hgb level at Week 10 has not normalized to at 
least the midpoint of the normal range for gender from their baseline value or the 
patient received a transfusion during the previous 4 weeks. 
6.6.2. 
Dose Escalation During Treatment Period 2  
• At the Week 18 Visit, if the patient’s Hgb level at Week 16 has not normalized to at 
least the midpoint of the normal range for gender from their baseline value (Day 1) or 
the patient received a transfusion during the previous 4 weeks. 
6.6.3. 
Dose Escalation During the LTE Period 
• Any patient who has not already been dose escalated up to 200 mg study drug may be 
escalated up to a maximum of 200 mg danicopan tid, if they have been on their 
previous dose for at least 4 weeks and the Investigator believes that additional 
efficacy can be achieved. Dose escalations after Week 24 visit will be discussed with 
the sponsor before being implemented.  
6.6.4. 
Monitoring After Drug Escalation  
• If a patient has been dose escalated, laboratory blood samples for measurement of 
standard laboratory safety assessments should be obtained at the next week visit 


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following the escalation, either in clinic or via the visiting healthcare service as per 
the schedule of assessments.  
At any time-point after the dose escalation, if patient safety or tolerability warrants dose 
reduction to the previous dose this may occur in consultation with the Sponsor. This dose 
reduction will only occur, if both Principal Investigator and the Sponsor agree that the patient 
will benefit from the lower dose. 
Any patient who is at a dose of 100 mg tid upon implementation of this amendment, should be 
escalated to 150 mg tid at the next clinic visit (an unscheduled visit may be used for this purpose) 
and subsequently should follow the dose escalation guidelines outlined above.  
6.7. 
Dose Interruptions 
If danicopan dose is interrupted for any reason, an assessment should be made if the stop is 
temporary or the patient is to be withdrawn based on the criteria described in Section 7. Discussion 
about the reasons for interruption and plans for potential re-initiation should occur between the 
Investigator and the Alexion Medical Monitor. Re-initiation of treatment with danicopan should 
be done under careful clinical monitoring, including laboratory monitoring and after consultation 
with the Alexion Medical Monitor. If upon resumption of treatment, the patient has a recurrence 
of the event, permanent discontinuation should be considered as described in Section 7.1. 
Any temporary preplanned treatment interruption should be discussed between the Investigator 
and the Alexion Medical Monitor and tapering should be considered (refer to Section 7.2). 
The patient should continue participation until the end of the study unless the prespecified events 
for treatment discontinuation have been met. Any interruption of study drug and the reason for the 
interruption should be fully documented in the source documents and eCRF. 
6.8. 
Transfusion Guidelines Before and During the Study 
It is recommended to administer pRBC transfusion when a subject 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. If further matching for Kell and JK antigens can be conducted without delaying 
making the blood available for emergent transfusion, this additional testing is recommended. 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 pRBCs to be transfused. In 
the event of a transfusion is required, a blood sample for central lab is to be collected as an 
assessment prior to transfusion. Administration of transfusion including the reason for 


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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 
If study drug (danicopan or placebo) is discontinued for any reason, the dose will be tapered over 
a 6-day period as described in Section 7.2 below. Study drug will not be provided to the patients 
after the last scheduled dosing. After the end of therapy visit or Early Termination visit, all 
patients will be followed for an additional 30 days after the last dose of study drug.  


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7. 
DISCONTINUATION OF STUDY DRUG AND PATIENT 
DISCONTINUATION OR WITHDRAWAL 
In rare instances, it may be necessary for a patient to permanently discontinue study intervention. 
If study intervention is permanently discontinued, the patient will taper the dose as described in 
Section 7.2, and will remain in the study for 30 days after last dose of study drug 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 Principal Investigator (or designee) may decide, for reasons of medical 
prudence or patient noncompliance, to discontinue dosing of study drug for an individual patient. 
The Principal Investigator will discontinue dosing study drug in any patient who meets an any 
reasons listed below, and should notify the Medical Monitor immediately, and if possible, before 
dosing is terminated. Patients will continue to receive C5 inhibitor therapy, as per the Principal 
Investigator’s judgment but the study drug will be permanently discontinued. 
Reasons for patient withdrawal may include: 
• Intercurrent illness that would, in the judgment of the Investigator, affect assessment 
of clinical status to a significant degree 
• Development of any of the following liver function test abnormalities in the absence 
of hemolysis:  
− ALT > 8 × ULN 
− ALT > 5 × ULN for more than 2 weeks 
- Increase of ALT > 3 × ULN and > 3 × from baseline and total bilirubin 
> 2 × ULN or INR > 1.5, in the absence of warfarin anticoagulation 
- Increase of ALT > 3 × ULN and > 3 × from baseline with the appearance of 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (> 5%)  
• Patient withdrawal from their background C5 inhibitor. Investigators should follow 
the instructions on discontinuation and monitoring of the patient as outlined in the 
approved corresponding Summary of Product Characteristics (SmPC)/Local Product 
Information for eculizumab or ravulizumab. 
• Persistent Grade 3-4 toxicity (including a clinically significant laboratory 
abnormality) despite appropriate intervention 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 non-compliance 
• Discontinuation of the study at the request of the Sponsor, regulatory agency, or 
Ethics Committee or IRB 


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• Any other condition or circumstance that would jeopardize the welfare of the patient 
if s/he were to continue in the study 
• The reason for any patient’s discontinuation and the date of withdrawal will be 
recorded in the patient’s eCRF. The patient’s eCRF, 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 2 for 
treatment Week 24 should be performed as an early termination visit. 
Upon first observation of ALT 3 × baseline, a repeat test must be performed (ALT, AST, direct 
bilirubin, and INR) within 48 to 72 hours. The site should contact the patient and inquire about 
the presence of any symptoms (fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, or rash). 
If necessary for safety reasons, local laboratories are permitted to identify patients that may need 
to be discontinued from the study and results need to be discussed with the Medical Monitor, 
however the final discontinuation from the study requires central laboratory determinations and 
discussion with the Medical Monitor  
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. 
7.1. 
Study Stopping Criteria 
A consideration for the dosing to be terminated may be implemented based on DMC 
recommendation, if one or more of the following occurs (see Section 2.3.2 on risks of liver 
enzyme elevations): 
• Two or more patients discontinue study therapy due to liver function test 
abnormalities as detailed below 
− ALT > 8 × ULN 
− ALT > 5 × ULN for more than 2 weeks 
- Increase of ALT > 3 × ULN and > 3 × from baseline and total bilirubin 
> 2 × ULN or INR > 1.5, in the absence of warfarin anticoagulation 
- Increase of ALT > 3 × ULN and > 3 × from baseline with the appearance of 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (> 5%)  
Because patients may experience hemolysis which may result in increased bilirubin AST and 
even ALT, increases in bilirubin AST and/or ALT during the study must be evaluated in the 
context of hemolysis. The Principal Investigator will evaluate LDH and Hgb levels, as well as 
baseline bilirubin AST and ALT levels, to determine if the increases observed are due to an 
effect on liver function or are secondary to hemolysis. Any liver function test elevation felt to be 
associated with hemolysis (and not caused by study drug) will not be included in study stopping 
decisions. 


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Anytime a patient has to discontinue the study drug, the dose tapering instructions and schedule 
(see Section 7.2 and Table 6) should be followed unless the patient cannot tolerate tapering of 
study drug or the discontinuation is due to an SAE. 
7.2. 
Dose Taper 
If the study drug is discontinued or the dose is interrupted (Section 6.7), the dose of danicopan or 
placebo will be tapered over a 6-day period. The dosing taper regimen is described in Table 6. In 
addition, the taper schedule may be adjusted to allow for slower taper in a patient who is not 
tolerating discontinuation of drug. 
If the patient withdraws from the study at any time, the patient will complete the Early 
Termination visit as soon as possible prior to tapering. Patients should take the study drug per 
protocol until the tapering period begins. 
Table 6: 
Study Drug Taper Schedule 
Danicopan or Placebo Dose at 
Termination 
Taper Period 1 (T1) 
(Taper Days 1-3) 
Taper Period 2 (T2) 
(Taper Days 4-6) 
150 mg tid 
100 mg tid 
50 mg tid 
200 mg tid 
100 mg tid 
50 mg tid 
Abbreviations: tid = three times per day; T = taper 
T1 and T2 visits may be 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. 
Patients will continue to receive their approved C5 inhibitor at the same dose and interval during 
the taper and follow-up period that they were receiving during the treatment period. 
7.2.1. 
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 (+ 7) days after the last dose of study drug (danicopan or 
placebo). During the Follow-up Period, physical examinations, assessment of vital signs, all 
required safety laboratory testing, and collection of blood and urine samples will be performed at 
various time points in the clinic as specified in Table 3. 
7.3. 
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 


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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 Appendix 1. 


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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 1.2.  
8.1. 
Screening Period  
The Principal Investigator or designee is responsible for administering and obtaining freely given 
informed consent before the patient enters the study and before any study-related procedures are 
performed. Each patient will sign (written or electronic) an ICF (see Section 10.1.3). This may 
include additional consent forms for human immunodeficiency virus testing or other procedures 
which may be performed prior to patients being accepted into the study. 
A window of up to 45 days is permitted to allow screening and any required vaccinations. 
Screening procedures may be spread over more than one visit within the 45-day screening 
period. The screening clinic and laboratory procedures listed in Section 10.2 must be performed 
and documented prior to dosing. 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 should include the patient's transfusion history of a 
minimum of 52 weeks prior to screening. 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 B12 supplementation are eligible 
for the study if on a stable dose for at least 30 days prior to Day 1.  
For women of childbearing potential, a serum pregnancy test must be negative to be eligible for 
the study. 
All laboratory assessments for eligibility are performed by the central laboratory. However, use 
of local laboratories to determine eligibility will be permitted if the central laboratory cannot 
initially provide results for the following assessments: platelets, ANC, direct Coombs, D-dimer, 
and INR. If local laboratories are used to determine eligibility for the assessments stated above, a 
central laboratory sample should be obtained pre-dose on Day 1 to establish the patient’s 
baseline values. Use of local laboratory values for eligibility s will need to be discussed with the 
Medical Monitor. 
If screening laboratory assessments show elevated indirect bilirubin levels in conjunction with 
normal liver function tests (AST and ALT), or if the patient has a history of unexplained 
jaundice, unexplained high bilirubin levels, or a history otherwise suggestive of Gilbert's 
syndrome, the patient will be tested for this condition. If the patient has a history of Gilbert’s 
syndrome it should be documented as the patient’s medical history. Refer to the Laboratory 
Manual for testing procedure. 
If the patient is unable to receive study drug within 45 days of screening, the patient may be 
rescreened once. The repeating of individual screening laboratory results that fall outside the 
reported normal range may be permitted on a case-by-case basis with the written preapproval of 
the Medical Monitor (or designee). 
As part of the screening process, patients will be evaluated for vaccination requirements as 
detailed in Section 6.5.2. 


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8.2. 
Efficacy Assessments 
Blood will be collected according to the Schedule of Assessments (see Section 1.2) to assess the 
efficacy endpoints of change in hemoglobin, reticulocyte counts, bilirubin, and lactate 
dehydrogenase. PNH RBC clone size, C3 fragment deposition on PNH RBCs, AP and classical 
pathway activities, and Bb, C3, FD, and free C5 levels will also be assessed. Blood collection 
procedures are described in Section 8.4.1.1. 
Transfusion data, including the number of RBC units transfused, the associated pre-transfusion 
hemoglobin value (with reticulocyte count, if available) and the reason for transfusion will be 
collected from the time of screening until follow-up (from study site records and any other 
location where the patient receives any transfusions) and recorded in each patient’s eCRF. 
Given that the primary endpoint of the study is change from baseline in Hgb after treatment with 
danicopan vs placebo, and PNH RBCs are more prone to hemolysis during sample collection, 
management, and/or shipment, a backup central hematology sample must be obtained at the 
Week 12 and Week 24 visits for all patients.  
8.3. 
Patient-Reported Outcomes 
All patients enrolled in the study will self-administer questionnaires for the FACIT-Fatigue 
(Version 4), European Organization for Research and Treatment of Cancer (EORTC) Quality of 
Life Questionnaire-Core 30 Scale (QLQ-C30), and EQ-5D-3L (Visual Analogue Scale and Time 
Trade Off scores) scales and Work Productivity and Activity Impairment Questionnaire: Anemic 
Symptoms V2.0 (WPAI: ANS) (see Section 1.2). Local language versions of each of the tools 
will be provided separately. 
Health Resource Utilization data will be collected as per schedule shown in Section 1.2. For 
HRU, the Investigator or designee will record for each participant the number of clinic visits, 
emergency services utilized, hospitalization, missed work and also record the number of times 
the patient had darkened urine. Local language versions of each of the tools will be provided 
separately. 
All PROs and QoL assessments (written or electronic) will be administered before the treatment 
dose on Day 1. On other clinic visits, PROs and QoLs should be administered as early as 
possible. If patient is to receive infusion of their C5 inhibitor agent on a clinic visit where PROs 
and QoLs will be obtained, it is recommended that patients fill out the PRO and QoL instruments 
before the C5 inhibitor infusion.  
8.4. 
Safety Assessments and Procedures 
Safety will be evaluated by monitoring and assessment of AEs, clinical laboratory tests, physical 
examination findings, and vital signs measurements. Planned time points for all safety 
assessments are provided in Section 1.2. All findings must be recorded in the patient’s source 
documents and in the patient’s eCRF. 
8.4.1. 
Clinical Laboratory Tests 
Blood and urine samples will be collected for efficacy, safety, and PD laboratory evaluation as 
listed in Table 7 in Appendix 2 at the times indicated in Section 1.2. 


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If measurement of a serum complement pathway indicator is considered necessary by the 
Investigator, it should be discussed with the Medical Monitor and the procedures described for 
unblinding (see Section 6.3) and discontinuation of the patient from the study (see Section 7) 
should be followed. 
8.4.1.1. 
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 
at an unscheduled visit and analyzed locally. See the laboratory manual for additional 
information. 
Unanticipated additional blood may be collected throughout the study for safety monitoring and 
additional PD assessments, if necessary. 
8.4.2. 
Physical Examinations 
A complete physical examination will be performed at Screening and on Day 1 and will include 
an assessment of general appearance and a review of systems. Height (at screening only) and 
weight will also be measured and recorded. Measurements of height and weight should be taken 
with the patients in light clothing or underwear and without shoes. 
A brief physical examination will be conducted at all other in-clinic visits, as indicated in 
Section 1.2. 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. 
8.4.3. 
Vital Signs 
The Principal Investigator or designee will obtain blood pressure, heart rate, and respiration rate 
at the visits indicated in Section 1.2. Vital signs will be measured following a 5-minute rest. 
Vital sign values will be recorded in the patient’s source documents and in patient’s eCRF. 
8.4.4. 
Electrocardiograms 
The Principal Investigator or designee will obtain electrocardiogram (ECG) measurements at the 
times indicated in Section 1.2. 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: HR, RR, PR, 
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 as contributing to the 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 Principal Investigator or designee. All ECG parameters and 
assessments must be recorded or stored in the patient’s source documents and in patient’s eCRF. 
Any clinically significant finding must be reported as an adverse event. 


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8.5. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE are in Appendix 3. Adverse events will be reported 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 on all AEs including those that are serious, considered related to the study intervention or 
study procedures, or that caused the patient to discontinue the study intervention. 
8.5.1. 
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 drug, at the time points specified in Section 1.2. 
Medical occurrences, including pregnancies, that begin before the start of study intervention but 
after obtaining informed consent will be recorded as AEs. This does not include pre- or post-
treatment complications that occur as a result of protocol-mandated procedures (e.g., invasive 
procedures, such as venipuncture or biopsy), which should be reported as AEs. Pregnancy is not 
considered an AE. A pregnancy occurring after the start of study intervention should be reported 
on the pregnancy forms, as described in Section 10.3.8. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3. The investigator will 
submit any updated SAE data to the sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek AEs or SAEs 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 intervention or study participation, the Investigator must promptly notify the 
sponsor, (i.e., within 24 hours of the Investigator becoming aware of the event); such events are 
not entered into the eCRF). 
8.5.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3. 
8.5.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each patient at 
subsequent visits/contacts. All SAEs will be followed 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 given in Appendix 3. 
8.5.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of a study 
intervention under clinical investigation are met. 


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The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will ensure compliance with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics 
Committees (IEC), and investigators. 
Suspected unexpected serious adverse reactions (SUSARs) will 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 a SAE or other specific 
safety information (e.g., 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. 
8.5.5. 
Pregnancy 
Details of any pregnancy in female patients and/or female partners of male patients that occurs or 
is confirmed within the timelines listed in Section 8.5.1 will be collected. If a pregnancy is 
reported, the investigator should inform the sponsor within one business day of learning of the 
pregnancy and should follow the procedures outlined in Appendix 3 and Appendix 4. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.6. 
Treatment of Overdose 
For this study, any dose of study drug greater than the prescribed dose within a 24-hour period 
will be considered an overdose. 
The Sponsor does not recommend specific treatment for an overdose; general supportive 
measures are recommended as below. 
In the event of an overdose, the Investigator/treating physician should: 
1. Based on the Investigator’s judgement, contact the Sponsor’s Medical Monitor  
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 untoward effects of the overdose 
4. Any overdose reported by the patient (purposeful or accidental) should be recorded as an 
AE at minimum and assessed for seriousness as appropriate  
5. If necessary, based on consultation with the Sponsor’s Medical Monitor, obtain a plasma 
sample for PK analysis or safety labs 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Sponsor’s Medical Monitor. 


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8.7. 
Pharmacokinetics 
Pharmacokinetics (PK) will be evaluated using plasma from whole blood collected during the 
study as outlined in Section 1.2. Study drug concentration information that may unblind the 
study will not be reported to investigative sites or blinded personnel until the study has been 
unblinded. Additional information on sample collection and shipping instructions will be 
provided in a separate laboratory manual.  
8.8. 
Pharmacodynamics 
Pharmacodynamics will be evaluated using serum (for AP activity, C3, CP activity, and free C5) 
and plasma (for Bb and FD) from whole blood collected during the study as outlined in 
Section 1.2. PD assessments that may unblind the study will not be reported to investigative sites 
or blinded personnel until the study has been unblinded. Additional information on sample 
collection and shipping instructions will be provided in a separate laboratory manual. The 
Sponsor may store samples for other biomarker tests for future research subject to local and 
regional regulatory approval.  
8.9. 
Genetic Samples 
Subject to patient consent, a sample will be collected at baseline (Day 1) for potential genetic 
analysis Appendix 5: Genetics. Genetic analyses may be conducted: 1) if a patient does not 
respond to the investigative drug; 2) if a patient experiences drug-related toxicity; or 3) to further 
characterize the underlying disease.  


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9. 
STATISTICAL CONSIDERATIONS  
9.1. 
Statistical Hypotheses 
The null statistical hypothesis is the improvement in hemoglobin level from baseline at Week 12 
for danicopan being similar to the improvement for placebo; defined as the difference in mean 
change from baseline between danicopan and placebo at Week 12 is zero. 
9.2. 
Sample Size Determination 
The PNH literature indicates that patients with PNH who have received an approved C5 inhibitor 
but are still anemic have hemoglobin levels, on the average, of 10.5 g/dL (McKinley, 2017). All 
patients entering this study will have a hemoglobin level of ≤ 9.5 g/dL. A minimum of 2 g/dL in 
difference between danicopan and placebo treatments in terms of mean improvement from 
baseline after 12 weeks of treatment is, considered clinically meaningful. 
A total of approximately 84 patients will be enrolled into this study and randomized in a 2:1 ratio 
to danicopan and placebo study arms. It is anticipated that approximately 10% of patients will 
discontinue prior to the primary endpoint. For the primary endpoint of change from baseline to 
Week 12 in hemoglobin level, the statistical power using a two-sample t-test is 99% to detect the 
difference in mean change from baseline of 2 g/dL (alternative hypothesis), assuming the 
statistical significance level of 0.05 (two-sided) and the standard deviation of 1.6 g/dL, which is 
estimated from study ACH471-101. For the key secondary endpoint of patients with Hgb 
increase of ≥ 2 g/dL at Week 12 in the absence of transfusions, the study has >95% power 
assuming at least 35% of patients in the danicopan arm and 5% of patients in the placebo arm 
can meet the criterion. For the key secondary endpoint of patients with TA, the study has 70% 
power for the TA endpoint assuming 90% of patients in the danicopan arm and 64% of patients 
in the placebo arm will have TA. For the key secondary endpoint of change from baseline to 
Week 12 in FACIT-Fatigue score, the study has 91% power with a two-sample t-test to detect a 
9-point difference between treatment arms in mean change from baseline, which is considered 
clinically meaningful. The power calculation is based on the assumption of a standard deviation 
of 11 for FACIT-Fatigue change, which was observed in Study ALXN1210-PNH-301 in PNH 
patients. The power is 80% based on the standard deviation assumption of 13, which was 
observed in Study ACH471-101. 
9.3. 
Populations for Analyses 
The analysis populations are as follows: 
• Intent-to-treat (ITT) population: All randomized patients; data will be analyzed by the 
treatment groups to which patients are randomly assigned, even if the patient does not 
take the assigned treatment, does not receive the correct treatment, or does not 
comply with the protocol.  
• Per Protocol population: Intent-to-treat (ITT) patients who do not have protocol 
deviations expected to affect the primary efficacy endpoint (Week 12). Such protocol 
deviations will be prespecified in the statistical analysis plan prior to database lock. 
• Safety population: All patients who take at least one dose of danicopan or placebo. 


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If the ITT population and Per Protocol population have a similar number of patients (<5% 
difference), analyses will not be performed using the Per Protocol population. 
9.4. 
Statistical Analyses 
Categorical variables will be summarized with counts and percentages. Continuous variables will 
be summarized with univariate statistics (e.g., mean, median, standard error). 
Longitudinal summaries of efficacy and safety parameters will use pre-defined visit weeks. Visit 
windows around planned measurement times will be constructed, if appropriate, based on the 
midpoint between planned study visits. 
Efficacy and safety analysis results will be presented for both Treatment Periods of the study and 
by treatment group (danicopan and placebo). 
9.4.1. 
Patient Disposition and Demographic/Baseline Characteristics 
The number and percentages of patients will be provided for patient disposition for each study 
population. For enrolled patients who are not randomized, reasons for not being randomized will 
be listed and summarized. For patients who are randomized but do not receive study therapy, 
reasons for not receiving study therapy will be listed and summarized. For patients who are 
excluded from Per Protocol population, primary reasons of being excluded will be listed and 
summarized.  
Frequency distribution and summary statistics for demographic and baseline variables will be 
summarized. Key demographic and baseline variables to be summarized include geographic 
region, age, gender, race, height, weight, body mass index, RBC transfusion history 52 weeks 
prior to screening, approved C5 inhibitor prior to screening, hemoglobin level, reticulocyte 
count, platelet count, and neutrophil count. 
The summaries will be tabulated for the safety population and also for the Per Protocol 
population if the analysis is performed on the Per Protocol population. 
9.4.2. 
Study Drug Exposure, Compliance, and Concomitant and Background 
Therapies 
Overall percent compliance to danicopan and placebo dosage regimen, calculated as the 
percentage of doses taken relative to doses scheduled to be taken, will be summarized. Extent of 
exposure in days will be evaluated and summarized from the first dose date to the last dose date 
of danicopan or placebo during both treatment periods. 
Concomitant medication/therapy and background therapy verbatim terms will be coded using the 
latest version of the World Health Organization Drug Dictionary. The numbers and percentages 
of patients in each treatment group taking concomitant/background medications will be 
summarized by anatomic and therapeutic chemical classification and preferred term. 
Note that an approved C5 inhibitor taken regularly with danicopan or placebo during double-
blind and open-label treatment periods is considered background therapy. The extent of exposure 
of approved C5 inhibitors taken during treatment periods will be presented separately from 
concomitant therapies. 


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9.4.3. 
Efficacy Analyses 
Summary statistics for the baseline and post-baseline measurements, and changes from baseline 
will be presented by pre-defined visit for all continuous efficacy variables to be analyzed. 
9.4.3.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint is change in hemoglobin at Week 12 relative to baseline (defined 
as the lowest Hgb value, between and including screening and Day 1) between danicopan and 
placebo. The longitudinal changes from baseline in hemoglobin will be analyzed using a mixed 
model for repeated measures (MMRM) (Mallinckrodt, 2001, Mallinckrodt, 2004) which includes 
the fixed, categorical effects of treatment, study visit, and study visit by treatment group 
interaction as well as the continuous, fixed covariate of baseline hemoglobin value and the 
stratification randomization indicator of transfusion history in the model. The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom.  
The primary objective is to evaluate the efficacy of danicopan as compared to placebo on change 
in hemoglobin after a 12-week of treatment. To address the impact of transfusion on hemoglobin 
values, for patients who are transfused on or after Week 8, the hemoglobin value collected at 
Week 12 will not be included in the primary efficacy analysis. This rule will also apply to 
longitudinal observations collected at earlier visits, ie, hemoglobin values collected within 4 
weeks after transfusion will not be included in the primary efficacy analysis. 
The primary test for statistical significance of the treatment group difference between danicopan 
and placebo in Hgb change from baseline to Week 12 will be conducted via a re-randomization 
test method at the 2-sided 0.05 significance level. Iterations of re-randomized treatment 
assignments will be simulated for all randomized patients using the same original randomization 
algorithm, while keeping patient stratification factors values and entry order as observed and 
used in the actual randomization. For each set of the re-randomized treatment assignments, an 
estimate of treatment group difference will be obtained by using the same MMRM model as 
specified above. The p-value for the re-randomization test will be calculated as the number of re-
randomized treatment group differences that are more extreme than the treatment group 
difference calculated under the actual randomization (ie, absolute value of re-randomized group 
difference larger than the absolute value of group difference under the actual randomization) 
divided by the total number of simulated re-randomizations. 
With the relatively small sample size and short duration of blinded treatment (12 weeks), all 
efforts will be made to minimize missing Week 12 measurements. Longitudinal graphic 
presentations will also be provided to examine the hemoglobin profile throughout 12 weeks of 
treatment with danicopan or placebo, plus an approved C5 inhibitor. 
The primary efficacy analysis will be based on the ITT population. The re-randomization test for 
treatment group differences will be considered as the primary analysis. The test for treatment 
group differences directly from the MMRM model using the actual treatment assignments will 
also be reported as a sensitivity analysis. A supportive analysis will be carried out for the 
primary efficacy endpoint, changes in Hgb measurement, based on the Per Protocol population to 
examine the impact of major protocol deviations. Additional sensitivity analyses will be 
performed to assess the treatment effect under alternative missing data mechanism assumptions. 
The details of such analyses will be specified in the statistical analysis plan. 


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9.4.3.2. 
Secondary Efficacy Analysis 
The secondary efficacy endpoints are listed in Section 3. The secondary efficacy analysis will be 
conducted on the ITT population. 
Key secondary efficacy endpoints, in order of importance, are described below. Hierarchical 
fixed sequence test procedure is utilized to determine the statistical significance at two-sided 
level of 0.05 for each endpoint sequentially. 
1. Difference in proportion of patients with Hgb increase of ≥ 2 g/dL at Week 12 in the 
absence of transfusions 
2. Difference in proportion of patients with RBC transfusion avoidance between 
danicopan and placebo groups during the 12 weeks of treatment 
3. Difference in changes from baseline in FACIT-Fatigue scores between danicopan and 
placebo groups at Week 12. 
4. Difference in changes from baseline in absolute reticulocyte counts between danicopan 
and placebo groups at Week 12. 
For the parameter of proportions such as patients with Hgb increase of ≥ 2 g/dL at Week 12 in 
the absence of transfusions (defined as achieving ≥ 2 g/dL increase in Hgb from baseline to 
Week 12 and remaining transfusion free during 12-week Treatment Period 1), patients achieving 
transfusion avoidance and Hgb normalization at Week 12, the Cochrane-Mantel-Haenszel test 
will be used to compare between danicopan and placebo arms. 
For the changes in RBC transfusion units/instances from 12 weeks prior to initiation of treatment 
to 12-week Treatment Period 1, an analysis of covariance (ANCOVA) model including 
treatment arms and transfusion units/instances from 12 weeks prior to treatment initiation will be 
used to compare between danicopan and placebo arms. 
For change from baseline in numeric endpoints such as FACIT-Fatigue scores, EQ-5D-3L 
scores, EORTC QLQ-C30 scores, absolute reticulocyte count, total and direct bilirubin, or other 
PNH-related biomarkers at Week 12 the MMRM model as specified in the primary efficacy 
analysis will be employed to compare the mean difference between danicopan and placebo. 
The hierarchical fixed sequence test procedure calls for the current hypothesis to be rejected; that 
is, if the p-value for test statistic is < 0.05, then proceed to test the significance of the next 
hypothesis from the key secondary endpoints listed above by clinical importance. The sequential 
testing process will be stopped when the hypothesis cannot be rejected. 
Results based on various statistical procedures used to analyze data for the remaining secondary 
efficacy and exploratory endpoints will be descriptive as follows: 
• Number and proportion of patients with hemoglobin stabilization during the last 
12 weeks of treatment, for patients receiving 24 weeks of danicopan treatment. 
Hemoglobin stabilization is defined as avoidance of no more than a 1.0 g/dL decrease 
in Hgb levels at Week 24 from Week 12. 
• Change in RBC transfusion units/instances from 24 weeks prior to initiation of 
treatment to the 24-week treatment period for patients receiving 24 weeks of 
danicopan treatment. 


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• Proportion of patients with Hgb increase of ≥ 2 g/dL at Week 24 in the absence of 
transfusions, proportion of patients with transfusion avoidance through 24 weeks 
treatment period and proportion of patients with hemoglobin normalization at Week 
24  
• Change in FACIT-Fatigue, absolute reticulocyte count, total and direct bilirubin, 
LDH and other PNH-related biomarkers relative to baseline (Day 1) for patients 
receiving 24 weeks of danicopan treatment. 
• Change from baseline in PNH RBC clone size, C3 fragment deposition on PNH 
RBCs, measures of alternate pathway and classical pathway activity, Bb, C3, and FD 
levels at Week 12 and Week 24. 
• Change from baseline in exploratory PRO and QoL endpoints at Week 12 and 
Week 24. 
9.4.4. 
Analyses of Safety 
All safety analyses will be conducted on the safety population. The evaluation of safety will be 
performed separately for the 12-week blinded Treatment Period 1, subsequent 12-week 
Treatment Period 2, and the LTE for all patients exposed to danicopan, from the first dose to the 
end of the LTE. The safety analysis will be based primarily on the frequency of adverse events, 
clinical laboratory assessments, vital signs, and 12-lead ECG. Other safety data will be 
summarized if deemed clinically meaningful. 
Descriptive statistics using summary statistics will be calculated for quantitative safety data as 
well as for the difference to baseline by visit. Frequency tables will be provided for categorical 
variables. No inferential statistical analysis of safety data is planned. 
Adverse events will be coded using latest version of the Medical Dictionary for Regulatory 
Activities (MedDRA). Reports will be provided to the medical monitor for approval of the coded 
terms after the database is clean, prior to database lock. Treatment-emergent adverse events (i.e., 
those adverse events that newly occur or worsen in severity after the first dose of the study drug 
will be summarized by system organ class and preferred term. Tabulated listing of patients with 
SAEs and those who discontinue from the study due to an adverse event will be provided. 
Incidence of clinical laboratory abnormalities Grade 3 and above (based on version 5.0 of the 
National Cancer Institute Common Terminology Criteria for Adverse Events [CTCAE]) will be 
summarized. For laboratory tests with CTCAE toxicity grades available, laboratory 
abnormalities will be summarized by worst treatment emergent grade. Any laboratory adverse 
event will also be classified by the site based on clinical adverse event severity in addition to 
CTCAE and will be reported with the clinical adverse events.  
Shift tables will be provided for liver function test results and other selected laboratory test 
results based on CTCAE grades. In addition, shift tables based on multiple of ULN will also be 
produced for liver function test measurements.  
Data on vital signs and ECGs will be examined through subject listings and by summary 
statistics of selected parameters. 


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Other exploratory techniques (eg, graphic presentations), may also be used to facilitate clinical 
interpretations of the safety results. 
9.4.5. 
Analyses of Pharmacokinetics (PK) and Pharmacodynamics (PD) 
Individual plasma concentration data for all patients who receive at least 1 dose of study drug (ie, 
danicopan) and who have evaluable PK data will be included in the PK analysis for danicopan. 
Descriptive statistics will be calculated for plasma concentration data at each sampling time, as 
appropriate. Population-PK modeling will be conducted using data from this study and/or in 
combination with data from other studies. 
PD analyses will be performed for all patients who receive at least 1 dose of danicopan and who 
have evaluable baseline and post dose PD data. Descriptive statistics will be presented for all 
danicopan PD endpoints at each sampling time. The PD effects of ALXN2040 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 
danicopan PK-PD relationships may be explored using data from this study or in combination 
with data from other studies. 
9.5. 
Interim Analyses 
An interim analysis may be conducted at the discretion of the study sponsor (based on 
enrollment progression) when approximately 75% of patients have been randomly assigned to 
study treatment and have had the opportunity to complete the 12-week Treatment Period 1 
(information fraction = 0.75). The purpose of the interim analysis is to evaluate the study for 
stopping early for efficacy. If conducted, the primary endpoint of change in Hgb levels at Week 
12, as well as the key secondary endpoints will be evaluated using the alpha-spending methods 
specified below to control family-wise error rate. 
• The evaluation of primary endpoint at interim analysis will be using the gamma 
family alpha-spending function (Hwang, 1990) with parameter -4. 
• The evaluation of key secondary endpoints at interim analysis will be using the 
gamma family alpha-spending function with parameter 1. 
Due to the hierarchical nature of primary and key secondary endpoints, and proper alpha-
spending function used to control error rate at one-sided 0.025 level for each endpoint, the 
overall family-wise error rate is controlled at one-sided 0.025 level across primary and key 
secondary endpoints among interim and final analyses (Glimm, 2010, Tamhane, 2010). 
The recommendation of stopping study enrollment and placebo-controlled Treatment Period 1 
for efficacy can be made only if, at a minimum, the primary endpoint of change in Hgb levels at 
Week 12 and the key secondary endpoints of proportion of patients with Hgb increase ≥ 2g/dL in 
the absence of transfusion and proportion of patients with transfusion avoidance through 12week 
Treatment Period 1 meet the prespecified significance level. If the interim analysis is conducted 
with the timing and alpha-spending methods specified above, there is minimal change to the 
overall power for the primary endpoint, about 2-4% overall power decrease for the transfusion 
avoidance endpoint, and about 2-4% overall power decrease for the FACIT-Fatigue endpoint. 


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The sponsor will decide whether to perform the interim analysis based on enrollment 
progression. If full enrollment is already completed or close to completion by the time of the 
interim analysis specified above, the study will go directly to full analysis without an interim 
analysis. 
The interim analysis will be conducted under the auspices of an independent DMC. The final 
decision to stop the study enrollment and placebo-controlled Treatment Period 1 for efficacy will 
be at the recommendation of the DMC. If such decision is made, the study may be modified to 
allow patients in the placebo arm to receive danicopan. The DMC review of the data will be 
independent of the Sponsor as the Sponsor will remain blinded. Details of the DMC’s 
responsibilities and logistics will be outlined in the DMC charter before the dosing of the first 
patient. 
9.6. 
Staged Population PK/PD Analysis 
The staged population PK/PD analysis is planned prior to interim analysis, as well as prior to 
database lock. Pharmacodynamics will include AP activity, Bb, FD, C3, CP activity, and free 
C5.  


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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: 
• 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 Brochure, and other relevant 
documents (e.g., 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 (written or electronic) 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 or electronic informed consent was 
obtained before the patient was enrolled in the study and the date the consent was obtained. The 
authorized person obtaining the informed consent must also sign (written or electronic) the ICF. 
If the ICF is revised, patients must be re-consented (written or electronic) to the most current 
version of the ICF during their active participation in the study. 
A hard or digital 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. 
Alexion as a data controller has implemented privacy and security controls designed to help 
protect patient personal data, including information security controls, firewalls, incident 
detection, secure transfer measures, etc. 
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 
Company-sponsored study information and tabular study data will be posted on the US National 
Institutes of Health's website (www.ClinicalTrials.gov) and/or other publicly-accessible sites as 
required by the laws and regulations of the countries in which the study is conducted. 
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 FDA, other 
government agencies, or foreign drug regulatory authorities, or to the public. No publication of 
study design or results is permitted without specific approval of the Sponsor. 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 (e.g., 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 (e.g., Contract 
Research Organizations). 
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 study completion 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 entered in 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 request 
previous medical records or transfer records, depending on the study. Also, current medical 
records must be available. 


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Definition of what constitutes source data can be found in the Medical Monitoring and Clinical 
Monitoring Plans. 
10.1.8. 
Study and Site Closure 
The sponsor or designee 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 intervention development 
10.1.9. 
Publication Policy 
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 
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 approval by the Sponsor. To gain approval, a 
copy of the manuscript for review must, therefore, be sent to the Sponsor 60 days before 
submission for publication. 
It is the intent of the Sponsor. to present the results of this study at future scientific meetings. 
Additionally, it is the intent of the Sponsor to publish the results of this study in leading scientific 
journals. The Investigator of each investigative site will be invited to be an author in conjunction 
with the Investigator(s) from the Sponsor. The Sponsor will determine additional authors. 
Presentations and manuscripts will be provided and agreed to by the authors and by the Sponsor 
10.2. 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 7 will be performed by the central 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. 
 


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Table 7: 
Protocol-Required Laboratory Assessments 
Hematology 
Chemistry 
Urinalysis 
Other Assessments1 
Complete blood count 
(CBC), including: 
Red blood cell (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 (GGT) 
Glucose5 
Lactate dehydrogenase 
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 
Analysis including: 
Bilirubin 
Color 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
pH 
Protein 
Specific gravity 
Urobilinogen 
Microscopic examination 
of sediment 
 
Alternative pathway (AP) 
activity 
Bb 
C3 
C3 fragment deposition 
Classical pathway (CP) 
activity  
Free C5 
D-dimer 
Direct Coombs 
Factor D  
Free hemoglobin 
Haptoglobin 
PNH clone size 
PT/PTT/INR  
Urine pregnancy test6 
Iron studies: 
-Serum ferritin 
-Serum iron 
-Transferrin saturation 
-TIBC 
-Total Iron Binding 
Capacity (TIBC) 
Serology: 
-HCV and HBV 
antibodies 
-HIV-1 and HIV-2 
antibodies 
-UGT1A1 (Gilbert’s) 
1 Check the Schedule of Assessments for specific times when these tests should be done. 
2 Fractionate and obtain measurements of direct and indirect bilirubin for all patients. If indirect bilirubin levels are 
> ULN at Screening but ALT and AST are normal, test for Gilbert’s syndrome. 
3 Provide estimated glomerular filtration rate (eGFR) based on 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 Day 1, 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. 
 


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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures  
for Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definitions 
Adverse events (AEs) 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 considered drug related. An AE can arise with any use of the drug (e.g., 
off-label use, use in combination with another drug) and with any route of administration, 
formulation, or dose, including an overdose. 
Medical occurrences, including pregnancies, that begin before the start of study intervention but 
after obtaining informed consent will be recorded as a pre-treatment AE. While pregnancy itself 
is not considered an AE, for the purposes of safety monitoring, a pregnancy occurring after 
signing the ICF should be reported on the pregnancy forms and sent to Alexion Global Drug 
Safety (
 or fax 
). 
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 danicopan until 30 days after the last dose 
of study drug 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 (e.g., 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 (e.g., headache) not present at 
baseline. 
• Any case of abuse of alcohol, illicit drugs, or prescription drugs; abuse of study 
drug(s) or protocol-specified drug(s); addiction. 
• A pregnancy that occurs or becomes confirmed during a clinical study (see 
Section 1.2). 
• Laboratory test or other clinical test (e.g., ECG or X-ray) with a clinically significant 
abnormality (as defined below). 
• An effect of the study drug, including comparator. 
• Any dose of medication (study drug or other concomitant medication) that is taken at 
a dose higher than the prescribed dose (i.e., an overdose). Overdose should be 
reported as an AE whether or not it is associated with any symptoms or signs. 


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The following are not considered to be AEs: 
• Medical or surgical procedures (e.g., surgery, endoscopies, tooth extraction, 
transfusion, etc.) - the condition which leads to the procedure is the AE; 
• 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 (e.g., 
hospitalization for elective surgery, social and/or convenience admissions, etc.) 
Clinically significant changes in objective findings (e.g., 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 drug 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 AE, 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 participant’s 
medical record. In the latter case, the condition should be reported as medical history. 
All participants 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 


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• Is life-threatening i.e., the participant 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. 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 participant who was exposed to the 
study drug) 
• Is an important medical event or reaction 
10.3.3. 
Documentation and Reporting of Adverse Events 
AEs, including TEAEs, may be reported by a participant or his/her representative, or to the 
Investigator elicited by the Investigator during questioning and examination of a participant. 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 study and follow-up period must be fully recorded and 
described on the appropriate CRF page. The AE should 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 should be reported as a single AE (e.g., fever, elevated WBC, cough, abnormal chest 
X-ray, etc. can all be reported as “pneumonia”). 
If a definitive diagnosis is not possible, the individual symptoms and signs should be recorded. 
Documentation must be supported by an entry in the participant’s medical record. The 
relationship to study drug or study procedures should be assessed using the definitions in 
Section 10.3.7. 


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10.3.4. 
Treatment and Follow-Up of Adverse Events 
All AEs should 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 Medical 
Monitor (or designee). The Sponsor may request that certain AEs be followed until resolution or 
stabilization. 
10.3.5. 
Timeframe for Collection of Adverse Events 
AEs include events that have appeared or worsened during the course of the clinical study. AEs 
may also include pre- or post-treatment complications that occur as a result of protocol-mandated 
procedures (e.g., invasive procedures, such as venipuncture, biopsy, etc.). 
Any AE (i.e., a new event or an exacerbation of a preexisting condition) with an onset date after 
the participant provides informed consent through the 30 days following the participant’s last 
study drug 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 drug dose 
must 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 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 drug (s), the PI (or designee) should 
promptly document and report the event to Alexion Global Drug Safety 
(
 or fax 
). 
10.3.6. 
Severity and Grading of Adverse Events 
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 participant. If a lab abnormality is 
deemed to be clinically significant, it should be reported as an AE and the AE grade reported 
should correspond to the grade of the lab abnormality on the CTCAE grading scale. 
10.3.7. 
Assessment of Causality 
The Investigator must assess the likelihood that the study drug caused or contributed to each AE, 
and document this assessment assigning one of the binary criteria to each AE: 
− Not related: There is no reasonable possibility the study intervention caused 
the adverse event.  
 The adverse event 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 
adverse event. 


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 The adverse event 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 
For the purposes of determining expedited reporting status to Health Authorities, Sponsor 
considers the assessments of ‘unrelated’ and ‘unlikely’ as unrelated to study drug and ‘possible’, 
‘probable’, and ‘definite’ as related to study drug. 
In addition, for any analyses of AE data in which only two categories of ‘related’ and ‘unrelated’ 
are used, the assessments of ‘unrelated’ and ‘unlikely’ will be combined into the category of 
‘unrelated’, and the assessments of ‘possible’ and ‘probable’ and ‘definite’ will be combined into 
the category of ‘related’. 
10.3.8. 
Pregnancy 
Any pregnancy, including in a female partner of a male participant, that occurs or becomes 
confirmed during a clinical study (time frames outlined in Section 1.2) must be reported to 
Alexion Global Drug Safety (GDS) within 24 hours of first knowledge of the pregnancy. The 
report should be provided on the Pregnancy/Breastfeeding Outcome form. While pregnancy 
itself is not considered an AE, for the purposes of safety monitoring, it should be reported to 
Alexion GDS on the pregnancy forms. 
All pregnancies temporally related to study drug should be followed and discussed with the 
medical monitor as follows: 
• The Investigator will follow up with the participant or the participant’s female partner 
approximately every 3 months throughout the pregnancy and report to Alexion GDS 
using the Pregnancy/Breastfeeding Outcome form. A follow up on the status of the 
baby will be collected at 3 months of age of the baby. 
• The Investigator will report any information on the status of the pregnancy including 
outcome to Alexion GDS (
 or fax 
  
• Any termination of pregnancy will be reported, regardless of fetal status (i.e., 
presence or absence of anomalies) or indication for the procedure. 
Any SAEs related to the pregnancy (see below), or occurring during the participant’s pregnancy, 
or after delivery, must be documented and reported to Alexion GDS both electronically via the 
Rave Safety Gateway and via the Pregnancy/Breastfeeding Outcome form. SAEs occurring in 
the child (e.g., congenital anomalies or other conditions present at birth, whether genetically 
inherited or occurring in utero) must also be reported to Alexion GDS both electronically via the 
Rave Safety Gateway and via the Pregnancy/Breastfeeding Outcome form. 
• Reportable SAEs associated with pregnancy include, but are not limited to: 
• Pregnancy losses (e.g., spontaneous abortion, late fetal death, elective termination) 
• Life-threatening developments (e.g., placental abruption, fetal distress) 


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• Congenital anomalies 
• Neonatal or maternal death, or 
• Any event resulting in maternal or neonatal hospitalization/prolonged hospitalization. 
10.3.9. 
Reporting Serious Adverse Events and Pregnancies 
The Sponsor has requirements for the expedited reporting of safety events meeting specific 
requirements to worldwide regulatory authorities, and therefore, must be notified immediately 
regarding the occurrence of any SAE and/or pregnancy that occurs during the study (time frames 
outlined in Section 1.2). 
For SAEs and/or pregnancies occurring during the study, the Investigator or delegate will enter 
all relevant information in the eCRF. 
All SAEs that occur during the course of the study, whether or not causally related to the 
investigational product, must be entered into the eCRF immediately (within 24 hours of the 
investigator becoming aware of the event) and electronically transmitted to Alexion GDS via the 
Rave Safety Gateway. 
In addition, the Investigator must: 
• Report all site-specific SAEs to the relevant Institutional Review Board (IRB) / 
Independent Ethics Committee (IEC) within the timeframe specified by the IRB / IEC 
as per local procedures/policies. 
• If the subject is an active participant in the study: 
• Enter follow-up information in the eCRF until the SAE has resolved, or, in the case of 
permanent impairment, until stabilized.  
• Ensure that the causality assessment for all SAEs is entered in the eCRF. 
• If the patient is no longer participating in the study, report the follow-up information 
to the sponsor. 
In the case of a medical emergency, the Medical Monitor must be contacted. 
10.3.10. 
Investigator Reporting Requirements for SUSARs 
The Sponsor is responsible for ensuring that Investigators and central ECs/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 ECs 
or IRBs as per EC 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 
consent requires revision. The PI should also comply with EC or IRB procedures for reporting 
any other safety information. 
10.3.11. 
Concomitant/Background Medication Assessments 
Details of all concomitant/background medication use, including all medications administered 
for the treatment of AEs, will be recorded in the participant’s CRF at each study visit. 


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10.3.12. 
Monitoring Participant Safety 
The safety of participants will be monitored by Investigators and by Sponsor’s medical monitor 
(or designee) on an ongoing basis while participants are receiving the study drug.  
10.3.13. 
Removal of Participants from the Study or Study Drug 
A participant 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 participant 
noncompliance, to discontinue dosing in a participant. The PI should also stop dosing in any 
participant who meets an individual stopping rule. In either case, whenever possible, the 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 protocol, whichever is considered to be in the best interest of the participant. When 
dosing is terminated, study participation is not necessarily immediately terminated. Instead, 
whenever possible, the participant 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 
Appendix 1. 
Reasons for participant withdrawal include (but are not limited to): 
• One or more of the stopping criteria described in the protocol is met 
• Intercurrent illness that would, in the judgment of the Investigator, affect assessments 
of clinical status to a significant degree 
• Unacceptable toxicity (including a clinically significant laboratory abnormality) 
necessitating discontinuation of study 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 participant’s best interest to continue the study  
• Participant request to discontinue for any reason 
• A female participant becomes pregnant or wishes to become pregnant 
• Participant noncompliance 
• Discontinuation of the study at the request of the Sponsor, regulatory agency, or 
Ethics Committee or IRB 
• Any other condition or circumstance that would jeopardize the welfare of the 
participant if s/he were to continue in the study 
The reason for any participant’s discontinuation and the date of withdrawal will be recorded in 
the participant’s CRF. The participant’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: Contraception Guidance and Collection of Pregnancy 
Information 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following at least 6 months prior to dosing: 
• Documented hysterectomy 
• Documented bilateral salpingo-oophorectomy  
• Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(e.g., Mullerian agenesis, androgen insensitivity), Investigator discretion should be applied to 
determining study entry. 
Note: Documentation must come from the site personnel’s: review of the patient’s medical 
records. 
Postmenopausal female meeting both of the criteria below: 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
• A high follicle stimulating hormone (FSH) level in the postmenopausal range must be 
used to confirm a postmenopausal state. 
Females on HRT and whose menopausal status is in doubt will be required to use one of the non-
estrogen hormonal 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. 
Contraception Guidance: Patients on C5 inhibitor therapy should adhere to the 
contraception guidelines as per local country label requirements 
Contraception for Male Patients 
All non-sterile male patients must use highly effective or acceptable methods of contraception 
with their partner(s) of childbearing potential from the first day of dosing (Day 1) through 
90 days (a spermatogenesis cycle) after their last dose of study drug. 
Sterile is defined as having bilateral orchiectomy. 
Highly effective contraception for males is defined as any of the following:  


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• Vasectomy with confirmed medical assessment of surgical success 
• 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 refraining from heterosexual intercourse during the 
entire period from the first day of dosing (Day 1) through 90 days after their last dose 
of study drug. Periodic abstinence (e.g., calendar, symptothermal, post-ovulation 
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.  
Acceptable contraceptive methods include:  
• A combination of male condom with either cap, diaphragm, or sponge with 
spermicide (double barrier methods) 
Male patients must agree to refrain from sperm donation while enrolled in this study and for 
90 days (a spermatogenesis cycle) after their last dose of study drug. 
Contraception for Female Patients 
Female patients of childbearing potential must use a highly effective or acceptable method of 
contraception from the date of signing the informed consent until the specified duration after the 
last dose of their background C5 inhibitor as per the product labelling. 
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 
• IUD or 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. 
Periodic abstinence (e.g., calendar, symptothermal, post-ovulation methods) is not an 
acceptable method of contraception. The reliability of sexual abstinence needs to be 


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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. 
Acceptable contraceptive methods include:  
• A combination of male condom with either cap, diaphragm, or sponge with 
spermicide (double barrier methods) 
Female patients of childbearing potential must have a negative urine pregnancy test in order to 
enter the study and must have urine pregnancy tests throughout the study at the intervals defined 
in the Schedule of Assessments. 
Female patients of non-childbearing potential need not employ a method of contraception. 
Collection of Pregnancy Information 
Any pregnancy, including female partner pregnancies of male patients, that occurs or becomes 
confirmed during a clinical study must be reported to the Sponsor (or designee) within one 
business day of first knowledge of the pregnancy, as described in Section 8.5.5. The report 
should be provided on the pregnancy form. While pregnancy itself is not considered an AE, for 
the purposes of tracking, it should be captured as an AE as well as reported on the pregnancy 
forms. 
All pregnancies temporally related to taking study drug 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 6-8 weeks 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 (i.e., 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. SAEs occurring in the child (e.g., 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 (e.g., spontaneous abortion, late fetal death, elective termination) 
• Life-threatening developments (e.g., placental abruption, fetal distress) 
• Congenital anomalies 
• Neonatal or maternal death 


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• Any event resulting in maternal or neonatal hospitalization/prolonged hospitalization. 
10.5. 
Appendix 5: Genetics 
Subject to patient consent, a sample will also be collected at screening for potential genetic 
analysis. 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): 
• 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 (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. 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: 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 participant 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 8. 
Table 8: 
Potential Risks and Mitigation Measures due to COVID-19 
Risks Category 
Summary of Data/ 
Rationale for Risk 
Mitigation Strategy 
Potential risks 
Potentially higher risk 
population for 
SARS-CoV-2 
infection 
Participants in this study have to be vaccinated 
against meningococcal infections prior to treatment 
with a C5 inhibitor.  
It is unknown how this may impact their risk for 
SARS-CoV-2 infection. 
During the time that the 
COVID-19 pandemic is active, 
Alexion will recommend that 
sites in a position to start the 
study and enroll participants 
follow the national and 
institutional guidances 
regarding prevention of 
SARS-CoV-2 infection. 
Additionally, during that time 
period, it is expected that 
Investigators and their staff will 
take all possible precautions in 
order to minimize a 
participant’s potential exposure 
to SARS-CoV-2 infection. 
Depending on the site, this will 
consist of measures such as 
social distancing, temperature 
screening, enhanced cleaning, 
and use of personal protective 
equipment for participants, 
staff, and caregivers as 
necessary. 
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 
resourcing and capabilities to 
implement the study per 
protocol. 


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Table 8: 
Potential Risks and Mitigation Measures due to COVID-19 
Risks Category 
Summary of Data/ 
Rationale for Risk 
Mitigation Strategy 
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 
eCRF that explains the reason 
the data is missing (eg, missed 
study visits or participant study 
discontinuations due to 
COVID-19). 
Abbreviations: C5 = complement protein 5; COVID-19 = coronavirus disease 2019; eCRF = electronic case report 
form; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2. 


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10.7. 
Appendix 7: 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 
danicopan administration, based on danicopan’s mechanism of action. There is currently no 
information available evaluating the safety and efficacy of COVID-19 vaccines in participants 
treated with danicopan. Same precautions should be taken as described in Section 6.5.2. 
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 9: . 
Table 9: 
Potential Risk and Mitigation Measures due to COVID-19 Vaccination 
Risk Category 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Potential risk 
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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10.8. 
Appendix 8: Abbreviations 
 
Abbreviation 
Definition 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
ANCOVA 
Analysis of covariance 
AP 
Alternative pathway (of complement)  
AST 
Aspartate aminotransferase 
Bb 
Bb fragment of complement factor B 
C3 
C3 complement protein 
C5 
C5 complement protein 
C3G 
C3 glomerulopathy 
CIOMS 
Council for International Organizations of Medical Sciences  
CP 
Complement classical pathway 
CRF 
Case report form 
CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
electronic case report form  
eGFR 
Estimated glomerular filtration rate 
EORTC 
European Organization for Research and Treatment of Cancer 
EQ-5D-3L 
Three-level version of EuroQoL 5 Dimensions questionnaire 
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 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
Hct 
Hematocrit 
HCV 
Hepatitis C virus 
Hgb 
Hemoglobin  
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
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 
INR 
International normalized ratio 
IRB 
Institutional review board 
IRT 
Interactive response technology 
ITT 
Intent-to-treat 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
LDH 
Lactate dehydrogenase 
LTE 
Long-Term extension 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model for repeated measures 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 


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Abbreviation 
Definition 
PNH 
Paroxysmal nocturnal hemoglobinuria 
pRBC 
Packed red blood cells 
PRO 
Patient-reported outcome 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QLQ-C30 
Quality of Life Questionnaire-Core 30 Scale  
QoL 
Quality of life 
QRS 
Group of electrocardiogram waves comprising the Q, R, and S waves 
QT 
Period (in milliseconds) from the beginning of the QRS complex until the end of the T wave 
QTcF 
QT interval Fridericia Correction Formula  
RBC  
Red blood cells 
RR 
Respiration rate 
SAE  
Serious adverse event 
SUSAR 
Suspected unexpected serious adverse reaction 
TA 
Transfusion avoidance 
TEAE 
Treatment-emergent adverse event 
tid 
Three times per day 
ULN 
Upper limit of normal 
WBC 
White blood cell 
Wk 
Week 
VHA 
Visit Healthcare Assessment 
 
 


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10.1182/blood.V130.Suppl_1.3471.3471. 
16. 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. 
17. Nishimura J, Yamamoto M, Hayashi S, Ohyashiki K, Ando K, Brodsky AL, et al. 
Genetic variants in C5 and poor response to eculizumab. N Engl J Med. 
2014;370(7):632-9. doi: 10.1056/NEJMoa1311084. 
18. 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. 
19. Risitano AM, Roth A, Soret J, Friere C, de Fontbrune FS, Marano L, Rozenberg I, 
Milojevic J, End P, Nidamarthy PK, Junge G, De Latour RP. A new oral complement 
factor-b inhibitor normalizes hemoglobin in paroxysmal nocturnal hemoglobinuria 
patients with poor response to eculizumab, both as add-on and monotherapy. 46th Annual 
Meeting of the European Society for Blood and Marrow Transplantation (EBMT); 29 
August - 1 September2020. 
20. 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. 
21. 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. 
22. 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. 
23. Socié G, Caby-Tosi MP, Marantz JL, Cole A, Bedrosian CL, Gasteyger C, et al. 
Eculizumab in paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic 
syndrome: 10-year pharmacovigilance analysis. Br J Haematol. 2019;185(2):297-310. 
doi: 10.1111/bjh.15790. 
24. 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. 
25. Tamhane AC, Mehta CR, Liu L. Testing a primary and a secondary endpoint in a group 
sequential design. Biometrics. 2010;66(4):1174-84. doi: 10.1111/j.1541-
0420.2010.01402.x. 
26. Volanakis JE, Narayana SV. Complement factor D, a novel serine protease. Protein Sci. 
1996;5(4):553-64. doi: 10.1002/pro.5560050401. 
27. 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: 
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Alexion Pharmaceuticals, Inc. 
STATISTICAL ANALYSIS PLAN 
PROTOCOL NUMBER: ALXN2040-PNH-301 
A PHASE 3 STUDY OF DANICOPAN (ALXN2040) AS ADD-ON THERAPY 
TO A C5 INHIBITOR (ECULIZUMAB OR RAVULIZUMAB) IN 
PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA 
WHO HAVE CLINICALLY EVIDENT EXTRAVASCULAR HEMOLYSIS 
(EVH) 
Product Name:   
Danicopan (ALXN2040, previously ACH-0144471) 
Protocol Version: 
Amendments 6.0 (25 Feb 2022), 6.2 (30 Mar 2022) 
and 6.3 (08 Aug 2022) 
Author: 
 
Date: 10 Aug 2022 
Version: 2.0 
NCT #: NCT04469465


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1. 
APPROVAL SIGNATURES 
 
 
 
 
 
 
 
 
 
 
Date dd Mmm yyyy 
 
 
 
 
 
 
 
 
 
 
Date dd Mmm yyyy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date dd Mmm yyyy 
 
11-Aug-2022 | 12:12:02 EDT
11-Aug-2022 | 12:57:40 EDT
11-Aug-2022 | 11:56:28 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 
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 SAP ....................10 
5. 
DEFINITIONS ...........................................................................................................11 
5.1. 
Efficacy .......................................................................................................................11 
5.1.1. 
Primary Endpoint ........................................................................................................11 
5.1.2. 
Key Secondary Endpoints ...........................................................................................11 
5.1.3. 
Other Secondary Endpoints ........................................................................................11 
5.1.4. 
Exploratory Endpoints ................................................................................................12 
5.2. 
Pharmacokinetic and Pharmacodynamic Endpoints ...................................................12 
5.3. 
Safety ..........................................................................................................................12 
5.3.1. 
Adverse Events ...........................................................................................................13 
5.3.2. 
Vital Signs ..................................................................................................................13 
5.3.3. 
Laboratory Assessments .............................................................................................13 
5.3.4. 
Electrocardiograms .....................................................................................................13 
5.3.5. 
Physical Examination .................................................................................................14 
5.3.6. 
Immunogenicity ..........................................................................................................14 
6. 
DATASETS ANALYZED (STUDY POPULATIONS) ............................................15 
6.1. 
Full Analysis Set .........................................................................................................15 
6.2. 
Per Protocol Set ..........................................................................................................15 
6.3. 
Safety Set ....................................................................................................................15 
6.4. 
Other Sets ....................................................................................................................15 
7. 
STATISTICAL ANALYSIS ......................................................................................16 
7.1. 
Study Patients .............................................................................................................16 


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7.1.1. 
Disposition of Patients ................................................................................................16 
7.1.2. 
Protocol Deviations ....................................................................................................16 
7.1.3. 
Demographics, Disease Characteristics, and History .................................................16 
7.1.3.1. 
Demographics and Baseline Characteristics ...............................................................16 
7.1.3.2. 
Disease Characteristics ...............................................................................................17 
7.1.3.3. 
Medical/Surgical History and Baseline Physical Examination ..................................18 
7.1.4. 
Prior and Concomitant Medications/Therapies ..........................................................18 
7.1.4.1. 
C5 Inhibitor .................................................................................................................18 
7.2. 
Efficacy Analyses .......................................................................................................19 
7.2.1. 
Primary Endpoint Analysis .........................................................................................19 
7.2.1.1. 
Handling of Dropouts or Missing Data ......................................................................20 
7.2.1.2. 
Subgroup Analysis ......................................................................................................20 
7.2.1.3. 
Multicenter Studies .....................................................................................................21 
7.2.1.4. 
Hypothesis Testing and Significance Level ...............................................................21 
7.2.1.5. 
Sensitivity Analyses ....................................................................................................21 
7.2.2. 
Secondary Endpoint Analyses ....................................................................................24 
7.2.2.1. 
Key Secondary Endpoint Analyses ............................................................................24 
7.2.2.2. 
Other Secondary Endpoint Analyses ..........................................................................25 
7.2.3. 
Exploratory Endpoint Analyses ..................................................................................27 
7.2.4. 
Other Efficacy Analyses .............................................................................................27 
7.2.5. 
Pharmacokinetic and Pharmacodynamic Analyses ....................................................27 
7.2.6. 
Handling of Samples With Table-top Hemolysis .......................................................28 
7.3. 
Safety Analyses ..........................................................................................................28 
7.3.1. 
Study Duration, Treatment Compliance, and Exposure .............................................28 
7.3.2. 
Adverse Events ...........................................................................................................29 
7.3.2.1. 
Overall Summary of AEs ............................................................................................29 
7.3.2.2. 
AEs and SAEs by SOC and PT ..................................................................................30 
7.3.2.3. 
AEs and SAEs by SOC, PT, and Relationship ...........................................................30 
7.3.2.4. 
AEs by SOC, PT, and Severity ...................................................................................30 
7.3.2.5. 
Deaths, Other SAEs, and Other Significant AEs ........................................................30 
7.3.3. 
Other Safety ................................................................................................................31 
7.3.3.1. 
Analyses for Laboratory Tests ....................................................................................31 
7.3.3.2. 
Vital Signs ..................................................................................................................31 


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7.3.3.3. 
Electrocardiograms .....................................................................................................32 
7.3.3.4. 
Nondrug Therapies and Procedures ............................................................................32 
7.3.3.5. 
Patients Enrolled Under Local Amendment ...............................................................32 
7.4. 
COVID-19-Related Data Analysis .............................................................................32 
8. 
INTERIM ANALYSIS ...............................................................................................34 
9. 
REFERENCES ...........................................................................................................36 
10. 
APPENDICES ............................................................................................................38 
10.1. 
Protocol Schedule of Assessments .............................................................................38 
10.2. 
Changes from Analyses Specified in the Previous Version of the SAP .....................38 
10.3. 
Sample Size, Power, and Randomization ...................................................................38 
10.4. 
Technical Specifications for Derived Variables .........................................................39 
10.4.1. 
Age ..............................................................................................................................39 
10.4.2. 
Disease Duration .........................................................................................................39 
10.4.3. 
Definition of Baseline Values .....................................................................................40 
10.4.4. 
Change From Baseline ................................................................................................40 
10.4.5. 
Percent Change From Baseline ...................................................................................40 
10.4.6. 
Analysis Visits ............................................................................................................40 
10.4.7. 
Adverse Events ...........................................................................................................41 
10.4.8. 
Concomitant Medications/Therapies ..........................................................................41 
10.5. 
Additional Details on Statistical Methods ..................................................................42 
10.5.1. 
FACIT-Fatigue Calculations ......................................................................................42 
10.5.2. 
EORTC QLQ-C30 Scoring Calculations ....................................................................42 
10.5.3. 
EQ-5D-3L Scoring Calculations.................................................................................43 
10.5.3.1. 
Health State Index .......................................................................................................43 
10.5.3.2. 
EuroQoL Visual Analog Scale ...................................................................................45 
10.5.4. 
SAS Code for MMRM Analysis.................................................................................45 
10.5.5. 
SAS Code for Tipping Point Sensitivity Analysis ......................................................45 
10.6. 
Additional Analyses for Japanese Subgroup ..............................................................47 
 


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LIST OF TABLES 
Table 1: 
Abbreviations and Acronyms .......................................................................................7 
Table 2: 
Estimand Attributes for the Primary and Key Secondary Endpoints .........................22 
Table 3: 
Age and Reference Date .............................................................................................39 
Table 4: 
Scoring the EORTC QLQ-C30 ...................................................................................42 
Table 5: 
Definition for Variables Used in Calculating Health State Index Using US 
Population Estimates ..................................................................................................44 
Table 6: 
Definition for Variables Used in Calculating Health State Index Using UK 
Population Estimates ..................................................................................................44 
 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and acronyms are used in this statistical analysis plan (SAP).  
Table 1: 
Abbreviations and Acronyms 
Abbreviation or Acronym 
Explanation 
ADA 
antidrug antibodies 
AE 
adverse event 
ALT 
alanine aminotransferase 
APH 
alternate pathway activity 
ANCOVA 
Analysis of Covariance 
AST 
aspartate aminotransferase 
Bb 
Bb fragment of complement factor B 
BP 
blood pressure 
C3 
complement C3 
CH50 
classical pathway activity 
CI 
confidence interval 
CMH 
Cochrane-Mantel-Haenszel 
COVID-19 
Coronavirus Disease 2019 
CSR 
clinical study report  
CTCAE 
Common Terminology Criteria for Adverse Events  
CV% 
coefficient of variation percentage 
DBL 
database lock 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
EORTC 
European Organization for Research and Treatment of Cancer 
EQ-5D-3L 
Three-level EuroQoL 5-dimension 
EQ VAS 
EuroQoL visual analog scale 
EVH 
extravascular hemolysis 
FAS 
full analysis set 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FD 
factor D 
Hgb 
hemoglobin 
HR 
heart rate 
HRU 
healthcare resource utilization 
IMP 
investigational medicinal product 
ITT 
intent-to-treat 
LDH 
lactate dehydrogenase 
LTE 
long-term extension 
MAR 
missing-at-random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model for repeated measures 
MI 
multiple imputation 
MNAR 
missing not at random 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PNH 
paroxysmal nocturnal hemoglobinuria 
PP 
per protocol 
pRBC 
packed red blood cells 
PT 
preferred term 
PTAE 
pretreatment adverse event 


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Table 1: 
Abbreviations and Acronyms 
Abbreviation or Acronym 
Explanation 
QLQ-C30 
Quality of Life Questionnaire-Core 30 Scale 
QoL 
quality of life 
QTcF 
corrected QT interval by Fridericia formula 
RBC 
red blood cell 
RR 
respiratory rate 
SAE 
serious adverse event 
SAS® 
Statistical Analysis Software® 
SAP 
statistical analysis plan 
SMQ 
standardized MedDRA query 
SoA 
schedule of assessments 
SOC 
system organ class 
SS 
safety set 
TA 
transfusion avoidance 
TEAE 
treatment-emergent adverse event 
tid 
thrice daily 
TTH 
table-top hemolysis 
ULN 
upper limit of normal 
WHO-DRUG 
World Health Organization Drug 
WPAI:ANS 
Work Productivity and Activity Impairment Questionnaire: Anemic 
Symptoms 


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4. 
DESCRIPTION OF THE PROTOCOL 
ALXN2040-PNH-301 is a multiple-region, randomized, double-blind, placebo controlled, 
multiple-dose, Phase 3 study to evaluate the efficacy and safety of danicopan versus placebo in 
patients with paroxysmal nocturnal hemoglobinuria (PNH) who have clinically evident 
extravascular hemolysis (EVH) on a C5 inhibitor (eculizumab or ravulizumab). This study will 
include approximately 84 patients who are receiving C5 inhibitor therapy according to the usual 
dose and schedule and who continue to experience anemia with or without the need of 
transfusion support. Randomization will be stratified by transfusion history (ie, > 2 or 
≤ 2 transfusions within 6 months of Screening) and hemoglobin (Hgb) level (ie, < 8.5 and 
≥ 8.5 g/dL) at Screening and Japanese patients (defined as patients enrolled from 
Japan)/non-Japanese patients.  
Patients will be randomized to danicopan thrice daily (tid) or placebo tid in a 2:1 ratio for 
12 weeks (Treatment Period 1) in addition to their C5 inhibitor therapy (eculizumab or 
ravulizumab). At Week 12, patients randomized to receive placebo will be switched to danicopan 
in addition to their C5 inhibitor for an additional 12 weeks (Treatment Period 2) and patients 
randomized to danicopan will continue on danicopan for an additional 12 weeks while remaining 
on their ongoing C5 inhibitor therapy. At the end of the Treatment Period 2 (Week 24), patients 
may enter the Long-Term Extension (LTE) Period and continue to receive danicopan and their 
C5 inhibitor therapy. 
The starting dose of danicopan or placebo is 150 mg tid. The dose may be escalated to 200 mg 
tid based on safety and clinical effects at any of the protocol-specified time points (Weeks 6, 12, 
and 18 and after Week 24). If a patient discontinues from the study, dosing of danicopan or 
placebo should be tapered over 6 days (Taper Visits 1 and 2), and a Follow-up Visit will be 
conducted approximately 30 days after the last dose of study drug. Refer to Protocol Section 6.6 
for more details on dose escalation.  
The primary objective of this study is to evaluate the efficacy of danicopan as compared to 
placebo as add-on therapy to a C5 inhibitor on change in Hgb after 12 weeks of treatment. The 
key secondary objectives are to evaluate the treatment effect of danicopan as compared to 
placebo as add-on therapy to a C5 inhibitor on an Hgb increase of ≥ 2 g/dL in the absence of 
transfusion, transfusion avoidance (TA), Functional Assessment of Chronic Illness Therapy 
(FACIT) Fatigue score, and absolute reticulocyte count after 12 weeks of treatment.  
An interim analysis, performed under the auspices of the independent Data Monitoring 
Committee (DMC), may be conducted when approximately 75% of patients (planned as N = 63) 
have been randomly assigned to study treatment and have had the opportunity to complete the 
12-week placebo-controlled Treatment Period 1. The purpose of the interim analysis is to 
evaluate the study for efficacy. The alpha-spending method and success criteria for the interim 
analysis are specified in Section 8. If the decision is made to stop the study enrollment early for 
efficacy per DMC recommendation based on this interim analysis, enrollment will be stopped, 
the study will be unblinded, and all study endpoints (efficacy, safety, pharmacokinetics [PK], 
and pharmacodynamics [PD]) analyses will be conducted based on interim data available as of 
the database lock (DBL) and an interim clinical study report (CSR) will be produced. For 
additional details on the interim analysis, please refer to Section 8.  


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If the interim analysis does not meet the prespecified success criteria defined in Section 8, the 
study will continue as planned with no modifications. A study DBL is planned to occur after full 
enrollment is achieved and all patients (planned as N = 84) have reached the end of the 12-week 
randomized placebo-controlled period (Treatment Period 1). A CSR will be produced and will 
include efficacy, safety, PK, and PD analyses based on full enrollment and data collected up to 
the database cut-off date (including available data for patients already in Treatment Period 2 and 
LTE Period).  
4.1. 
Changes From Analyses Specified in the Protocol 
Not applicable. 
4.2. 
Changes From Analyses Specified in the Previous Version of the SAP 
Refer to Section 10.2. 


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5. 
DEFINITIONS 
5.1. 
Efficacy 
5.1.1. 
Primary Endpoint 
The primary efficacy endpoint of the study is the change in Hgb relative to Baseline after 
12 weeks of treatment with danicopan compared to placebo.  
5.1.2. 
Key Secondary Endpoints 
The key secondary efficacy endpoints of the study (to be tested in a hierarchical manner) are as 
follows: 
1. Proportion of patients with an Hgb increase of ≥ 2 g/dL at Week 12 in the absence of 
transfusion 
2. Proportion of patients with TA, defined as patients who remain transfusion free and do 
not require a transfusion as per protocol-specified guidelines through Week 12  
For the purpose of this analysis, 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 cell (pRBC) transfusion when a 
subject has any of the following: 
• An Hgb value of < 7 g/dL regardless of the presence of clinical signs or symptoms 
• An Hgb value of < 9 g/dL with signs or symptoms of sufficient severity to warrant a 
transfusion 
3. Change from Baseline in FACIT Fatigue scores at Week 12 
4. Change from Baseline in absolute reticulocyte counts at Week 12 
5.1.3. 
Other Secondary Endpoints 
Other secondary efficacy endpoints of the study are as follows: 
• Change in the number of red blood cell (RBC) units transfused and transfusion 
instances during the 24 weeks of treatment with danicopan compared to the 24 weeks 
prior to the initiation of treatment in patients randomized to the danicopan arm 
• Percentage of patients who have TA through 24 weeks of treatment in patients 
randomized to danicopan arm 
• Change in the number of RBC units transfused and transfusion instances during the 
12 weeks of treatment with danicopan compared to the 12 weeks while receiving 
placebo 
• Change from Baseline in FACIT Fatigue scores at Week 24 in all patients 


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• Percentage of patients with Hgb stabilization during the last 12 weeks of treatment in 
patients receiving 24 weeks of danicopan 
• Proportion of patients with an Hgb increase of ≥ 2 g/dL at Week 24 in the absence of 
transfusion 
• Change from Baseline of danicopan-treated patients compared to placebo in total and 
direct bilirubin at 12 weeks 
• Changes in PNH RBC clone size and complement C3 (C3) fragment deposition on 
PNH RBCs at 12 weeks of treatment with danicopan compared to placebo 
• Changes in lactate dehydrogenase (LDH) at 12 weeks 
• Percentage of patients with Hgb normalization at 12 and 24 weeks 
5.1.4. 
Exploratory Endpoints 
The exploratory endpoints of the study are as follows: 
• Change from Baseline relative to placebo in 3-level EuroQoL 5-dimension 
(EQ-5D-3L) scores at Week 12 
• Change from Baseline in EQ-5D-3L scores at Week 24 
• Change from Baseline relative to placebo in European Organization for Research and 
Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 Scale 
(QLQ-C30) scores at Week 12 
• Change from Baseline in EORTC QLQ-C30 scores at Week 24 
• Change from Baseline relative to placebo in Work Productivity and Activity 
Impairment Questionnaire: Anemic Symptoms (WPAI:ANS) scores at Week 12 
• Change from Baseline in WPAI:ANS scores at Week 24 
• Change from Baseline relative to placebo in Healthcare Resource Utilization (HRU) 
at Week 12 
• Change from Baseline in HRU scores at Week 24 
5.2. 
Pharmacokinetic and Pharmacodynamic Endpoints 
The PK and PD endpoints of the study are as follows: 
• Plasma concentrations of danicopan over time 
• Changes from Baseline in PD biomarkers (Bb fragment of complement factor B [Bb], 
factor D [FD], C3, free C5, hemolytic alternate pathway activity [APH], hemolytic 
classical pathway activity [CH50]) 
5.3. 
Safety 
The safety and tolerability of danicopan compared with placebo will be evaluated by physical 
examination, vital signs, electrocardiograms (ECGs), laboratory assessments, and incidence of 


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adverse events (AEs) and serious adverse events (SAEs). Incidence of antidrug antibodies 
(ADAs) to ravulizumab will be reported as specified in Section 5.3.6. 
5.3.1. 
Adverse Events 
An AE is defined as any unfavorable and unintended sign (eg, including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product. 
Situations in which an untoward medical occurrence did not occur (eg, hospitalization for 
elective surgery if planned before the start of the study and admissions for social reasons or for 
convenience) and anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen are not AEs. 
The severity of AEs will be graded using Common Terminology Criteria for Adverse Events 
(CTCAE) v4.03 or higher. 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
• Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
• Grade 3: Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
selfcare activities of daily living 
• Grade 4: Life-threatening consequences; urgent intervention indicated 
• Grade 5: Death related to AE 
AEs are further defined in Protocol Section 10.3. 
5.3.2. 
Vital Signs 
Vital signs will include assessments of systolic and diastolic blood pressures (BPs), temperature, 
respiratory rate (RR), and heart rate (HR). Systolic and diastolic BPs will be documented in 
millimeters of mercury. Temperature will be obtained in degrees Celsius or Fahrenheit. HR will 
be documented in beats per minute. RR will be documented in breaths per minute. 
5.3.3. 
Laboratory Assessments 
Samples for the analysis of serum pregnancy, hematology, chemistry, coagulation, and urinalysis 
will be collected (see Protocol Section 10.2 for a listing of all clinical laboratory parameters). A 
central laboratory will be used to evaluate all laboratory assessments. 
5.3.4. 
Electrocardiograms 
A single 12-lead ECG will be conducted as per the schedule of assessments (SoA) in the study 
protocol. HR, PR interval, QRS duration, and QT interval will be measured, and corrected QT 
interval by Fridericia formula (QTcF) and RR interval will be calculated. 


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5.3.5. 
Physical Examination 
A physical examination will be performed assessing general appearance; skin; head, eyes, ears, 
nose, and throat; neck; lymph nodes; chest; heart; abdominal cavity; limbs; central nervous 
system; and musculoskeletal system. An abbreviated physical examination will be performed 
consisting of a body system-relevant examination based on Investigator judgment and patient 
symptoms. 
5.3.6. 
Immunogenicity 
For patients enrolled under local protocol amendment 4.1 and receiving background therapy 
ravulizumab as investigational medicinal product (IMP) in the study, blood samples will be 
collected to test for the presence and titer of ADAs to ravulizumab. Incidence of ADAs will be 
reported. Further characterization of antibody responses may be conducted as appropriate, 
including binding and neutralizing antibodies, PK/PD, safety, and activity of ravulizumab. 


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6. 
DATASETS ANALYZED (STUDY POPULATIONS) 
6.1. 
Full Analysis Set 
The full analysis set (FAS) or all randomized population will consist of all enrolled patients that 
are randomized to either the danicopan or placebo treatment group. 
The primary population for assessment of efficacy is the FAS, and the analyses will follow 
intent-to-treat (ITT) principle (ie, data will be analyzed by the treatment groups to which patients 
are randomly assigned) even if the patient does not take the assigned treatment, does not receive 
the correct treatment, or does not comply with the protocol.  
6.2. 
Per Protocol Set 
The per protocol (PP) set will consist of all randomized patients in the FAS that meet all the 
following criteria: 
• Took ≥ 80% of total danicopan dose amount assigned per protocol during the 
12-week randomized Treatment Period 1 
• Met all inclusion and did not meet any exclusion criteria of the study 
• Never received the wrong randomized treatment during the 12-week randomized 
Treatment Period 1 (ie, all patients who received assigned treatment) 
• Had no inadvertent unblinding of treatment assignment 
• Had no other important protocol deviations that may impact the assessment of the 
primary and key secondary endpoints  
The primary efficacy endpoint analysis, as well as key secondary endpoint analyses, will be 
performed on both the FAS and PP set. If the FAS, based on ITT principle, and the PP set have a 
similar number of patients (< 5% difference), analyses will not be performed using the PP set. 
6.3. 
Safety Set 
The safety set (SS) will consist of all patients that received at least 1 dose of study drug 
(danicopan or placebo). Safety analysis will be performed on the SS and will be based on the 
treatment patients actually received. 
6.4. 
Other Sets 
The PK analysis set will consist of all patients who received at least 1 dose of danicopan and 
who have evaluable PK data. 


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7. 
STATISTICAL ANALYSIS 
All data collected in this study will be presented using summary tables, figures, and data listings. 
For categorical variables, frequencies and percentages will be presented by treatment group and 
overall. For continuous variables, descriptive statistics (n, mean, median, SD, minimum, and 
maximum) will be presented by treatment group and overall.  
7.1. 
Study Patients 
7.1.1. 
Disposition of Patients 
A summary of the number of the screened patients (patients who signed informed consent of the 
study), screen failures, randomized patients, and treated patients (received at least 1 dose of 
study drug) will be tabulated. For all randomized patients, a summary of patient disposition will 
be presented by treatment group and overall. The number and percentage of patients that 
completed the study through the end of the randomized Treatment Period 1 or 
discontinued/withdrew early before the end of the randomized Treatment Period 1, along with 
reason for discontinuation/withdrawal will be presented. Similar patient disposition summary 
will be provided for Treatment Period 2, LTE Period, and the entire study. 
A table summarizing the number of patients screened, randomized, treated, and completed 
treatment by region will be provided. Region will be defined based on study sites at which 
patients receive study drug and will include North America, Europe, Japan, the rest of Asia 
Pacific, and Latin America. A similar summary by country will also be produced.  
The number and percentage of patients in each analysis set will be tabulated. For patients that are 
excluded from the PP set, the primary reasons for exclusion will be listed and summarized. 
By-patient data listings with disposition will be provided as well as a listing of patients that did 
not meet the inclusion/exclusion criteria. 
7.1.2. 
Protocol Deviations 
Protocol deviations from monitoring reports and other relevant sources will be reviewed. All 
important protocol deviations will be summarized by category and listed for all patients in the 
FAS.  
7.1.3. 
Demographics, Disease Characteristics, and History 
All demographic and baseline characteristic information will be summarized using the FAS and 
SS. Summary statistics will be presented by treatment group and overall. Demographic and 
baseline characteristics will also be summarized by treatment group and stratification groups for 
the FAS, SS, and PP set. By-patient listings of demographic information, disease characteristics, 
PNH medical history, and medical/surgical history will be produced. 
7.1.3.1. 
Demographics and Baseline Characteristics 
The following demographic and baseline characteristic variables will be summarized: 
• Sex 
• Race 


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• Ethnicity 
• Age (years) at informed consent and frequency of patients in the following categories: 
< 65 and ≥ 65 years (65 to 74, 75 to 84, and 85 years and older) 
• Baseline weight 
• Baseline height 
• Baseline body mass index 
• Transfusion history stratification (> 2 or ≤ 2 transfusions within 6 months of 
Screening) 
• Screening Hgb level stratification (< 8.5 and ≥ 8.5 g/dL) 
• Japanese patients (patients enrolled from Japan [Yes/No]) 
7.1.3.2. 
Disease Characteristics 
The following PNH disease characteristics will be summarized: 
• Age (years) at PNH diagnosis 
• Method of PNH diagnosis 
• Years from PNH diagnosis to informed consent 
• Age (years) at the first C5 inhibitor infusion 
• Duration (years) from the initial C5 inhibitor treatment to the first dose of study drug 
• Current C5 inhibitor background therapy (including dose level and frequency) 
• Duration (years) from the start of current C5 inhibitor to the first dose of study drug 
• PNH clone sizes (RBC Types II and III and granulocyte) at Baseline 
• Hgb at Baseline 
• Absolute reticulocyte counts at Baseline 
• LDH at Baseline 
• FACIT-fatigue scores at Baseline 
• pRBC transfusion requirements during the year and 24-week period prior to receiving 
study drug including number of transfusion instances and units transfused 
• All PNH symptoms experienced at any time prior to informed consent 
• All PNH associated conditions that were diagnosed at any time prior to informed 
consent 


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7.1.3.3. 
Medical/Surgical History and Baseline Physical Examination 
Medical history will be summarized by system organ class (SOC) and preferred term (PT) using 
the latest available version of standardized Medical Dictionary for Regulatory Activities 
(MedDRA; version 23.1 or above) and will be reported by treatment group and overall.  
Likewise, baseline physical examination information will be summarized by treatment group and 
overall. 
7.1.4. 
Prior and Concomitant Medications/Therapies 
Prior and concomitant medications will be summarized. Prior medications are defined as 
medications taken prior to the first dose of study drug and include all medications taken within 
28 days prior to informed consent as well as all Neisseria meningitidis vaccinations administered 
within 3 years of dosing with danicopan. Concomitant medications are defined as medications 
received by the patients during the study on/after the date of the first dose of the study drug. No 
concomitant medications are specifically prohibited by the protocol. 
Medications will be coded using the World Health Organization Drug (WHO-DRUG) Dictionary 
version in use by Alexion at the time of the analysis. Medication summaries by treatment group, 
(ie, number [%] of patients using prior and concomitant medications) will be presented by 
WHO-DRUG Anatomical Therapeutic Chemical Level 3 and by WHO-DRUG generic name. 
Concomitant medication summary will be produced for the 12-week randomized Treatment 
Period 1, Treatment Period 2, LTE Period, and throughout the entire study treatment. 
Listings of prior and concomitant medications will be produced. A by-patient listing of 
N meningitidis vaccination will be produced showing the date(s) of vaccinations for each patient. 
A by-patient listing of nondrug therapies and procedures will be produced by treatment group. 
7.1.4.1. 
C5 Inhibitor 
Summary statistics (mean, SD, median, minimum, and maximum) will be produced for each C5 
inhibitor (eculizumab and ravulizumab) in the randomized Treatment Period 1, Treatment Period 
2, and LTE Period by treatment group for the following using the FAS and SS: 
• Number of infusions  
• Total dose administered (milligrams) 
• Total infusion volume administered (milliliters) 
• Total time on C5 inhibitor (days) calculated as the time in days from the first C5 
inhibitor infusion date until the last infusion date 
For patients who are receiving C5 inhibitor as an IMP, the total number of patients with an 
infusion interruption as well as the total number of infusions interrupted will be summarized. In 
addition, the frequency and percentage of patients that had a percentage of drug compliance 
range by increments of 10% (ie, ≥ 90% to ≤ 100%; ≥ 80% to < 90%, etc) will also be 
summarized. This will be calculated as follows: 
Percent compliance = Total number of infusions taken / Total number of expected infusions  
By-patient listings will be produced for C5 inhibitor exposure. 


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7.2. 
Efficacy Analyses 
The FAS is the primary population for all efficacy analyses. The primary efficacy endpoint 
analysis, as well as key secondary endpoint analyses, will also be conducted using the PP set as 
supportive analysis for those endpoints. Unless otherwise specified, Baseline is defined as the 
last available assessment prior to the initiation of study treatment (the first dose of study drug). 
In general, the baseline assessment will be the Day 1 assessment. If the Day 1 assessment is 
missing, the latest observation during the Screening Period, where available, will be used as the 
baseline assessment. In general, when evaluating mean change from Baseline in numeric 
laboratory parameters, only values reported by the central laboratory will be included in the 
analysis. 
Unless otherwise specified, statistical tests for treatment comparisons will be conducted at a 
2-sided 0.05 significance level. 
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 treatment group using 
descriptive statistics (n, mean, median, SD, minimum, and maximum for continuous variables 
and frequencies and percentages for categorical variables). 
7.2.1. 
Primary Endpoint Analysis 
The primary efficacy endpoint of the study is the change in Hgb relative to Baseline after 
12 weeks of treatment with danicopan compared to placebo in patients who are receiving 
background C5 inhibition treatment. The estimand attributes for the primary endpoint are 
described in Table 2 below. For this analysis, Baseline is defined as the lowest Hgb value 
observed between and including Screening and Day 1. The longitudinal changes from Baseline 
in Hgb collected at postbaseline visits during the 12-week randomized Treatment Period 1 will 
be analyzed using an MMRM method (Mallinckrodt, 2001; Mallinckrodt, 2004). The model 
includes the fixed, categorical effects of treatment group, study visit, and study 
visit-by-treatment group interaction, as well as the fixed, continuous covariate of a baseline Hgb 
value and the randomization stratification factor of transfusion history. An unstructured 
covariance matrix will be used to model the within-patient errors. If this analysis model fails to 
converge, the covariance matrix structures will be evaluated in the following order until model 
convergence is met: Toeplitz, first-order autoregressive, and compound symmetry. The order is 
specified according to decreasing number of covariance parameters in the structure.  
The Kenward-Roger approximation will be used to estimate the denominator degrees of 
freedom. The treatment comparison for the primary efficacy analysis will be based on the 
difference between danicopan and placebo groups at Week 12. The difference between treatment 
groups in least-square mean estimates and its associated SE will be calculated along with a 2-
sided 95% confidence interval (CI). The test will be conducted at a 2-sided 0.05 significance 
level. 
Under the US local protocol amendment, the primary test for statistical significance of the 
treatment group difference between danicopan and placebo will be conducted via a re-
randomization test method at the 2-sided 0.05 significance level. Re-randomized treatment 
assignments will be simulated for all randomized patients for 1500 iterations using the same 
original randomization algorithm, while keeping patient stratification factors values and entry 


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order as observed and used in the actual randomization. For each set of the re-randomized 
treatment assignments, an estimate of treatment group difference will be obtained by using the 
same MMRM model as specified above. The p-value for the re-randomization test will be 
calculated as the number of re-randomized treatment group differences that are more extreme 
than the treatment group difference calculated under the actual randomization (ie, absolute value 
of re-randomized group difference larger than the absolute value of group difference under the 
actual randomization) divided by the total number of simulated re-randomizations. 
The primary objective of this study is to evaluate the efficacy of danicopan as compared to 
placebo as add-on therapy to a C5 inhibitor on change in Hgb after 12 weeks of treatment in 
patients with PNH who have clinically evident EVH on a C5 inhibitor. 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 MMRM model for the primary efficacy analysis. 
With the relatively small sample size and 12-week placebo-controlled treatment period, all 
efforts will be made to minimize missing Week 12 measurements. Longitudinal graphic 
presentations will also be provided to examine the Hgb profile throughout 12 weeks of treatment 
with danicopan or placebo, plus a C5 inhibitor. 
The primary efficacy analysis will be based on the FAS with ITT principle. For the US local 
protocol amendment, the re-randomization test for treatment group differences will be 
considered as the primary analysis. The test for treatment group differences directly from the 
MMRM model using the actual treatment assignments will also be reported as a sensitivity 
analysis. For ex-US countries, the test for treatment group differences directly from the MMRM 
model using the actual treatment assignments will be considered as the primary analysis, while 
the re-randomization test for treatment group differences will be reported as a sensitivity 
analysis. A supportive analysis will be carried out for the primary efficacy endpoint of change in 
Hgb based on the PP set, using the same method described above.  
7.2.1.1. 
Handling of Dropouts or Missing Data 
For the primary endpoint of change in Hgb from Baseline to Week 12, missing Hgb assessments 
for a particular patient at a particular visit will not be imputed. The specified MMRM analysis 
can produce valid statistical inference under the missing-at-random (MAR) missing data 
mechanism assumption. Sensitivity analyses to assess treatment effects under alternative missing 
data mechanism assumptions are specified in Section 7.2.1.5. 
Missing data for QoL instruments will be handled as specified in the instructions for each 
instrument (see also Section 10.5). 
Missing data for secondary endpoints will be handled as specified in Section 7.2.2. 
7.2.1.2. 
Subgroup Analysis 
Subgroup analysis of efficacy endpoints will be performed on the FAS. Summaries of observed 
Hgb values and change from Baseline at each study visit will be produced for the subgroups 
defined by the randomization stratification factors of transfusion history (> 2 or ≤ 2 transfusions 
within 6 months of Screening), screening Hgb level (< 8.5 and ≥ 8.5 g/dL), and Japanese patients 
(patients enrolled from Japan [Yes/No]). Similar summaries of the primary endpoint and the key 


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secondary endpoints will also be produced for subgroups based on sex, race, region, age at 
informed consent (< 65 and ≥ 65 years), and background C5 inhibitor therapy (eculizumab or 
ravulizumab). 
7.2.1.3. 
Multicenter Studies 
While this is a multicenter study, a very small number of patients are anticipated to be enrolled at 
each study site. Therefore, center will not be used as an explanatory factor in the efficacy 
analyses. 
7.2.1.4. 
Hypothesis Testing and Significance Level 
The treatment comparison test for the primary efficacy endpoint will be conducted based on a 
2-sided Type I error rate of 0.05. If statistical significance is achieved for the primary endpoint, 
the 4 key secondary endpoints described in the study protocol will be tested for treatment 
comparison (danicopan versus placebo) at a 2-sided 0.05 level. To control the overall Type I 
error across study endpoints, the tests will be conducted using a closed-testing procedure in the 
order as specified in Section 7.2.2.1 so that the lack of significance of a test precludes statistical 
significance of subsequent tests. 
If the interim analysis for efficacy is conducted, the significance level for the primary and key 
secondary endpoints will be adjusted using the alpha-spending method specified in Section 8. 
7.2.1.5. 
Sensitivity Analyses 
The MMRM analysis specified for the primary endpoint analysis assumes MAR for the missing 
data mechanism. A tipping point sensitivity analysis will be performed to evaluate the robustness 
of the primary efficacy analysis by assessing the treatment effect under alternative missing data 
assumptions. The analysis will be performed based on the delta-adjusted stress testing method, 
and the missing data mechanism assumption will be missing not at random (MNAR). This 
approach assumes that patients that discontinue from danicopan treatment experience worsening, 
defined by a prespecified adjustment (delta) in the primary efficacy endpoint compared with the 
observed values from patients that continue the study to next visit (Ratitch, 2014; Ratitch, 2013). 
Since a reduction in Hgb indicates worsening, the prespecified value of delta will be a negative 
quantity. A fixed set of delta values (from less conservative to more conservative) will be used to 
encapsulate the change in Hgb associated with missing values for the active treatment group, and 
the tipping point multiple imputation analysis as described by Ratitch et al will be applied 
(Ratitch, 2013). For each value of delta, imputed values for missing Hgb at each time point will 
be obtained by first sampling from an MAR-based multiple imputation (MI) model including the 
variables of treatment, baseline values, and values observed at all scheduled visits during the 
12-week randomized Treatment Period 1 and then subtracting the value of delta from all imputed 
values in the danicopan arm. The mean change from Baseline in Hgb will then be analyzed using 
the same MMRM model specified above based on data observed, as well as data imputed. The 
treatment effect will be determined, and the value of delta for which the result is no longer 
statistically significant will be considered as the “tipping point” in the sense that the positive 
conclusion drawn from the primary analysis is reversed when patients who drop out are assumed 
to experience this fixed worsening after the discontinuation visit. After such a tipping point is 
determined, clinical judgment will be applied as to the plausibility of the assumptions underlying 
this tipping point. This methodology is expected to inform what it would take to overturn study 


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conclusions based on varying assumptions about missing data. A 0 value of delta will be 
considered equivalent to the primary analysis. For this analysis, a series of delta values for Hgb 
decreasing in increments of -0.5 g/dL will be applied (ie, -0.5, -1, -1.5, …). Refer to Appendix 
Section 10.5.5 for further illustration of the tipping point sensitivity analysis. 
Individual patient profiles of Hgb values over time during the randomized controlled Treatment 
Period 1 will be plotted to examine the pattern of missingness. 
In addition, as a supplemental analysis, the MMRM analysis for the primary efficacy endpoint 
will be performed by including all longitudinal Hgb values collected at scheduled visits during 
the randomized Treatment Period 1 (ie, including values collected within 4 weeks after 
transfusion). 
Table 2: 
Estimand Attributes for the Primary and Key Secondary Endpoints 
Endpoint 
Treatment 
Regimens 
Targeted 
Patient 
Populations 
Patient-Level 
Outcome 
Measure 
Handling of 
Intercurrent 
Events 
Population- 
Level 
Summary 
Measure 
Primary: Hgb 
Danicopan vs. 
placebo as 
add-on therapy 
to a C5 inhibitor 
All randomized 
PNH patients 
with CE-EVH 
while on C5 
inhibitor 
treatment 
Change from 
Baseline to 
Week 12 in Hgb 
Analysis 
includes all 
values collected 
at scheduled 
visits while 
patients remain 
on the study 
treatment during 
the randomized 
Treatment 
Period 1. 
Hgb values 
collected within 
4 weeks after 
transfusion will 
be excluded. 
Treatment group 
difference in the 
mean change 
from Baseline to 
Week 12 in Hgb 
Key secondary: 
An Hgb increase 
of ≥ 2 g/dL at 
Week 12 in the 
absence of 
transfusion 
Danicopan vs. 
placebo as 
add-on therapy 
to C5 inhibitor 
All randomized 
PNH patients 
with CE-EVH 
while on C5 
inhibitor 
treatment 
Binary indicator 
(Yes/No) of 
patient 
achieving an 
Hgb increase of 
≥ 2 g/dL at 
Week 12 in the 
absence of 
transfusion 
The criterion is 
defined as 
achieving an 
increase of 
≥ 2 g/dL in Hgb 
from Baseline to 
Week 12 and 
remaining 
transfusion free 
during the 
12-week 
randomized 
Treatment 
Period 1. 
Patients that 
withdraw from 
the study early 
during the 
12-week 
Treatment group 
difference in the 
proportion of 
patients 
achieving the 
criterion 


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Table 2: 
Estimand Attributes for the Primary and Key Secondary Endpoints 
Endpoint 
Treatment 
Regimens 
Targeted 
Patient 
Populations 
Patient-Level 
Outcome 
Measure 
Handling of 
Intercurrent 
Events 
Population- 
Level 
Summary 
Measure 
randomized 
Treatment 
Period 1 will be 
considered as 
not achieving 
the criterion. 
Key secondary: 
TA 
Danicopan vs. 
placebo as add-
on therapy to C5 
inhibitor 
All randomized 
PNH patients 
with CE-EVH 
while on C5 
inhibitor 
treatment 
Binary indicator 
(Yes/No) of 
achieving TA 
through the 
randomized 
Treatment 
Period 1, 
defined as 
remaining 
transfusion free 
and not 
requiring a 
transfusion as 
per protocol- 
specified 
guidelines 
TA is defined as 
remaining 
transfusion free 
and not 
requiring a 
transfusion as 
per protocol- 
specified 
guidelines while 
remaining on 
the study 
treatment during 
the randomized 
Treatment 
Period 1.  
Patients that 
withdraw from 
the study early 
during the 
12-week 
randomized 
Treatment 
Period 1 will be 
considered as 
not achieving 
TA. 
Treatment group 
difference in the 
proportion of 
patients 
achieving TA 
Key secondary: 
FACIT-Fatigue 
scores 
Danicopan vs. 
placebo as add-
on therapy to C5 
inhibitor 
All randomized 
PNH patients 
with CE-EVH 
while on C5 
inhibitor 
treatment 
Change from 
Baseline to 
Week 12 in 
FACIT-fatigue 
scores 
The analysis 
includes all 
values collected 
at scheduled 
visits while 
patients remain 
on the study 
treatment during 
the randomized 
Treatment 
Period 1. 
Values collected 
after transfusion 
will be included. 
Treatment group 
difference in the 
mean change 
from Baseline to 
Week 12 in 
FACIT-fatigue 
scores 
Key secondary: 
absolute 
Danicopan vs. 
placebo as add-
All randomized 
PNH patients 
Change from 
Baseline to 
The analysis 
includes all 
Treatment group 
difference in the 


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Table 2: 
Estimand Attributes for the Primary and Key Secondary Endpoints 
Endpoint 
Treatment 
Regimens 
Targeted 
Patient 
Populations 
Patient-Level 
Outcome 
Measure 
Handling of 
Intercurrent 
Events 
Population- 
Level 
Summary 
Measure 
reticulocyte 
counts 
on therapy to C5 
inhibitor  
with CE-EVH 
while on C5 
inhibitor 
treatment 
Week 12 in 
absolute 
reticulocyte 
counts 
values collected 
at scheduled 
visits while 
patients remain 
on the study 
treatment during 
the randomized 
Treatment 
Period 1.  
Values collected 
after transfusion 
will be included. 
mean change 
from Baseline to 
Week 12 in 
absolute 
reticulocyte 
counts 
Abbreviations: CE-EVH = clinically evident extravascular hemolysis; FACIT = Functional Assessment of Chronic 
Illness Therapy; Hgb = hemoglobin; PNH = paroxysmal nocturnal hemoglobinuria; TA = transfusion avoidance; 
vs. = versus 
7.2.2. 
Secondary Endpoint Analyses 
7.2.2.1. 
Key Secondary Endpoint Analyses 
The 4 key secondary efficacy endpoints of the study are as follows: 
• Difference in proportion of patients with an Hgb increase of ≥ 2 g/dL at Week 12 in 
the absence of transfusion 
• Difference in proportion of patients with RBC TA between danicopan and placebo 
groups during 12 weeks of treatment 
• Difference in changes from Baseline in FACIT-Fatigue scores between danicopan 
and placebo groups at Week 12 
• Difference in changes from Baseline in absolute reticulocyte counts between 
danicopan and placebo groups at Week 12 
The estimand attributes for the key secondary endpoints are described in Table 2. The key 
secondary endpoints will be tested in a hierarchical manner provided that statistical significance 
was declared for the primary endpoint. The tests will be conducted using a closed-testing 
procedure in the rank order specified above so that the lack of significance of a test precludes 
statistical significance of subsequent tests.  
The proportion of patients achieving TA throughout the 12-week randomized Treatment Period 1 
will be compared between treatment groups using the Cochrane-Mantel-Haenszel (CMH) test 
stratified by randomization stratification factors of transfusion history (> 2 or ≤ 2 transfusions 
within 6 months of Screening) and screening Hgb level (< 8.5 or ≥ 8.5 g/dL). The 95% CI for the 
difference in the proportions between the treatment arms will be calculated using the Miettinen 
and Nurminen method (Miettinen, 1985). Patients who withdraw from the study treatment early 
or have missing transfusion occurrence assessment during the 12-week randomized Treatment 


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Period 1 will be considered as not achieving TA for Treatment Period 1. In addition, a supportive 
analysis will be conducted using alternative handling of early discontinuation in TA definition: 
Patients who withdraw from the study due to lack of efficacy during the 12-week randomized 
Treatment Period 1will be considered as not achieving TA for Treatment Period 1. For patients 
who withdraw from the study for any other reason during Treatment Period 1, their data up to the 
time of withdrawal will be used to assess TA. 
The proportion of patients with an Hgb increase of ≥ 2 g/dL at Week 12 in the absence of 
transfusion (defined as achieving an increase of ≥ 2 g/dL in Hgb from Baseline to Week 12 and 
remaining transfusion free during the 12-week randomized Treatment Period 1) will be 
compared between treatment groups via the CMH test, and the 95% CI for difference between 
treatment arms will be produced using the Miettinen and Nurminen method as described above. 
Patients that withdraw from the study treatment early during the 12-week randomized Treatment 
Period 1 or have a missing Hgb value at Week 12 will be considered as not achieving the 
criterion.  
For the endpoints of change from Baseline in FACIT fatigue scores and change from Baseline in 
absolute reticulocyte counts, the longitudinal postbaseline changes collected during 12-week 
randomized Treatment Period 1 will be analyzed using the same MMRM method used for the 
primary endpoint analysis. The model includes the fixed, categorical effects of treatment group, 
study visit, and study visit-by-treatment group interaction, as well as the fixed, continuous 
covariate of baseline value and the randomization stratification factors of transfusion history and 
screening Hgb level. An unstructured covariance matrix will be used to model the within-patient 
errors. If this analysis fails to converge, the following covariance matrix structures will be 
evaluated in the following order until model convergence is met: Toeplitz, first-order 
autoregressive, and compound symmetry. The Kenward-Roger approximation will be used to 
estimate the denominator degrees of freedom. The difference between treatment groups in 
least-square mean estimates at Week 12 and its associated SE will be calculated along with the 
test p-value and 2-sided 95% CI. 
7.2.2.2. 
Other Secondary Endpoint Analyses 
Other secondary endpoints are listed in Section 5.1.3. 
7.2.2.2.1. Other Secondary Endpoints at Week 12 
Patients’ transfusion burden characterized by the number of transfusion instances and the number 
of RBC units transfused during the 12 weeks after the start of study treatment (ie, Treatment 
Period 1) and 12 weeks prior to the initiation of study treatment will be summarized by treatment 
group. Change in the number of transfusion units/instances from 12 weeks prior to 12 weeks 
after the initiation of study treatment will be compared between treatment groups via an 
ANCOVA model. The model will include treatment group and transfusion units/instances from 
12 weeks prior.  
For the endpoints of change from Baseline to Week 12 in total bilirubin, direct bilirubin, PNH 
RBC clone sizes (Types II and III), C3 fragment deposition on PNH RBCs, and LDH, the 
longitudinal changes collected during 12-week randomized Treatment Period 1 will be analyzed 
using the same MMRM method specified in Section 7.2.2.1. Baseline for LDH is defined as the 
average of all available assessments prior to the first dose of study drug. 


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The proportion of patients with Hgb normalization (defined as an Hgb value above lower limit of 
normal reference range) at Week 12 will be summarized and compared between treatment 
groups via the CMH test described in Section 7.2.2.1. Patients with transfusions within 4 weeks 
prior to Week 12 will be considered as not meeting Hgb normalization regardless of the actual 
value observed at Week 12.  
In addition, the proportion of patients who showed an improvement of at least 3 points and the 
proportion of patients who showed an improvement of at least 5 points on the FACIT Fatigue 
scores during the 12-week randomized Treatment Period 1 will be summarized by study visit and 
treatment group. 
7.2.2.2.2. Other Secondary Endpoints at Week 24 
For patients randomized to the danicopan group and entered in Treatment Period 2, the 
proportion of patients with TA during the 12-week Treatment Period 2, the proportion of patients 
with TA through the 24-week Treatment Period 1 and Treatment Period 2, the proportion of 
patients with Hgb stabilization from Week 12 to Week 24, the proportion of patients with an Hgb 
increase of ≥ 2 g/dL at Week 24 in the absence of transfusion, and the proportion of patients with 
Hgb normalization at Week 24 will be summarized, and 95% CI will be provided based on exact 
confidence limits using the Clopper-Pearson method. Hgb stabilization is defined as avoidance 
of more than a 1 g/dL decrease in Hgb levels at Week 24 from Week 12. Patients with 
transfusions within 4 weeks prior to Week 24 will be considered as not meeting Hgb stabilization 
or Hgb normalization regardless of the actual value observed at Week 24.  
For patients randomized to the danicopan group, change in transfusion burden (the number of 
transfusion instances and the number of RBC units transfused) from 24 weeks prior to 24 weeks 
after the initiation of study treatment and change in FACIT Fatigue scores from Baseline to 
Week 24 will be summarized. The mean change estimate and its associated 95% CI will be 
provided. 
For patients randomized to the placebo group and switched to active danicopan during Treatment 
Period 2, the proportion of patients with TA during the 12-week Treatment Period 2, as well as 
the change in transfusion burden from the 12-week randomized Treatment Period 1 to 12-week 
Treatment Period 2, will be summarized.  
For numeric endpoints with longitudinal values collected during Treatment Period 2 (Hgb, 
reticulocyte count, FACIT Fatigue scores, total bilirubin, direct bilirubin, RBC clone sizes 
(Types II and III), C3 fragment deposition on PNH RBCs, and LDH), the longitudinal changes 
from Baseline during the 12-week Treatment Period 2 will be analyzed using MMRM method 
within each treatment arm. The model includes the randomization stratification factors of 
transfusion history and screening Hgb level, study visit, and baseline value. The least-square 
mean estimate for the change from Baseline to Week 24 will be provided with 95% CI. 
For numeric endpoints, the longitudinal least-square mean change profiles throughout the 
24-week Treatment Period 1 and Treatment Period 2 from the MMRM analyses will be graphed 
in spaghetti plots. 
At the time of DBL for the placebo-controlled Treatment Period 1, it is anticipated that some 
patients may still be ongoing during Treatment Period 2 (between Week 12 and Week 24). In 
this scenario, the analysis described above for efficacy endpoints at Week 24 will be conducted 


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on a subset of patients who already reached the end of Treatment Period 2 (either completed or 
discontinued from Treatment Period 2), that is, excluding patients still ongoing during Treatment 
Period 2. 
7.2.3. 
Exploratory Endpoint Analyses 
Exploratory endpoints are listed in Section 5.1.4. 
For EQ-5D-3L scores (visual analog scale and US and UK health state index), EORTC-QLQ-C30 
scores, WPAI:ANS scores, and HRU scores, the observed values and changes from Baseline will 
be summarized descriptively by study visit and treatment group for both Treatment Period 1 and 
Treatment Period 2.   
The longitudinal changes collected during 12-week randomized Treatment Period 1 in 
EQ-5D-3L scores and EORTC-QLQ-C30 scores will also be analyzed using the same MMRM 
method specified in Section 7.2.2.1.   
The proportion of patients who showed an improvement of at least 10 points for the following 
3 subscales from the EORTC-QLQ-C30 will be summarized by study visit and treatment group: 
global health status, physical functioning, and EORTC-Fatigue.  
Refer to Section 10.5 for a more detailed description of the scales and the scoring methods. 
7.2.4. 
Other Efficacy Analyses 
For patients randomized to the placebo group and switched to active danicopan during Treatment 
Period 2, the proportion of patients who had an increase of ≥ 2 g/dL in Hgb from Week 12 to 
Week 24 in the absence of transfusion during the 12-week Treatment Period 2 will be 
summarized.  
All primary, secondary, and exploratory efficacy endpoints will be descriptively summarized for 
the LTE Period, as well as for Treatment Period 1 and Treatment Period 2. 
7.2.5. 
Pharmacokinetic and Pharmacodynamic Analyses 
Predose and postdose PK samples will be taken at the time points as listed in the SoA in the 
study protocol. Individual plasma concentration data for all patients who received at least 1 dose 
of study drug (ie, danicopan) and who have evaluable PK data will be included in the PK 
analysis for danicopan. All individual predose trough concentrations (Ctrough) will be listed, and 
descriptive statistics (number of nonmissing observations [N], arithmetic mean, SD, median, 
coefficient of variation percentage [CV%], minimum, maximum, geometric mean, and geometric 
CV%) will be used to summarize the predose concentrations at each visit. Similarly, all 
individual postdose (2-hour) concentrations will be listed and summarized for each visit using 
descriptive statistics. Population PK modeling will be conducted using data from this study 
and/or in combination with data from other studies. 
PD analyses will be performed for all patients who received at least 1 dose of study drug and 
who have evaluable baseline and postdose PD data. Predose and postdose PD samples will be 
taken at the time points as listed in the SoA in the study protocol and Protocol Table 4. 
Concentrations of the biomarkers (Bb, FD, C3, and free C5) at Baseline and over time, activities 
of APH and CH50 relative to positive control and relative to Baseline, and percentage changes in 


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APH, CH50, and Bb from Baseline will be listed for all individuals and mean ± SD for each 
treatment group will be presented in figures. Descriptive statistics (number of nonmissing 
observations [N], arithmetic mean, SD, median, CV%, minimum, maximum, geometric mean, 
and geometric CV%) will be summarized by study visit and treatment group. 
Assessments of danicopan PK-PD relationships may be explored using data from this study or in 
combination with data from other studies. 
Analyses for population-PK and PK-PD relationships are out of scope of the current SAP and 
will be specified in a separate document. 
7.2.6. 
Handling of Samples With Table-top Hemolysis 
It is possible that a small proportion of central laboratory chemistry samples can undergo in vitro 
erythrocyte lysis or table-top hemolysis (TTH) caused by sample mishandling. This is unrelated 
to hemolysis due to PNH. The reasons for TTH vary and include delayed or improper 
centrifugation and traumatic blood draws. In addition, PIGA-deficient erythrocytes from patients 
with PNH are more susceptible to mechanical lysis than non-PNH erythrocytes (Smith, 1985). If 
such TTH occurs, it results in release of RBC contents including LDH, potassium, and aspartate 
aminotransferase (AST). In contrast to hemolysis in patients with PNH, in which serum 
potassium is normal, for samples affected by TTH, both potassium and LDH are markedly and 
proportionally increased (Goyal, 2015; Oostendorp, 2012). Marked hyperkalemia (defined as 
≥ 6 mmol/L) seen in TTH, but not PNH hemolysis, differentiates TTH (in vitro) from PNH 
hemolysis (in vivo) and is not clinically significant (Hollander-Rodriguez, 2006; 
Kovesdy, 2014).  
For analysis purposes, samples from the central laboratory with serum potassium ≥ 6 mmol/L 
and LDH ≥ 2× upper limit of normal (ULN) will be defined as having TTH. Due to the 
artefactual increase in certain chemistry laboratory values in samples affected by TTH, 
potassium, alanine aminotransferase (ALT), AST, magnesium, phosphorous, and LDH values in 
samples affected by TTH will not be used in the analysis of any efficacy or safety endpoints. 
7.3. 
Safety Analyses 
All safety analyses will be conducted on the SS. For the 12-week randomized Treatment Period 1 
DBL, all safety data available at the time of data cut-off will be provided in patient listings. AEs 
will be coded in MedDRA (version 23.1 or above) and presented by MedDRA SOC and PT. No 
formal hypothesis testing is planned. Unless otherwise specified, Baseline is defined as the last 
available assessment prior to the first dose of study drug. 
7.3.1. 
Study Duration, Treatment Compliance, and Exposure 
Treatment exposure duration (days for a specific period) is calculated as date of the last dose for 
the period − date of the first dose for the period + 1. Treatment exposure duration will be 
summarized by treatment group with descriptive statistics for Treatment Period 1, Treatment 
Period 2, LTE Period, and throughout the entire study treatment. In addition, treatment exposure 
duration will also be summarized by dose level for all patients treated with danicopan. 
Treatment compliance percentage based on actual danicopan dosage is defined as the total dose 
amount of danicopan received divided by the total dose amount of danicopan expected to be 


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received by a patient during a specific period, such as a visit period or a treatment period. 
Specifically,  
Expected total dose amount = assigned dose level × daily frequency × period duration in 
number of days 
Received total dose amount = tablet dosage level × number of tablets received 
where the number of tablets received is calculated as number of tablets dispensed - number of 
tablets returned for a specific period. 
In addition, treatment compliance percentage based on tablet counts only is defined as the total 
number of tablets received divided by the total number of tablets expected to be received by a 
patient during a specific period, such as a visit period or a treatment period.   
Treatment compliance percentage will be calculated for each visit interval with study drug 
accountability assessment and for Treatment Period 1, Treatment Period 2, and LTE Period for 
each patient and will be summarized by treatment group. In addition, the number and proportion 
of patients who had treatment compliance percentage in range by increments of 10% (ie, ≥ 90% 
to ≤ 100%; ≥ 80% to < 90%; ≥ 70% to < 80%, etc) during Treatment Period 1 and Treatment 
Period 2 will also be summarized by treatment group.  
By-patient listings will be produced for study treatment duration and treatment compliance. 
7.3.2. 
Adverse Events 
AEs will be classified by SOC and PT using the latest available version of MedDRA (version 
23.1 or above) and will be reported by treatment group and overall. AEs determined to have 
occurred before the first dose of the study drug will be classified as pretreatment adverse events 
(PTAEs). AEs that occur on or after the first dose of study drug or placebo will be considered 
treatment-emergent adverse events (TEAEs) as described in Section 10.4.7. Analyses of PTAEs 
and TEAEs will be tabulated and presented separately. Patients having multiple AEs within a 
category (eg, overall, SOC, and 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 SS within a cohort 
and overall. Tables will be sorted by alphabetical order of SOC and by descending frequency of 
PT within SOC. PTs with the same frequency will be sorted in alphabetical order. Listings will 
be provided for all TEAEs and PTAEs for the SS. TEAE summaries will be produced for the 
12-week randomized Treatment Period 1, Treatment Period 2, and LTE Period. Any TEAEs 
spanning across treatment periods will be only counted once in the treatment period the event 
started. 
AEs will include the displays described in the following subsections. 
7.3.2.1. 
Overall Summary of AEs 
An overall summary table of TEAEs will be presented using summary statistics (n, %). The 
number of events (n) and the number of patients with events (n, %) will be displayed for the 
following event subcategories: 
• Total number of TEAEs and patients with TEAEs 


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• Related TEAEs 
• Not related TEAEs 
• Grade 1 TEAEs 
• Grade 2 TEAEs 
• Grade 3 TEAEs 
• Grade 4 TEAEs 
• Grade 5 TEAEs 
The number and percentage of patients who withdraw from the study due to an AE, who have 
any TEAE leading to study treatment discontinuation, who have any TEAE leading to study drug 
dose reduction, or who died on the study will be presented. The overall summary described 
above will also be produced separately for SAEs, with the exception of severity grading. 
7.3.2.2. 
AEs and SAEs by SOC and PT 
The number of TEAEs and the number and percentage of patients with events will be presented 
by SOC and PT. Patients are counted once in each SOC and PT. Percentages will be based on the 
total number of patients who received at least 1 dose of study drug (danicopan or placebo) in the 
treatment group. SAEs will be summarized similarly. 
In addition, the summary described above will also be produced for nonserious TEAEs for 
clinicaltrials.gov results posting purpose. 
Additional summary tables stratifying AEs by age, sex, and race will also be provided. For all 
patients received danicopan treatment during the study, TEAEs will also be summarized by the 
dose levels the patients were on when AE started. 
7.3.2.3. 
AEs and SAEs by SOC, PT, and Relationship 
The number of TEAEs and the number and percentage of patients with events will be presented 
by SOC and PT as described above by relationship to study treatment (related or not related). If a 
patient has > 1 occurrence of an AE, the strongest relationship to study treatment will be used in 
the summary table. SAEs will be summarized similarly. 
7.3.2.4. 
AEs by SOC, PT, and Severity 
The number of TEAEs and the number and percentage of patients with events will be presented 
by SOC and PT as described above by severity (Grade 1, 2, 3, 4, or 5). If a patient has 
> 1 occurrence of an AE, the highest grade will be used in the summary table. 
7.3.2.5. 
Deaths, Other SAEs, and Other Significant AEs 
A listing of patient deaths will be produced. 
Events of interest in this study include TEAEs of meningococcal infections and liver enzyme 
elevations. These events of interest will be summarized by treatment group in tabular form. See 
Section 10.4.7 for a list of AE MedDRA terms that will be considered for these summaries. 


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7.3.3. 
Other Safety 
7.3.3.1. 
Analyses for Laboratory Tests 
Observed values and changes from Baseline in numeric central laboratory parameters will be 
summarized descriptively at each visit by treatment group. Baseline is defined as the last 
nonmissing assessment value prior to the first dose of study drug. All laboratory values will be 
classified as normal, below normal, or above normal based on normal ranges supplied by the 
central laboratory. 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 on standardized units will be used.  
Incidence of clinical laboratory abnormalities Grade 3 and above (based on version 5.0 of the 
National Cancer Institute CTCAE) will be summarized. For laboratory tests with CTCAE 
toxicity grades available, laboratory abnormalities will be summarized by worst treatment 
emergent grade. 
Box plots will be presented for the following central laboratory parameters by visit: Hgb, LDH, 
bilirubin (total and direct), creatinine, estimated glomerular filtration rate, AST, ALT, 
gamma-glutamyl transferase, absolute neutrophil count, platelets, D-dimer, and prothrombin 
time/partial thromboplastin time/international normalized ratio. Additionally, scatter plots of the 
worst value after the first study drug versus Baseline will be provided for the aforementioned 
parameters. 
The number and percentage of patients who had postbaseline laboratory values meeting any of 
the following criteria will be summarized by treatment group: 
• ALT > 3× ULN, 5× ULN, and 8× ULN 
• AST > 3× ULN, 5× ULN, and 8× ULN 
• ALT > 3× ULN and total bilirubin > 2× ULN 
• ALT > 3× ULN and total bilirubin > 2× ULN and alkaline phosphatase < 2× ULN 
In addition, the liver enzyme elevation summary described above will also be produced by the 
subgroups of patients who had and did not have ALT > 2× ULN at Baseline. 
All central and local laboratory data will be presented in by-patient listings. 
7.3.3.2. 
Vital Signs 
Absolute values and changes from Baseline in vital signs (BP, HR, RR, and temperature) at each 
visit will be summarized descriptively by treatment group. Baseline is defined as the last 
nonmissing assessment value prior to the first dose of study drug.  
A listing of vital signs will be presented.  
Absolute values and changes from Baseline in weight will be summarized by visit and treatment 
group. A listing of weight will be produced.  
Adverse changes from Baseline in physical examination findings will be classified as AEs and 
analyzed accordingly. 


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7.3.3.3. 
Electrocardiograms 
Descriptive statistics by visit and treatment group will be presented for each ECG parameter 
(including PR interval, QRS duration, RR interval, QT interval, and QTcF interval) value and for 
change from baseline values.  
The number and percentage of patients who had postbaseline abnormal ECG values meeting any 
of the following criteria will be summarized by treatment group: 
• QT and QTcF intervals > 450 milliseconds 
• QT and QTcF intervals > 480 milliseconds 
• QT and QTcF intervals > 500 milliseconds 
• QT and QTcF interval increases from Baseline > 30 milliseconds 
• QT and QTcF interval increases from Baseline > 60 milliseconds 
A by-patient listing of ECG results will be presented. 
7.3.3.4. 
Nondrug Therapies and Procedures 
By-patient listings of nondrug therapies and procedures will be produced. 
7.3.3.5. 
Patients Enrolled Under Local Amendment 
For patients enrolled under local protocol amendments and receiving background therapy 
ravulizumab as IMP in the study, the number and percentage of patients developing ADA and 
antidrug-neutralizing antibodies, where applicable, will be summarized by treatment group and 
overall. A by-patient listing of ADA laboratory results will be produced. 
The number of TEAEs and the number and percentage of patients with events will be presented 
by SOC and PT and by relationship to ravulizumab background therapy (related or not related). 
7.4. 
COVID-19-Related Data Analysis 
The following Coronavirus Disease 2019 (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-19 related or other) will be summarized by treatment group and overall. Similarly, the 
number of subjects with missed study visits and the reasons for missed study visits (COVID-19 
related or other) will be summarized by treatment group and overall.  


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The number of subjects with discontinuation status impacted by COVID-19 will be summarized 
by treatment group and overall.  
Treatment compliance percentage will be summarized for subjects with COVID-19 exposure 
during the study by treatment group 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 PDs specified in 
Section 7.1.2. 


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8. 
INTERIM ANALYSIS 
An interim analysis may be conducted when approximately 75% of patients (planned as N = 63) 
have been randomly assigned to study treatment and have had the opportunity to complete the 
12-week, placebo-controlled, randomized Treatment Period 1 (information fraction = 0.75). The 
purpose of the interim analysis is to evaluate the study for stopping early for efficacy. If 
conducted, the primary endpoint of change in Hgb levels at Week 12, as well as the 4 key 
secondary endpoints, will be evaluated using the alpha-spending methods specified below to 
control family-wise error rate. 
• The evaluation of the primary endpoint at the interim analysis will use the gamma 
family alpha-spending function (Hwang, 1990) with parameter -4. Specifically, the 
alpha level assigned for the primary endpoint at interim is 2-sided 0.018. 
Correspondingly, if the interim analysis is conducted, the nominal significance level 
for the primary endpoint at the final analysis is 2-sided 0.046.  
• The evaluation of key secondary endpoints at the interim analysis will use the gamma 
family alpha-spending function with parameter 1. Specifically, the alpha level 
assigned for key secondary endpoint at interim is 2-sided 0.042. Correspondingly, if 
the interim analysis is conducted, the nominal significance level for key secondary 
endpoints at the final analysis is 2-sided 0.024. 
Due to the hierarchical nature and closed-testing procedure of the primary and key secondary 
endpoints described in Section 7.2.1 and Section 7.2.2 and proper alpha-spending function used 
to control the error rate at a 2-sided 0.05 level for each endpoint, the overall family-wise error 
rate is controlled at a 2-sided 0.05 level across the primary and key secondary endpoints among 
the interim and final full enrollment analyses (Glimm, 2010; Tamhane, 2010). 
The interim analysis DBL will include all data collected up to the data cut-off date mentioned 
above. For the interim analysis on efficacy, 75% of patients (planned as N = 63) who have been 
randomly assigned to study treatment and have had the opportunity to complete the 12-week, 
placebo-controlled, randomized Treatment Period 1 will form the interim efficacy analysis set. 
The efficacy analyses on the primary and key secondary endpoints will be conducted on the 
interim analysis set using the same methods specified in Section 7.2.1 and Section 7.2.2. The 
interim analysis for efficacy is considered successful if the tests of the primary endpoint of 
change in Hgb levels at Week 12 (as assessed by both the re-randomization test and the test 
directly from the MMRM model using the actual treatment assignments) and the key secondary 
endpoints of patients with an Hgb increase of ≥ 2 g/dL at Week 12 in the absence of transfusion 
and patients with TA through the 12-week randomized Treatment Period 1 are all statistically 
significant based on the significance levels specified above.  
If there are more than 63 patients reaching the end of Treatment Period 1 by the interim analysis 
data cut-off described above (e.g., due to multiple patients randomized or completed randomized 
Treatment Period 1 on the same day), the actual number of patients included will be used to 
calculate the actual information fraction and the alpha spending thresholds for interim analysis 
based on the same gamma functions specified above. For example, if N=64 (64/84=76%) 
patients are included in the interim analysis for efficacy, the interim alpha level will be 2-sided 
0.019 for primary endpoint and 0.042 for key secondary endpoints. If interim analysis is 


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conducted, the nominal alpha level for full enrollment analysis will be 0.044 for primary 
endpoint and 0.024 for key secondary endpoints.   
The interim analysis will be conducted under the auspices of an independent DMC. The final 
decision to stop the study enrollment and placebo-controlled Treatment Period 1 for efficacy will 
be made by Alexion after reviewing the recommendation from the DMC. If such decision is 
made, the study will be unblinded and all efficacy, PK, and PD endpoint analyses will be 
conducted using the interim analysis set based on available data collected up to interim DBL cut-
off date. All patients dosed by the interim database cut-off date will form the interim safety 
analysis set. Safety analyses will be conducted based on available data collected up to the cut-off 
date. A CSR will be produced based on the interim analysis results.  
If the interim analysis did not meet the success criteria specified above, the study will continue 
as planned to full enrollment with no modifications.  
The decision on whether to perform the efficacy interim analysis will be based on enrollment 
progression. If full enrollment is already completed or close to complete by the time of the 
interim analysis specified above, the study will go directly to the final full analysis without an 
interim analysis. If the interim analysis for efficacy is not conducted, a full alpha level of 2-sided 
0.05 will be used for the final analysis with full enrollment. 


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9. 
REFERENCES 
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10.1097/00005650-199711000-00002. 
Glimm E, Maurer W, Bretz F. Hierarchical testing of multiple endpoints in group-sequential 
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Goyal T, Schmotzer CL. Validation of hemolysis index thresholds optimizes detection of 
clinically significant hemolysis. Am J Clin Pathol. 2015;143(4):579-83. doi: 
10.1309/ajcpdude1hra0ymr. 
Hollander-Rodriguez JC, Calvert JF, Jr. Hyperkalemia. Am Fam Physician. 2006;73(2):283-90. 
Hwang IK, Shih WJ, De Cani JS. Group sequential designs using a family of type I error 
probability spending functions. Stat Med. 1990;9(12):1439-45. doi: 10.1002/sim.4780091207. 
Kovesdy CP. Management of hyperkalaemia in chronic kidney disease. Nat Rev Nephrol. 
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Mallinckrodt CH, Clark WS, David SR. Accounting for dropout bias using mixed-effects 
models. J Biopharm Stat. 2001;11(1-2):9-21. doi: 10.1081/bip-100104194. 
Mallinckrodt CH, Kaiser CJ, Watkin JG, Molenberghs G, Carroll RJ. The effect of correlation 
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likelihood-based repeated measures compared with last observation carried forward ANOVA. 
Clin Trials. 2004;1(6):477-89. doi: 10.1191/1740774504cn049oa. 
McKinley CE, Richards SJ, Munir T, Griffin M, Mitchell LD, Arnold L, et al. Extravascular 
hemolysis due to C3-loading in patients with PNH treated with eculizumab: Defining the clinical 
syndrome. Blood. 2017;130(Supplement 1):3471. doi: 10.1182/blood.V130.Suppl_1.3471.3471. 
Miettinen O, Nurminen M. Comparative analysis of two rates. Statist Med. 1985;4:213-226. 
https://doi.org/10.1002/sim.4780040211. 
Oostendorp M, van Solinge WW, Kemperman H. Potassium but not lactate dehydrogenase 
elevation due to in vitro hemolysis is higher in capillary than in venous blood samples. Arch 
Pathol Lab Med. 2012;136(10):1262-5. doi: 10.5858/arpa.2011-0319-OA. 
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. 
Ratitch B, O'Kelly M. Clinical Trials with Missing Data: A Guide for Practitioners. Clinical 
Trials with Missing Data: A Guide for Practitioners: Wiley & Sons; 2014. p. i-xxix. 
Ratitch B, O'Kelly M, Tosiello R. Missing data in clinical trials: from clinical assumptions to 
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Shaw JW, Johnson JA, Coons SJ. US valuation of the EQ-5D health states: development and 
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Smith BD. Abnormal erythrocyte fragmentation and membrane deformability in paroxysmal 
nocturnal hemoglobinuria. Am J Hematol. 1985;20(4):337-43. doi: 10.1002/ajh.2830200404. 
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10. 
APPENDICES 
10.1. 
Protocol Schedule of Assessments 
Refer to the protocol for a schedule of assessments. 
10.2. 
Changes from Analyses Specified in the Previous Version of the SAP 
• Re-randomization test is specified as the primary method for treatment comparison for 
primary endpoint analysis in Section 7.2.1 and the treatment comparison test directly 
from the MMRM model is specified as sensitivity analysis according to the US local 
protocol amendment. It is also clarified that the treatment comparison test directly from 
the MMRM model is the primary analysis while the re-randomization test is sensitivity 
analysis for ex-US countries. 
• The efficacy interim analysis success criterion in Section 8 is updated to require 
significance from both the re-randomization test and the test directly from the MMRM 
model for the primary endpoint. 
• Patient profile plots of Hgb values over time are added in Section 7.2.1.5. 
• The definition of TEAE of Interest – Liver Enzyme Elevation is updated in 
Section 10.4.7. 
• A summary of TEAEs by dose level for all patients treated with danicopan is added in 
Section 7.3.2.2. 
• An analysis of patients with an improvement of at least 5 points on the FACIT Fatigue 
scores during the 12-week randomized Treatment Period 1 is added in Section 7.2.2.2.1. 
• Section 10.6 is added to specify additional summary outputs to be produced for Japanese 
subgroup to support PMDA submission.  
 
10.3. 
Sample Size, Power, and Randomization 
The PNH literature indicates that patients with PNH who have received an approved C5 inhibitor 
but are still anemic have Hgb levels, on the average, of 10.5 g/dL (McKinley, 2017). All patients 
entering this study will have an Hgb level of ≤ 9.5 g/dL. A minimum difference of 2 g/dL 
between danicopan and placebo treatments in terms of mean improvement from Baseline after 
12 weeks of treatment is considered clinically meaningful. 
A total of approximately 84 patients will be enrolled into this study and randomized in a 2:1 ratio 
to receive danicopan or placebo. It is anticipated that approximately 10% of patients will 
discontinue prior to the primary endpoint at Week 12. For the primary endpoint of change from 
Baseline to Week 12 in Hgb level, the statistical power using 2-sample t-test is 99% to detect the 
difference in mean change from Baseline of 2 g/dL (alternative hypothesis), assuming the 
2-sided statistical significance level of 0.05 and the SD of 1.6 g/dL, which was estimated from 
results of Study ACH471-101. For the key secondary endpoint of patients with an Hgb increase 
of ≥ 2 g/dL at Week 12 in the absence of transfusion, the study has > 95% power for significant 
difference between treatment groups under a 2-sided 0.05 level, assuming at least 35% of 


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patients in the danicopan arm and 5% of patients in the placebo arm can meet the criterion. For 
the key secondary endpoint of patients with TA, the study has 70% power for significant 
difference between treatment groups, assuming 90% of patients in the danicopan arm and 64% of 
patients in the placebo arm will have TA. For the key secondary endpoint of change from 
Baseline to Week 12 in FACIT-Fatigue scores, the study has 91% power with 2-sample t-test to 
detect 9-point difference between treatment arms in mean change from Baseline, which is 
considered clinically meaningful. The power calculation is based on the assumption of an SD of 
11 for FACIT-Fatigue change, which was observed in Study ALXN1210-PNH-301 in PNH 
patients. The power is 80% based on the SD assumption of 13, which was observed in Study 
ACH471-101. 
The randomization for treatment group assignment will be stratified by transfusion history 
(ie, > 2 or ≤ 2 transfusions within 6 months of Screening), screening Hgb level (ie, < 8.5 and 
≥ 8.5 g/dL) at Screening, and Japanese patients (defined as patients enrolled from 
Japan)/non-Japanese patients. The stochastic dynamic allocation rules (ie, minimization) on the 
stratification factor will be used to assign patients to either danicopan or placebo treatment group 
at a 2:1 ratio through an interactive response technology system on Study Day 1.  
Although all patients will receive the active drug during Treatment Period 2 and LTE Period, the 
treatment arm assignment during Treatment Period 1 will not be unblinded until after DBL 
occurs. 
10.4. 
Technical Specifications for Derived Variables 
The following derived data will be calculated prior to analysis.  
10.4.1. 
Age 
Age will be presented as the number of years between date of birth and the reference date. The 
following ages (in years) may be computed using the formula (reference date − date of 
birth + 1) / 365.25, with reference dates indicated as follows in Table 3: 
Table 3: 
Age and Reference Date 
Age 
Reference Date 
Age at informed consent 
Date of signing ICF 
Age at randomization 
Date of randomization 
Age at PNH diagnosis 
Date of PNH diagnosis 
Age at the first dose of study drug 
Date of the first dose of study drug 
Abbreviations: ICF = informed consent form; PNH = paroxysmal nocturnal hemoglobinuria 
For all 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 month 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. 
10.4.2. 
Disease Duration 
PNH disease duration will be presented as the number of years between the date of the first 
infusion and the date of PNH diagnosis (ie, INT [(date of the first infusion − date of PNH 


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diagnosis + 1) / 365.25] or a similar formula using months and years or years only in the event of 
partial dates for PNH diagnosis). 
10.4.3. 
Definition of Baseline Values 
In general, Baseline is defined as the last nonmissing 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 the first dose date. Baseline for LDH is defined as the average of all 
available assessments prior to the first dose of study drug. 
10.4.4. 
Change From Baseline 
Change in values from Baseline will be calculated as follows.  
Change in value = (subsequent value − baseline value), given that both the baseline value and 
subsequent value are nonmissing. 
10.4.5. 
Percent Change From Baseline 
Percent change in values from Baseline will be calculated as follows. 
% Change in value = (change in value) / (baseline value) × 100  
where change in value = (subsequent value − baseline value), given that the baseline value is 
nonmissing and nonzero and the subsequent value is nonmissing. 
10.4.6. 
Analysis Visits 
Summaries over postbaseline time points or analyses at specific postbaseline time points will be 
performed based on the list of visits described in the SoA in the study protocol. For all 
assessments, the number of days from Baseline will be calculated using the following formula: 
(date of assessment) - (date of first study treatment) + 1. This number of days will be used to 
assign analysis visit. This may not always correspond to the electronic case report form visit. 
All postbaseline records including those that occurred outside the specified protocol windows 
will be assigned to an appropriate analysis visit by using the following scheme and will be 
included in the analysis of the specific assessment. 
For all visits, the lower bound and the upper bound for the analysis visit windows are defined as 
the midpoints of the target date of scheduled visits. If the date of assessment falls between the 
lower bound and the upper bound for a visit as defined in the SoA in the study protocol, then it 
will be assigned to that visit. If the interval separating 2 scheduled visits is an even number of 
days, that middle day will be included in the lower bound of the next visit window. 
For example, for an assessment with a scheduled visit Day 127, a prior scheduled visit Day 113, 
and a subsequent scheduled visit Day 141, the window will start at 120 days from Baseline and 
will go to 133 days from Baseline. 
If only 1 record is within an analysis visit window, the data from that record will be used in the 
analysis. If > 1 record is within the same analysis visit window, the record closest to the 


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midpoint of the interval will be used in the analysis. If 2 records are “tied” before and after the 
middle of the interval, the earlier record will be used in the analysis. 
10.4.7. 
Adverse Events 
The analysis of AEs is described in detail in Section 7.3.2. 
Treatment-emergent AEs (TEAEs) are events with start dates and start times on or after the date 
and time of the first study drug dose. 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 PTAEs.  
Patient percentages are based on the total number of treated patients in the particular treatment 
group. The rate of AEs adjusted by patient exposure is defined as number of events per 100 
patient-years (i.e., number of events x 100/Total patient-years). Total patient-years is summed 
across all individual patient exposure duration. 
The following provides a list of AESIs. In addition, a medical review will be done to ensure that 
no relevant events were missed: 
Meningococcal infections: MedDRA PTs of Meningococcal bacteraemia, Meningitis 
meningococcal, Meningococcal infection, Meningococcal sepsis, Meningococcal carditis, 
Encephalitis meningococcal, Endocarditis meningococcal, Myocarditis meningococcal, Optic 
neuritis meningococcal, and Pericarditis meningococcal.  
Liver enzymes elevation: MedDRA PTs fall under the following two SMQs 
• SMQ Drug related hepatic disorders - severe events only [narrow] [20000007] 
• SMQ Liver related investigations, signs and symptoms [narrow] [20000008] 
10.4.8. 
Concomitant Medications/Therapies 
The analysis of concomitant medications and therapies is described in detail in Section 7.1.4. 
Concomitant medications or therapies are defined as any nonstudy medications or therapies that 
were taken or given while the patient also received study medication. A medication or therapy 
will be considered concomitant if the start date is on or after the date of the first study drug 
infusion, or if the start date is before the first infusion date and the end (stop) date is after the 
first infusion date. If the start date of a medication/therapy is partially or completely missing and 


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the end (stop) date of the medication/therapy does not indicate that it ended prior to first 
infusion, then the determination of the concomitant status will be based on the following: 
• If the start year is after the year of the first study drug infusion, then the 
medication/therapy is concomitant; else, 
• If the start year is the same as the year of the first study drug infusion and 
− The start month is missing, then the medication/therapy is concomitant, else if 
− The start month is present and is the same or after the month of the first study 
drug infusion, then the medication/therapy is concomitant; else, 
• If the start date is completely missing, then the medication/therapy is concomitant. 
All other medications/therapies are considered Prior Medications/Therapies. 
10.5. 
Additional Details on Statistical Methods 
10.5.1. 
FACIT-Fatigue Calculations 
The FACIT-Fatigue questionnaire consists of 13 items scored on a 5-point Likert scale (0 = not 
at all, 4 = very much). The FACIT-Fatigue subscale scoring guideline (version 4) will be used as 
follows: 
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 as long as > 50% of the items were answered. The 
score has a range of 0 through 52 and the higher the score, the better the QoL. 
10.5.2. 
EORTC QLQ-C30 Scoring Calculations 
The EORTC QLQ-C30 (version 3.0) consists of a total of 30 questions related to QoL, scored on 
a 4-point Likert scale for the first 28 questions (1 = not at all, 4 = very much) and scored on a 
scale of 1 (very poor) to 7 (excellent) for the final 2 questions that probe the patient’s overall 
health and QoL. It is composed of both multi-item scales and single-item measures. These 
include 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales 
(fatigue, pain, and nausea and vomiting), a global health status and a number of single items 
assessing additional symptoms (dyspnea, loss of appetite, insomnia, constipation, and diarrhea), 
and financial difficulties. The following Table 4 explains the scoring procedure. 
Table 4: 
Scoring the EORTC QLQ-C30 
EORTC QLQ-C30 Scales 
Scale 
Item Rangea 
Item 
Numbers 
Raw Scoreb 
 
 
 
 
 
Global health status/QoL 
QL2 
6 
29 and 30 
(Q29 + Q30) / 2 
Functional scales 
Physical functioning 
PF2 
3 
1 to 5 
(Q1 + Q2 + Q3 + Q4 + 
Q5) / 5 


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Table 4: 
Scoring the EORTC QLQ-C30 
EORTC QLQ-C30 Scales 
Scale 
Item Rangea 
Item 
Numbers 
Raw Scoreb 
Role functioning 
RF2 
3 
6 and 7 
(Q6 + Q7) / 2 
Emotional functioning 
EF 
3 
21 to 24 
(Q21 + Q22 + Q23 + 
Q24) / 4 
Cognitive functioning 
CF 
3 
20 and 25 
(Q20 + Q25) / 2 
Social functioning 
SF 
3 
26 and 27 
(Q26 + Q27) / 2 
Symptom scales 
Fatigue 
FA 
3 
10, 12, and 18 
(Q10 + Q12 + Q18) / 3 
Nausea and vomiting 
NV 
3 
14 and 15 
(Q14 + Q15) / 2 
Pain 
PA 
3 
9 and 19 
(Q9 + Q19) / 2 
Dyspnea 
DY 
3 
8 
Q8 
Insomnia 
SL 
3 
11 
Q11 
Appetite loss 
AP 
3 
13 
Q13 
Constipation 
CO 
3 
16 
Q16 
Diarrhea 
DI 
3 
17 
Q17 
Financial difficulties 
FI 
3 
28 
Q28 
a Item range is the difference between the possible maximum and the minimum response to individual items. 
b Raw score is the mean of the component items. 
Abbreviations: EORTC = European Organization for Research and Treatment of Cancer; QLQ-C30 = Quality of 
Life Questionnaire-Core 30 Scale; QoL = Quality of Life 
Once the raw scores are calculated, a linear transformation from 0 through 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% through 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 so long as > 50% of the items were answered. Thus, 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. 
10.5.3. 
EQ-5D-3L Scoring Calculations 
The EQ-5D-3L essentially consists of 2 pages - the EQ-5D descriptive system (page 2) and the 
EuroQoL visual analog scale (EQ VAS; page 3).  
10.5.3.1. 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 US general population will be applied 
using individual health profiles. This scoring algorithm was derived from time tradeoff 


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assessments of EQ-5D health states made by a population sample of some 4000 US 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 5. 
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 5: 
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 
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 6. 
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 6: 
Definition for Variables Used in Calculating Health State Index Using UK 
Population Estimates 
Variable 
Definition 
a 
Constant: associated with any move away from full health. a=1 if any of the responses to the 5 
domains is Level 2 or 3; a=0 if responses to all the 5 domains are Level 1. 
 
MO 
1 if mobility is Level 2; 2 if mobility is Level 3; 0 otherwise 
SC 
1 if self-care is Level 2; 2 if self-care is Level 3; 0 otherwise 
UA 
1 if usual activities are Level 2; 2 if usual activities are Level 3; 0 otherwise 
PD 
1 if pain/discomfort is Level 2; 2 if pain/discomfort is Level 3; 0 otherwise 
AD 
1 if anxiety/depression is Level 2; 2 if anxiety/depression is Level 3; 0 otherwise 
 
M2 
1 if mobility is Level 3; 0 otherwise 
S2 
1 if self-care is Level 3; 0 otherwise 
U2 
1 if usual activities are Level 3; 0 otherwise 
P2 
1 if pain/discomfort is Level 3; 0 otherwise 


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Table 6: 
Definition for Variables Used in Calculating Health State Index Using UK 
Population Estimates 
Variable 
Definition 
A2 
1 if anxiety/depression is Level 3; 0 otherwise 
 
N3 
1 if any dimension is Level 3; 0 otherwise 
10.5.3.2. EuroQoL Visual Analog Scale 
The EQ VAS records the respondent’s self-rated health on a vertical, visual analog scale where 
the endpoints are labeled “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, the number written in 
the box will be used for VAS. 
10.5.4. 
SAS Code for MMRM Analysis 
The main analysis method for the primary endpoint of change from Baseline to Week 12 in Hgb 
and several numeric secondary endpoints is the MMRM analysis. The basic Statistical Analysis 
Software® (SAS®) code for the MMRM analysis of change in Hgb is given by: 
proc mixed data = ADEFF method = reml; 
class subjid trt01pn avisitn; 
model chg = trt01pn avisitn trt01pn * avisitn base txstrata / ddfm = kr solution; 
repeated avisitn / type = un subject = subjid; 
lsmeans trt01pn * avisitn / cl diff; 
run; 
where subjid is the patient identifier, trt01pn is the randomized treatment group, avisitn is the 
visit variable, base is the value at Baseline, txstrata is the randomization stratification factor of 
transfusion history, and chg is the visit-wise change from Baseline in Hgb. 
10.5.5. 
SAS Code for Tipping Point Sensitivity Analysis 
The following illustrates the tipping point sensitivity analysis for the primary endpoint of change 
from Baseline to Week 12 in Hgb where a search is conducted for a tipping point that reverses 
the study conclusion from being favorable to active danicopan to being unfavorable. For the 
tipping point sensitivity analysis, the missing data mechanism for the missing change from 
baseline values at Week 12 will be MNAR.  
Markov Chain Monte Carlo imputation method will first be used to fill in the intermittent 
missing values under the assumption of MAR and generate a monotone missing data pattern 
(eg, 100 datasets will be generated). Below is sample code: 
proc mi data = ADEFF out = mono seed = 123 nimpute = 100; 
by trt01pn; 


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mcmc impute = monotone; 
var base Week1 - Week12; 
run; 
where trt01pn is the randomized treatment group, base is the Hgb value at Baseline, and 
Week 1 − Week 12 are the changes from Baseline in Hgb at the scheduled postbaseline visits 
from Week 1 to Week 12.  
Subsequently, for a specific shift parameter value of delta, imputations are performed for missing 
change observations at all visits sequentially for all patients by sampling from an MAR-based MI 
model including the variables of randomized treatment group, baseline value, and values 
observed at all scheduled visits during the 12-week randomized Treatment Period 1, then 
applying delta adjustments at each visit for patients treated in the danicopan arm. The following 
is a partial SAS code for the multiple imputation analysis for a specified shift parameter value of 
delta at Weeks X and Y: 
proc mi data = mono out = outmi seed = 123 nimpute = 1; 
by _imputation_; 
class trt01pn; 
monotone method = reg; 
var trt01pn base Week 1 – Week12; 
mnar adjust (Week X / shift = delta adjustobs = (trt01pn = 'danicopan')); 
mnar adjust (Week Y / shift = delta adjustobs = (trt01pn = 'danicopan')); 
run; 
Once completed datasets are generated, each of the 100 imputed datasets will then be analyzed 
separately using the MMRM model specified for the primary endpoint analysis (refer to 
Section 10.5.4 for SAS code), and inferences from each complete dataset will be combined via 
PROC MIANALYZE procedure to obtain an overall test statistic for the specified shift 
parameter value of delta. 
proc mianalyze data = diff2; 
by avisitn; 
modeleffects estimate; 
stderr; 
run; 
Multiple shift parameter values will be tested until the inference concludes that statistical 
significance disappears. In the tipping point analysis for the primary endpoint, a series of delta 
values for Hgb decreasing in increments of -0.5 g/dL will be applied (ie, -0.5, -1, -1.5, …). 


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10.6. 
Additional Analyses for Japanese Subgroup 
In addition to the subgroup analysis described in Section 7.2.1.2, the following summary outputs 
will be produced for the subgroup of Japanese patients. Unless otherwise specified, the endpoints 
and variables definitions and methods used for these outputs will be the same as described in 
Section 7. These outputs may be used to support PMDA submission but will not be required to 
be included in study CSR. 
• Summaries of study disposition, protocol deviations, demographics and baseline 
characteristics, disease characteristics, medical history, prior and concomitant 
medications, and C5 inhibitor background therapy as described in Section 7.1. 
• Summaries of danicopan PK concentration and PD biomarkers over time as described in 
Section 7.2.5 for the subgroup of Japanese patients and the subgroup of non-Japanese 
patients. 
• Summary of study drug exposure as described in Section 7.3.1 . 
• Summaries of AE overview; TEAEs and SAEs by SoC and preferred term; TEAEs by 
severity; TEAEs by relationship to study treatment; TEAEs leading to study drug 
discontinuation; TEAEs leading to study drug dose reduction; TEAEs of Interest 
(meningococcal infections and liver enzyme elevations) as described in Section 7.3.2. 
• Summary of patients with postbaseline laboratory values meeting the liver enzyme 
elevation criteria as described in Section 7.3.3.1.