Clinical trial NCT05131204
Conditions: Paroxysmal Nocturnal Hemoglobinuria
Keywords: PNH
Sponsor: Regeneron Pharmaceuticals
Start date: 2022-10-06; Completion date: 2023-07-12
Enrollment: 3 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study is:

To evaluate the effect of pozelimab and cemdisiran combination therapy on hemolysis, as assessed by lactate dehydrogenase (LDH), after 36 weeks of treatment, in patients with PNH who switch from eculizumab or ravulizumab therapy versus patients who continue their eculizumab or ravulizumab therapy

The secondary objectives of the study are to:

* Evaluate the effect of pozelimab and cemdisiran combination treatment versus anti-C5 standard-of-care treatment (eculizumab or ravulizumab) on the following:

  * Transfusion requirements and transfusion parameters
  * Measures of hemolysis: LDH control, breakthrough hemolysis, and inhibition of CH50
  * Hemoglobin levels
  * Fatigue as assessed by Clinical Outcome Assessments (COAs)
  * Health-related quality of life (HRQoL) as assessed by COAs
  * Safety and tolerability
* To assess the concentrations of total pozelimab and either total eculizumab or total ravulizumab in serum and total cemdisiran and total C5 protein in plasma
* To assess the immunogenicity of pozelimab and cemdisiran

Detailed description:

Arms: arm 1: Randomized 1:1 arm 2: Randomized 1:1
Interventions: intervention 1: Cemdisiran intervention 2: Eculizumab intervention 3: Pozelimab intervention 4: Ravulizumab
Intervention descriptions: intervention 1: Administered per protocol intervention 2: Administered per protocol intervention 3: Administered per protocol intervention 4: Administered per protocol

Protocol documents:
Prot_000.pdf: 
NCT05131204
EudraCT 2020-002761-33 
IND Number: 151173 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A RANDOMIZED, OPEN-LABEL ECULIZUMAB AND RAVULIZUMAB 
CONTROLLED, NON-INFERIORITY STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF POZELIMAB AND CEMDISIRAN 
COMBINATION THERAPY IN PATIENTS WITH PAROXYSMAL 
NOCTURNAL HEMOGLOBINURIA WHO ARE CURRENTLY 
TREATED WITH ECULIZUMAB OR RAVULIZUMAB 
Compound: 
Pozelimab (REGN3918) 
Cemdisiran (ALN-CC5) 
Clinical Phase: 
3 
Protocol Number: 
R3918-PNH-2022 
Study Name: 
ACCESS-2 
Protocol Version: 
R3918-PNH-2022 Amendment 1 
Amendment 1 Date of Issue: 
See appended electronic signature page 
Original Date of Issue: 
11 Aug 2021 
Medical /Study Director: 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
Confidential: This submission contains confidential and proprietary commercial information 
and/or trade secrets which are subject to protection under laws and regulations worldwide 
including, but not limited to TRIPS Article 39 and regional, national or state laws whether by 
legislation or in equity. For the purposes of compliance with all applicable freedom of 
information laws, and regulations, and their equivalents anywhere in the world including but not 
limited to the US Freedom of Information Act 5 U.S.C. §552, Regeneron expects that, prior to 
disclosure to third parties of any information and/or data related to, or contained within, this 
submission, it will be given every opportunity under applicable laws to protect its commercial 
interests and/or its trade secrets including the opportunity to object to such disclosure and/or 
provide redaction proposals. 
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Clinical Study Protocol 
 
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REGENERON CONFIDENTIAL 
 
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AMENDMENT HISTORY 
Primary Rationale for Amendment 1 
The main purpose for this amendment is to include new secondary endpoints and provide details 
on the planned analyses for the phase 3 development program. 
Description of Change 
Brief Rationale  
Section # and Name  
Added new endpoints on 
“maintenance of adequate control”. 
Language is added to clarify the 
difference between the following 
endpoints relating to adequate control 
of LDH: 
• Maintenance of adequate control 
of hemolysis assesses the 
proportion of patients who 
consistently had an LDH 
≤1.5xULN at each study visit 
during the analysis period 
• Adequate control of hemolysis 
presents the model-adjusted odds 
ratio of the proportion of patients 
meeting LDH criteria of ≤1.5 x 
ULN at each study visit specified 
in the analysis period 
Additional clarification is provided to 
explain the differences in analysis 
methodology for these two endpoints 
pertaining to control of LDH. 
Section 11.2 Justifications of 
Sample Size and Non-Inferiority 
Margins 
Revised language to clarify how the 
analyses for the following key 
secondary endpoints will be 
performed: 
• Maintenance of adequate control 
of hemolysis, defined as LDH 
≤1.5 × ULN from week 8 through 
week 36, inclusive 
• Transfusion avoidance after day 1 
through week 36, inclusive 
(defined as not requiring a red 
blood cell [RBC] transfusion as 
per protocol algorithm based on 
hemoglobin values after day 1) 
Changes are made to clarify how these 
analyses will be performed: 
• A patient’s LDH is followed 
longitudinally to assess the 
maintenance of adequate control of 
hemolysis over time; this revised 
wording will also help distinguish 
this endpoint from a newly added 
secondary endpoint assessing 
adequacy of hemolysis control by 
visit. 
• For transfusion avoidance, patients 
who meet the protocol-defined 
transfusion criteria will be included 
in the analysis, regardless of 
whether a transfusion was 
administered. 
Clinical Study Protocol Synopsis: 
Endpoints 
Section 4.1.2 Key Secondary 
Endpoints  
 
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Description of Change 
Brief Rationale  
Section # and Name  
 For endpoints on maintenance of 
adequate control of hemolysis, 
adequate control of hemolysis, and 
normalization of LDH: 
• Timeframe for key secondary 
analysis for these endpoints is 
revised to the period from week 8 
to week 36 
• Timeframe for the period from 
after day 1 to week 36 are retained 
as other secondary endpoints 
The changes were made to prioritize 
the evaluation of efficacy to the period 
after the combination of pozelimab 
and cemdisiran has been introduced.  
The efficacy endpoints including the 
time period after the first introduction 
of cemdisiran, but prior to the 
introduction of the combination, have 
been reprioritized as other secondary 
endpoints.  
Clinical Study Protocol Synopsis: 
Endpoints, Statistical Analysis 
Section 4.1.2 Key Secondary 
Endpoints 
Section 4.1.3 Other Secondary 
Endpoints 
Section 11.2 Justification of 
Sample Size and Non-Inferiority 
Margins 
For the endpoint on breakthrough 
hemolysis: 
• Removed definition of 
breakthrough hemolysis from 
endpoint 
• Specified this endpoint will only 
be evaluated in patients with 
baseline LDH ≤1.5 x ULN 
The first change reduces redundancy, 
as the definition of breakthrough 
hemolysis is provided in Section 6.3. 
Since an event of breakthrough 
hemolysis requires an increase in LDH 
after achievement of LDH ≤1.5 x 
ULN, patients entering the study 
without adequate control of LDH on 
eculizumab or ravulizumab (LDH 
>1.5 x ULN at baseline) may not 
achieve the required level of LDH 
control and therefore will not be 
susceptible to meet the criteria for 
breakthrough hemolysis.  Limiting the 
endpoint analysis to those patients 
meeting an LDH threshold of ≤1.5 x 
ULN at baseline will ensure that there 
is a balance in the number of patients 
in each treatment group that may be 
susceptible to a breakthrough 
hemolysis event 
Clinical Study Protocol Synopsis: 
Endpoints 
Section 4.1.2 Key Secondary 
Endpoints 
Section 4.1.3 Other Secondary 
Endpoints 
 
Wording added describing how the 
non-inferiority margins for the 
endpoints of maintenance of 
adequate control of hemolysis and 
adequate control of hemolysis were 
derived 
This change is needed to 
accommodate the addition of the 
endpoint of adequate control of 
hemolysis. Justification for the non-
inferiority margin for the endpoint of 
maintenance of adequate control of 
hemolysis is also added 
Section 11.1 Statistical Hypothesis 
Section 11.2 Justifications of 
Sample Size and Non-Inferiority 
Margins 
Non-inferiority margins were 
recalculated for the endpoint of 
hemoglobin stabilization to improve 
the preservation of treatment effect to 
50%  
Per FDA Guidance on Non-Inferiority 
Trials (2016), 50% is the minimum 
recommended amount of benefit to be 
preserved in order to claim non-
inferiority 
Table 5: Summary of Data for 
Non-Inferiority Margin 
Calculations 
Table 4 was updated to capture 
revisions to non-inferiority margin 
calculations for key secondary 
endpoints 
Changes are made to correct errors in 
the prior version and to include 
calculations for all key secondary 
endpoints 
Table 5 Summary of Data for Non-
Inferiority Margin Calculations 
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Description of Change 
Brief Rationale  
Section # and Name  
Wording added to describe the 
analysis method for the endpoint of 
normalization of LDH 
As normalization of LDH is a 
secondary endpoint, a description of 
this analysis is added 
Clinical Study Protocol Synopsis: 
Statistical Plan 
Section 11.4.3.2 Secondary 
Efficacy Analysis 
Clarified the definition of baseline 
for LDH for patients taking 
eculizumab or ravulizumab at entry. 
In Sections 9.1.1.1 (footnote #2), 
9.2.1, and 11.4.3, information 
regarding baseline is removed to 
reduce redundancy. 
For safety and other efficacy 
analyses, baseline is the last value of 
the assessment preceding the first 
study drug administration (note: the 
value must be on or before day 1).  
 
Language was added to clarify that the 
baseline LDH is the pre-dose 
parameter.  Given the different dose 
administration frequency of 
eculizumab and ravulizumab, the 
timing of these baseline assessments 
differs (ie, a pre-study drug 
administration value for patients 
taking eculizumab at entry and a 
screening value for patients taking 
ravulizumab at entry). 
Section 6.1.1 Screening Period 
Section 6.3 Breakthrough 
Hemolysis 
Section 9.1.1.1 Table 1 Schedule 
of Events for the Open-Label 
Treatment Period, Footnote #2  
Section 9.2.1 Procedures 
Performed Only at the Screening 
Period 
Section 11.4.3 Efficacy Analyses 
Section 11.4.5 Safety Analysis 
Removed from the primary endpoint 
details regarding the definition of 
baseline  
This change reduces redundancy in the 
protocol providing a common location 
for the definition of baseline. 
Section 4.1 Primary and Secondary 
Endpoints 
Section 4.1.1 Primary Endpoint 
Section 6.3 Breakthrough 
Hemolysis 
For the safety endpoint referenced 
below, specified that the time period 
of the analysis corresponds to 36 
weeks, which is the duration of the 
open-label treatment period, instead 
of indicating more generically 
‘throughout the study’ 
• Incidence and severity of 
treatment-emergent SAEs, TEAEs 
of special interest and TEAEs 
leading to treatment 
discontinuation over 36 weeks 
This change clarifies the endpoint 
duration to be 36 weeks, which is the 
duration of the open label treatment 
period of the study 
Section 4.1.3 Other Secondary 
Endpoints 
Added new exploratory endpoint 
 
 
 
 
This new endpoint 
 
 
 
 
 
 
 
 
 
 
Section 4.1.4 Exploratory 
Endpoints 
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Description of Change 
Brief Rationale  
Section # and Name  
Revised wording of endpoints to 
remove “proportion of patients” from 
the endpoint in order to present the 
endpoints in terms of patient-level 
metrics 
 
This is a template change to revise 
endpoints to be patient-level metrics. 
The statistical metric to be presented 
as the outcome of the analysis will be 
described in the description of the 
analysis. 
Clinical Study Protocol Synopsis: 
Endpoints 
Section 4.1.2 Key Secondary 
Endpoints 
Section 4.1.4 Exploratory 
Endpoints 
Clarified that patients who are 
currently being treated with 
eculizumab or ravulizumab may be 
considered for this study 
Removed from eligibility criteria #3 
language regarding the timing of the 
last administration of ravulizumab in 
the parent study (R3918-PNH-2021) 
prior to the entry into this study 
(R3918-PNH-2022). 
This is a minor correction for 
clarification to ensure that patients are 
included only if treatment with 
eculizumab or ravulizumab is 
ongoing. 
Additional changes made to align with 
revisions to the last ravulizumab dose 
administration in the R3918-PNH-
2021 study. 
Section 7.2.1 Inclusion Criteria, #3  
 
Revised exclusion criterion to clarify 
that patients will be excluded if they 
are receiving acute treatment such as 
platelet transfusions and granulocyte 
colony stimulating factors 
Patients receiving these acute 
treatments are excluded because the 
effect of these treatments may 
confound the screening value upon 
which patient eligibility is based 
resulting in a screening value that 
might not be a true reflection of the 
patient’s clinical status/bone marrow 
function  
Section 7.2.2 Exclusion Criteria, 
#6  
Modified exclusion criteria to 
provide alternative units for 
reticulocyte count 
This change clarifies the reticulocyte 
count in units consistent with those 
reported by the central laboratory to 
facilitate appropriate assessment of 
patient eligibility by the study site 
Section 7.2.2 Exclusion Criteria, 
#6.c  
Modified exclusion to allow a subset 
of patients with human 
immunodeficiency virus (HIV) to 
participate in the study. 
 
This change was requested by a health 
authority to allow patients with HIV to 
participate in the study if their 
condition would not put them at a 
greater risk of developing adverse 
events 
Section 7.2.2 Exclusion Criteria, 
#13  
Clarified the exclusion criterion on 
liver transaminase abnormalities to 
exclude patients with alanine 
aminotransferase (ALT) or aspartate 
aminotransferase (AST) 
abnormalities that are elevated due to 
conditions unrelated to PNH or its 
complications 
The exclusion criterion is revised to 
clarify that patients with abnormalities 
in liver transaminases related to 
Paroxysmal nocturnal hemoglobinuria 
(PNH) or its complications are not 
excluded 
Section 7.2.2 Exclusion Criteria, 
#17  
Added a sub-criterion to exclude 
patients who are ineligible for 
clinical trial participation due to local 
regulations. 
This exclusion criterion accounts for 
protected populations that are 
ineligible for clinical trials per local 
regulations.  This change is requested 
by an ethics committee for clarity. 
Section 7.2.2 Exclusion Criteria, 
#26.e  
 
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Description of Change 
Brief Rationale  
Section # and Name  
In the list of highly effective 
contraceptive measures, added “tubal 
ligation or tubal occlusion”. Clarified 
that regnancy testing and 
contraception are required for women 
of childbearing potential but not 
required for women who are post-
menopausal or permanently sterile. 
This is a template update. Tubal 
ligation is a permanent and 
irreversible contraceptive method; 
however, neither are considered 
sterilization. Therefore, women with 
bilateral tubal ligation or tubal 
occlusion will require pregnancy 
testing. 
Section 7.2.2 Exclusion Criteria, 
#29.c  
Section 9.2.4.7 Laboratory Testing 
 
Added exclusion criterion to exclude 
patients who are non-responsive to 
eculizumab or ravulizumab. 
Patients who are non-responsive to 
eculizumab or ravulizumab would not 
be appropriate for this study, as they 
may be randomized to continue a 
treatment that has been shown to be 
ineffective for their condition. Patients 
with C5 polymorphisms non-
responsive to eculizumab or 
ravulizumab will be evaluated in a 
separate study. 
Section 7.2.2 Exclusion Criteria, 
#30  
Section 9.1.1.1 Footnotes for 
Table 1, Schedule of Events for the 
Open-Label Treatment Period, #4  
Added exclusion criterion for 
patients with hemoglobin ≤7 g/dL.  
The exclusion criterion clarifies that 
patients are allowed to receive a 
blood transfusion during the 
screening period and are eligible if a 
repeat hemoglobin test is >7 g/dL 
prior to randomization. 
This change is made to minimize a 
patient entering the study meeting the 
criteria for a blood transfusion at the 
outset and to facilitate the 
determination of endpoint 
achievement for transfusion avoidance 
Section 7.2.2 Exclusion Criteria, 
#31  
 
Clarified in the primary objective and 
hypothesis that patients will be 
switching from eculizumab or 
ravulizumab therapy to the 
pozelimab/cemdisiran combination 
treatment. 
This change is requested by an ethics 
committee for clarity. 
Clinical Study Protocol Synopsis: 
Objectives 
Section 2.1 Primary Objective 
Section 3.1 Hypothesis 
Modified the text in the rationale for 
dose selection section to indicate that 
the PK/PD modeling that was 
performed to support the dose 
rationale 
 
 
 
 
 
This is a correction. 
 
 
 
 
 
 
Section 3.2.2 Rationale for Dose 
Selection 
Added clarification that patients who 
discontinue study treatment 
(including those who complete the 
study but decline to participate in the 
next study) will proceed to the 
follow-up period. 
For study diagram, added 
clarification that the transition period 
is for patients who plan to enroll into 
the extension study. 
These changes clarify the intended 
next steps for patients who discontinue 
study drug and those who complete 
the open-label treatment period. 
Section 6.1 Study Description and 
Duration 
Figure 1 Study Diagram 
Section 6.1.4 Post-Open-Label 
Treatment Period (Post-OLTP) 
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Description of Change 
Brief Rationale  
Section # and Name  
Provide guidance regarding the 
timing of screening visit 1, visit 
2e/2r, and day 1.  
• For patients taking eculizumab, 
screening visit 1 should be 
scheduled on the day of or the day 
prior to an eculizumab dose and 
visit 2e should be scheduled when 
all information are available to 
assess eligibility. Day 1 should be 
scheduled on or up to 2 days prior 
to an eculizumab dose. 
Last dose of eculizumab will be at 
day 15 (week 2) visit 
• For patients taking ravulizumab, 
screening visit 1 should be 
scheduled about 6 weeks after the 
last administered ravulizumab 
dose and visit 2r should be 
scheduled on the day of or up to 
2 days before the patient’s next 
scheduled ravulizumab dose. Day 
1 should be scheduled 26 to 28 
days after the last ravulizumab 
dose at visit 2r. 
Language is revised for 
emphasis/clarity, to ensure that sites 
are aware of the timing of drug 
administration relative to treatment 
visits.   
Clinical Study Protocol Synopsis: 
Study Design 
Section 6.1.1 Screening Period 
Section 6.1.3 Open-Label 
Treatment Period (OLTP) 
Section 9.1.1.1 Table 1 Schedule 
of Events for the Open-Label 
Treatment Period, footnote #2, #3, 
#36 
Section 9.2.1 Procedures 
Performed Only at the Screening 
Period 
Moved language 
 
 
 
 
from Section 6.1.1 to 
Sections 7.2 and 8.5. 
This is a reorganization. Text was 
originally located in Section 6.1.1 and 
moved to Sections 7.2 and 8.5 for 
clarity. There is no change to the 
enrollment process or sample size. 
Clinical Study Protocol Synopsis: 
Study Design, Population 
Section 6.1.1 Screening Period 
Section 7.2 Study Population 
Section 8.5 Method of Treatment 
Assignment 
Revised the wording of stratification 
factors to be based on the time of 
randomization.   
Removed details regarding 
stratification from Sections 6.1.2 and 
7.2 to reduce redundancy. 
Because randomization occurs on 
day 1, there is no change to study 
conduct. This change clarifies that 
patients are stratified at the time of 
randomization. 
Section 6.1.1 Randomization 
Section 11.4.2 Demography and 
Baseline Characteristics 
Included language regarding the 
timing of screening visits for patients 
who plan to enroll into the next 
clinical study. 
This change provides guidance for 
patients who are near completion of 
this study to initiate the screening 
process for the next study. 
Section 6.1.4 Post-Open-Label 
Treatment Period (Post-OLTP) 
Section 9.1.1.1 Table 1 Schedule 
of Events for the Open-Label 
Treatment Period, footnote #1  
Added study stopping rules, in which 
the independent data monitoring 
committee will review unblinded 
data on a regular basis and may 
recommend changes in study conduct 
including halting the study 
This change addresses a comment 
from a health authority to include 
study stopping rules 
Section 6.1.5 Study Stopping Rules 
[new] 
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Clinical Study Protocol 
 
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Description of Change 
Brief Rationale  
Section # and Name  
For the transfusion algorithm, 
clarified that transfusions may be 
performed as clinically indicated. 
However, to meet the endpoint 
criteria for the evaluation of blood 
transfusion, patients with hemoglobin 
>7 to ≤9 g/dL should have onset of 
new or worsening signs/symptoms of 
anemia after day 1. 
 
This change was made to ensure that a 
patient that is counted as a non-
responder for transfusion avoidance 
has experienced a change in clinical 
status and is not receiving a 
transfusion on the basis of a 
hemoglobin value and symptoms that 
remain unchanged from baseline. 
Section 6.4 Transfusion Algorithm 
 
Clarified that enrollment will 
continue until approximately 
140 patients have been randomized 
and received at least 1 dose of study 
treatment. 
The revised language assures that 
sufficient data from treated patients 
will be collected for the statistical 
analysis. There is no change to the 
study sample size. 
Clinical Study Protocol Synopsis: 
Study Design, Population 
Section 7.1 Number of Patients 
Planned 
Section 8.5 Method of Treatment 
Assignment 
Clarified that study treatment refers 
only to the investigational medicinal 
products (ie, pozelimab, cemdisiran, 
eculizumab, and ravulizumab) 
provided for use in this study. 
This change is to differentiate study 
drug provided for use in this study 
from the patient’s standard of care 
treatment (eculizumab or 
ravulizumab) that they receive. 
Section 8.1 Investigational and 
Reference Treatments 
Table 1 Schedule of Events for the 
Open-Label Treatment Period 
Clarified that eculizumab and 
ravulizumab will be provided by the 
study sponsor but may be sourced 
locally by the study site in 
exceptional circumstances 
This update clarifies that eculizumab 
and ravulizumab will be provided by 
the study sponsor but allows the 
flexibility of local sourcing by sites. 
Section 8.1.3 Eculizumab 
Section 8.1.4 Ravulizumab 
 
Added citations to the approved 
prescribing information for 
eculizumab and ravulizumab (such as 
the summary of product 
characteristics) 
This provides additional reference 
information for the comparator drugs 
used in this study. 
Section 8.1.3 Eculizumab 
Section 8.1.4 Ravulizumab 
Added language to clarify that no 
interaction is expected between 
antibiotic prophylaxis and cemdisiran 
or pozelimab. 
This change aligns with language from 
other studies in the pozelimab/ 
cemdisiran combination program. 
Section 8.2.4 Oral Antibiotics for 
Meningococcal Infection 
Added language to clarify that 
investigators should use their clinical 
judgment when resuming study 
treatment after a temporary 
discontinuation and encourages 
investigators to discuss with the 
Sponsor’s medical monitor. 
 
The study medical monitor should be 
involved upon resumption of the study 
treatment after a period of treatment 
interruption 
 
 
 
 
 
 
 
 
Section 8.3.2.2 Reasons for 
Temporary Discontinuation of 
Study Drug 
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Description of Change 
Brief Rationale  
Section # and Name  
Suggested that vaccination against 
COVID-19 may be given 2 
to 3 weeks after a dose of 
pozelimab/cemdisiran or 
ravulizumab, or up to 1 week after 
administration of eculizumab. 
This change clarifies the suggested 
timing of COVID-19 vaccination for 
patients on eculizumab, which is 
dosed every 2 weeks. 
Section 8.8.2 Permitted 
Medications and Procedures 
Added a timepoint to review 
inclusion/exclusion criteria at 
screening visit 2. 
This change allows patients to be 
excluded earlier if they do not meet 
the eligibility requirements for this 
study. 
Table 1 Schedule of Events for the 
Open-Label Treatment Period 
• Separate Tables were included to 
describe the transition from 
eculizumab or ravulizumab to the 
combination of pozelimab and 
cemdisiran for patients 
participating in the follow-up 
open label extension study 
(R3918-PNH-2050). 
- New Table 2 to describe the 
transition period for patients 
included in the eculizumab arm 
- New Table 3 to describe the 
transition period for patients 
included in the ravulizumab arm 
• Added monthly urine pregnancy 
testing at week 8t during the 
transition period for ravulizumab 
arm (Table 3) 
The original table describing the 
transition period is separated into two 
individual tables for patients in the 
eculizumab arm or the ravulizumab 
arm for clarity. 
 
Monthly pregnancy testing was 
clarified to address a comment from a 
health authority.  
Table 2 Schedule of Events for the 
Transition Period: Patients on 
Eculizumab in OLTP who Plan to 
Enroll in the OLE 
Table 3 Schedule of Events for the 
Transition Period: Patients on 
Ravulizumab in OLTP who Plan to 
Enroll in the OLE 
Renumbered visits in the safety 
follow up period to start at follow-up 
visit 1 (rather than follow-up visit 0) 
for consistency with other study 
periods. 
This is a minor change for alignment 
with the visit numbering system for 
other study periods. 
Table 4 Schedule of Events for the 
Safety Off-Treatment Follow-up 
Period 
Section 9.1.4.1 Table 4 Schedule 
of Events for the Safety Off-
Treatment Follow-up Period, 
footnote #1 , #2  
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Description of Change 
Brief Rationale  
Section # and Name  
• Added D-dimer as part of 
coagulation panel for laboratory 
analysis as well as for any 
suspected drug hypersensitivity 
event 
• Added drug concentration and 
anti-pozelimab antibodies 
assessments in the event of a 
suspected drug hypersensitivity or 
a suspected event of breakthrough 
hemolysis 
• Added magnesium as an analyte 
to blood chemistry to monitor 
electrolytes per request from a 
health authority 
• Added immunogenicity sample 
(anti-pozelimab antibodies) as part 
of laboratory analysis for any 
suspected breakthrough hemolysis 
event 
• Added urobilinogen to list of 
analytes for urinalysis and noted 
when to perform macroscopy, 
microscopy, and urine culture 
• Clarified the assessments to be 
performed for bilirubin 
These changes clarify details 
regarding sample collection. 
Section 6.2 Large Drug-Target-
Drug Immune Complexes 
Section 9.1.1.1 Table 1 Schedule 
of Events for the Open-Label 
Treatment Period, Footnote #23, 
#31   
Section 9.1.2.1 Table 2 Schedule 
of Events for the Transition Period: 
Patients on Eculizumab in OLTP 
who Plan to Enroll in the OLE, 
Footnote #8 
Section 9.2.4.7 Laboratory Testing 
 
For Open label treatment period 
(OLTP, Table 1): 
• Added time points for D-dimer 
• Added time points for 
immunoglobulin G in order to 
assess protein catabolism 
• Reorganized the collection of 
samples for drug concentration, 
ADA, and total C5 to separate the 
schedule by treatment arm. 
For transition period (Table 2): 
• Removed anti-drug antibody 
(ADA) time points from the 
transition period 
• Updated the time points for total 
C5 
• Reorganized the collection of 
samples for drug concentration, 
ADA, and total C5 to separate the 
schedule by treatment arm. 
These changes describe updates made 
to sample collection. 
Table 1 Schedule of Events for the 
Open-Label Treatment Period 
Table 2 Schedule of Events for the 
Transition Period: Patients on 
Eculizumab in OLTP who Plan to 
Enroll in the OLE 
Section 9.1.2.1 Table 2 Schedule 
of Events for the Transition Period: 
Patients on Eculizumab in OLTP 
who Plan to Enroll in the OLE, 
Footnote #14 [removed] 
Section 9.2.4.7 Laboratory Testing 
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Description of Change 
Brief Rationale  
Section # and Name  
Removed specification that C5 
mutation (if needed during study) 
must be performed by a local 
laboratory. This test may also be 
done by a central laboratory. 
This change allows flexibility for C5 
mutation testing to be performed by a 
central laboratory.  
Section 9.1.1.1 Footnotes for 
Table 1, Schedule of Events for the 
Open-Label Treatment Period, #4  
Included in the schedule of events the 
labs that are required to be conducted 
for patients taking ravulizumab prior 
to the dose of ravulizumab at week -4 
(visit 2r).  
Removed information about baseline 
laboratory assessments from 
Section 9.2.1 and Section 9.1.1.1 
(footnote #16) because the timing 
and details for these assessments are 
incorporated into Table 1. 
This change was added to clarify that 
for patients taking ravulizumab, 
laboratory samples are to be collected 
at visit 2r (week -4, the day of or prior 
to ravulizumab dosing), to ensure that 
pre-dose assessments are obtained 
before randomization.  
Table 1 Schedule of Events for the 
Open-Label Treatment Period  
Section 9.1.1.1 Table 1 Schedule 
of Events for the Open-Label 
Treatment Period, footnote #16  
Section 9.2.1 Procedures 
Performed Only at the Screening 
Period 
Added footnote in schedule of events 
to clarify additional sampling: 
• Added footnote to collect samples 
at week 36 visit to assess ADA in 
patients randomized to the 
pozelimab/cemdisiran 
combination arm as well as 
patients randomized to the 
standard-of-care arm who will be 
continuing in the transition period 
• Sample for the measurement of 
concentrations of cemdisiran and 
its metabolites will be collected at 
the week 36 visit only for patients 
who are receiving eculizumab 
treatment and willing to continue 
in the transition period and into 
the open-label extension (OLE) 
This change clarifies additional 
sampling that is needed 
Table 1 Schedule of Events for the 
Open-Label Treatment Period 
Section 9.1.1.1 Table 1 Schedule 
of Events for the Open-Label 
Treatment Period, Footnote #32 
[new], #33 [new] 
 
Revised language to ask that an LDH 
assessment be repeated if it is ≥2 × 
ULN in association with a potassium 
≥6 mmol/L. 
This change provides guidance on 
when laboratory assessments may 
need to be repeated. 
Section 9.1.1.1 Table 1 Schedule 
of Events for the Open-Label 
Treatment Period, Footnote #24  
Added footnote to clarify that a dose 
is only given at week 36 to patients 
who plan to continue into the OLE 
study. 
This change clarifies the requirements 
for receiving study drug at week 36. 
Section 9.1.1.1 Table 1 Schedule 
of Events for the Open-Label 
Treatment Period, Footnote #37  
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Description of Change 
Brief Rationale  
Section # and Name  
Added the following screening 
procedures to align with changes to 
the schedule of events: 
• Added a bullet for a blood sample 
to measure titers for Neisseria 
meningitidis if required by local 
practice/regulations (this 
procedure is described in the 
schedule of events and was 
inadvertently omitted in this 
section) 
•  
These changes are made to align with 
the schedule of events. 
Section 9.2.1 Procedures 
Performed Only at the Screening 
Period 
 
Clarified that electronic devices for 
recording patient-reported 
questionnaires during the study will 
be provided to the patients at 
Screening Visit 2e or 2r (instead of 
Screening Visit 2).    
This is a minor clarification to align 
with the schedule of events since 
Screening Visit 2 was separated into 2 
visits, one for patients taking 
eculizumab at entry and one for 
patients taking ravulizumab at entry. 
Section 9.2.1 Procedures 
Performed Only at the Screening 
Period  
Section 9.2.3 Clinical Outcome 
Assessments 
Removed language indicating that 
laboratory samples will be obtained 
in countries where sample collection 
and export are permitted.   
 
This change allows the collection of 
laboratory samples even in countries 
where export of samples is not 
permitted. This provides flexibility for 
the samples to be collected and 
analyzed locally. 
Section 9.2.4.7 Laboratory Testing 
Section 9.2.5.1 Concentrations of 
Total Pozelimab, Total 
Eculizumab, Total Ravulizumab 
and Total C5 
Section 9.2.5.2 Concentrations of 
Cemdisiran and Cemdisiran 
Metabolites 
Section 9.2.6 Immunogenicity 
Measurements and Samples 
Section 9.2.7 Pharmacodynamic 
Biomarker Procedures 
Added procedure for distribution of a 
patient safety brochure for 
participants randomized to the 
standard-of-care arm (for eculizumab 
or ravulizumab, respectively) and 
provision of prescriber safety 
brochures to all investigators 
As part of the commitment to centrally 
source eculizumab and ravulizumab, 
provision of the patient safety 
brochure is required for all patients 
randomized to receive standard-of-
care treatment. Prescriber safety 
brochures for eculizumab and 
ravulizumab will also be provided to 
investigators 
Section 6.1.3 Open-Label 
Treatment Period (OLTP) 
Section 8.1.3 Eculizumab 
Section 8.1.4 Ravulizumab 
Section 8.2.3 Monitoring for 
Meningococcal Infection 
Table 1 Schedule of Events for the 
Open-Label Treatment Period 
Section 9.2.1 Procedures 
Performed Only at the Screening 
Period 
Section 9.2.4.6 Safety Monitoring 
Removed language related to Risk 
Evaluation and Mitigation Strategy 
(REMS) for eculizumab and 
ravulizumab 
REMS is related to post-marketing use 
and is not applicable for clinical trials. 
Risk mitigation strategies for this 
study are described in the protocol 
Section 3.3 
Section 6.1.1 Screening Period 
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Description of Change 
Brief Rationale  
Section # and Name  
Removed fasting requirement for 
blood chemistry sample 
This change reduces study complexity 
as the results of the endpoints should 
not be impacted in a meaningful way 
by fasting status 
Section 9.2.4.7 Laboratory Testing 
Revised description of Functional 
Assessment of Chronic Illness 
Therapy – Fatigue (FACIT-Fatigue) 
to a 5-point Likert scale. A higher 
score indicates a higher quality of life 
This is a correction 
Section 9.2.3.1 Functional 
Assessment of Chronic Illness 
Therapy-Fatigue (FACIT-Fatigue) 
Removed the collection of pregnancy 
data for the female partner of a male 
patient from protocol 
This is an error. The collection of 
safety data for the pregnant partner of 
a male study patient is not needed 
given that the study does not require 
male contraception 
Section 10.1.3 Events that Require 
Expedited Reporting to Sponsor 
Added details on metrics that will be 
collected for patient disposition 
Changes are made to provide 
additional details and to align with the 
analysis plan 
Section 11.3.1 Patient Disposition 
Updated descriptions of analysis sets 
to provide additional details 
This change provides additional 
details regarding analysis sets defined 
in the study 
Section 11.3.1 Full Analysis Set 
Section 11.3.2 Safety Analysis Set 
Section 11.3.3 Pharmacokinetic 
Analysis Set 
Section 11.3.4 Immunogenicity 
Analysis Set 
Section 11.3.5 Per-Protocol Set 
Section 11.3.6 Biomarker Endpoint 
Analysis Set [new] 
Revisions were made to align the 
description of the efficacy analysis 
with the planned approach. The 
statistical analysis plan is referenced 
for additional details 
Brief descriptions of the analyses are 
included for endpoints, with full 
details planned for the analysis plan 
Section 11.4.3.1 Primary Efficacy 
Analysis 
Section 11.4.3.2 Secondary 
Efficacy Analysis 
Removed details regarding the 
control of multiplicity. The statistical 
analysis plan is referenced for 
additional details 
This change reduces the level of detail 
on the control of multiplicity. A robust 
description will be provided in the 
analysis plan 
Section 11.4.4 Control of 
Multiplicity 
Provided additional details on safety 
analysis 
This change describes additional 
tabular summaries planned as part of 
the safety analysis  
Section 11.4.5 Safety Analysis 
Section 11.4.5.1 Adverse Events 
• Removed description of study 
duration from section on Study 
Design and to include the follow-
up period in the Study Duration 
section for completeness 
• Included a description of the 
pozelimab 
 mg/kg IV dose in 
the Treatment section to align 
with the regimen for the transition 
period 
These are editorial changes to align 
the synopsis with the protocol body 
and to avoid repetition of details that 
are presented elsewhere in the 
synopsis 
Clinical Study Protocol Synopsis: 
Study Design, Study Duration, 
Treatments 
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Description of Change 
Brief Rationale  
Section # and Name  
Removed program-level details that 
are provided in the investigator’s 
brochure 
This change removes details that are 
already provided in the investigator’s 
brochure to avoid repetition and the 
potential for discrepancy 
Section 1 Introduction 
Removed “total” in reference to drug 
concentration for cemdisiran 
 
This is a correction. The mechanism 
of action of cemdisiran is not by 
binding, and hence there is no free and 
bound or total cemdisiran. 
Throughout document 
Updated name of the global principal 
investigator 
This is an administrative update 
Clinical Study Protocol Synopsis: 
Principal Investigator 
Included “non-inferiority” in the 
study title. 
This change addresses a request from 
a health authority 
Title page 
Clinical Study Protocol Synopsis: 
Title 
Section 20 Investigator’s 
Agreement 
Signature of Sponsor’s 
Responsible Officers 
Added study name 
ACCESS-2 is the official study name 
Title page 
Editorial and formatting changes 
These are minor changes including 
clarifications,  corrections, 
reorganization, and template updates 
Throughout document 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
 
 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BW 
Body weight 
C3 
Complement component 3 
C5 
Complement factor 5 
CBC 
Complete blood count 
C9 
Complement component 9 
CH50 
Complement hemolytic activity 
CI 
Confidence Interval 
COA 
Clinical outcome assessment 
COVID-19 
Coronavirus disease 2019 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
CRP 
C-reactive protein 
CSR 
Clinical study report 
DTD 
Drug-target-drug 
Dxt 
Day x of transition period 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
EOS 
End of study 
EOT 
End-of-treatment 
EORTC-QLQ-
C30 
European organization for research and treatment of cancer quality-of-Life 
questionnaire core 30 items 
EOS 
End of study 
 
 
EU 
European Union 
FACIT-Fatigue 
Functional Assessment of Chronic Illness Therapy-Fatigue 
FAS 
Full analysis set 
FBR 
Future biomedical research 
FDA 
U.S. Food and Drug Administration 
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FIH 
First-in-human 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GHS 
Global health status 
GPI 
Glycophosphatidylinositol 
HCP 
Health care provider 
HRQoL 
Health-related quality of life 
HSC 
Hematopoietic stem cell 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent data monitoring committee 
IgG4P 
Immunoglobulin G4P 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
IWRS 
Interactive web response system 
LDH 
Lactate dehydrogenase 
LTBI 
Latent tuberculosis infection 
mAbs 
Monoclonal antibodies 
MAC 
Membrane-attack complex 
MAVE 
Major adverse vascular events 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeated Measures 
mRNA 
Messenger ribonucleic acid 
NAb 
Neutralizing antibody 
NIM 
Non-Inferiority Margin 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
OLE 
Open-label extension 
OLTP 
Open label treatment period 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamic 
PF 
Physical function 
 
 
 
 
PIGA 
Phosphatidylinositol glycan anchor 
PK 
Pharmacokinetic 
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PNH 
Paroxysmal nocturnal hemoglobinuria 
PPS 
Per-protocol set 
PRO 
Patient-reported outcomes 
PT 
Preferred Term 
Q2W 
Every 2 weeks 
Q4W 
Every 4 weeks 
Q8W 
Every 8 weeks 
QoL 
Quality of life 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
RBQM 
Risk-Based Quality Monitoring 
RNA 
Ribonucleic acid 
RT-PCR 
Reverse transcriptase polymerase chain reaction 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SC 
Subcutaneous 
SD 
Standard deviation 
siRNA 
Small interfering ribonucleic acid 
SOC 
System organ class 
Spp 
Species 
SUSAR 
Suspected unexpected serious adverse reaction 
TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 
 
 
ULN 
Upper Limit of Normal 
US 
United States 
Vxt 
Visit x of transition period 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................15 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................24 
1. 
INTRODUCTION ......................................................................................................31 
2. 
STUDY OBJECTIVES ..............................................................................................36 
2.1. 
Primary Objective .......................................................................................................36 
2.2. 
Secondary Objectives .................................................................................................36 
2.3. 
Exploratory Objectives ...............................................................................................36 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................38 
3.1. 
Hypothesis ..................................................................................................................38 
3.2. 
Rationale .....................................................................................................................38 
3.2.1. 
Rationale for Study Design .........................................................................................38 
3.2.2. 
Rationale for Dose Selection ......................................................................................40 
3.3. 
Risk-Benefit ................................................................................................................41 
3.3.1. 
Risk Benefit for Eculizumab and Ravulizumab Active Comparators ........................42 
3.3.2. 
Potential Risk of Neisseria Infection ..........................................................................42 
3.3.3. 
Liver Function Test Abnormalities .............................................................................43 
3.3.4. 
Infusion Reactions ......................................................................................................43 
3.3.5. 
Other Risks .................................................................................................................44 
3.3.6. 
Study Conduct in Response to Coronavirus Disease 2019 .........................................44 
4. 
ENDPOINTS ..............................................................................................................45 
4.1. 
Primary and Secondary Endpoints..............................................................................45 
4.1.1. 
Primary Endpoint ........................................................................................................45 
4.1.2. 
Key Secondary Endpoints ...........................................................................................45 
4.1.3. 
Other Secondary Endpoints ........................................................................................45 
4.1.4. 
Exploratory Endpoints ................................................................................................46 
5. 
STUDY VARIABLES................................................................................................48 
5.1. 
Demographic and Baseline Characteristics ................................................................48 
5.2. 
Efficacy Variables ......................................................................................................48 
5.2.1. 
Laboratory Variables for the Assessment of Efficacy ................................................48 
5.2.2. 
Transfusion Record .....................................................................................................48 
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5.2.3. 
Clinical Outcome Assessments ...................................................................................48 
5.3. 
Safety Variables and Anthropometric Variables ........................................................48 
5.4. 
Pharmacokinetic Variables .........................................................................................49 
5.5. 
Immunogenicity Variables ..........................................................................................49 
5.6. 
Pharmacodynamic and Other Biomarker Variables ...................................................49 
6. 
STUDY DESIGN .......................................................................................................50 
6.1. 
Study Description and Duration .................................................................................50 
6.1.1. 
Screening Period .........................................................................................................51 
6.1.2. 
Randomization ............................................................................................................52 
6.1.3. 
Open-Label Treatment Period (OLTP) .......................................................................52 
6.1.4. 
Post-Open-Label Treatment Period (Post-OLTP) ......................................................54 
6.1.5. 
Study Stopping Rules .................................................................................................55 
6.1.6. 
End of Study Definition ..............................................................................................55 
6.2. 
Large Drug-Target-Drug Immune Complexes ...........................................................55 
6.3. 
Breakthrough Hemolysis ............................................................................................56 
6.4. 
Transfusion Algorithm ................................................................................................56 
6.5. 
Planned Interim Analysis ............................................................................................57 
6.6. 
Study Committees .......................................................................................................57 
6.6.1. 
Independent Data Monitoring Committee ..................................................................57 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............58 
7.1. 
Number of Patients Planned .......................................................................................58 
7.2. 
Study Population .........................................................................................................58 
7.2.1. 
Inclusion Criteria ........................................................................................................58 
7.2.2. 
Exclusion Criteria .......................................................................................................59 
7.3. 
Premature Withdrawal from the Study .......................................................................62 
7.4. 
Replacement of Patients .............................................................................................63 
8. 
STUDY TREATMENTS............................................................................................64 
8.1. 
Investigational and Reference Treatments ..................................................................64 
8.1.1. 
Pozelimab ...................................................................................................................64 
8.1.2. 
Cemdisiran ..................................................................................................................64 
8.1.3. 
Eculizumab .................................................................................................................64 
8.1.4. 
Ravulizumab ...............................................................................................................64 
8.2. 
Risk Mitigation and Background Treatments .............................................................65 
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8.2.1. 
Meningococcal Vaccinations ......................................................................................65 
8.2.2. 
Streptococcus Pneumoniae and Haemophilus Influenzae Type B Vaccination ..........65 
8.2.3. 
Monitoring for Meningococcal Infection ...................................................................65 
8.2.4. 
Oral Antibiotics for Meningococcal Infection ............................................................65 
8.2.5. 
Risk Management of Neisseria Gonorrhea ................................................................66 
8.2.6. 
Guidance on Abnormalities in Transaminases and Other Liver Function 
Tests ............................................................................................................................66 
8.2.7. 
Guidance on Large Drug-Target-Drug Immune Complexes ......................................67 
8.3. 
Dose Modification and Study Treatment Discontinuation Rules ...............................67 
8.3.1. 
Dose Modification ......................................................................................................67 
8.3.2. 
Study Drug Discontinuation .......................................................................................67 
8.4. 
Management of Acute Reactions ................................................................................69 
8.4.1. 
Acute Intravenous Infusion Reactions ........................................................................69 
8.4.2. 
Acute Injection Reactions ...........................................................................................70 
8.5. 
Method of Treatment Assignment ..............................................................................71 
8.6. 
Blinding ......................................................................................................................71 
8.7. 
Treatment Logistics and Accountability .....................................................................71 
8.7.1. 
Packaging, Labeling, and Storage ..............................................................................71 
8.7.2. 
Supply and Disposition of Treatments .......................................................................71 
8.7.3. 
Treatment Accountability ...........................................................................................72 
8.7.4. 
Treatment Compliance ................................................................................................72 
8.8. 
Concomitant Medications and Procedures .................................................................72 
8.8.1. 
Prohibited Medications and Procedures .....................................................................72 
8.8.2. 
Permitted Medications and Procedures ......................................................................72 
8.9. 
Poststudy Treatments and Procedures ........................................................................73 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................74 
9.1. 
Schedule of Events .....................................................................................................74 
9.1.1. 
Open-Label Treatment Period ....................................................................................75 
9.1.2. 
Transition Period: Patients on Eculizumab in OLTP who Plan to Enroll in 
the OLE .......................................................................................................................85 
9.1.3. 
Transition Period: Patients on Ravulizumab in OLTP who Plan to Enroll in 
the OLE .......................................................................................................................88 
9.1.4. 
Safety Off-Treatment Follow-up Period .....................................................................91 
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9.1.5. 
Early Termination Visit ..............................................................................................92 
9.1.6. 
Unscheduled Visits .....................................................................................................92 
9.2. 
Study Procedures ........................................................................................................92 
9.2.1. 
Procedures Performed at the Screening Period ..........................................................92 
9.2.2. 
Efficacy Procedures ....................................................................................................93 
9.2.3. 
Clinical Outcome Assessments ...................................................................................93 
9.2.4. 
Safety Procedures .......................................................................................................96 
9.2.5. 
Drug Concentration and Measurements .....................................................................99 
9.2.6. 
Immunogenicity Measurements and Samples ............................................................99 
9.2.7. 
Pharmacodynamic Biomarker Procedures ................................................................100 
9.2.8. 
Future Biomedical Research (Optional) ...................................................................100 
9.2.9. 
Pharmacogenomic Analysis (Optional) ....................................................................101 
10. 
SAFETY EVALUATION AND REPORTING .......................................................102 
10.1. 
Recording and Reporting Adverse Events ................................................................102 
10.1.1. 
General Guidelines ...................................................................................................102 
10.1.2. 
Reporting Procedure .................................................................................................103 
10.1.3. 
Events that Require Expedited Reporting to Sponsor ..............................................103 
10.1.4. 
Other Adverse Events of Special Interest that do not Require Expedited 
Reporting to Sponsor ................................................................................................104 
10.2. 
Definitions ................................................................................................................104 
10.2.1. 
Adverse Event ...........................................................................................................104 
10.2.2. 
Serious Adverse Event ..............................................................................................104 
10.2.3. 
Adverse Events of Special Interest ...........................................................................105 
10.2.4. 
Infusion Reactions ....................................................................................................105 
10.2.5. 
Severity .....................................................................................................................105 
10.2.6. 
Causality ...................................................................................................................106 
10.3. 
Safety Monitoring .....................................................................................................107 
10.4. 
Notifying Health Authorities, Institutional Review Board /Ethics Committee, 
and Investigators .......................................................................................................107 
11. 
STATISTICAL PLAN..............................................................................................109 
11.1. 
Statistical Hypothesis ................................................................................................109 
11.2. 
Justification of Sample Size and Non-Inferiority Margins .......................................109 
11.3. 
Analysis Sets .............................................................................................................112 
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11.3.1. 
Full Analysis Set .......................................................................................................112 
11.3.2. 
Safety Analysis Set ...................................................................................................112 
11.3.3. 
Pharmacokinetic Analysis Set ..................................................................................112 
11.3.4. 
Immunogenicity Analysis Sets .................................................................................112 
11.3.5. 
Per-Protocol Set ........................................................................................................112 
11.3.6. 
Biomarker Endpoint Analysis Set ............................................................................113 
11.4. 
Statistical Methods ....................................................................................................113 
11.4.1. 
Patient Disposition ....................................................................................................113 
11.4.2. 
Demography and Baseline Characteristics ...............................................................113 
11.4.3. 
Efficacy Analyses .....................................................................................................114 
11.4.4. 
Control of Multiplicity ..............................................................................................116 
11.4.5. 
Safety Analysis .........................................................................................................116 
11.4.6. 
Pharmacokinetics ......................................................................................................120 
11.4.7. 
Analysis of Immunogenicity Data ............................................................................120 
11.4.8. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data ............................121 
11.5. 
Statistical Considerations Surrounding the Premature Termination of a Study .......121 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................122 
12.1. 
Data Management and Electronic Systems ..............................................................122 
12.1.1. 
Data Management .....................................................................................................122 
12.1.2. 
Electronic Systems ....................................................................................................122 
12.2. 
Study Monitoring ......................................................................................................122 
12.2.1. 
Monitoring of Study Sites .........................................................................................122 
12.2.2. 
Source Document Requirements ..............................................................................123 
12.2.3. 
Case Report Form Requirements ..............................................................................123 
12.3. 
Audits and Inspections ..............................................................................................123 
12.4. 
Study Documentation ...............................................................................................124 
12.4.1. 
Certification of Accuracy of Data .............................................................................124 
12.4.2. 
Retention of Records ................................................................................................124 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................125 
13.1. 
Good Clinical Practice Statement .............................................................................125 
13.2. 
Informed Consent .....................................................................................................125 
13.3. 
Patients Confidentiality and Data Protection ............................................................125 
13.4. 
Institutional Review Board/Ethics Committee .........................................................126 
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13.5. 
Clinical Study Data Transparency ............................................................................126 
14. 
PROTOCOL AMENDMENTS ................................................................................127 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSEOUT OF A 
SITE ..........................................................................................................................128 
15.1. 
Premature Termination of the Study .........................................................................128 
15.2. 
Close-out of a Site ....................................................................................................128 
16. 
CONFIDENTIALITY ..............................................................................................128 
17. 
FINANCING AND INSURANCE ...........................................................................128 
18. 
PUBLICATION POLICY ........................................................................................128 
19. 
REFERENCES .........................................................................................................129 
20. 
INVESTIGATOR’S AGREEMENT ........................................................................133 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS ...................................................134 
 
LIST OF TABLES 
Table 1: 
Schedule of Events for the Open-Label Treatment Period .........................................75 
Table 2: 
Schedule of Events for the Transition Period: Patients on Eculizumab in 
OLTP who Plan to Enroll in the OLE ........................................................................85 
Table 3: 
Schedule of Events for the Transition Period: Patients on Ravulizumab in 
OLTP who Plan to Enroll in the OLE ........................................................................88 
Table 4: 
Schedule of Events for the Safety Off-Treatment Follow-up Period .........................91 
Table 5: 
Summary of Data for Non-Inferiority Margin Calculations .....................................110 
 
LIST OF FIGURES 
Figure 1: 
Study Diagram ............................................................................................................50 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS  
Title 
A Randomized, Open-Label, Eculizumab and Ravulizumab Controlled, 
Non-Inferiority Study to Evaluate the Efficacy and Safety of Pozelimab and 
Cemdisiran Combination Therapy in Patients with Paroxysmal Nocturnal 
Hemoglobinuria Who are Currently Treated with Eculizumab or 
Ravulizumab 
Site Location(s) 
 
Principal Investigator 
Globally at multiple sites. 
Morag Griffin, MBChB, FRCPath 
Objectives 
The primary objective of the study is: 
• To evaluate the effect on hemolysis, as assessed by lactate 
dehydrogenase (LDH), of pozelimab and cemdisiran combination 
therapy after 36 weeks of treatment in Paroxysmal Nocturnal 
Hemoglobinuria (PNH) patients who switch from eculizumab or 
ravulizumab therapy to the combination treatment versus patients who 
continue their eculizumab or ravulizumab therapy. 
The secondary objectives of the study are to: 
• Evaluate the effect of pozelimab and cemdisiran combination 
treatment versus anti-complement factor 5 (C5) standard-of-care 
treatment (eculizumab or ravulizumab) on the following: 
− Transfusion requirements and transfusion parameters 
− Measures of hemolysis: LDH control, breakthrough hemolysis, 
and inhibition of complement hemolytic activity (CH50) 
− Hemoglobin levels 
− Fatigue as assessed by clinical outcome assessments (COAs) 
− Health-related quality of life (HRQoL) as assessed by COAs  
− Safety and tolerability 
• To assess the concentrations of total pozelimab and either total 
eculizumab or total ravulizumab in serum and cemdisiran and total C5 
protein in plasma 
• To assess the immunogenicity of pozelimab and cemdisiran 
Study Design 
This 
study 
is 
a 
randomized, 
open-label, 
eculizumab 
and 
ravulizumab-controlled, non-inferiority study. The study plans to enroll 
patients with PNH who are currently treated with either eculizumab or 
ravulizumab at the labeled posology. 
Screening Period (up to 6 weeks) 
 
The first screening visit should take place up to 6 weeks prior to day 1. 
Screening visit 1 should be scheduled based on the patient’s eculizumab or 
ravulizumab dosing regimen prior to the study.  
For patients taking eculizumab at screening:    
• Screening visit 1 should be scheduled on the day of or the day prior to 
an eculizumab dose and may take place up to 6 weeks prior to day 1.  
• At visit 2e, patients will be provided with an eCOA device to take 
home. 
• Day 1 shall be scheduled on the day of or up to 2 days prior to the 
patient’s scheduled eculizumab administration. 
For patients taking ravulizumab at screening:  
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• Screening visit 1 should be scheduled ~6 weeks after a ravulizumab 
dose  
• Visit 2r should be scheduled on the day of or up to 2 days prior to the 
patient’s next scheduled ravulizumab dose. This will be the last non-
study ravulizumab dose. Additional laboratory samples (including for 
baseline LDH assessment) will be taken at this visit and eCOA device 
will be provided to the patient to take home. 
• The day 1 visit should be scheduled 26 to 28 days after the last 
administration of ravulizumab at visit 2r. 
Additional interim screening visit(s) may take place as needed.  
Due to the risk of Neisseria meningitidis infection, patients will require 
administration of meningococcal vaccination(s) in accordance with the local 
eculizumab or ravulizumab prescribing information (where applicable) and 
in accordance with current national vaccination guidelines for vaccination 
use with complement inhibitors or local practice and at the very least, within 
a period of 5 years prior to screening. 
In addition to Neisseria meningitidis infection, fatal or serious infections 
with Neisseria gonorrhea have been reported in patients taking complement 
inhibitor therapy. Patients should therefore undergo a risk assessment and 
counseling regarding the potential risk of Neisseria gonorrhea as per local 
practice or national guidelines. 
Patients who have not been vaccinated against Streptococcus pneumoniae 
and Haemophilus influenzae type B may receive these vaccinations during 
the screening period or on the day of randomization based on investigator 
discretion and taking into consideration the available national guidelines. 
Patients will be assessed for active or latent tuberculosis (TB) infection 
based on local practice or applicable guidelines. 
Open-Label Treatment Period (OLTP, 36 weeks) 
On day 1, after all baseline assessments have been performed, eligible 
patients will be randomized in a 1:1 ratio to continue their current 
anti-C5 standard-of-care (eculizumab or ravulizumab, as applicable) or 
switch to treatment with pozelimab and cemdisiran. The treatment period is 
36 weeks. Treatment administration is based on a patient’s PNH treatment 
prior to screening as well as their treatment assignment and is described in 
the section on Treatments below. 
After the first administration with the study drugs, subsequent 
administrations may be continued by the site personnel or a healthcare 
professional at the patient’s home (if possible and approved by the sponsor) 
or additionally, for the combination of pozelimab and cemdisiran, 
administered by the patient or designated person, at the patient’s preferred 
location (in which case, the patient shall be contacted by the study site to 
ensure study drug administration, as planned).  
Patients should be closely monitored for infusion reactions, potential 
drug-target-drug complexes, and early signs and symptoms of 
meningococcal infection. Patients should be evaluated immediately if an 
infection is suspected. Consideration should be given to the use of 
antimicrobial prophylaxis for meningococcal infection, to be initiated at the 
start of the study treatment and continued for the duration of the study, 
unless the risks outweigh the benefits, or such use is inconsistent with local 
practice. In this study, antibiotic use will be at the discretion of the 
investigator. 
Assessments for the primary analysis will be completed at week 36.  
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Post-OLTP  
Patients who complete the OLTP will be offered the opportunity to enroll in 
another study, a follow-on OLE study. 
For patients who complete the 36-week OLTP on the pozelimab and 
cemdisiran arm, the transition of treatment from the current study to the OLE 
study is planned to be uninterrupted, whereby the day 1 visit of the OLE will 
correspond to the end-of-treatment (EOT) period/end of study (EOS) visit 
(week 36) in the current study.  
Patients who complete the 36-week OLTP on the anti-C5 standard-of-care 
arm and plan to participate in the OLE study will undergo a transition period 
in order to switch to cemdisiran and pozelimab combination treatment in the 
same manner as those switching to the combination at study initiation. 
Patients who discontinue treatment as well as patients who decline 
enrollment into the follow-on study of the OLE will undergo a safety 
off-treatment follow up period of up to 52 weeks. Patients discontinuing the 
combination treatment should be treated in accordance with local standards 
of care while continuing to be monitored in the 52-week off-treatment safety 
follow-up period. Investigators switching patients from the combination 
treatment to another anti-C5 mAb should have a heightened awareness for 
possible adverse events resulting from the formation of large DTD immune 
complexes. 
Study Duration 
The duration of the study including the screening period (up to 6 weeks), 
and the OLTP period (36 weeks) may be up to 42 weeks.  
Patients who complete the 36-week OLTP on the anti-C5 standard-of-care 
arm and plan to participate in the OLE study will undergo a transition to 
switch to cemdisiran and pozelimab combination treatment in the same 
manner as those switching to the combination at study initiation. 
Patients who discontinue study treatment as well as patients who decline 
enrollment into the OLE study will undergo a safety off-treatment follow-up 
period of up to 52 weeks. 
End of Study Definition 
The EOS is defined as the date the last patient completes the last study visit, 
withdraws from the study, or is lost to follow-up (ie, the study patient can 
no longer be contacted by the investigator). 
Population 
The study will consist of adult male and female patients with a confirmed 
diagnosis of PNH currently being treated at the labeled dose regimen with 
either eculizumab for the past 12 weeks or ravulizumab for at least 24 weeks 
with any level of LDH control. 
 
Sample Size: 
Enrollment will continue until approximately 140 patients have been 
randomized and received at least 1 dose of study treatment. Patients will be 
randomized in a 1:1 ratio to the combination arm (pozelimab and 
cemdisiran) or continue their anti-C5 standard-of-care therapy with either 
eculizumab 900 mg intravenous (IV) or IV ravulizumab. Randomization 
will be stratified based on screening visit LDH, history of RBC/whole blood 
transfusion in the past year, and anti-C5 standard-of-care therapy at 
screening. Enrollment of patients who have a screening visit LDH level >1.5 
× Upper Limit of Normal (ULN) 
 
 
 
Target Population: 
Eligible patients will consist of adult male and female patients with a 
confirmed diagnosis of PNH who are currently treated with either 
eculizumab or ravulizumab at the labeled dose for the past 12 or 24 weeks, 
respectively. 
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Treatments 
Study treatment refers only to drugs (pozelimab, cemdisiran, eculizumab, 
and ravulizumab) provided for use in this study. 
 
 
Study Drug (eculizumab at 
screening) 
 
Dose/Route/Schedule: 
Pozelimab + cemdisiran arm (patients on eculizumab at screening) 
 
 
  
 
 
 
 
 
 
 
Study Drug (ravulizumab 
at screening) 
 
Dose/Route/Schedule: 
Pozelimab + cemdisiran arm (patients on ravulizumab at screening) 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reference Drug 
(eculizumab at screening) 
 
Dose/Route/Schedule: 
Eculizumab 
 
Eculizumab 900 mg IV every 2 weeks (Q2W) 
 
Reference Drug 
(ravulizumab at screening) 
 
Dose/Route/Schedule: 
Ravulizumab 
 
Ravulizumab IV every 8 weeks (Q8W) per labeled weight-based dosage 
Endpoints 
 
 
Primary: 
The primary endpoint is the percent change in LDH from baseline to EOT 
period at week 36 (day 253) 
 
Key Secondary: 
The key secondary endpoints are: 
• Transfusion avoidance after day 1 through week 36, inclusive (defined 
as not requiring an RBC transfusion as per protocol algorithm based 
on hemoglobin values after day 1)  
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• Breakthrough hemolysis, in patients with a baseline LDH ≤1.5 × 
ULN,  after day 1 through week 36, inclusive 
• Hemoglobin stabilization (defined as patients who do not receive an 
RBC transfusion and have no decrease in hemoglobin level from 
baseline of ≥2 g/dL) after day 1 through week 36, inclusive 
• Maintenance of adequate control of hemolysis, defined as LDH ≤1.5 
× ULN from week 8 through week 36, inclusive 
• Adequate control of hemolysis (defined as LDH ≤1.5 × ULN) from 
week 8  through week 36, inclusive 
• Normalization of LDH (defined as LDH ≤ 1.0 × ULN) from week 8 
through week 36, inclusive 
• Change in fatigue as measured by the Functional Assessment of 
Chronic Illness Therapy-Fatigue (FACIT)-Fatigue Scale from 
baseline to week 36 
• Change in physical function (PF) score on the European organization 
for research and treatment of cancer quality-of-Life questionnaire core 
30 items (EORTC QLQ-C30) from baseline to week 36 
• Change in global health status (GHS)/QoL scale score on the EORTC 
QLQ-C30 from baseline to week 36 
 
Other Secondary: 
Other secondary endpoints are: 
• Transfusion avoidance from week 4 through week 36, inclusive 
(defined as not requiring an RBC transfusion as per protocol algorithm 
based on hemoglobin values after day 1) 
• Breakthrough hemolysis, in patients with a baseline LDH ≤1.5× ULN, 
from week 4 through week 36, inclusive 
• Hemoglobin stabilization (defined as patients who do not receive an 
RBC transfusion and have no decrease in hemoglobin level from 
baseline of ≥2 g/dL) from week 4 through week 36, inclusive 
• Maintenance of adequate control of LDH, defined as LDH ≤1.5 × 
ULN after day 1 through week 36, inclusive 
• Adequate control of hemolysis (defined as LDH ≤1.5 × ULN) after 
day 1 through week 36, inclusive  
• Normalization of LDH (defined as LDH ≤1.0 × ULN) after day 1 
through week 36, inclusive 
• Rate and number of units of RBCs transfused per protocol algorithm 
after day 1 through week 36, and from week 4 through week 36 
• Change in hemoglobin levels from baseline to week 36 
• Incidence and severity of treatment-emergent serious adverse events 
(SAEs), treatment-emergent adverse events (TEAEs) of special 
interest and TEAEs leading to treatment discontinuation over 36 
weeks 
• Change and percent change in total CH50 from baseline to week 36 
• Concentration of total C5 in plasma assessed throughout the study 
• Concentrations of total pozelimab in serum assessed throughout the 
study 
• Concentrations of cemdisiran in plasma assessed throughout the study 
• Concentrations of total eculizumab or ravulizumab in serum assessed 
throughout the study 
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• Incidence of treatment emergent anti-drug antibodies (ADAs) to 
pozelimab assessed throughout the study 
• Incidence of treatment emergent ADAs to cemdisiran assessed 
throughout the study 
Procedures and Assessments 
Efficacy assessments include laboratory evaluations of LDH and 
hemoglobin, as well as blood transfusions. Efficacy as measured by certain 
COAs including FACIT-Fatigue and EORTC-QLQ-C30. 
Safety procedures include measurement of body weight and routine safety 
assessments (vital signs, physical examination, electrocardiogram). 
Laboratory assessments of safety include coagulation panel, chemistry, 
hematology, urinalysis, and pregnancy (if applicable). Adverse events and 
concomitant medications and procedures will be monitored throughout the 
study. Other procedures include collection of blood samples for the 
measurement of drug concentrations, biomarkers, immunogenicity, and 
exploratory assessments. In addition, an exploratory research serum and 
plasma sample should be collected. 
Patients may participate in up to 2 optional sub-studies: for future 
biomedical research and for pharmacogenomic analysis. 
Statistical Plan 
Justification of the Sample Size 
The primary endpoint is percent change from baseline to EOT period 
(week 36) in LDH. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1. 
INTRODUCTION 
Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic, progressive, life-threatening, and rare 
multisystem disease. It is characterized by uncontrolled complement activation on red blood cells 
(RBCs), resulting in intravascular hemolysis (Sahin, 2016), and on white blood cells (WBCs) and 
platelets, resulting in an increased risk of thrombosis. The estimated incidence of PNH is 1.3 cases 
per million individuals per year, and the estimated prevalence is 15.9 cases per million individuals 
(Preis, 2014). 
Paroxysmal nocturnal hemoglobinuria originates from a multipotent, hematopoietic stem cell 
(HSC) that acquires a mutation of the phosphatidylinositol glycan anchor biosynthesis class A 
(PIGA) gene and that becomes numerous enough so that the effects of its mutation are 
symptomatic. The PIGA gene product is required for the biosynthesis of the 
glycophosphatidylinositol (GPI) anchor, a glycolipid moiety that attaches dozens of proteins to the 
plasma membrane of cells. Consequently, the PNH stem cell and all of its progeny have a reduction 
or absence of GPI-anchored proteins. The mature blood cells derived from the hematopoietic clone 
can have a complete deficiency (type III) or a partial deficiency (type II) of GPI-linked proteins 
(Hillmen, 2004). Two of the proteins that are affected by the absence of GPI anchors are CD55 and 
CD59, complement regulatory proteins. CD55 regulates complement activation by inhibiting 
complement component 3 (C3) convertases, whereas CD59 inhibits the assembly of the 
membrane-attack complex (MAC) C5b–complement component 9 (C9) by interacting with 
complement component 8 (C8) and C9 (Brodsky, 2009). Their absence renders PNH erythrocytes 
susceptible to complement-mediated intravascular hemolysis. This intravascular hemolysis in 
patients with PNH causes anemia (frequently requiring blood transfusion) and hemoglobinuria. 
Symptoms of PNH include, abdominal pain, dysphagia, erectile dysfunction. Longer term 
complications include chronic kidney disease and pulmonary hypertension (Hillmen, 2006). 
Thromboembolism is the most common cause of mortality in patients with PNH and accounts for 
approximately 40% to 67% of attributable deaths. Potential mechanisms for thromboembolism 
include platelet activation, toxicity of free hemoglobin, nitric oxide depletion, absence of other 
GPI-linked proteins, and endothelial dysfunction (Hill, 2013). PNH usually arises on the 
background of bone marrow dysfunction (Luzzatto, 2018). Evidence suggests that loss of PIGA 
provides protection for the PNH clone against HSC loss (by removing a putative GPI-anchored 
autoantigen serving as a target for an autoimmune response against the HSC). In this manner, the 
PNH clone becomes predominant. 
An accepted definition of active disease is lactate dehydrogenase (LDH) ≥1.5 × upper limit of 
normal (ULN) in the presence of 1 or more of the following PNH-related signs or symptoms within 
3 months: fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), anemia 
(hemoglobin <10 g/dL), history of a major adverse vascular event (MAVE; including thrombosis), 
dysphagia, or erectile dysfunction (Almeida, 2017). Alternatively, activity can be established by a 
history of RBC transfusion due to PNH within 3 months. 
Eculizumab and Ravulizumab 
The benefit of blocking complement factor 5 (C5) complement activity in PNH has been clearly 
established by eculizumab (Soliris® Eculizumab (Prescribing information)) and ravulizumab 
(Ultomiris® (Prescribing information)), (Kulasekararaj, 2019) (Lee, 2019) which are humanized 
monoclonal antibodies directed against C5. Their effectiveness has been evidenced by reduction 
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of LDH levels and transfusion requirements. In addition, long-term data in eculizumab treated 
patients have shown a reduction in the need for blood transfusion, decrease in the incidence of 
thrombosis, improvement in anemia, quality of life (QoL), and survival (Hillmen, 2004), 
(Griffin, 2017) (Hillmen, 2007) (Hillmen, 2013) (Brodsky, 2008). Eculizumab is approved for use 
in complement-mediated serious ultra-rare conditions (prevalence of 1 to 5 per million), including 
PNH. Ravulizumab is modified from eculizumab to have 4 amino-acid substitutions that act to 
prolong its half-life (Kulasekararaj, 2019). Ravulizumab is also approved in PNH. While 
eculizumab has been demonstrated to be an effective therapy for these patients, it is administered 
by intravenous (IV) infusion every 2 weeks and has been described as being burdensome for 
patients and may negatively impact QoL (Groth, 2017). Also, up to 27% of eculizumab treated 
patients may experience breakthrough hemolysis, which is a recurrence of the patient’s 
intravascular hemolysis and associated signs and symptoms. Up to 20% of patients on eculizumab 
therapy require significant increases in dose or dose frequency due to insufficient efficacy 
(Hill, 2013) (Nakayama, 2016) (Peffault de Latour, 2015). Twenty-five percent of patients still 
need recurrent, albeit less frequent, blood transfusions. The heterogeneity in these hematological 
responses may be related to underlying aplastic anemia, C3b-mediated extravascular hemolysis or 
incomplete pharmacologic blockade of C5 (Al-Ani, 2016). While the regulatory approval of 
ravulizumab (Ultomiris® (Prescribing information)) for PNH in the United States (US) in 
December 2018 and the European Union (EU) in July 2019 has improved convenience with an IV 
dosing frequency of every 8 weeks, patients still experience some hemolytic breakthrough. In 
head-to-head studies of ravulizumab versus eculizumab in both complement inhibitor naïve and 
complement inhibitor experienced PNH patients, ravulizumab was found to be non-inferior to 
eculizumab on all primary and key secondary endpoints. Demonstration of superiority was not 
achieved (Ultomiris® (Prescribing information)) (Lee, 2019) (Kulasekararaj, 2019). Additionally, 
in rare instances, eculizumab, and presumably ravulizumab, is ineffective due to polymorphic 
variation in the gene encoding C5 such that the protein is not recognized by the 2 monoclonal 
antibodies (mAbs) (Nishimura, 2014). Although ravulizumab is not approved in many countries 
around the world, regulatory approval and utilization of ravulizumab is increasing over time. 
Pozelimab 
Pozelimab is a human monoclonal immunoglobulin G4P (IgG4P) antibody directed against C5, 
which inhibits terminal complement activation by preventing C5 cleavage by C5 convertase into 
C5a (anaphylatoxin) and C5b, thereby blocking the formation of the MAC – C5b-9, a structure 
mediating cell lysis. Pozelimab can be administered by IV or subcutaneous (SC) administration. 
Additionally, pozelimab binds to polymorphic variations in C5 due to differences in binding sites 
compared to eculizumab and ravulizumab. 
A phase 1 study in healthy volunteers evaluated single ascending IV and SC doses of up to 
30 mg/kg and 600 mg, respectively, and a repeat dose regimen of pozelimab 400 mg SC weekly 
for 4 weeks preceded by a loading dose of 15 mg/kg one week before. Dose dependent inhibition 
of C5 as measured by complement hemolytic activity assay (CH50) was established and the repeat 
dosing regimen was shown to completely inhibit CH50 throughout the dosing period. A regimen 
of 30 mg/kg IV loading dose followed by 800 mg SC weekly was effective in a phase 2 study in 
complement treatment naïve patients with PNH (R3918-PNH-1852) at reducing serum LDH to 
<1.5 × ULN in all patients and <1.0 × ULN in most patients. However, the regimen represents 
relatively high doses for a biologic agent. The currently approved anti-C5 mAbs, eculizumab and 
ravulizumab, are similarly dosed at high levels (maintenance dose of 900 mg IV Q2W and 
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3000 mg to 3600 mg IV Q8W for eculizumab and ravulizumab, respectively). The requirement for 
such high dosing is driven by 2 factors. First, the objective is to have sufficient coverage of 
participants with very high serum concentrations of C5 (80 µg/mL to 120 µg/mL) even during 
intercurrent illness such as infection. Second, it is necessary to have near 100% inhibition of C5 at 
all times to achieve the desired therapeutic effect in PNH (Peffault de Latour, 2015). 
Study R3918-PNH-1852 in patients with PNH who are naïve to complement inhibitor therapy or 
have not recently received complement inhibitor therapy in the past 6 months has been completed. 
Patients received pozelimab as an IV loading dose of 30 mg/kg followed by weekly administration 
of 800 mg SC. An interim analysis was performed with a total of 17 patients enrolled, among 
whom 10 patients completed 26 weeks (182 days) of treatment/study and 7 patients received at 
least 10 weeks (70 days) of pozelimab treatment. The mean baseline LDH was 6.1 × ULN, 
hemoglobin was 97.0 g/L and nearly 60% of patients had an RBC transfusion during the previous 
year. Treatment with pozelimab led to a rapid and sustained reduction in LDH through study week 
26. Normalization of LDH levels was observed at study day 29 in all 17 patients, including a 
patient with a C5 variant known to be resistant to blockade by eculizumab/ravulizumab 
(Jang, 2020). LDH reduction was sustained <1.5 × ULN until study day 183. Hemoglobin levels 
were also increased with mean (standard deviation [SD]) increase of 8.6 (14.1 g/L) from baseline 
to week 26 (hemoglobin levels from a subset of 9 patients were available at the time of the analysis 
and used for the calculation). Following the pozelimab treatment, an improvement in the 
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) score (a 13-item, 
clinical outcome assessment (COA) measure assessing an individual’s level of fatigue over the 
past week) was observed with mean change (SD) of 13.1 (13.7) from baseline to week 26 (N=9). 
Complement inhibition was 100% as measured by CH50 and was sustained post pozelimab IV 
infusion on day 1 throughout day 183 (N=9).  
Additional background information on pozelimab and the development program can be found in 
the Investigator’s Brochure (IB) for pozelimab. 
Cemdisiran 
Cemdisiran is a synthetic small interfering ribonucleic acid (siRNA) targeting C5 messenger 
ribonucleic acid (mRNA) that is covalently linked to a triantennary N-acetylgalactosamine 
(GalNAc) ligand. Cemdisiran is designed to suppress liver production of C5 protein, when 
administered via SC injection. Complement factor 5 is encoded by a single gene and is expressed 
and secreted predominantly by hepatocytes. Through the ribonucleic acid (RNA) interference 
pathway, cemdisiran leads to the degradation of C5 mRNA by RNases, thereby reducing 
C5 protein production, leading to reduced levels of circulating C5 protein. In study 
ALN-CC5-001 (Badri, 2021) (Cemdisiran IB), 32 healthy volunteers were treated with single SC 
doses of cemdisiran ranging from 50 mg to 900 mg, 24 healthy volunteers were treated with 
multiple doses of cemdisiran ranging from 100 mg to 600 mg (dosing weekly, every other week 
or monthly), 6 patients with PNH were treated with cemdisiran at cumulative doses of 3200 mg to 
4200 mg (eculizumab-naïve patients) and 1200 mg to 2400 mg (patients on background 
eculizumab treatment). A single dose of 600 mg cemdisiran achieved a C5 concentration of 
12.3 ± 1.47 μg/mL by day 14 and nadir at 2.3 ± 0.76 μg/mL by day 56. The reduction in C5 protein 
was durable, with >90% knockdown of C5 beginning on day 21 and persisting through day 238. 
The relationship between C5 concentrations and complement activity is non-linear, such that, even 
with greater than 90% reduction in C5 levels, there is still incomplete inhibition of complement 
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activity and >90% suppression of C5 expression was not sufficient in achieving adequate reduction 
of LDH in PNH patients. Cemdisiran monotherapy in patients not receiving eculizumab was 
ineffective as a monotherapy treatment for PNH. However, patients with PNH who were receiving 
eculizumab were able to reduce their eculizumab dose and/or increase the interval between 
eculizumab doses while maintaining clinically meaningful inhibition of complement activity and 
LDH level control. These data support the efficacy and clinical utility of combining an siRNA and 
a mAb targeting C5 and lend support to the current study design.  
Additional background information on cemdisiran and the development program can be found in 
the IB for cemdisiran. 
Pozelimab/Cemdisiran Combination Treatment in Patients with PNH 
By reducing the production of C5 with cemdisiran, the pharmacological goal of the 
pozelimab/cemdisiran combination therapy is to reduce concentration of active C5 in circulation 
to biologically inactive levels, while concurrently slowing the rate of pozelimab:C5 complex 
formation, thus allowing for an extended dosing interval at a lower pozelimab dose level. 
Pharmacokinetic/pharmacodynamic (PK/PD) modeling based on observed data from both 
pozelimab and cemdisiran first-in-human (FIH) studies in healthy subjects and patients with PNH 
who are naïve to anti-C5 treatment or on a background therapy of eculizumab suggests that by 
combining cemdisiran and pozelimab, the dose of both agents may be significantly reduced and 
the interval for SC dosing of pozelimab may be significantly increased from once weekly to every 
4 weeks, while still maintaining desired C5 suppression. 
The biologic mechanism that drives clinical efficacy of an anti-C5 therapy is the ability to 
completely and durably suppress the cell lytic activity of terminal portion of the complement 
pathway, the MAC. This biology is measured using the CH50 assay and other assays measuring 
complement pathway activity. The relationship of CH50, as a pharmacodynamic measure of active 
C5, with clinical efficacy has been demonstrated for pozelimab and for cemdisiran in patients with 
PNH. In separate studies of pozelimab and cemdisiran in active patients with PNH, clinical 
efficacy, as measured by reduction in LDH, a marker of hemolysis, correlated with reduction in 
CH50 or other complement activity assays. In the cemdisiran study, incomplete CH50 inhibition 
was associated with suboptimal LDH reduction. In the pozelimab study, complete CH50 inhibition 
was associated with optimal LDH reduction. Therefore, the CH50 assay can be reliably used to 
follow the degree of inhibition of the complement pathway and should translate into reduction in 
LDH which is a marker of hemolysis. 
The combination treatment of cemdisiran and pozelimab is being developed in patients with PNH 
for the following reasons; 1) both drugs work via a complementary approach on a validated 
pathway with the possibility of complete inhibition of the pathway over a longer duration, which 
may translate into optimal efficacy in nearly all patients and anticipated better control of 
breakthrough hemolysis, 2) cemdisiran is insufficient to treat PNH as monotherapy, 3) pozelimab 
was effective as monotherapy in treatment of PNH in a Phase 2 study, however, the weekly higher 
volume injection regimen was considered potentially burdensome, 4) the pozelimab and 
cemdisiran combination therapy will address significant unmet needs for patients by providing a 
self-administered Q4W dosing regimen for patients who require chronic long-term treatment, 5) 
efficacy is expected in patients with polymorphic variant C5 protein (eg, p.Arg885His and 
p.Arg885Cys) for which eculizumab and presumably ravulizumab are ineffective 6) the 
combination therapy may be associated with an improved safety profile for adverse events (AEs) 
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related to injection site reactions as the combination is expected to allow for a lower volume and 
less frequent dosing of pozelimab compared to that associated with pozelimab monotherapy 
regimens required for the treatment of PNH, and 7) with respect to other safety events, the risk of 
C5 inhibition is shared by all anti-C5 agents. The pozelimab/cemdisiran combination is not 
expected to be associated with risks beyond that of the individual agents. 
Ongoing Clinical Studies and Study Design 
The combination of pozelimab and cemdisiran is being evaluated in the following phase 2 studies: 
REGN-PNH-2092: A randomized, open-label, 2-arm, 28-week study to evaluate the safety, 
efficacy, and PD effects of 2 dose regimens of pozelimab and cemdisiran combination treatment 
in approximately 24 patients with PNH who had been receiving treatment with pozelimab 
monotherapy in study R3918-PNH-1868. Eligible patients will be randomized 1:1 to 1 of 2 dose 
regimens with the pozelimab and cemdisiran combination. Pozelimab
 mg will be administered 
subcutaneously either every 4 weeks (Q4W) or Q2W in combination with cemdisiran 
 mg 
Q4W subcutaneously.  
REGN-PNH-20105: A single-arm, open-label, 32-week study to evaluate the safety, efficacy, and 
PD effects of pozelimab and cemdisiran combination therapy in approximately 12 patients with 
PNH who are currently receiving eculizumab and who will be switched to pozelimab and 
cemdisiran combination therapy. 
Additional background information on the combination of pozelimab and cemdisiran and the 
development program can be found in the respective IB. 
This study is being performed to evaluate whether treatment with the combination of pozelimab 
and cemdisiran in patients who switch from eculizumab or ravulizumab treatment is non-inferior 
to continued treatment with anti-C5-standard-of-care therapy (eculizumab or ravulizumab) in the 
control of intravascular hemolysis, as assessed by the change in LDH over time.  
This study is a randomized, eculizumab and ravulizumab controlled study with a 36-week 
open-label treatment period (OLTP). The choice of primary endpoint is an accepted, objective 
laboratory measure that reflects control of intravascular hemolysis (LDH). Key secondary 
endpoints were selected in order to evaluate stabilization of the patient’s hemolysis over time (ie, 
transfusion avoidance, the avoidance of clinically important breakthrough hemolysis events, 
hemoglobin stabilization, measures of LDH control), as well as to evaluate changes in parameters 
central to the QoL of patients with PNH (ie, fatigue, physical function [PF] and other health-related 
quality of life [HRQoL] assessments). 
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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of the study is: 
• To evaluate the effect of pozelimab and cemdisiran combination therapy on hemolysis, 
as assessed by LDH, after 36 weeks of treatment, in patients with PNH who switch 
from eculizumab or ravulizumab therapy to the combination treatment versus patients 
who continue their eculizumab or ravulizumab therapy. 
2.2. 
Secondary Objectives 
The secondary objectives of the study are to: 
• Evaluate the effect of pozelimab and cemdisiran combination treatment versus 
anti-C5 standard-of-care treatment (eculizumab or ravulizumab) on the following: 
− Transfusion requirements and transfusion parameters 
− Measures of hemolysis: LDH control, breakthrough hemolysis, and inhibition of 
CH50 
− Hemoglobin levels 
− Fatigue as assessed by Clinical Outcome Assessments (COAs) 
− HRQoL as assessed by COAs 
− Safety and tolerability 
• To assess the concentrations of total pozelimab and either total eculizumab or total 
ravulizumab in serum and cemdisiran and total C5 protein in plasma 
• To assess the immunogenicity of pozelimab and cemdisiran  
2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
• 
  
• 
  
• 
 
  
• 
  
• 
 
 
 
 
 
 
  
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• 
 
 
  
• 
 
 
 
 
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3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypothesis 
The primary hypothesis is that PNH disease control as assessed by LDH after a 36-week treatment 
period with pozelimab and cemdisiran combination therapy in patients with PNH who switch from 
their current eculizumab or ravulizumab treatment to the combination treatment is not inferior to 
continued eculizumab or ravulizumab treatment. 
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
The study is a randomized, open-label, eculizumab and ravulizumab-controlled, non-inferiority 
study. 
This study is open-label and thus patients and investigators will be aware of treatment allocation. 
The study is not blinded for patients and investigators, as it would require double-dummy 
administration which would lead to a large number of sham IV infusions to patients receiving 
pozelimab and cemdisiran combination along with sham IV and SC injections for patients assigned 
to the anti-C5 standard-of-care arm. An open-label design is deemed acceptable by the sponsor as 
the primary endpoint of the study is an objective laboratory-based parameter (ie, LDH) that is 
unlikely to be biased by knowledge of treatment assignment. 
The use of eculizumab and ravulizumab as the two comparators is justified as these options are 
considered as standard-of-care treatment for PNH. As the trial will recruit patients who are 
currently being treated with either eculizumab or ravulizumab, a reasonable comparison is the 
continued use of their prior standard-of-care therapy (eculizumab or ravulizumab) versus 
pozelimab and cemdisiran combination therapy. It is believed that the combination of pozelimab 
and cemdisiran will have similar efficacy to eculizumab and ravulizumab in patients with PNH.  
Rationale for Primary Objective and Primary Endpoints 
The primary objective of this study is an assessment of the control of hemolysis, as measured by 
LDH, which is central to the clinical monitoring of PNH (Rother, 2005), including during 
eculizumab or ravulizumab therapy. An LDH of at least 1.5 × ULN along with related clinical 
symptoms is considered a criterion for diagnosis of PNH, and for treatment with complement 
inhibition (Sahin, 2016). Furthermore, reductions in LDH below the 1.5 × ULN threshold with 
complement inhibitor therapy have been shown to correlate with improvement in patient’s 
symptoms, QoL measures, and transfusion requirements (Brodsky, 2008). 
The primary endpoint is the percent change in LDH from baseline to end-of-treatment (EOT) 
period. Baseline and EOT LDH assessments will be performed at the end of dosing period for each 
treatment, ensuring a fair comparison across arms. 
Lactate dehydrogenase (LDH), as a measure of hemolysis allows for an objective and precise 
means to gauge if the control in hemolysis with eculizumab and ravulizumab is sustained when 
patients switch to pozelimab and cemdisiran treatment. If anti-C5 therapy were to be discontinued, 
patients would experience a return of their manifestations of PNH prior to week 36. Thus, the 
absence of a clinically significant rise in LDH in patients switching from eculizumab or 
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ravulizumab to pozelimab and cemdisiran treatment supports the efficacy of the combination 
approach. 
In the clinical trial of ravulizumab vs eculizumab in C5-inhibitor–experienced adult patients with 
PNH (Kulasekararaj, 2019), patients treated with eculizumab were either switched to ravulizumab 
or continued eculizumab. The percent change in LDH from baseline to week 26, the primary 
endpoint of the study, in the eculizumab arm was 8.4% relative to -0.8% in the ravulizumab arm 
(95% confidence interval [CI] for the difference, -0.42, 18.84).  
Rationale for Treatment Duration 
The study treatment duration of 36 weeks is considered sufficient to provide an adequate 
understanding of the efficacy and safety of pozelimab and cemdisiran. It is expected that by week 
36, there will be no contribution of eculizumab or ravulizumab in pozelimab and cemdisiran 
combination treated patients towards efficacy on LDH based on the known dosing interval and 
half-lives of these drugs. By the EOT period, the effect on LDH in the pozelimab and cemdisiran 
combination arm will be due to the sole contribution of the combination maintenance regimen. 
The long-term safety and efficacy of pozelimab and cemdisiran combination therapy will be 
assessed by enrolling patients from this study into an open-label extension (OLE) study. 
Rationale for Study Population 
The study population includes patients with PNH currently being treated at the labeled dose 
regimen with either eculizumab for at least the prior 12 weeks or ravulizumab for at least the prior 
24 weeks with any level of LDH control. Eculizumab and ravulizumab are both administered as 
an IV infusion. IV administration places a burden on the health care system as it requires 
administration in an infusion center or by a healthcare professional at the patient’s home. 
Pozelimab and cemdisiran combination maintenance therapy is expected to remove the 
requirement for resource consuming visits to infusion centers or home nurse visits and time off for 
the patient from their work/school and away from their families. In addition, the inconvenience 
and interruptions associated with IV infusions may impact compliance, which is expected to be 
addressed with every 4 weeks self-administered pozelimab and cemdisiran combination therapy. 
Disruptions due to the coronavirus disease 2019 (COVID-19) pandemic and requirements from 
governments on travel restrictions, stay-at-home orders and maintaining social distancing can 
impact any infusion therapy such as eculizumab or ravulizumab administration whereas this 
impact would be minimized with self-administered pozelimab and cemdisiran combination 
therapy. These disruptions are particularly impactful in PNH where continuous inhibition of 
complement is important to avoid breakthrough hemolysis events. Additionally, the PK/PD profile 
of the combination is expected to provide advantages in dosing flexibility; a delayed dose is 
expected to have less negative clinical impact compared to patients treated with current 
anti-C5 standard-of-care. Intravenous (IV) access issues may be encountered with eculizumab or 
ravulizumab infusions making it difficult to complete its administration. 
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3.2.2. 
Rationale for Dose Selection 
The dosage regimen of pozelimab/cemdisiran combination therapy in patients with PNH who 
switch from eculizumab or ravulizumab treatment is as follows: 
Eculizumab switch to combination therapy: 
• 
 
 
• 
 
• 
 
 
 
Ravulizumab switch to combination therapy: 
• 
 
  
• 
 
 
The proposed dosage regimen was selected based on safety, efficacy, and PK/PD data from 
completed and on-going studies for each individual agent in healthy subjects and in patients with 
PNH. The primary objective of the chosen regimen is to ensure complete suppression of hemolysis 
after the initiation of the combination treatment and throughout the dosing intervals. More 
information regarding the results of the completed and on-going studies of pozelimab and 
cemdisiran is provided in the pozelimab IB and cemdisiran IB, respectively.  
To inform the choice of the dosing regimen for the combination therapy in patients with PNH, a 
target-mediated drug disposition (TMDD) population PK model for pozelimab and a population 
PK/PD model for cemdisiran were developed based on respective FIH data. PK/PD modeling of 
observed data from both pozelimab and cemdisiran FIH studies in healthy subjects and patients 
with PNH (naïve to anti-C5 treatment or on a background therapy of eculizumab) suggests that, 
by combining cemdisiran and pozelimab, the desired C5 suppression may be durable with 
significantly lower doses of both agents and a longer dosing interval. 
 
 
 
  
 
 
 
 
 
 
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Mitigation of Potential High Molecular Weight Complex Formation During Treatment 
Switch 
While the overall goal of the proposed dosing regimen is to prevent hemolysis, the initiation of 
therapy is also designed to mitigate the potential for the formation of large drug-target-drug (DTD) 
immune complexes of eculizumab-C5-pozelimab or ravulizumab-C5-pozelimab during the 
treatment switch. 
 
 Refer to the 
Pozelimab IB and Cemdisiran IB for details.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.3. 
Risk-Benefit 
A risk-benefit statement with respect to the overall development program is provided in the IB for 
pozelimab and the IB for cemdisiran. The following sections describe potential risks and strategies 
for mitigation. 
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3.3.1. 
Risk Benefit for Eculizumab and Ravulizumab Active Comparators 
Eculizumab and ravulizumab have been selected as the active comparators in this study as they are 
the current standard-of-care therapy in the treatment of adult patients with PNH. In countries where 
eculizumab and ravulizumab have been granted marketing authorization, the regulatory bodies 
have considered that the benefit of therapy has outweighed the risk for the indications granted. 
When left untreated, PNH is a life-threatening condition with a median survival time of 10 years 
from diagnosis (Hillmen, 1995). Long-term treatment with complement inhibition has 
demonstrated an improvement/normalization in survival with eculizumab (Kelly, 2011). While 
anticipated to behave similarly to eculizumab due to the same mechanism of action and structural 
similarities, longer term data for ravulizumab including its impact on survival is still unknown 
given that ravulizumab has only recently been granted marketing authorization (first approval 
2018). 
Since pozelimab shares the same mechanism of action as eculizumab and ravulizumab, the risk 
profile for these agents is expected to be similar, as outlined below. 
The following sections describe potential risks and strategies for mitigation. 
3.3.2. 
Potential Risk of Neisseria Infection 
An established risk of blocking C5 complement activity with eculizumab or ravulizumab is 
increased susceptibility to infections, specifically to encapsulated organisms, the most potentially 
severe of which is infection with Neisseria meningitidis (Figueroa, 1991). The risk for 
meningococcal infection is largely driven by the degree of inhibition of C5. Two different agents 
acting on C5 through independent pathways (ie, pozelimab and cemdisiran) are not expected to 
increase the risk for meningococcal infection above that of each of the individual agents. This 
expectation is based on the goal of complement inhibition therapy and human genetic data. The 
objective of pozelimab and cemdisiran combination therapy is complete inhibition of C5 activity. 
Once this is achieved, then further inhibition is not possible, and the anticipated risk is not expected 
to increase further. Human genetic data reveals that the increased risk of infections with Neisseria 
species (spp) occurs when there is homozygous loss of C5.  
Experience with eculizumab and ravulizumab suggests that pretreatment with appropriate 
vaccinations covering multiple serotypes is effective at substantially mitigating this risk 
(Hillmen, 2013) 
(McNamara, 
2017) 
(NHS 
England, 
2013) 
(Soliris® 
Eculizumab 
(Prescribing information)) (Ultomiris® (Prescribing information)). Concurrent therapy with oral 
antibiotics is also recommended. Current treatment guidelines for PNH and the eculizumab and 
ravulizumab package inserts recommend such vaccinations prior to dosing. Because vaccination 
does not provide 100% coverage to all strains and there are no proven titer levels associated with 
100% protection, prophylactic oral antibiotics are also commonly given to patients with genetic or 
pharmacologic deficiency in terminal complement activity. In various disease settings such as 
asplenia in sickle cell disease, and with terminal complement deficiency, use of long-term 
prophylactic antibiotics has been safely implemented for the prevention of infections with 
encapsulated organisms, including N. meningitidis (Gaston, 1986) (Wedzicha, 2008).  
In this study, vaccination prior to study treatment initiation (or at the time of administration, based 
on local practice, see Section 8.2.1) will be required to mitigate the risk of infection by 
encapsulated organisms to a level that has been considered acceptable in other anti-C5 clinical 
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development programs. In addition to vaccination, monitoring for early signs and symptoms of 
infection (Section 8.2.3), providing a patient safety card that describes the signs and symptoms of 
infection and steps to follow in case of suspected infection, as well as concurrent therapy with 
recommended oral antibiotics (Section 8.2.4) will further mitigate this risk. These risk mitigation 
strategies have been acceptable and well tolerated in the precedent healthy volunteer and PNH 
patient studies for pozelimab and cemdisiran individually as well as in other anti-C5 clinical 
development programs. 
Recently, serious infections with Neisseria spp (other than N. meningitidis), including 
disseminated gonococcal infections, have been reported during eculizumab treatment 
(Soliris® Eculizumab (Prescribing information)). Therefore, patients will undergo a risk 
assessment and counseling regarding the potential risk of Neisseria gonorrhea as per the 
investigator’s local guidelines. Patients will be counseled about N. gonorrhea prevention and 
regular testing will be advised for at-risk patients. A risk-factor assessment will be based on local 
practice or national guidelines to determine if the patient is at risk, which would lead to further 
management of prevention, testing, and treatment of N. gonorrhea (Section 8.2.5). 
3.3.3. 
Liver Function Test Abnormalities 
 
 
 
 
 
 
 
 
 
  
In this study, patients will be closely monitored for ALT and AST abnormalities. Those with 
significant ALT or AST abnormalities, or known liver function impairment, will be excluded from 
participating in the study (Section 7.2.2). Levels of ALT and AST will be closely followed 
throughout the trial. Patients who develop abnormalities in liver function tests should undergo 
additional investigations or consultation (Section 8.2.6). Individual patient stopping rules will 
include a mandatory discontinuation of study treatment if specific thresholds for ALT or AST are 
met as per protocol (Section 8.3.2). These mitigation steps are considered sufficient to address this 
potential risk. 
3.3.4. 
Infusion Reactions 
 
 
 
 In the 13- and 26-week toxicology studies dosed up to 
100 mg/kg/week in cynomolgus monkeys, no adverse effects were reported. Infusion reactions 
may occur with ravulizumab and eculizumab. In clinical trials, no patients experienced 
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infusion-related reactions requiring discontinuation of therapy. Additional details may be found in 
the IB for pozelimab and the respective prescribing information for eculizumab and ravulizumab. 
3.3.5. 
Other Risks 
Other risks are described under Safety Considerations in Section 6.1.3. 
3.3.6. 
Study Conduct in Response to Coronavirus Disease 2019 
Recognizing that the COVID-19 pandemic will have an impact on the conduct of clinical trials, 
the sponsor does not intend to screen any patients in this study until the impact of the 
COVID-19 pandemic is deemed manageable and no longer interfering with the conduct of trials 
at individual sites, and patients can safely participate in this study. Until then, the sponsor plans to 
obtain approvals from Health Authorities/Ethics Committees to enable initiation of study sites for 
this study, as allowed by local laws and regulations. 
For additional information related to the continuity of clinical study conduct and oversight during 
the COVID-19 pandemic, see Section 6.1.3. 
For information regarding the permitted timing of COVID-19 vaccinations, see Section 8.8.2 
Permitted Medications. 
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4. 
ENDPOINTS 
4.1. 
Primary and Secondary Endpoints 
The definition of baseline for efficacy variables is provided in Section 11.4.3. 
4.1.1. 
Primary Endpoint 
Percent change in LDH from baseline  to EOT period at week 36 (day 253). 
4.1.2. 
Key Secondary Endpoints 
The key secondary endpoints are: 
• Transfusion avoidance after day 1 through week 36, inclusive (defined as not requiring 
an RBC transfusion as per protocol algorithm based on hemoglobin values after day 1)  
• Breakthrough hemolysis, in patients with a baseline LDH ≤ 1.5× ULN, after day 1 
through week 36, inclusive 
• Hemoglobin stabilization (defined as patients who do not receive an RBC transfusion 
and have no decrease in hemoglobin level from baseline of ≥2 g/dL) after day 1 through 
week 36, inclusive 
• Maintenance of adequate control of hemolysis, defined as LDH ≤1.5 × ULN from 
week 8 through week 36, inclusive 
• Adequate control of hemolysis (defined as LDH ≤1.5 × ULN) from week 8 through 
week 36, inclusive  
• Normalization of LDH, defined as LDH ≤1.0 × ULN from week 8 through week 36, 
inclusive 
• Change in fatigue as measured by the FACIT-Fatigue Scale from baseline to week 36 
• Change in PF score on the EORTC-QLQ-C30 from baseline to week 36 
• Change in global health status (GHS)/QoL scale score on the EORTC-QLQ-C30 from 
baseline to week 36 
4.1.3. 
Other Secondary Endpoints 
Other secondary endpoints are: 
• Transfusion avoidance from week 4 through week 36, inclusive (defined as not 
requiring an RBC transfusion as per protocol algorithm based on hemoglobin values 
after day 1) 
• Breakthrough hemolysis, in patients with a baseline LDH ≤1.5× ULN, from week 4 
through week 36, inclusive 
• Hemoglobin stabilization (defined as patients who do not receive an RBC transfusion 
and have no decrease in hemoglobin level from baseline of ≥2 g/dL) from week 4 
through week 36, inclusive 
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• Maintenance of adequate control of hemolysis, defined as LDH ≤1.5 × ULN after day 1 
through week 36, inclusive 
• Adequate control of hemolysis (defined as LDH ≤1.5 × ULN) after day 1 through 
week 36, inclusive  
• Normalization of LDH (defined as LDH ≤1.0 × ULN) after day 1 through week 36, 
inclusive 
• Rate and number of units of RBCs transfused per protocol algorithm after 
day 1 through week 36, and from week 4 through week 36 
• Change in hemoglobin levels from baseline to week 36 
• Incidence and severity of treatment-emergent SAEs, TEAEs of special interest and 
TEAEs leading to treatment discontinuation over 36 weeks 
• Change and percent change in total CH50 from baseline to week 36 
• Concentration of total C5 in plasma assessed throughout the study 
• Concentrations of total pozelimab in serum assessed throughout the study 
• Concentrations of cemdisiran in plasma assessed throughout the study 
• Concentrations of total eculizumab or ravulizumab in serum assessed throughout the 
study 
• Incidence of treatment emergent anti-drug antibodies (ADAs) to pozelimab assessed 
throughout the study 
• Incidence of treatment emergent ADAs to cemdisiran assessed over 36 weeks 
4.1.4. 
Exploratory Endpoints 
The exploratory endpoints are: 
• 
 
 
• 
 
 
• 
 
 
• 
 
• 
 
• 
 
• 
 
• 
 
 
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• 
 
• 
 
• 
 
• 
 
 
• 
 
 
 
  
• 
 
 
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5. 
STUDY VARIABLES 
5.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will be collected and will include standard demography (eg, age, sex, race, 
ethnicity, weight, height, etc), disease characteristics, medical history, and medication history for 
each patient. The data will be used to describe the patient population under study and may inform 
whether there are differences in the safety or efficacy profile based on the defined patient 
characteristics. In addition, collection of data on race and ethnicity is required by certain regulatory 
agencies, such as the US Food and Drug Administration (FDA). 
5.2. 
Efficacy Variables 
5.2.1. 
Laboratory Variables for the Assessment of Efficacy 
Efficacy in this study is evaluated by the following laboratory assessments: 
• LDH (serum): LDH as a measure of intravascular hemolysis allows for an objective 
and precise means to gauge whether the control of intravascular hemolysis is sustained 
when the patients are switched to pozelimab and cemdisiran combination treatment 
• Hemoglobin: Hemolytic anemia is a hallmark of PNH 
These laboratory variables are relevant to the characterization and disease mechanisms of PNH 
(Brodsky, 2014). 
5.2.2. 
Transfusion Record 
Hemolytic anemia is a clinical manifestation of PNH, and patients often require blood transfusion 
for symptomatic management. The frequency of blood transfusion has been used in other studies 
of PNH to assess efficacy (Hillmen, 2006) (Röth, 2018). 
5.2.3. 
Clinical Outcome Assessments 
Brief descriptions of COAs are provided in Section 9.2.3 and include the following: 
• FACIT-Fatigue 
• EORTC-QLQ C30 
• 
 
• 
 
• 
 
5.3. 
Safety Variables and Anthropometric Variables 
Safety and anthropometric variables in this study include: 
• Vaccination/revaccination for Neisseria meningitidis,  
• Vaccination against Streptococcus pneumoniae and Haemophilus influenzae type B 
(if needed) 
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• Concomitant medications and procedures 
• Height 
• Body weight 
• Vital Signs 
• Physical Examination 
• Electrocardiogram (ECG) 
• AEs 
• Breakthrough hemolysis assessment 
• Routine safety laboratory tests (hematology, chemistry, coagulation parameters, direct 
antiglobulin test, urinalysis, and pregnancy testing [for women of childbearing 
potential or WOCBP]) 
5.4. 
Pharmacokinetic Variables 
The PK variables are the concentrations of total pozelimab, total C5 (target), cemdisiran, 
cemdisiran metabolites, total eculizumab, total ravulizumab, and time. 
5.5. 
Immunogenicity Variables 
The immunogenicity variables are ADA status, titer, neutralizing antibody (NAb), and nominal 
sampling time point/visit. 
5.6. 
Pharmacodynamic and Other Biomarker Variables 
Pharmacodynamic and biomarker variables are:  
• CH50 (an assay assessing the activity of the classical pathway of complement) will be 
used to measure C5 activity. This is the principal PD marker for the study. 
• 
 
 
• 
 
 
• 
 
 
• 
 
 
The list may be altered or expanded, as it is recognized that more relevant or novel biomarkers 
may be discovered during the course of this study. The biomarkers studied will be ones believed 
to be relevant to the understanding of efficacy, pathophysiology of indication, target engagement, 
mechanism of action, and possible toxicities of pozelimab and cemdisiran. 
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6. 
STUDY DESIGN 
6.1. 
Study Description and Duration 
The study is a randomized, open-label, eculizumab and ravulizumab-controlled, non-inferiority 
study: 
• Patients treated with eculizumab will be eligible if they are taking eculizumab at the 
labeled posology of 900 mg IV Q 14 days for at least 12 weeks prior to screening visit.  
• Patients treated with ravulizumab will be eligible if they are taking IV ravulizumab at 
the labeled posology Q8W based on body weight (BW) as follows: 3000 mg for BW 
≥40 kg to <60 kg, 3300 mg for BW ≥60 kg to <100, 3600 mg for BW ≥100 kg for at 
least 24 weeks prior to screening visit. 
The study (Figure 1) consists of the following periods: a 6-week screening period and a 36-week 
open label treatment period (OLTP). Patients who complete the OLTP in the anti-C5 standard-of-
care arm and plan to enroll in the follow-on open-label long-term extension study with pozelimab 
and cemdisiran combination must participate in a post-OLTP transition period. Patients who 
discontinue study treatment as well as patients who decline enrollment into the OLE study will 
undergo a safety off-treatment follow-up period of up to 52 weeks. 
Figure 1: 
Study Diagram 
# Patients who complete anti-C5 Standard of Care arm and plan to enroll into the open-label extension with 
pozelimab and cemdisiran combination will undergo a transition period to phase in combination treatment 
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6.1.1. 
Screening Period 
The first screening visit should take place up to 6 weeks prior to day 1 (Table 1). Screening visit 1 
should be scheduled based on the patient’s eculizumab or ravulizumab dosing regimen prior to the 
study.  
For patients taking eculizumab at screening:  
• Screening visit 1 should be scheduled on the day of or the day prior to an eculizumab 
dose and may take place up to 6 weeks prior to day 1.  
• At visit 2e, patients will be provided with an eCOA device to take home. 
• Day 1 shall be scheduled on the day of or up to 2 days prior to the patient’s scheduled 
eculizumab administration. 
For patients taking ravulizumab at screening:  
• Screening visit 1 should be scheduled about 6 weeks after a ravulizumab dose  
• Visit 2r should be scheduled on the day of or up to 2 days prior to the patient’s next 
scheduled ravulizumab dose. This will be the last non-study ravulizumab dose. 
Additional laboratory samples for baseline assessments will be taken at this visit and 
eCOA device will be provided to the patient to take home. 
• The day 1 visit should be scheduled 26 to 28 days after the last administration of 
ravulizumab at visit 2r.  
Additional interim screening visit(s) may take place as needed, for instance, for repeat blood 
collection.  
Historical data will be collected such as but not limited to eculizumab or ravulizumab 
administration, concomitant medications, hemolytic parameters, and RBC transfusions. 
Due to the risk of Neisseria meningitidis infection, patients will require administration of 
meningococcal vaccination(s) in accordance with the local eculizumab or ravulizumab prescribing 
information, where applicable, and in accordance with current national vaccination guidelines for 
vaccination use with complement inhibitors or local practice and at the very least, within a period 
of 5 years prior to screening. For patients who require administration with meningococcal 
vaccination(s) during the screening period, administration should occur preferably at least 2 weeks 
prior to day 1, or at another time point according to local practice or national guidelines/local 
eculizumab or ravulizumab prescribing information (as applicable). If vaccination precedes the 
initiation of study treatment by less than 2 weeks, then the patient must receive antibiotic 
prophylaxis for a minimum of 2 weeks from the date of vaccine administration as described in 
Section 8.2.4. 
In addition to Neisseria meningitidis infection, fatal or serious infections with Neisseria gonorrhea 
have been reported in patients taking complement inhibitor therapy. Patients should therefore 
undergo a risk assessment and counseling regarding the potential risk of Neisseria gonorrhea as 
per local practice or national guidelines. 
Patients who have not been vaccinated against Streptococcus pneumoniae and Haemophilus 
influenzae type B may receive these vaccinations during the screening period or on the day of 
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randomization, based on investigator discretion and taking into consideration the available national 
guidelines.  
Patients will be assessed for active or latent tuberculosis (TB) infection based on local practice or 
applicable guidelines. Based on the risk assessment, the need for screening with either tuberculin 
skin test or T-cell interferon-gamma release assay will be made. The interpretation of these results, 
as applicable, will be made by the investigator. Further management and treatment of TB will be 
the responsibility of the investigator. 
6.1.2. 
Randomization 
Day 1 (randomization) must take place on the day of the patient’s scheduled eculizumab 
administration or 4 weeks (ie, 26 to 28 days) after the last administration of ravulizumab, as 
applicable. If the day of randomization cannot be scheduled on the day of the patient’s next 
eculizumab dose or exactly 4 weeks after the last ravulizumab dose, a window of 1 to 2 days is 
allowed such that the day of randomization may take place 1 to 2 days prior to the next scheduled 
eculizumab dose or 26-28 days after the last ravulizumab dose, as applicable. 
Patients who fulfill all the eligibility criteria will be randomized in a 1:1 ratio to 
anti-C5 standard-of-care (ie, continue existing treatment with eculizumab or ravulizumab) or 
treatment with pozelimab and cemdisiran.  
Randomization will be stratified based on the criteria described in 8.5.   
6.1.3. 
Open-Label Treatment Period (OLTP) 
The treatment period is 36 weeks. Treatment administration is based on a patient’s PNH treatment 
prior to screening as well as their treatment assignment: 
• Pozelimab and cemdisiran arm: 
− Patients who were on eculizumab at screening will receive the following during the 
study: 
 
 
 
 
 
 
 
 
 
 
 
 
− Patients who were on ravulizumab at screening will receive the following during 
the study: 
 
 
 
 
 
 
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• Anti-C5 standard-of-care arm: 
− Patients who were on eculizumab at screening will continue to receive eculizumab 
during the study:  
 
 
 
 
 
− Patients who were on ravulizumab at screening will continue to receive 
ravulizumab during the study: 
 
 
Administration of Pozelimab and Cemdisiran 
 
 
 After the first 
administration with the study drugs, subsequent administrations may be continued by the site 
personnel or a healthcare professional at the patient’s home (if possible and approved by the 
sponsor) or additionally, for the combination of pozelimab and cemdisiran administered by the 
patient or designated person, at the patient’s preferred location. These various options for 
administration will depend on preference of the investigator and patient, local regulations as well 
as availability of healthcare professional with sponsor endorsement. If self-administration/ 
administration by patient/designated person is undertaken for the combination of pozelimab and 
cemdisiran, then sufficient injection training at the scheduled administration(s) with pozelimab 
and cemdisiran maintenance regimen will be provided. After training, observation of self-
administration/administration by patient/designated person will be conducted by clinical site 
personnel or visiting healthcare professional/virtual visit (if available). Once this observation is 
considered satisfactory, the pozelimab and cemdisiran maintenance regimen can be subsequently 
administered independently by patient/designated person for the remainder of the study. Patients 
who self-administer/have the study drug administered by a designated person shall complete a 
patient diary to collect information on study treatment administration. They shall also be contacted 
by the study site to ensure study drug administration as planned. 
Safety Considerations 
During the transition of therapy from eculizumab or ravulizumab to pozelimab, investigators 
should have heightened awareness for possible AEs as a result of the risk of formation of large 
multimers of complexes of eculizumab-C5-pozelimab (ie, large DTD immune complexes) (see 
Section 6.2).  
Breakthrough hemolysis is assessed by the investigator throughout the study and is defined in 
Section 6.3.  
The decision to transfuse with RBCs during the study should proceed according to the predefined 
criteria in Section 6.4.  
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Patients should be closely monitored for the entire study for early signs and symptoms of 
meningococcal infection (and other infections related to encapsulated organisms) and evaluated 
immediately if an infection is suspected (Section 8.2.3 and Section 8.2.5). Patients will be provided 
a patient safety card describing signs and symptoms of suspected meningococcal infection along 
with instructions to follow in case of a potential meningococcal infection as well as information 
for non-investigator health care provider (HCP) for awareness. Patients should be instructed to 
carry the patient safety card at all times and to show this card to any HCP involved in their 
treatment. Additionally, patients who are randomized to standard-of-care will receive a patient 
safety brochure for eculizumab or ravulizumab, as applicable, prior to treatment initiation. Daily 
oral antibiotic prophylaxis is recommended (Section 8.2.4). 
COVID-19 
In light of the public health emergency related to COVID-19, the continuity of clinical study 
conduct and oversight may require implementation of temporary or alternative mechanisms. 
Examples of such mechanisms may include, but are not limited to, any of the following: phone 
contact, virtual visits, telemedicine visits, online meetings, non-invasive remote monitoring 
devices, use of local clinic or laboratory locations, and home visits by skilled staff. Additionally, 
no waivers to deviate from protocol enrollment criteria due to COVID-19 will be granted. All 
temporary mechanisms utilized, and deviations from planned study procedures in response to 
COVID-19 are to be documented as being related to COVID-19 and will remain in effect only for 
the duration of the public health emergency.  
A patient who has a documented, positive reverse transcriptase polymerase chain reaction 
(RT-PCR) or antigen test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on-
study should follow protocol guidance regarding interruption and discontinuation of study 
treatment (see Section 8.3.2). The investigator, with possible input from the sponsor, should 
determine what is most appropriate to do with the study treatment in accordance with the protocol. 
6.1.4. 
Post-Open-Label Treatment Period (Post-OLTP) 
Patients who complete the OLTP (ie, end of study [EOS] visit at day 253) will be offered the 
opportunity to enroll in another study, a follow-on OLE study. Screening for the next study may 
be conducted while the patient is in the OLTP, as described in Section 9.1.1.1 footnote #1.  
For patients who complete the 36-week OLTP on the pozelimab and cemdisiran arm, the transition 
of treatment from the current study to the OLE is planned to be uninterrupted, whereby day 1 visit 
of the OLE will correspond to the EOT period/EOS visit in the current study.  
Patients who complete the 36-week OLTP on the anti-C5 standard-of-care arm and plan to 
participate in the OLE study will undergo a transition period in order to switch to cemdisiran and 
pozelimab combination treatment in the same manner as those switching to the combination at 
study initiation as follows:  
 
• 
 
 
• 
 
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• 
 
 
 
 
• 
 
 
• 
 
• 
 
 
 
This approach for patients randomized to the anti-C5 standard-of-care arm and who plan to enroll 
in the OLE study, ensures a consistent dosing approach when switching from eculizumab or 
ravulizumab to pozelimab and cemdisiran combination therapy and has no impact on study 
efficacy analysis for the randomized treatment period. Patients who discontinue treatment as well 
as patients who decline enrollment into the follow-on study of the OLE will undergo a safety off-
treatment follow up period (FUP) of up to 52 weeks according to Table 4. Patients discontinuing 
the study treatment should be treated in accordance with local standards of care while continuing 
to be monitored in the 52-week off-treatment safety FUP. Investigators switching patients from 
the combination treatment to another anti-C5 mAb should have a heightened awareness for 
possible adverse events resulting from the formation of large DTD immune complexes. 
The main study is considered finished, when all patients either complete the 36-week treatment 
period or prematurely discontinue the study. Additional data collected during the transition period 
and safety off-treatment FUP will be described separately.  
6.1.5. 
Study Stopping Rules 
The independent data monitoring committee (IDMC), which may also be referred to as Data and 
Safety Monitoring Board (DSMB), will monitor unblinded data on a regular basis to assess the 
benefit-risk profile of the combination regimen of pozelimab and cemdisiran. If at any time the 
IDMC has significant concerns regarding a meaningful imbalance in TEAEs or 
treatment-emergent SAEs, the IDMC may make a recommendation to the sponsor to halt the study 
or make recommendations for other changes in the study conduct. This will prompt a review by 
the sponsor. Applicable regulatory procedures will be adhered to as required by local laws in 
relation to any decisions related to a change in study conduct, temporary halt, study termination, 
or study restart. 
6.1.6. 
End of Study Definition 
The EOS is defined as the date the last patient completes the last study visit withdraws from the 
study, or is lost to follow-up (ie, the study patient can no longer be contacted by the investigator).  
6.2. 
Large Drug-Target-Drug Immune Complexes 
During the transition of therapy from eculizumab or ravulizumab to pozelimab, investigators 
should have heightened awareness for possible AEs as a result of the risk of formation of large 
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multimers of complexes of eculizumab-C5-pozelimab or ravulizumab-C5-pozelimab (ie, large 
DTD immune complexes). Patients may present with a variety of signs and symptoms such as 
fever, malaise, rash, and polyarthralgia. Investigators should also consider meningococcal 
infection as the cause of the aforementioned symptoms. If a rash does develop, the site may 
consider taking pictures of the skin lesions as allowed based on local requirements and/or perform 
a skin biopsy if clinically indicated. If photos are obtained, then copies should be kept as source 
documents, which may later be collected by the sponsor. If there is a suspicion of an AE potentially 
due to large DTD immune complexes, unscheduled laboratory tests should be obtained as 
described in “Other Laboratory Tests” (Section 9.2.4.7). It is recommended that the investigator 
consult with a rheumatologist or nephrologist if needed and inform the Sponsor. However, further 
investigations are at the discretion of the investigator. Investigators should administer an additional 
dose of pozelimab 
 mg/kg IV if systemic corticosteroids are administered for a type III 
hypersensitivity reaction (see below), with Sponsor approval. This additional dose will likely 
establish conditions of pozelimab excess in the circulation and thereby minimize the risk of further 
formation of immune complexes. Further management should be based on clinical experience with 
type III hypersensitivity reactions (ie, serum sickness) which includes antihistamines, 
non-steroidal anti-inflammatory drugs (NSAIDs), topical corticosteroids for localized skin rash, 
and systemic corticosteroids for generalized skin rash or systemic manifestations. 
6.3. 
Breakthrough Hemolysis 
Breakthrough hemolysis is defined below as an increase in LDH with concomitant signs or 
symptoms associated with hemolysis: 
• An increase in LDH occurs when: 
− LDH ≥2 × ULN if baseline LDH is ≤1.5 × ULN or 
− LDH ≥2 × ULN after initial achievement of LDH ≤1.5 × ULN if baseline LDH is 
>1.5 × ULN  
Note: Baseline is defined in Section 11.4.3. 
• The signs or symptoms are those known to be associated with intravascular hemolysis 
due to PNH (limited to the following: new onset or worsening fatigue, headache, 
dyspnea, hemoglobinuria, abdominal pain, scleral icterus, erectile dysfunction, chest 
pain, confusion, dysphagia, new thrombotic event, anemia including hemoglobin value 
significantly lower (ie, ≥2 g/dL decrease) as compared to patient’s known baseline 
hemoglobin values). 
6.4. 
Transfusion Algorithm 
Transfusions with RBCs during the study (including during the screening period) may proceed 
according to the following predefined criteria that will trigger a transfusion, as clinically indicated, 
however, the actual number of units to be transfused is at the discretion of the investigator: 
• Transfuse with RBCs if hemoglobin level is >7 to ≤9 g/dL with new onset or worsening 
signs or symptoms resulting from anemia that are of sufficient severity to warrant 
transfusion (Note:  the onset of new or worsening signs/symptoms of anemia must 
occur post-baseline after day 1 to be considered as meeting the endpoint criteria for 
transfusion), or 
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• Transfuse with RBCs if hemoglobin level is ≤7 g/dL with or without signs or symptoms 
from anemia 
6.5. 
Planned Interim Analysis 
No interim analysis is planned. 
6.6. 
Study Committees 
6.6.1. 
Independent Data Monitoring Committee 
Given the concern of monitoring for suspected immune AEs potentially related to suspected high 
molecular weight complex formation, an IDMC will be used for safety monitoring. In addition to 
formal safety reviews throughout the study, the IDMC will review the safety data from first 
12 patients treated for 8 weeks. 
The IDMC will monitor unblinded data on an ongoing basis to assess the risk/benefit profile of 
pozelimab/cemdisiran. If at any time the IDMC has significant concerns regarding TEAEs, 
treatment-emergent SAEs, or treatment-emergent adverse events of special interest (AESIs), the 
IDMC may make a recommendation to sponsor to halt the study or make other changes in the 
study conduct. This will prompt a review by sponsor who will decide to implement, modify, or 
reject the recommendation. Applicable regulatory procedures will be adhered to as required by 
local laws in relation to any decisions related to a change in study conduct, temporary halt, study 
termination, or study restart. 
The makeup of the IDMC will be at least 3 members who will be external to the sponsor; 
1 immunologist or rheumatologist, 1 statistician and 1 hematologist. This may be modified based 
on availability of specialists to participate to the IDMC. 
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7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
7.1. 
Number of Patients Planned 
Enrollment will continue until approximately 140 patients have been randomized and have 
received at least 1 dose of study treatment. 
7.2. 
Study Population 
The study population will consist of adult male and female patients with a confirmed diagnosis of 
PNH currently being treated at the labeled dose regimen with either eculizumab for at least the 
prior 12 weeks or ravulizumab for at least 24 weeks with any level of LDH control. Treatment 
assignment and stratification factors are described in Section 8.5. 
 
 
7.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Male or female ≥18 years of age or legal age of majority, whichever is greater, at the time 
of consent 
2. Diagnosis of PNH confirmed by a history of high-sensitivity flow cytometry from prior 
testing  
3. Ongoing treatment with eculizumab* 900 mg IV Q 14 days for at least 12 weeks prior to 
screening visit.  
or 
Ongoing treatment with ravulizumab* IV Q8W based on BW as follows; 3000 mg for BW 
≥40 kg to <60 kg, 3300 mg for BW ≥60 kg to <100, 3600 mg for BW ≥100 kg for at least 
24 weeks prior to screening visit.  
Note: Patients opting to participate from the R3918-PNH-2021 trial (A Randomized, Open-
Label, Ravulizumab-Controlled Study to Evaluate the Efficacy and Safety of Pozelimab 
and Cemdisiran Combination Therapy in Patients with Paroxysmal Nocturnal 
Hemoglobinuria who are Complement Inhibitor Treatment-Naive or Have Not Recently 
Received Complement Inhibitor Therapy) who were randomized to the ravulizumab arm 
must complete the open-label treatment period to be considered for eligibility in this study.  
*Biosimilars are not permitted, unless approved by the Sponsor. 
4. Provide informed consent signed by study patient. 
5. Willing and able to comply with clinic/remote visits and study-related procedures. 
6. Able to understand study-related questionnaires. 
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7.2.2. 
Exclusion Criteria 
Note:  If a patient screen fails, and if the study is still ongoing, they may be rescreened (up to 
2 times) if the Principal Investigator determines the patient may be eligible upon rescreening.  
A patient who meets any of the following criteria will be excluded from the study: 
1. Patients with a screening LDH >1.5 × ULN who have not taken their C5 inhibitor within 
the labeled dose interval at the dose prior to the screening LDH assessment. 
2. Receipt of an organ transplant, history of bone marrow transplantation or other hematologic 
transplant. 
3. Body weight < 40 kilograms at screening visit. 
4. Current plans for modification (initiation, discontinuation, or dose/dosing interval change) 
of the following background concomitant medications, as applicable, during screening and 
treatment 
period: 
erythropoietin, 
immunosuppressive 
drugs, 
corticosteroids, 
anti-thrombotic agents, anticoagulants, iron supplements, and folic acid. 
5. Any use of complement inhibitor therapy other than eculizumab or ravulizumab in the 
26 weeks prior to the screening visit or planned use during the study with the exception of 
study treatments. 
6. Any of the following abnormalities at the screening visit (two repeat measurements are 
allowed per parameter during screening period): 
a. Peripheral blood absolute neutrophil count (ANC) <500/μL (<0.5 × 109/L) or 
b. Peripheral blood platelet count <30,000/μL or 
c. Peripheral blood reticulocyte count abnormality defined as <60,000/μL (<0.06 × 
106/µL, <60 × 109/L) 
Note:  a patient will not be excluded if upon repeat testing the parameter no longer meets 
the exclusion criterion.  
Note: Patients receiving acute treatment (eg, platelet transfusions, granulocyte colony 
stimulating factors) for these conditions during screening and in the 1-month preceding 
screening will not be eligible. 
7. Not meeting meningococcal vaccination requirements for eculizumab or ravulizumab 
according to the current local prescribing information (where available) and at a minimum 
documentation of meningococcal vaccination within 5 years prior to screening visit.  
Note:  Patients without prior vaccination will be eligible provided they are willing to 
undergo vaccination prior to initiation of study treatment and vaccination is documented 
prior to randomization. 
8. Any contraindication for receiving Neisseria meningitidis vaccination. 
9. Unable to take antibiotics for meningococcal prophylaxis (if required by local eculizumab 
or ravulizumab prescribing information, where applicable or national guidelines/local 
practice or if vaccination is less than 2 weeks from study treatment initiation). 
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10. Any active, ongoing infection or a recent infection requiring ongoing systemic treatment 
with antibiotics, antivirals, or antifungals within 2 weeks prior to screening or during the 
screening period. 
11. Documented history of systemic fungal disease or unresolved tuberculosis, or evidence of 
active or latent tuberculosis infection (LTBI) (ie, if not having completed treatment for 
LTBI) during screening period. Assessment for active TB and LTBI should accord with 
local practice or guidelines, including those pertaining to risk assessment, and the use of 
tuberculin skin test or T-cell interferon gamma release assay. 
12. Positive hepatitis B surface antigen or hepatitis C virus RNA during screening.  
Note: Cases with unclear interpretation should be discussed with the medical monitor. 
13. Patients with known HIV with history of opportunistic infections in the last 1 year, any 
history of HIV related malignancy, documented history of CD4 count <500 cells/µL or 
detectable viral load within the last 6 months (note:  CD4 count and viral load must be 
available within the last 6 months, and may be conducted by a local laboratory during 
screening if needed). 
Note: Local testing for HIV may be conducted in patients if required locally or by local 
regulations.  
14. Documented* history of positive RT-PCR, antigen or serology test, or other health 
authority authorized test for SARS-CoV-2 and:  
a. Have not recovered from COVID-19 (all COVID-19-related symptoms and major 
clinical findings which can potentially affect the safety of the patient should be 
resolved to baseline), and  
b. Did not have 2 negative results from a health authority-authorized nucleic acid 
amplification (RT-PCR) test or other health authority authorized test for 
COVID-19 taken at least 48 hours apart prior to day 1. 
*Note: Screening for COVID-19 will not be performed as part of eligibility 
assessments for this study 
15. Known hereditary complement deficiency  
16. Documented history of active, uncontrolled, ongoing systemic autoimmune diseases 
17. Documented history of liver cirrhosis or patients with liver disease with evidence of current 
impaired liver function or patients with ALT or AST (unrelated to PNH or its 
complications) greater than 3 × ULN at the screening visit (if the AST or ALT returns >3 
× ULN, one repeat assessment of the abnormal parameter(s) is allowed during screening). 
18. Patients with an eGFR of < 30 mL/min/1.73m2 (according to Chronic Kidney 
Disease - Epidemiology Collaboration equation 2009) at screening visit (one repeat 
assessment allowed during screening). 
19. Recent, unstable medical conditions, excluding PNH and PNH related complications, 
within the past 3 months prior to screening visit (eg, myocardial infarction, congestive 
heart failure with New York Heart Association Class ≥ III or IV, serious uncontrolled 
cardiac arrhythmia, cerebrovascular accident, active gastrointestinal bleed) 
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20. Anticipated need for major surgery during the study 
21. History of cancer within the past 5 years, except for adequately treated basal cell skin 
cancer, squamous cell skin cancer, or in situ cervical cancer 
22. Participation in another interventional clinical study (except R3918-PNH-2021) or use of 
any experimental therapy within 30 days before screening visit or within 5 half-lives of 
that investigational product, whichever is greater, with the exception of eculizumab or 
ravulizumab.  
23. Known hypersensitivity to eculizumab or ravulizumab (as applicable), pozelimab, 
cemdisiran or to any components of their respective formulations. 
24. Patients with functional or anatomic asplenia 
25. Any clinically significant abnormality identified at the time of screening that in the 
judgment of the Investigator or sub-Investigator(s) would preclude safe completion of the 
study or constrain endpoints assessment such as major systemic diseases, or patients with 
short life expectancy 
26. Considered by the Investigator or sub-Investigator(s) as inappropriate for this study for any 
reason, eg, 
a. Deemed unable to meet specific protocol requirements, such as scheduled visits. 
b. Deemed unable to administer or tolerate need for chronic injections  
c. Presence of any other conditions (eg, geographic, social etc.) actual or anticipated, 
that the Investigator feels would restrict or limit the patient’s participation for the 
duration of the study. 
d. Part of a vulnerable population such as the institutionalized (this may also include 
patients who are committed to an institution by order issued either by the judicial 
or the administrative authorities, as applicable) 
e. Patient ineligible for clinical trial participation due to local regulations (eg, under 
legal protection measures [such as L1121-8 or L1121-8-1 in France], etc). 
27. Members of the clinical site study team and/or his/her immediate family, unless prior 
approval granted by the Sponsor. 
28. Pregnant or breastfeeding women. 
29. Women of childbearing potential (WOCBP)* who are unwilling to practice highly 
effective contraception prior to the initial dose/start of the first study treatment, during the 
study, and for at least 52 weeks after the last dose. Highly effective contraceptive measures 
include:  
a. stable use of combined (estrogen and progestogen containing) hormonal 
contraception (oral, intravaginal, transdermal) or progestogen-only hormonal 
contraception (oral, injectable, implantable) associated with inhibition of ovulation 
initiated 2 or more menstrual cycles prior to screening; 
b. intrauterine device (IUD); intrauterine hormone-releasing system (IUS); 
c. bilateral tubal ligation or tubal occlusion; 
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d. vasectomized partner (provided that the male vasectomized partner is the sole 
sexual partner of the WOCBP study participant and that the vasectomized partner 
has obtained medical assessment of surgical success for the procedure); and/or 
e. sexual abstinence†, ‡. 
*WOCBP are defined as women who are fertile following menarche until becoming 
postmenopausal, unless permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy. However, in the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient to determine the occurrence 
of a postmenopausal state. The above definitions are according to the Clinical Trial 
Facilitation Group (CTFG) guidance.  
Pregnancy testing and contraception are required for WOCBP. Pregnancy testing and 
contraception are not required for women who are post-menopausal or permanently 
sterile. 
†Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
drugs. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject. 
‡Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are 
not acceptable methods of contraception. Female condom and male condom should not 
be used together. 
30. 
Non-responsive to eculizumab or ravulizumab treatment (note: non-responsive refers 
to patients with no reduction in LDH after receiving treatment with eculizumab or 
ravulizumab;  patients with a response to eculizumab or ravulizumab that is sub-
optimal are not excluded provided all other eligibility criteria are satisfied) 
31. 
Hemoglobin ≤7 g/dL (Note: A patient may receive a blood transfusion during the 
screening period and is eligible if repeat hemoglobin returns >7 g/dL prior to 
randomization. More than 2 repeat measurements are allowed.) 
7.3. 
Premature Withdrawal from the Study 
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and/or sponsor have the right to withdraw a patient from the study if it is no longer 
in the interest of the patient to continue in the study, or if the patient’s continuation in the study 
places the scientific outcome of the study at risk (eg, if a patient does not or cannot follow study 
procedures). An excessive rate of withdrawals would render the study uninterpretable; therefore, 
unnecessary withdrawal of patients should be avoided. 
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Patients who are withdrawn prematurely from the study will be asked to complete the early 
termination visit, as described in Section 9.1.5. 
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 8.3.2. 
7.4. 
Replacement of Patients 
Patients enrolled and withdrawn from study any time prior to first dose of study drug will not be 
considered evaluable for assessment and will be replaced with another patient. All patients who 
have received a dose of study drug will be included in an as treated analysis. 
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8. 
STUDY TREATMENTS 
8.1. 
Investigational and Reference Treatments 
Study treatment refers only to investigational medicine product (IMP, ie. pozelimab, cemdisiran, 
eculizumab, and ravulizumab) provided for use in this study.  
8.1.1. 
Pozelimab 
 
 
8.1.2. 
Cemdisiran 
 
 
8.1.3. 
Eculizumab 
30 mL of concentrate (10 mg/mL) in a Type I glass vial. 
Eculizumab will be provided to the study sites by the sponsor (but may be sourced locally by the 
study site in exceptional circumstances). 
Biosimilars are not permitted unless approved by the sponsor. 
Instructions on dose preparation are provided in the pharmacy manual. 
Please see the latest approved prescribing information for eculizumab (where available) for 
additional information (Soliris® Eculizumab (Prescribing information)), Summary of Product 
Characteristics. A prescriber safety brochure for eculizumab will be provided to all investigators. 
8.1.4. 
Ravulizumab  
Ravulizumab 11 mL of concentrate (100 mg/mL) or 3 mL of concentrate (100 mg/mL) in a 
single-dose vial. 
Ravulizumab will be provided to the study sites by the sponsor (but may be sourced locally by 
the study site in exceptional circumstances). 
Biosimilars are not permitted unless approved by sponsor. 
Instructions on dose preparation are provided in the pharmacy manual. 
Please see the latest approved prescribing information for ravulizumab (where available) for 
additional information (Ultomiris® (Prescribing information)), (Ultomiris® (Summary of Product 
Characteristics)). A prescriber safety brochure for ravulizumab will be provided to all 
investigators. 
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8.2. 
Risk Mitigation and Background Treatments 
8.2.1. 
Meningococcal Vaccinations 
Patients will require administration of meningococcal vaccination unless there is documentation 
of prior immunization within the past 5 years, or a shorter duration as required by current national 
vaccination guidelines for vaccination use with complement inhibitors or local practice.  
For patients requiring vaccination, administration should occur, preferably, at least 2 weeks prior 
to initiation of study treatment, or at another time point according to local practice or regional 
guidelines. If administration of the vaccine is less than 2 weeks of receiving study treatment, then 
antibiotic prophylaxis is required for a period of at least 2 weeks from the date of vaccine 
administration. Patients should undergo vaccination for serotypes A, C, Y, W, and serotype B if 
available. The vaccinations will be generally sourced locally by the investigator or designee and 
reimbursed by the Sponsor.  
During the course of the study, the investigator should ensure the patient continues to meet the 
requirement for vaccination as stated above. Patients who require revaccination during the course 
of the study should receive the vaccination and continue study treatment. 
8.2.2. 
Streptococcus Pneumoniae and Haemophilus Influenzae Type B Vaccination 
Patients who have not been vaccinated against Streptococcus pneumoniae and Haemophilus 
influenzae type B may receive these vaccinations during the screening period or on the day of 
randomization based on investigator discretion and taking into consideration the available national 
guidelines. 
8.2.3. 
Monitoring for Meningococcal Infection 
Patients should be closely monitored for early signs and symptoms of meningococcal infection 
and evaluated immediately if an infection is suspected.  
Patients and investigators will be provided with educational materials describing signs and 
symptoms of meningococcal infection, along with instructions to follow in case of a potential 
meningococcal infection.  
Information will also be provided for the non-investigator healthcare provider for awareness. 
8.2.4. 
Oral Antibiotics for Meningococcal Infection 
It is recommended that antimicrobial prophylaxis for meningococcal infection be initiated at the 
start of study treatment, unless the risks outweigh the benefits, or such treatment is inconsistent 
with local practice. It is recommended that prophylaxis be continued for up to 52 weeks after the 
last dose of pozelimab and cemdisiran combination treatment, including for patients who 
prematurely discontinue pozelimab/cemdisiran. For post-treatment prophylaxis for eculizumab or 
ravulizumab, follow the local prescribing information/national guidelines/local practice. If the 
investigator prescribes antibiotic prophylaxis, then the investigator should follow the local 
prescribing information, particularly as it relates to warnings, precautions, monitoring, etc., which 
may necessitate additional monitoring, attention to drug-drug interactions, and other 
considerations. No interaction is expected between antibiotic prophylaxis and cemdisiran or 
pozelimab. Based on a mechanistic understanding of antibiotics and antibodies, as well as 
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nonclinical data on cemdisiran, neither the study treatments nor the prophylactic antibiotics are 
expected to interact with clearance pathways of either cemdisiran or pozelimab. 
Ultimately, the decision to administer prophylaxis with oral antibiotics, the start day of 
administration, the duration of prophylaxis, the choice and dosage regimen of antibiotics will be 
at the discretion of the investigator in accordance with national guidelines/local 
practice/eculizumab or ravulizumab prescribing information (as applicable), unless the patient 
receives vaccination within 2 weeks from day 1, in which case the patient must receive antibiotic 
prophylaxis for a minimum of 2 weeks from day of vaccination. Patients who require revaccination 
against Neisseria meningitidis during the study should receive the vaccination and continue the 
study treatment. 
8.2.5. 
Risk Management of Neisseria Gonorrhea  
Patients should be counseled about N. gonorrhea prevention and regular testing should be advised 
for at-risk patients.  
Risk assessment should be based on local practice or national guidelines. The investigator should 
make his/her own assessment of risk (and if needed, consultation with other HCP) to determine if 
the patient is at risk, which would lead to further management of prevention, testing, and treatment 
of N. gonorrhea.  
Testing and treatment should be in accordance with local practice or national guidelines.  
General preventive measures include abstinence and use of a condom. Additional preventive 
measures should be considered based on local practice or national guidelines. 
8.2.6. 
Guidance on Abnormalities in Transaminases and Other Liver Function Tests 
Patients who develop any of the following abnormalities below should undergo additional 
investigations or consultation, as clinically indicated, if considered by the investigator not due to 
PNH. Also refer to the criteria set forth with specific thresholds for ALT, AST, total bilirubin, and 
INR in Reasons for Permanent Discontinuation of Study Treatment (Section 8.3.2) and Events that 
Require Expedited Reporting to Sponsor (Section 10.1.3). 
• ALT ≥3 × ULN if baseline ALT < ULN 
• ALT ≥2 × baseline if baseline ALT ≥ ULN 
• Total bilirubin ≥2 × ULN considered hepatic in origin, as per investigator 
Additional investigations or consultation, as clinically indicated, should be undertaken as follows: 
• The above abnormalities should be confirmed by repeat testing, generally within 
72 hours, including ALT, AST, alkaline phosphatase, total bilirubin, and INR with 
continued monitoring every 48 to 72 hours as clinically indicated until stabilization. 
Hematology and chemistry may also be obtained as well as other assessments or 
evaluations per investigator discretion, as appropriate.  
• Consider the following alternative causes with focused history, and, as indicated, 
specialized laboratory tests and imaging (abdominal ultrasound with Doppler flow [or 
computed tomography or magnetic resonance imaging] including right upper 
quadrant): 
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− Acute viral hepatitis types A, B, C, D, and E  
− Other causes of infection such as cytomegalovirus, Epstein Barr virus, herpes 
simplex virus 1 and 2, and herpes zoster 
− Autoimmune hepatitis 
− Alcoholic hepatitis  
− Hepatic injury due to concomitant medications, supplements, or environmental 
exposures 
− Non-alcoholic steato-hepatitis (NASH) 
− Hypoxic/ischemic hepatopathy 
− Biliary tract disease 
− Cardiovascular disease such as heart failure 
• Consider gastroenterology or hepatology consultations 
Completion of case report forms with more detailed information will be collected (eg, focused 
history of symptoms, travel history, use of any potentially hepatotoxic concomitant medications, 
work-related exposures, alcohol consumption, etc.). 
8.2.7. 
Guidance on Large Drug-Target-Drug Immune Complexes 
During the transition of therapy from eculizumab or ravulizumab to pozelimab, investigators 
should have heightened awareness for possible AEs as a result of the risk of formation of large 
multimers of complexes of eculizumab-C5-pozelimab or ravulizumab-C5-pozelimab (ie, large 
DTD immune complexes, see Section 6.2).  
8.3. 
Dose Modification and Study Treatment Discontinuation Rules 
8.3.1. 
Dose Modification 
Dose modification for an individual patient is not allowed. 
8.3.2. 
Study Drug Discontinuation 
Patients who permanently discontinue from study drug should be encouraged to remain in the 
study. Those who agree and do not withdraw from the study will be asked to return to the clinic 
for all remaining study visits per the visit schedule. 
Patients who permanently discontinue from study drug and who opt to withdraw from the study 
will be asked to complete study assessments, per Section 6.1.5 and Section 9.1.4.1. 
Patients who permanently discontinue study treatment should be treated in accordance with local 
standards of care. 
8.3.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
Study drug dosing will be permanently stopped for all patients in the event of: 
• Evidence of pregnancy 
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• Patient withdraws consent 
• Patient noncompliance as determined by the investigator (eg, not complying with 
protocol-required visits, assessments, and/or dosing instructions)  
• Investigator’s clinical judgment that it is in the best interest of the patient  
Study drug dosing will also be permanently stopped for patients receiving pozelimab and 
cemdisiran in the event of: 
• Serious or severe allergic reactions considered related to study drug 
− Note that AEs potentially due to large DTD immune complexes are not considered 
as an automatic reason for permanent treatment discontinuation. The investigator 
should review the particular case and consult with the medical monitor prior to 
deciding on permanent treatment discontinuation.  
• Liver impairment as evidenced by 1 or more of the following criteria and no other 
reason can be found to explain the following lab abnormalities, such as viral hepatitis 
A, B, or C; pre-existing or acute liver disease; PNH-related complication; or another 
drug capable of causing the observed injury (Section 8.2.6): 
− ALT or AST >8 × ULN, or 
− ALT or AST >5 × ULN for >2 weeks, or 
− ALT or AST >3 × ULN and total bilirubin > 2 × ULN (or international 
normalized ratio [INR] > 1.5)  
Study drug dosing will also be permanently stopped for patients receiving eculizumab or 
ravulizumab in the event of: 
• Any additional reasons for mandatory drug discontinuation outlined in the local 
prescribing information for eculizumab or ravulizumab, as applicable 
Note: A documented, positive RT-PCR or equivalent test per local recommendations for COVID-
19 is not considered an automatic reason for permanent discontinuation and should be discussed 
with the medical monitor. It may be a reason for permanent discontinuation if the benefit-risk 
assessment of continuing treatment with study drug is deemed unfavorable. 
8.3.2.2. 
Reasons for Temporary Discontinuation of Study Drug 
Temporary discontinuation may be considered by the investigator because of suspected AEs. After 
the condition leading to temporary discontinuation of study treatment resolves, study treatment 
dosing may resume. Alternatively, the investigator can reinitiate study treatment under close and 
appropriate clinical and/or laboratory monitoring once the investigator has considered, according 
to his/her best medical judgment, that there is an unlikely relationship between the occurrence of 
the AE and the study treatment. 
After temporary discontinuation with pozelimab/cemdisiran, consultation with the medical 
monitor should take place prior to re-initiation of study drug 
 
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In general, after a decision is made that it is safe to reinitiate study treatment, the patient should 
receive any missed dose as soon as possible. It is recommended that the patient returns to the 
original dosing schedule with administration of the next scheduled dose at the end of the respective 
dosing window. Ultimately, the investigator should exercise their clinical judgment as it relates to 
the exact  timing of the dose administration after treatment re-initiation. In all cases, discussion 
with the Sponsor’s medical monitor is advised 
 
. 
Note regarding infection with SARS-CoV-2: if in the investigator’s medical judgement, it is in the 
patient’s 
best 
interest 
to 
interrupt 
treatment 
with 
cemdisiran/pozelimab 
or 
eculizumab/ravulizumab (as applicable) until the patient recovers from SARS-CoV-2, then it is 
advisable that two repeat COVID-19 RT-PCR tests, or equivalent tests depending on regional 
recommendations, be conducted to confirm the patient is negative for SARS-CoV-2. If 
COVID-19 RT-PCR testing is not feasible, it is advised that at least three months have transpired 
since the initial diagnosis. The investigator may resume treatment with pozelimab/cemdisiran 
under close clinical monitoring if the investigator feels that the benefit of resuming therapy 
outweighs the risk, and the patient has no new contraindications to treatment. Input from the 
sponsor’ medical monitor regarding the permissible duration of interruption to allow resumption 
of treatment should be sought. 
8.4. 
Management of Acute Reactions  
8.4.1. 
Acute Intravenous Infusion Reactions 
Emergency equipment and medication for the treatment of infusion reactions must be available at 
the clinical site for immediate use. All infusion reactions must be reported as AEs (as defined in 
Section 10.2.4) and graded using the grading scales as instructed in Section 10.2.5. 
8.4.1.1. 
Interruption of the Intravenous Infusion 
The pozelimab infusion should be interrupted if any of the following AEs are observed: 
• Sustained/severe cough 
• Rigors/chills 
• Rash, pruritus (itching) 
• Urticaria (hives, welts, wheals) 
• Diaphoresis (sweating) 
• Hypotension 
• Dyspnea (shortness of breath) 
• Vomiting 
• Flushing 
The reaction(s) should be treated symptomatically, and the pozelimab infusion may be restarted at 
50% of the original rate.   
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If investigators feel there is a medical need for treatment or discontinuation of the infusion other 
than described above, they should use clinical judgment to provide the appropriate response 
according to typical clinical practice.  
Management of infusion reactions related to eculizumab or ravulizumab should follow the 
approved local prescribing information/local standards of care.   
8.4.1.2. 
Termination of the Intravenous Infusion 
The infusion should be terminated and NOT restarted if any of the following AEs occur: 
• Anaphylaxis* 
• Laryngeal/pharyngeal edema 
• Severe bronchospasm 
• Chest pain 
• Seizure 
• Severe hypotension 
• Other neurological symptoms (confusion, loss of consciousness, paresthesia, 
paralysis, etc.) 
• Any other symptom or sign that, in the opinion of the investigator, warrants 
termination of the IV infusion 
*Consider anaphylaxis if the following is observed (Sampson, 2006): acute onset of an illness 
(minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, generalized 
hives, pruritus or ﬂushing, swollen lips-tongue-uvula) AND AT LEAST ONE OF THE 
FOLLOWING  
• Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia) 
• Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence) 
8.4.2. 
Acute Injection Reactions 
8.4.2.1. 
Systemic Injection Reactions 
Emergency equipment and medication for the treatment of systemic reactions must be available at 
the clinical site for immediate use. All injection reactions must be reported as AEs (as defined in 
Section 10.2.1) and graded using the grading scales as instructed in Section 10.2.5. 
Acute systemic reactions following injection of study drug (SC and IV) should be treated using 
clinical judgment to determine the appropriate response according to typical clinical practice.  
8.4.2.2. 
Local Injection Site Reactions 
Local injection site reactions must be reported as AEs and graded according to Section 10.2.5. 
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8.5. 
Method of Treatment Assignment 
Eligible patients will be randomized in a 1:1 ratio to receive either the combination treatment with 
SC pozelimab 
 mg and cemdisiran 
 mg Q4W or continue their anti-C5 standard-of-care 
therapy with either eculizumab 900 mg IV Q2W or IV ravulizumab according to the labeled 
weight-based dosing algorithm according to a central randomization scheme provided by an 
Interactive Web Response System (IRWS) to the designated study pharmacist (or qualified 
designee). Randomization will be stratified according to the following factors:  
• 
 
 
 
• 
  
• 
 
8.6. 
Blinding 
This is an open-label study. The sponsor considers this open-label design as acceptable since the 
primary endpoint of the study is an objective laboratory-based parameter (ie, LDH) that is unlikely 
to be biased by knowledge of treatment assignment. Efforts will be made by the Sponsor to 
minimize bias due to the open-label study design. These efforts will be detailed in a separate 
study-related document/study plan. 
8.7. 
Treatment Logistics and Accountability 
8.7.1. 
Packaging, Labeling, and Storage 
Open-label study drug (pozelimab, cemdisiran, ravulizumab, and eculizumab) will display the 
product lot number on the label. 
Pozelimab and cemdisiran will be stored at the site at a temperature of 2ºC to 8ºC; storage 
instructions will be provided in the pharmacy manual.  
Ravulizumab and eculizumab will be stored at the site at a temperature of 2ºC to 8ºC; storage 
instructions will be provided in the pharmacy manual and the package insert.  
8.7.2. 
Supply and Disposition of Treatments 
Pozelimab and cemdisiran will be shipped at a temperature of 2ºC to 8ºC to the investigator or 
designee at regular intervals or as needed during the study. At specified time points during the 
study (eg, interim site monitoring visits), at the site close-out visit, and following drug 
reconciliation and documentation by the site monitor, all opened and unopened pozelimab and 
cemdisiran will be returned to the sponsor or designee or destroyed with sponsor’s approval. 
Ravulizumab and eculizumab will either be shipped at a temperature of 2ºC to 8ºC to the 
investigator or designee at regular intervals or as needed during the study by the Sponsor's depot, 
or it will be sourced locally by the sites. At specified time points during the study (eg, interim site 
monitoring visits), at the site close-out visit, and following drug reconciliation and documentation 
by the site monitor, all centrally sourced opened and unopened ravulizumab and eculizumab will 
be returned to the sponsor or designee or destroyed with sponsor’s approval. 
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8.7.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened pozelimab, cemdisiran, 
ravulizumab, and eculizumab. These records should contain the dates, quantity, and study 
medication 
• dispensed to each patient 
• returned from each patient (if applicable), and 
• disposed of at the site or returned to the sponsor or designee. 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
8.7.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the sponsor 
and regulatory agency inspectors. 
8.8. 
Concomitant Medications and Procedures 
Any treatment administered from the time of the first dose of study drug to the final study visit 
will be considered concomitant medication. This includes medications that were started before the 
study and are ongoing during the study. Any medication that the patient has taken within 3 months 
of the screening visit or during the screening period shall be collected in the electronic case report 
form (eCRF). In addition, to the extent that it is possible, any complement inhibitor therapy taken 
at any time prior to screening or during the screening period should be recorded along with any 
vaccinations against the following:  Neisseria meningitidis, Haemophilus influenzae type B, 
Streptococcus pneumoniae, and SARS-CoV-2.  
8.8.1. 
Prohibited Medications and Procedures 
The following medications are prohibited, with the exception of those listed in Section 8.8.2: 
• Beginning on day 1 and continuing throughout the study, while the patient is receiving 
the study treatment, the patient should not take any other complement inhibitor therapy 
• Other investigational treatments during the course of the study 
In addition, within 24 hours prior to each clinic visit when blood is drawn, the patient should not 
consume any alcohol. It is suggested that strenuous exercise be avoided 24 hours prior to obtaining 
samples for laboratory assessments, if possible.   
8.8.2. 
Permitted Medications and Procedures 
The following medications and procedures will be permitted, under the following conditions: 
• Any medication required to treat an AE, including systemic corticosteroids, at the 
discretion of the investigator  
• Meningococcal vaccination, as described in Section 8.2.1 
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• Oral antibiotic prophylaxis for meningococcal infection, per the investigator, as 
described in Section 8.2.4  
• Oral contraceptives and hormone-replacement therapy may continue  
• Acetaminophen/paracetamol, aspirin, or ibuprofen at the recommended dose per the 
local prescribing information 
• Erythropoietin, immunosuppressive drugs, corticosteroids, anti-thrombotic agents, 
anticoagulants, iron supplements, and folic acid are permitted and, if possible, should 
be kept constant throughout the study; any changes to these concomitant medications 
will be at the discretion of the investigator and consistent in the prior 26 weeks from 
enrollment. Any other medications may undergo dose adjustment or discontinuation at 
the discretion of the investigator.  
• Vitamin and electrolyte supplementation as needed 
• Any other medication required for the treatment of patient’s background medical 
conditions 
• COVID-19 vaccination and influenza vaccination can be administered as deemed 
necessary per the investigator based on his/her practice, standard-of-care or as required 
based on mandatory vaccination programs. Vaccination is suggested to be administered 
preferably 2 to 3 weeks after a dose of pozelimab/cemdisiran combination or 
ravulizumab, or up to 1 week after administration of eculizumab.  
• Other vaccinations against Streptococcus pneumoniae and Haemophilus influenzae 
type B may be administered based on investigator discretion and taking into 
consideration the available national guidelines  
8.9. 
Poststudy Treatments and Procedures 
All patients who complete the study without having prematurely discontinued the study treatment 
will be offered to participate in the follow on long-term, OLE study of the combination treatment.  
Patients randomized to the anti-C5 standard-of-care arm, who complete the 36-week OLTP and 
plan to enroll into the OLE study, will enter into a transition period (Table 2).  
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9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
9.1. 
Schedule of Events 
In light of the public health emergency related to COVID-19, the continuity of clinical study 
conduct, and oversight may require implementation of temporary or alternative mechanisms. 
Examples of such mechanisms may include, but are not limited to, any of the following:  phone 
contact, virtual visits, telemedicine visits, online meetings, non-invasive remote monitoring 
devices, use of local clinic or laboratory locations, and home visits by skilled staff. Additionally, 
no waivers to deviate from protocol enrollment criteria due to COVID-19 will be granted. All 
temporary mechanisms utilized, and deviations from planned study procedures are to be 
documented as being related to COVID-19 and will remain in effect only for the duration of the 
public health emergency. 
Study assessments and procedures are presented by study period and visit in Table 1 (OLTP), 
Table 2 (transition period for eculizumab arm), Table 3 (transition period for ravulizumab arm), 
and Table 4 (FUP). 
 
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9.1.1. 
Open-Label Treatment Period 
Table 1: 
Schedule of Events for the Open-Label Treatment Period 
Study Procedure (Visit)1 
Screening   
Open Label Treatment Period (OLTP) 
 
For ravu For ecu 
 
 
 
 
 
 
 
 
 
 
 
 
EOS 
Visit # 
V12 
V2r 
V2e 
V3 
V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 
Week 
Up 
to -6 
-4 
-4 to -2 
0 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
32 
36 
Day 
Up 
to -42 
-28 
-28 
to -14 
13 
15 
29 
43 
57 
71 
85 113 141 169 197 225 253 
Window (day) 
 
+2 
 
 
±2 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±3 
±3 
Screening/Baseline2: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eCOA device dispensation 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FBR informed consent (optional) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genomics informed consent (optional) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medications5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B and C testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccination / revaccinate for Neisseria meningitidis6 
<-------------- X -------------> 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccination against Streptococcus pneumoniae and 
Haemophilus influenzae type B (if needed) 7 
<-------------- X --------------> 
 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis history and assessment8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Risk assessment for Neisseria gonorrhea9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
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Study Procedure (Visit)1 
Screening   
Open Label Treatment Period (OLTP) 
 
For ravu For ecu 
 
 
 
 
 
 
 
 
 
 
 
 
EOS 
Visit # 
V12 
V2r 
V2e 
V3 
V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 
Week 
Up 
to -6 
-4 
-4 to -2 
0 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
32 
36 
Day 
Up 
to -42 
-28 
-28 
to -14 
13 
15 
29 
43 
57 
71 
85 113 141 169 197 225 253 
Window (day) 
 
+2 
 
 
±2 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±3 
±3 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IVRS/IWRS 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Timing of 
ecu/ravu (non-
IMP) during 
screening 
Pozelimab and 
cemdisiran arm 
Anti-C5 SOC: 
Eculizumab 
IMP arm 
Anti-C5 SOC: 
Ravulizumab 
IMP arm 
Injection Training/patient instructions17 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Patient diary18 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant meds and treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Transfusion record update 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Study Procedure (Visit)1 
Screening   
Open Label Treatment Period (OLTP) 
 
For ravu For ecu 
 
 
 
 
 
 
 
 
 
 
 
 
EOS 
Visit # 
V12 
V2r 
V2e 
V3 
V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 
Week 
Up 
to -6 
-4 
-4 to -2 
0 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
32 
36 
Day 
Up 
to -42 
-28 
-28 
to -14 
13 
15 
29 
43 
57 
71 
85 113 141 169 197 225 253 
Window (day) 
 
+2 
 
 
±2 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±3 
±3 
Antibiotics prophylaxis (recommended)19 
 
 
 
<------------------------------------------X------------------------------------> 
Clinical outcome assessments (COAs): 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FACIT-Fatigue 
 
 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
EORTC-QLQ-C30 
 
 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Safety and Anthropometric: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient safety card for Neisseria meningitidis10 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
For ravulizumab arm only: Provide patient safety brochure 
for ravulizumab 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
For eculizumab arm only: Provide patient safety brochure 
for eculizumab 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Vital signs21 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination22 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
X 
  
 
 
 
 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Breakthrough hemolysis assessment23 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Study Procedure (Visit)1 
Screening   
Open Label Treatment Period (OLTP) 
 
For ravu For ecu 
 
 
 
 
 
 
 
 
 
 
 
 
EOS 
Visit # 
V12 
V2r 
V2e 
V3 
V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 
Week 
Up 
to -6 
-4 
-4 to -2 
0 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
32 
36 
Day 
Up 
to -42 
-28 
-28 
to -14 
13 
15 
29 
43 
57 
71 
85 113 141 169 197 225 253 
Window (day) 
 
+2 
 
 
±2 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±3 
±3 
Laboratory Testing24: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Titers to measure N. meningitidis (only if required per 
local practice/regulations) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For patients receiving 
ravulizumab prior to 
screening: Additional 
samples  
(drawn pre-ravu dose) 
Blood chemistry 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation panel 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Free hemoglobin 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Haptoglobin 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology25 
X 
 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Coagulation panel 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry (long panel) including LDH26 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
D-dimer 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
Immunoglobulin G 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
Pregnancy test (applicable patients)27 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
Direct antiglobulin test (DAT or Coombs test) 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
Pharmacokinetics, ADA and Total C5 Sampling28: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pozelimab and 
cemdisiran arm 
Blood samples for conc. of pozelimab 
 
 
 
X 
 
X29  
X 
 
X 
X 
X 
X 
X 
X 
X 
Blood samples for conc. of cemdisiran 
and metabolites30 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
Blood samples for ADA of pozelimab31 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Blood samples for ADA of cemdisiran31 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
  
 
X 
Blood samples for conc. of total C5 
 
 
 
X 
X 
X  
X 
 
X 
X 
X 
X 
X 
X 
X 
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Study Procedure (Visit)1 
Screening   
Open Label Treatment Period (OLTP) 
 
For ravu For ecu 
 
 
 
 
 
 
 
 
 
 
 
 
EOS 
Visit # 
V12 
V2r 
V2e 
V3 
V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 
Week 
Up 
to -6 
-4 
-4 to -2 
0 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
32 
36 
Day 
Up 
to -42 
-28 
-28 
to -14 
13 
15 
29 
43 
57 
71 
85 113 141 169 197 225 253 
Window (day) 
 
+2 
 
 
±2 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±3 
±3 
Anti-C5 
standard-of-
care arm 
Blood samples for conc. of eculizumab 
(for patients taking eculizumab only) 
 
 
 
X 
X 
X  
 
 
X 
 
 
X 
 
 
X 
Blood samples for conc. of ravulizumab 
(for patients taking ravulizumab only) 
 
 
 
X 
X 
X  
 
 
X 
 
 
 
X 
 
X 
Blood samples for conc. of cemdisiran 
and metabolites30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X32 
Blood samples for ADA of pozelimab31 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X33 
Blood samples for ADA of cemdisiran31 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
X33 
Blood samples for conc. of total C5 
 
 
 
X 
X 
X  
X 
 
X 
X 
X 
X 
X 
X 
X 
Biomarkers: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional pharmacogenomics (DNA AND RNA):  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood for DNA isolation (optional)35 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood for RNA isolation (optional) 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
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9.1.1.1. 
Table 1 Schedule of Events for the Open-Label Treatment Period 
1. Study Procedures visits on days 15, 43, 71, 141, 169, and 225 may be at the clinical site, 
or another preferred location such as patient’s home. The location will be dependent on 
availability (and if approved by the sponsor) of home healthcare visiting professional, and 
preferences of the investigator and patient. Visits may also be conducted at another 
preferred 
location 
depending 
on 
extenuating 
circumstances 
such 
as 
due 
SARSCoV2 infection, in all cases, provided that the home healthcare professional is able 
to conduct all required assessments for that visit. Also, when multiple procedures are 
performed on the same day, the sequence of procedures is as follows: Clinical outcome 
assessments, electrocardiogram (ECG) and/or vital signs, blood collection, and study 
treatment administration. Patients who are being screened in this study (R3918-PNH-2022) 
who complete the R3918-PNH-2021 study will have all assessments performed as 
indicated in the SOE. This implies that the Screening Visit 1 in the R3918-PNH-2022 study 
may take place at week 24 of the R3918-PNH-2021 study and V2r of the R3918-PNH-
2022 study take place at the time of week 26 of the R3918-PNH-2021 study prior to the 
ravulizumab dose administration.  Assessments that are common to both studies should not 
be duplicated. 
2. Screening visit 1 should be scheduled based on the patient’s dosing regimen prior to the 
study. For patients taking eculizumab, screening visit 1 should be scheduled on the day of 
or the day prior to an eculizumab dose. For patients taking ravulizumab, screening visit 1 
should be scheduled about 6 weeks after the last ravulizumab dose. Additional screening 
visits may be scheduled as needed. 
3. For patients taking ravulizumab, the day 1 visit should occur 4 weeks (ie, 26 to 28 days) 
after the last administration of ravulizumab. 
4. Medical history including, transfusions, breakthrough hemolysis history, and laboratory 
parameters for measurement of hemolysis (such as LDH, bilirubin, haptoglobin, 
reticulocyte count, and hemoglobin) should be obtained for the past 52 weeks, if possible. 
Prior history of thrombosis and infections of the Neisseria spp. will be collected. Patients 
who have a C5 mutation confirmed while the study is ongoing should have the information 
included as part of the patient’s medical history. Patients who are poor responders to 
eculizumab or ravulizumab treatment during the study may be asked for a mutation analysis 
to be conducted as part of the study, if the patient agrees to such testing.  
5. Including detailed eculizumab or ravulizumab administration history and Neisseria 
meningitidis vaccination and other vaccinations as applicable. 
6. Patients will require administration with meningococcal vaccination unless documentation 
is provided of prior immunization in the past 5 years, or less than 5 years if required 
according to current national vaccination guidelines for vaccination use with complement 
inhibitors/local eculizumab or ravulizumab prescribing information. For patients who 
require administration with meningococcal vaccination(s) during the screening period, 
administration should occur preferably at least 2 weeks prior to day 1, or at another time 
point according to local eculizumab or ravulizumab prescribing information/national 
guidelines.  
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7. Vaccination for Streptococcus pneumoniae and Haemophilus influenzae type B should be 
initiated per current national/local vaccination guidelines. 
8. Tuberculosis history and assessment: Screening by tuberculin skin test or T-cell 
interferon-gamma release assay may be performed according to local practice or guidelines 
at the discretion of the investigator 
9. A risk factor assessment for Neisseria gonorrhea will be performed in accordance with 
local practice/national guidelines, and regular testing and counseling is advised for at-risk 
patients. 
10. Patient safety card: provide the patient safety card for Neisseria meningitidis infection to 
the patient on day 1 and any other visit when needed. Site should review the instructions 
on the safety card with the patient at each visit.  
11. 
 
 
 
  
12. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
13. 
 
 
 
 
 
 
 
 
 
 
 
 
  
14. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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15. 
 
 
 
 
 
 
 
  
16. 
 
 
 
  
 
 
 
17. If the sponsor has endorsed self-injection, injection training will be provided to patients 
randomized/enrolled to pozelimab and cemdisiran combination therapy and who desire 
self-injection or injection by a designated person. Site should observe patient syringe 
preparation and self-injection or injection by a designated person and confirm adequacy. 
Patient instruction materials will be provided. 
18. Patient diary: If needed, for self-administration or administration by a designated person 
with pozelimab and cemdisiran combination treatment only, a patient diary may be 
provided to collect information on study treatment administration. Patient diary may be 
provided at day 57 visit or a subsequent visit. If patient diary is provided to the patient, 
then it should be reviewed at each clinic visit and data collected into the case report forms 
(CRFs). On the final visit, the diary should be collected by the site.  
19. Daily oral antibiotic prophylaxis against Neisseria meningitidis is recommended starting 
on the first day of dosing with study treatment and continuing until up to 52 weeks after 
discontinuation of pozelimab/cemdisiran. For post-treatment prophylaxis for eculizumab 
or ravulizumab follow the local prescribing information/national guidelines/local practice. 
If vaccination for Neisseria meningitidis occurs less than 2 weeks prior to day 1, then 
antibiotic prophylaxis must be administered for at least 2 weeks from the day of 
vaccination.  
20. 
 
 
21. Vital signs include temperature, sitting blood pressure, and pulse. Vital signs will be 
obtained pre-dose after the patient has been sitting quietly for at least approximately 
5 minutes, where applicable.  
22. Physical examination will include an evaluation of the head and neck, lungs, heart, 
abdomen, extremities, and skin. Care should be taken to examine and assess any 
abnormalities that may be present, as indicated by the patient’s medical history. 
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23. Breakthrough hemolysis assessment: If a patient is suspected of having a breakthrough 
hemolysis event, then in addition to the required laboratory collection, additional samples 
for CBC, coagulation parameters (including D-dimer), chemistry, reticulocyte count, total 
C5, CH50, drug concentrations of pozelimab/cemdisiran/eculizumab/ravulizumab 
(depending on the patient’s randomization/enrollment), ADA (against pozelimab), and 
exploratory research serum and plasma will be collected unless already noted in the 
schedule of events for that visit. If the suspected event does not occur at a scheduled visit 
then an unscheduled visit should occur with an evaluation of the patient and collection of 
CBC, coagulation parameters (including D-dimer), chemistry, reticulocyte count, total C5, 
CH50, drug concentrations of pozelimab/cemdisiran/eculizumab/ravulizumab, and ADA 
(against pozelimab), as applicable, and exploratory research serum and plasma.  
24. During lab collection, handling and processing, the same methodology will be applied 
across study visits, as best as possible, to preserve the quality of sample and avoid 
hemolysis during sample processing. If the investigator or sponsor suspects that the lab 
result is not an accurate reflection of the patient’s condition, consideration should be given 
to repeat the lab sample if clinically warranted, and in all cases where an LDH is ≥2 × ULN 
in association with a potassium ≥6 mmol/L. Blood collection should always be obtained 
prior to study treatment administration, unless otherwise noted. The coagulation blood 
sample must always be collected first, followed immediately by the blood chemistry 
sample. 
25. Hemoglobin will be assessed as part of the hematology analysis. Hematology sample 
should be collected before study treatment administration. 
26. Serum LDH, CRP, and bilirubin will be assessed as part of the blood chemistry analysis. 
During the screening period, obtain chemistry including LDH on the day of (or if not 
possible, one day before) eculizumab or ravulizumab administration. On day 1 and all 
subsequent visits, obtain chemistry including LDH prior to any study treatment 
administration, as applicable.  
27. Pregnancy test: A serum test will be done at screening visit and a urine test will be done at 
all other visits.  
28. 
 
 
 
 
 
 
 
  
29. For patients who receive pozelimab IV infusion: obtain blood samples where permitted, 
prior to IV administration of pozelimab and also within 15 minutes after the end of the IV 
infusion. 
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30. Blood samples for concentrations of cemdisiran and its metabolites will be collected, where 
permitted, prior to any study treatment administration (pre-dose) and at 1 to 4 hours post 
dose. The post dose sample may be collected at the clinic or by a visiting health care 
professional (if available). 
31. Blood samples for ADA will be collected, where permitted, before the administration of 
any study drug (pre-dose). In the event of suspected SAEs, such as anaphylaxis or 
hypersensitivity, additional blood samples may be collected at or near the onset of the event 
for PK, ADA, and other analyses. 
32. Samples for the measurement of concentrations of cemdisiran and its metabolites will be 
collected at this visit only for patients who are receiving eculizumab treatment and willing 
to continue in the transition period and into the OLE 
33. Pozelimab and cemdisiran ADA samples will also be collected predose at this visit for 
patients who are received eculizumab or ravulizumab treatment and willing to continue in 
the transition period and into the OLE.  
34. 
  
35. Whole blood samples for DNA extraction (optional) should be collected on day 1 (predose) 
but can be collected at a later study visit. 
36. 
 
 
 
 
37. 
 
 
 
 
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9.1.2. 
Transition Period: Patients on Eculizumab in OLTP who Plan to Enroll in the 
OLE 
Table 2: 
Schedule of Events for the Transition Period: Patients on Eculizumab in 
OLTP who Plan to Enroll in the OLE 
Study Procedure (Visit) 1 
Transition period for patients on eculizumab in OLTP 
(only for patients who complete OLTP and plan to 
enroll in OLE) 
Visit # 
(2 weeks after last dose of  
eculizumab at OLTP week 36) 
TV1e2 
TV2e 
Weeks (after last dose of study treatment at OLTP 
week 36) 
2t 
4t 
Day 
15t 
29t 
Window (day) 
±2 
±2 
Baseline: 
 
 
Patient safety card for Neisseria meningitidis3 
X 
X 
Treatment: 
 
 
IVRS/IWRS 
X 
X 
Anti-C5 
standard-of-
care arm:  
Eculizumab4 
Concomitant meds and treatment 
X 
X 
Transfusion record update 
X 
X 
Antibiotics prophylaxis (recommended)7 
X 
X 
Safety and Anthropometric: 
 
 
Body Weight 
X 
X 
Vital signs 
X 
X 
Adverse events 
X 
X 
Breakthrough hemolysis assessment8 
X 
X 
Laboratory Testing9: 
 
 
Hematology10 
X 
X 
Coagulation panel 
X 
X 
Blood chemistry (long panel) including LDH11 
X 
X 
Pregnancy test (applicable patients)12 
 
X 
Pharmacokinetics and Total C5 Sampling: 
 
 
Patients 
previously 
taking 
eculizumab 
Blood samples for conc. of pozelimab13 
 
X 
Blood samples for conc. of eculizumab 
 
X 
Total C5 sample14 
 
X 
CH50 
X 
X 
 
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9.1.2.1. 
Table 2 Schedule of Events for the Transition Period: Patients on Eculizumab in 
OLTP who Plan to Enroll in the OLE 
1. When multiple procedures are performed on the same day, the sequence of procedures is 
as follows: vital signs, blood collection (first coagulation draw then chemistry draw 
followed by all other labs) and study drug administration. It is particularly important that 
the scheduled blood draws are obtained prior to the administration of study treatment, 
especially efficacy parameters such as LDH (ie, measurements reflect a time point at the 
end of the dosing interval).  
2. Transition period day 1 is the day of the week 36 eculizumab dose given in the OLTP. 
During the transition period, eculizumab may be administered within 2 days of all visits 
where eculizumab administration applies. If eculizumab administration does not coincide 
with the day of clinic visit, as applicable, then the clinic visit should always precede the 
infusion of eculizumab.  
3. Patient safety card: provide the patient safety card for Neisseria meningitidis infection to 
the patient at any visit when needed. Site should review the instructions on the safety card 
with the patient at each visit.  
4. 
 
 
 
 
 
 
  
5. 
 
 
 
 
  
6. Intentionally left blank 
7. Daily oral antibiotic prophylaxis against Neisseria meningitidis is recommended starting 
on the first day of dosing with study treatment and continuing until up to 52 weeks after 
discontinuation of pozelimab/cemdisiran. For post-treatment prophylaxis for eculizumab 
or ravulizumab follow the local prescribing information/national guidelines/local practice.  
8. If a patient is suspected of having a breakthrough hemolysis event, then in addition to the 
required laboratory collection, additional samples for CBC, coagulation parameters 
(including D-dimer), chemistry, reticulocyte count, total C5, CH50 and drug 
concentrations of pozelimab, cemdisiran, eculizumab or ravulizumab, ADA (against 
pozelimab), and exploratory research serum and plasma will be collected unless already 
noted in the schedule of events for that visit. If the suspected event does not occur at a 
scheduled visit then an unscheduled visit should occur to evaluate the patient and to collect 
CBC, coagulation parameters (including D-dimer), chemistry, reticulocyte count, total C5, 
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CH50 and drug concentrations of eculizumab or ravulizumab/pozelimab/cemdisiran, and 
ADA (against pozelimab) as applicable, and exploratory research serum and plasma.  
9. During lab collection, handling and processing, the same methodology will be applied 
across study visits, as best as possible, to preserve the quality of sample and avoid 
hemolysis during sample processing. If the investigator or sponsor suspects that the lab 
result is not an accurate reflection of the patient’s condition, consideration should be given 
to repeating the lab sample if clinically warranted and, in all cases, where an LDH is ≥2 × 
ULN in association with potassium ≥6 mmol/L. Blood collection should always be 
obtained prior to study treatment administration, unless otherwise noted.  
10. Hemoglobin will be assessed as part of the hematology analysis. Hematology sample 
should be collected before study treatment administration.  
11. Serum LDH, CRP, and bilirubin will be assessed as part of the blood chemistry analysis. 
Obtain chemistry including LDH prior to any study treatment administration.  
12. Pregnancy test: A urine test will be done.  
13. For patients who receive pozelimab IV infusion: obtain blood samples prior to IV 
administration of pozelimab and also within 15 minutes after the end of the IV infusion. 
14. Blood sample for CH50 and total C5 will be collected pre-dose. 
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9.1.3. 
Transition Period: Patients on Ravulizumab in OLTP who Plan to Enroll in the 
OLE 
Table 3: 
Schedule of Events for the Transition Period: Patients on Ravulizumab in 
OLTP who Plan to Enroll in the OLE 
Study Procedure (Visit) 1 
Transition period for patients on ravulizumab in OLTP 
(only for patients who complete OLTP and plan to 
enroll in OLE) 
Visit # 
(4 weeks after last dose of 
ravulizumab at OLTP week 36) 
TV1r2 
TV2r 
Weeks (after last dose of study treatment at OLTP 
week 36) 
4t 
8t 
Day 
29t 
57t 
Window (day) 
±2 
±2 
Baseline: 
 
 
Patient safety card for Neisseria meningitidis3 
X 
X 
Treatment: 
 
 
IVRS/IWRS 
X 
X 
Anti-C5 
standard-of-
care arm:  
Ravulizumab6 
Concomitant meds and treatment 
X 
X 
Transfusion record update 
X 
X 
Antibiotics prophylaxis (recommended)7 
X 
X 
Safety and Anthropometric: 
 
 
Body Weight 
X 
X 
Vital signs 
X 
X 
Adverse events 
X 
X 
Breakthrough hemolysis assessment8 
X 
X 
Laboratory Testing9: 
 
 
Hematology10 
X 
X 
Coagulation panel 
X 
X 
Blood chemistry (long panel) including LDH11 
X 
X 
Pregnancy test (applicable patients)12 
X 
X 
Pharmacokinetics and Total C5 Sampling: 
 
 
Patients 
previously 
taking 
ravulizumab 
Blood samples for conc. of pozelimab13 
 
X 
Blood samples for conc. of 
ravulizumab 
 
X 
Total C5 sample14 
 
X 
CH50 
X 
X14 
 
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9.1.3.1. 
Table 3 Schedule of Events for the Transition Period: Patients on Ravulizumab in 
OLTP who Plan to Enroll in the OLE 
1. When multiple procedures are performed on the same day, the sequence of procedures is 
as follows: vital signs, blood collection (first coagulation draw then chemistry draw 
followed by all other labs) and study drug administration. It is particularly important that 
the scheduled blood draws are obtained prior to the administration of study treatment, 
especially efficacy parameters such as LDH (ie, measurements reflect a time point at the 
end of the dosing interval).  
2. Transition period day 1 is the day of the week 36 ravulizumab dose given in the OLTP. 
3. Patient safety card: provide the patient safety card for Neisseria meningitidis infection to 
the patient at any visit when needed. Site should review the instructions on the safety card 
with the patient at each visit.  
4. Intentionally left blank 
5. 
 
 
 
 
  
6. 
 
 
 
 
 
 
 
 
 
7. Daily oral antibiotic prophylaxis against Neisseria meningitidis is recommended starting 
on the first day of dosing with study treatment and continuing until up to 52 weeks after 
discontinuation of pozelimab/cemdisiran. For post-treatment prophylaxis for eculizumab 
or ravulizumab follow the local prescribing information/national guidelines/local practice.  
8. If a patient is suspected of having a breakthrough hemolysis event, then in addition to the 
required laboratory collection, additional samples for CBC, coagulation parameters 
(including D-dimer), chemistry, reticulocyte count, total C5, CH50 and drug 
concentrations of pozelimab, cemdisiran, eculizumab or ravulizumab, ADA (against 
pozelimab), and exploratory research serum and plasma will be collected unless already 
noted in the schedule of events for that visit. If the suspected event does not occur at a 
scheduled visit then an unscheduled visit should occur to evaluate the patient and to collect 
CBC, coagulation parameters (including D-dimer), chemistry, reticulocyte count, total C5, 
CH50 and drug concentrations of eculizumab or ravulizumab/pozelimab/cemdisiran, and 
ADA (against pozelimab) as applicable, and exploratory research serum and plasma.  
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9. During lab collection, handling and processing, the same methodology will be applied 
across study visits, as best as possible, to preserve the quality of sample and avoid 
hemolysis during sample processing. If the investigator or sponsor suspects that the lab 
result is not an accurate reflection of the patient’s condition, consideration should be given 
to repeating the lab sample if clinically warranted and in all cases where an LDH is ≥2 × 
ULN in association with potassium ≥6 mmol/L. Blood collection should always be 
obtained prior to study treatment administration, unless otherwise noted.  
10. Hemoglobin will be assessed as part of the hematology analysis. Hematology sample 
should be collected before study treatment administration.  
11. Serum LDH, CRP, and bilirubin will be assessed as part of the blood chemistry analysis. 
Obtain chemistry including LDH prior to any study treatment administration.  
12. Pregnancy test: A urine test will be done.  
13. For patients who receive pozelimab IV infusion: obtain blood samples prior to IV 
administration of pozelimab and also within 15 minutes after the end of the IV infusion. 
14. Blood sample for CH50 and total C5 will be collected pre-dose. 
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9.1.4. 
Safety Off-Treatment Follow-up Period 
The FUP is for patients who discontinue treatment for any reason, including those who 
complete the OLTP but decline enrollment into the OLE. 
• Patients in the ravulizumab arm who complete OLTP (ie, last dose of study drug at 
week 28 and EOS at week 36) will enter FUP at visit FU-3 (ie, 12 weeks after last 
dose of study drug) 
• Patients in the eculizumab arm who complete OLTP (ie, last dose of study drug at 
week 32 and EOS at week 36) will enter FUP at visit FU-2 (ie, 8 weeks after last dose 
of study drug) 
• Patients in the pozelimab/cemdisiran arm who complete OLTP (ie, last dose of study 
drug at week 32 and EOS at week 36) will enter FUP at visit FU-2 (ie, 8 weeks after 
last dose of study drug) 
• For patients who discontinue and did not complete OLTP, they will have an ET visit. 
Thereafter, their entry point into the FUP will depend on the number of weeks that 
have elapsed after their final dose of study treatment 
Table 4: 
Schedule of Events for the Safety Off-Treatment Follow-up Period  
Visit  
FU-1 
FU-2 
FU-3 
FU-4 
FU-5 
Phone 
visit 
FU-6 
Phone 
visit  
FU-7 
Weeks (after the last dose of study drug)  
4 
8 
12 
16 
26 
38 
52 
Window (day) 
±10 
±10 
±10 
±10 
±10 
±10 
±10 
Body weight 
X 
X 
X 
X 
X 
 
 
Vital signs 
X 
X 
X 
X 
X 
 
 
Physical examination  
 
 
X 
 
X 
 
 
Concomitant meds/treatment 
X 
X 
X 
X 
X 
X 
X 
Adverse event reporting 
X 
X 
X 
X 
X 
X 
X 
Pregnancy reporting 
X 
X 
X 
X 
X 
X 
X 
Antibiotics prophylaxis (recommended)1 
X 
X 
X 
X 
X 
X 
X 
Patient safety card for Neisseria meningitidis2 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing 
 
 
 
 
 
 
Hematology 
X 
X 
X 
X 
X 
 
 
Blood chemistry 
X 
X 
X 
X 
X 
 
 
Monthly urine pregnancy test (WOCBP)3 
<------------------------------------X--------------------------------> 
Pharmacokinetics, and ADA Sampling: 
Pozelimab PK sample 
 
 
 
 
X 
 
 
ADA sample for pozelimab 
 
 
 
 
X 
 
 
ADA sample for cemdisiran 
 
 
 
 
X 
 
 
Total C5 (plasma) 
 
 
 
 
X 
 
 
 
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9.1.4.1. 
Table 4 Schedule of Events for the Safety Off-Treatment Follow-up Period 
1. Antibiotics prophylaxis (recommended): Daily oral antibiotic prophylaxis against 
Neisseria meningitidis is recommended starting at FU-1 and continuing until up to 
52 weeks after discontinuation of pozelimab/cemdisiran. For post-treatment prophylaxis 
for eculizumab or ravulizumab follow the local prescribing information/national 
guidelines/local practice.  
2. Patient safety card for Neisseria meningitidis: Patient safety card: provide the patient safety 
card for Neisseria meningitidis infection to the patient at FU-1 or any other visit when 
needed. Site should review the instructions on the safety card with the patient at each visit.  
3. Pregnancy testing: Monthly urine pregnancy testing will be conducted for WOCBP only. 
If performed via at-home testing kits, patients should be reminded to call the study staff 
each month with the results of their pregnancy test, and as soon as possible if their 
pregnancy test result is positive. 
9.1.5. 
Early Termination Visit 
Patients who are withdrawn from the study before the primary endpoint visit (week 36) will be 
asked to return to the clinic: once for an early termination visit consisting of the end of study 
assessments described in Table 1. 
9.1.6. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule. Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for any 
other reason, as warranted. In the event of suspected treatment-related SAEs, such as anaphylaxis 
or hypersensitivity, additional drug concentration and immunogenicity samples may be collected 
at or near the onset and the resolution of the event.  
9.2. 
Study Procedures 
9.2.1. 
Procedures Performed at the Screening Period 
Screening visit 1 must be scheduled based on the patients’ dosing regimen prior to study: please 
see scheduling requirements in Section 6.1.1. 
• eCOA device dispensation at visit 2e (for eculizumab patients) or visit 2r (for 
ravulizumab patients) 
• Informed consent (including optional sub-studies) 
• Medical history, including disease characteristics 
• Height 
• Demographics 
• Prior medications  
• Vaccination against Streptococcus pneumoniae and Haemophilus influenza type B (if 
needed) 
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• Hepatitis B and C testing 
• Tuberculosis history and assessment 
• Titers to measure N. meningitidis (only if required per local practice/regulations) 
• Risk assessment for Neisseria gonorrhea 
• Other assessments as described in Table 1 
9.2.2. 
Efficacy Procedures 
9.2.2.1. 
Laboratory Assessments of Efficacy 
Laboratory assessments of efficacy will be performed at scheduled visits according to Table 1 
(OLTP), Table 2 (Transition Period [eculizumab arm]), and Table 3 (Transition Period 
[ravulizumab arm]). 
9.2.2.1.1. Lactate Dehydrogenase 
Samples for LDH testing are collected as part of the blood chemistry panel (Section 9.2.4.5) and 
will be collected prior to study drug administration at scheduled visits. Levels of LDH in serum 
will be analyzed by a central laboratory. Care must be taken with the collection of LDH as it is the 
primary endpoint in the study. 
 
 
 
 
 
 
9.2.2.1.2. Hemoglobin 
Samples for hemoglobin testing are collected as part of the hematology panel (Section 9.2.4.5) and 
will be collected prior to study drug administration at scheduled visits. 
9.2.3. 
Clinical Outcome Assessments 
The following clinical outcome assessments are self-reported and will be completed by the patient 
at time points according to Table 1 (OLTP). Questionnaires will be completed using electronic 
devices, pre-loaded with COA questionnaires, that will be supplied to patients at Screening Visit 
2e (for eculizumab patients) or Visit 2r (for ravulizumab patients). 
9.2.3.1. 
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) 
The FACIT-Fatigue is a 13 item, self-administered COA assessing an individual’s level of fatigue 
during their usual daily activities over the past week. This questionnaire is part of the FACIT 
measurement system, a compilation of questions measuring health related QoL in patients with 
cancer and other chronic illnesses. The FACIT-Fatigue assesses the level of fatigue using a 5-point 
Likert scale ranging from 0 (not at all) to 4 (very much). Scores range from 0 to 52, with higher 
scores indicating higher quality of life. Although the FACIT-Fatigue was originally developed to 
assess fatigue in patients with cancer, it has been used in trials evaluating the efficacy of 
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eculizumab (Brodsky, 2008) (Hillmen, 2006). The FACIT-Fatigue has demonstrated content 
validity among patients with PNH (Weitz, 2013). 
9.2.3.2. 
European Organization for the Research and Treatment of Cancer: Quality of 
Life of Cancer Patients Questionnaire-30 (EORTC-QLQ C30) 
The EORTC-QLQ-C30 is a 30 item, self-administered, generic questionnaire originally designed 
to 
assess 
HRQoL 
in 
patients 
with 
cancer 
(Stead, 
1999) 
(Cocks, 
2007). 
The 
EORTC-QLQ-C30 assesses HRQoL across multiple domains, including GHS/global QoL, 
functioning (physical, role, emotional, cognitive, and social functioning), symptom scales (fatigue, 
nausea and vomiting, pain), and single items (dyspnea, insomnia, appetite loss, constipation, 
diarrhea, sleep, financial impact). Although the EORTC-QLQ-30 was originally developed to 
assess health-related QoL in patients with cancer, it has been used in trials evaluating the efficacy 
of eculizumab (Brodsky, 2008) (Hillmen, 2006). The EORTC-QLQ-C30 also has demonstrated 
content validity among patients with PNH (Weitz, 2013). 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
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9.2.4. 
Safety Procedures 
9.2.4.1. 
Body-Weight 
Body weight will be assessed using calibrated scales. Subjects should void (empty bladder) prior 
to weight assessment. Subjects should be wearing light clothing/undergarments and no shoes 
during weight assessments. Body weight will be recorded to the nearest 0.1 kg. 
9.2.4.2. 
Vital Signs 
Vital signs, including temperature, sitting blood pressure, and pulse will be collected pre-dose at 
time points according to Table 1 (OLTP), Table 2 (Transition Period [eculizumab arm]), and 
Table 3 (Transition Period [ravulizumab arm]), and Table 4 (FUP). 
9.2.4.3. 
Physical Examination 
A thorough and complete physical examination including an evaluation of the head and neck, 
lungs, heart, abdomen, extremities, and skin will be performed at time points according to Table 1 
(OLTP), Table 2 (Transition Period [eculizumab arm]), and Table 3 (Transition Period 
[ravulizumab arm]), and Table 4 (FUP). Care should be taken to examine and assess any 
abnormalities that may be present, as indicated by the patient’s medical history. 
9.2.4.4. 
Electrocardiogram 
A standard 12-lead ECG will be performed at time points according to Table 1 (OLTP), Table 2 
(Transition Period [eculizumab arm]), and Table 3 (Transition Period [ravulizumab arm]), and 
Table 4 (FUP). Heart rate will be recorded from the ventricular rate and the PR, QRS, and QT 
(QTcF) intervals will be recorded. The ECG strips or reports will be retained with the source. 
9.2.4.5. 
Blood Transfusion 
Transfusions with RBCs during the study should proceed according to the predefined criteria in 
Section 6.4. Any blood transfusion will be captured in the transfusion record CRF. 
9.2.4.6. 
Safety Monitoring 
For all patients, a patient safety card for Neisseria meningitidis infection will be provided to the 
patient on day 1 and any other visit when needed. Site should review the instructions on the safety 
card with the patient at each visit. Additionally, for patients randomized into the anti-C5 standard-
of-care arm only, a patient safety brochure for eculizumab or ravulizumab will be provided on 
day 1, as applicable. 
At every visit, AEs will be collected and assessed as described in Section 10. Unscheduled visits 
may be scheduled to collect blood samples as part of safety monitoring (Section 9.1.6). 
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In addition, at each visit during the OLTP (Table 1) or Transition Period (Table 2 [eculizumab 
arm] or Table 3 [ravulizumab arm]) or FUP (Table 4), changes to concomitant medications or 
procedures will be recorded (Section 8.8). 
9.2.4.7. 
Laboratory Testing 
Samples for laboratory testing will be collected at scheduled visits according to Table 1 (OLTP), 
Table 2 (Transition Period [eculizumab arm]), and Table 3 (Transition Period [ravulizumab arm]), 
and Table 4 (FUP). The coagulation blood sample must always be collected first, followed 
immediately by the blood chemistry sample. 
During blood collection, handling, and processing, the same methodology will be applied across 
study visits, as best as possible, to preserve the quality of the sample and avoid hemolysis 
(Section 9.2.2.1).  
Detailed instructions for blood sample collection, including the sequence in which blood draws 
must be performed, are in the laboratory manual provided to study sites. Unscheduled visits may 
be scheduled to collect blood samples as part of safety monitoring (Section 9.2.4.6). 
Hematology, chemistry, and urinalysis samples are planned to be analyzed by a central laboratory 
whenever possible. A local laboratory may be acceptable in special circumstances (eg, for 
eligibility) after discussion and agreement from the sponsor. Pregnancy testing may be performed 
at a central or a local laboratory. 
Other testing (eg, total C5, CH50, AH50) will be done by a specialized laboratory as outlined in 
study-related documents provided to the site. 
Samples will be obtained on the specified days where permitted. Tests will include: 
Blood Chemistry 
Sodium 
Total protein, serum 
Bilirubin* 
Potassium 
Creatinine** 
Uric acid 
Chloride 
Blood urea nitrogen (BUN)/blood urea 
C-reactive protein 
Carbon dioxide/bicarbonate 
Aspartate aminotransferase (AST) 
Magnesium 
Calcium 
Alanine aminotransferase (ALT) 
 
Glucose 
Alkaline phosphatase 
 
Albumin 
Lactate dehydrogenase (LDH) 
 
* Obtain total, direct, and indirect bilirubin  
** In addition, the estimated glomerular filtration rate will be calculated with the CKD-EPI equation (Levey, 2009)  
Hematology 
Hemoglobin  
Differential:  
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
Reticulocyte count 
 
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Urinalysis 
Color 
Glucose 
RBC 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBC 
Yeast 
Hemosiderin 
Urobilinogen 
 
Note: If macroscopy (urine dipstick) is abnormal, urine microscopy will be performed. A urine culture should 
be performed if there is a clinical suspicion of infection, per the Investigator judgment. 
 
Other Laboratory Tests 
Other laboratory tests include: 
• Coagulation panel: prothrombin time/international normalized ratio (INR) and 
activated partial thromboplastin time (aPTT) 
• D-dimer: This will be collected as part of the coagulation panel 
• Immunoglobulin G 
• Direct antiglobulin test 
• Hepatitis B and C testing  
• Pregnancy testing (WOCBP only): serum human chorionic gonadotrophin pregnancy 
testing, urine pregnancy testing. Any positive urine pregnancy test will be confirmed 
with a serum test.  
Note: Postmenopausal women must be amenorrheic for at least 12 months in order 
not to be considered of childbearing potential. Pregnancy testing and contraception 
are not required for women with documented hysterectomy. 
• FSH level (only if needed per the investigator to help assess post-menopausal status) 
• Unscheduled blood collection for suspected drug hypersensitivity events including 
suspicion of an AE potentially due to large DTD immune complexes. At minimum to 
include: CBC, CRP, chemistry, D-dimer, C3, C4, drug concentration, ADA (against 
pozelimab), and urinalysis (including microscopic evaluation). In addition, an 
exploratory research serum and plasma sample should be collected. 
• Unscheduled blood collection for suspected breakthrough hemolysis events should 
include, at a minimum, CBC, reticulocyte count, chemistry, coagulation parameters 
(including D-dimer), total C5, CH50, ADA (against pozelimab), and drug 
concentrations of pozelimab/cemdisiran and eculizumab or ravulizumab, as 
applicable. In addition, an exploratory research serum and plasma sample should be 
collected. 
• Titers to measure N. meningitidis (only if required per local practice/regulations) 
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• Drug concentration measurements (Section 9.2.5) 
• Immunogenicity measurements (Section 9.2.6) 
• Pharmacodynamic and exploratory biomarkers (Section 9.2.7) 
• Optional: pharmacogenomic and future biomarker research (Section 9.2.8 and 
Section 9.2.9) 
Abnormal Laboratory Values and Laboratory Adverse Events 
All laboratory values must be reviewed by the investigator or authorized designee. 
Significantly abnormal test results that occur after start of treatment must be repeated to confirm 
the nature and degree of the abnormality. When necessary, appropriate ancillary investigations 
should be initiated. If the abnormality fails to resolve or cannot be explained by events or 
conditions unrelated to the study medication or its administration, the Medical/Study Director must 
be consulted.  
The clinical significance of an abnormal test value, within the context of the disease under study, 
must be determined by the investigator. 
Criteria for reporting laboratory values as an AE are provided in Section 10.1.1. 
9.2.5. 
Drug Concentration and Measurements 
9.2.5.1. 
Concentrations of Total Pozelimab, Total Eculizumab, Total Ravulizumab and 
Total C5 
Samples to measure the concentration of total pozelimab, total eculizumab, total ravulizumab and 
total C5 will be collected prior to any IV or SC study drug administration at time points specified 
in Table 1 (OLTP), Table 2 (transition period for eculizumab), Table 3 (transition period for 
ravulizumab), and Table 4 (FUP).  
Samples will be obtained on the specified days prior to eculizumab, ravulizumab or the 
combination administration, as applicable where permitted.  
9.2.5.2. 
Concentrations of Cemdisiran and Cemdisiran Metabolites 
Samples to measure the concentration of cemdisiran and cemdisiran metabolites will be collected 
at time points specified in Table 1 (OLTP), Table 2 (transition period for eculizumab), and Table 3 
(transition period for ravulizumab). At each time point, blood samples will be collected prior to 
any SC study drug administration and 1 to 4 hours after study drug administration. 
Samples will be obtained on the specified days prior to ravulizumab or the combination 
administration where permitted. 
9.2.6. 
Immunogenicity Measurements and Samples 
Samples for ADA assessment will be collected separately for pozelimab and for cemdisiran at time 
points listed in Table 1 (OLTP), Table 2 (transition period for eculizumab), and Table 3 (transition 
period for ravulizumab). 
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Samples that are positive in the pozelimab ADA assay will be banked for the analysis of NAb, 
until the pozelimab NAb assay is available. Samples that are positive in the cemdisiran ADA assay 
will not be analyzed for anti-cemdisiran neutralizing activity.  
Samples will be obtained on the specified days prior to ravulizumab or the combination 
administration where permitted. 
9.2.7. 
Pharmacodynamic Biomarker Procedures 
Samples for biomarkers will be collected at time points specified in Table 1 (OLTP), Table 2 
(transition period for eculizumab), and Table 3 (transition period for ravulizumab). Biomarker 
variables are described in Section 5.6 and include: 
• CH50 (serum) 
− Samples for CH50 testing will be collected prior to study drug administration at 
scheduled visits. The CH50 tests the function of the terminal complement pathway 
by assessing the ability of the patient’s serum to lyse antibody coated sheep red 
blood cells (RBC sensitized with rabbit immunoglobulin M). The CH50 value/titer 
is reported as the reciprocal of the dilution of serum required to lyse 50% of 
antibody coated sheep red blood cells. 
The results of analysis performed on these samples will be presented in the clinical study report 
(CSR). 
Samples will be obtained on the specified days where permitted. 
9.2.7.1. 
Exploratory Biomarkers  
 
 
 
 
  
 
 
9.2.8. 
Future Biomedical Research (Optional) 
Patients who agree to participate in the future biomedical research (FBR) sub-study will be 
required to consent to this optional sub-study before samples are banked for FBR. Residual 
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biomarker samples for study-related research, as well as unused PK and ADA samples, will be 
stored for up to 15 years after the final date of the database lock (or for a shorter time period if 
required per regional laws and regulations). The samples may be utilized for FBR that may or may 
not be directly related to the study, including being used as reference samples and assay 
development or validation. The results of these future biomedical research analyses will not be 
presented in the CSR. 
9.2.9. 
Pharmacogenomic Analysis (Optional) 
Patients who agree to participate in the genomics sub-study will be required to consent to this 
optional sub-study before collection of the samples. Whole blood samples for DNA extraction 
should be collected on day 1/baseline (predose) but can be collected at a later study visit. Whole 
blood samples for RNA extraction will be collected at time points according to Table 1 (OLTP). 
DNA and RNA samples will be collected for pharmacogenomics analyses to understand the 
genetic determinants of efficacy and safety associated with the treatments in this study and the 
molecular basis of PNH and related diseases. These samples will be single-coded as defined by 
the International Council for Harmonisation (ICH) guideline E15. Samples will be stored for up to 
15 years after the final date of the database lock (or for a shorter time period if required per regional 
laws and regulations). If there are specific site or country requirements involving the 
pharmacogenomic analyses which the sponsor is unable to comply with, samples will not be 
collected at those sites. 
The purpose of the pharmacogenomic analyses is to identify genomic associations with clinical or 
biomarker response to pozelimab and cemdisiran, other PNH clinical outcome measures and 
possible AEs. In addition, associations between genomic variants and prognosis or progression of 
PNH as well as related diseases may also be studied. These data may be used or combined with 
data collected from other studies to identify and validate genomic markers related to the study 
drug, target pathway, or PNH and related diseases.  
Analyses may include sequence determination or single nucleotide polymorphism studies of 
candidate genes and surrounding genomic regions. Other methods, including whole-exome 
sequencing, whole-genome sequencing, DNA copy number variation, and transcriptome 
sequencing (or other methods for quantitating RNA expression) may also be performed. The list 
of methods may be expanded to include novel methodology that may be developed during the 
course of this study or sample storage period. Results from the genomic analyses will not be 
reported in the CSR. 
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10. 
SAFETY EVALUATION AND REPORTING 
10.1. 
Recording and Reporting Adverse Events 
10.1.1. 
General Guidelines 
The investigator must promptly record all adverse events occurring during the study data 
collection, from the time of signing the ICF to the end of study (see Section 11.4.5.1). Medical 
conditions that existed or were diagnosed prior to the signing of the Informed Consent will be 
recorded as part of medical history. Abnormal laboratory values and vital signs observed at the 
time of Informed Consent should also be recorded as medical history. Any subsequent worsening 
(ie, any clinically significant change in frequency and/or intensity) of a pre-existing condition that 
is temporally associated with the use of the study drug should also be recorded as an AE. 
At each visit, the investigator will determine whether any AEs have occurred by evaluating the 
patient. Adverse events may be directly observed, reported spontaneously by the patient, or by 
questioning the patient at each study visit. Patients should be questioned in a general way, without 
asking about the occurrence of any specific symptoms. The Investigator must assess all AEs to 
determine seriousness, severity, and causality, in accordance with the definitions in Section 10.2. 
The Investigator’s assessment must be clearly documented in the site’s source documentation with 
the Investigator’s signature. The Investigator should follow up on SAEs (and AESIs) until they 
have resolved or are considered clinically stable; AEs should be followed until they are resolved 
or last study visit, whichever comes first. 
Always report the diagnosis as the AE or SAE term. When a diagnosis is unavailable, report the 
primary sign or symptom as the AE or SAE term with additional details included in the narrative 
until the diagnosis becomes available. If the signs and symptoms are distinct and do not suggest a 
common diagnosis, report them as individual entries of AE or SAE.  
Laboratory results, vital signs, and other diagnostic results or findings should be appraised by the 
Investigator to determine their clinical significance. Isolated abnormal laboratory results, vital sign 
findings, or other diagnostic findings (ie, not part of a reported diagnosis) should be reported as 
AEs if they are symptomatic, lead to study drug discontinuation, dose reduction, require corrective 
treatment, or constitute an AE in the investigator’s clinical judgment. 
For events that are serious due to hospitalization, the reason for hospitalization must be reported 
as the serious adverse event (diagnosis or symptom requiring hospitalization). A procedure is not 
an AE or SAE, but the reason for the procedure may be an AE or SAE. Pre-planned (prior to 
signing the Informed Consent Form) procedures, treatments requiring hospitalization for 
pre-existing conditions that do not worsen in severity, and admission for palliative or social care 
should not be reported as SAEs (see Section 10.2 for Definitions).  
For deaths, the underlying or immediate cause of death should always be reported as an SAE.  
Any SAE that may occur subsequent to the reporting period (end of the on-treatment period) that 
the Investigator assesses as related to study drug should also be reported. 
All AEs, serious adverse events (SAEs), AESIs, and pregnancy reports are to be reported according 
to the procedures in Section 10.1.3.  
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10.1.2. 
Reporting Procedure 
All events (serious and non-serious) must be reported with investigator’s assessment of the event’s 
seriousness, severity, and causality to the study drug. For SAEs and AESIs, a detailed narrative 
summarizing the course of the event, including its evaluation, treatment, and outcome should be 
provided on the AE CRF. Specific or estimated dates of event onset, treatment, and resolution 
should be included, when available. Medical history, concomitant medications, and laboratory data 
that are relevant to the event should also be summarized in the narrative. For fatal events, the 
narrative should state whether an autopsy was or will be performed, and include the results if 
available. Information not available at the time of the initial report must be documented in a 
follow-up report. Source documents (including hospital or medical records, diagnostic reports, 
etc.) will be summarized in the narrative on the AE CRF, and retained at the study center and 
available upon request.  
Urgent safety queries must be followed up and addressed promptly. Follow-up information and 
response to non-urgent safety queries should be combined for reporting to provide the most 
complete data possible within each follow-up.  
10.1.3. 
Events that Require Expedited Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of learning 
of the event: 
• SAEs. 
• Selected AESIs (serious and nonserious):  Adverse events of special interest for this 
study include the following:   
− Moderate or severe hypersensitivity reactions potentially related to study 
treatment 
− Moderate or severe infusion reactions potentially related to study treatment 
− Suspected Neisseria infection  
− Any MAVE:  Includes thrombophlebitis/deep vein thrombosis, pulmonary 
embolus, myocardial infarction, unstable angina, renal vein or artery thrombosis, 
acute peripheral vascular occlusion, hepatic vein thrombosis, portal vein 
thrombosis mesenteric/visceral vein thrombosis or infarction, mesenteric/visceral 
arterial thrombosis or infarction, transient ischemic attack, cerebral arterial 
occlusion/cerebrovascular accident, cerebral venous occlusion, gangrene 
(nontraumatic; non-diabetic), amputation (nontraumatic; non-diabetic) 
− Adverse events potentially related to suspected large DTD immune complexes 
(Section 3.2.2 [Mitigation of Potential High Molecular Weight Complex 
Formation During Treatment Switch]) 
− Liver transaminase elevations as evidenced by 1 or more of the following criteria: 
o ALT or AST >8 × ULN, or 
o ALT or AST >5 × ULN for >2 weeks, or 
o ALT or AST >3 × ULN and total bilirubin >2 × ULN (or INR >1.5) 
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Note: This AESI must be reported to Sponsor within 24 hours once the 
investigator confirms the abnormal laboratory value.  
• Pregnancy:  Although pregnancy is not considered an AE, it is the responsibility of 
the investigator to report to the sponsor (or designee), within 24 hours of identification, 
any pregnancy occurring in a female during the study or within 52 weeks of the last 
dose of study drug. Any complication of pregnancy affecting a female study patient, 
and/or fetus and/or newborn that meets the SAE criteria must be reported as an SAE. 
Outcome for all pregnancies should be reported to the sponsor.  
• Symptomatic overdose:  Accidental or intentional overdose of at least 2 times the 
intended dose of study treatment within the intended therapeutic window, if associated 
with an AE.  
10.1.4. 
Other Adverse Events of Special Interest that do not Require Expedited 
Reporting to Sponsor 
Although these AESIs do not require expedited reporting to sponsor, the following events are of 
interest and may involve the collection of additional details in separate CRFs: 
• Injection Site Reactions (ISRs) potentially related to study treatment administration 
• Mild infusion reactions potentially related to study treatment  
• Mild hypersensitivity reactions potentially related to study treatment 
10.2. 
Definitions 
10.2.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug which may or 
may not have a causal relationship with the study drug. Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease which is temporally 
associated with the use of a study drug, whether or not considered related to the study drug (ICH 
E2A Guideline. Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting, Oct 1994). 
10.2.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death – includes all deaths, even those that appear to be completely 
unrelated to study drug (eg, a car accident in which a patient is a passenger). 
• Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event. This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
• Requires in-patient hospitalization or prolongation of existing hospitalization. 
Inpatient hospitalization is defined as a hospital admission (any duration) or an 
emergency room visit for longer than 24 hours. Prolongation of existing 
hospitalization is defined as a hospital stay that is longer than was originally 
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anticipated for the event or is prolonged due to the development of a new AE as 
determined by the investigator or treating physician. 
• Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions).  
• Is a congenital anomaly/birth defect 
• Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or 
may require intervention to prevent one of the other serious outcomes listed above 
(eg, intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development 
of drug dependency or drug abuse). 
Criteria for reporting SAEs must be followed for these events.  
10.2.3. 
Adverse Events of Special Interest 
An adverse event of special interest (AESI; serious or non-serious) is one of scientific and medical 
interest specific to the sponsor’s product or program, for which ongoing monitoring and rapid 
communication by the investigator to the sponsor can be appropriate. Such an event might warrant 
further investigation in order to characterize and understand it.  
10.2.4. 
Infusion Reactions 
Infusion reactions are defined as any relevant AE that occurs during the infusion or within 2 hours 
after the infusion is completed.  
10.2.5. 
Severity 
The severity of AEs will be graded according to the following scale: 
Mild:  Does not interfere in a significant manner with the patient normal functioning level. It may 
be an annoyance. Prescription drugs are not ordinarily needed for relief of symptoms but may be 
given because of personality of the patient. 
Moderate:  Produces some impairment of functioning but is not hazardous to health. It is 
uncomfortable or an embarrassment. Treatment for symptom may be needed. 
Severe:  Produces significant impairment of functioning or incapacitation and is a definite hazard 
to the subject’s health. Treatment for symptom may be given and/or patient hospitalized. 
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
Infusion Reactions 
The severity of infusion reactions will be graded according to the following scale (semi-colon 
indicates “or” within description of the grade): 
Mild:  Mild transient reaction; infusion interruption not indicated; intervention not indicated. 
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Moderate:  Therapy or infusion interruption indicated but responds promptly to symptomatic 
treatment (eg, antihistamines, NSAIDs, narcotics, IV fluids); prophylactic medications indicated 
for ≤24 hours. 
Severe:  Prolonged (eg, not rapidly responsive to symptomatic medication and/or brief interruption 
of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for 
clinical sequelae; life-threatening consequences; urgent intervention indicated; death. 
Injection Site Reactions 
The severity of injection site reactions will be graded according to the following scale (semi-colon 
indicates “or” within description of grade: 
Mild:  Pain that does not interfere with activity; mild discomfort to touch; <5 cm of erythema or 
induration that does not interfere with activity 
Moderate:  Pain that requires repeated use of non-narcotic pain reliever >24 hours or interferes 
with activity; discomfort with movement; 5.1 cm to 10 cm erythema or induration or induration 
that interferes with activity 
Severe:  Pain that requires any use of narcotic pain reliever or that prevents daily activity; 
significant discomfort at rest; > 10 cm erythema or induration; prevents daily activity; requires ER 
visit or hospitalization; necrosis or exfoliative dermatitis 
10.2.6. 
Causality 
The investigator must provide causality assessment as whether or not there is a reasonable 
possibility that the drug caused the adverse event, based on evidence or facts, his/her clinical 
judgment, and the following definitions. The causality assessment must be made based on the 
available information and can be updated as new information becomes available. 
The following factors should be considered when assessing causality: 
• Temporal relationship: time to onset vs time drug was administered 
• Nature of the reactions: immediate vs. long term 
• Clinical and pathological features of the events  
• Existing information about the drug & same class of drugs  
• Concomitant medications  
• Underlying and concurrent illnesses  
• Response to dechallenge (drug discontinuation) or dose reduction  
• Response to rechallenge (re-introduction of the drug) or dose increase, when 
applicable  
• Patient’s medical and social history  
Causality to the study drug (including study drug administration): 
• Related: 
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− The AE follows a reasonable temporal sequence from study drug administration 
and cannot be reasonably explained by the nature of the reaction, patient’s clinical 
state (eg, disease under study, concurrent diseases, concomitant medications), or 
other external factors. 
or 
− The AE follows a reasonable temporal sequence from study drug administration 
and is a known reaction to the drug under study or its class of drugs or is 
predicted by known pharmacology. 
• Not Related: 
− The AE does not follow a reasonable sequence from study drug administration or 
can be reasonably explained by the nature of the reaction, patient’s clinical state 
(eg, disease under study, concurrent diseases, and concomitant medications) or 
other external factors. 
Causality to the study conduct (protocol specified procedure): 
• Related: 
− The AE follows a reasonable temporal sequence from a protocol specified 
procedure and cannot be reasonably explained by the nature of the reaction, 
patient’s clinical state (eg, disease under study, concurrent diseases, concomitant 
medications), or other external factors. 
• Not Related: 
− The AE does not follow a reasonable sequence from a protocol specified 
procedure or can be reasonably explained by the nature of the reaction, patient’s 
clinical state (eg, disease under study, concurrent diseases, and concomitant 
medications) or other external factors. 
10.3. 
Safety Monitoring 
The investigator will monitor the safety of study patient at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP). Any questions or 
concerns should be discussed with the sponsor in a timely fashion. The sponsor will monitor the 
safety data from across all study sites. The Medical/Study Director will have primary responsibility 
for the emerging safety profile of the compound, but will be supported by other departments (eg, 
GPS; Biostatistics and Data Management). Safety monitoring will be performed on an ongoing 
basis (eg, individual review of SAEs) and on a periodic cumulative aggregate basis. 
10.4. 
Notifying Health Authorities, Institutional Review Board /Ethics 
Committee, and Investigators 
During the study, the sponsor and/or the contract research organization (CRO) will inform health 
authorities, IECs/IRBs, and the participating investigators of any SUSARs (Suspected Unexpected 
Serious Adverse Reactions) occurring in other study centers or other studies of the active study 
drug (pozelimab and cemdisiran) and comparators (eculizumab and ravulizumab), as appropriate 
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per local reporting requirements. In addition, the sponsor and/or CRO will comply with any 
additional local safety reporting requirements.  
Upon receipt of the sponsor’s notification of a SUSAR that occurred with the study drug, the 
investigator will inform the Institutional Review Board (IRB)/Ethics Committee (EC) unless 
delegated to the sponsor. 
Event expectedness for study drug (pozelimab and cemdisiran), are assessed against the Reference 
Safety Information section of the Investigator’s Brochure that is effective for expedited safety 
reporting. Event expectedness for comparators (eculizumab and ravulizumab) are assessed against 
the summary of product characteristics (SmPC). 
At the completion of the study, the sponsor will report all safety observations made during the 
conduct of the trial in the Clinical Study Report to health authorities and IECs/IRB as appropriate. 
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11. 
STATISTICAL PLAN 
This section provides a high-level description of the planned analysis and will serve as the basis 
for the statistical analysis plan (SAP) for the study.  
Endpoints are listed in Section 4. Analysis variables are listed in Section 5.  
11.1. 
Statistical Hypothesis 
For the primary endpoint of percent change in LDH from baseline to EOT period at week 36 (day 
253), the statistical hypotheses being tested in this study are: the null hypothesis is that treatment 
with pozelimab and cemdisiran combination therapy in patients with PNH who switch from 
eculizumab or ravulizumab treatment is inferior to treatment with anti-C5 standard-of-care on the 
primary endpoint, 
 
 
. The 
alternative hypothesis is that treatment with pozelimab and cemdisiran combination therapy is 
non-inferior to anti-C5 standard-of-care, 
 
 
.  
11.2. 
Justification of Sample Size and Non-Inferiority Margins 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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11.3. 
Analysis Sets 
The following analysis sets will be utilized in the analysis of this study. 
11.3.1. 
Full Analysis Set 
The full analysis set (FAS) includes all patients who are randomized and have received at least 
one dose of any investigational study drug (pozelimab, cemdisiran, eculizumab, or ravulizumab).  
The FAS is the main analysis set used for the efficacy analysis in this study. For analyses utilizing 
the FAS, the treatment assignments are defined to be those assigned via the randomization (as 
randomized). 
11.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all patients who received at least one dose of any 
investigational study drug (pozelimab, cemdisiran, eculizumab, or ravulizumab). The SAF is the 
main analysis set used for the safety analysis in this study. For analyses utilizing the SAF, the 
treatment assignments are determined to be as-treated.  
11.3.3. 
Pharmacokinetic Analysis Set 
The PK analysis population includes all patients who received any amount of study drug 
(pozelimab, cemdisiran, eculizumab, and ravulizumab) and who had at least 1 non-missing analyte 
measurement following the first dose of study drug.  The PK analysis set is based on the actual 
treatment received (as-treated). 
11.3.4. 
Immunogenicity Analysis Sets 
The ADA analysis set includes all patients who received any study drug (pozelimab and/or 
cemdisiran as applicable) and have at least 1 non-missing ADA result following the first dose of 
study drug.  
The NAb analysis set includes all patients who received any study drug (pozelimab and/or 
cemdisiran as applicable) and who are negative in the ADA assay or positive in the ADA assay 
with at least 1 non-missing result in the NAb assay [patients who are ADA negative are set to 
negative in the NAb analysis set]. 
11.3.5. 
Per-Protocol Set 
The per-protocol set (PPS) includes all patients in the FAS who do not experience any important 
protocol deviations throughout the course on or prior to week 36 of the study that significantly 
impact the reliability and/or interpretability of the primary efficacy analysis. Protocol deviations 
that lead to exclusion for the PPS will be identified prior to database lock. 
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11.3.6. 
Biomarker Endpoint Analysis Set 
The biomarker endpoint (pharmacodynamic) analysis set includes all patients who received any 
amount of study drug (pozelimab, cemdisiran, eculizumab, or ravulizumab) and who had at least 
1 non-missing analyte measurement following the first dose of study drug. 
11.4. 
Statistical Methods 
Continuous variables will be summarized within each treatment group, presenting the following 
descriptive statistics: the sample size (ie, number of observations with an available value of the 
variable), mean, standard deviation, median, minimum, maximum, 1st quartile and 3rd quartile. 
Categorical data will be summarized within each treatment group by presenting the frequency (ie, 
total number of observations within each level of the categorical variable within a given treatment 
group). All levels of the categorical variable will be included. For categorical variables that are 
ordinal in nature, the order in which the levels of the categories are displayed will be consistent 
with their natural ordering. Percentages will also be calculated for each level of the categorical 
variables with respect to the total sample size of the respective treatment arm. Category levels with 
frequencies of 0 will have the corresponding percentage displayed as 0%.  
11.4.1. 
Patient Disposition 
Patient disposition for this study will be summarized by reporting metrics describing patients’ 
status at major milestone throughout the study. The following metrics will be collected: 
• Number of patients screened (defined as having signed the ICF) 
• Number of screen failed patients categorized by reason for screen failing 
• Number of randomized patients (defined as having received a randomization number 
per IWRS) 
• Number of non-randomized but treated patients (if applicable) 
• Number of randomized but not treated patients (if applicable) 
• Number of patients completing the OLTP  
− Number of patients who took study medication until the end of the OLTP 
− Number of patients discontinuing the treatment early during the OLTP along with 
reasons for early treatment discontinuation  
• Number of patients who withdrew from the study early along with reasons for early 
study withdrawal.  
11.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group 
and overall using the FAS. The demographic and baseline characteristics variables are:  
• Age at screening (year) 
• Age category (<35, 35 to 65, ≥65) 
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• Sex (Male, Female) 
• Race (American Indian/Alaskan Native, Asian, Black/African American, Native 
Hawaiian/Other Pacific Islander, White and Other) 
• Ethnicity (Hispanic or Latino, non-Hispanic or Latino, Not Reported, Unknown) 
• Baseline Weight (kg) 
• Baseline Height (cm) 
• Baseline Body mass index (BMI)  
Baseline disease characteristics will be summarized descriptively by treatment group and overall 
using the FAS. The baseline disease characteristics variables are:   
• Duration of PNH at screening 
• Age at onset of PNH 
• Stratification factors as indicated in the IWRS system for presence of RBC/whole blood 
transfusion within the past year prior to randomization (yes/no)  
• Stratification factor as indicated in the IWRS system for LDH levels (≤1.5 × ULN or 
>1.5 × ULN)  
• Stratification factor as indicated in the IWRS system for anti-C5 standard-of-care 
therapy taken at screening (eculizumab versus ravulizumab) 
• Number of RBC/whole blood transfusion within the past year prior to randomization 
(0, 1 to 14; >14) 
• Number of units of RBC transfused (0, 1 to 14, >14) 
• Baseline LDH level 
• PNH clone size 
• History of aplastic anemia 
• History of venous thromboembolism 
• Baseline hemoglobin level 
• Baseline renal function 
Patient medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Medical history will be descriptively summarized by treatment group and overall 
using the FAS, showing patient counts and percentages by primary System Organ Class (SOC) 
and Preferred Term (PT).  
11.4.3. 
Efficacy Analyses 
Unless stated otherwise, analysis of all efficacy variables will be performed using the FAS. 
Treatment differences are defined as taking the value of the relevant summary statistic in the 
pozelimab + cemdisiran treatment arm minus the corresponding value in the anti-C5 standard-of-
care arm. 
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For LDH, the baseline value is defined as follows: 
• For patients entering the study who were previously treated with eculizumab: the last 
value of the assessment in the screening period immediately preceding randomization. 
• For patients entering the study who were previously treated with ravulizumab: last 
value of the assessment immediately preceding their last dose of ravulizumab in the 
screening period. 
For all other efficacy variables, baseline is the last value of assessment immediately preceding 
randomization. 
11.4.3.1. Primary Efficacy Analysis 
 
 
 
 
 
 
 
. 
 
 
 
 
. 
 
 
 
 
 
   
11.4.3.2. Secondary Efficacy Analysis 
Secondary Efficacy Analysis: 
 
 
 
 
 
 
 
 
 
 
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11.4.4. 
Control of Multiplicity 
Details of the testing strategy will be specified in the SAP. 
11.4.5. 
Safety Analysis 
Unless stated otherwise, analysis of all safety variables will be performed using the SAF. 
The baseline value of a safety parameter is defined to be the value of its last available assessment 
prior to randomization.   
In addition to the study periods defined in Section 6.1, the following observation periods are also 
defined and will be utilized for analysis as applicable: 
• The pretreatment period is defined as the time from signing the ICF up to the time of 
randomization. 
• The on-treatment period is defined as from the time of randomization to either: 
− the last dose of IMP plus 52 weeks for those not continuing into R3918-PNH-2050 
(the OLE study). 
− the End of the OLTP Visit for those continuing into R3918-PNH-2050. 
• The mono-treatment period is defined as starting at the time of randomization and 
concludes at the initiation of study drug administration during the week 4 visit. 
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• The combination-treatment period is defined as starting after study drug administration 
at week 4 up until the end of the OLTP. 
• The post-treatment period applies to all patients who are not continuing into 
R3918PNH-2050 and is defined as any time after the end of the on-treatment period. 
• The transition period applies to patients receiving anti-C5 standard-of-care who plan 
on continuing into R3918-PNH-2050 and is defined as the period after the on-treatment 
period to the first dose of IMP in R3918-PNH-2050. 
11.4.5.1. Adverse Events 
Adverse events summaries will be presented with incidence tables. Adverse event incidence tables 
will present the number (n) and percentage (%) of patients in each treatment arm experiencing an 
AE, sorted by decreasing frequency of SOC and PT in the anti-C5 standard-of-care arm. Multiple 
occurrences of the same event in a patient will only be counted once in the tables within a treatment 
period. In AE incidence tables by severity, the worst severity will be counted for multiple events 
occurring in a patient. The denominator for percentage computation is the number of patients in 
the SAF receiving the respective treatment. An AE will be considered as occurring in a respective 
period if either: 
• The onset of the initial instance of that AE was within the time period 
• The AE was already present/occurred and then worsened in severity within the time 
period 
• The AE was already present/occurred and then became serious within the time period 
Treatment-emergent adverse events (TEAEs) are defined as follows for patients allocated to: 
• Combination Therapy 
− Adverse events that develop or worsen after the first dose of investigational 
medicinal product (IMP) administered in the R3918-PNH-2022 study  
• Anti-C5 SOC therapy 
− Eculizumab 
− Adverse events that develop or worsen after the first dose of IMP 
administered in the R3918-PNH-2022 study  
− Ravulizumab 
− Adverse events that develop or worsen post-randomization on or after day 1 in 
the R3918-PNH-2022 study  
Please note that the definition of the start of the TEAE period for patients randomized to anti-C5 
SOC therapy taking ravulizumab differs from the start of the TEAE period for patients randomized 
to anti-C5 SOC therapy taking eculizumab and those randomized to the combination therapy given 
that the first day of IMP for those randomized to Anti-C5 SOC therapy taking ravulizumab will 
start at week 4 given the Q8W administration of ravulizumab and not on day 1.  
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Summaries of AE incidence by treatment arm will include: 
• Overview of TEAEs during the OLTP, summarizing number of events and percentage 
of patients within the specified category 
− Total number of TEAEs 
− Total number of serious TEAEs 
− Total number of treatment-emergent AESIs 
− Total number of severe TEAEs 
− Total number of patients with any TEAEs 
− Total number of patients with any serious TEAEs 
− Total number of patients with any treatment-emergent AESIs 
− Total number of patients with any severe TEAEs 
− Patients with any TEAEs leading to permanent discontinuation of study drug 
− Patients with any TEAEs leading to withdrawal from study 
− Patients with any TEAEs leading to death 
• TEAEs during the OLTP by SOC and PT 
− TEAEs 
− TEAEs by maximum severity: mild, moderate, or severe 
− TEAEs resulting in permanent study treatment discontinuation 
• Serious TEAEs during the OLTP by SOC and PT 
• AESIs by SOC and PT 
− Treatment-emergent AESIs during the OLTP 
− AESIs resulting in permanent study treatment discontinuation 
− Treatment-emergent AESIs during the transition period 
• All pretreatment AEs by SOC and PT 
• All AEs during the Transition Period by SOC and PT (for anti-C5 standard-of-care 
patients continuing into the OLEs study) 
• All TEAEs during the FUP by SOC and PT (for patients not continuing into either 
R3918-PNH-2022 or the R3918-PNH-2050) 
• TEAEs leading to death 
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11.4.5.2. Other Safety 
Vital Signs 
Vital signs (temperature, pulse, and blood pressure) will be summarized by baseline and change 
from baseline to each scheduled assessment time with descriptive statistics. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics. 
Number and percentage of patients with a potentially clinically significant value (PCSV) at any 
post-randomization time point will be summarized for each clinical laboratory test for all patients 
and separately for patients in whom the PCSV criterion was normal or missing at baseline.  
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
11.4.5.3. Treatment Exposure 
Study treatment exposure is measured by the total number of complete and incomplete injections 
administered for infusions and SCs. SC injection location is also recorded. 
The total number of complete and incomplete injections during the on-treatment period 
administered for IV infusions and SC, will be summarized by treatment group using descriptive 
statistics. 
The duration of study participation will be calculated as: [date of last study contact] – [first dose 
day] + 1, where the ‘date of last study contact’ is taken from the respective Study Completion 
CRF. The duration of study participation will be summarized by treatment group using descriptive 
statistics. 
11.4.5.4. Treatment Compliance 
Compliance to protocol-defined investigational study drug dosing will be calculated as follows: 
Treatment Compliance=(Number of investigational study drug doses taken during the 
on-treatment period)/(Number of investigational study drug doses planned for the on-treatment 
period)  100%. 
The number of planned investigational study drug doses does not include doses that were missed 
because study drug was temporarily withheld. Similarly, doses at timepoints subsequent to when 
a patient discontinues study treatment or withdraws from the study will not be counted in the 
number of planned doses. 
Treatment compliance will be summarized via descriptive statistics for each interventional study 
drug administered in this study using for the appropriate treatment arm. 
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11.4.6. 
Pharmacokinetics 
11.4.6.1. Analysis of Drug Concentration Data 
The concentrations of total pozelimab, cemdisiran, cemdisiran metabolites, total ravulizumab, total 
eculizumab and total C5 over time and selected pharmacokinetic parameters will be summarized 
by descriptive statistics for each of the treatment groups for the purpose of estimating exposures 
in these groups. This descriptive statistical assessment will include the geometric means and ratios 
of the geometric means for selected PK parameters, as deemed appropriate. 
No formal statistical hypothesis testing will be performed.  
11.4.7. 
Analysis of Immunogenicity Data 
Immunogenicity will be characterized by the ADA response, titer and NAb response observed:  
• Pre-existing immunoreactivity, defined as a positive ADA assay response at baseline, 
with all post-dose ADA results negative, or a positive assay response at baseline, with 
all post-dose ADA assay responses less than 4-fold for anti-cemdisiran antibody 
assay or less than 9-fold for anti-pozelimab antibody assay over baseline titer levels 
• Treatment-emergent ADA response, defined as any post-dose positive ADA assay 
response when the baseline results are negative 
− Treatment-emergent ADA response may be further characterized as persistent, 
transient, or indeterminate 
• Treatment boosted ADA response, defined as any post-dose positive ADA assay 
response that is 4-fold for anti-cemdisiran antibody assay or 9-fold for anti-pozelimab 
antibody assay over baseline titer levels when baseline is positive in the ADA assay  
• Maximum ADA Titer values 
− Low (titer <1,000) 
− Moderate (1,000≤ titer ≤10,000) 
− High (titer >10,000)  
• NAb status in the pozelimab NAb assay, for samples that are positive in the 
pozelimab ADA assay 
Listings of pre-existing, treatment-boosted, and treatment-emergent ADA responses, ADA titers 
and NAb positivity presented by patient, time point, and dose group will be provided. Incidence 
of treatment-emergent ADA and NAb will be assessed as absolute occurrence (N) and percent of 
patients (%), grouped by study cohorts and ADA titer level. 
Plots of drug concentrations will be examined and the influence of ADAs and NAbs on individual 
PK profiles evaluated. Assessment of impact of ADA and NAbs on safety and efficacy may be 
provided. 
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11.4.8. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data 
Analysis of PD and exploratory biomarker data is defined in the SAP. Unless specified as a 
secondary endpoint, the results of other biomarkers may not be presented in the CSR. 
11.5. 
Statistical Considerations Surrounding the Premature Termination 
of a Study 
If the study is terminated prematurely, only those parameters required for the development 
program will be summarized. Investigator and sponsor responsibilities surrounding the premature 
termination of a study are presented in Section 15.1. 
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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
In accordance with ICH E6, the sponsor is responsible for quality assurance to ensure that the 
study is conducted and the data generated, recorded, and reported in compliance with the protocol, 
GCP, and any applicable regulatory requirement(s). The planned quality assurance and quality 
control procedures for the study are described in this section.  
12.1. 
Data Management and Electronic Systems 
12.1.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation [quality-checking], cleaning, correcting, releasing) will be maintained and stored 
at Regeneron (Sponsor). 
A medical coding plan will specify the processes and the dictionary used for coding. All data 
coding (eg, AEs, baseline findings, medication, medical history/surgical history) will be done 
using internationally recognized and accepted dictionaries. 
The CRF data for this study will be collected with an electronic data capture (EDC) Medidata 
Rave. 
12.1.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
• IVRS/IWRS system – randomization, study drug supply 
• EDC system – data capture – Medidata Rave 
• Statistical Analysis System (SAS) – statistical review and analysis 
• Pharmacovigilance safety database 
• Electronic Clinical Outcome Assessment (eCOA) system – electronic device. 
12.2. 
Study Monitoring 
12.2.1. 
Monitoring of Study Sites 
Regeneron uses a study-specific risk-based approach to study monitoring and oversight, aligned 
with risk-based quality principles, outlined in ICH E6 (R2) Guideline for Good Clinical Practice. 
Risk-Based Quality Monitoring (RBQM) methodology focuses on employing a fit-for-purpose 
monitoring strategy, supported either directly by Regeneron as sponsor, or via our CRO partners. 
RBQM strategies include: reduced source data verification (SDV), targeted source data review 
(SDR), the use of off-site/remote and triggered on-site monitoring visits, and Centralized 
Monitoring to identify site level risks and study level trends. The investigator must allow 
study-related monitoring activities to occur. 
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
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accordance with the current approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements. 
12.2.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). The site is responsible to ensure quality within their records and systems and are 
accountable for ensuring that all source data and CRF data are timely, accurate and complete. 
The investigator must keep all source documents on file with the CRF (throughout this protocol, 
CRF refers to either a paper CRF or an electronic CRF). Case report forms and source documents 
must be available at all times for inspection by authorized representatives of the sponsor and 
regulatory authorities. 
12.2.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic Case Report 
Forms (CRFs) within the EDC system by trained site personnel. All required CRFs must be 
completed for each and every patient enrolled in the study. The investigator must ensure the 
accuracy, completeness, and timeliness of the data reported to the sponsor in the CRFs. After 
review of the clinical data for each patient, the investigator must provide an electronic signature. 
A copy of each patient CRF casebook is to be retained by the investigator as part of the study 
record and must be available at all times for inspection by authorized representatives of the sponsor 
and regulatory authorities. 
Corrections to the CRF will be entered in the CRF by the investigator or an authorized designee. 
All changes, including date and person performing corrections, will be available via the audit trail, 
which is part of the EDC system. For corrections made via data queries, a reason for any alteration 
must be provided. 
12.3. 
Audits and Inspections 
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities. Should this occur, the investigator is responsible for: 
• Informing the sponsor of a planned inspection by the authorities as soon as 
notification is received, and authorizing the sponsor’s participation in the inspection 
• Providing access to all necessary facilities, study data, and documents for the 
inspection or audit 
• Communicating any information arising from inspection by the regulatory authorities 
to the sponsor immediately 
• Taking all appropriate measures requested by the sponsor to resolve the problems 
found during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, CRFs, 
medical records, correspondence, ICFs, IRB/EC files, documentation of certification and quality 
control of supporting laboratories, and records relevant to the study maintained in any supporting 
pharmacy facilities. Conditions of study material storage are also subject to inspection. In addition, 
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representatives of the sponsor may observe the conduct of any aspect of the clinical study or its 
supporting activities both within and outside of the investigator's institution. 
In all instances, the confidentiality of the data must be respected. 
12.4. 
Study Documentation 
12.4.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the eCRF must be signed 
electronically by the investigator. This signed declaration accompanies each set of patient final 
eCRF that will be provided to the sponsor.  
12.4.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of CRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
regulatory authorities. The investigator must obtain written approval from the sponsor before 
discarding or destroying any essential study documents during the retention period following study 
completion or discontinuation. Records must be destroyed in a manner that ensures confidentiality. 
If the investigator's personal situation is such that archiving can no longer be ensured, the 
investigator must inform the sponsor (written notification) and the relevant records will be 
transferred to a mutually agreed-upon destination.  
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13. 
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1. 
Good Clinical Practice Statement 
It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory 
requirements. 
13.2. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC. A copy of the IRB/EC -approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient prior to his/her participation in the study and after the 
aims, methods, objectives, and potential hazards of the study have been explained to the patient in 
language that he/she can understand. The ICF should be signed and dated by the patient and by the 
investigator or authorized designee who reviewed the ICF with the patient.  
• Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
• Patients who can understand but who can neither write nor read will have the ICF 
read to them in presence of an impartial witness, who will sign and date the ICF to 
confirm that informed consent was given. 
The original ICF must be retained by the investigator as part of the patient’s study record, and a 
copy of the signed ICF must be given to the patient. 
If new safety information results in significant changes in the risk/benefit assessment, or if there 
are significant changes to the study procedures, the ICF must be reviewed and updated 
appropriately. All study patients must be informed of the new information and provide their written 
consent if they wish to continue in the study. The original signed revised ICF must be maintained 
in the patient’s study record and a copy must be given to the patient. 
13.3. 
Patients Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained. Patients should be identified by a patient identification number only, 
on CRFs or other documents submitted to the sponsor. Documents that will not be submitted to 
the sponsor (eg, signed ICF) must be kept in strict confidence. 
The patient’s 's and investigator's personal data, which may be included in the sponsor database, 
will be treated in compliance with all applicable laws and regulations. The sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third party. 
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13.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve: 
• The protocol, ICF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
• Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patient, in which 
case the IRB/EC should be informed as soon as possible  
• Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
In addition, the IRB/EC should be informed of any event likely to affect the safety of patients or 
the continued conduct of the clinical study. 
A copy of the IRB/EC approval letter with a current list of the IRB/EC members and their functions 
must be received by the sponsor prior to shipment of drug supplies to the investigator. The approval 
letter should include the study number and title, the documents reviewed, and the date of the 
review. 
Records of the IRB/EC review and approval of all study documents (including approval of ongoing 
studies) must be kept on file by the investigator. 
13.5. 
Clinical Study Data Transparency 
Final study results will be published on a public clinical trial website according to applicable local 
guidelines and regulations. Treatment codes will be disseminated to each investigation site 
thereafter. 
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14. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an 
IRB/EC-approved amendment. Where required per local legislation, regulatory authority approval 
will also be sought.  
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15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSEOUT 
OF A SITE 
15.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely. Reasons may include efficacy, safety, 
or futility, among others. Should the sponsor decide to terminate the study, the investigator(s) will 
be notified in writing. 
15.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
Investigator’s Decision 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at least 
30 days’ notice. The final decision should be made through mutual agreement with the sponsor. 
Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing. Reasons 
may include the following, among others:  
• The investigator has received all items and information necessary to perform the 
study, but has not enrolled any patient within a reasonable period of time 
• The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines  
• The total number of patients required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB/EC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection of 
the patients’ interests. 
16. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
17. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
18. 
PUBLICATION POLICY 
Publication rights and procedures will be outlined in a separate clinical study agreement. 
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19. 
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20. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: A Randomized, Open-label Eculizumab and Ravulizumab 
Controlled, Non-Inferiority Study to Evaluate the Efficacy and Safety of Pozelimab and 
Cemdisiran Combination Therapy in Patients with Paroxysmal Nocturnal Hemoglobinuria who 
are Currently Treated with Eculizumab or Ravulizumab and agree to abide by all provisions set 
forth therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, state, 
or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor or a partnership 
in which the sponsor is involved. I will immediately disclose it in writing to the sponsor if any 
person who is involved in the study is debarred, or if any proceeding for debarment is pending, or, 
to the best of my knowledge, threatened. 
This document contains confidential information of the sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the IRB/EC. I agree to ensure that this 
information will not be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the sponsor. 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
 
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SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Medical/Study Director, Regulatory Representative, Clinical Study Lead, 
and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the planned conduct of the study. 
Study Title: 
 A Randomized, Open-Label Eculizumab and Ravulizumab Controlled, Non-
Inferiority Study to Evaluate the Efficacy and Safety of Pozelimab and Cemdisiran Combination 
Therapy in Patients with Paroxysmal Nocturnal Hemoglobinuria Who are Currently Treated with 
Eculizumab or Ravulizumab 
 
Protocol Number: 
R3918-PNH-2022  
Protocol Version: 
R3918-PNH-2022 Amendment 1 
 
See appended electronic signature page 
Sponsor’s Responsible Medical/Study Director 
 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Liaison 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
 
 
                                        VV-RIM-00181803-2.0 Approved - 21 Jun 2022 GMT-5:00


Signature Page for VV-RIM-00181803 v2.0
Signature Page for VV-RIM-00181803 v2.0 Approved
Approval/eSignature
21-Jun-2022 12:47:19 GMT+0000
Approval/eSignature
21-Jun-2022 13:30:59 GMT+0000
Approval/eSignature
21-Jun-2022 16:34:02 GMT+0000
Approval/eSignature
21-Jun-2022 17:20:24 GMT+0000
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SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
CONFIDENTIAL 
Page 1 of 32 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-3.0 
July 1, 2022 
STATISTICAL ANALYSIS PLAN 
VERSION: 1.0 
Clinical Study Protocol Title: A Randomized, Open-Label Eculizumab and Ravulizumab 
Controlled, Non-Inferiority Study to Evaluate the Efficacy and Safety of Pozelimab and 
Cemdisiran Combination Therapy in Patients with Paroxysmal Nocturnal Hemoglobinuria who 
are Currently Treated with Eculizumab or Ravulizumab 
Compound: 
Pozelimab (REGN3918) Cemdisiran (ALN-CC5) 
Protocol Number: 
R3918-PNH-2022 
Clinical Phase:  
Phase 3 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician:  
 
Clinical Trial Manager: 
 
Study Medical Director: 
 
Version/Date:  
1.0  / 18JUL2023 
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NCT05131204


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PNH-2022 
Statistical Analysis Plan 
 
Date: 18JUL2023 
 
REGENERON CONFIDENTIAL 
Page 2 
The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
 
 
See appended electronic signature page 
  
 
 
 
See appended electronic signature page 
 
 
 
 
See appended electronic signature page 
 
 
 
 
See appended electronic signature page 
 
 
 
 
See appended electronic signature page 
 
 
 
 
See appended electronic signature page 
  
 
 
 
See appended electronic signature page 
 
 
 
                                        VV-RIM-00307940-1.0 Approved - 22 Jul 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PNH-2022 
Statistical Analysis Plan 
 
Date: 18JUL2023 
 
REGENERON CONFIDENTIAL 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................5 
1. 
OVERVIEW .................................................................................................................7 
1.1. 
Study Description and Objectives ................................................................................7 
1.1.1. 
Primary Objective .........................................................................................................7 
1.1.2. 
Secondary Objectives ...................................................................................................7 
1.2. 
Statistical Hypothesis ....................................................................................................8 
1.3. 
Interim Analysis ............................................................................................................8 
1.4. 
Modifications from the Statistical Section in the Final Protocol ..................................8 
1.5. 
Revision History for SAP Amendments .......................................................................9 
2. 
INVESTIGATION PLAN ..........................................................................................10 
2.1. 
Study Design ...............................................................................................................10 
3. 
ANALYSIS SETS ......................................................................................................12 
3.1. 
Full Analysis Set .........................................................................................................12 
3.2. 
Safety Analysis Set .....................................................................................................12 
3.3. 
Pharmacokinetic Analysis Sets ...................................................................................12 
3.4. 
Immunogenicity Analysis Sets ...................................................................................12 
4. 
GENERAL STATISTICAL ANALYSIS CONSIDERATIONS ...............................13 
5. 
PATIENT DISPOSITION ..........................................................................................14 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................15 
6.1. 
Demographics .............................................................................................................15 
6.2. 
Baseline Disease Characteristics ................................................................................15 
6.3. 
Medical History ..........................................................................................................16 
7. 
EFFICACY .................................................................................................................17 
7.1. 
Description of Efficacy Data ......................................................................................17 
7.1.1. 
Primary Efficacy Data ................................................................................................17 
7.1.2. 
Secondary Efficacy Data ............................................................................................17 
8. 
SUMMARY OF EXPOSURE DATA ........................................................................18 
8.1. 
Investigational Study Drug Exposure .........................................................................18 
8.2. 
Duration of Follow-up ................................................................................................18 
8.3. 
Prior and Concomitant Medications ...........................................................................18 
8.4. 
Prior and Concurrent Procedures ................................................................................18 
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Protocol: R3918-PNH-2022 
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9. 
ANALYSIS OF SAFETY DATA ..............................................................................19 
9.1. 
Adverse Events ...........................................................................................................19 
9.2. 
Laboratory Parameters ................................................................................................19 
9.3. 
Vital Signs ..................................................................................................................19 
9.4. 
Electrocardiogram (ECG) ...........................................................................................19 
9.5. 
Other Safety Data .......................................................................................................19 
9.6. 
Immunogenicity Data .................................................................................................20 
9.6.1. 
Immunogenicity Variables ..........................................................................................20 
9.6.2. 
Analysis of Immunogenicity Data ..............................................................................20 
9.6.2.1. 
Analysis of ADA Data ................................................................................................20 
9.7. 
Pharmacokinetic Data .................................................................................................21 
10. 
DATA CONVENTIONS ............................................................................................22 
10.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................22 
10.2. 
Data Handling Conventions ........................................................................................22 
10.3. 
Missing Data Conventions for Non-Efficacy Endpoints ............................................22 
10.4. 
Assignment of Data to Visit Windows and Unscheduled Assessments .....................22 
10.5. 
Pooling of Categorical Variables for Statistical Analyses ..........................................22 
11. 
TECHNICAL DETAILS PERTAINING TO INTERIM ANALYSIS ......................23 
12. 
REFERENCES ...........................................................................................................24 
13. 
APPENDIX.................................................................................................................25 
13.1. 
Schedule of Time and Events .....................................................................................25 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................11 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ATC 
Anatomical Therapeutic Chemical 
CH50 
Total Complement hemolytic activity assay 
COA 
Clinical outcome assessment 
CRF 
Case report form (electronic or paper) 
ECG 
Electrocardiogram 
EORTC 
European Organisation for Research and Treatment of Cancer 
EoS 
End of study 
eGFR 
Estimated glomerular filtration rate 
FACIT-Fatigue 
Functional Assessment of Chronic Illness Therapy-Fatigue 
FAS 
Full analysis set 
HRQoL 
Health-related quality of life 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IV 
Intravenous 
IWRS 
Interactive web response system 
LDH 
Lactate dehydrogenase 
OLE 
Open-label extension 
 
 
 
 
PK 
Pharmacokinetic 
PNH 
Paroxysmal nocturnal hemoglobinuria 
PRO 
Patient reported outcome 
PT 
Preferred term 
Q2W 
Every 2 weeks 
Q4W 
Every 4 weeks 
Q8W 
Every 8 weeks 
QLQ-C30 
Quality of life questionnaire-core 30 
QW 
Once weekly 
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RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
 
 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WHODD 
World Health Organization Drug Dictionary 
 
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1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to support the credibility of the study results 
by pre-specifying the statistical approaches for the analysis of data generated from the R3918-
PNH-2022 (ACCESS-2) clinical trial as described in Amendment 1 of the corresponding 
protocol, dated 21JUN22.  
Due to feasibility challenges related to enrollment and not due to any efficacy or safety reasons, 
the sponsor decided to cease enrollment for the study effective 20DEC2022. As a result, only 
three patients were enrolled. As the study was terminated prematurely the objectives stated in the 
protocol will not be analyzed as planned but instead, will be summarized descriptively as 
outlined in this plan.   
1.1. 
Study Description and Objectives  
The objective of the study was to evaluate the efficacy, safety, PK and immunogenicity of 
pozelimab and cemdisiran (combination therapy) in adult patients with Paroxysmal Nocturnal 
Hemogloburinia (PNH) who switch from eculizumab or ravulizumab therapy to the combination 
treatment versus patients who continue their eculizumab or ravulizumab therapy. Additional 
information can be found in the study protocol. Due to early termination and small sample size, 
the original primary and secondary objectives will not be analyzed as planned. 
1.1.1. 
Primary Objective 
The primary objective of the study was to evaluate the effect of pozelimab and cemdisiran 
combination therapy on hemolysis, as assessed by LDH (lactate dehydrogenase), after 36 weeks 
of treatment, in patients with PNH who switch from eculizumab or ravulizumab therapy versus 
patients who continue their eculizumab or ravulizumab therapy.  
1.1.2. 
Secondary Objectives 
The secondary objectives of the study were to: 
• Evaluate the effect of pozelimab and cemdisiran combination treatment versus 
anti-complement factor 5 (C5) standard-of-care treatment (eculizumab or ravulizumab) 
on the following: 
− Transfusion requirements and transfusion parameters 
− Measures of hemolysis: LDH control, breakthrough hemolysis, and inhibition of 
CH50 
− Hemoglobin levels 
− Fatigue as assessed by Clinical Outcome Assessment (COA) 
− Health-related quality of life (HRQoL) as assessed by COA 
− Safety and tolerability 
• To assess the concentrations of total pozelimab and either total eculizumab or total 
ravulizumab in serum and total cemdisiran and total C5 protein in plasma 
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• To assess the immunogenicity of pozelimab and cemdisiran  
Exploratory objectives are considered out of scope of this SAP. Additional details on exploratory 
objectives can be found in the protocol Section 2.3.   
1.2. 
Statistical Hypothesis 
The primary hypothesis was that PNH disease control as assessed by LDH after a 36-week 
treatment period with pozelimab and cemdisiran combination therapy in patients with PNH who 
switch from their current eculizumab or ravulizumab treatment to the combination treatment is 
not inferior to continued eculizumab or ravulizumab treatment. Due to early termination and 
small sample size, no hypothesis testing will be conducted.  
1.3. 
Interim Analysis 
No interim analysis was planned for this study. 
1.4. 
Modifications from the Statistical Section in the Final Protocol 
As this study was terminated prematurely, the study objectives stated in the study protocol will not 
be analyzed as planned. Demographic, safety and efficacy data will be provided in the listings. 
The efficacy analysis as specified in Protocol Amendment 1 for this study (dated 21JUN2022) as 
well as country specific amendment 2 for Germany (dated 03NOV2022) is modified to remove 
the following primary and secondary endpoints:  
Primary Endpoints to be removed: 
• Percent change in LDH from baseline to EOT period at week 36 (day 253). 
Key Secondary Endpoints to be removed: 
• Transfusion avoidance after day 1 through week 36, inclusive (defined as not 
requiring an RBC transfusion as per protocol algorithm based on hemoglobin values 
after day 1)  
• Breakthrough hemolysis, in patients with a baseline LDH ≤ 1.5× ULN, after day 1 
through week 36, inclusive 
• Hemoglobin stabilization (defined as patients who do not receive an RBC transfusion 
and have  to decrease in hemoglobin level from baseline of ≥2 g/dL) after day 1 
through week 36, inclusive 
• Maintenance of adequate control of hemolysis, defined as LDH ≤1.5 × ULN from 
week 8 through week 36, inclusive 
• Adequate control of hemolysis (defined as LDH ≤1.5 × ULN) from week 8 through 
week 36, inclusive 
• Normalization of LDH, defined as LDH ≤1.0 × ULN from week 8 through week 36, 
inclusive 
• Change in fatigue as measured by the FACIT-Fatigue Scale from baseline to week 36  
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• Change in PF score on the EORTC-QLQ-C30 from baseline to week 36 
• Change in global health status (GHS)/QoL scale score on the EORTC-QLQ-C30 
from baseline to week 36 
Other Secondary Endpoints to be removed: 
• Transfusion avoidance from week 4 through week 36, inclusive (defined as not 
requiring an RBC transfusion as per protocol algorithm based on hemoglobin values 
after day 1) 
• Breakthrough hemolysis, in patients with a baseline LDH ≤1.5× ULN, from week 4 
through week 36, inclusive 
• Hemoglobin stabilization (defined as patients who do not receive an RBC transfusion 
and have no decrease in hemoglobin level from baseline of ≥2 g/dL) from week 4 
through week 36, inclusive 
• Maintenance of adequate control of hemolysis, defined as LDH ≤1.5 × ULN after day 
1 through week 36, inclusive 
• Adequate control of hemolysis (defined as LDH ≤1.5 × ULN) after day 1 through 
week 36, inclusive 
• Normalization of LDH (defined as LDH ≤1.0 × ULN) after day 1 through week 36, 
inclusive 
• Rate and number of units of RBCs transfused per protocol algorithm after day 1 
through week 36, and from week 4 through week 36 
• Change in hemoglobin levels from baseline to week 36 
• Incidence and severity of treatment-emergent SAEs, TEAEs of special interest and 
TEAEs leading to treatment discontinuation over 36 weeks 
• Change and percent change in total CH50 from baseline to week 36 
• Concentration of total C5 in plasma assessed throughout the study 
• Concentrations of total pozelimab in serum assessed throughout the study 
• Concentrations of cemdisiran in plasma assessed throughout the study 
• Concentrations of total eculizumab or ravulizumab in serum assessed throughout the 
study 
• Incidence of treatment emergent anti-drug antibodies (ADAs) to pozelimab assessed 
throughout the study 
• Incidence of treatment emergent ADAs to cemdisiran assessed over 36 weeks 
1.5. 
Revision History for SAP Amendments 
This section is not applicable as this is the original version of the SAP. 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design 
This was an open-label, active-controlled (ravulizumab or eculizumab), non-inferiority study of 
pozelimab in combination with cemdisiran in patients with a confirmed diagnosis of PNH who 
were currently being treated with anti-C5 standard of care (SOC) (either ravulizumab or 
eculizumab).  
The study consisted of the following periods: up to 6-week screening period and a 36-week 
open-label treatment period (OLTP) with either anti-C5 SOC or the combination of pozelimab 
and cemdisiran.  
On day 1 (the day of randomization), patients who complete the screening period and were deemed 
eligible for enrollment, were randomized in a 1:1 ratio to one of the following treatment regimens:  
• Pozelimab and Cemdisiran arm: 
− Patients who were on eculizumab at screening will receive the following during the 
study: 
 
 
 
 
 
 
 
 
 
 
 
 
− Patients who were on ravulizumab at screening will receive the following during 
the study: 
 
 
 
 
 
 
 
 
• Anti-C5 Standard-of-Care arm: 
− Patients who were on eculizumab at screening will continue to receive eculizumab 
during the study:  
 
 
 
 
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− Patients who were on ravulizumab at screening will continue to receive 
ravulizumab during the study: 
 
 
Randomization was stratified based on the following factors: 
1. The screening visit LDH value used for randomization (≤ 1.5 × ULN, > 1.5 × ULN) 
2. RBC/whole blood transfusion within the past 1 year prior to day 1 (yes, no) 
3. Anti-C5 standard-of-care therapy taken at screening (eculizumab, ravulizumab)  
Presented below in Figure 1 is the study flow diagram depicting the different periods of the study 
with the scheduled visits and treatment administrations.  
Figure 1: 
Study Flow Diagram 
 
 
 
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3. 
ANALYSIS SETS 
In accordance with guidance from the International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (ICH, 1998), the following populations will be used for 
statistical analysis: 
3.1. 
Full Analysis Set 
The full analysis set (FAS) is comprised of all patients who were randomized who received at least 
one dose of any investigational study drug (pozelimab, cemdisiran, eculizumab or ravulizumab). 
For analyses utilizing the FAS, the treatment assignments are defined to be those assigned via the 
randomization (as-randomized).   
3.2. 
 Safety Analysis Set  
The safety analysis set (SAF) includes all randomized participants who received any 
investigational study drug (pozelimab, cemdisiran, eculizumab or ravulizumab). It is based on 
the treatment received (as-treated).  
3.3. 
Pharmacokinetic Analysis Sets 
The PK analysis population includes all patients who received any investigational study drug 
(pozelimab, cemdisiran, eculizumab, and ravulizumab) and who had at least 1 non-missing result 
following the first dose of study drug. 
3.4. 
Immunogenicity Analysis Sets 
The ADA analysis sets are defined for each study drug separately (pozelimab or cemdisiran) 
includes all patients who received any study drug and had at least one non-missing ADA result 
following the first dose of the respective study drug. The ADA analysis set is based on the actual 
treatment received (as treated) rather than as randomized. 
 
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4. 
GENERAL STATISTICAL ANALYSIS CONSIDERATIONS 
As the scope of the analysis is limited to listings, the data displayed will simply be a reiteration 
of the data captured in the study databases. 
 
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5. 
PATIENT DISPOSITION 
Due to early termination of the study, a total of 3 patients were enrolled. A patient disposition 
listing and listing of screen-failed patients will be provided.  
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6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
6.1. 
Demographics 
The following demographic variables were recorded in the study and presented in a listing:  
• Age at screening (year) 
• Age category (<35, 35 to 65, ≥65) 
• Sex (Male, Female) 
• Race (American Indian/Alaskan Native, Asian, Black/African American, Native 
Hawaiian/Other Pacific Islander, White and Other) 
• Ethnicity (Hispanic or Latino, non-Hispanic or Latino, Not Reported, Unknown) 
• Baseline Weight (kg) 
• Baseline Height (cm) 
• Baseline Body mass index (BMI) (kg/m2) 
6.2. 
Baseline Disease Characteristics 
The following baseline disease characteristcs were recorded in the study: 
• Duration of PNH at screening 
• Age at onset of PNH 
• Stratification factors as indicated in the IWRS system for presence of RBC/whole blood 
transfusion within the past year prior to day 1 (yes or no)  
• Stratification factor as indicated in the IWRS system for LDH levels (≤1.5 × ULN or 
>1.5 × ULN)  
• Stratification factor as indicated in the IWRS system for anti-C5 standard-of-care 
therapy taken at screening (eculizumab or ravulizumab) 
• Number of RBC/whole blood transfusion within the past year prior to day 1 (0, 1 to 14; 
>14) 
• Number of units of RBC transfused within the past year prior to day 1 (0, 1 to 14, 
>14) 
• Baseline LDH level 
• Baseline renal function (ie, Creatinine and eGFR) 
• PNH clone size 
• History of venous thromboembolism 
• Baseline hemoglobin level  
• History of aplastic anemia 
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• History of breakthrough hemolysis 
Listings will be generated for baseline disease characteristics of interest.  
6.3. 
Medical History 
Patient medical history were recorded and coded to a Preferred Term (PT) and associated 
primary System Organ Class (SOC) according to the Medical Dictionary for Regulatory 
Activities (MedDRA®). All reported patient medical history will be presented in a listing.  
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7. 
EFFICACY  
Due to early termination, efficacy variables will not be analyzed. Listings of important efficacy 
variables will be provided.  
7.1. 
Description of Efficacy Data 
7.1.1. 
Primary Efficacy Data 
LDH (Lactate Dehydrogenase) 
LDH (serum) is a lab-based measure ascertained from analysis of patients’ blood samples that is a 
measure of intravascular hemolysis. Blood samples from patients will be drawn at the first 
screening visit (V1) and all visits post-randomization (V3 – V15).  These samples will be sent to 
a lab for analysis to determine the amount of LDH in the serum (LDH value).   
Transfusion Record  
Transfusions with RBCs during the study (including the screening period) may proceed 
according to the following predefined criteria that will trigger a transfusion (referred 
subsequently as the protocol algorithm), as clinically indicated, however, the actual number of 
units to be transfused is at the discretion of the investigator: 
• Transfuse with RBCs if hemoglobin level is >7 to ≤9 g/dL with new onset or 
worsening signs or symptoms resulting from anemia that are of sufficient severity to 
warrant transfusion (Note: the onset of new or worsening signs/symptoms of anemia 
must occur post-baseline after day 1 to be considered as meeting the endpoint criteria 
for transfusion), or 
• Transfuse with RBCs if hemoglobin level is ≤7 g/dL with or without signs or 
symptoms from anemia 
LDH assessments were collected per the Schedule of Events in Section 13.1.  Listings that 
contain relevant information pertaining to all LDH and Blood Transfusions will be provided. 
7.1.2. 
Secondary Efficacy Data 
The following are secondary efficacy measures that were captured in the study:  
• Hemoglobin 
• FACIT-Fatigue Scale 
• EORTC-QLQ-C30 
The assessments were collected per the Schedule of Events in Section 13.1.  Detailed description 
of these measurements can be found in section 9.2.3 of the study protocol.   
Listings will be provided for the assessments listed above.  
 
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8. 
SUMMARY OF EXPOSURE DATA 
8.1. 
Investigational Study Drug Exposure 
Listings will be provided for IV infusions 
 and the 
number of SC injections during the OLTP for each investigational study drug.  
8.2. 
Duration of Follow-up 
Not Applicable 
8.3. 
Prior and Concomitant Medications 
Medications usage, dictionary coded by WHODD, will be classified according to the time of 
usage.  Prior medications are medications taken prior to the date of randomization with a stop 
date prior to the date of randomization. Concomitant medications are medications taken between 
the date of randomization and the EOS visit (inclusive for both dates). This includes medications 
with a start date before administration of study drug. Listings will be provided.  
8.4. 
Prior and Concurrent Procedures 
Procedures undergone by the patient, dictionary coded by MedDRA, will be classified according 
to the time of occurrence.  Prior procedures are procedures performed prior to the date of 
randomization.  Concomitant procedures are procedures performed between the date of 
randomization and the EOS visit (inclusive for both dates). Listings will be provided.  
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9. 
ANALYSIS OF SAFETY DATA 
9.1. 
Adverse Events 
All AEs will be reported and coded using Medical Dictionary for Regulatory Activities 
(MedDRA®). A listing of all AEs will be included.  
9.2. 
Laboratory Parameters 
The clinical laboratory data consists of blood chemistry, hematology, urinalysis, coagulation, 
pregnancy test and other tests and will be collected according to the Schedule Events in 
Section 13.1. 
Listings will be provided for lab tests of interest. Abnormal lab values will be noted.  
9.3. 
Vital Signs 
Body weight and vital signs (temperature, pulse, and sitting blood pressure) were collected at 
scheduled visits according to the schedule of events in Section 13.1. 
Body weight, BMI and vital signs values will be included in a listing.  
9.4. 
Electrocardiogram (ECG) 
The following standard 12-lead ECG parameters were recorded and analyzed according to the 
Schedule Events in Section 13.1: 
• Ventricular rate 
• Heart rate 
• QRS interval 
• QT corrected for heart using Fridericia’s formula (QTcF) defined as  
QTcF (ms) = QT/RR1/3  
where QT is the uncorrected QT interval measured in ms, and RR is 60/HR with HR 
being the heart rate in beats per minutes. 
• Overall ECG status along with findings.  
Listings of ECG parameters (PR interval, QT interval, QTcF interval, QRS interval, and heart 
rate [from ventricular rate]) will be provided.  
9.5. 
Other Safety Data 
Not applicable 
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9.6. 
Immunogenicity Data 
9.6.1. 
Immunogenicity Variables 
The Immunogenicity variables include ADA status and titer at nominal sampling time/visit. 
Serum samples for ADA were collected at the clinic visits specified in Section 13.1. For each 
study drug, samples positive in the ADA assay will be further characterized for ADA titers. 
9.6.2. 
Analysis of Immunogenicity Data 
9.6.2.1. 
Analysis of ADA Data 
The immunogenicity variables described in Section 9.6.1 will be summarized using descriptive 
statistics. Immunogenicity will be characterized per study drug by ADA status, ADA category 
and maximum titer observed in participants in the ADA analysis sets. For samples confirmed as 
drug specific ADA positive, but found negative at the lowest titer dilution, the lowest dilution in 
the titer assay is imputed. 
The ADA status of each participant may be classified as one of the following:  
• Positive 
• Pre-existing - If the baseline sample is positive and all post baseline ADA titers are 
reported as less than 4-fold (for anti-cemsiran) and 9-fold (for anti-pozelimab) over 
the baseline titer value 
• Negative - If all samples are found to be negative in the ADA assay. 
The ADA category of each positive participant is classified as: 
• Treatment-boosted - A positive result at baseline in the ADA assay with at least one 
post baseline titer result ≥4-fold (for anti-cemsiran) and 9-fold (for anti-pozelimab) 
over the baseline titer value  
• Treatment-emergent - A negative result or missing result at baseline with at least one 
positive post baseline result in the ADA assay. Participants that are treatment-
emergent will be further categorized as follows: 
Treatment-emergent is further sub-categorized as: 
• Persistent - A positive result in the ADA assay detected in at least 2 consecutive post 
baseline samples separated by at least a16-week post baseline period [based on 
nominal sampling time], with no ADA-negative results in-between, regardless of any 
missing samples 
• Indeterminate - A positive result in the ADA assay at the last collection time point 
only, regardless of any missing samples 
• Transient - Not persistent or indeterminate, regardless of any missing samples 
The maximum titer category of each participant is classified as: 
• Low (titer <1,000) 
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• Moderate (1,000 ≤ titer ≤ 10,000) 
• High (titer >10,000) 
The following will be summarized by treatment group and ADA titer level: 
• Number (n) and percent (%) of ADA-negative participants 
• Number (n) and percent (%) of pre-existing participants 
• Number (n) and percent (%) of treatment-emergent ADA positive participants 
− Number (n) and percent (%) of persistent treatment-emergent ADA positive 
subjects/patients 
− Number (n) and percent (%) of indeterminate treatment-emergent ADA positive 
subjects/patients 
− Number (n) and percent (%) of transient treatment-emergent ADA positive 
subjects/patients 
• Number (n) and percent (%) of treatment-boosted ADA positive participants 
Listing of all ADA titer levels will be provided for participants with pre-existing, treatment-
emergent and treatment-boosted ADA response. 
9.7. 
Pharmacokinetic Data 
Listings of relevant parameters will be provided .  
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10. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis.  
10.1. 
Definition of Baseline for Efficacy/Safety Variables 
For LDH, the baseline value is defined as follows: 
• For patients entering the study who were previously treated with eculizumab: the last 
value of the assessment in the screening period immediately preceding 
randomization. 
• For patients entering the study who were previously treated with ravulizumab: last 
value of the assessment immediately preceding their last dose of ravulizumab in the 
screening period. 
For all other efficacy/safety variables, baseline is the last value of assessment immediately 
preceding randomization.  When scores are used, this rule applies to scores, not individual 
variables. 
10.2. 
Data Handling Conventions  
In the event there are multiple assessments for the same endpoint within an analysis window, the 
assessment occurring on the day of the corresponding study visit will be utilized in the efficacy 
analysis.  In the event there is no assessment on the day of the study visit, the assessment closest 
in temporal proximity to the day of study visit will be utilized in the efficacy analysis, and will 
prioritize measurements taken pre-dose if applicable. If there are two assessments that are 
equidistant from the day of study visit (one assessment prior and one assessment after the day of 
study visit), the prior assessment will be utilized in the efficacy analysis.   
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified. When relevant, the number of patients with missing data 
is presented. 
Missing data will not be imputed in listings.  
10.3. 
Missing Data Conventions for Non-Efficacy Endpoints 
Not Applicable  
10.4. 
Assignment of Data to Visit Windows and Unscheduled Assessments 
Not Applicable 
10.5. 
Pooling of Categorical Variables for Statistical Analyses 
Not Applicable 
                                        VV-RIM-00307940-1.0 Approved - 22 Jul 2023 GMT-5:00


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Protocol: R3918-PNH-2022 
Statistical Analysis Plan 
 
Date: 18JUL2023 
 
REGENERON CONFIDENTIAL 
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11. 
TECHNICAL DETAILS PERTAINING TO INTERIM ANALYSIS 
Not applicable 
                                        VV-RIM-00307940-1.0 Approved - 22 Jul 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PNH-2022 
Statistical Analysis Plan 
 
Date: 18JUL2023 
 
REGENERON CONFIDENTIAL 
Page 24 
12. 
REFERENCES 
1. ICH. (1996, July 30). ICH Harmonized tripartite guideline: Structure and content of 
clinical study reports (E3). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
2. ICH. (1997, July 17). ICH Harmonized tripartite guideline: General considerations for 
clinical trials (E8). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
3. ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for 
clinical trials (E9). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
4. Bretz F, Maurer W, Brannath W,Posch M. A graphical approach to sequentially rejective 
multiple test procedures. Stat Med 2009; 28(4):586-604. 
5. Jong Wook Lee, Flore Sicre de Fontbrune, Lily Wong Lee Lee, Viviani Pessoa, Sandra 
Gualandro, Wolfgang Füreder, Vadim Ptushkin, Scott T. Rottinghaus, Lori Volles, Lori 
Shafner, Rasha Aguzzi, Rajendra Pradhan, Hubert Schrezenmeier, Anita Hill; 
Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to 
complement inhibitors: the 301 study. Blood 2019; 133 (6): 530–539.  
6. Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, Pessoa V, Gualandro S, Füreder W, et 
al. Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to 
complement inhibitors: the 301 study. Blood 2019; 133(6):530-539. 
7. Hillmen P, Young NS, Schubert J, Brodsky RA, Socie G, Muus P, et al. The complement 
inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 2006; 
355(12):1233-1243. 
8. Röth A, Nishimura JI, Nagy Z, Gaàl-Weisinger J, Panse J, Yoon SS, et al. The 
complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria. Blood 
2020; 135(12):912-920. 
9. Schrezenmeier H, Kulasekararaj A, Mitchell L, Sicre de Fontbrune F, Devos T, Okamoto 
S, et al. One-year efficacy and safety of ravulizumab in adults with paroxysmal nocturnal 
hemoglobinuria naïve to complement inhibitor therapy: open-label extension of a 
randomized study. Ther Adv Hematol 2020. 
10. US Food and Drug Administration (FDA). Multi‐Disciplinary Review and Evaluation 
BLA 761108 (Reference ID: 4366451).  2018. 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PNH-2022 
Statistical Analysis Plan 
 
Date: 18JUL2023 
 
REGENERON CONFIDENTIAL 
Page 25 
13. 
APPENDIX 
13.1. 
Schedule of Time and Events 
Table 1: 
Schedule of Events for the Open-Label Treatment Period 
Schedule of Events for the Open-Label Treatment Period 
Study Procedure (Visit)1 
Screening 
Period2 
Open Label Treatment Period (OLTP) 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOLTP / 
EOS  
Visit # 
V1 
V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 
V15 
Week 
Up to -6 
-2 
0 
2 
4 
6 8 10 12 16 20 24 28 32 
36 
Day 
Up to -42 -14 13 15 29 43 57 71 85 113 141 169 197 225 
253 
Window (day) 
 
+2 
 
±2 ±3 ±3 ±3 ±3 ±3 ±7 ±7 ±7 ±7 ±3 
±3 
Screening/Baseline: 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
eCOA device dispensation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FBR informed consent (optional) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genomics informed consent (optional) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medications5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B and C testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccination / revaccinate for Neisseria meningitidis6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccination against Streptococcus pneumoniae and Haemophilus influenzae 
type B (if needed) 7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis history and assessment8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Risk assessment for Neisseria gonorrhea9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient safety card for Neisseria meningitidis10 
 
 
X X X X X X X X 
X 
X 
X 
X 
X 
Randomization  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment: 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
IVRS/IWRS 
X 
 
X X X X X X X X 
X 
X 
X 
X 
X 
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Statistical Analysis Plan 
 
Date: 18JUL2023 
 
REGENERON CONFIDENTIAL 
Page 26 
Study Procedure (Visit)1 
Screening 
Period2 
Open Label Treatment Period (OLTP) 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOLTP / 
EOS  
Visit # 
V1 
V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 
V15 
Week 
Up to -6 
-2 
0 
2 
4 
6 8 10 12 16 20 24 28 32 
36 
Day 
Up to -42 -14 13 15 29 43 57 71 85 113 141 169 197 225 
253 
Window (day) 
 
+2 
 
±2 ±3 ±3 ±3 ±3 ±3 ±7 ±7 ±7 ±7 ±3 
±3 
Pozelimab and cemdisiran 
arm 
Anti-C5 standard-of-care arm: 
Eculizumab  
Anti-C5 standard-of-care arm: 
Ravulizumab  
Concomitant meds and treatment 
X 
X 
X X X X X X X X 
X 
X 
X 
X 
X 
Transfusion record update 
X 
 
X X X X X X X X 
X 
X 
X 
X 
X 
Antibiotics prophylaxis (recommended)19 
 
<----------------------------------------X--------------------------------> 
Clinical outcome assessments (COAs): 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
FACIT-Fatigue 
 
 
X X X 
 
X 
 
X X 
X 
X 
X 
X 
X 
EORTC-QLQ-C30 
 
 
X X X 
 
X 
 
X X 
X 
X 
X 
X 
X 
Safety and Anthropometric: 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
 
 
 
X 
 
X 
 
X X 
X 
X 
X 
X 
X 
Vital signs21 
X 
 
X X X X X X X X 
X 
X 
X 
X 
X 
Physical examination22 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
Electrocardiogram 
X 
 
 
 
 
 
 
 
X 
  
 
 
 
 
X 
                                        VV-RIM-00307940-1.0 Approved - 22 Jul 2023 GMT-5:00


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Statistical Analysis Plan 
 
Date: 18JUL2023 
 
REGENERON CONFIDENTIAL 
Page 27 
Study Procedure (Visit)1 
Screening 
Period2 
Open Label Treatment Period (OLTP) 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOLTP / 
EOS  
Visit # 
V1 
V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 
V15 
Week 
Up to -6 
-2 
0 
2 
4 
6 8 10 12 16 20 24 28 32 
36 
Day 
Up to -42 -14 13 15 29 43 57 71 85 113 141 169 197 225 
253 
Window (day) 
 
+2 
 
±2 ±3 ±3 ±3 ±3 ±3 ±7 ±7 ±7 ±7 ±3 
±3 
Adverse events 
X 
X 
X X X X X X X X 
X 
X 
X 
X 
X 
Breakthrough hemolysis assessment23 
X 
X 
X X X X X X X X 
X 
X 
X 
X 
X 
Laboratory Testing24: 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
Titers to measure N. meningitidis (only if required per local 
practice/regulations) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology25 
X 
 
X X X 
 
X 
 
X X 
X 
X 
X 
X 
X 
Coagulation panel 
X 
 
X X X X X X X X 
X 
X 
X 
X 
X 
Blood chemistry (long panel) including LDH26 
X 
 
X X X X X X X X 
X 
X 
X 
X 
X 
Pregnancy test (applicable patients)27 
X 
 
X 
 
X 
 
X 
 
X X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
X X X 
 
X 
 
X X 
X 
X 
 
X 
X 
Direct antiglobulin test (DAT or Coombs test) 
 
 
X 
 
X 
 
X 
 
X X 
X 
X 
 
X 
X 
Pharmacokinetics, ADA and Total C5 Sampling28: 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
Blood samples for conc. of pozelimab 
 
 
X 
 X29  
X 
 
X X 
X 
X 
X 
X 
X 
Blood samples for conc. of cemdisiran and metabolites30 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
Blood samples for conc. of eculizumab 
 
 
X X X 
 
 
 
X 
 
 
X 
 
 
X 
Blood samples for conc. of ravulizumab 
 
 
X X X 
 
 
 
X 
 
 
X 
 
 
X 
Blood samples for conc. of total C5 
 
 
X X X 
 
X 
 
X X 
X 
X 
X 
X 
X 
Blood samples for ADA of pozelimab31 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Blood samples for ADA of cemdisiran31 
 
 
X 
 
 
 
 
 
X 
 
 
X 
  
 
X 
Biomarkers: 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
                                        VV-RIM-00307940-1.0 Approved - 22 Jul 2023 GMT-5:00


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Protocol: R3918-PNH-2022 
Statistical Analysis Plan 
 
Date: 18JUL2023 
 
REGENERON CONFIDENTIAL 
Page 28 
Study Procedure (Visit)1 
Screening 
Period2 
Open Label Treatment Period (OLTP) 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOLTP / 
EOS  
Visit # 
V1 
V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 
V15 
Week 
Up to -6 
-2 
0 
2 
4 
6 8 10 12 16 20 24 28 32 
36 
Day 
Up to -42 -14 13 15 29 43 57 71 85 113 141 169 197 225 
253 
Window (day) 
 
+2 
 
±2 ±3 ±3 ±3 ±3 ±3 ±7 ±7 ±7 ±7 ±3 
±3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional pharmacogenomics (DNA AND RNA):  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
Whole blood for DNA isolation (optional genomics sub-study)33 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood for RNA isolation (optional genomics sub-study) 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
1. 
When multiple procedures are performed on the same day, the sequence of procedures is as follows: Clinical outcome 
assessments, electrocardiogram (ECG) and/or vital signs, blood collection, and study treatment administration. Patients who 
are being screened in this study (R3918-PNH-2022) who complete the R3918-PNH-2021 study will have all assessments 
performed as indicated in the SOE. Assessments common to both studies (screening visit of R3918 PNH-2022 and V1t of the 
R3918-PNH-2021) will not be duplicated.  
2. 
Additional screening visits may be needed such as to obtain LDH one day before or on the day of eculizumab or 
ravulizumab administration, repeat blood collection, vaccination, etc. 
3. 
For patients taking ravulizumab, the randomization visit should occur 4 weeks after the last administration of 
ravulizumab. 
4. 
Medical history including, transfusions, breakthrough hemolysis history, and laboratory parameters for measurement of 
hemolysis (such as LDH, bilirubin, haptoglobin, reticulocyte count, and hemoglobin) should be obtained for the past 52 weeks, 
if possible. Prior history of thrombosis and infections of the Neisseria spp. will be collected. Patients with a known C5 
mutation (ie, C5 variants R885H/C) or those who have a C5 mutation confirmed while the study is ongoing should have the 
information included as part of the patient’s medical history. Patients who are poor responders to eculizumab or ravulizumab 
treatment who have not previously had testing for a C5 mutation may be asked for a mutation analysis to be conducted locally 
as part of the study, if the patient consents to such testing.  
5. 
Including detailed eculizumab or ravulizumab administration history and Neisseria meningitidis vaccination and other 
vaccinations as applicable. 
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REGENERON CONFIDENTIAL 
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6. 
Patients will require administration with meningococcal vaccination unless documentation is provided of prior 
immunization in the past 5 years, or less than 5 years if required according to current national vaccination guidelines for 
vaccination use with complement inhibitors/local eculizumab or ravulizumab prescribing information. For patients who require 
administration with meningococcal vaccination(s) during the screening period, administration should occur preferably at least 
2 weeks prior to day 1, or at another time point according to local eculizumab or ravulizumab prescribing information/national 
guidelines.  
7. 
Vaccination for Streptococcus pneumoniae and Haemophilus influenzae type B should be initiated per current 
national/local vaccination guidelines. 
8. 
Tuberculosis history and assessment: Screening by tuberculin skin test or T-cell interferon gamma release assay may be 
performed according to local practice or guidelines at the discretion of the investigator 
9. 
A risk factor assessment for Neisseria gonorrhea will be performed in accordance with local practice/national 
guidelines, and regular testing and counseling is advised for at-risk patients. 
10. 
Patient safety card: provide the patient safety card for Neisseria meningitidis infection to the patient on day 1 or any 
other visit when needed. Site should review the instructions on the safety card with the patient at each visit.  
11. 
 
 
 
12. 
Pozelimab administration: administer study treatment to patients previously taking eculizumab or ravulizumab and 
randomized to pozelimab/cemdisiran arm.  
13. 
Cemdisiran administration: administer study treatment to patients randomized to pozelimab/cemdisiran arm.  
14. 
 
 
 
 
 
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Statistical Analysis Plan 
 
Date: 18JUL2023 
 
REGENERON CONFIDENTIAL 
Page 30 
 
 
 
15. 
 
 
 
 
 
 
16. 
 
 
 
 
 
 
17. 
Intentionally left blank 
18. 
Intentionally left blank  
19. 
Daily oral antibiotic prophylaxis against Neisseria meningitidis is recommended starting on the first day of dosing with 
study treatment and continuing until up to 52 weeks after discontinuation of pozelimab/cemdisiran. For post-treatment 
prophylaxis for eculizumab or ravulizumab follow the local prescribing information/national guidelines/local practice. If 
vaccination for Neisseria meningitidis occurs less than 2 weeks prior to day 1, then antibiotic prophylaxis must be 
administered for at least 2 weeks from the day of vaccination.  
20. 
 
 
21. 
Vital signs include temperature, sitting blood pressure, and pulse. Vital signs will be obtained pre-dose after the patient 
has been sitting quietly for at least approximately 5 minutes, where applicable.  
                                        VV-RIM-00307940-1.0 Approved - 22 Jul 2023 GMT-5:00


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Protocol: R3918-PNH-2022 
Statistical Analysis Plan 
 
Date: 18JUL2023 
 
REGENERON CONFIDENTIAL 
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22. 
Physical examination will include an evaluation of the head and neck, lungs, heart, abdomen, extremities, and skin. 
Care should be taken to examine and assess any abnormalities that may be present, as indicated by the patient’s medical 
history. 
23. 
Breakthrough hemolysis assessment: If a patient is suspected of having a breakthrough hemolysis event, then in 
addition to the required laboratory collection, additional samples for CBC, coagulation parameters, chemistry, reticulocyte 
count, total C5, CH50, drug concentrations of pozelimab/cemdisiran/eculizumab/ravulizumab (depending on the patient’s 
randomization/enrollment), and exploratory research serum and plasma will be collected unless already noted in the schedule 
of events for that visit. If the suspected event does not occur at a scheduled visit then an unscheduled visit should occur with an 
evaluation of the patient and collection of CBC, coagulation parameters, chemistry, reticulocyte count, total C5, CH50 and 
drug concentrations of pozelimab/cemdisiran/eculizumab/ravulizumab, as applicable, and exploratory research serum and 
plasma.  
24. 
During lab collection, handling and processing, the same methodology will be applied across study visits, as best as 
possible, to preserve the quality of sample and avoid hemolysis during sample processing. If the investigator or sponsor 
suspects that the lab result is not an accurate reflection of the patient’s condition, the lab sample should be repeated. Blood 
collection should always be obtained prior to study treatment administration, unless otherwise noted. The coagulation blood 
sample must always be collected first, followed immediately by the blood chemistry sample. 
25. 
Hemoglobin will be assessed as part of the hematology analysis. Hematology sample should be collected before study 
treatment administration. 
26. 
Serum LDH, CRP, and bilirubin will be assessed as part of the blood chemistry analysis. During screening, obtain 
chemistry including LDH on the day of (or if not possible, one day before) eculizumab or ravulizumab administration. On day 
1 and all subsequent visits, obtain chemistry including LDH prior to any study treatment administration.  
27. 
Pregnancy test: A serum test will be done at screening visit and a urine test will be done at all other visits.  
28. 
 
 
 
 
 
  
29. 
For patients who receive pozelimab IV infusion: obtain blood samples where permitted, prior to IV administration of 
pozelimab and also within 15 minutes after the end of the IV infusion. 
                                        VV-RIM-00307940-1.0 Approved - 22 Jul 2023 GMT-5:00


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Statistical Analysis Plan 
 
Date: 18JUL2023 
 
REGENERON CONFIDENTIAL 
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30. 
Blood samples for concentrations of cemdisiran and its metabolites will be collected, where permitted, prior to any 
study treatment administration (pre-dose) and at 1-4 hours post dose. The post dose sample may be collected at the clinic or by 
a visiting health care professional (if available). 
31. 
Blood samples for ADA will be collected, where permitted, before the administration of any study drug (pre-dose). In 
the event of suspected SAEs, such as anaphylaxis or hypersensitivity, additional ADA and PK samples may be collected at or 
near the onset of the event. 
32. 
  
33. 
Whole blood samples for DNA extraction (optional) should be collected on day 1 (pre dose) but can be collected at a 
later study visit. 
 
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