A Phase III, Multicenter, Single Arm Study Evaluating the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Crovalimab in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) Not Previously Treated With Complement Inhibition
Phase: PHASE3
Conditions: Paroxysmal Nocturnal Hemoglobinuria
Sponsor: Hoffmann-La Roche

 
Official Title: 
A Phase III, Multicenter, Single Arm Study Evaluating the Efficacy, 
Safety, Pharmacokinetics, and Pharmacodynamics of Crovalimab in 
Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) Not 
Previously Treated With Complement Inhibition 
NCT Number: 
NCT04654468 
Document Date: 
Protocol Amendment Version 5: 23-November-2022 
 
 
 

CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Crovalimab
F. Hoffmann-La Roche Ltd 
Protocol YO42311, Version 5 
PROTOCOL 
TITLE: 
A PHASE III, MULTICENTER, SINGLE ARM STUDY 
EVALUATING THE EFFICACY, SAFETY, 
PHARMACOKINETICS, AND 
PHARMACODYNAMICS OF CROVALIMAB IN 
PATIENTS WITH PAROXYSMAL NOCTURNAL 
HEMOGLOBINURIA (PNH) NOT PREVIOUSLY 
TREATED WITH COMPLEMENT INHIBITION 
PROTOCOL NUMBER: YO42311 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
Not Applicable 
IND NUMBER: 
Not Applicable 
NCT NUMBER: 
NCT04654468 
TEST PRODUCT: 
Crovalimab (RO7112689) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
APPROVAL: 
See electronic signature and date stamp on the final 
page of this document. 

 
Crovalimab
F. Hoffmann-La Roche Ltd 
2/Protocol YO42311, Version 5 
PROTOCOL HISTORY 
 
Protocol 
Version 
Date Final 
5 
See electronic date stamp on the 
final page of this document. 
4 
14 February 2022 
3 
13 August 2021 
2 
5 November 2020 
1 
1 June 2020 

 
Crovalimab
F. Hoffmann-La Roche Ltd 
3/Protocol YO42311, Version 5 
PROTOCOL AMENDMENT, VERSION 5: 
RATIONALE 
Protocol YO42311 has been primarily amended to reflect changes associated with the 
re-estimated half-life of crovalimab.   
Based on the emergent pharmacokinetic (PK) data, the terminal half-life of crovalimab 
was re-estimated from approximately 30 days to approximately 59 days.  The population 
PK model was updated due to the availability of the primary analysis data from the 
Phase III Study YO42311 (this study) in patients with paroxysmal nocturnal 
hemoglobinuria (PNH).  Model parameters were re-estimated using pooled PK data from 
treatment-naive patients with PNH from the Phase I/II Study BP39144, and 
Study YO42311.  The update in the half-life estimate was driven by a more informative 
PK sampling that was implemented in Study YO42311 and a larger dataset that was 
available for the model update (Sections 1.2.2.2).   
Changes to the protocol based on the above rationale for the re-estimated half-life are 
summarized below. 
 
The safety follow-up period has been extended from 24 to 46 weeks (approximately 
10.5 months) to maintain 5.5 half-lives of follow-up.  As a result, a safety telephone 
call has been added to collect safety information 46 weeks (approximately 
10.5 months) after the final dose of crovalimab.  The safety telephone call 46 weeks 
after the final dose of crovalimab will assess adverse events and changes to 
concomitant medications.  A urine pregnancy test will be performed by the patient 
no more than two days before the safety telephone call (female patients of 
childbearing potential only), and the patient should report the result during the safety 
telephone call (Sections 3.1, 4.4, 4.5, 4.5.2, 4.5.8, 4.6.1, 5.1, 5.1.1.1, 5.3.1, 5.4.2.2, 
and 5.6; Appendices 1 and 2). 
 
Section 3.2 has been simplified to remove subsections and provide clear definition 
of the end of this study and length of the study.  The expected end of the study and 
total length of the study have been extended to 6 years and 7 years, respectively, as 
a consequence of the amended safety follow-up period (Section 3.2). 
 
The time frame in which female patients of childbearing potential must remain 
abstinent or use contraception has been extended from 6 months to 46 weeks 
(approximately 10.5 months) after the final dose of crovalimab (Section 4.1.1). 
 
The time frame for the exclusion of patients who are intending to become pregnant 
has been extended from 6 months to 46 weeks (approximately 10.5 months) after 
the final dose of crovalimab (Section 4.1.2). 
 
The reporting period for pregnancies has been updated from 6 months to 46 weeks 
(approximately 10.5 months) after the final dose of crovalimab (Section 5.4.3.1). 
Additional changes to the protocol, along with a rationale for each change, are 
summarized below: 
 
The efficacy objectives were clarified to state that lactate dehydrogenase values 
from the central laboratory will be utilized (Sections 2.1.3 and 6.4.1). 

 
Crovalimab
F. Hoffmann-La Roche Ltd 
4/Protocol YO42311, Version 5 
 
The exploratory immunogenicity objective has been clarified to include 
pharmacodynamic endpoints (Sections 2.4 and 6.7).  
 
Text has been added so that the Sponsor may propose and conduct exploratory 
substudies associated with the YO42311 study protocol; each substudy will be 
introduced in a separate substudy protocol (Section 3.1). 
 
Requirements regarding vaccination currency against Neisseria meningitidis have 
been clarified (Sections 4.1.1 and 4.5.5.1; Appendix 1). 
 
It has been clarified that crovalimab, which is required by the patient for continued 
study participation, could be shipped directly to the patient under certain 
circumstances (Section 4.3.2.1). 
 
Text has been added to specify that, for transfusions that occur during the study 
period, the signs and symptoms of anemia associated with the patient's need for a 
transfusion, the hemoglobin results, the administration of the transfusion, and the 
number of units transfused should be documented in the electronic Case Report 
Form (Section 4.5.7). 
 
Personal identifiable information (i.e., name and telephone number) for the Medical 
Monitors has been removed from the protocol.  Medical Monitor contact information 
has been replaced with a sentence indicating that this information will be provided 
separately to sites (Section 5.4.1). 
 
A description of the technical and organizational security measures taken to protect 
personal data has been added to align with current guidelines (Section 8.4). 
 
Due to certain local requirements and an alignment of Sponsor process, it has been 
clarified that summaries of clinical study results may be available in health authority 
databases for public access in addition to redacted Clinical Study Reports 
(Sections  9.6).   
 
Additional minor changes have been made to improve clarity and consistency. 
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.

 
Crovalimab
F. Hoffmann-La Roche Ltd 
5/Protocol YO42311, Version 5 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 12 
PROTOCOL SYNOPSIS .................................................................................... 13 
1. 
BACKGROUND ............................................................................ 23 
1.1 
Background on Paroxysmal Nocturnal Hemoglobinuria ........... 23 
1.2 
Background on Crovalimab ..................................................... 25 
1.2.1 
Molecule and Nonclinical Data ................................................. 25 
1.2.2 
Clinical Experience with Crovalimab ........................................ 26 
1.2.2.1 
Safety Data from Study BP39144 ............................................ 28 
1.2.2.2 
Pharmacokinetic and Pharmacodynamic Data from 
Study BP39144 and YO42311 ................................................. 31 
1.2.2.3 
Immunogenicity and Anti-Drug Antibody from 
Study BP39144 ........................................................................ 32 
1.2.2.4 
Efficacy Results from Study BP39144 ..................................... 32 
1.3 
Study Rationale and Benefit Risk Assessment ....................... 34 
1.3.1 
Study Rationale and Benefit .................................................... 34 
1.3.2 
Risk .......................................................................................... 35 
1.3.3 
Benefit and Risk ....................................................................... 35 
1.3.3.1 
Benefit and Risk with COVID-19 .............................................. 35 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 36 
2.1 
Efficacy Objectives .................................................................. 36 
2.1.1 
Primary Efficacy Objective ....................................................... 36 
2.1.2 
Secondary Efficacy Objective .................................................. 36 
2.1.3 
Other Efficacy Objective .......................................................... 37 
2.1.4 
Supportive Historical Objective ................................................ 37 
2.2 
Safety Objective ....................................................................... 37 
2.3 
Pharmacokinetic Objectives..................................................... 38 
2.4 
Immunogenicity Objectives ...................................................... 38 
2.5 
Biomarker Objective ................................................................ 38 
2.6 
Health Status Utility Objective .................................................. 39 
3. 
STUDY DESIGN ........................................................................... 39 
3.1 
Description of the Study ........................................................... 39 

 
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3.2 
End of Study and Length of Study ........................................... 40 
3.3 
Rationale for Study Design ...................................................... 41 
3.3.1 
Rationale for Crovalimab Dose and Schedule ......................... 41 
3.3.2 
Rationale for Patient Population .............................................. 41 
3.3.2.1 
Primary Population .................................................................. 41 
3.3.2.2 
Inclusion of Adolescents .......................................................... 41 
3.3.3 
Rationale for Co-Primary Endpoints ........................................ 41 
3.3.4 
Rationale for Biomarker Assessments ..................................... 42 
3.3.5 
Rationale for Patient-Reported Outcomes ............................... 43 
4. 
MATERIALS AND METHODS ...................................................... 43 
4.1 
Patients .................................................................................... 43 
4.1.1 
Inclusion Criteria ...................................................................... 43 
4.1.2 
Exclusion Criteria ..................................................................... 45 
4.2 
Method of Treatment Assignment ............................................ 47 
4.3 
Study Treatment ...................................................................... 47 
4.3.1 
Study Treatment Formulation, Packaging, and Handling ......... 47 
4.3.1.1 
Crovalimab............................................................................... 47 
4.3.2 
Study Treatment Dosage, Administration, and Compliance .... 48 
4.3.2.1 
Crovalimab............................................................................... 48 
4.3.3 
Rescue Dosing: Crovalimab IV ................................................ 50 
4.3.4 
Investigational Medicinal Product Handling and 
Accountability ........................................................................... 50 
4.3.5 
Continued Access to Crovalimab ............................................. 51 
4.4 
Concomitant Therapy .............................................................. 51 
4.4.1 
Permitted Therapy ................................................................... 51 
4.4.2 
Cautionary Therapy ................................................................. 52 
4.4.2.1 
Medications Given with Precaution due to Effects Related 
to CYP Enzymes ...................................................................... 52 
4.4.2.2 
Herbal Therapies ..................................................................... 52 
4.4.3 
Prohibited Therapy .................................................................. 52 
4.5 
Study Assessments ................................................................. 52 
4.5.1 
Informed Consent Forms and Screening Log .......................... 53 
4.5.2 
Medical History, Baseline Conditions, Concomitant 
Medication, and Demographic Data ......................................... 53 

 
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4.5.3 
Physical Examinations ............................................................. 54 
4.5.4 
Vital Signs ................................................................................ 54 
4.5.5 
Immunizations .......................................................................... 54 
4.5.5.1 
N. meningitidis, H. influenzae Type B, and S. pneumonia 
Vaccinations ............................................................................ 54 
4.5.5.2 
Other Vaccinations .................................................................. 55 
4.5.6 
Breakthrough Hemolysis .......................................................... 55 
4.5.7 
Transfusions ............................................................................ 55 
4.5.8 
Laboratory, Biomarker, and Other Biological Samples ............ 56 
4.5.9 
Electrocardiograms .................................................................. 58 
4.5.10 
Patient-Reported Outcomes .................................................... 59 
4.5.10.1 
Data Collection Methods for Patient-Reported Outcomes ....... 59 
4.5.10.2 
Description of Patient-Reported Outcome Instruments ............ 60 
4.6 
Treatment, Patient, Study, and Site Discontinuation ................ 62 
4.6.1 
Study Treatment Discontinuation ............................................. 62 
4.6.2 
Patient Discontinuation from the Study .................................... 63 
4.6.3 
Study Discontinuation .............................................................. 63 
4.6.4 
Site Discontinuation ................................................................. 63 
5. 
ASSESSMENT OF SAFETY ......................................................... 64 
5.1 
Safety Plan .............................................................................. 64 
5.1.1 
Risks Associated with Crovalimab ........................................... 64 
5.1.1.1 
Meningococcal Infection .......................................................... 64 
5.1.1.2 
Type III Hypersensitivity Reactions Associated with 
Drug-Target-Drug Complex Formation .................................... 65 
5.1.1.3 
Other Hypersensitivity Reactions and Infusion-Related 
Reactions ................................................................................. 66 
5.1.1.4 
Injection-Site Reactions ........................................................... 66 
5.1.1.5 
Other Infections ....................................................................... 66 
5.1.1.6 
Immunogenicity ........................................................................ 66 
5.1.1.7 
Treatment Discontinuation from Crovalimab without 
Switching to Another Complement Inhibitor ............................. 66 
5.1.2 
Management of Patients Who Experience Adverse Events ..... 67 
5.1.2.1 
Dose Modifications .................................................................. 67 
5.1.2.2 
Treatment Interruption ............................................................. 68 

 
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5.1.2.3 
Management Guidelines .......................................................... 68 
5.2 
Safety Parameters and Definitions .......................................... 71 
5.2.1 
Adverse Events ........................................................................ 71 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) .................................................................................. 71 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ...................................................... 72 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................... 73 
5.3.1 
Adverse Event Reporting Period .............................................. 73 
5.3.2 
Eliciting Adverse Event Information ......................................... 73 
5.3.3 
Assessment of Severity of Adverse Events ............................. 73 
5.3.4 
Assessment of Causality of Adverse Events............................ 74 
5.3.5 
Procedures for Recording Adverse Events .............................. 75 
5.3.5.1 
Infusion-Related and Injection-Site Reactions ......................... 75 
5.3.5.2 
Diagnosis versus Signs and Symptoms ................................... 75 
5.3.5.3 
Adverse Events That Are Secondary to Other Events ............. 76 
5.3.5.4 
Persistent or Recurrent Adverse Events .................................. 76 
5.3.5.5 
Abnormal Laboratory Values ................................................... 76 
5.3.5.6 
Abnormal Vital Sign Values ..................................................... 77 
5.3.5.7 
Abnormal Liver Function Tests ................................................ 78 
5.3.5.8 
Deaths ..................................................................................... 78 
5.3.5.9 
Preexisting Medical Conditions ................................................ 78 
5.3.5.10 
Lack of Efficacy or Worsening of Paroxysmal Nocturnal 
Hemoglobinuria ........................................................................ 79 
5.3.5.11 
Hospitalization or Prolonged Hospitalization ............................ 79 
5.3.5.12 
Cases of Overdose, Medication Error, Drug Abuse, or 
Drug Misuse ............................................................................. 80 
5.3.5.13 
Patient-Reported Outcome Data .............................................. 82 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................... 82 
5.4.1 
Medical Monitors and Emergency Medical Contacts ............... 82 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest .......................................... 83 
5.4.2.1 
Events That Occur prior to Study Drug Initiation ...................... 83 

 
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5.4.2.2 
Events That Occur after Study Drug Initiation .......................... 83 
5.4.3 
Reporting Requirements for Pregnancies ................................ 83 
5.4.3.1 
Pregnancies in Female Patients .............................................. 83 
5.4.3.2 
Abortions.................................................................................. 84 
5.4.3.3 
Congenital Anomalies/Birth Defects ........................................ 84 
5.5 
Follow-Up of Patients after Adverse Events............................. 84 
5.5.1 
Investigator Follow-Up ............................................................. 84 
5.5.2 
Sponsor Follow-Up .................................................................. 85 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period ...................................................................... 85 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............... 85 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ......... 85 
6.1 
Determination of Sample Size ................................................. 85 
6.2 
Summaries of Conduct of Study .............................................. 87 
6.3 
Summaries of Demographic and Baseline Characteristics ...... 87 
6.4 
Efficacy Analyses ..................................................................... 87 
6.4.1 
Primary Estimand.................................................................... 87 
6.4.2 
Primary Efficacy Analyses ....................................................... 88 
6.4.2.1 
Hemolysis Control .................................................................... 88 
6.4.2.2 
Transfusion Avoidance ............................................................ 89 
6.4.3 
Secondary Efficacy Analyses ................................................... 89 
6.4.4 
Other Efficacy Analyses ........................................................... 90 
6.4.5 
Supportive Historical Analyses ................................................ 90 
6.4.6 
Handling Missing Data ............................................................. 91 
6.5 
Safety Analyses ....................................................................... 91 
6.6 
Pharmacokinetic Analyses ....................................................... 92 
6.7 
Immunogenicity Analyses ........................................................ 93 
6.8 
Biomarker Analyses ................................................................. 93 
6.9 
Health Status Utility Analyses .................................................. 93 
6.10 
Interim Analyses ...................................................................... 93 
7. 
DATA COLLECTION AND MANAGEMENT ................................. 93 
7.1 
Data Quality Assurance ........................................................... 93 

 
Crovalimab
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11/Protocol YO42311, Version 5 
 
 
LIST OF FIGURES 
Figure 1 
Study BP39144 Schema ............................................................. 27 
Figure 2 
Study Design ............................................................................... 39 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Activities ................................................................ 105 
Appendix 2 
Schedule of Activities for Patients Who Discontinue 
Crovalimab and Switch to Other C5 Inhibitors .......................... 115 
Appendix 3 
Anaphylaxis Precautions ........................................................... 116 
Appendix 4 
Major Adverse Vascular Events (MAVEs) ................................. 117 

 
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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE: 
A PHASE III, MULTICENTER, SINGLE ARM STUDY 
EVALUATING THE EFFICACY, SAFETY, 
PHARMACOKINETICS, AND 
PHARMACODYNAMICS OF CROVALIMAB IN 
PATIENTS WITH PAROXYSMAL NOCTURNAL 
HEMOGLOBINURIA (PNH) NOT PREVIOUSLY 
TREATED WITH COMPLEMENT INHIBITION 
PROTOCOL NUMBER: YO42311 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
Not Applicable 
IND NUMBER: 
Not Applicable 
NCT NUMBER: 
NCT04654468 
TEST PRODUCT: 
Crovalimab (RO7112689) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator's Name  (print) 
 
 
 
 
 
Principal Investigator's Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form to your local study monitor. 
 

 
Crovalimab
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PROTOCOL SYNOPSIS
TITLE: 
A PHASE III, MULTICENTER, SINGLE ARM STUDY EVALUATING 
THE EFFICACY, SAFETY, PHARMACOKINETICS, AND 
PHARMACODYNAMICS OF CROVALIMAB IN PATIENTS WITH 
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) NOT 
PREVIOUSLY TREATED WITH COMPLEMENT INHIBITION 
PROTOCOL NUMBER: 
YO42311 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
Not Applicable 
IND NUMBER: 
Not Applicable 
NCT NUMBER: 
NCT04654468 
TEST PRODUCT: 
Crovalimab (RO7112689) 
PHASE: 
III 
INDICATION: 
Paroxysmal nocturnal hemoglobinuria (PNH) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
OBJECTIVES AND ENDPOINTS 
This is a Phase III, multicenter, single-arm study designed to evaluate the efficacy, safety, 
pharmacokinetics, pharmacodynamics, and health status of crovalimab in patients with 
paroxysmal nocturnal hemoglobinuria (PNH) aged 12 years and 40 kg who have not been 
previously treated with a complement-inhibitor therapy. 
Specific objectives and corresponding endpoints for the study are outlined below. 
EFFICACY OBJECTIVES 
PRIMARY EFFICACY OBJECTIVE 
The primary efficacy objective for this study is to evaluate the effect of crovalimab based on 
crossing the threshold of the co-primary endpoint hemolysis control and the superiority 
intra patient assessment of the co-primary endpoint of transfusion avoidance (TA) on the basis 
of following endpoints: 
 
Mean proportion of patients with hemolysis control, measured by 
lactate dehydrogenase (LDH) 1.5 upper limit of normal (ULN) from Week 5 through 
Week 25 (as measured at the central laboratory) 
 
The difference in the proportion of patients who achieve TA from baseline through Week 25 
(after 24 weeks on treatment) and proportion of patient who were TA within 24 weeks prior 
to screening. 
TA is defined as patients who are packed red blood cell (pRBC) transfusion-free and do 
not require transfusion per protocol-specified guidelines. 
TA within 24 weeks prior to screening is based on the pRBC transfusion history in the 
medical records. 
 
SECONDARY EFFICACY OBJECTIVE 
The secondary efficacy objectives for this study are to evaluate the efficacy of crovalimab on the 
basis of the following endpoints: 

 
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Proportion of patients with breakthrough hemolysis (BTH) from baseline through Week 25
BTH is defined as at least one new or worsening symptom or sign of intravascular 
hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], 
anemia [hemoglobin 10 g/dL], a major adverse vascular event [MAVE; including 
thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated 
LDH 2 ULN after prior reduction of LDH to 1.5 ULN on treatment. 
 
Proportion of patients with stabilized hemoglobin from baseline through Week 25  
Stabilized hemoglobin is defined as avoidance of a  2 g/dL decrease in hemoglobin 
level from baseline, in the absence of transfusion. 
 
Mean change from baseline to Week 25 in fatigue as assessed through the use of the 
Functional Assessment of Chronic Illness Therapy Fatigue (adults aged 18 years) 
 
OTHER EFFICACY OBJECTIVES 
The other efficacy objective for this study is to evaluate the efficacy of crovalimab on the basis 
of the following endpoints: 
 
Total number of units of pRBCs transfused per patient from baseline to Week 25 
 
Mean proportion of patients with central LDH 1 ULN from Week 5 through Week 25 (as 
measured at the central laboratory) 
 
Mean LDH levels from baseline to Week 25 by visit  
 
Percent change from baseline to Week 25 in central LDH levels by visit 
 
Time from baseline to first reach of central LDH 1 ULN  
 
Time from baseline to first reach of central LDH 1.5 ULN 
 
Proportion of patients who reach a hemoglobin level of at least 10 g/dL, without subsequent 
decrease below 9 g/dL, in the absence of a transfusion from baseline to Week 25 
 
Proportion of patients with MAVE from baseline to Week 25 
 
Mean change from baseline to Week 25 in Physical Function, Role Function, and Global 
Health Status/Quality of Life scales of the European Organisation for Research and 
Treatment of Cancer Quality of Life-Core 30 Questionnaire (for adults aged 18 years) 
 
Mean change from baseline to Week 25 in Pediatric Quality of Life (PedsQL) 
Multidimensional Fatigue Scale, and the Physical Functioning scale of the PedsQL Core 
(for adolescents aged 12 17 years) 
 
Proportion of patients with a 
 5 point improvement from baseline in the FACIT-Fatigue at 
Week 25 (for adults aged 
 18 years) 
 
SUPPORTIVE HISTORICAL OBJECTIVES 
The supportive historical objectives are to characterize the efficacy of best supportive care and 
intra-patient comparison based on the following endpoints: 
 
Mean LDH, and hemoglobin within 24 weeks prior to screening 
 
Mean number of blood transfusion and number of units of pRBC transfused within 24 weeks 
prior to screening 
 
Proportion of patients who had MAVE as documented in the medical records within 
24 weeks prior to screening 
 
SAFETY OBJECTIVE 
The safety objective for this study is to evaluate the overall safety of crovalimab on the basis of 
the following endpoints: 
 
Incidence and severity of adverse events, with severity determined according to National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), 
Version 5 
 
Change from baseline in targeted vital signs 

 
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Change from baseline in targeted clinical laboratory test results
 
Incidence and severity of injection-site reactions, infusion-related reactions, hypersensitivity, 
and infections (including meningococcal meningitis) 
 
Incidence of adverse events leading to study drug discontinuation 
 
PHARMACOKINETIC OBJECTIVES 
The pharmacokinetic (PK) objective for this study is to evaluate the pharmacokinetics of 
crovalimab on the basis of the following endpoints: 
 
Trough serum concentrations of crovalimab over time 
 
Serum concentrations of crovalimab at specified timepoints 
 
The other PK objective for this study is as follows: 
 
To evaluate potential relationships between drug exposure and the efficacy and safety of 
crovalimab 
 
IMMUNOGENICITY OBJECTIVES 
The immunogenicity objective for this study is to evaluate the immune response to crovalimab 
on the basis of the following endpoint: 
 
Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs during the 
study 
 
The other immunogenicity objective for this study is to evaluate the potential effects of ADA on 
efficacy, safety, PK, and PD endpoints. 
BIOMARKER OBJECTIVE 
The biomarker objective for this study is to identify and/or evaluate biomarkers that can provide 
evidence of crovalimab activity (i.e., pharmacodynamic [PD] biomarkers) on the basis of the 
following endpoints: 
 
Change over time in PD biomarkers, including complement activity measured by a liposome 
immunoassay (LIA) 
 
Change over time in total and free C5 concentration 
 
Observed value and absolute change from baseline to Week 25 in parameters reflecting 
hemolysis (reticulocyte count, free hemoglobin, haptoglobin) 
 
The other biomarker objectives for this study are as follows: 
 
To evaluate the change over time in red cell clone size by flow cytometry and markers from 
the coagulation system (D-dimer) 
 
To evaluate the change over time in additional biomarkers of the complement system and 
markers for intra andextra vascular hemolysis (e.g., C3d on RBCs). 
 
Additionally, the relationship between blood biomarkers and efficacy, safety, pharmacokinetics, 
and immunogenicity will be investigated. 
HEALTH STATUS UTILITY OBJECTIVE 
The health status utility objective for this study is to evaluate health status utility scores of 
adolescent and adult patients treated with crovalimab on the basis of the following endpoint: 
 
Health status of patients according to EuroQoL 5-Dimension Questionnaire, 5-level version 
index based and visual analog scale scores at specified timepoints 
 
STUDY DESIGN 
DESCRIPTION OF STUDY 
This single-arm, multicenter, China Phase III study is designed to evaluate the efficacy, safety, 
PK/PD of crovalimab in patients with PNH, aged 12 years or older, with a body weight 40 kg, 
who have not been previously treated with complement-inhibitor therapy. 

 
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This study will enroll approximately 50 patients with PNH who will be treated with crovalimab for 
at least 24 weeks.  The primary efficacy analysis will take place when all patients have either 
completed 24 weeks of treatment with crovalimab or discontinued from the treatment, whichever 
occurs first.  Patients must have received at least one dose of treatment with crovalimab and 
have at least one central LDH level assessment after the first intravenous (IV) infusion to be 
included in the primary efficacy analysis. 
At screening, all the medical records should be provided to the investigators in the site for 
eligibility check and medical history data collection.  The screening period of the study will be up 
to 28 days in length for each screening.  A maximum of two re-screenings, for a total of three 
screenings, will be allowed.  At screening, LDH testing will be performed for two times with at 
least 2 weeks interval between the measurements by central laboratory. 
An initial IV loading dose will be administered on Week 1 Day 1, followed by four weekly 
crovalimab subcutaneous (SC) doses on Week 1 Day 2, then on Weeks 2, 3 and 4.  
Maintenance dosing will begin at Week 5 and will continue every 4 weeks (Q4W) thereafter, for 
a total of at least 24 weeks of study treatment.  All patients who receive crovalimab as part of 
this study will do so according to a weight-based tiered dosing approach schedule.  
After completing 24 weeks of treatment with crovalimab (i.e., Week 25 visit), patients will be 
allowed to continue crovalimab Q4W until they can switch to an open-label extension study (if 
available), to commercial product, or receive crovalimab as per the Roche Global Policy on 
Continued Access to Investigational Medicinal Products.  
Treatment discontinuation date is defined as the last day the patient receives a dose of 
medication on the study.  All patients who discontinue from crovalimab treatment while on the 
study will return for a safety follow-up site visit 24 weeks after treatment discontinuation and a 
safety telephone call 46 weeks (approximately 10.5 months) after treatment discontinuation.  
If these patients switch to a different C5 inhibitor, they should remain in safety follow-up and be 
monitored. 
Efficacy assessments will include TA, centrally analyzed LDH levels, occurrence of BTH, 
number of blood transfusions, hemoglobin levels, and health-related quality of life outcome 
measures.  Safety assessments will include vital signs, physical examination, blood sample 
analysis for hematological and biochemical abnormalities, urine analysis, and monitoring for 
adverse events, including those of special interest graded per NCI CTCAE v5. 
As a supportive measure, all the medical records including data of PNH history should be 
provided to the investigators in the site for eligibility check and medical history data collection.  
NUMBER OF PATIENTS 
Approximately 50 patients with PNH will be enrolled in this study. 
TARGET POPULATION 
Inclusion Criteria 
All patients must meet the following criteria for study entry: 
 
Signed Informed Consent Form (ICF) 
 
Signed Assent Form when appropriate, as determined by patient's age and individual site 
and country standards 
 
Age 12 years at time of signing ICF or Assent Form 
 
Body weight 40 kg at screening 
 
Willingness and ability to comply with all the study visits and procedures 
 
Documented diagnosis of PNH, confirmed by high sensitivity flow cytometry evaluation of 
WBCs with granulocyte or monocyte clone size of 10%, within 6 months prior to screening 
 
LDH level 2 ULN at screening (as per central assessment) 
 
Patients who have at least four transfusions during 12 months prior to screening 
(documented in the medical record) 
 
Presence of one or more of the following PNH-related signs or symptoms within 3 months 
of screening:  fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), 
anemia (hemoglobin 10 g/dL), history of a MAVE (including thrombosis), dysphagia, or 
erectile dysfunction, or history of pRBC transfusion because of PNH 

 
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Vaccination against Neisseria meningitidis serotypes A, C, W, and Y 3 years prior to 
initiation of study treatment (Day 1).  Vaccination against serotype B should be 
administered in accordance with the most current local guidelines or SOC, as applicable 
in patients with complement deficiency.  If not previously administered or no longer 
current, vaccination must be completed no later than 1 week after the first study drug 
administration.  Vaccination currency with vaccination against serotypes A, C, W, Y and 
B should be maintained throughout the study, according to local guidelines or SOC a s 
applicable in patients with complement deficiency.  In the absence of clear local guidelines 
for Neisseria meningitidis, the Advisory Committee on Immunization Practices 2020 
Guidelines are recommended. 
If vaccination is completed 
 2 weeks prior to initiation or after the start of study 
treatment, appropriate antibiotic prophylaxis must be maintained from first study drug 
administration, continuing for at least 2 weeks after completion of vaccination or 
according to local SOC as applicable in patients with complement deficiency, whichever is 
longer.  If vaccination is administered during screening, and prophylactic antibiotics are 
not to be administered, the vaccination must take place at least 2 weeks prior to the first 
dose of study drug.  Patients who refuse vaccination against Neisseria meningitidis are 
not eligible for the study. 
 
Vaccination against Haemophilus influenzae type B and Streptococcus pneumonia 
according to national vaccination recommendations 
 
Patients who have been vaccinated (partially or in full) against severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) with a locally approved vaccine are eligible to be 
enrolled in the study, 3 days or longer after inoculation.  Patients who have not been 
vaccinated against SARS-CoV-2 are also eligible to be in the study. 
 
Platelet count 
 30,000/mm3 at screening without transfusion support within 7 days of lab 
testing. 
 
ANC 
 500/ l at screening 
- 
Short-acting granulocyte colony-stimulating factors (G-CSFs) must not have been 
administered within 14 days of lab testing. 
- 
Long-acting G-CSFs must not have been administered within 28 days of lab testing.  
 
For patients receiving other therapies (e.g., immunosuppressants, corticosteroids, iron 
supplements, anticoagulants, erythrocyte-stimulating agents):  stable dose for 28 days 
prior to screening and up to the first drug administration 
 
Adequate hepatic function, with ALT 3 ULN at the time of screening; no clinical signs or 
known laboratory/radiographic evidence consistent with cirrhosis 
 
Adequate renal function, defined as serum creatinine 2.5 ULN and creatinine clearance by 
Cockcroft-Gault formula 30 mL/min 
 
For female patients of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, as defined below: 
Female patients of childbearing potential must remain abstinent or use contraceptive 
methods with a failure rate of 1% per year during the treatment period and for 6 
months after the final dose of crovalimab. 
A female patient is considered to be of childbearing potential if the patient is 
postmenarcheal, has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not permanently 
infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or 
another cause as determined by the investigator (e.g., Müllerian agenesis).  The 
definition of childbearing potential may be adapted for alignment with local guidelines 
or regulations. 
Examples of contraceptive methods with a failure rate of 1% per year include bilateral 
tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices. 

 
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The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.  If required per local guidelines or 
regulations, locally recognized acceptable methods of contraception and information 
about the reliability of abstinence will be described in the local Informed Consent Form. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Current or previous treatment with a complement inhibitor 
 
History of allogeneic bone marrow transplantation 
 
History of N. meningitidis infection within 6 months prior to screening and up to first drug 
administration 
 
Known or suspected immune deficiency (e.g., history of frequent recurrent infections) 
 
Known or suspected hereditary complement deficiency 
 
Known HIV infection with CD4 count   200 cells/ L within 24 weeks prior to screening 
Patients with HIV infection who have CD4   200 cells/ L and meet all other criteria are 
eligible. 
 
Infection requiring hospitalization or treatment with IV antibiotics within 28 days prior to 
screening and up to the first drug administration, or oral antibiotics within 14 days prior to 
screening and up to the first drug administration 
 
Active systemic bacterial, viral, or fungal infection within 14 days before first drug 
administration 
 
Presence of fever ( 38 C) within 7 days before the first drug administration 
 
Splenectomy 6 months before screening 
 
Immunized with a live attenuated vaccine within 1 month before first drug administration 
 
History of malignancy within 5 years prior to screening and up to the first drug 
administration, with the following exceptions: 
Patients with any malignancy treated with curative intent and the malignancy has been 
in remission without treatment for 5 years prior to the first drug administration are 
eligible. 
Patients with curatively treated basal or squamous cell carcinoma of the skin or in situ 
carcinoma of the cervix at any time prior to the first drug administration, with no 
evidence of recurrence, are eligible. 
Patients with low-grade, early-stage prostate cancer (Gleason score 6 or below, 
Stage 1 or 2) with no requirement for therapy at any time prior to the first drug 
administration are eligible. 
 
History of myelodysplastic syndrome with Revised International Prognostic Scoring System 
(IPSS-R) prognostic risk categories of intermediate, high, and very high  
 
History of hypersensitivity, allergic, or anaphylactic reactions to any ingredient contained in 
crovalimab, including hypersensitivity to human, humanized, or murine monoclonal 
antibodies or known hypersensitivity to any constituent of the product 
 
Pregnant, breastfeeding, or intention of becoming pregnant during the study or within 
46 weeks (or approximately 10.5 months) after the final dose of the study treatment 
Women of childbearing potential must have a negative serum pregnancy test result 
within 28 days prior to initiation of study drug. 
 
Participation in another interventional treatment study with an investigational agent or use of 
any experimental therapy within 28 days of screening or within 5 half-lives of that 
investigational product, whichever is greater 
 
 

 
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Concurrent disease, treatment, procedure or surgery, or abnormality in clinical laboratory 
tests that could interfere with the conduct of the study, may pose any additional risk for the 
in and completion of the study 
 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date 
at which the last data point required for the final statistical analysis is collected, whichever 
occurs later.  The end of the study is expected to occur 6 years after the last patient is 
enrolled. 
In addition, the Sponsor may decide to terminate the study at any time. 
Investigational Medicinal Product 
The investigational medicinal product for this study is crovalimab. 
TEST PRODUCT (CROVALIMAB) 
Crovalimab will be supplied by the Sponsor as a formulation suitable for IV and SC 
administration.  For information on the formulation and handling of crovalimab, see the 
pharmacy manual and the Crovalimab Investigator's Brochure. 
Crovalimab for IV infusion and SC Administration 
Crovalimab vials will be supplied by the Sponsor as a solution for infusion (IV)/solution for 
injection (SC) from a single-use vial, which contains extractable volume of 1 mL (170 mg 
[nominal]) crovalimab or an extractable volume of 2 mL (340 mg [nominal]) crovalimab. 
For IV infusion, crovalimab solution for infusion is diluted in 0.9% (w/v) sodium chloride solution 
prior to administration. 
For SC administration, crovalimab solution for injection is used undiluted.  In order to minimize 
the number of SC injections for patients, the administration per single injection of up to 2 mL 
drug product solution is permitted.  Considerations for vial pooling are as follows: 
 
The 1 mL (170 mg) configuration will require combining of crovalimab drug product solution 
(vial pooling) from two 1-mL vials into a single syringe, as described in the pharmacy 
manual. 
 
The 2 mL (340 mg) configuration will not require the vial-pooling step.  The pharmacy 
manual will be adapted accordingly. 
STATISTICAL METHODS 
PRIMARY EFFICACY ANALYSIS 
The primary efficacy analysis will take place when all patients have either completed 24 weeks 
of treatment with crovalimab or have discontinued the study drug, whichever occurs first. 
Hemolysis Control 
The co-primary endpoint of the mean proportion of patients with hemolysis control is defined as 
LDH 1.5 ULN from Week 5 through Week 25 (as measured at the central laboratory). 
For each patient at each visit, a binary variable will be created with the value of 1, if 
LDH 1.5 ULN, and 0, otherwise.  A Generalized Estimating Equation (GEE) will be used to 
estimate the mean proportion of hemolysis control (i.e., LDH 1.5 ULN from Week 5 through 
Week 25 and 95% confidence interval). 
The primary analysis will use the standard GEE based on the available LDH assessments, 
assuming the missing data are missing completely at random. 
Transfusion Avoidance 
The co-primary endpoint of proportion of patients who achieve TA consists of proportion of 
patients who achieve TA from baseline through Week 25 (after 24 weeks on treatment) and 
proportion of patients who were TA within 24 weeks prior to screening.  TA is defined as 
patients who are pRBC transfusion-free and do not require transfusion per protocol-specified 
guidelines. 
The intra-patient comparison between proportion of patients with TA from baseline through 
Week 25 and proportion of patients who were TA within 24 weeks prior to screening will be 

 
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made using a paired McNemar test at two-sided Type 1 error level of 0.05. The proportion of 
TA and c
 
For the primary analysis, patients who withdrew early before Week 25 independent of the 
reason for withdrawal will be included in the analysis as non responders (i.e., requiring 
transfusion). 
DETERMINATION OF SAMPLE SIZE 
Approximately 50 patients with PNH will be enrolled in the study. 
Assuming 86% of patients receiving eculizumab and 20% of untreated patients will reach 
LDH 1.5 ULN, the minimum proportion of patients with LDH 1.5 ULN being crossing the 
efficacy threshold of 60% will preserve about 60% of the effect of eculizumab with sample size 
of 50.  The study will be regarded as reaching the co-primary endpoint of hemolysis control 
(based on LDH 1.5 ULN) if the 95%CI lower bound is at least 60%. 
Proportion of patients who achieve TA from baseline through Week 25 will be compared with 
proportion of patients who were TA within 24 weeks prior to screening.  The study will be 
regarded as reaching the co-primary endpoint of TA if the intra-patient difference of proportions 
of patients with TA is significant at the two-sided Type 1 error level of 0.05 using a paired 
McNemar test. 
INTERIM ANALYSES 
There are no planned interim analyses for this study. 

 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
anti-drug antibody 
AUCSS 
area under the concentration time curve at steady 
state 
BTH 
breakthrough hemolysis 
C5 
component 5 
CBC 
complete blood count 
CCOD 
clinical cutoff date 
Cmax, SS 
maximum concentration observed at steady state 
COVID-19 
coronavirus disease 2019 
CTCAE 
Common Terminology Criteria for Adverse Events 
DTDC 
drug-target-drug complex 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EORTC QLQ-C30 
European Organisation for Research and Treatment of 
Cancer Quality of Life Core 30 Questionnaire 
EQ-5D-5L 
EuroQoL 5-Dimension Questionnaire, 5 level 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FcRn 
neonatal fragment crystallizable receptor 
G-CSF 
granulocyte colony-stimulating factor 
GEE 
Generalized Estimating Equation 
GPI 
glycosylphosphatidylinositol 
HCP 
health care provider 
HRQoL 
health-related quality of life 
HV 
healthy volunteer 
ICE 
inter-current event 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IMP 
Investigational Medicinal Product 
IFUIRB 
Institutional Review Board 
IV 
intravenous 
IxRS 
Interactive Voice/Web Response System 
LDH 
lactate dehydrogenase 
LIA 
liposome immunoassay 
MAC 
membrane attack complex 
MAVE 
major adverse vascular event 
MCAR 
missing completely at random 
MFS 
Multidimensional Fatigue Scale 
NCI 
National Cancer Institute 

 
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Abbreviation 
Definition 
OLE 
open-label extension 
PD 
pharmacodynamics 
PedsQL 
Pediatric Quality of Life 
PK 
pharmacokinetic 
PNH 
paroxysmal nocturnal hemoglobinuria 
popPK 
population pharmacokinetic 
pRBC 
packed red blood cell 
PRO 
patient-reported outcome 
Q2W 
every 2 weeks 
Q4W 
every 4 weeks 
QoL 
Quality of Life 
QLQ-C30 
Quality of Life-Core 30 
QTcF 
QT interval corrected through use of Fridericia's 
formula 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SC 
subcutaneous 
SmPC 
Summary of Product Characteristics 
SMR 
standard mortality ratio 
SNP 
single nucleotide polymorphism 
SOC 
standard of care 
TA 
transfusion avoidance 
ULN 
upper limit of normal 
VAS 
visual analog scale 
 

 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON PAROXYSMAL NOCTURNAL 
HEMOGLOBINURIA 
Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-rare, acquired, clonal, 
hematopoietic stem cell disorder.  In PNH, hematopoietic cells acquire a somatic 
mutation in the gene encoding phosphatidylinositol glycan anchor biosynthesis class A 
located on chromosome X.  Consequently, progeny of affected stem cells (erythrocytes, 
granulocytes, monocytes, platelets, and lymphocytes) are deficient in all 
glycosylphosphatidylinositol (GPI)-anchored proteins that are normally expressed on 
hematopoietic cells, including the complement regulatory proteins CD55 and CD59.  
CD59 blocks the formation of the terminal complement complex (also known as the 
membrane attack complex [MAC]) on the cell surface, thereby preventing 
complement-mediated damage to erythrocyte and platelets.  Therefore, the absence of 
CD59 on erythrocytes or platelets leads to intravascular hemolysis resulting in anemia 
and hemoglobinuria or the risk of potentially life-threatening thromboembolic events.  
The hallmark of classic PNH is intravascular hemolysis.  While there are no certain 
predictors of clinical manifestations, clone size (i.e., the proportion of circulating cells 
that arise from the GPI-anchored protein deficient clone) correlates with severity of 
symptoms (Parker 2016).  Survival appears to be related to severity of symptoms, 
including anemia, impaired renal function, dyspnea, and thromboembolic events; bone 
marrow failure may dominate the course of the disease (Nishimura et al. 2004; 
de Latour et al. 2008; Jang et al. 2016).  In general, a larger clone size suggests that 
there is a large enough population of hematopoietic cells lacking functional GPI, which 
are susceptible to complement-mediated injury.  Moreover, clone size combined with 
symptomatology may guide initiation of treatment for the disease (Brodsky 2009). 
Data from the international PNH Registry suggest that thrombotic events and impaired 
renal function are major complications of the disease.  Prior to the introduction of 
eculizumab, PNH had been fatal in about 35% of patients within 5 years of diagnosis.  
Thromboembolic events were the leading cause of death in patients with PNH 
(40% 67%) of deaths with known cause (Hillmen et al. 2007) and were reported in 
patients despite prophylactic anticoagulation therapy.  Quality of life, as well as the 
ability to work, are impaired in many patients with PNH without treatment of 
component 5 (C5) inhibitor (Hill et al. 2017).  The only curative treatment for PNH 
remains bone marrow transplantation, which is associated with significant morbidity and 
mortality (de Latour et al. 2012). 
Data on prevalence are scarce, but it is estimated that overall in the United States, 
Europe, and Japan, there are about 10,000 patients with this disease.  There is no 
reported incidence or prevalence in China in the past two decades.  Incidence in China 
is expected to be similar to global estimate (approximate 1.3/1,000,000; data from 

 
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Great Britain/France).  Data from the international PNH Registry suggest that the median 
age of disease onset is 32 years (range:  3 87 years; Schrezenmeier et al. 2014). 
Inhibition of the complement C5 has been proven to be a successful therapeutic 
intervention in patients with PNH.  The current standard of care (SOC) for treatment of 
patients with PNH with symptomatic hemolysis or thrombosis is C5 inhibition with 
eculizumab or ravulizumab.  However, eculizumab is not yet available in China.  In 
China, glucocorticoids are still the first-line drug for the treatment of PNH to control 
hemolysis attacks though there is significant inferiority to C5 inhibitors.  Eculizumab 
significantly reduces intravascular hemolysis as measured by serum lactate 
dehydrogenase (LDH), stabilizes hemoglobin, reduces the need for RBC transfusions, 
and improves fatigue (Functional Assessment of Chronic Illness Therapy [FACIT]) and 
health-related quality of life (HRQoL); European Organisation for Research and 
Treatment of Cancer Quality of Life Core 30 Questionnaire [EORTC QLQ-C30]).  In 
addition, long-term data show a significant reduction of thromboembolic events and a 
reduced mortality rate with chronic eculizumab treatment (Hillmen et al. 2013).  
Ravulizumab is a longer-acting humanized anti-C5 antibody that was approved by the 
U.S. Food and Drug Administration (FDA; December 2018) and recently received a 
positive European Commission Decision (July 2019).  Both approved C5 inhibitors target 
the same epitope on C5 and demonstrate similar efficacy in complement inhibition, but 
ravulizumab is engineered with amino acid substitutions resulting a terminal half-life of 
approximately four times that of eculizumab and favorable pharmacokinetics (Hill et al. 
2017). 
Treatment with C5 inhibitors is highly effective in the majority of patients in decreasing 
symptoms and complications of PNH.  Importantly, it does not affect the natural history 
of the disease because C5 inhibition does not affect the PNH clone (Brodsky et al. 2008; 
Brodsky 2009).  Rather, the clonally derived cells survive longer with C5 inhibitors due to 
reduced complement-mediated injury, while the phosphatidylinositol glycan anchor 
biosynthesis class A mutated hematopoietic stem cell is not affected.  Therefore, 
patients with PNH require lifelong treatment to prevent complications and symptoms.  
Continuous treatment with C5 inhibitors for patients with PNH results in similar life 
expectancy compared with age-matched controls (Kelly et al. 2011). 
Despite these significant improvements in the treatment of PNH, there remains a high 
unmet medical need.  Approximately 35% 50% of patients continue to require regular 
transfusions despite eculizumab treatment (Brodsky et al. 2008).  Reasons for the 
continued need for transfusion include breakthrough hemolysis (BTH) caused by one or 
more of the following:  infections, inadequate C5 inhibition by eculizumab, surgery, 
pregnancy, underlying bone marrow failure, and extravascular hemolysis.  Hemolytic 
activity remains detectable in many patients during treatment with eculizumab, which 
may be related to incomplete C5 blockage and extravascular hemolysis (de Latour et al. 
2015).  Higher LDH, lower hemoglobin levels, higher bilirubin levels, and higher 
reticulocyte counts were noted in cases of incomplete blockage.  In ex vivo studies using 

 
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plasma from healthy donors and patients with PNH, eculizumab concentrations of 
40 g/mL and higher resulted in C5 inhibition.  In clinical practice, some patients with 
PNH require either a higher dose of eculizumab than is approved, or need to be dosed 
more frequently, to control BTH (Kelly et al. 2011).  In addition, approximately 3% of 
Japanese patients (lower in other ethnicities) with PNH have a C5 polymorphism 
(c.2654G to A), which predicts the amino acid substitution pArg885His (Nishimura et al. 
2014) that precludes eculizumab binding to C5 resulting in no response to eculizumab 
treatment (Karczewski et al. 2019). 
1.2 
BACKGROUND ON CROVALIMAB 
1.2.1 
Molecule and Nonclinical Data 
Crovalimab is a novel humanized anti-C5 monoclonal antibody.  Crovalimab binds to 
complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b 
and preventing the generation of the terminal complement complex C5b-9 (MAC).  It 
inhibits terminal complement-mediated intravascular hemolysis in patients with PNH.  
Crovalimab is based on SMART-Ig (RecyclingAntibody ; Fukuzawa et al. 2017) with 
pH-dependent antigen binding allowing for efficient target disposal, and enhancement of 
neonatal fragment crystallizable receptor (FcRn) binding to improve antibody recycling 
efficiency, which results in a prolonged half-life and prolonged complement inhibition.  
The physicochemical properties of crovalimab support the development of 
high-concentration formulation.  The combination of the SMART-Ig and the high 
concentrated formulation enable every 4 weeks (Q4W) subcutaneous (SC) dosing.  
Based on clinical data, nonclinical pharmacology, and pharmacodynamic (PD) data, 
crovalimab is expected to lead to consistent and complete complement protein C5 
inhibition resulting in suppression of intravascular hemolysis at the targeted dosing 
regimens.  
Additionally, crovalimab binds to a different C5 epitope than eculizumab or ravulizumab.  
In vitro studies with C5 variants (including Arg885His and also V145I, R449G, V802I, 
R928Q, D966Y, S1310N, and E1437D) have shown that crovalimab binds comparably 
with these as to wild-type C5 (Fukuzawa et al. 2017).  Crovalimab has been shown in 
ex vivo experiments to block hemolysis in patients who have a single missense C5 
heterozygous mutation that predicts an arginine at 885 (Arg885His missense mutation).  
In Study BP39144, 4 patients with PNH who have a single missense C5 heterozygous 
mutation were enrolled.  Complement inhibition was achieved and generally maintained 
throughout the observation period for all 4 patients.  Therefore, crovalimab may be an 
effective complement inhibitor for patients with C5 R885 single nucleotide 
polymorphisms (SNPs) (and similar C5 variants) who are failed by currently available 
complement inhibitors and therefore have a very high unmet medical need. 
Refer to the Crovalimab Investigator's Brochure for details on nonclinical and clinical 
studies. 

 
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1.2.2 
Clinical Experience with Crovalimab 
The clinical data obtained for crovalimab to date are from Study BP39144.  
Study BP39144 is an ongoing Phase I/II study designed to assess the safety, tolerability, 
pharmacokinetics, pharmacodynamics, and efficacy of crovalimab in healthy volunteers 
(HVs) and patients with PNH.  Study BP39144 consists of four sequential parts and an 
open-label extension (OLE) for patients with PNH, as shown in Figure 1.

 
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Figure 1 Study BP39144 Schema 
 
D 
 day; IV 
 intravenous; PNH 
 paroxysmal nocturnal hemoglobinuria; QW 
 every week; Q2W 
 every 2 weeks; Q4W 
 every 4 weeks; 
SC 
 subcutaneous. 
 

 
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crovalimab except upper respiratory tract infection.  All serious adverse events had 
resolved while on treatment. 
Refer to the Crovalimab Investigator's Brochure for the most updated clinical safety 
data. 
Drug-Target-Drug Complexes 
Crovalimab and eculizumab bind different epitopes on C5.  This was identified early 
in the clinical development program as a potential safety concern due to formation of 
drug-target-drug complexes (DTDCs).  When both are present in the circulation, 
complexes comprised of the two antibodies bridged by C5 are formed.  These DTDCs 
comprise of one or more crovalimab-C5-eculizumab units.  Large DTDCs are of 
particular clinical importance as they clear more slowly than small complexes, and in 
general, small immune complexes tend to be inert and are less likely to trigger a Type III 
hypersensitivity reaction (Nangaku and Couser 2005).  Larger DTDCs (i.e., DTDCs 
constituted of more than a single motif) are expected to be cleared within approximately 
7 to 8 weeks, while smaller DTDCs (i.e., single motif) are expected to be cleared 
within hours. 
Formation of DTDCs has two main consequences:  1) transient enhancement of 
crovalimab clearance resulting in a transient exposure drop and 2) potential for 
development of Type III hypersensitivity.  
The goal of the dosing regimen for patients switching from eculizumab to crovalimab is 
to maintain crovalimab trough concentrations above approximately 100 g/mL 
associated with complete complement activity inhibition despite the transient formation 
of DTDCs.   
Part 3 of Study BP39144 (CCOD of 29 January 2020) included patients who were 
previously treated with eculizumab and switched to treatment with crovalimab.  The 
dosing regimen included a loading dose of crovalimab 1000 mg IV and maintenance 
doses of 680 mg Q4W SC or 340 mg every 2 weeks (Q2W) SC or 170 mg once a week 
SC. 
Two out of 19 patients in Part 3 had developed events of mild to moderate severity 
compatible with a Type III hypersensitivity reactions.   
One patient experienced a mild urticaria of the right palm that started on study Day 6 
and resolved on Day 10.  The patient also developed mild purpura involving the lower 
extremities that starting on Day 10 and resolved on Day 21 without sequelae.  
A second patient with a history of hepatitis C and hepatitis B experienced a moderate 
small vessel vasculitis that started on Day 9 and resolved on Day 31, and an event of 

 
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mild joint pain (with associated fatigue and headache) that started on Day 13 and 
resolved on Day 29.  All events resolved without sequelae.   
Both patients were treated with topical steroids and with antihistamine medications for 
symptoms.  Importantly, they continued crovalimab without modification or interruption of 
dosing, or reoccurrence of the clinical manifestation described above.  Neither patient 
had evidence of associated organ dysfunction.  Specifically, no change was observed in 
creatinine levels, and neither developed hematuria, proteinuria, or hypertension. 
As expected, DTDCs were transiently detected in all patients switching from eculizumab 
to crovalimab in Study BP39144.  Their amount and size distribution were 
indistinguishable between asymptomatic patients and the 2 individuals with Type III 
hypersensitivity reaction.  All complexes cleared within approximately 10 weeks.  
To minimize the risk for patients, enhanced monitoring during study and proper 
management of clinical manifestations of DTDCs were implemented (see Section 5.1.1.2 
for details).  
Due to the potential risk of DTDC-mediated Type III hypersensitivity reactions, it is 
recommended that patients who discontinue from the study and switch to another 
C5 inhibitor also be monitored, and guidelines have been incorporated into this Phase III 
protocol. 
Based on the results of Part 3 of Study BP39144, dose and dosing regimen were further 
optimized to ensure maintaining crovalimab trough concentrations above concentration 
associated to full complement activity inhibition throughout the dosing interval in the 
majority of the patients despite the initial concentration drop triggered by DTDCs 
formation and variability between patients while reducing the formation of large DTDCs 
using a dual modeling approach (see Section 3.3.1 for details).  
The identified dose and dosing regimen were investigated in Study BP39144 Part 4.  
Preliminary data from Study BP39144 Part 4 indicate that the exposure of crovalimab 
was maintained over 100 g/mL, a concentration associated with complement activity 
inhibition.  Complement inhibition was generally maintained in all patients over time. 
In addition, available DTDC data show a reduced proportion of large DTDCs and faster 
clearance in patients from Part 4 compared with patients from Part 3, as predicted by the 
model.  The median percentage of the large DTDCs (the sum of Fraction 1 to 4) was 
reduced by 67% in patients switching from eculizumab in Part 4 who received the 
optimized crovalimab dose and dosing regimen as compared with data from patients 
in Part 3. 

 
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None of the 7 patients who switched from eculizumab to crovalimab in Part 4 had clinical 
manifestations suggestive of Type III hypersensitivity reaction or other adverse 
consequences. 
Refer to the Crovalimab Investigator's Brochure for the most updated clinical safety 
data. 
1.2.2.2 
Pharmacokinetic and Pharmacodynamic Data from 
Study BP39144 and YO42311 
A population pharmacokinetic (popPK) model (legacy popPK model) was initially 
developed based on data from Study BP39144 including the HVs, treatment-naïve 
patients with PNH , and patients with PNH switching from eculizumab to crovalimab 
(CCOD:  29 January 2020) .  At the time of the primary analysis of Study YO42311, 
the legacy popPK model was updated by pooling data from the Phase III study YO42311 
(up to the CCOD:  10 February 2022) and data from Study BP39144 (Part 1, Part 2, 
and Part 4A, up to the CCOD:  01 November 2021) in treatment-naive patients with 
PNH only.  Patients switching from eculizumab to crovalimab in Study BP39144 
(Parts 3 and 4B) were excluded from the updated popPK analysis.  This was done in 
order to support the regulatory submission of Study YO42311 in treatment-naive 
patients with PNH. 
For both the legacy and updated popPK model, the concentration time profile of 
crovalimab is best described by a two compartment model with first-order elimination 
and first-order absorption to describe SC absorption.   
Body weight was a significant covariate on the clearance and volume of distribution; and 
was introduced using allometric scaling.  Consequently, for a given dose, crovalimab 
systemic exposure is expected to vary 
 with lower systemic 
exposure in patients with higher body weight.  To compensate for the effect of body 
weight on the disposition parameters, a body weight tiered dosing was used (see 
Section 3.3.1).  Age was also found as a significant covariate on the absorption rate and 
constant.  Simulations showed that exposure was similar across age groups, and no 
dose adaptation was required to compensate for the effect of age.  Anti-drug antibody 
(ADA) was also tested as a covariate for clearance but had no significant impact.  
Based on the updated popPK model, bioavailability after SC administration is estimated 
to be 73.5%.  The terminal half-life is estimated at approximately 59 days.  
Pharmacodynamic data indicate that crovalimab can potently inhibit terminal 
complement activity in HVs and patients with PNH, inducing a concentration-dependent 
inhibition of serum hemolytic activity as measured by an ex vivo liposome immunoassay 
(LIA).  A preliminary assessment of the exposure-response relationship suggests that 
approximately 100 g/mL of crovalimab achieves complement inhibition that reduces 
hemolytic activity to  
 10 U/mL (limit of quantification of the assay). 

 
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PK profiles in patients who switched from eculizumab to crovalimab (Part 3) show a 
transient faster clearance that is not observed in HVs and treatment-naive patients with 
PNH, which is considered to be related to the formation of DTDCs.  The formation of 
DTDCs presents a safety concern in patients who switched from eculizumab to 
crovalimab, which could lead to the development of type III hypersensitivity reactions.  
Dosing was optimized in Part 4 to minimize formation of large DTDCs and maintain 
crovalimab concentrations required for complement inhibition. 
1.2.2.3 
Immunogenicity and Anti-Drug Antibody from Study BP39144 
Anti-crovalimab antibodies were detected in 6 of 10 HVs (60%), 10 of 18 treatment-naïve 
patients (56%), and 5 of 25 patients (20%)  who switched from eculizumab to 
crovalimab, as of the CCOD of 29 January 2020.  In the majority of patients with 
detectable anti-crovalimab antibodies there is no evidence of exposure loss, PD effect 
loss, or correlation with observed adverse events.  One patient with ADAs had a 
decrease in complement inhibition concomitant to a decrease in drug exposure from 
Weeks 12 to 36 and then achieved complement inhibition again at Week 52 concomitant 
to a drug exposure normalization.  This patient had positive ADA starting at Week 8.  
The ADA titer started to decrease at Week 52. 
Thirteen patients who switched from eculizumab to crovalimab had detectable ADAs at 
baseline but were considered ADA-negative per protocol as described below: 
 
Patients are considered to be ADA-negative if they are ADA-negative at baseline 
and all postbaseline samples are negative, or if they are ADA-positive at baseline 
but do not have any post-baseline samples with a titer that is at least 4-fold greater 
than the titer of the baseline sample (treatment unaffected). 
 
The presence of ADAs at baseline in these samples is likely due to an assay artifact 
resulting from the simultaneous presence of eculizumab and high C5 levels in these 
patients.   
In the majority of ADA-positive patients, ADAs were detected at late timepoints, and 
there was no evidence of exposure loss, PD effect loss, nor correlation with observed 
adverse events.  One patient was noted to have a decrease in crovalimab exposure and 
complement inhibition concomitant with ADA-positive titers from Weeks 12 to 36, which 
resolved by Week 52. 
1.2.2.4 
Efficacy Results from Study BP39144 
The following results are as of the CCOD of 4 September 2019: 
LDH:  In Part 2 of the study (C5-inhibitor treatment-naive patients), mean LDH levels 
reached 1.5 upper limit of normal (ULN) by Day 15 and remained 1 1.5 ULN 
throughout the remaining of the study and was maintained during the OLE phase.  
Seventy percent of the patients reached LDH 1.5 ULN by Day 22, and LDH levels 
remained relatively stable through the open label treatment and OLE.  Similarly, in 
patients enrolled in Part 3 (switching from eculizumab therapy), the mean LDH levels 

 
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remained 1 1.5 ULN throughout the duration of the study.  Seventy-five percent of the 
patients enrolled in Part 3 had reached LDH 1.5 ULN. 
By Day 15, mean LDH levels in both arms of Part 4 (C5-inhibitor treatment-naive and 
eculizumab-pretreated patients, respectively) were stable at 1 1.5 ULN.  All 
6 treatment-naive patients in Arm A had reached LDH levels 1.5 ULN by Day 22, and 
this was maintained through the open-label period (except on Day 29 for 1 patient in the 
context of an adverse event of hemolytic crisis with concurrent adverse event bronchitis).  
Among the 7 pretreated patients in Arm B, LDH 1.5 ULN was maintained throughout 
the duration of the observation period, with the exception of 2 patients whose LDH rose 
above 1.5 ULN at Days 15 and 29: one patient had an increase in hemolysis 
parameters in the context of febrile syndrome; a second patient had an adverse event of 
hemolytic crisis with concurrent adverse event bronchitis.  At the time of CCOD, 30% of 
the treatment-naive patients and 50% of the patients who switched from eculizumab had 
achieved an LDH 1 ULN. 
Transfusions:  Among patients in Part 4 who completed at least 4 weeks of study 
treatment, transfusion avoidance (TA) was achieved in 3 of 5 treatment-naive 
patients and in 3 of 4 eculizumab-pretreated patients.  Similarly, TA through Week 28 
was achieved in 8 of 10 treatment-naive patients in Part 2 and 13 of 19 
eculizumab-pretreated patients in Part 3. 
Breakthrough hemolysis:  The analysis of BTH was post hoc, and BTH was defined as 
the presence of elevated LDH 2 ULN after a prior decrease to LDH 1.5 ULN from 
start of study treatment, with either concurrent drop in hemoglobin 10 g/dL OR at least 
one new or worsening clinical symptom or sign of intravascular hemolysis.  A total of 
four BTH events meeting the criteria above occurred in eculizumab-pretreated patients 
(Part 3; three of these events were an elevated LDH with concurrent drop in 
hemoglobin 10 g/dL (at Days 15, 223, and 403 on crovalimab treatment) and one event 
was an elevated LDH with at least one clinical symptom of intravascular hemolysis (dark 
urine and fatigue, at Day 181).  The BTH rate in patient-years was 
0.18 (95% CI:   0.05 0.47).  No BTH events in treatment-naive patients meeting the 
post-hoc criteria have been observed in Parts 2 and 4 (Arm A) at the CCOD. 
Hemoglobin stabilization:  Of the 9 patients who completed 5 weeks of treatment in 
Part 4 of the study, hemoglobin stabilization from baseline to Day 29 of treatment was 
observed in 3 of 5 treatment-naïve patients and in 3 of 4 eculizumab-pretreated patients.  
Similar results were observed in Parts 2 and 3 of the study, among patients who 
completed at least 28 weeks of treatment 8 of 10 treatment-naive patients (Part 2) and 
14 of 19 eculizumab-pretreated patients (Part 3) achieved or maintained hemoglobin 
stabilization. 
Four patients with PNH who have a single missense C5 heterozygous mutation and 
whose hemolysis was not controlled by previous eculizumab treatment, were enrolled in 

 
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the Study BP39144.  Complement inhibition was achieved and generally maintained 
throughout the observation period for all 4 patients, accordingly all 4 patients achieved 
and maintained control of intravascular hemolysis. 
the most updated details on clinical 
studies. 
1.3 
STUDY RATIONALE AND BENEFIT RISK ASSESSMENT 
1.3.1 
Study Rationale and Benefit 
The main objective of effective PNH treatment is to provide immediate, complete, and 
sustained inhibition of terminal complement activity to block hemolysis and prevent 
thrombotic events.  The current SOC for adult and pediatric patients with PNH is chronic, 
continuous C5-inhibitor therapy.  In China, eculizumab is not yet available.  Patients 
treated with eculizumab are required to receive maintenance infusions Q2W and 
patients treated with ravulizumab are required to receive maintenance infusions every 8 
weeks.  Approximately 10% to 15% of patients treated with the labeled dose of 
eculizumab experience an increase in hemolysis near the end of the dosing interval and 
may require either a higher-than-approved dose of eculizumab or more frequent dosing 
to prevent BTH events (Kelly et al. 2011; Hillmen et al. 2013). 
The traditional treatment of PNH is aimed at protecting PNH clones, reducing 
complement attack and destruction, and alleviating hemolysis.  Glucocorticoids are still 
the first-line drugs for the treatment of PNH to control hemolysis attacks, though there is 
significant inferiority to C5 inhibitors on reduced intravascular hemolysis, reduced or 
eliminated the need for transfusion, and improved anemia, fatigue, and the quality of life 
in patients with PNH.  The most common adverse events that occurred during 
glucocorticoid treatment were Iatrogenic Cushing's syndrome, infection, osteoporosis, 
and hyperglycemia. 
Crovalimab binds with high affinity to complement protein C5, preventing generation of 
the terminal complement complex C5b-9 (MAC) and inhibiting terminal 
complement-mediated intravascular hemolysis in patients with PNH.  
 high 
SC bioavailability, prolonged half-life, and extended complement inhibition through 
reduced target (C5) accumulation, coupled with physiochemical properties that support 
the development of a high-concentration formulation, allow for low-volume SC dosing 
Q4W.  This has the potential to substantially reduce treatment burden, offering a 
meaningful potential benefit to individuals with PNH. 
Additionally, crovalimab has been shown to block hemolysis in patients with C5 R885 
SNPs (and other C5 variants) who are unresponsive to currently available complement 
inhibitors and may be an effective treatment option in these patients who experience a 
very high unmet medical need. 

 
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1.3.2 
Risk 
Treatment with crovalimab was safe and well tolerated in both HVs (Part 1 of 
Study BP39144) and treatment-naive patients with PNH (Parts 2 and 4 [Arm A] of 
Study BP39144). 
As a class effect of complement inhibitors, there is a risk of meningococcal infection; the 
same mitigation strategies used for other C5 inhibitor therapies (vaccination, high clinical 
suspicion for infection with monitoring) have been applied to patients treated with 
crovalimab, with no observed cases of meningococcal infection to date. 
In Study BP39144, development of DTDC (that comprise eculizumab-C5-crovalimab) 
occurred transiently in all patients who switch from eculizumab to crovalimab (Parts 3 
and 4 [Arm A]).  Optimized dosing strategy and risk minimization strategy including 
patient selection, monitoring, and management of clinical manifestation of DTDC (see 
Section 1.2.2.1) were implemented after the occurrence of two DTDC-related adverse 
events in Study BP39144.  No further clinical manifestations of DTDC were observed.  
In this study, the risk of DTDC is relevant only to patients who discontinue crovalimab 
and switch to other C5 inhibitor that binds to a different C5 epitope. 
1.3.3 
Benefit and Risk 
Crovalimab has shown promising clinical efficacy with effective reduction in intravascular 
hemolysis and effective terminal complement inhibition to patients with PNH in 
Study BP39144.  Current clinical experience in patients treated with crovalimab indicate 
that the drug is well tolerated in PNH patients, with no significant adverse events 
observed.  The potential class effect of meningococcal infections can be effectively 
managed with established risk mitigation strategies.  Based upon the available data, 
crovalimab may provide a treatment option with promising efficacy and manageable 
safety in Chinese patients with PNH, where C5 inhibitors have demonstrated significant 
superiority compared with supportive care including glucocorticoid treatment.  Moreover, 
crovalimab has shown promising efficacy in patients with C5 R885 polymorphisms who 
do not benefit from treatment with eculizumab.  In addition, the benefit of reduced 
treatment burden with optimal disease control could be substantial in many patients with 
PNH who require lifelong complement inhibition.  In conclusion, the overall benefit-risk 
may be considered positive in Chinese treatment-naive patients with PNH. 
1.3.3.1 
Benefit and Risk with COVID-19 
Crovalimab is not expected to increase the likelihood of patients becoming infected with 
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Risitano et al. 2020).  
Thus, the benefit and risk profile of crovalimab remains the same, and no changes to 
study conduct specifically related to coronavirus disease 2019 (COVID-19) are 
considered necessary. 

 
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2. 
OBJECTIVES AND ENDPOINTS 
This is a Phase III, multicenter, single-arm study designed to evaluate the efficacy, 
safety, pharmacokinetics, pharmacodynamics, and health status of crovalimab in 
patients with PNH aged 12 years and 40 kg who have not been previously treated 
with a complement-inhibitor therapy. 
2.1 
EFFICACY OBJECTIVES 
2.1.1 
Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the efficacy of crovalimab 
based on crossing the threshold of the co-primary endpoint hemolysis control and the 
superiority intra-patient assessment of the co-primary endpoint of TA on the basis of 
following endpoints: 
 
Mean proportion of patients with hemolysis control, measured by LDH 1.5 ULN 
from Week 5 through Week 25 (as measured at the central laboratory) 
 
The difference in the proportion of patients who achieve TA from baseline through 
Week 25 (after 24 weeks on treatment) and the proportion of patients who were TA 
within 24 weeks prior to screening 
TA is defined as patients who are packed red blood cell (pRBC) 
transfusion free and do not require transfusion per protocol specified 
guidelines. 
TA within 24 weeks prior to screening is based on the pRBC transfusion history 
in the medical records. 
 
2.1.2 
Secondary Efficacy Objective 
The secondary efficacy objectives for this study are to evaluate the efficacy of 
crovalimab on the basis of the following endpoints: 
 
Proportion of patients with BTH from baseline through Week 25 
BTH is defined as at least one new or worsening symptom or sign of 
intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of 
breath [dyspnea], anemia [hemoglobin 10 g/dL], a major adverse vascular 
event [MAVE; as defined in Appendix 4 including thrombosis], dysphagia, or 
erectile dysfunction) in the presence of elevated LDH 2 ULN after prior 
reduction of LDH to 1.5 ULN on treatment. 
 
Proportion of patients with stabilized hemoglobin from baseline through Week 25 
Stabilized hemoglobin is defined as avoidance of a 2 g/dL decrease in 
hemoglobin level from baseline, in the absence of transfusion. 
 
Mean change from baseline to Week 25 in fatigue as assessed through the use of 
the FACIT-Fatigue (adults aged 18 years) 
 

 
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2.1.3 
Other Efficacy Objective 
The other efficacy objective for this study is to evaluate the efficacy of crovalimab on the 
basis of the following endpoints: 
 
Total number of units of pRBCs transfused per patient from baseline to Week 25 
 
Mean proportion of patients with central LDH 1 ULN from Week 5 through Week 
25 (as measured at the central laboratory) 
 
Mean LDH levels from baseline to Week 25 by visit  
 
Percent change from baseline to Week 25 in central LDH levels by visit 
 
Time from baseline to first reach of central LDH 1 ULN 
 
Time from baseline to first reach of central LDH 1.5 ULN 
 
Proportion of patients who reach a hemoglobin level of at least 10 g/dL, without 
subsequent decrease below 9 g/dL, in the absence of a transfusion from baseline to 
Week 25. 
 
Proportion of patients with MAVE from baseline to Week 25 
 
Mean change from baseline to Week 25 in Physical Function, Role Function, and 
Global Health Status/Quality of Life (QoL) scales of the European Organisation for 
Research and Treatment of Cancer Quality of Life-Core 30 (EORTC QLQ-C30) (for 
adults aged 18 years) 
 
Mean change from baseline to Week 25 in Pediatric Quality of Life (PedsQL) 
Multidimensional Fatigue Scale (MFS), and the Physical Functioning scale of the 
PedsQL Core (for adolescents aged 12 17 years) 
 
Proportion of patients with a 
 5-point improvement from baseline in the 
FACIT-Fatigue at Week 25 (for adults aged 
 18 years) 
 
2.1.4 
Supportive Historical Objective 
The supportive historical objectives are to characterize the efficacy of best supportive 
care and intra-patient comparison based on the following endpoints:  
 
Mean LDH, and hemoglobin within 24 weeks prior to screening 
 
Mean number of blood transfusion and number of units of pRBC transfused within 
24 weeks prior to screening 
 
Proportion of patients who had MAVE as documented in the medical records within 
24 weeks prior to screening 
 
2.2 
SAFETY OBJECTIVE 
The safety objective for this study is to evaluate the overall safety of crovalimab on the 
basis of the following endpoints: 
 
Incidence and severity of adverse events, with severity determined according to  
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, 
(CTCAE), Version 5 
 
Change from baseline in targeted vital signs 

 
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Change from baseline in targeted clinical laboratory test results 
 
Incidence and severity of injection-site reactions, infusion-related reactions, 
hypersensitivity, and infections (including meningococcal meningitis) 
 
Incidence of adverse events leading to study drug discontinuation 
 
2.3 
PHARMACOKINETIC OBJECTIVES 
The PK objective for this study is to evaluate the pharmacokinetics of crovalimab on the 
basis of the following endpoints: 
 
Trough serum concentrations of crovalimab over time 
 
Serum concentrations of crovalimab at specified timepoints 
 
The other PK objective for this study is as follows: 
 
To evaluate potential relationships between drug exposure and the efficacy and 
safety of crovalimab 
 
2.4 
IMMUNOGENICITY OBJECTIVES 
The immunogenicity objective for this study is to evaluate the immune response to 
crovalimab on the basis of the following endpoint: 
 
Prevalence of ADAs at baseline and incidence of ADAs during the study 
 
The other immunogenicity objective for this study is to evaluate the potential effects of 
ADA on efficacy, safety, PK, and PD endpoints. 
2.5 
BIOMARKER OBJECTIVE 
The biomarker objective for this study is to identify and/or evaluate biomarkers that can 
provide evidence of crovalimab activity (i.e., PD biomarkers) on the basis of the following 
endpoints: 
 
Change over time in PD biomarkers, including complement activity measured by LIA 
 
Change over time in total and free C5 concentration 
 
Observed value and absolute change from baseline to Week 25 in parameters 
reflecting hemolysis (reticulocyte count, free hemoglobin, haptoglobin) 
 
The other biomarker objectives for this study are as follows: 
 
To evaluate the change over time in red cell clone size by flow cytometry and 
markers from the coagulation system (D dimer) 
 
To evaluate the change over time in additional biomarkers of the complement 
system and markers for intra- and extra-vascular hemolysis (e.g., C3d on RBCs). 
 
Additionally, the relationship between blood biomarkers and efficacy, safety, 
pharmacokinetics, and immunogenicity will be investigated. 

 
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or older, with a body weight 40 kg, diagnosed with PNH, who have not been previously 
treated with a complement-inhibitor therapy.  The primary efficacy analysis will be 
performed when all patients have either completed 24 weeks of treatment with 
crovalimab or discontinued from the treatment, whichever occurs first.  Patients must 
have received at least one dose of treatment with crovalimab and have at least one 
central LDH level assessment after the first crovalimab administration to be included in 
the primary efficacy analysis. 
An initial IV loading dose will be administered on Week 1 Day 1, followed by four weekly 
crovalimab SC doses on Week 1 Day 2, then on Weeks 2, 3, and 4.  Maintenance 
dosing will begin at Week 5 and will continue Q4W thereafter, for a total of at least 
24 weeks of study treatment.  All patients who receive crovalimab as part of this study 
will do so according to a weight-based tiered dosing approach schedule (see Table 1).  
Additional PK samples will be drawn in up to a maximum of 20 patients to characterize 
crovalimab PK profiles in Chinese patients.  More details are provided in Section 6.6.  
After completing 24 weeks of treatment with crovalimab (i.e., Week 25 visit), patients will 
be allowed to continue crovalimab Q4W until they can switch to an OLE study (if 
available), to a commercial product, or receive crovalimab as per the Roche Global 
Policy on Continued Access to Investigational Medicinal Products. 
The treatment discontinuation date is defined as the last day the patient receives a dose 
of medication on the study.  All patients who discontinue from crovalimab treatment 
while on the study will return for a safety follow-up site visit 24 weeks after treatment 
discontinuation and a safety telephone call 46 weeks (approximately 10.5 months) after 
treatment discontinuation.  If these patients switch to a different C5 inhibitor, they 
should remain in safety follow-up and be monitored as detailed in Section 5.1.1.2.  More 
details are provided in Section 4.6. 
At selected sites, the Sponsor may propose and conduct exploratory substudies 
associated with the YO42311 study protocol.  Each substudy will be introduced in a 
separate substudy protocol and will have a separate associated Informed Consent Form.  
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date 
the date at which the last data point required for the final statistical analysis is collected, 
whichever occurs later.  The end of the study is expected to occur 6 years after the last 
patient is enrolled. 
In addition, the Sponsor may decide to terminate the study at any time. 
The total length of the study, from screening of the first patient to the end of the study, 
is expected to be approximately 7 years. 

 
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3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Crovalimab Dose and Schedule 
The goal of treatment with C5 inhibitor therapy is to achieve a rapid and sustained 
suppression of C5 activity and to maintain this suppression throughout the dosing 
interval. 
Data from Phase I/II Study BP39144 indicate that with a crovalimab concentration of 
above approximately 100 g/mL, complete complement inhibition was achieved. 
This study will include two weight-based doses for crovalimab (see Table 1). 
3.3.2 
Rationale for Patient Population 
3.3.2.1 
Primary Population 
Patients with PNH who were never treated with a C5-inhibitor therapy prior to study entry 
will comprise the primary population for this Phase III study.  Patients will be included if 
their LDH at screening is at least 2 ULN and have had at least four transfusions in the 
12 months prior to screening.  The requirements were specifically chosen to ensure 
inclusion of patients who have significant hemolysis and therefore have the highest 
therapeutic need and chance to benefit from C5 inhibition treatment. 
3.3.2.2 
Inclusion of Adolescents 
PNH onset during adolescence is rare.  However, when occurring, PNH in adolescents 
is indistinguishable from adults.  Regardless of age of onset, PNH is defined by the 
occurrence of PIGA mutations in the hematopoietic stem cell resulting in loss of 
GPI-anchored proteins.  Therefore, the clinical manifestations and the response to 
treatment with C5 inhibitors is similar in patients with PNH across the age continuum 
justifying inclusion of adolescents in this trial.  Importantly, for these young individuals 
the potential for reduced treatment burden offered by crovalimab may be particularly 
meaningful.  Adolescents will be included in the primary efficacy population. 
The Sponsor anticipates that, because of the rarity of disease among adolescents, only 
a few of them will be enrolled.  Their data will be aggregated with data from adult 
patients given 1) similar disease process, 2) similar response to intervention, and 
3) anticipated similar crovalimab PK and PD in adolescents and adults.  The inclusion of 
adolescent patients in the crovalimab Phase III studies will also provide an important 
age-specific safety experience. 
3.3.3 
Rationale for Co-Primary Endpoints 
The goal of the study is to demonstrate that in previously C5-inhibitor therapy untreated 
patients with PNH crovalimab can establish control of hemolysis.  This will be done 
through complementary co-primary endpoints.  TA is a disease-related event for patients 
with PNH and is a clinically significant measure of disease control, has high clinical 
interpretability, and can be used by physicians and patients to make treatment decisions.  
Serum LDH is the primary biochemical marker of intravascular hemolysis and therefore 

 
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linked to the clinical manifestations of disease.  As such, it is commonly used as a 
clinical measure for intravascular hemolysis. 
LDH normalization (defined as patients achieving LDH ULN) was used in 
NCT02946463 to demonstrate response to treatment (Lee et al. 2019).  However, the 
exact definition of LDH cutoff point that carries clinical significance is not clear.  
Lee et al. (2019) found that LDH normalization was achieved only in 49% 54% of the 
patients, while 66% to 74% of the patients achieved TA and only 4% to 11% had a BTH 
event.  These results underscore that LDH normalization has suboptimal sensitivity as a 
marker to define clinical response.  Conversely, data from Jang et al. (2016) 
demonstrate that LDH 1.5 ULN was the most sensitive and specific predictor of 
mortality (standard mortality ratio [SMR] of 4.81 for patients with PNH compared to 
age- and sex-matched general population at or above this LDH threshold, and SMR 
of 1.17 below this threshold), making this a clinically meaningful threshold of disease 
control.  Lee et al. (2011, 2013) also demonstrated that LDH values 1.5 ULN are 
associated with significantly reduced risks of thromboembolic events and mortality, and 
the same threshold was used by Schrezenmeier et al. (2014) to further investigate the 
relationship between LDH increase and disease-related characteristics and morbidity.  
Recognizing the inherent subjectivity of choosing an LDH cutoff that defines adequate 
hemolysis control, LDH 1.5 ULN was selected given the available literature supporting 
its clinical relevance, and exploratory analyses using LDH ULN will investigate the 
sensitivity of results to the choice of cut point.  Importantly, the clinical value will be 
further supported by the co-primary endpoint of TA. 
Using TA and hemolysis control (LDH level 1.5 ULN) as co-primary endpoints and 
supplementing secondary endpoints (BTH, hemoglobin stabilization and FACIT-Fatigue) 
provides a complete and meaningful picture of drug efficacy, integrating the assessment 
of the effect on hemolysis with that on clinical outcomes. 
3.3.4 
Rationale for Biomarker Assessments 
Inadequate C5 inhibition and detectable hemolytic activity have been reported in patients 
with PNH during standard-of-care treatment (de Latour et al. 2015).  Thus, PD 
biomarkers will be assessed to monitor the biologic activity of crovalimab treatment.  To 
monitor complement inhibition, the capacity of patie
enzyme-containing liposomes ex vivo will be determined.  The activity of the liberated 
marker enzyme is proportional to the complement activity in the sample 
(Jaskowski et al. 1999) and thus, a surrogate for the complement inhibitory activity of 
to assess the interaction with the target.  Moreover, plasma free hemoglobin and serum 
haptoglobin will also be examined to complement the LDH end point in evaluating 
intravascular hemolysis prevention. 
Additional other biomarkers, including red cell clone size, markers from the complement 
system, and markers for intra- and extra-vascular hemolysis (e.g., C3d on RBCs) may 

 
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be measured in blood samples.  An interplay between the complement and coagulation 
systems may contribute to thrombosis in PNH (Keragala et al. 2018).  Thus, D-dimer, the 
marker from the coagulation system, may also be measured. 
3.3.5 
Rationale for Patient-Reported Outcomes 
Patients with PNH experience persistent intravascular hemolysis that causes anemia, 
hemoglobinuria, and a variety of disease-related symptoms that can negatively impact 
their day-to-day functioning and QoL.  Patients report significant fatigue that is 
disproportionate to their degree of anemia (Hillmen et al. 2006), as well as dyspnea, 
headaches, abdominal pain, dysphagia, chest pain, and erectile dysfunction in men 
(Weitz et al. 2013; Schrezenmeier et al. 2014; Yenerel et al. 2017).  Experience of these 
symptoms, particularly fatigue, is in turn associated with decreased functioning and 
HRQoL (Schrezenmeier et al. 2014). 
To characterize the HRQoL of adult patients in this study, fatigue will be assessed using 
the FACIT-Fatigue while physical functioning, role functioning, and general health 
status/QoL will be assessed using selected scales of the EORTC QLQ-C30.  These are 
validated patient-reported outcome (PRO) measures that have been shown to be 
relevant to patients with PNH (Weitz et al. 2013).  Age appropriate, self-report pediatric 
measures, the PedsQL MFS and physical functioning scale of the PedsQL Core, will be 
used to assess fatigue and physical functioning in adolescent patients, respectively.  The 
EQ-5D-5L will be administered for the purpose of producing health utility scores for 
economic modeling. 
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
Approximately 50 patients with PNH will be enrolled in this study. 
4.1.1 
Inclusion Criteria 
All patients must meet the following criteria for study entry: 
 
Signed Informed Consent Form (ICF) 
 
Signed Assent Form when appropriate, as determined by patient's age and 
individual site and country standards 
 
Age 12 years at time of signing ICF or Assent Form 
 
Body weight 40 kg at screening 
 
Willingness and ability to comply with all the study visits and procedures 
 
Documented diagnosis of PNH, confirmed by high sensitivity flow cytometry 
evaluation of WBCs with granulocyte or monocyte clone size of 10%, within 
6 months prior to screening 
 
LDH level 2 ULN at screening (as per central assessment) 

 
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Patients who have at least four transfusions during 12 months prior to screening 
(documented in the medical record) 
 
Presence of one or more of the following PNH-related signs or symptoms within 
3 months of screening:  fatigue, hemoglobinuria, abdominal pain, shortness of 
breath (dyspnea), anemia (hemoglobin 10 g/dL), history of a MAVE (including 
thrombosis), dysphagia, or erectile dysfunction, or history of pRBC transfusion 
because of PNH 
 
Vaccination against Neisseria meningitidis serotypes A, C, W, and Y 3 years prior 
to initiation of study treatment (Day 1).  Vaccination against serotype B should be 
administered in accordance with the most current local guidelines or SOC, as 
applicable in patients with complement deficiency.  If not previously administered 
or no longer current, vaccination must be completed no later than 1 week after the 
first study drug administration.  Vaccination currency with vaccination against 
serotypes A, C, W, Y and B should be maintained throughout the study, according 
to local guidelines or SOC as applicable in patients with complement deficiency.  
In the absence of clear local guidelines for Neisseria meningitidis, the Advisory 
Committee on Immunization Practices 2020 Guidelines are recommended. 
If vaccination is completed 
 2 weeks prior to initiation or after the start of study 
treatment, appropriate antibiotic prophylaxis must be maintained from first study 
drug administration, continuing for at least 2 weeks after completion of 
vaccination or according to local SOC as applicable in patients with complement 
deficiency, whichever is longer.  If vaccination is administered during screening, 
and prophylactic antibiotics are not to be administered, the vaccination must take 
place at least 2 weeks prior to the first dose of study drug.  Patients who refuse 
vaccination against Neisseria meningitidis are not eligible for the study. 
 
Vaccination against Haemophilus influenzae type B and Streptococcus pneumonia 
according to national vaccination recommendations  
 
Patients who have been vaccinated (partially or in full) against SARS-CoV-2 with a 
locally approved vaccine are eligible to be enrolled in the study, 3 days or longer 
after inoculation.  Patients who have not been vaccinated against SARS-CoV-2 are 
also eligible to be in the study. 
 
Platelet count 
 30,000/mm3 at screening without transfusion support within 7 days 
of lab testing. 
 
ANC 
 500/ l at screening 
 
Short-acting granulocyte colony-stimulating factors (G-CSFs) must not have 
been administered within 14 days of lab testing. 
 
Long-acting G-CSFs must not have been administered within 28 days of lab 
testing.  
 
For patients receiving other therapies (e.g., immunosuppressants, corticosteroids, 
iron supplements, anticoagulants, erythrocyte-stimulating agents):  stable dose for 
28 days prior to screening and up to the first drug administration 

 
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Adequate hepatic function, with ALT 3 ULN at the time of screening; no clinical 
signs or known laboratory/radiographic evidence consistent with cirrhosis 
 
Adequate renal function, defined as serum creatinine 2.5 ULN and creatinine 
clearance by Cockcroft-Gault formula 30 mL/min 
 
For female patients of childbearing potential:  agreement to remain abstinent (refrain 
from heterosexual intercourse) or use contraception, as defined below: 
Female patients of childbearing potential must remain abstinent or use 
contraceptive methods with a failure rate of 1% per year during the treatment 
period and for 46 weeks (approximately 10.5 months) after the final dose of 
crovalimab. 
A female patient is considered to be of childbearing potential if the patient is 
postmenarcheal, has not reached a postmenopausal state ( 12 continuous 
months of amenorrhea with no identified cause other than menopause), and is 
not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations. 
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.  If 
required per local guidelines or regulations, locally recognized acceptable 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form. 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Current or previous treatment with a complement inhibitor 
 
History of allogeneic bone marrow transplantation 
 
History of N. meningitidis infection within 6 months prior to screening and up to first 
drug administration  
 
Known or suspected immune deficiency (e.g., history of frequent recurrent infections) 
 
Known or suspected hereditary complement deficiency 
 
Known HIV infection with CD4 count<200 cells/ L within 24 weeks prior to screening 
Patients with HIV infection who have CD4>200 cells/ L and meet all other 
criteria are eligible 

 
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Infection requiring hospitalization or treatment with intravenous (IV) antibiotics within 
28 days prior to screening and up to the first drug administration, or oral antibiotics 
within 14 days prior to screening and up to the first drug administration 
 
Active systemic bacterial, viral, or fungal infection within 14 days before first drug 
administration  
 
Presence of fever ( 38 C) within 7 days before the first drug administration 
 
Splenectomy 6 months before screening 
 
Immunized with a live attenuated vaccine within 1 month before first drug 
administration  
 
History of malignancy within 5 years prior to screening and up to the first drug 
administration, with the following exceptions: 
Patients with any malignancy treated with curative intent and the malignancy 
has been in remission without treatment for 5 years prior to the first drug 
administration are eligible. 
Patients with curatively treated basal or squamous cell carcinoma of the skin or 
in situ carcinoma of the cervix at any time prior to the first drug administration, 
with no evidence of recurrence are eligible. 
Patients with low-grade, early-stage prostate cancer (Gleason score 6 or below, 
Stage 1 or 2) with no requirement for therapy at any time prior to the first drug 
administration are eligible. 
 
History of myelodysplastic syndrome with Revised International Prognostic Scoring 
System (IPSS-R) prognostic risk categories of intermediate, high, and very high 
 
History of hypersensitivity, allergic, or anaphylactic reactions to any ingredient 
contained in crovalimab, including hypersensitivity to human, humanized, or murine 
monoclonal antibodies or known hypersensitivity to any constituent of the product 
 
Pregnant, breastfeeding, or intention of becoming pregnant during the study or 
within 46 weeks (or approximately 10.5 months) after the final dose of the study 
treatment 
Female patients of childbearing potential must have a negative serum 
pregnancy test result within 28 days prior to initiation of study drug. 
 
Participation in another interventional treatment study with an investigational agent 
or use of any experimental therapy within 28 days of screening or within 5 half lives 
of that investigational product, whichever is greater 
 
 
 
Concurrent disease, treatment, procedure or surgery, or abnormality in clinical 
laboratory tests that could interfere with the conduct of the study, may pose any 
additional risk for the patient, or would, in the opinion of the investigator, preclude 
ticipation in and completion of the study 
 

 
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4.2 
METHOD OF TREATMENT ASSIGNMENT 
This is a single-arm study.  Patients with PNH who have never received anti C5 
treatment prior to study entry and fulfill the entry criteria at screening will be enrolled to 
receive crovalimab treatment. 
After written informed consent has been obtained and eligibility has been established, 
the study site will enter demographic and baseline characteristics in the Interactive 
Voice/Web Response System (IxRS).  For those patients who are eligible for enrollment, 
 
Patients should be screened within 28 days prior to the first drug administration; 
otherwise, patients must be re-screened to determine if they continue to meet the 
inclusion and exclusion criteria.  Patients who do not meet the criteria for participation in 
this study (screen failure) may qualify for two re-screening opportunities (for a total of 
three screenings per patient) at the investigator's discretion.  If a patient has previously 
been enrolled in this study, they cannot be re-screened. 
4.3 
STUDY TREATMENT 
The investigational medicinal product (IMP) for this study is crovalimab. 
4.3.1 
Study Treatment Formulation, Packaging, and Handling 
4.3.1.1 
Crovalimab 
Crovalimab will be supplied by the Sponsor in a formulation suitable for IV and SC 
administration.  For information on the formulation and handling of crovalimab, see the 
pharmacy manual and the 
 
Crovalimab for IV Infusion and SC Administration 
Crovalimab vials will be supplied by the Sponsor as a solution for infusion (IV)/solution 
for injection (SC) from a single-use vial, which contains an extractable volume of 1 mL 
(170 mg [nominal]) crovalimab or an extractable volume of 2 mL (340 mg [nominal]) 
crovalimab. 
For IV infusion, crovalimab solution for infusion is diluted in 0.9% (w/v) sodium chloride 
solution prior to administration.  
For SC administration, crovalimab solution for injection is used undiluted.  In order to 
minimize the number of SC injections for patients, the administration per single injection 
of up to 2 mL drug product solution is permitted.  Considerations for vial pooling are as 
follows: 
 
The 1 mL (170 mg) configuration will require combining of crovalimab drug product 
solution (vial pooling) from two 1-mL vials into a single syringe, as described in the 
pharmacy manual.  

 
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For all patients, weight will be assessed at screening, at Weeks 13, 25, 33, and every 
8-12 
changes by 10% or more (compared with screening or the visit when the latest dose 
modification occurred, whichever is later), to exceed or become equal to 100 kg or to fall 
below 100 kg during the course of therapy. 
Patients with two or more qualifying intravascular hemolysis events that occur in 
24 weeks without an identifiable trigger (such as an infectious trigger) and patients with 
sustained intravascular hemolysis also occurring without an identifiable trigger may be 
considered for an increased maintenance dose in consultation with the Medical Monitor 
(Section 5.1.2.1). 
If a dose of crovalimab is missed, administer as soon as possible and then resume usual 
doing schedule.  Do not administer two doses on the same day to make up for missing 
doses.  Resuming treatment after longer than 28 days of interruption should be done in 
consultation with the Medical Monitor.  
Training for At-Home Administration 
The first five SC doses (Day 2 of Week 1, and Weeks 2, 3, 4, and 5) must be 
administered in a monitored setting, such as an infusion center, clinic, or hospital, 
Over the course of the first five SC doses, patients will be trained in SC administration of 
crovalimab by a HCP.  The HCP will explain the process used for SC injection, facilitated 
by Instructions for Use written specifically for crovalimab.  Through this process under 
supervision, the patient and/or caregiver will gain proficiency in the correct and safe 
self-administration of SC crovalimab.   
Crovalimab is intended to be self-administered as an SC injection Q4W in the home 
setting, after in-clinic training and supervised self-administration.  The SC 
administrations should be performed by the patient under the observation of a HCP prior 
to starting home administration.  At that time, the HCP will evaluate the self-injection 
capability of each patient and/or caregiver.  Self-injection by the patient or injection by 
the caregiver will be allowed only once the HCP certifies that adequate proficiency was 
achieved.  At Week 9, SC injections may be self-administered at home by the patient or 
caregiver if the HCP has confirmed proficiency.  Additional training and guidance by a 
HCP will be available to each patient, at the discretion of the patient or the investigator.  
Patients have the option to come to the clinic for treatment administration, if he/she 
prefers.   
Patient compliance with at-home-administration will be assessed in two ways during the 
study:  1) patients will record self-administered doses in a patient diary and will bring this 
diary to each clinic visit as a record of self-administration and 2) patients will bring their 
used drug vials in their boxes (including the labels) to each clinic visit for verification of 
use.   

 
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Under certain circumstances, crovalimab, which is required by the patient for 
continued study participation, could be shipped directly to the patient.  Circumstances 
that may necessitate shipments to the patient include, but are not limited to:  home 
visits due to the COVID-19 pandemic or reduction of patient burden and/or obligation 
in attending study site(s) for the sole purpose of drug administration.   
The schedule of activities is provided in Appendix 1. 
4.3.3 
Rescue Dosing: Crovalimab IV 
If a patient experiences signs and symptoms of his or her underlying PNH, such as BTH, 
which may be due to an acute event such as acute illness, trauma, or surgery, one or 
more additional IV doses of crovalimab may be administered based on investigator 
assessment.  Prior to this IV dose, unscheduled laboratory assessments (e.g., LDH, PK, 
ADA, biomarker [refer to Section 4.5.8 and Appendix 1] and other appropriate clinical 
investigations) should be done to further characterize the BTH and evaluate the 
underlying cause.  The recommended dose to be administered is crovalimab IV 340 mg 
(regardless of body weight) to be infused over 30 minutes. 
The investigator should inform the Sponsor within 24 hours of the time of the decision to 
administer a rescue IV dose and record this additional dose on the eCRF.  For situations 
in which a patient requires more than one additional dose in less than 1 month, the 
investigator needs to justify the need with the Sponsor before initiation of another dose. 
In general, investig
clinically indicated, per local standard practice (see Section 4.4.1). 
4.3.4 
Investigational Medicinal Product Handling and Accountability 
The IMP for this study is crovalimab.  Crovalimab required for completion of this study 
will be provided by the Sponsor.  The study site will acknowledge receipt of IMP supplied 
by the Sponsor using the IxRS to confirm the shipment condition and content.  Any 
damaged shipments will be replaced. 
The IMP will either be disposed of at the study site according to the study site's 
institutional standard operating procedure or be returned to the Sponsor with the 
appropriate documentation.  The site's method of destroying Sponsor-supplied IMP must 
be agreed to by the Sponsor.  The site must obtain written authorization from the 
Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must be 
documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log. 

 
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4.3.5 
Continued Access to Crovalimab 
The Sponsor will offer continued access to Roche IMP (crovalimab) free of charge to 
eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below. 
A patient will be eligible to receive Roche IMP (crovalimab) after completing the study if 
all of the following conditions are met: 
 
The patient has a life-threatening or severe medical condition and requires 
continued Roche IMP treatment for his or her well-being 
 
There are no appropriate alternative treatments available to the patient 
 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
 
A patient will not be eligible to receive Roche IMP (crovalimab) after completing the 
study if any of the following conditions are met: 
 
The Roche IMP is commercially marketed in the patient's country and is 
reasonably accessible to the patient (e.g., is covered by the patient's insurance 
or would not otherwise create a financial hardship for the patient) 
 
The Sponsor has discontinued development of the IMP or data suggest that the 
IMP is not effective for PNH 
 
The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
PNH 
 
Provision of the Roche IMP is not permitted under the laws and regulations of the 
patient's country 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
4.4 
CONCOMITANT THERAPY 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from the first 
screening visit prior to initiation of study drug until 46 weeks (approximately 
10.5 months) after the final dose of crovalimab.  All such medications should be 
reported to the investigator and recorded on the Concomitant Medications eCRF. 
4.4.1 
Permitted Therapy 
Patients are permitted to use the following therapies during the study: 
 
Oral contraceptives with a failure rate of 1% per year (see Section 4.1.1) 
 
Immunosuppressant therapy 

 
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Corticosteroids 
 
Iron supplements 
 
Folic acid 
 
pRBC transfusion 
 
Patients may receive other concomitant medication which must be recorded in the 
Concomitant Medication eCRF. 
In general, investigators should manage a patient's care with supportive therapies as 
clinically indicated, per local standard practice.  Patients who experience 
infusion associated symptoms may be treated symptomatically with acetaminophen, 
ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, 
cimetidine), or equivalent medications per local standard practice.  Serious 
infusion-associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen 
and 
2-adrenergic agonists). 
4.4.2 
Cautionary Therapy 
4.4.2.1 
Medications Given with Precaution due to Effects Related to 
CYP Enzymes 
To date, no PD drug drug interaction studies have been conducted. 
4.4.2.2 
Herbal Therapies 
Concomitant use of herbal therapies (such as traditional Chinese medicine) is strongly 
not recommended because their pharmacokinetics, safety profiles, and potential 
drug drug interactions are generally unknown.  However, herbal therapies may be used 
during the study at the discretion of the investigator and in consultation with the 
Medical Monitor. 
4.4.3 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited as described below: 
 
Investigational therapy (other than protocol-mandated study treatment) is 
prohibited within 28 days (or 5 half-lives) prior to initiation of study treatment and 
during study treatment 
 
Other complement inhibitors  
 
4.5 
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each patient. 
At the Week 46 safety follow-up telephone call, female patients of childbearing potential 
will independently conduct a home pregnancy study assessment within two days prior 

 
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to the scheduled call, the results of which will be reported during the call (see 
Appendix 1). 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  ICFs for 
enrolled patients and for patients who are not subsequently enrolled will be maintained 
at the study site.  Adolescent patients aged 12 17 years will complete and sign an 
Informed Assent Form, and their parent or a legally authorized representative will 
complete an Informed Consent Form. 
All screening evaluations must be completed within 28 days prior to the first dose and 
reviewed to confirm that patients meet all eligibility criteria before enrollment.  If 
re screening is required, then viral testing from the initial screening may be acceptable 
for screening assessment if performed 60 days prior to the first drug administration.  
The investigator will maintain a detailed record of all patients screened and document 
eligibility or record reasons for screening failure, as applicable. 
4.5.2 
Medical History, Baseline Conditions, Concomitant Medication, 
and Demographic Data 
All the medical records should be provided to the investigators in the site for eligibility 
check and medical history data collection, including data of PNH history, covering the 
date of diagnosis, and clone size by high sensitivity flow cytometry within 6 months prior 
to screening (if available) should be recorded, as well as documentation of the details of 
transfusion treatment, transfusion episodes, number of pRBC units used and dates of 
transfusion within the past 12 months prior to screening.  Transfusion history should 
meet the transfusion criteria specified in Section 4.5.7.  Records of LDH, hemoglobin, 
BTH and thrombotic events with dates within 24 weeks prior to screening will also be 
collected.  
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
immunization history, use of alcohol and drugs of abuse, will be recorded at screening.  
In addition, all medications (e.g., prescription drugs, over-the-counter drugs, vaccines, 
herbal or homeopathic remedies, and nutritional supplements) used by the patient from 
when the Informed Consent Form is signed until 46 weeks (approximately 10.5 months) 
after the final dose of crovalimab will be recorded.  At the time of each follow up 
physical examination, an interval medical history should be obtained and any changes in 
medications and medical conditions should be recorded. 
Demographic data will include age, sex, and self-reported race/ethnicity. 

 
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4.5.3 
Physical Examinations 
A complete physical examination will be performed at screening in all patients and 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems.  For all patients, weight will be measured at 
screening, at Weeks 13, 25, 33, and every 8 12 weeks thereafter.  Any abnormality 
identified at baseline should be recorded on the General Medical History and Baseline 
Conditions eCRF.  Special focus should be on signs and symptoms of infections as 
detailed in the Crovalimab 
 Brochure. 
Limited, symptom-directed physical examinations should be performed at post baseline 
visits and as clinically indicated.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF. 
4.5.4 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, temperature, and 
systolic and diastolic blood pressure while the patient is in a seated position.  Record 
abnormalities observed at baseline on the General Medical History and Baseline 
Conditions eCRF.  At subsequent visits, record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF. 
4.5.5 
Immunizations 
Vaccination may further activate complement.  As a result, patients with 
complement-mediated diseases, including PNH, may experience increased signs and 
symptoms of their underlying disease, such as hemolysis.  Patients should be closely 
monitored for disease symptoms after receiving vaccination.  
4.5.5.1 
N. meningitidis, H. influenzae Type B, and S. pneumonia 
Vaccinations 
Vaccination against N. meningitidis serotypes A, C, W, and Y must be administered 
 3 years prior to initiation of study treatment; or, if not previously done, vaccination must 
be administered no later than one week after the first drug administration.  Vaccination 
against serotype B should be administered in accordance with the most current local 
guidelines or SOC, as applicable in patients with complement deficiency.  Vaccination 
currency with vaccination against serotypes A, C, W, Y and B should be maintained 
throughout the study in accordance with the most current local guidelines or SOC as 
applicable in patients with complement deficiency.   
In the absence of clear local guidelines for N. meningitidis, the Advisory Committee on 
Immunization Practices 2020 Guidelines are recommended (Mbaeyi et al. 2020).  If 
vaccination is completed 
 2 weeks prior to initiation or after the start of study 
treatment, appropriate antibiotic prophylaxis must be maintained from first study drug 
administration, continuing for at least 2 weeks after completion of vaccination or 

 
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according to local SOC as applicable in patients with complement deficiency, whichever 
is longer.  If vaccination is administered during screening, and prophylactic antibiotics 
are not to be administered, the vaccination must take place at least 2 weeks prior to the 
first dose of study drug. 
H. infuenzae type B, and S. pneumonia vaccinations should be done in accordance with 
current local guidelines or standard of care as applicable in patients with complement 
deficiency.  These vaccinations may be administered any time between Screening Day 
28 and one week after the first drug administration.   
Patients who receive the vaccines within 2 weeks prior to initiating study treatment or 
after the start of study treatment must receive appropriate prophylactic antibiotics from 
initiation of study treatment, continuing for at least 2 weeks after the vaccination.  
Additional infection prevention measures per local guidelines are permissible. 
4.5.5.2 
Other Vaccinations 
Any other vaccines (with the exception of vaccines discussed in Section 4.5.5.1) should 
not be administered on the same day as a crovalimab administration but, ideally, at a 
time point between Day 3 after a maintenance dose and Day 3 before the next 
maintenance dose administration.  Live vaccinations should be discussed with the 
Medical Monitor.   
Vaccinations against SARS-CoV-2 (including locally approved vaccines) are permissible 
during the course of the study.  The administration of the vaccine against SARS-CoV-2 
should ideally follow the schedule recommended above for other vaccines. 
4.5.6 
Breakthrough Hemolysis 
Monitoring of BTH will occur on an ongoing basis during the study.  Investigators will 
document symptoms of BTH and provide the local LDH, hemoglobin, total and direct 
bilirubin results, once available, in the eCRF.   
In addition, as soon as possible, blood samples will have to be drawn for central testing:  
LDH, free hemoglobin and haptoglobin, pharmacokinetics, ADA, and PNH clone size.  
Biomarkers from the complement system, and biomarkers for intra and extra-vascular 
hemolysis (e.g., C3d on RBCs) as well as the marker of endothelial cell activation and 
markers from the coagulation system (e.g., D dimer) may be also tested.  If blood 
transfusions are required, the number of units of pRBCs will be documented in the 
eCRF. 
4.5.7 
Transfusions 
A pRBC transfusion can be administered when a patient meets either of the following 
criteria: 
 
Hemoglobin value 9 g/dL, with signs and symptoms of sufficient severity to 
warrant a transfusion per the clinical judgment of the investigator 

 
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Hemoglobin value 7 g/dL, regardless of presence of clinical signs or symptoms 
 
The clinical signs and symptoms of anemia that may warrant a transfusion include 
angina, syncope, lightheadedness, confusion, severe or worsening shortness of breath, 
severe or worsening fatigue, stroke, transient ischemic attack, or new or worsening heart 
failure. 
If a patient meets either of the transfusion criteria above, the investigator will determine 
the appropriate number of units of pRBCs to be administered.  It is recommended that 
the transfusion be administered within 48 hours of the hemoglobin determination 
precipitating the transfusion. 
If there is a compelling need to deviate from these transfusion guidelines, the 
Medical Monitor should be consulted before the transfusion is administered. 
Prior to enrollment and within 5 days of Week 1 Day 1 of study drug administration, the 
meets the criteria above for transfusion, the patient must be transfused with pRBCs to a 
post-transfusion hemoglobin value should be confirmed to be above the transfusion 
threshold. 
For transfusions during the study, the signs and symptoms of anemia associated with a 
transfusion, and the number of units transfused should all be documented in the eCRF. 
4.5.8 
Laboratory, Biomarker, and Other Biological Samples 
Laboratory assessments for LDH, potassium, hematology, chemistry, coagulation, 
urinalysis, biomarker, and PK assessments will be taken as specified in the schedule of 
activities (Appendix 1).  Refer to the laboratory manual for additional details on 
laboratory assessments and sample handling.  On days of study drug administration, 
laboratory samples should be drawn before the administration of the study drug. 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
 
Hematology:  RBC count, hemoglobin, hematocrit, platelet count, reticulocytes 
absolute count (percentage count may be reported if the absolute count is not 
available), WBC count and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells) 
 
Chemistry panel (serum or plasma):  sodium, potassium, chloride, bicarbonate or 
total carbon dioxide (if considered SOC for the region), glucose, BUN or urea, 
creatinine, total protein, albumin, phosphate, calcium, total and direct bilirubin, ALP, 
ALT, AST, and LDH 

 
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Coagulation:  partial thromboplastin time (PTT)/activated PTT (aPTT), prothrombin 
time (PT)/international normalized ratio (INR) 
 
Screening PNH clone size 
 
LDH levels 
This sample should also be taken for unplanned events, such as BTH or for 
other unforeseen events as clinically appropriate 
If unscheduled LDH measurements are taken for determination of sustained 
intravascular hemolysis (see Section 5.1.2.1), they must be recorded on the 
eCRF. 
 
Pregnancy test (urine and/or serum) 
All female patients of childbearing potential will have a serum pregnancy test at 
screening.  Either urine or serum pregnancy tests will be performed at specified 
subsequent visits.  Additionally, at the end of the study, a urine pregnancy 
test will be performed by the patient no more than 2 days before the 46-week 
(approximately 10.5 months) safety telephone call.  The patient should report 
the result of the pregnancy test during the telephone call.  If a urine pregnancy 
test is positive, including the home urine pregnancy test at week 46 of the 
safety follow-up, it must be confirmed by a serum pregnancy test. 
 
Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, blood) 
If there is a clinically significant positive result (i.e., confirmed by a positive 
repeat sample), urine will be sent to the laboratory for microscopy and culture 
(sediment, RBCs, WBCs, casts, crystals, epithelial cells, bacteria).  If there is a 
known explanation for the positive dipstick result (e.g., menses), it should be 
recorded and there is no need to perform laboratory for microscopy and culture. 
For patients randomized or enrolled to receive crovalimab treatment, during the 
first 10 weeks on crovalimab, a urine sample should be sent directly to the 
laboratory for microscopy, urine protein, urine creatinine, and urine 
micro-albumin.  No prior dipstick test is needed.  
 
The following samples will be sent to one or several central laboratories, to the Sponsor, 
or to a designee for analysis: 
 
Serum sample for measurement of LDH and potassium levels 
 
Serum sample for measurement of total and free C5 concentration 
 
Serum sample for measurement of LIA 
 
Serum sample for measurement of haptoglobin levels 
 
Plasma sample for measurement of free hemoglobin 
 
Blood sample for PNH clone size with C3d on RBC for all post-screening 
measurements 
 
Plasma sample for D-dimer testing 
 
Serum ADA sample for crovalimab immunogenicity analysis 

 
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Serum PK sample for crovalimab PK analysis 
 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional other research, biological samples will be destroyed no later than 5 years after 
the final Clinical Study Report has been completed. 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4. 
Given the complexity and exploratory nature of other biomarker analyses, data derived 
from these analyses will generally not be provided to study investigators or patients 
unless required by law.  The aggregate results of any conducted research will be 
available in accordance with the effective Sponsor policy on study data publication. 
4.5.9 
Electrocardiograms 
Single electrocardiogram (ECG) recordings will be obtained at specified timepoints, as 
outlined in the schedule of activities (see Appendix 1), and may be obtained at 
unscheduled timepoints as indicated. 
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes.  
All ECGs are to be obtained prior to other procedures (except PROs) scheduled at that 
same time (e.g., vital sign measurements, blood draws) and should not be obtained 
within 3 hours after any meal.  Circumstances that may induce changes in heart rate, 
including environmental distractions (e.g., television, radio, conversation) should be 
avoided during the pre-ECG resting period and during ECG recording. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Digital recordings will be stored at site.  The following should be 
recorded in the appropriate eCRF:  heart rate, RR interval, QRS interval, PR duration, 
uncorrected QT interval, and QT interval corrected through use of Fridericia's formula 
(QTcF) based on the machine readings of the individual ECG tracings.  Any morphologic 

 
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waveform changes or other ECG abnormalities must be documented on the eCRF.  If 
considered appropriate by the Sponsor, ECGs may be analyzed retrospectively at a 
central laboratory. 
If at a particular timepoint the mean QTcF is  
 500 ms and/or  
 60 ms longer than the 
baseline value, another ECG must be recorded, ideally within the next 5 minutes, and 
ECG monitoring should continue until QTcF has stabilized on two successive ECGs.  
The Medical Monitor should be notified.  SOC treatment may be instituted per the 
discretion of the investigator.  If a PK sample is not scheduled for that timepoint, an 
unscheduled PK sample should be obtained.  A decision on study drug discontinuation 
should be made, as described in Section 5.1.  The investigator should also evaluate the 
patient for potential concurrent risk factors (e.g., electrolyte abnormalities, 
co-medications known to prolong the QT interval, severe bradycardia). 
4.5.10 
Patient-Reported Outcomes 
PRO instruments will be completed to assess the treatment benefit of crovalimab.  In 
addition, PRO instruments (Section 4.5.10.2) will enable the capture of each patient's 
direct experience with crovalimab. 
PRO data will be collected through use of the following instruments: 
 
For adult patients (aged 18 years):  FACIT-Fatigue, EORTC QLQ-C30 (select 
scales) 
 
For adolescent patients (aged 12-17 years): PedsQL Core and the PedsQL MFS 
(Physical Functioning scale) 
 
EQ-5D-5L 
 
4.5.10.1 
Data Collection Methods for Patient-Reported Outcomes 
PRO instruments will be self-administered at the clinic at the specified timepoints during 
the study (see schedule of activities in Appendix 1).  At the clinic visits, instruments will 
be administered before the patient receives any information on disease status and prior 
to the administration of study treatment.  Instruments should be administered prior to the 
performance of non-PRO assessments whenever possible. 
PRO instruments, translated into the local language and validated as appropriate, will be 
provided by the Sponsor in pre-printed booklets to enable the instrument to be 
administered at each specified timepoint.  The booklets will be labeled with the timepoint 
of administration.  Following completion, data will be entered into the study database by 
site personnel. 
During clinic visits, PRO instruments should be administered as outlined below: 
 
Patients' health status should not be discussed prior to administration of the 
instruments. 

 
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Sites must administer the official version of each instrument, as provided by the 
Sponsor.  Instruments must not be copied from the protocol. 
 
Sites should allow sufficient time for patients to complete the instruments, estimated 
to be about 10 minutes at each specified visit to complete them all. 
 
Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions. 
 
Patients should be instructed to answer questions to the best of their ability; there 
are no right or wrong answers. 
 
Site staff should not interpret or explain questions, but may read questions verbatim 
upon request. 
 
Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments. 
 
Site staff should review all completed instruments and should ask the patient to 
rectify any response that is not clearly marked in the appropriate location.  If a 
response is missing, site staff should ask the patient to complete the item or confirm 
that the item was intentionally left blank. 
 
4.5.10.2 
Description of Patient-Reported Outcome Instruments 
FACIT-Fatigue 
The FACIT-Fatigue (Version 4) is a validated, reliable self-report measure for use in a 
variety of conditions, including anemia (Yellen et al. 1997; Cella et al. 2005; 
Lai et al. 2011; Acaster et al. 2015).  Recent content validation research supports its use 
in patients with PNH finding it is well understood and comprehensively covers 
PNH related fatigue (Weitz et al. 2013).  The FACIT-Fatigue consists of 13 items that 
assess fatigue using a 7-day recall period.  Items are scored on a response scale that 
ranges from 0 
and all items are summed to create a total score, with a higher score indicative of better 
functioning (i.e., less fatigue).  This instrument will be administered to adult patients only. 
EORTC QLQ-C30 
The EORTC QLQ-C30 (Version 3) is a validated, reliable self-report measure 
(Aaronson et al. 1993; Fitzsimmons et al. 1999).  Although the measure was originally 
developed for use in patients undergoing cancer treatment, recent content validation 
research supports its use in patients with PNH (Weitz et al. 2013).  It consists of 
30 questions that assess five aspects of patient functioning (physical, emotional, role, 
cognitive, and social), three symptom scales (fatigue, nausea and vomiting, and pain), 
global health status and QoL, and six single items (dyspnea, insomnia, appetite loss, 
constipation, diarrhea, and financial difficulties), with a recall period of the previous 
week.  Scale scores can be obtained for the multi-item scales.  The functioning and 
symptom items are scored on a 4-
and the global health status/QoL items are scored on a 7-point scale that ranges from 
her scores indicate higher response levels (i.e., higher 

 
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health-related QoL, higher symptom severity).  This measure will be administered to 
adult patients only.  Patients will complete a truncated version of the measure (EORTC 
IL17) that includes only the physical functioning, role functioning, and global health 
status/QoL scales. 
PedsQL Core 
The PedsQL Core (Version 4) is a valid, reliable measure for assessing HRQoL in 
healthy children and adolescents, and those with acute or chronic health conditions 
(Varni et al. 2001, 2007).  Self-report versions are available for children and adolescents 
that contain developmentally appropriate language for defined age groups (i.e., 5 7, 
8 12, 13 18 years).  This version contains 23 items that are scored into four respective 
domains: physical functioning (8 items), emotional functioning (5 items), social 
functioning (5 items), and school functioning (5 items).  Physical and psychosocial health 
summary scores, as well as an overall total score, can be created by further combining 
domains.  Domain and total scores are converted to a 0 100 scale, with higher scores 
indicative of better functioning.  For this study, only the physical functioning scale of the 
adolescent self-report version with a 1-week recall period (i.e., acute adolescent version) 
will be used for patients 12 17 years old, as the wording is the same for this scale in the 
8 12 and 13 17 self-report versions. 
PedsQL MFS 
The PedsQL MFS is a valid, reliable measure for assessing fatigue in healthy children 
and adolescents, and those with a range of acute and chronic health conditions 
(e.g., Varni et al. 2002, 2004, 2009, 2013; Panepinto et al. 2014).  Self-report versions 
are available for children and adolescents that contain developmentally appropriate 
language for defined age groups (i.e., 5 7, 8 12, 13 18 years).  This version contains 
18 items that are scored into three respective domains: general fatigue (6 items), 
sleep/rest fatigue (6 items), and cognitive fatigue (6 items).  Domains can be further 
combined into an overall total fatigue score.  Domain and total scores are converted to a 
0 100 scale, with higher scores indicative of lower fatigue.  For this study, the 
adolescent self-report version with a 1-week recall period (i.e., acute adolescent version) 
will be used for patients 12 17 years old, as the wording is the same in the 8 12 and 
13 17 self-report versions. 
EQ-5D-5L 
The EQ-5D-5L, is a validated self-reported health status questionnaire that is used to 
calculate a health status utility score for use in health economic analyses 
(EuroQol Group 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013).  There 
are two components to the EQ-5D-5L:  a five-item health state profile that assesses 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, as well as a 
VAS that measures health state.  The EQ-5D-5L is designed to capture the patient's 
current health status.  Published weighting systems allow for creation of a single 
composite score of the patient's health status.  The EQ 5D 5L will be administered to 

 
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adult and adolescent patients and takes approximately 3 minutes to complete.  It will be 
used in this study for informing pharmacoeconomic evaluations. 
4.6 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment if they experience any of the 
following: 
 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment 
 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient 
 
Symptomatic deterioration attributed to disease progression, if judged by the 
investigator that continuation with treatment is not in the pat
 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 
Discontinuation from crovalimab:  All patients who discontinue from crovalimab 
treatment while on the study will return for a safety follow-up visit 24 weeks after 
treatment discontinuation and a safety telephone call 46 weeks (approximately 
10.5 months) after treatment discontinuation.  Patients who discontinue crovalimab and 
switch to treatment with another C5 inhibitor should remain in safety follow up.  See 
detailed monitoring guidance in Section 5.1.1 and Appendix 2. 
Pregnancy and study treatment continuation:  If a female patient becomes pregnant, 
study treatment will continue only if it is in the best interest of the patient after an 
assessment of the risks and benefits conducted by the investigator.  For this decision, 
the investigator must consider the potential risks related to the study treatment, the risks 
related to discontinuing treatment, and the risks related to switching to another 
C5-inhibitor (e.g., DTDC-mediated Type III hypersensitivity reactions) in a pregnant 
patient with PNH.  The investigator should counsel the patient regarding the risks to the 
pregnancy and the possible effects on the fetus.  If the investigator decides to continue 
treatment, he or she must consult with the Medical Monitor before proceeding.   
For all patients, the day of the safety follow-up visit represents study discontinuation 
date. 
Patients who discontinue crovalimab without switching to another complement inhibitor 
should be monitored for signs and symptoms of serious intravascular hemolysis for at 
least 20 weeks (see details in Section 5.1.1.7).  

 
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Hemolysis occurring after treatment discontinuation and until completion of the safety 
follow-up visit should be recorded in the eCRF. 
4.6.2 
Patient Discontinuation from the Study 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time. 
Reasons for patient discontinuation from the study may include, but are not limited to, 
the following: 
 
Patient withdrawal of consent 
 
Study termination or site closure 
 
Adverse event 
 
Loss to follow-up 
 
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor 
 
Every effort should be made to obtain a reason for patient discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.  Patients 
who withdraw from the study will not be replaced. 
4.6.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients 
 
Patient enrollment is unsatisfactory 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.   
4.6.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 

 
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5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PLAN 
Crovalimab is not approved by any health authority, and clinical development is ongoing.  
The safety plan for patients in this study is based on clinical experience with crovalimab 
in the ongoing Study BP39144 as well as on the known class effects of available 
marketed C5 inhibitors.  The anticipated important safety risks for crovalimab, as well as 
measures intended to avoid or minimize such toxicities, are outlined below.  Please refer 
to the Crovalimab Investigator's Brochure for a complete summary of safety information. 
Several measures will be taken to ensure the safety of patients participating in this 
study, including the use of stringent inclusion and exclusion criteria (see Section 4.1.1 
and Section 4.1.2 respectively) and close monitoring (see Section 5.1).  Details 
regarding safety reporting for this study are provided in Section 5.4. 
All adverse events and serious adverse events will be recorded during the study and for 
up to 46 weeks (approximately 10.5 months) after the final dose of crovalimab.  After 
this period, investigators should report serious adverse events and adverse events of 
special interest that are believed to be related to prior treatment with crovalimab. 
5.1.1 
Risks Associated with Crovalimab 
5.1.1.1 
Meningococcal Infection 
patients will likely have increased susceptibility to infections, especially with 
encapsulated bacteria. 
Life-threatening and fatal meningococcal infections have occurred in patients treated 
with eculizumab, (Soliris Summary of Product Characteristics [SmPC]; Soliris U.S. 
Prescribing Information [USPI]).  Meningococcal infection may become rapidly 
life-threatening or fatal if not recognized and treated early. 
Patients in clinical studies of crovalimab will receive meningococcal vaccinations as 
described in Section 4.5.5.1. 
All patients should be counseled about the risks and common signs and symptoms of 
meningococcal infections as well as antibiotics therapy. 
Closely monitor patients for early signs and symptoms of meningococcal infection and 
evaluate subjects immediately if an infection is suspected and treat with antibiotics if 
necessary.  Monitoring of subjects for meningococcal infections should be continued for 
at least 46 weeks (approximately 10.5 months) after the last dose of crovalimab.  
Discuss continuation of crovalimab with the Medical Monitor for patients who are 
undergoing treatment for serious meningococcal infections. 

 
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All patients should be counseled about the risks and common signs and symptoms of 
meningococcal infections as well as antibiotics therapy. 
Guidelines for the management of meningococcal infections are provided in Table 2. 
5.1.1.2 
Type III Hypersensitivity Reactions Associated with 
Drug-Target-Drug Complex Formation 
To those patients who have access and switch to other C5-inhibitors after 
discontinuation of crovalimab, Type III hypersensitivity may occur due to the transient 
formation of DTDCs made of other C5-inhibitor, C5 and crovalimab (more details of 
DTDCs could be found in the Crovalimab I
Brochure v4 Section 6.7.2).  To 
minimize the risk, monitoring and management guidelines are provided and only 
applicable to patients who discontinued crovalimab and switched to other C5 inhibitors.  
Characteristics of Type III hypersensitivity reactions associated with DTDC formation 
may include: 
 
Typical onset is delayed by a week or more after dose administration, and the 
reaction may persist for days to over a week 
 
Reactions may involve the skin, joints, and/or kidneys 
 
Typical signs and symptoms may include: purpura; petechial or urticarial rashes 
affecting the lower extremities bilaterally; arthralgia; enlarged and/or tender lymph 
nodes/spleen 
 
Histopathological finding of small vessel vasculitis and laboratory evidence of 
glomerulonephritis  
 
Type III hypersensitivity reactions are not expected to occur after the clearance 
period of DTDCs (see Section 1.2.2.1) 
 
Monitoring for Patients who Discontinue Crovalimab and Switch to Other C5 
Inhibitors 
Generic signs and symptoms of Type III hypersensitivity reactions can include fever, 
malaise, enlarged and tender lymph nodes, enlarged spleen, arthralgias, neuralgias, 
vasculitis, urticarial rashes, purpura, gastrointestinal distress, and glomerulonephritis.  
Laboratory findings could include leukopenia, leukocytosis with eosinophilia, proteinuria, 
and lowered serum C3, C4, and complement hemolytic activity (from consumption). 
Patients might discontinue study treatment with crovalimab and switch to treatment with 
a different C5 inhibitor that binds to a different epitope to crovalimab, at the discretion of 
the treating physician.  Such patients should remain in safety follow-up because of the 
potential risk of developing a DTDC mediated Type III hypersensitivity reaction, 
especially within the first few weeks of switching from crovalimab to other C5 inhibitor.  
Blood samples for monitoring will be collected after the first administration of the 
C5 inhibitor, then once weekly for the first 5 weeks (Weeks 1 5), and then Week 7 and 
Week 9 after switching from crovalimab to another C5 inhibitor (as detailed in 

 
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Appendix 2).  Biopsies of skin manifestations can be done, if considered clinically 
indicated. 
Guidelines for the management of Type III hypersensitivity reactions are provided in 
Table 2. 
Due to the potential risk of DTDC-mediated Type III hypersensitivity reactions, it is 
recommended that patients who discontinue from study and choose not to remain in 
safety follow-up while switching to another C5-inhibitor also be monitored by the treating 
physician in the same manner. 
5.1.1.3 
Other Hypersensitivity Reactions and Infusion-Related 
Reactions 
As with any biologic, there is a risk of hypersensitivity reactions and infusion-related 
reactions, which can range from a mild rash to life-threatening anaphylaxis.  For the first 
IV infusion and the first four SC injections, crovalimab should be administered in a 
clinical environment where resuscitation equipment is available for immediate use. 
Patients and caregivers should be instructed to recognize the signs and symptoms of 
hypersensitivity reactions and to seek immediate medical attention if the patient 
develops symptoms of serious allergic reactions. 
Guidelines for the management of hypersensitivity and infusion-related reactions are 
provided in Table 2. 
5.1.1.4 
Injection-Site Reactions 
As with any SC injections, there is a possible risk of injection-site reactions, which can 
range from slight irritation to possible necrosis. 
Guidelines for the management of injection-site reactions are provided in Table 2. 
5.1.1.5 
Other Infections 
Crovalimab blocks terminal complement activation.  Therefore, patients may have 
increased susceptibility to infections, especially with encapsulated bacteria. 
Guidelines for the management of infections are provided in Table 2. 
5.1.1.6 
Immunogenicity 
Neutralizing antibodies may develop in crovalimab-treated patients, leading to decrease 
or loss of crovalimab exposure with potential impact on clinical response.  
5.1.1.7 
Treatment Discontinuation from Crovalimab without Switching 
to Another Complement Inhibitor 
If patients discontinue treatment with crovalimab, without switching to another 
complement inhibitor, they should be monitored for at least 20 weeks for signs and 

 
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symptoms of serious intravascular hemolysis (e.g., elevated LDH, sudden decrease in 
hemoglobin, or re-appearance of hemolysis symptoms).  
Hemolysis occurring after treatment discontinuation and until completion of the safety 
follow-up visit should be recorded in the eCRF. 
5.1.2 
Management of Patients Who Experience Adverse Events 
Guidelines for the management of adverse events related to crovalimab are outlined in 
Table 2. 
5.1.2.1 
Dose Modifications 
ght changes by 10% or above 
to exceed or become equal to 100 kg or to fall below 100 kg during the course of 
therapy. 
In consultation with the Medical Monitor, dosing modification may also be considered for: 
 
Patients with two or more qualifying intravascular hemolysis events in 24 weeks that 
occur without an identifiable trigger (such as an infectious episode).   
Qualifying intravascular hemolysis events are those consistent with the definition of 
BTH described in Section 2.1.2) that occur within 1 week before the next 
maintenance dose.   
 
Patients with sustained intravascular hemolysis that occur without an identifiable 
trigger.   
Sustained intravascular hemolysis is defined as LDH 
 2 ULN measured at 
3 consecutive assessments and persisting for at least 4 weeks, where each 
LDH 
 2 ULN measurement is accompanied by at least one sign or symptom of 
intravascular hemolysis (listed as part of the BTH definition in Section 2.1.2), during 
the maintenance phase of crovalimab treatment (Week 5 or thereafter).  Local LDH 
measurement at unscheduled assessments may be used to determine the presence 
of sustained intravascular hemolysis, and must be recorded on the eCRF. 
Patients for whom a dose modification is appropriate based on the criteria described 
above will increase their maintenance dosing regimen indefinitely, for the duration of the 
crovalimab treatment, as follows:   
 
Patients with body weight 
 40 kg to 
 100 kg would increase their maintenance 
dose from 680 mg Q4W to 1020 mg Q4W 
 
Patients with body weight  
 100 kg would increase their maintenance dose from 
1020 mg Q4W to 1360 mg Q4W. 
 
Patients whose maintenance dose is increased due to experiencing two or more 
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have additional laboratory assessments performed as follows (also see Appendix 1, 
Tables 1 and 2):   
 
The patient’s LDH, PK, PD, and ADA should be assessed centrally before the first 
administration of the increased maintenance dose and four weeks after the first 
administration of the increased maintenance dose.   
 
CBC and LDH should be assessed locally before the first administration of the 
increased dose, at four weeks after the first administration of the increased 
maintenance dose, and as clinically indicated thereafter to monitor clinical response.  
Locally assessed CBC and LDH should be recorded on the eCRF.   
 
For patients with persistent sustained intravascular hemolysis after 4 weeks of treatment 
with the increased dose, the risks and benefits of continuing crovalimab treatment 
should be evaluated, in consultation with the Medical Monitor. 
5.1.2.2 
Treatment Interruption 
There are no planned treatment interruptions of crovalimab in this study. 
If a dose of crovalimab is missed administer as soon as possible and then resume usual 
dosing schedule.  Do not administer two doses on the same day to make up for a 
missed dose.  Resuming treatment after longer than 28 days of interruption, should be 
done in consultation with the Medical Monitor. 
5.1.2.3 
Management Guidelines 
Crovalimab (for the initial IV infusion and the first five vial-SC administrations) should be 
administered in a clinical environment where resuscitation equipment is available for 
immediate use. 
Guidelines for management of specific adverse events related to crovalimab are outlined 
in Table 2.  Additional guidelines are provided in the subsections below. 

 
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Table 2 
Guidelines for Management of Patients Who Experience Adverse 
Events 
Event 
Action to Be Taken 
Anaphylaxis 
 
If an anaphylactic reaction occurs, stop administration and 
permanently discontinue crovalimab. 
 
Follow anaphylaxis treatment guidelines in Appendix 3. 
Infusion-Related Reactions 
IRR:  Grade 1, 2, or 3 
 
The crovalimab infusion should be temporarily held until 
resolution of symptoms to Grade 1 or better. 
 
Provide full supportive care according to institutional practice. 
 
Monitor patient until complete resolution. 
 
Crovalimab may be continued at the investigator’s discretion. 
IRR:  Grade 4 
 
The crovalimab infusion should be stopped and not re-initiated.  
 
Provide full supportive care according to institutional practice. 
 
Monitor patient until complete resolution. 
 
Discontinue crovalimab. 
Injection-Site Reactions 
Injection-site reaction 
Grade 1 or 2 
 Provide full supportive care according to institutional practice. 
 Monitor patient until complete resolution. 
 Crovalimab may be continued at the investigator’s discretion. 
Injection-site reaction 
Grade 3a or 4 
 Provide full supportive care according to institutional practice. 
 Monitor patient until complete resolution. 
 Crovalimab may be continued at the investigator’s discretion and in 
discussion with Medical Monitor for Grade 3 ISR. 
 Discontinue crovalimab if Grade 4 ISR occurs. 
Type III Hypersensitivity Reactions (Serum Sickness b) 
General Guideline 
 Upon clinical presentation of a suspected Type III hypersensitivity 
reaction (initial manifestation of vasculitis, purpura, pruritus, 
arthralgia, etc.), treat according to severity  a 
Grade 1 or 2 signs and 
symptoms 
 For arthralgia, administer analgesics and nonsteroidal 
anti-inflammatory agents. 
 For pruritus and rash, administer antihistamines and topical 
corticosteroids. 
 Monitor kidney function and perform urinalysis (Section 4.5.8). 
 Continue crovalimab. 

 
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5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events, and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol specified tests that are deemed critical to the 
safety evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
 
Any unfavorable and unintended sign (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 
 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Section 5.3.5.9 and 
Section 5.3.5.10 for more information) 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
BTH, transfusion, anemia, or MAVE due to PNH should not be considered adverse 
events unless serious (see Section 5.2.2) and should be reported in the appropriate 
dedicated eCRF pages. 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
 
Is fatal (i.e., the adverse event actually causes or leads to death) 
 
Is life-threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death. 

 
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Requires or prolongs inpatient hospitalization (see Section 5.3.5.11) 
 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions) 
 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4 for reporting instructions).  Adverse events of special interest for this study 
are as follows: 
 
Type III hypersensitivity reactions are described in Section 5.1.1.2. 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.7) 
 
Suspected transmission of an infectious agent by the study drug, as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
 

 
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5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2 for 
definitions) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Section 5.4 through 
Section 5.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4). 
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of crovalimab, only 
serious adverse events caused by a protocol mandated intervention (e.g., invasive 
procedures, discontinuation of medications) should be reported (see Section 5.4.2 for 
instructions for reporting serious adverse events). 
After initiation of crovalimab, all adverse events will be reported until 46 weeks after the 
final dose of crovalimab. 
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?" 
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5) will be used for 
assessing adverse event severity.  Table 3 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 

 
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Table 3 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE 
 National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are not 
bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
  
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also 
Table 4): 
 
Temporal relationship of event onset to the initiation of study drug 
 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
 
Known association of the event with the study drug or with similar treatments 
 
Known association of the event with the disease under study 
 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 

 
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Table 4 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified 
below. 
Evidence exists that the adverse event has an etiology other than the study drug (e.g., 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
medication); and/or the adverse event has no plausible temporal relationship to 
administration of the study drug (e.g., cancer diagnosed 2 days after first dose of study 
drug). 
 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Infusion-Related and Injection-Site Reactions 
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug infusion or injection should be captured as a 
diagnosis 
infusion-related reaction , 
 injection-site reaction , or anaphylactic 
reaction ) on the Adverse Event eCRF.  If possible, avoid ambiguous terms such as 
"systemic reaction."  Associated signs and symptoms should be recorded on the 
dedicated Infusion-Related Reaction or Injection Reaction eCRF.  If a patient 
experiences both a local and systemic reaction to the same dose of study drug, each 
reaction should be recorded separately on the Adverse Event eCRF, with signs and 
symptoms also recorded separately on the dedicated Infusion-Related Reaction or 
Injection Reaction eCRF. 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
For adverse events other than infusion-related or injection-site reactions 
(see Section 5.3.5.1), a diagnosis (if known) should be recorded on the Adverse Event 
eCRF rather than individual signs and symptoms (e.g., record only liver failure or 
hepatitis rather than jaundice, asterixis, and elevated transaminases).  However, if a 
constellation of signs and/or symptoms cannot be medically characterized as a single 
diagnosis or syndrome at the time of reporting, each individual event should be recorded 
on the Adverse Event eCRF.  If a diagnosis is subsequently established, all previously 
reported adverse events based on signs and symptoms should be nullified and replaced 

 
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by one adverse event report based on the single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 

 
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Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment  
 
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment 
 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.  
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 

 
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Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3 ULN) in combination with either an elevated 
total bilirubin ( 2 ULN) or clinical jaundice in the absence of cholestasis or other causes 
of hyperbilirubinemia is considered to be an indicator of severe liver injury (as defined by 
Hy's Law).  Therefore, investigators must report as an adverse event the occurrence of 
either of the following: 
 
Treatment-emergent ALT or AST 3 ULN in combination with total bilirubin 2 ULN 
 
Treatment-emergent ALT or AST 3 ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.5) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4). 
5.3.5.8 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period 
(see Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4).  This 
includes death attributed to progression of PNH. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
If the death is attributed solely to progression of PNH, "paroxysmal nocturnal 
hemoglobinuria progression" should be recorded on the Adverse Event eCRF.   
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.9 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 

 
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A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.10 
Lack of Efficacy or Worsening of Paroxysmal Nocturnal 
Hemoglobinuria 
Medical occurrences or symptoms of deterioration that are anticipated as part of PNH 
should be recorded as an adverse event if judged by the investigator to have 
unexpectedly worsened in severity or frequency or changed in nature at any time during 
the study.  When recording an unanticipated worsening of PNH on the Adverse Event 
eCRF, it is important to convey the concept that the condition has changed by including 
applicable descriptors (e.g., "accelerated worsening of paroxysmal nocturnal 
hemoglobinuria"). 
An exception to this is events of BTH or MAVE (i.e., anemia, smooth muscle dystonia, 
hemoglobinuria, and thrombosis), which should not be recorded as an adverse event 
unless serious.  These data will be captured as efficacy assessment data only on the 
Breakthrough Hemolysis Monitoring eCRF.  If there is any uncertainty as to whether the 
event is due to disease progression, it should be reported as an adverse event. 
5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event per the definition of serious adverse event in Section 5.2.2 except as outlined 
below. 
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
 
The patient has not experienced an adverse event 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 

 
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5.3.5.12 
Cases of Overdose, Medication Error, Drug Abuse, or Drug 
Misuse 
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as special situations ), are defined as follows: 
 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
 
Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose 
 
Medication error:  accidental deviation in the administration of a drug  
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
 
Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm 
 
Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse 
In cases where drug is to be self-administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient. 
 
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria or qualifies as an adverse event of special interest, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4).  For crovalimab, adverse events associated with special 
situations should be recorded as described below for each situation: 
 
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes. 
 
Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box. 
 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
 
Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box. 
 
Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes. 
 
Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box. 

 
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Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes. 
 
In addition, all special situations associated with crovalimab, regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF as described 
below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
 
Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box. 
 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details. 
 
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details. 
 
Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box. 
 
Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes. 
 
Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes. 
 
Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box. 
 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 

 
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5.3.5.13 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data by the Sponsor.  Sites are not 
expected to review the PRO data for adverse events. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
 
Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements). 
 
Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements). 
 
Pregnancies (see Section 5.4.3 for details on reporting requirements). 
 
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following: 
 
New signs or symptoms or a change in the diagnosis 
 
Significant new diagnostic test results 
 
Change in causality based on new information 
 
Change in the event's outcome, including recovery 
 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and Institutional Review Board (IRB)/ Ethics 
Committee (EC). 
5.4.1 
Medical Monitors and Emergency Medical Contacts 
To ensure the safety of study patients, access to the Medical Monitors is available 
24 hours per day, 7 days per week.  Details will be provided separately. 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 

 
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7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators.  
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Adverse Event/Special Situations provided to investigators 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the event), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators. 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 46 weeks (approximately 10.5 months) after the final dose 
of crovalimab.  Investigators should record all case details that can be gathered 
immediately (i.e., within 24 hours after learning of the event) on the Adverse Event eCRF 
and submit the report via the electronic data capture (EDC) system.  A report will be 
generated and sent to Roche Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Adverse 
Event/Special Situations provided to investigators should be completed and submitted to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.  Once the EDC system is available, all 
information will need to be entered and submitted via the EDC system. 
Instructions for reporting serious adverse events that occur 46 weeks (approximately 
10.5 months) after the final dose of crovalimab are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study or 
within 46 weeks (approximately 10.5 months) after the final dose of crovalimab.  A 
paper Clinical Trial Pregnancy Reporting Form should be completed and submitted to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax number 
or email address provided to investigators.  Pregnancy should not be recorded on the 
Adverse Event eCRF.   
Continuation on study treatment may be permitted based on i
judgment in consultation with the Medical Monitor.  The investigator should counsel the 

 
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patient and discuss the risks of the pregnancy and the possible effects on the fetus.  
Monitoring of the patient should continue until conclusion of the pregnancy.  Any serious 
adverse event associated with the pregnancy (e.g., an event in the fetus, an event in the 
mother during or after the pregnancy, or a congenital anomaly/birth defect in the child) 
should be reported on the Adverse Event eCRF.  In addition, the investigator will submit 
a Clinical Trial Pregnancy Reporting Form when updated information on the course and 
outcome of the pregnancy becomes available. 
5.4.3.2 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic 
or elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.  
5.4.3.3 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome. 

 
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5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
46 weeks [approximately 10.5 months] after the final dose of crovalimab), if the event is 
believed to be related to prior study drug treatment.  These events should be reported 
through use of the Adverse Event eCRF.  However, if the EDC system is not available, 
the investigator should report these events directly to the Sponsor or its designee, either 
by faxing or by scanning and emailing the paper Clinical Trial Adverse Event/Special 
Situations using the fax number or email address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the Crovalimab Investigator's Brochure (for crovalimab). 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
6.1 
DETERMINATION OF SAMPLE SIZE 
The primary efficacy objective for this study is to evaluate the effect of crovalimab based 
on crossing the threshold of the co-primary endpoint hemolysis control and the 
superiority intra patient assessment of the co-primary endpoint of TA.  The study will be 

 
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Table 6 shows the 95% CI around a potential range in the percentage of patients that 
would avoid transfusions while on the study.  In the TRIUMPH study 
(Hillmen et al. 2006), TA was achieved in 22 of 43 of patients (51%) in the eculizumab 
treated arm and none of the patients from the Placebo arm (n 44) were transfusion free 
at Week 25.  
Table 6 
Summary of 95% CI (Wilson method) for Potentially Observable TA 
Proportions Given N 50 
No. of Patients with 
TA 
Proportion of 
Patients with TA 
Lower 95% CI 
Upper 95% CI 
20 
40% 
28 
54 
22 
44% 
31 
58 
25 
50% 
37 
63 
26 
52% 
39 
65 
28 
56% 
40 
67 
30 
60% 
46 
72 
CI confidence interval; N no. of patients; TA transfusion avoidance.
  
6.2 
SUMMARIES OF CONDUCT OF STUDY 
The number of patients who enroll, discontinue, or complete the study will be 
summarized and displayed in a CONSORT diagram.  In addition, reasons for premature 
study withdrawal will be listed and summarized.  Enrollment and major protocol 
deviations will be listed and evaluated for their potential effects on the interpretation of 
study results. 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographic and baseline characteristics (including age, sex, race, ethnicity, weight, 
temperature, history of pRBC transfusions, total number of pRBC transfused, and 
baseline LDH category) will be summarized using number of records per variable, 
means, standard deviations, medians, and ranges (continuous variables) or proportions 
(categorical variables), as appropriate. 
6.4 
EFFICACY ANALYSES 
The analysis population for the primary and key secondary efficacy analyses will include 
all enrolled patients who received at least one dose of crovalimab and have at least one 
centrally processed LDH level assessment after the first IV infusion.  
6.4.1 
Primary Estimand 
The primary efficacy estimand in this study has been defined as follows:  
 
Population:  All patients who have met the inclusion and exclusion criteria 
(Section 4.1), received at least one dose of crovalimab, and have at least one 
centrally processed LDH level assessment after the first IV infusion.  

 
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Variable:  central LDH measured at pre-specified hospital visits from Week 5 to 
Week 25 and any transfusion event from 24 weeks prior to the screening to Week 
25. 
 
Inter-current events (ICEs):   
 
TA:  early withdrawal from study treatment 
 
Hemolysis control:  
 
Early withdrawal from study treatment 
 
Dose modification due to experiencing two or more qualifying intravascular 
hemolysis events or sustained intravascular hemolysis 
 
Handling of ICEs:  
 
TA:  composite strategy 
Patients with data missing due to an ICE will be hypothetically assumed to 
have experienced an unfavorable outcome, i.e., have required transfusion 
in the unobserved period, assuming transfusion had not been observed 
prior to ICE. 
 
Hemolysis control:   
 
Early withdrawal from treatment:  hypothetical strategy 
Any data missing due to an ICE will not be imputed for the primary 
analysis; rather, the generalised estimating equation (GEE) model uses all 
observed data in order to provide estimates for the full 24 week period.  
 
Dose modification due to experiencing two or more qualifying intravascular 
hemolysis events or sustained intravascular hemolysis:  treatment policy 
strategy 
Per treatment policy strategy, data collected after dose modification due to 
sustained or qualifying intravascular hemolysis (see Section 5.1.2.1 on 
dose modifications) will be included in the primary analysis.  
 
Population-level summary (estimate):  Mean proportion of patients with hemolysis 
control, i.e., LDH 1.5 ULN from Week 5 through Week 25 and the difference in the 
proportion of patients with TA from baseline through Week 25 and the proportion of 
patient who were TA within 24 weeks prior to screening. 
 
6.4.2 
Primary Efficacy Analyses 
The primary efficacy analysis will take place when all patients have either completed 
24 weeks of treatment with crovalimab or have discontinued the study drug, whichever 
occurs first. 
6.4.2.1 
Hemolysis Control 
The co-primary endpoint of the mean proportion of patients with hemolysis control is 
defined as LDH 1.5 ULN from Week 5 through Week 25 (as measured at the central 
laboratory). 

 
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For each patient at each visit, a binary variable will be created with the value of 1, if 
LDH 1.5 ULN, and 0, otherwise.  A Generalized Estimating Equation (GEE) will be 
used to estimate the mean proportion of hemolysis control (i.e., LDH 1.5 ULN from 
Week 5 through Week 25 and 95% confidence interval). 
The primary analysis will use the standard GEE based on the available LDH 
assessments, assuming the missing data are missing completely at random (MCAR).  
Sensitivity analyses will be performed based on different missing data handling rules to 
assess the robustness of the primary analysis results.  These sensitivity analyses will be 
described in more detail in the Statistical Analysis Plan (SAP). 
6.4.2.2 
Transfusion Avoidance 
The co-primary endpoint of proportion of patients who achieve TA consists of proportion 
of patients who achieve TA from baseline through Week 25 (after 24 weeks on 
treatment) and proportion of patients who were TA within 24 weeks prior to screening.  
TA is defined as patients who are pRBC transfusion-free and do not require transfusion 
per protocol-specified guidelines. 
The intra-patient comparison between proportion of patients with TA from baseline 
through Week 25 and proportion of patient who were TA within 24 weeks prior to 
screening will be made using a paired McNemar test at two-sided Type 1 error level of 
0.05.  The proportion of TA and the 
(1927) will be provided.  
For the primary analysis, patients who withdrew early before Week 25 independent of 
the reason for withdrawal will be included in the analysis as non responders 
(i.e., requiring transfusion). 
Sensitivity analyses will be performed according to the causes for dropping out of the 
study before Week 25.  These sensitivity analyses will be described in more detail in the 
SAP. 
6.4.3 
Secondary Efficacy Analyses 
The secondary efficacy endpoints are: 
 
Proportion of patients with BTH from baseline through Week 25 
 
Proportion of patients with stabilized hemoglobin from baseline through Week 25 
 
Mean change from baseline to Week 25 in fatigue as assessed through the use of 
the FACIT-Fatigue (adults aged 18 years) 
 
The definitions of BTH and stabilized hemoglobin are provided in Section 2.1.2. 
Proportion of patients with BTH will be reported with 95% CI, and are calculated with the 
number of subjects as the denominator.  

 
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The proportion of patients with stabilization of hemoglobin will be analyzed using the 
same methodology as the secondary efficacy endpoint of BTH. 
Change from baseline in FACIT-Fatigue total scores (range of 0 52) will be summarized 
over time with means, standard deviations, medians, and ranges.  Graphs of the mean 
changes and standard errors over time will also be provided. 
6.4.4 
Other Efficacy Analyses 
All other efficacy endpoints have been defined in Section 2.1.3.  
 
Continuous data, including total number of units of pRBC transfused from baseline to 
Week 25 will be summarized by the group mean, standard deviation, median, and range.   
Time from baseline to first reach of LDH 1 ULN and LDH 1.5 ULN will be analyzed 
using Kaplan-Meier methodology. 
Mean proportion of patients with LDH 1 ULN from Week 5 through Week 25 (as 
measured at the central laboratory) will use the same method as co-primary endpoint 
hemolysis control. 
Proportion of patients with MAVE and proportion of patients who reach a hemoglobin 
level of at least 10 g/dL, without subsequent decrease below 9 g/dL, in the absence of a 
transfusion from baseline to Week 25 will use the same method as the second efficacy 
endpoint BTH. 
The other endpoints regarding absolute value and change from baseline will be 
summarized over time with means, standard deviations, medians, and ranges.  Graphs 
of the mean absolute value and changes and standard errors over time from the 
baseline assessment will provide visual description.  Details will be provided in the SAP.  
6.4.5 
Supportive Historical Analyses 
Historical medical record data from the study population will be used to characterize the 
efficacy of crovalimab versus best supportive care via intra-patient analyses.  Before any 
intra-patient comparison, data collection frequency, consistency and completeness of 
the medical history data will be examined to assess the quality.  The intra-patient 
comparison other than TA between historical data and post baseline data will be used as 
supportive evidence only, as the different methods of data collection (retrospective vs 
prospective) might limit the interpretability of the statistical analysis results.   
Historical medical record data including LDH, and hemoglobin within 24 weeks prior to 
screening will be presented by summary statistics (N, mean, median, standard deviation, 
range) by nominal timepoints.  Spaghetti plots (plots of individual patients over-laid with 
mean and median plots of the same individuals) with reference lines for the normal 

 
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range for absolute value will be provided for LDH and hemoglobin collected both within 
24 weeks prior to screening and 24 weeks post baseline.  
Number of transfusions and number of RBC units in 24 weeks prior to screening will be 
summarized using number of records, means, standard deviations, medians, and 
ranges.  The comparison between 24 weeks prior to screening and 24 week post 
baseline will be summarized by the average difference as well as the corresponding 
95%CI calculated on the basis of the t-distribution.  
The proportion of patients who had MAVE as documented in the medical records within 
24 weeks prior to screening will be provided if applicable.  The comparison between 24 
weeks prior to screening and 24 week post baseline will be provided with a difference 
between the proportions and 95% CI on the basis of a normal approximation to the 
binomial distribution.  
The comparison between historical data and post-baseline data will be described in 
detail in the SAP.  
6.4.6 
Handling Missing Data 
For the co-primary endpoint of hemolysis control (based on LDH 1.5xULN), the primary 
analysis will use the standard GEE based on the available LDH assessments, assuming 
missing data are MCAR.  For the co-primary endpoint of TA, patients who withdrew early 
from baseline through Week 25 independent of the reason for withdrawal will be 
included in the analysis as non-responders (i.e., requiring transfusion) for the primary 
analysis. 
The detailed missing data handling rules will be described in the SAP. 
6.5 
SAFETY ANALYSES 
Safety analyses will be performed on the safety evaluable population, defined as all 
enrolled patients who received at least one dose of crovalimab. 
Safety will be assessed through summaries of exposure to study treatment, adverse 
events, changes in laboratory test results, and changes in vital signs and ECGs. 
Study treatment exposure (such as treatment duration, total dose received, and number 
of cycles and dose modifications) will be summarized. 
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms, and adverse event severity will be graded 
according to scale in NCI CTCAE v5.  All adverse events, serious adverse events, 
adverse events leading to death, adverse events of special interest, and adverse events 
leading to study treatment discontinuation that occur on or after the first dose of study 
treatment (i.e., treatment-emergent adverse events) will be summarized by mapped 

 
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term, appropriate thesaurus level, and severity grade.  For events of varying severity, the 
highest grade will be used in the summaries.  Deaths and cause of death will be 
summarized. 
Relevant laboratory, vital sign (pulse rate, respiratory rate, blood pressure, 
and temperature), and ECG data will be displayed by time, with grades identified where 
appropriate.  Additionally, a shift table of selected laboratory tests will be used to 
summarize the baseline and worst post baseline severity grade.  Changes in vital signs 
and ECGs will be summarized.  
6.6 
PHARMACOKINETIC ANALYSES 
The pharmacokinetic analyses will be performed on the PK-evaluable population, 
defined as all patients who received at least one dose of crovalimab and who took 
at least one PK blood sample, as data allow and where appropriate.  
Patients may be excluded from the PK analysis population if, in the opinion of the clinical 
pharmacologist, they significantly violate the inclusion or exclusion criteria, deviate 
significantly from the protocol, or if data are unavailable or incomplete, where the PK 
analysis might be influenced.  Excluded cases will be documented, including the reason 
for exclusion.  All decisions on exclusions from the analysis will be made prior to 
database closure. 
For all patients, serum trough concentrations of crovalimab will be presented 
descriptively, including arithmetic and geometric means, median, range, standard 
deviations, and coefficients of variation. 
To characterize crovalimab steady state pharmacokinetics in Chinese patients, 
additional PK samples will be collected at Weeks 21 (Day 4), 22, 23, and 24 in up to a 
maximum of 20 patients. Summary descriptive statistics of serum PK parameters 
including maximum concentration observed at steady state (Cmax, SS), area under the 
concentration time curve at steady state (AUCSS) derived using non compartmental 
analysis will be presented including means, geometric means, standard deviation, 
coefficient of variation, medians and ranges.  
Non-linear mixed effects modeling will be used to analyze the dose-concentration-time 
profiles of crovalimab and evaluate the potential influence of ethnicity on population PK 
parameters, such as clearance and volume of distribution.  Data will be pooled with data 
from other studies that enrolled patients from different ethnic groups to investigate the 
influence of ethnicity on population PK parameter estimates. 
The influence of other covariates such as age, sex and body weight on population PK 
parameter estimates will also be investigated.  Inter-patient variability will be evaluated. 
The relationship between PK and efficacy or safety endpoints may also be explored. 

 
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Additional PK analysis may be conducted as appropriate.  These PK analyses will be 
reported in a dedicated report. 
6.7 
IMMUNOGENICITY ANALYSES 
The immunogenicity analysis population will consist of all patients with at least one ADA 
assessment.   
The numbers and proportions of ADA positive patients and ADA negative patients at 
baseline (baseline prevalence) and after drug administration (postbaseline incidence) 
will be summarized.  When determining post-baseline incidence, patients are considered 
to be ADA positive if they are ADA negative or have missing data at baseline but 
develop an ADA response following study drug exposure (treatment-induced ADA 
response), or if they are ADA positive at baseline and the titer of one or more 
post baseline samples is at least 4-fold greater than the titer of the baseline sample 
(treatment-enhanced ADA response).  Patients are considered to be ADA negative if 
they are ADA negative or have missing data at baseline and all postbaseline samples 
are negative, or if they are ADA positive at baseline but do not have any post-baseline 
samples with a titer that is at least 4-fold greater than the titer of the baseline sample 
(treatment unaffected). 
The relationship between ADA status and safety, efficacy, PK, and PD endpoints may 
be analyzed and reported via descriptive statistics. 
6.8 
BIOMARKER ANALYSES 
Change over time in PD parameters (e.g., complement inhibition by LIA, C5 levels) and 
other biomarkers will be presented using summary statistics (e.g., arithmetic and 
geometric means, median, range, standard deviations, and coefficients of variation).  
Data may be analyzed in aggregate with data from other studies.   
6.9 
HEALTH STATUS UTILITY ANALYSES 
Summary statistics will be calculated for the EQ-5D-
VAS scores, and changes in scores over the course of the study will be summarized 
descriptively.  Additional economic modeling analyses will be conducted post hoc to 
support the integrated evidence plan and detailed in relevant analysis plans outside of 
the study SAP. 
6.10 
INTERIM ANALYSES 
No interim efficacy analysis is planned.   
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 

 
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eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor's standard procedures to handle and process 
the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures. 
PRO data will be collected on paper questionnaires.  The data from the questionnaires 
will be entered into the EDC system by site staff.  
7.2 
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required. 
7.3 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.4 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents.  

 
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Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 9.6. 
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper PRO data (if applicable), Informed Consent 
Forms, laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for at least 15 years after completion or discontinuation of the 
study or for the length of time required by relevant national or local health authorities, 
whichever is longer.  After that period of time, the documents may be destroyed, subject 
to local regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer. 

 
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8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting). 
8.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form will be provided to each site.  If 
applicable, it will be provided in a certified translation of the local language.  The 
Sponsor or its designee must review and approve any proposed deviations from the 
Sponsor's sample Informed Consent Forms or any alternate consent forms proposed by 
the site (collectively, the "Consent Forms") before IRB/EC submission.  The final 
IRB/EC approved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
If the Consent Forms are revised (through an amendment or an addendum) while a 
patient is participating in the study, the patient or a legally authorized representative 
must re-consent by signing the most current version of the Consent Forms or the 
addendum, in accordance with applicable laws and IRB/EC policy.  For any updated or 
revised Consent Forms, the case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
using the updated/revised Consent Forms for continued participation in the study. 

 
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A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.7). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file.  
8.4 
CONFIDENTIALITY 
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect such 
data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access.  In the event of a data security breach, appropriate mitigation measures will be 
implemented. 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes. 

 
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Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.6). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted Clinical Study Reports and other summary reports will be provided 
upon request (see Section 9.6). 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health 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 (see definition of end of 
study in Section 3.2). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 

 
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prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
9.3 
MANAGEMENT OF STUDY QUALITY 
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  Prior 
to study initiation, the Sponsor will identify potential risks associated with critical trial 
processes and data and will implement plans for evaluating and controlling these risks.  
Risk evaluation and control will include the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters prior to study initiation.  Detection of deviations 
from quality tolerance limits will trigger an evaluation to determine if action is needed.  
Details on the establishment and monitoring of quality tolerance limits will be provided in 
a Quality Tolerance Limit Management Plan. 
9.4 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.5 
ADMINISTRATIVE STRUCTURE 
This trial will be managed by F. Hoffmann-La Roche Ltd.  The Sponsor will provide 
clinical operations management (involving clinical research organization), data 
management, and medical monitoring.  
Approximately 10 sites will participate to enroll approximately 50 patients.  Enrollment 
will occur through an IxRS. 
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in Section 4.5.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected. 
9.6 
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and/or other summaries of clinical study results may be 
available in healthy authority databases for public access, as required by local 

 
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regulation, and will be provided upon request.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Study Information at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/ 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.7 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only. 

 
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10. 
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Lee JW, Jang JH, Kim JS, et al. Clinical signs and symptoms associated with increased 
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Appendix 1: Schedule of Activities 
Table 1: Overall Schedule of Activities for Patients Until Study Discontinuation/Safety Follow-Up (Cont.) 
  
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ADA 
 anti-drug antibody; ALP alkaline phosphatase; aPTT activated partial thromboplastin time; BTH 
 breakthrough hemolysis; BUN blood urea 
nitrogen; ECG electrocardiogram; eCRF 
 electronic Case Report Form; EoI 
 end of injection; EORTC QLQ-C30 
 European Organisation for 
Research and Treatment of Cancer Quality of Life Core 30 Questionnaire; EQ-5D-5L  EuroQoL 5-Dimension Questionnaire, 5 level; 
FACIT 
 Functional Assessment of Cancer Therapy; INR international normalized ratio; IV intravenous; LDH lactate dehydrogenase; 
LIA liposome immunoassay; MFS Multidimensional Fatigue Scale; PD pharmacodynamic; PE 
 physical examination; PedsQL Pediatric Quality 
of Life; PK pharmacokinetic; PNH 
 paroxysmal nocturnal hemoglobinuria; pRBC 
 packed red blood cell; PRO patient-reported outcome; 
PT prothrombin time; PTT partial thromboplastin time; QW 
 every week; Q4W 
 every 4 weeks; Q8W 
 every 8 weeks; Q16W 
 every 16 weeks; 
Screen 
 screening.  
Note:  All assessments should be performed within 2 days of the scheduled visit for the first 24 weeks and then 7 days thereafter.  All 
assessments should be performed prior to dosing, unless otherwise specified.  Crovalimab may be administered within 2 days of the scheduled 
dose. 
a 
adolescent patients 18 years old) 
before collection of any data.  Patients will be enrolled after giving informed consent or assent (when appropriate). 
b Vaccination against N. meningitidis serotypes A, C, W, and Y must be administered <3 years prior to initiation of study treatment. 
Vaccination against serotype B must be administered in accordance with most current local guidelines or SOC as applicable for  patients with 
complement deficiency.  Vaccination currency with vaccination against serotypes A, C, W, Y and B should be maintained throughout the 
study according to local guidelines or SOC as applicable in patients with complement deficiency.  Vaccination against Haemophilus 
influenzae type B and S. pneumonia should be administered according to national vaccination recommendations.  If not previously 
administered or no longer current, vaccination must be completed no later than one week after the first study drug administra tion..  Patients 
who receive a vaccine less than 2 weeks before initiating treatment must receive treatment with appropriate prophylactic antibiotics until at least 
2 weeks after the vaccination or according to local SOC as applicable in patients with complement deficiency, whichever is longer .  If 
vaccination is administered during screening, and prophylactic antibiotics are not to be administered, the vaccination must take place at least 
2 weeks prior to the first dose of study drug. 
c For the collection of medical historical data and baseline condition, refer to Section 4.5.2 for details. 
d Demographics include age, sex, and self-reported race/ethnicity. 
e Blood sample to determine PNH clone size.  At screening only, historical data collected no more than 6 months prior to screening may be 
reported; if no historical data are available, a sample will be collected at screening and tested locally.  At all the other timepoints, including Day 1, 
a sample will be collected, PNH RBC clone size and C3d on RBCs may be measured centrally. 
f A complete physical examination, including evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems, is required at screening; thereafter, only a limited physical 
examination will be required.  Height and weight will be recorded at screening and at Weeks 13 and 25. 

Appendix 1: Schedule of Activities 
Table 1: Overall Schedule of Activities for Patients Until Study Discontinuation/Safety Follow-Up (Cont.) 
  
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g Vital signs include measurements of blood pressure (systolic and diastolic) while the patient is in a seated position, pulse rate, respiratory rate, 
and body temperature. 
h To be collected prior to study drug dose administration.  Prior to enrollment and within 5 days of Week 1 Day 1 of study drug administration, the 
patient s hemoglobin will be evaluated. 
i Pregnancy tests will be conducted for female patients of childbearing potential prior to dosing.  A serum pregnancy test should be performed at 
the screening visit.  Subsequent pregnancy tests will be urine or serum tests performed locally.  A urine pregnancy test will also be performed 
by the patient within 2 days prior to the final telephone call follow-up (i.e., 46 weeks [approximately 10.5 months] after the final dose of 
crovalimab).  The patient should report the result of the pregnancy test during the telephone call.  If a urine pregnancy test is positive, it must 
be confirmed by a serum pregnancy test. 
j If screening and Week 1 ECG assessments occur on the same day, do not repeat. 
k Report any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) 
used by a patient in addition to protocol-mandated treatment from first screening visit prior to initiation of the study drug until 46 weeks 
(approximately 10.5 months) after the final dose of crovalimab.  Report previous and concurrent pRBC transfusions.  
l Hematology will be assessed locally.  It includes RBC count, hemoglobin, hematocrit, platelet count, reticulocytes count (or percentage count if 
absolute count is not available, WBC count, and differential count.  
m Sample will be sent to a central laboratory for analysis. 
n Coagulation includes locally assessed pTT/aPTT and PT/INR. 
o Chemistry panel (serum or plasma) will be assessed locally.  It includes sodium, potassium, chloride, bicarbonate or total carbon dioxide (if 
considered standard of care for the region), glucose, BUN or urea, creatinine, total protein, albumin, phosphate, calcium, total and direct bilirubin, 
ALP, ALT, AST and LDH.  Serum bicarbonate may be omitted for screening or on-study serum measurements if it is not considered a standard 
chemistry measurement.  If unscheduled LDH measurements are taken for determination of sustained intravascular hemolysis, they must be 
recorded on the eCRF. 
p Urinalysis includes dipstick (pH, specific gravity, glucose, protein, ketones, and blood).  If there is a clinically significant positive result (i.e., 
confirmed by a positive repeat sample), urine will be sent to the laboratory for microscopy and culture (sediment, RBCs, WBCs, casts, crystals, 
epithelial cells, bacteria).  If there is a known explanation for the positive dipstick result (e.g., menses), it should be recorded, and there is no 
need to perform laboratory for microscopy and culture. 

Appendix 1: Schedule of Activities 
Table 1: Overall Schedule of Activities for Patients Until Study Discontinuation/Safety Follow-Up (Cont.) 
  
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q After informed consent has been obtained but prior to initiation of the study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  Subsequently, all adverse events will be reported until 46 weeks (approximately 10.5 months) after the final 
dose of the study drug, unless the patient continues crovalimab treatment as part of an open-label extension study, or as per the Roche Global 
Policy on Continued Access to Investigational Medicinal Products or as commercial product.  In addition, the Sponsor should be notified if the 
investigator becomes aware of any serious adverse event that is believed to be related to crovalimab at any time point (see Section 5 for 
additional details and reporting requirements). 
r Symptoms of BTH and confirmation of blood sampling for local LDH, hemoglobin, and bilirubin measurements, as well as the local results of 
these tests, once available, should be documented in the eCRF.  Blood samples will be drawn for central testing for LDH, free hemoglobin, 
haptoglobin, pharmacokinetics, ADAs, and biomarkers (may be included).  If blood transfusions are required, the number of units of pRBCs will 
be also documented in the eCRF. 
s At screening, LDH and potassium testing will be performed for 2 times with at least 2 weeks interval between the measurements by central 
laboratory.  Additional LDH and potassium samples for all the visits will be obtained and sent to a central laboratory for analysis. 
t In case of an adverse event of BTH or a hypersensitivity reaction on a patient treated with crovalimab, an additional sample for 
pharmacokinetics, ADAs, and biomarkers (total free C5 D-dimer and liposome) should be drawn as close as possible to the onset of the event.  
In the event of BTH accompanied by an IV rescue dose of crovalimab, the sampling should occur prior to the drug administration. 
u See Table 3 of Appendix 1. 
v Completion of PRO questionnaires should occur prior to the performance of non-PRO assessments whenever possible.  PRO questionnaires will 
be self-administered before a patient receives any information on disease status and prior to the administration of crovalimab.  
w Only for patients who discontinue at or before Week 25.  All other patients should follow schedules in Table 2 of Appendix 1 for assessments 
after Week 25.  For patients who discontinue from crovalimab treatment, follow up safety assessments should be taken 24 weeks (site visit) and 
46 weeks (safety telephone call) after the final dose of crovalimab.  Note that patients who continue crovalimab after discontinuation from the 
study treatment do not need to return for the safety follow-up visit. 
x Patients continue to receive crovalimab.  At the Week 25 visit (after completion of 24 weeks of study treatment), crovalimab will be administered 
every 4 weeks.  Assessments will be taken Q8W or Q12W following Week 25 (see Table 2 of Appendix 1 for schedule of activities for patients 
continuing crovalimab treatment at Weeks 25). 
y For patients whose maintenance dose is increased due to experiencing two or more qualifying intravascular hemolysis events or sustained 
intravascular hemolysis, additional samples for central LDH, potassium, PK (for crovalimab), ADAs (for crovalimab), and PD biomarkers should 
be drawn prior to the first administration of the increased maintenance dose and 4 weeks after the first administration, unless these have already 
been collected as part of a scheduled assessment.  CBC and LDH should be assessed locally prior to the first administration of the increased 
maintenance dose, at four weeks after the first administration, and as clinically indicated thereafter to monitor clinical response.  Locally 
assessed CBC and LDH should be recorded on the eCRF.   
 

Appendix 1: Schedule of Activities 
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Table 2: Schedule of Activities for Patients Continuing Treatment with Crovalimab at Weeks 25 
Study Week 
Week 25  
Week 33 and 
Q8W Thereafter 
Week 49 and 
Q12W Thereafter 
Safety 
Follow-Up Site 
Visit (24 Weeks 
after Last 
Dose)r 
Safety Follow-Up 
Telephone Call 
(46 Weeks after 
Last Dose) r 
Blood sample for PNH clone size a 
Follow Table 1 
Week 25 
Schedule for 
each 
corresponding 
row 
 
 
x 
 
Limited PE b 
x 
x 
x 
 
Vital signs c 
x 
x 
x 
 
Pregnancy test d, e 
x 
x 
x 
x 
12-Lead ECG  
 
 
 
 
Concomitant medications f 
x 
x 
x 
x 
pRBC transfusions g 
x 
x 
x 
 
Hematology d, h, s 
x 
x 
x 
 
Free hemoglobin, haptoglobin d, i 
x 
x 
x 
 
Coagulation d, j 
x 
x 
x 
 
Chemistry d, k, s 
x 
x 
x 
 
Urinalysis d, l 
x 
x 
x 
 
Adverse events m 
x 
x 
x 
x 
Assessment and documentation of BTH d, n 
x 
x 
x 
 
Serum sample for central LDH and potassium d, o, s 
x 
x 
x 
 
Plasma and serum sample set for biomarkers d, p, s 
x 
x 
x 
 
Serum ADA sample for crovalimab d, p, s 
x 
x 
x 
 
Serum PK sample for crovalimab d, p, s 
x 
x 
x 
 
FACIT-Fatigue, and EORTC QLQ-C30 scales, 
(adults only) q 
x 
x 
x 
 
PedsQL Core and PedsQL MFS  
(adolescents only) q 
x 
x 
x 
 
EQ-5D-5L q 
x 
x 
x 
 

Appendix 1: Schedule of Activities 
Table 2: Schedule of Activities for Patients Continuing Treatment with Crovalimab at Weeks 25 (cont.) 
  
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Study Week 
Week 25  
Week 33 and 
Q8W Thereafter 
Week 49 and 
Q12W Thereafter 
Safety 
Follow-Up Site 
Visit (24 Weeks 
after Last 
Dose)r 
Safety Follow-Up 
Telephone Call 
(46 Weeks after 
Last Dose) r 
Crovalimab administration 
Q4W 
 
 
 
ADA  anti-drug antibody; aPTTactivated partial thromboplastin time; BTH  breakthrough hemolysis; BUNblood urea nitrogen; 
DTDC  drugtarget-drug complex; ECGelectrocardiogram; eCRF  electronic Case Report Form; EoI  end of injection; 
EORTC QLQC30  European Organisation for Research and Treatment of Cancer Quality of LifeCore 30 Questionnaire; 
EQ5D5LEuroQoL 5-Dimension Questionnaire, 5level; FACIT  Functional Assessment of Cancer Therapy; INRinternational normalized ratio; 
LDHlactate dehydrogenase; MFS  Multidimensional Fatigue Scale; PD  pharmacodynamic; PE  physical examination; PK  pharmacokinetic; 
PNH  paroxysmal nocturnal hemoglobinuria; pRBC  packed red blood cell; PROpatient-reported outcome; PTprothrombin time; PTTpartial 
thromboplastin time; Q4W  every 4 weeks; Q8W  every 8 weeks;.  
Note:  All assessments should be performed within  7 days of the scheduled visit.  All assessments should be performed prior to dosing unless 
otherwise specified.  Crovalimab may be administered within  2 days of the scheduled dose. 
a Blood sample to determine PNH clone size.  A sample will be collected, and PNH clone size (RBC) and C3d on RBCs may be measured 
centrally.   
b Height and weight will be recorded at each specified assessment. 
c Vital signs include measurements of blood pressure (systolic and diastolic) while the patient is in a seated position, pulse rate, respiratory rate, 
and body temperature. 
d To be collected prior to study drug dose administration. 
e Urine or serum pregnancy tests will be conducted locally for female patients of childbearing potential prior to dosing and Q4W thereafter.  A 
urine pregnancy test will also be performed by the patient within 2 days prior to the final telephone call follow -up (i.e., 46 weeks 
[approximately 10.5 months] after the final dose of crovalimab).  The patient should report the result of the pregnancy test during the 
telephone call.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
f Report any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) 
used by a patient in addition to protocol-mandated treatment until 46 weeks (approximately 10.5 months) after the final dose of crovalimab. 
g  Report previous and concurrent pRBC transfusions. 
h Hematology will be assessed locally.  It includes RBC count, hemoglobin, hematocrit, platelet count, reticulocytes count (or percentage count if 
absolute count is not available), WBC count, and differential count. 

Appendix 1: Schedule of Activities 
Table 2: Schedule of Activities for Patients Continuing Treatment with Crovalimab at Weeks 25 (cont.) 
  
Crovalimab—F. Hoffmann-La Roche Ltd 
112/Protocol YO42311, Version 5 
i Sample will be sent to a central laboratory for analysis. 
j Coagulation includes locally assessed PTT/aPTT and PT/INR. 
k Chemistry panel (serum or plasma) will be assessed locally.  It includes sodium, potassium, chloride, bicarbonate or total carbon dioxide (if 
considered standard-of-care for the region), glucose, BUN or urea, creatinine, total protein, albumin, phosphate, calcium, total and direct 
bilirubin, ALP, ALT, AST, and LDH.  Serum bicarbonate may be omitted for screening or on-study serum measurements if it is not considered a 
standard chemistry measurement.  If unscheduled LDH measurements are taken for determination of sustained intravascular hemolysis, they 
must be recorded on the eCRF. 
l Urinalysis will be performed through dipstick (pH, specific gravity, glucose, protein, ketones, and blood).  If there is a clinically significant positive 
result (i.e., confirmed by a positive repeat sample), urine will be sent to the laboratory for microscopy and culture (sediment, RBCs, WBCs, casts, 
crystals, epithelial cells, bacteria).  If there is a known explanation for the positive dipstick result (e.g., menses), it should be recorded, and there 
is no need to perform laboratory for microscopy and culture. 
m All adverse events will be reported until 46 weeks (approximately 10.5 months) after the final dose of the study drug, unless the patient 
continues crovalimab treatment as part of an open-label extension study, or as per the Roche Global Policy on Continued Access to 
Investigational Medicinal Products or as commercial product.  In addition, the Sponsor should be notified if the investigator becomes aware of 
any serious adverse event that is believed to be related to crovalimab at any timepoint.  See Section 5 for additional details and reporting 
requirements. 
n Symptoms of BTH and confirmation of blood sampling for local LDH, hemoglobin, and bilirubin measurement, as well as the local results of these 
tests, once available, should be documented in the eCRF.  Blood samples will be drawn for central testing for LDH, free hemoglobin, 
haptoglobin, pharmacokinetics, ADA, and biomarkers (may be included).  If blood transfusions are required, the number of units of pRBCs will be 
also documented in the eCRF. 
o Additional LDH and potassium samples will be obtained and sent to a central laboratory for analysis. 
p In case of an adverse event of BTH or a hypersensitivity reaction on a patient treated with crovalimab, an additional sample of PK, ADA, and 
biomarkers should be drawn as close as possible to the onset of the event.  In the event of BTH, accompanied by an IV rescue dosing of 
crovalimab, the sampling should occur prior to the drug administration. 
q Completion of PRO questionnaires should occur prior to the performance of non-PRO assessments whenever possible.  PRO questionnaires will 
be self-administered before a patient receives any information on disease status and prior to the administration of crovalimab.  
r Follow-up safety assessments to be taken 24 weeks after the final dose of crovalimab.  Note that patients who continue crovalimab after 
discontinuation from the study treatment do not need to return for the safety follow-up visit. 

Appendix 1: Schedule of Activities 
Table 2: Schedule of Activities for Patients Continuing Treatment with Crovalimab at Weeks 25 (cont.) 
  
Crovalimab
F. Hoffmann-La Roche Ltd 
113/Protocol YO42311, Version 5 
s For patients whose maintenance dose is increased due to experiencing two or more qualifying intravascular hemolysis events or sustained 
intravascular hemolysis, additional samples for central LDH, potassium, PK (for crovalimab), ADA (for crovalimab), and PD biomarkers should be 
drawn prior to the first administration of the increased maintenance dose and 4 weeks after the first administration, unless these have already 
been collected as part of a scheduled assessment.  CBC and LDH should be assessed locally prior to the first administration of the increased 
maintenance dose, at four weeks after the first administration, and as clinically indicated thereafter to monitor clinical response.  Locally 
assessed CBC and LDH should be recorded on the eCRF.  

Appendix 1: Schedule of Activities 
Crovalimab
F. Hoffmann-La Roche Ltd 
114/Protocol YO42311, Version 5 
TABLE 3:  SCHEDULE OF ACTIVITIES FOR PHARMACOKINETIC PARAMETERS FROM WEEK 1 THROUGH WEEK 
25 
 
Screen 
Crovalimab Treatment Period  
Study Week 
4 to 1 
1 
2 
3 
4 
5 
9 
13 
17 
21 
21 a 
22 a 
23 a 
24 a 
25 
Day 
 
1 
2 
1 
1 
1 
1 
1 
1 
1 
1  
4 
1  
1  
1  
1  
Serum PK 
sampleb, c 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PK pharmacokinetic. 
a PK samples at Week 21 Day 4, Weeks 22, 23, and 24 is limited for the enrolled Chinese patients (maximum of 20 patients) in addition to 
the other PK sampling from Weeks 1 through Week 25.  PK samples (Week 21 Day 4, Day 1 of Week 22, 23, 24) for crovalimab at these 
visits should be collected 24 hours. 
b At Week 1 Day 1 visit, the PK samples for crovalimab IV should be collected before the start of infusion (within 2-hour pre-dose) and 
within 30 minutes after the end of infusion. 
c PK samples at Day 1 of Week 2, 3, 4, 5, 9, 13, 17, 21, and 25 visits should be collected within 2 hours before the administration. 

 
Crovalimab
F. Hoffmann-La Roche Ltd 
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Appendix 2  
Schedule of Activities for Patients Who Discontinue Crovalimab 
and Switch to Other C5 Inhibitors 
Week
Treatment with Other C5 Inhibitor 
1 
2 
3 
4 
5 
7 
9 
Physical examination a, b 
x 
x 
x 
x 
x 
x 
x 
Vital signs b, c 
x 
x 
x 
x 
x 
x 
x 
Safety laboratory assessments b, d 
x 
x 
x 
x 
x 
x 
x 
Urinalysis b, e 
x 
x 
x 
x 
x 
x 
x 
Adverse events f 
x 
x 
x 
x 
x 
x 
x 
C5 
 component 5. 
a Only a limited physical examination is required. 
b Assessment/sampling should be performed before the C5 inhibitor dose. 
c Vital signs include measurements of blood pressure (systolic and diastolic) while the patient is 
in a seated position, pulse rate, respiratory rate, and body temperature. 
d Safety laboratory assessments include hematology and chemistry panels as per i
judgement in order to monitor the safety of a patient. 
e Urinalysis includes dipstick (pH, specific gravity, glucose, protein, ketones, and blood).  If 
there is a clinically significant positive result (i.e., confirmed by a positive repeat sample), urine 
will be sent to the laboratory for microscopy and culture (sediment, RBCs, WBCs, casts, 
crystals, epithelial cells, bacteria).  If there is a known explanation for the positive dipstick 
result (e.g., menses), it should be recorded and there is no need to perform laboratory for 
microscopy and culture. 
f All adverse events will be reported until 24 weeks after the final dose of the study drug.  In 
addition, the Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that is believed to be related to crovalimab.  See Section 5 for additional details 
and reporting requirements.
 

 
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F. Hoffmann-La Roche Ltd 
116/Protocol YO42311, Version 5 
Appendix 3  
Anaphylaxis Precautions 
These guidelines are intended as a reference and should not supersede pertinent local 
or institutional standard operating procedures. 
REQUIRED EQUIPMENT AND MEDICATION 
The following equipment and medication are needed in the event of a suspected 
anaphylactic reaction during study treatment infusion: 
 
Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer 
 
Oxygen 
 
Epinephrine for subcutaneous, intramuscular, intravenous, and/or endotracheal 
administration in accordance with institutional guidelines 
 
Antihistamines 
 
Corticosteroids 
 
Intravenous infusion solutions, tubing, catheters, and tape 
 
PROCEDURES 
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed: 
1. 
Stop the study treatment infusion. 
2. 
Call for additional medical assistance. 
3. 
Maintain an adequate airway. 
4. 
Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring if possible. 
5. 
Administer antihistamines, epinephrine, or other medications and IV fluids as 
required by patient status and as directed by the physician in charge. 
6. 
Continue to observe the patient and document observations. 
 

 
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F. Hoffmann-La Roche Ltd 
117/Protocol YO42311, Version 5 
Appendix 4  
Major Adverse Vascular Events (MAVEs) 
The description of the Major adverse vascular events (MAVEs) including the method of 
diagnosis (e.g., MRI, ultrasound, angiogram), date of diagnosis, and the date resolved 
to baseline).  A MAVE is defined as any of the following events: 
 
Thrombophlebitis/deep vein thrombosis 
 
Pulmonary embolus 
 
Myocardial infarction 
 
Transient ischemic attack 
 
Unstable angina 
 
Renal vein thrombosis 
 
Acute peripheral vascular occlusion 
 
Mesenteric/visceral vein thrombosis or infarction 
 
Mesenteric/visceral arterial thrombosis or infarction 
 
Hepatic/portal vein thrombosis (budd-Chiari syndrome) 
 
Cerebral arterial occlusion/cerebrovascular accident 
 
Cerebral venous occlusion 
 
Renal arterial thrombosis 
 
Gangrene (non-traumatic, non-diabetic) 
 
Amputation (non-traumatic, non-diabetic) 
 
Dermal thrombosis 
 
Other, specify 

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