Clinical trial NCT04209634
Conditions: CD55-deficient Protein-losing Enteropathy CHAPLE
Keywords: CD55-deficient PLE complement hyperactivation, angiopathic thrombosis, protein-losing enteropathy (CHAPLE disease)
Sponsor: Regeneron Pharmaceuticals
Start date: 2020-01-27; Completion date: 2024-05-02
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of the study is to determine the effect of pozelimab on active CD55-deficient protein-losing enteropathy (PLE; CHAPLE).

The secondary objectives of the study are:

* To evaluate the safety and tolerability of pozelimab in patients with CD55-deficient PLE disease
* To evaluate the effect of pozelimab on CD55-deficient PLE (both patients with active disease at baseline and those with inactive disease on eculizumab, switching to pozelimab)
* To determine the effects of pozelimab on albumin and other serum proteins (total protein, immunoglobulins)
* To determine the effects of pozelimab on ascites
* To determine the effects of pozelimab on stool consistency
* To determine the effect of pozelimab on health-related quality of life
* To determine the effect of pozelimab on lab abnormalities observed in CD55-deficient PLE such as hypertriglyceridemia, thrombocytosis, and hypovitaminosis B12
* To describe the effects of pozelimab on the sparing of concomitant medications and reduction in hospitalization days
* To determine the effects of pozelimab on growth
* To characterize the concentration of pozelimab in patients with CD55-deficient PLE
* To assess the incidence of treatment-emergent ADA for pozelimab in patients with CD55-deficient PLE disease

Detailed description:

Arms: arm 1: Patients aged 1 year and older with a clinical diagnosis of CD55-deficient PLE disease
Interventions: intervention 1: Pozelimab
Intervention descriptions: intervention 1: Single loading intravenous (IV) dose on day 1, then fixed doses sub-cutaneous (SC) (based on body weight) QW (±2 days) over the treatment period.

Protocol documents:
Prot_000.pdf: 
IND: 142063 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
AN OPEN-LABEL EFFICACY AND SAFETY STUDY OF POZELIMAB 
IN PATIENTS WITH CD55-DEFICIENT PROTEIN-LOSING 
ENTEROPATHY (CHAPLE DISEASE) 
Compound: 
REGN3918 (Pozelimab) 
Clinical Phase: 
2/3 
Protocol Number: 
R3918-PLE-1878 
Protocol Version: 
R3918-PLE-1878 Amendment 6 
Amendment 6 Date of Issue: 
See appended electronic signature page 
Amendment 5 Date of Issue: 
18 Feb 2021 
Amendment 4 Date of Issue: 
09 Jun 2020 
Amendment 3 Date of Issue: 
17 Mar 2020 
Amendment 2 Date of Issue: 
16 Dec 2019 
Amendment 1 Date of Issue: 
08 May 2019 
Original Date of Issue: 
02 Jan 2019 
Medical /Study Director: 
 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
 
VV-RIM-00158650-1.0 Approved - 01 Feb 2022 GMT-5:00
NCT04209634


Clinical Study Protocol 
 
R3918-PLE-1878 Amendment 6 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 2 of 109 
CONFIDENTIAL 
 
 
 
 
                                        VV-RIM-00158650-1.0 Approved - 01 Feb 2022 GMT-5:00


Clinical Study Protocol 
 
R3918-PLE-1878 Amendment 6 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 3 of 109 
CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 6 
The main purpose of this amendment is to extend the study duration to approximately 3 years. 
Description of Change 
Brief Rationale 
Sections Changed  
The duration of the treatment period is 
extended from 104 weeks to 144 weeks, 
with an end-of-study follow-up at 
week 164, to a total duration of 
approximately 3 years 
The longer term efficacy and 
safety of pozelimab treatment in 
CD55-deficient PLE are 
unknown; extending the on-
treatment study period allows for 
description of a third year of 
treatment 
Clinical Study Protocol Synopsis: 
Study Design, Study Duration 
Section 6.1 Study Description and 
Duration  
Figure 1 : Study Flow Diagram 
Section 9.1.1 Footnotes for the 
Schedule of Events Table: #1 , 
#12  
Section 9.1.2 Early Termination 
Visit 
Updated endpoints and analyses to 
include the full 144-week study treatment 
period 
Due to the extension of study 
duration, the end of treatment is 
at week 144 rather than 
week 104. Endpoints and 
analyses are updated to reflect 
this change 
Clinical Study Protocol Synopsis: 
Objectives, Endpoints 
Section 2.2 Secondary Objectives 
Section 5.2 Secondary Outcomes 
Section 5.3 Exploratory Outcomes 
Section 11.4.3.2 Secondary 
Efficacy Analysis 
Added a sample collection time point for 
pozelimab ADA at week 96 
The sampling schedule is 
adjusted due to the extension of 
the study duration 
Table 1 Schedule of Events 
Removed references to an open-label 
extension study 
 
Text specifying the mechanism 
of post trial access has been 
deleted as the Sponsor is 
evaluating a number of options 
regarding this provision 
Clinical Study Protocol Synopsis: 
Study Design 
Section 6.1 Study Description and 
Duration  
Section 9.1.2 Early Termination 
Visit 
Updated confidentiality statement 
This is a template language 
update for sponsor documents 
Title page 
Editorial changes and corrections 
These are minor corrections 
Throughout document 
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Clinical Study Protocol 
 
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Page 4 of 109 
CONFIDENTIAL 
Amendment 5 
The main purpose of this amendment is to remove the 1-year limitation on the study enrollment 
period and to align with prior correspondence with a regulatory agency. 
Description of Change 
Brief Rationale 
Sections Changed  
Removed the 1-year limitation on the 
recruitment period. 
This change was made to increase 
flexibility for study recruitment 
due to enrollment holds caused 
by the global pandemic. 
Clincal Study Protocol Synopsis: 
Study Design, Sample Size 
Section 6.1 Study Description 
and Duration  
Section 7.1 Number of Patients 
Planned 
The definition of evaluable for 
improvement for facial edema and 
peripheral edema was changed to require a 
severity of at least 3 points out of 5 at 
baseline rather than 2 points out of 5 at 
baseline. 
 
This was a correction on the 
definition of an evaluable patient 
for facial and peripheral edema 
assessments. The 5-point scale 
used would not be able to 
accommodate a 2-point 
worsening for a patient with a 
score of 2 at baseline. 
Clincal Study Protocol Synopsis: 
Outcomes/Endpoints 
Section 5.1 Primary Outcome 
 
For the primary endpoint, the definition 
was revised for improvement and 
worsening. An increase or decrease of 
25 points or more, respectively, will be 
used for improvement or worsening on the 
Pediatric Quality of Life Inventory 
(PedsQL) gastrointestinal (GI) Symptoms 
Scale for the stomach pain and hurt sub-
scale. 
For the secondary endpoint on 
improvement in each patient’s most 
bothersome sign/symptom, revised 
definition for improvement to an increase 
of 25 points or more on the PedsQL GI 
Symptoms Scale: nausea and vomiting 
subscale, and the definition for patients 
who are evaluable for improvement was 
revised to patients with a score of ≤75 at 
baseline. Correspondingly, for the diarrhea 
sub-scale, worsening is defined as a 
decrease of 25-points or more. 
This change was made to address 
a comment from a regulatory 
agency regarding a more 
clinically meaningful within-
patient change in scores. A 25-
point change on the transformed 
score reflects a 1-category change 
on the raw score scale. 
 
Corresponding changes were 
made for alignment to a related 
secondary endpoint on 
improvement in each patient’s 
most bothersome sign/symptom 
and secondary endpoints on the 
proportion of patients who 
maintain disease control. 
Clinical Study Protocol Synopsis: 
Outcomes/Endpoints 
Section 3.2.1 Rationale for Study 
Design 
Section 5.1 Primary Outcome 
Section 5.2 Secondary Outcomes 
 
Removed screening value from the 
definition of baseline for facial and 
peripheral edema. The baseline value will 
be used. 
This change was made to align 
the definitions of baseline for 
edema with those for albumin and 
symptom scales. 
Section 11.4.3.1 Primary Efficacy 
Analysis 
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Page 5 of 109 
CONFIDENTIAL 
Description of Change 
Brief Rationale 
Sections Changed  
Added time periods (12-48, 12-104, [new] 
24-48, [new] 48-104 weeks) to secondary 
endpoints on maintenance of control: 
• Proportion of patients with active 
disease at baseline who maintain disease 
control 
• Proportion of patients with inactive 
disease on eculizumab at baseline who 
maintain disease control 
These analyses were requested by 
a regulatory agency to evaluate 
durability of response during a 
review of the study analysis plan. 
Clinical Study Protocol Synopsis: 
Outcomes/Endpoints  
Section 5.2 Secondary Outcomes 
Replaced bowel movement with PedsQL 
GI Symptoms Scales diarrhea subscale in 
the definition of maintenance of disease 
control. A definition of worsening based 
on the PedsQL GI Symptoms Scales 
diarrhea subscale is provided. 
This correction was necessary as 
bowel movement e-diary is not 
continued after week 24. The 
definition of worsening for the 
PedsQL GI Symptoms Scales 
diarrhea subscale is provided. 
Clinical Study Protocol Synopsis: 
Outcomes/Endpoints  
Section 5.2 Secondary Outcomes 
 
Removed language to exclude patients 
without an evaluable core symptom from 
the primary efficacy analysis. 
This language was removed to 
align with regulatory agency 
feedback. 
Clinical Study Protocol Synopsis: 
Statistical Plan 
Section 11.4.3.1 Primary Efficacy 
Analysis 
Included details of evaluable and 
non-evaluable patients for the secondary 
efficacy analysis. 
Moved details on the identification of a 
patient’s most bothersome sign/symptom 
to secondary efficacy analysis. 
Details were included from the 
study statistical analysis plan. 
 
The text did not pertain to the 
primary efficacy analysis and was 
moved to the relevant section. 
Clinical Study Protocol Synopsis: 
Statistical Plan 
Section 11.4.3.1 Primary Efficacy 
Analysis  
Section 11.4.3.2 Secondary 
Efficacy Analysis 
Corrected timing of primary analysis to be 
conducted when patients complete 
24 weeks of treatment. 
This correction was to align the 
first database lock with the 
primary endpoint at week 24. 
Clinical Study Protocol Synopsis: 
Study Design 
Section 6.1 Study Description 
and Duration 
Section 11.6 Timing of Analyses 
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Clinical Study Protocol 
 
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Page 6 of 109 
CONFIDENTIAL 
Amendment 4 
The following table outlines the changes made to the protocol and the affected sections: 
Description of Change 
Brief Rationale 
Sections Changed  
Allowed an extended screening period up to 
approximately 10 weeks for patients who: 
(1) require additional time to complete 
meningococcal vaccinations  
(2) must physically relocate to the vicinity 
of a study center 
(3) are pending their screening laboratory 
results 
(4) have other requirements, which will be 
evaluated on a case by case basis after 
a discussion between the sponsor and 
investigator. 
This change allows flexibility 
in the screening period for 
patients who have extenuating 
circumstances but are 
otherwise eligible to participate 
in the study. 
Clinical Study Protocol Synopsis: 
Study Design 
Section 6.1 Study Description and 
Duration 
Figure 1 Study Flow Diagram 
Section 9.1.1 Footnotes for the 
Schedule of Events Table, #29  
Section 9.2.1 Procedures 
Performed Only at the 
Screening/Baseline Visit 
Revised exclusion criterion and study 
procedures to clarify that patients who are 
appropriately treated for an intercurrent 
illness (such as resolution of an infection) 
may be rescreened. 
This change clarifies the 
language about rescreening 
patients who had an 
intercurrent illness during 
screening. 
Section 7.2.2 Exclusion Criteria, 
#6 
Section 9.2.1 Procedures 
Performed Only at the 
Screening/Baseline Visit 
Incorporated exclusion criterion on 
hepatitis (and removed as a standalone 
exclusion), stating that viral hepatitis status 
should be determined by means of the 
patient’s medical history. 
Clarified that testing to establish activity 
status of hepatitis B or C may be performed 
at the discretion of the investigator. 
This change clarifies that 
hepatitis screening is based on 
medical history, but optional 
hepatitis testing may be 
performed if warranted to 
determine eligibility. 
Section 7.2.2 Exclusion Criteria, 
#14 (revised), #21 (removed) 
Table 1 Schedule of Events 
Section 9.1.1 Footnotes for the 
Schedule of Events Table, #8 
Section 9.2.1 Procedures 
Performed Only at the 
Screening/Baseline Visit 
Added PGIC and CGIC assessments at 
week 48. 
This change is a request from a 
health agency. 
Table 1 Schedule of Events 
 
Added clinical outcome assessments 
(CGIS, CGIC, PGIS, PGIC, and PedsQL 
questionnaires) at week 12. 
This change allows an analysis 
of clinical outcome 
assessments at week 12 as 
requested by a health agency. 
Table 1 Schedule of Events 
Revised sample collection for 
immunogenicity assessment from week 96 
to week 104 (end of treatment). 
This change aligns 
immunogenicity analysis with 
other end of treatment 
assessments. 
Table 1 Schedule of Events 
Added time point for exit interview to be 
performed at early termination. 
This change ensures that an 
exit interview is performed if a 
patient discontinues the study 
prior to the primary analysis at 
week 24 
Table 1 Schedule of Events 
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Page 7 of 109 
CONFIDENTIAL 
Description of Change 
Brief Rationale 
Sections Changed  
Included definitions for improvement in 
nausea, vomiting, and stool consistency for 
efficacy endpoint. 
This change provides 
additional detail for the 
analysis of efficacy endpoints 
as described in the Statistical 
Analysis Plan (v2.0). 
Clinical Study Protocol Synopsis: 
Outcomes/Endpoints  
Section 5.2 Secondary Outcomes 
Clarified the secondary endpoint on stool 
consistency to specify the parameter to be 
analyzed (number of days per week with 
≥1 bowel movement of loose/watery 
consistency) 
This change provides a more 
precise description of the 
secondary endpoint on stool 
consistency as described in the 
Statistical Analysis Plan (v2.0). 
Clinical Study Protocol Synopsis: 
Outcomes/Endpoints  
Section 5.2 Secondary Outcomes 
Increased the home dosing window to 
±2 days 
This change provides more 
flexibility for countries with 
2-day national holidays. 
Clinical Study Protocol Synopsis: 
Study Design, Treatment  
Section 6.1 Study Description and 
Duration 
Section 8.2 Drug Administration 
Section 9.1.1 Footnotes for the 
Schedule of Events Table, #1 
Added language that, if a patient becomes 
pregnant during the study, the benefits and 
risks for the patient should be assessed and 
discussed with the medical monitor to 
determine whether study treatment should 
be continued. 
This change provides guidance 
in the event that a patient 
becomes pregnant while on 
treatment. 
Section 8.6.2.1 Reasons for 
Permanent Discontinuation of 
Study Drug 
Section 10.1.3 Events that Require 
Expedited Reporting to Sponsor 
Included language to provide flexibility in 
study procedures to address the continuity 
of study conduct during the COVID-19 
pandemic. 
This language addresses 
changes to study conduct due 
to impact from the COVID-19 
pandemic, including screening 
and study visits.  
Section 3.2.3.1 Study Conduct in 
Response to COVID-19 (new) 
Section 9.1 Schedule of Events 
Revised description of the trained 
interviewer who will conduct concept 
elicitation and exit interviews to “a trained 
external or internal interviewer”. 
This is a correction. A trained 
interviewer will conduct the 
interviews. 
Section 9.2.3.3 Clinical Outcome 
Assessments 
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Page 8 of 109 
CONFIDENTIAL 
Amendment 3 
The following table outlines the changes made to the protocol and the affected sections: 
Description of Change 
Brief Rationale 
Sections Changed  
Included an exception to allow patients 
under 6 years of age presenting with life-
threatening disease to be enrolled into the 
study prior to the availability of week 12 
data from the first 2 patients. The decision 
to allow exceptions will be made in 
conjunction with the medical director, 
steering committee, and will require 
approval from senior Regeneron medical 
staff and Ethics Committee/Institution 
Review Board. Depending on local policy, 
input from health authority may be sought 
before proceeding. 
This change allows the 
enrollment of very young 
patients with life-threatening 
disease in exceptional cases.  
Clinical Study Protocol Synopsis: 
Study Design, Target Population 
Section 3.2.1 Rationale for Study 
Design 
Section 6.1 Study Description and 
Duration 
Section 7.2 Study Population 
Section 7.2.1 Inclusion Criteria, #1  
 
Removed prohibition on intravenous 
albumin infusions during screening. This 
bullet has been moved to Section 8.10.2 
Permitted Medications. 
Albumin infusion is clinically 
appropriate for patients with 
very severe disease and 
stopping the infusions in such 
cases could result in 
catastrophic edema with 
hemodynamic compromise.  
Section 8.10.1 Prohibited 
Medications 
Section 8.10.2 Permitted 
Medications 
 
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Clinical Study Protocol 
 
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Page 9 of 109 
CONFIDENTIAL 
Amendment 2 
The following table outlines the changes made to the protocol and the affected sections: 
Change and Rationale for Change 
Sections Changed  
Revised primary endpoint to address health authority 
comments: 
• Revised success criteria for normalization of serum 
albumin to include requirements for maintenance 
within normal range without the need for albumin 
infusion 
• Removed stool consistency, clinician global 
impression of severity, and patient/caregiver global 
impression of severity to limit the number of 
clinical components.  
• Provided pre-defined responder thresholds for the 
4 prevalent aspects of disease selected for the 
primary endpoint (bowel movement frequency, 
peripheral edema, facial edema, and abdominal 
pain frequency).  
Clinical Study Protocol Synopsis: Objectives, 
Outcomes/Endpoints, Statistical Plan  
Section 2.1 Primary Objectives 
Section 3.2.1 Rationale for Study Design 
Section 5.1 Primary Outcomes 
Section 11.1 Statistical Hypothesis 
Section 11.4.3.1 Primary Efficacy Analysis 
Added a secondary endpoint to evaluate improvement in 
the patient’s most bothersome symptom, as determined 
prior to baseline using a concept elicitation interview. 
This change was made to address health authority 
comments. 
Clinical Study Protocol Synopsis: Outcomes/Endpoints, 
Statistical Plan  
Section 5.2 Secondary Outcomes 
Section 9.2.3.3 Clinical Outcome Assessments 
Added a secondary objective and endpoints to evaluate 
maintenance of efficacy for patients with active disease 
at baseline (at weeks 48 and 104) as well as the 
subgroup of patients with inactive disease who switched 
from eculizumab to pozelimab at baseline (at weeks 24, 
48, and 104). Maintenance of disease control is based 
on normalization of serum albumin, no worsening of 
symptoms, and no increase of dosage of concomitant 
medication for the treatment of PLE. Medications 
considered concomitant medications for the treatment of 
PLE are clarified. This change was made to address 
health authority comments. 
Clinical Study Protocol Synopsis: Objectives,  
Outcomes/Endpoints 
Section 2.2 Secondary Objectives 
Section 5.2 Secondary Outcomes 
Section 8.10.2 Permitted Medications 
Section 11.4.3.2 Secondary Efficacy Analysis 
Increased minimum sample size to 6 patients and 
revised the study success criterion to show that at least 
4 out of 6 patients with active disease are responders. 
The 90% confidence interval (CI) for 4 out of 
6 responders is [0.27, 0.94]. Patients with fewer than 
5 available albumin measurements between week 12 
and week 24 will be considered non-evaluable for the 
primary endpoint. This change was made to address 
health authority comments. 
Clinical Study Protocol Synopsis: Study Design, 
Sample Size, Statistical Plan 
Section 6.1 Study Design 
Section 7.1 Number of Patients Planned 
Section 11.2 Justification of Sample Size 
Section 11.4.3.1 Primary Efficacy Analysis 
Section 11.6 Timing of Analyses 
Clarified baseline definitions for the primary efficacy 
analysis. This change was made to address health 
authority comments 
Section 11.4.3.1 Primary Efficacy Analysis 
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CONFIDENTIAL 
Change and Rationale for Change 
Sections Changed  
The following outcome assessments were moved from 
the primary and secondary outcomes to exploratory 
assessments: 
• Patient/caregiver assessment of severity of disease 
• Patient/caregiver assessment of change 
• Physician assessment of severity of disease 
• Physician assessment of change 
This change was made to address health authority 
comments. 
Section 2.3 Exploratory Objectives 
Section 5.3 Exploratory Outcomes 
Added Haemophilus influenzae and pneumococcal 
vaccinations as part of study pre-treatment 
requirements, unless the patient has adequate 
documentation of prior administration. This change was 
made to address health authority comments. 
Section 6.1 Study Description and Duration 
Section 8.3.1 Vaccinations 
Section 9.2.2 Study Drug Administration 
Included details regarding the composition of the 
steering committee. This change was made to address 
health authority comments. 
Section 6.3.1 Steering Committee 
Included additional details to help standardize physician 
assessment of edema and facial edema. Assessment of 
abnormal findings of facial edema, peripheral edema, 
and ascites should be accompanied by clinical 
photography, which will be read centrally by an 
independent physician blinded to the time point at 
which the photograph was taken. This change was made 
to address health authority comments. 
Clinical Study Protocol Synopsis: Statistical Plan  
Section 9.1.1 Footnotes for the Schedule of Events, #15  
Section 9.2.3.2 Physician Assessment of Edema and 
Ascites 
Section 11.4.3.1 Primary Efficacy Analysis 
Added individual patient stopping rules and study 
stopping rules. This change was made to address health 
authority comments. 
Section 6.1.1 Study Stopping Rules [new section] 
Section 6.1.1.1 Individual Patient Stopping Rules [new 
section] 
Section 6.1.1.2 Study Stopping Criteria [new section] 
Added a new footnote to allow for early monitoring of 
anti-drug antibody (ADA) response. This change was 
made to address health authority comments. 
Table 1 Schedule of Events  
Section 9.1.1 Footnotes for the Schedule of Events, #28   
(new footnote)  
Reordered effect on stool consistency as a secondary 
objective. This assessment was originally part of the 
primary objective. 
Clinical Study Protocol Synopsis: Objectives, 
Outcomes/Endpoints, Statistical Plan  
Section 2.2 Secondary Objectives 
Strengthened rationale for study design and revised to 
align with other changes to the protocol. 
Section 3.2.1 Rationale for Study Design 
Included additional details regarding clinical outcome 
assessments (concept elicitation interview and exit 
interview). 
Section 9.2.3.3 Clinical Outcome Assessments 
 
Revised secondary endpoint on total complement 
activity (CH50) for clarity. 
Clinical Study Protocol Synopsis: Outcomes/Endpoints 
Section 5.2 Secondary Outcomes 
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CONFIDENTIAL 
Change and Rationale for Change 
Sections Changed  
Removed the exclusion of patients with allergy or 
hypersensitivity to doxycycline as the incidence of 
serious hypersensitivity reactions is very low.  Exposure 
with Regeneron antibody administration is lower than 
levels of exposure from animal meat, milk, and fish. 
Section 7.2.2 Exclusion Criteria, #13  
Revised list of exploratory biomarkers and removed 
sampling time points to reduce the amount of blood 
volume collected per patient. 
Section 4.5 Exploratory Biomarker Variables 
Section 5.3 Exploratory Outcomes 
Table 1 Schedule of Events  
Section 9.1.1 Footnotes for the Schedule of Events, #24 
Section 9.2.7 Pharmacodynamic and Exploratory 
Biomarker Procedures 
Added C-reactive protein to routine chemistry 
laboratory analysis to monitor systemic inflammation. 
Section 9.2.4.4 Laboratory Testing 
Revised language to allow serum or urine pregnancy 
testing per local practice, and clarified that pregnancy 
testing is mandatory at screening and at baseline.  
Table 1 Schedule of Events  
Section 9.1.1 Footnotes for the Schedule of Events, #22  
Section 9.2.4.4 Laboratory Testing 
Added a note to assess for fractionated bilirubin if the 
total bilirubin is above the upper limit of normal. 
Section 9.2.4.4 Laboratory Testing 
Revised to allow the sponsor to be consulted regarding 
the interpretation of electrocardiograms (ECGs).   
Section 9.2.4.3 Electrocardiogram 
Updated REGN3918 with approved name, pozelimab 
Section 8.1 Investigational Treatment 
Clarified that samples for drug concentration and ADA 
analyses will be collected prior to study drug 
administration. In addition, samples for drug 
concentration and ADA analyses will be collected in the 
event of anaphylactic reactions, serious adverse events, 
or severe injection site reactions.  
Table 1 Schedule of Events  
Section 9.1.1 Footnotes for the Schedule of Events, #27 
(new footnote)  
Section 9.2.5 Drug Concentration and Measurements 
Revised to allow the storing of samples that are positive 
for ADA for further analysis when a neutralizing 
antibody (NAb) assay is available. 
Section 4.4 Immunogenicity Variables 
Section 9.2.6 Anti-Drug Antibody Measurements and 
Samples 
Clarified that albumin infusions may be permitted as 
described in Section 8.10.1, Prohibited Medications. 
Patients who receive an albumin infusion between 
week 12 and week 24 will be considered a non-
responder for the primary endpoint. 
Clinical Study Protocol Synopsis: Outcomes/Endpoints  
Section 5.2 Secondary Outcomes 
Added a section header to improve organization of 
statistical section related to the timing of analyses. 
Section 11.6 Timing of Analyses (new section header) 
Updated immunogenicity-related sections based on 
updates to the protocol template language.  
Section 2.2 Secondary Objectives 
Section 4.4 Immunogenicity Variables 
Section 11.3.4 Immunogenicity Analysis Sets 
Section 11.4.6 Analysis of Immunogenicity Data 
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Change and Rationale for Change 
Sections Changed  
Minor corrections 
Section 1 Introduction 
Section 3.2.1 Rationale for Study Design 
Section 3.2.3 Risk-Benefit Assessment 
Section 4.2 Outcome Variables 
Section 7.1 Number of Patients Planned 
Section 7.2 Exclusion Criteria, #3  
Table 1 Schedule of Events  
Section 9.2.1 Procedures Performed Only at the 
Screening/Baseline Visit 
Section 9.2.3.3 Clinical Outcome Assessments 
Section 9.2.4.4 Laboratory Testing 
Section 10.2.5 Severity 
Section 19 References 
Throughout document 
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Clinical Study Protocol 
 
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CONFIDENTIAL 
Amendment 1 
The following table outlines the changes made to the protocol and the affected sections: 
Change and Rationale for Change 
Sections Changed  
Provided additional details pertaining to the background 
of the disease and the study drug. 
Section 1 Introduction 
Section 3.2.1 Rationale for Study Design 
Study objectives, study outcomes/endpoints, and study 
design revised to include clinical outcomes as part of 
the primary analysis in keeping with Health Authority 
advice. 
 
Clinical Study Protocol Synopsis: Objectives, Study 
Design, Outcomes/Endpoints, Statistical Plan 
Section 2 Study Objectives 
Section 3.2.1 Rationale for Study Design 
Section 5 Primary and Secondary Outcomes 
Section 6.1 Study Description and Duration 
Section 7.1 Number of Patients Planned 
Table 1 Schedule of Events 
Section 9.1.1 Footnotes for the Schedule of Events 
Table, footnote 8 
Section 9.2.3.3 Clinical Outcome Assessments 
Section 11.1 Statistical Hypothesis 
Section 11.2 Justification of Sample Size 
Section 11.4.3.1 Primary Efficacy Analysis 
Section 11.5 Interim Analysis 
Amended study population to begin enrollment with 
older pediatric patients in order to mitigate the potential 
for risk in very young patients.  
Additionally, for patients switching from eculizumab, 
removed 3-month washout requirement to mitigate risks 
associated with the discontinuation of treatment. 
Section 3.2.1 Rationale for Study Design 
Section 6.1 Study Description and Duration 
Section 7.2 Study Population 
Section 7.2.1 Inclusion Criteria 
 
Screening procedures amended to remove nasal and 
throat swab screening for Nesseria meningitidis. 
Screening procedures amended to allow genetic testing 
for Inclusion Criterion #2 to be performed at screening 
if needed. 
Section 7.2.2 Exclusion Criterion #1  
Table 1 Schedule of Events 
Section 9.1.1 Footnotes for the Schedule of Events 
Table, footnote 5 
Section 9.2.1 Procedures Performed Only at the 
Screening/Baseline Visit 
Additional blood samples collected for laboratory 
analyses, enabled by optimization of blood volume 
requirements. 
Section 4.5 Exploratory Biomarker Variables 
Table 1 Schedule of Events 
Section 9.2.4.4 Laboratory Testing 
Section 9.2.7 Pharmacodynamic and Exploratory 
Biomarker Procedures 
Provide updated information about study drug. 
Section 8.1 Investigational Treatment 
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Change and Rationale for Change 
Sections Changed  
For consistency across the pozelimab development 
program, added exclusion criteria for hepatitis B/C and 
tuberculosis. 
Section 7.2.2 Exclusion Criteria #21 and #22  
Table 1 Schedule of Events 
Section 9.1.1 Footnotes for the Schedule of Events 
Table, footnote 7 (added) 
Section 9.2.1 Procedures Performed Only at the 
Screening/Baseline Visit 
For consistency across the pozelimab development 
program, amended follow-up period to 21 weeks after 
the last dose of study drug. 
Section 7.2.2 Exclusion Criteria 
Section 8.3.2 Oral Antibiotics 
Section 9.1.2 Early Termination Visit 
Section 11.4.4.1 Adverse Events 
For consistency across the pozelimab development 
program, revised language regarding recommended risk 
mitigation strategies for meningococcal vaccinations, 
oral antibiotic prophylaxis, and risk assessment of 
Neisseria gonorrhea. 
Section 6.1 Study Description and Duration 
Section 8.3.2 Oral Antibiotics 
Section 8.4 Risk Management of Neisseria Gonorrhea 
Table 1 Schedule of Events 
Section 9.1.1 Footnotes for the Schedule of Events 
Table, footnotes 6 and 9 
For consistency across the pozelimab development 
program, included clarification on methods of 
contraception. 
Section 7.2.2 Exclusion Criteria #20  
Revised sections with updated sponsor protocol 
template language for consistency with current 
processes. 
Section 4.4 Immunogenicity Variables 
Section 10 Safety Evaluation and Reporting 
Section 12 Quality Control and Quality Assurance 
Section 13.5 Clinical Study Data Transparency (added) 
Section 14 Protocol Amendments 
Corrected numbering of study days and updated 
Schedule of Events to reflect changes made in this 
amendment. 
Table 1 Schedule of Events 
Throughout document 
Revised to add clarification or correct inconsistencies 
Section 4.2 Outcome Variables 
Section 8.2 Drug Administration 
Section 8.6.1 Dose Modification 
Section 9.2.3.1 Serum Albumin, Total Protein, and 
Immunoglobulin 
Section 9.2.3.2 Physician Assessment of Edema and 
Ascites 
Section 9.2.4.2 Physical Examination and Body Weight 
Throughout document 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
An Open-Label Efficacy and Safety Study of Pozelimab in Patients with 
CD55-Deficient Protein-Losing Enteropathy (CHAPLE Disease) 
Site Locations 
 
Principal Investigator 
Multiple International Sites 
 
Objectives 
The primary objective of the study is to determine the effect of pozelimab on 
active CD55-deficient protein-losing enteropathy (PLE; CHAPLE), as 
measured by: 
1. Normalization of serum albumin, and 
2. Improvement in the following clinical outcomes that are evaluable 
for improvement at baseline, without worsening of the others, after 
24 weeks of treatment (assessed at week 24):  
• 
Daily bowel movement frequency  
• 
The presence and severity of facial or peripheral edema 
• 
The patient/caregiver assessment of abdominal pain frequency 
The secondary objectives of the study are: 
• 
To evaluate the safety and tolerability of pozelimab in patients 
with CD55-deficient PLE disease 
• 
To evaluate the effect of pozelimab on CD55-deficient PLE 
(both patients with active disease at baseline and those with 
inactive disease on eculizumab, switching to pozelimab) 
• 
To determine the effects of pozelimab on albumin and other 
serum proteins (total protein, immunoglobulins) 
• 
To determine the effects of pozelimab on ascites 
• 
To determine the effects of pozelimab on stool consistency 
• 
To determine the effect of pozelimab on health-related quality 
of life 
• 
To determine the effect of pozelimab on lab abnormalities 
observed in CD55-deficient PLE such as hypertriglyceridemia, 
thrombocytosis, and hypovitaminosis B12 
• 
To describe the effects of pozelimab on the sparing of 
concomitant medications and reduction in hospitalization days 
• 
To determine the effects of pozelimab on growth 
• 
To characterize the concentration of pozelimab in patients 
with CD55-deficient PLE 
• 
To assess the occurrence of anti-drug antibody (ADA) for 
pozelimab in patients with CD55-deficient PLE 
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Study Design 
R3918-PLE-1878 is an open label, single arm, 144-week treatment study in 
patients aged 1 year and older with active clinical signs and symptoms of 
CD55-deficient PLE/CHAPLE disease, and a CD55 loss-of-function 
mutation detected by genotype analysis (frameshift, nonsense mutations). In 
the case of missense or suspected splice site mutations, CD55-deficient PLE 
is to be confirmed by flow cytometry of peripheral blood cells. The first 
2 patients enrolled will be of age 6 years or older (exception will be made for 
patients under 6 years of age with life-threatening disease). 
A minimum of 6 patients with active PLE will be enrolled, up to 
approximately 20 patients. The primary analysis will occur when 
approximately 6 patients with active PLE have received 24 weeks of 
treatment. Subsequent analyses will occur 1 and 2 years after the first dose in 
the last patient enrolled. 
The study consists of a screening period (up to 4 weeks [or up to 10 weeks 
for patients with extenuating circumstances]) followed by a 144-week 
treatment period (from week 0 to week 144, with final dose at week 143), and 
a follow-up period (from week 145 to week 164).  
Patients will be given a single loading dose of pozelimab 30 mg/kg 
intravenously (IV) on day 1, then fixed doses subcutaneously (SC) (based on 
body weight) QW (±2 days) over the treatment period.  
Only patients with active PLE will be included in the primary analysis. Active 
PLE is defined as hypoalbuminemia of less than or equal to 3.2 g/dL within 
the screening period, and within the last 6 months, at least 7 days (which do 
not have to be consecutive) of 1 or more of the following symptoms or signs: 
diarrhea, vomiting, abdominal pain, peripheral or facial edema, an episode of 
infection with concomitant hypogammaglobulinemia, or a new thrombotic 
event.  
Study Duration 
The duration of the study for a patient is approximately 165 weeks (from 
week 0 to week 164), excluding the screening period. 
End of Study Definition 
The end of study is defined as the last visit of the last patient. 
Population 
 
 
Sample Size: 
A minimum of 6 patients with active PLE will be enrolled, up to 
approximately 20 patients.  
Eligible patients with inactive PLE may also be enrolled, but their data will 
not be included in the primary analysis. 
 
Target Population: 
Patients aged 1 year and older with a clinical diagnosis of CD55-deficient 
PLE disease, with CD55 loss of function mutation determined by genetic 
analysis (frameshift, nonsense mutations) and confirmed (only necessary in 
the case of missense or suspected splice site mutations) by flow cytometry or 
western blotting CD55 on peripheral blood cells. The first 2 patients must be 
aged 6 years and older (exception will be made for patients under 6 years of 
age with life-threatening disease). 
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Treatment 
 
 
Study Drug 
 
Dose/Route/Schedule: 
Pozelimab 
Patients will be given a single loading dose of pozelimab 30 mg/kg IV on 
day 1, then fixed doses SC (based on body weight) QW (±2 days) over the 
treatment period. 
Outcomes/Endpoints 
 
 
Primary: 
The primary endpoint at week 24 is the proportion of patients with active 
disease at baseline achieving both of the following: 
• 
Normalization of serum albumin, defined as  
− 
serum albumin within the normal range at at least 70% of 
measurements between week 12 and week 24, and 
− 
no single albumin measurement of <2.5 g/dL between 
week 12 and week 24, and 
− 
no requirement for albumin infusion between week 12 and 
week 24  
• 
Improvement in the following clinical outcomes that were evaluable 
for improvement at baseline, with no worsening of the others (ie, 
those not evaluable for improvement) at week 24: 
− 
The number of bowel movements per day, based on a 1-week 
average, captured by e-diary. Improvement is defined as a 
reduction of 50% or more in the number of daily bowel 
movements based on a 1-week average. Patients evaluable for 
improvement are defined as those with an average of 3 or 
more bowel movements per day at baseline. Worsening is 
defined as an increase of 30% or more 
− 
Physician assessment of facial edema (based on a 5-point 
Likert scale). Improvement is defined as a reduction of 
2 points or more. Patients evaluable for improvement are 
defined as those with a severity of at least 3 points out of 5 at 
baseline. Worsening is defined as an increase of 2 points or 
more 
− 
Physician assessment of peripheral edema (based on a 5-point 
Likert scale). Improvement is defined as a reduction of 
2 points or more. Patients evaluable for improvement are 
defined as those with a severity of at least 3 points out of 5 at 
baseline. Worsening is defined as an increase of 2 points or 
more 
− 
Patient/caregiver assessment of abdominal pain frequency as 
assessed by the Stomach pain and hurt sub-scale of the 
Pediatric Quality of Life Inventory (PedsQL™) 
Gastrointestinal (GI) Symptom Scale. Improvement is defined 
as an increase of 25 points or more. Patients evaluable for 
improvement are those with a score of 70 points or less at 
baseline. Worsening is defined as a decrease of 25 points or 
more 
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Secondary: 
• 
Incidence and severity of treatment-emergent adverse events 
(TEAEs) and other safety variables from baseline to week 144 
• 
Improvement in each patient’s most bothersome sign/symptom at 
week 24, as determined prior to baseline using a semi-structured 
concept elicitation interview, from amongst the ‘core’ clinical 
endpoints of frequency of bowel movements, peripheral edema, 
facial edema, abdominal pain frequency (as described previously), 
nausea, vomiting, and stool consistency: 
− Improvement in nausea and vomiting will be defined as an 
increase of 25 points or more on the 0 to 100 transformed 
nausea and vomiting subscale of the PedsQL GI Symptom 
Scale score where lower scores indicate worse nausea and 
vomiting. Patients will be evaluable for improvement in nausea 
and vomiting if they have a score ≤75 on the nausea and 
vomiting subscale at baseline 
− Improvement in stool consistency will be defined as a 
reduction of ≥50% in the number of days per week that the 
patient has a bowel movement of loose/watery consistency. A 
bowel movement is considered to be loose/watery if it 
corresponds to 3 images of loose or watery stools on the 
Brussels Infant and Toddler Stool Scale (BITSS), the images 
and descriptors for categories 4 or 5 on the modified Bristol 
Stool Form Scale for Children (mBSFS-C), and the images and 
descriptors for categories 6 or 7 of the Bristol Stool Form Scale 
(BSFS). To be evaluable for improvement in stool consistency, 
patients must have a bowel movement of loose/watery stool 
consistency for ≥2 days/week at baseline 
• 
The proportion of patients with active disease at baseline who 
maintain disease control in these time periods (in weeks) 12-48, 
12-144, 24-48, 48-96, 96-144 as defined by: 
− Normalization of serum albumin, defined as serum albumin 
within the normal range at at least 70% of measurements and 
no single albumin measurement of <2.5 g/dL and no 
requirement for albumin infusion . 
− No worsening (definitions in parentheses), from the beginning 
of the stated time period, at any single visit during the stated 
time period, of: facial or peripheral edema (≥2-point increase); 
or stomach pain and hurt sub-scale (≥25-point decrease); or 
diarrhea subscale of the PedsQL GI Symptom Scale (≥25-point 
decrease) 
− No increase in doses of permitted concomitant medications for 
the treatment of PLE at any time, no re-introduction of any 
permitted concomitant medication once withdrawn, where 
permitted concomitant medication is as follows: 
corticosteroids, IV or SC immunoglobulin, IV albumin, 
biologic immunomodulators (anti-tumor necrosis factor [TNF], 
vedolizumab), small molecule immunomodulators 
(eg, azathioprine, mesalazine), micronutrients, enteral or 
parenteral supplementation 
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• 
The proportion of patients with inactive disease on eculizumab at 
baseline who maintain disease control in these time periods (in 
weeks) 12-48, 12-144, 24-48, 48-96, 96-144 as defined by: 
− Normalization of serum albumin, defined as serum albumin 
within the normal range at at least 70% of measurements and no 
single albumin measurement of <2.5 g/dL and no requirement 
for albumin infusion and 
− No worsening (definitions in parentheses), from the beginning 
of the stated time period, at any single visit during the stated 
time period, of: facial or peripheral edema (≥2-point increase); 
or stomach pain and hurt sub-scale (≥25-point decrease); or 
diarrhea subscale of the PedsQL GI Symptom Scale (≥25-point 
decrease) 
− No increase in dose of permitted concomitant medication for the 
treatment of PLE at any time, no re-introduction of any 
permitted concomitant medication once withdrawn, where 
permitted concomitant medication is as follows: corticosteroids, 
IV or SC immunoglobulin, IV albumin, biologic 
immunomodulators (anti-TNF, vedolizumab), small molecule 
immunomodulators (eg, azathioprine, mesalazine), 
micronutrients, enteral or parenteral supplementation 
• 
The number of bowel movements per day, based on a 1-week 
average, captured by e-diary from baseline to week 24 
• 
The number of days/week with ≥1 bowel movement of 
loose/watery stool consistency, as measured by BSFS for patients 
who are 18 years of age and older, mBSFS-C for patients who are 
toilet-trained and less than 18 years of age, or the BITSS who are 
not toilet-trained, and captured by e-diary from baseline to 
week 24 
• 
Physician assessment of facial edema (based on a 5-point Likert 
scale) from baseline to week 144 
• 
Physician assessment of peripheral edema (based on a 5-point 
Likert scale) from baseline to week 144 
• 
Change in abdominal symptoms, as assessed by the PedsQL™ GI 
Symptom Scale stomach pain and hurt sub-scale and food and 
drink limits sub-scale from baseline to week 144 
• 
Health-related quality of life as measured by the PedsQL™ 
Generic Core Scales from baseline to week 144; additionally, the 
following sub-scales will be reported separately: 
− About my work/studies and school functioning sub-scale 
− Physical functioning sub-scale 
• 
Assessment of abdominal ascites (assessed by measurement of 
abdominal circumference) from baseline to week 24 
• 
Frequency of albumin infusions up to week 144, expressed as 
number per half-year. Albumin infusions are permitted during the 
treatment phase in the event that the albumin level is below 
3.0 g/dL at 2 consecutive visits with accompanying symptoms of 
facial or peripheral edema or ascites. Any albumin infusions 
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between week 12 and week 24 will render the patient a non-
responder for the primary endpoint. 
• 
Total albumin, protein, total Ig, IgG, IgM, IgA, expressed as:  
− Absolute value at every scheduled time point including week 24 
− Absolute and percent change from baseline over time 
− Time to first normalization 
• 
Vitamin B12, folate, iron, iron binding capacity, ferritin, 
magnesium, fasting cholesterol/triglycerides, expressed as: 
− Absolute value at every scheduled time point including week 24 
− Absolute and percent change from baseline over time 
− Time to first normalization 
• 
Alpha-1 antitrypsin levels in blood and stool, and change from 
baseline to week 12 and week 24 
• 
Use and dose/frequency from baseline to week 144 of: 
corticosteroids, IV or SC immunoglobulin, IV albumin, biologic 
immunomodulators (anti-TNF, vedolizumab), small molecule 
immunomodulators (eg, azathioprine, mesalazine), micronutrients, 
enteral or parenteral supplementation, anti-coagulants (eg, low-
molecular-weight heparin), antibiotics (with the exception of those 
used for the purpose of Neisserial prophylaxis), anti-platelet agents 
(eg, low-dose aspirin) 
• 
Hospitalization days (percentage of days hospitalized) over time 
• 
Body weight and height, (expressed as z scores) over time 
• 
Concentrations of total pozelimab in serum assessed throughout 
the study 
• 
Incidence of treatment-emergent ADAs to pozelimab in patients 
over time 
• 
Change and percent change from baseline of total complement 
CH50 assay over time 
Procedures and Assessments 
The efficacy procedures include laboratory measurements of serum albumin, 
protein, and immunoglobulins, and other laboratory abnormalities 
characteristic of PLE. Clinical assessments include those for global disease 
activity, edema, and ascites (characteristic clinical features of PLE). Patient 
or caregiver-reported outcomes include those for global disease assessment, 
common PLE symptoms, and health-related quality of life. Effect on 
healthcare utilization will be determined by quantifying the sparing and 
withdrawal of concomitant therapies and the reduction of hospitalization 
days. Effects on growth and maturation will be assessed using weight, height, 
and pubertal Tanner staging. Evaluation of dosing regimen will be assessed 
using blood concentration of pozelimab and CH50, a pharmacodynamic 
marker. 
Overall safety will be assessed by monitoring/evaluation of TEAEs, physical 
examinations, and clinical safety laboratory tests at prespecified time points. 
Samples for drug concentration will be collected, and the potential emergence 
of anti-pozelimab antibodies will also be evaluated. 
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Statistical Plan 
The primary objective of the study is to determine the effect of pozelimab on 
CD55-deficient PLE/CHAPLE disease in patients with active disease at 
baseline. The primary outcome is the achievement of both of the following: 
(1) normalization of serum albumin, and (2) improvement from baseline to 
week 24 in the prespecified clinical outcomes that were evaluable for 
improvement at baseline, with no worsening of the others. The primary 
endpoint is the proportion of patients achieving the primary outcome. 
Justification for the sample size. The study is regarded as successful if at 
least 4 of 6 patients achieve the primary endpoint. Unpublished patient-level 
data of 14 patients treated with eculizumab were made available to the study 
sponsor. In the historical control period before initiating eculizumab, 0 of 
14 patients met the primary endpoint (90% exact confidence interval (CI): 
[0.00, 0.19]). If 4 of 6 evaluable patients treated with pozelimab achieve the 
primary endpoint, the 90% exact CI for the probability of achieving the 
primary endpoint is (0.27, 0.94), with the lower limit of 0.27 clearly greater 
than the upper limit of 0.19 for the historical control period of the 14 patients. 
By a Bayesian analysis, a comparison between 4 of 6 pozelimab-treated 
patients achieving the primary endpoint and 0 of 14 in the historical data by 
a Beta-Binomial analysis with the Jefferys prior of Beta(0.5, 0.5) would 
conclude that there is a >99% posterior probability that pozelimab has a 
greater response rate than untreated patients. There would also be a 90% 
posterior probability that the response rate with pozelimab is at least 
0.37 higher than that of untreated patients. Thus, the study success criterion 
of observing at least 4 of 6 evaluable patients achieving the primary endpoint 
provides strong evidence of effectiveness. 
All of the 14 eculizumab-treated patients achieved a normalized serum 
albumin level by 12 weeks of treatment and required no albumin infusions 
subsequent to treatment initiation (90% exact CI: [0.81, 1.00]). If the true rate 
of achieving the primary endpoint for patients on pozelimab is 0.81 (the lower 
limit of the CI for eculizumab), then a sample size of 6 gives a probability of 
91% for achieving the study success criterion.  
Primary Efficacy Analysis. The subset of the full analysis set (FAS) with 
patients having active PLE at baseline will provide the data for the primary 
efficacy analysis. The percentage of patients achieving normalization of 
albumin and achieving improvement in the prespecified evaluable clinical 
outcomes will be calculated and its 90% CI will be reported.  
There are 7 planned albumin measurements between week 12 and week 24, 
inclusive. Patients will be considered non-evaluable for the primary analysis 
if there are fewer than 5 available albumin measurements between week 12 
and week 24. Albumin measurements outside of the visit windows and/or 
carried out at local laboratories will be considered as valid measurements. To 
be considered responders, at least 70% of available measurements must be 
normal (≥3.5 g/dL). Thus, patients with the minimum of 5 available 
measurements must have 4 out of 5 normal. Patients with the planned number 
of 7 measurements must have at least 5 normal. Patients who have more than 
7 available measurements (due to unplanned albumin measurement in local 
labs) must have at least 70% of all available measurements normal.  Non-
responder imputation for patients with fewer than 5 available albumin 
measurements between 12 and week 24 will be carried out as a sensitivity 
analysis. The mean changes from baseline in albumin over time and the mean 
number of albumin infusions per half-year will also be estimated. Patient 
profiles of albumin over time will be plotted. 
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There are 4 clinical outcomes that can contribute to the clinical improvement 
component of the primary endpoint. Patients are evaluable for improvement 
in each of these based on activity at baseline. Patients evaluable for only 1 of 
the 4 clinical outcomes must show improvement (as defined) in that clinical 
outcome and no worsening in the other 3. Patients evaluable for more than 1 
clinical outcome must show improvement for all of their evaluable outcomes 
and no worsening in any non-evaluable outcomes.  
For facial and peripheral edema, the primary analysis will be performed using 
the investigating physician’s report. Clinical photographs will be rated by a 
single, independent central reader blinded to the time point at which the 
photograph was taken. The correlation of central read to physician’s 
assessment will be described. The central read will be used as a sensitivity 
analysis on the primary endpoint. 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
aHUS 
Atypical hemolytic uremic syndrome 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BID 
Twice daily 
BITSS 
Brussels infant and toddler stool scale 
BSFS 
Bristol Stool Form Scale 
BUN 
Blood urea nitrogen 
BW 
Body weight 
CareGIC 
Caregiver global impression of change 
CareGIS 
Caregiver global impression of severity 
CGIC 
Clinical global impression of change 
CGIS 
Clinical global impression of severity 
ClinRO 
Clinical reported outcome 
COA 
Clinical Outcome Assessment 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case report form (electronic or paper) 
CRP 
C-reactive protein 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FPFD 
First patient first dose 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HBsAG 
Hepatitis B surface antigen 
HBeAg 
Hepatitis B e antigen 
HCV RNA 
Hepatitis C virus RNA 
HDL 
High-density lipoprotein 
HRQoL 
Health-related quality of life 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
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IRB 
Institutional Review Board 
IV 
Intravenous 
LDL 
Low-density lipoprotein 
LLOQ 
Lower limit of quantification 
mBSFS-C 
modified Bristol Stool Form Scale for Children 
MID 
Minimum important difference 
NAbs 
Neutralizing antibodies 
NOAEL 
No observable adverse effect level 
ObsOR 
Observer reported outcome 
PD 
Pharmacodynamics 
PedsQL™ 
Pediatric Quality of Life Inventory™ 
PGIC 
Patient global impression of change 
PGIS 
Patient global impression of severity 
PK 
Pharmacokinetic 
PNH 
Paroxysmal nocturnal hemoglobinuria 
PLE 
Protein-losing enteropathy 
PRO 
Patient reported outcome 
PT 
Preferred term 
PT/aPTT 
Prothrombin time/activated partial thromboplastin time 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SOC 
System organ class 
TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 
TNF 
Tumor necrosis factor 
WBC 
White blood cell 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................3 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................15 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................23 
1. 
INTRODUCTION ......................................................................................................31 
2. 
STUDY OBJECTIVES ..............................................................................................33 
2.1. 
Primary Objective .......................................................................................................33 
2.2. 
Secondary Objectives .................................................................................................33 
2.3. 
Exploratory Objectives ...............................................................................................34 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................35 
3.1. 
Hypothesis ..................................................................................................................35 
3.2. 
Rationale .....................................................................................................................35 
3.2.1. 
Rationale for Study Design .........................................................................................35 
3.2.2. 
Rationale for Dose Selection ......................................................................................38 
3.2.3. 
Risk-Benefit Assessment ............................................................................................40 
3.2.3.1. 
Study Conduct in Response to COVID-19 .................................................................41 
4. 
STUDY VARIABLES................................................................................................42 
4.1. 
Demographic and Baseline Characteristics ................................................................42 
4.2. 
Outcome Variables .....................................................................................................42 
4.3. 
Pharmacokinetic Variables .........................................................................................42 
4.4. 
Immunogenicity Variables ..........................................................................................42 
4.5. 
Exploratory Biomarker Variables ...............................................................................42 
5. 
PRIMARY AND SECONDARY OUTCOMES ........................................................43 
5.1. 
Primary Outcome ........................................................................................................43 
5.2. 
Secondary Outcomes ..................................................................................................44 
5.3. 
Exploratory Outcomes ................................................................................................47 
6. 
STUDY DESIGN .......................................................................................................48 
6.1. 
Study Description and Duration .................................................................................48 
6.1.1. 
Study Stopping Rules .................................................................................................49 
6.1.1.1. 
Individual Patient Stopping Rules ..............................................................................49 
6.1.1.2. 
Study Stopping Criteria ..............................................................................................49 
6.1.2. 
End of Study Definition ..............................................................................................49 
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6.2. 
Planned Interim Analysis ............................................................................................50 
6.3. 
Study Committees .......................................................................................................50 
6.3.1. 
Steering Committee ....................................................................................................50 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............51 
7.1. 
Number of Patients Planned .......................................................................................51 
7.2. 
Study Population .........................................................................................................51 
7.2.1. 
Inclusion Criteria ........................................................................................................51 
7.2.2. 
Exclusion Criteria .......................................................................................................52 
7.3. 
Premature Withdrawal from the Study .......................................................................54 
7.4. 
Replacement of Patients .............................................................................................54 
8. 
STUDY TREATMENTS............................................................................................55 
8.1. 
Investigational Treatment ...........................................................................................55 
8.2. 
Drug Administration ...................................................................................................55 
8.3. 
Pretreatments ..............................................................................................................56 
8.3.1. 
Vaccinations ...............................................................................................................56 
8.3.2. 
Oral Antibiotics ..........................................................................................................56 
8.4. 
Risk Management of Neisseria Gonorrhea ................................................................57 
8.5. 
Risk Management of Immune Complex Formation ...................................................57 
8.6. 
Dose Modification and Study Treatment Discontinuation Rules ...............................58 
8.6.1. 
Dose Modification ......................................................................................................58 
8.6.2. 
Study Drug Discontinuation .......................................................................................58 
8.6.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................58 
8.6.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................59 
8.7. 
Management of Acute Reactions ................................................................................59 
8.7.1. 
Acute Intravenous Infusion Reactions ........................................................................59 
8.7.1.1. 
Interruption of the Intravenous Infusion .....................................................................59 
8.7.1.2. 
Termination of the Intravenous Infusion ....................................................................60 
8.7.2. 
Acute Injection Reactions ...........................................................................................60 
8.7.2.1. 
Systemic Injection Reactions ......................................................................................60 
8.7.2.2. 
Local Injection Site Reactions ....................................................................................61 
8.8. 
Method of Treatment Assignment ..............................................................................61 
8.8.1. 
Blinding ......................................................................................................................61 
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8.9. 
Treatment Logistics and Accountability .....................................................................61 
8.9.1. 
Packaging, Labeling, and Storage ..............................................................................61 
8.9.2. 
Supply and Disposition of Treatments .......................................................................61 
8.9.3. 
Treatment Accountability ...........................................................................................62 
8.9.4. 
Treatment Compliance ................................................................................................62 
8.10. 
Concomitant Medications ...........................................................................................62 
8.10.1. 
Prohibited Medications ...............................................................................................62 
8.10.2. 
Permitted Medications ................................................................................................63 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................64 
9.1. 
Schedule of Events .....................................................................................................64 
9.1.1. 
Footnotes for the Schedule of Events Table ...............................................................69 
9.1.2. 
Early Termination Visit ..............................................................................................71 
9.1.3. 
Unscheduled Visits .....................................................................................................71 
9.2. 
Study Procedures ........................................................................................................71 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................71 
9.2.2. 
Study Drug Administration.........................................................................................72 
9.2.3. 
Efficacy Procedures ....................................................................................................72 
9.2.3.1. 
Serum Albumin, Total Protein, and Immunoglobulin ................................................72 
9.2.3.2. 
Physician Assessment of Edema and Ascites .............................................................72 
9.2.3.3. 
Clinical Outcome Assessments ...................................................................................73 
9.2.3.4. 
Tanner Stages ..............................................................................................................77 
9.2.4. 
Safety Procedures .......................................................................................................77 
9.2.4.1. 
Vital Signs ..................................................................................................................77 
9.2.4.2. 
Physical Examination, Height, and Body Weight ......................................................78 
9.2.4.3. 
Electrocardiogram .......................................................................................................78 
9.2.4.4. 
Laboratory Testing ......................................................................................................78 
9.2.5. 
Drug Concentration and Measurements .....................................................................80 
9.2.6. 
Anti-Drug Antibody Measurements and Samples ......................................................80 
9.2.7. 
Pharmacodynamic and Exploratory Biomarker Procedures .......................................80 
9.2.7.1. 
Future Biomedical Research (Optional) .....................................................................81 
9.2.7.2. 
Genomics Sub-Study (Optional) .................................................................................81 
10. 
SAFETY EVALUATION AND REPORTING .........................................................82 
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10.1. 
Recording and Reporting Adverse Events ..................................................................82 
10.1.1. 
General Guidelines .....................................................................................................82 
10.1.2. 
Reporting Procedure ...................................................................................................83 
10.1.3. 
Events that Require Expedited Reporting to Sponsor ................................................83 
10.2. 
Definitions ..................................................................................................................84 
10.2.1. 
Adverse Event .............................................................................................................84 
10.2.2. 
Serious Adverse Event ................................................................................................84 
10.2.3. 
Adverse Events of Special Interest .............................................................................84 
10.2.4. 
Infusion Reactions ......................................................................................................85 
10.2.5. 
Severity .......................................................................................................................85 
10.2.6. 
Causality .....................................................................................................................86 
10.3. 
Safety Monitoring .......................................................................................................87 
10.4. 
Notifying Health Authorities, Institutional Review Board /Ethics Committee, 
and Investigators .........................................................................................................87 
11. 
STATISTICAL PLAN................................................................................................88 
11.1. 
Statistical Hypothesis ..................................................................................................88 
11.2. 
Justification of Sample Size........................................................................................88 
11.3. 
Analysis Sets ...............................................................................................................89 
11.3.1. 
Efficacy Analysis Set ..................................................................................................89 
11.3.2. 
Safety Analysis Set .....................................................................................................89 
11.3.3. 
Pharmacokinetic Analysis Set ....................................................................................89 
11.3.4. 
Immunogenicity Analysis Sets ...................................................................................89 
11.3.5. 
Exploratory Analysis Sets ...........................................................................................89 
11.3.5.1. 
Exploratory Biomarker Endpoint Analysis Set ..........................................................89 
11.3.5.2. 
Exploratory Clinical Outcome Assessment Analysis Set ...........................................89 
11.4. 
Statistical Methods ......................................................................................................90 
11.4.1. 
Patient Disposition ......................................................................................................90 
11.4.2. 
Demography and Baseline Characteristics .................................................................90 
11.4.3. 
Efficacy Analyses .......................................................................................................90 
11.4.3.1. 
Primary Efficacy Analysis ..........................................................................................90 
11.4.3.2. 
Secondary Efficacy Analysis ......................................................................................91 
11.4.4. 
Safety Analysis ...........................................................................................................92 
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11.4.4.1. 
Adverse Events ...........................................................................................................92 
11.4.4.2. 
Other Safety ................................................................................................................93 
11.4.4.3. 
Treatment Exposure ....................................................................................................93 
11.4.4.4. 
Treatment Compliance ................................................................................................93 
11.4.5. 
Pharmacokinetics ........................................................................................................93 
11.4.5.1. 
Analysis of Drug Concentration Data .........................................................................93 
11.4.6. 
Analysis of Immunogenicity Data ..............................................................................94 
11.4.7. 
Analysis of Exploratory Pharmacodynamic and Biomarker Data ..............................94 
11.4.8. 
Analysis of Exploratory Clinical Outcome Assessment Data ....................................94 
11.5. 
Interim Analysis ..........................................................................................................94 
11.6. 
Timing of Analyses .....................................................................................................95 
11.7. 
Statistical Considerations Surrounding the Premature Termination of a Study .........95 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................96 
12.1. 
Data Management and Electronic Systems ................................................................96 
12.1.1. 
Data Management .......................................................................................................96 
12.1.2. 
Electronic Systems ......................................................................................................96 
12.2. 
Study Monitoring ........................................................................................................96 
12.2.1. 
Monitoring of Study Sites ...........................................................................................96 
12.2.2. 
Source Document Requirements ................................................................................97 
12.2.3. 
Case Report Form Requirements ................................................................................97 
12.3. 
Audits and Inspections ................................................................................................97 
12.4. 
Study Documentation .................................................................................................98 
12.4.1. 
Certification of Accuracy of Data ...............................................................................98 
12.4.2. 
Retention of Records ..................................................................................................98 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................99 
13.1. 
Good Clinical Practice Statement ...............................................................................99 
13.2. 
Informed Consent .......................................................................................................99 
13.2.1. 
Adult Patients ..............................................................................................................99 
13.2.2. 
Pediatric Patients ......................................................................................................100 
13.3. 
Patient Confidentiality and Data Protection .............................................................100 
13.4. 
Institutional Review Board/Ethics Committee .........................................................101 
13.5. 
Clinical Study Data Transparency ............................................................................101 
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14. 
PROTOCOL AMENDMENTS ................................................................................102 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ..........................................................................................................................103 
15.1. 
Premature Termination of the Study .........................................................................103 
15.2. 
Close-Out of a Site ....................................................................................................103 
16. 
CONFIDENTIALITY ..............................................................................................104 
17. 
FINANCING AND INSURANCE ...........................................................................104 
18. 
PUBLICATION POLICY ........................................................................................104 
19. 
REFERENCES .........................................................................................................105 
20. 
INVESTIGATOR’S AGREEMENT ........................................................................108 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS ...................................................109 
 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................65 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................49 
 
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1. 
INTRODUCTION 
CD55-deficient protein-losing enteropathy (CD55-deficient PLE) is a newly described disease and 
potential indication for C5 blockade, also referred to as complement hyperactivation, angiopathic 
thrombosis, protein-losing enteropathy (CHAPLE disease) (Kurolap, 2017) (Ozen, 2017b). Of the 
11 patients described by Ozen et al., 9 were from Turkey, 1 was from Syria and 1 was from 
Morocco. Eight of these patients were <2 years old at presentation. Unlike paroxysmal nocturnal 
hemoglobinuria (PNH), another disease being evaluated for REGN3918 (also known as 
pozelimab), hemolysis has not been observed in CD55-deficiency patients. 
CD55-deficient PLE/CHAPLE disease is caused by biallelic loss-of-function mutations in the 
CD55 gene. Clinically, it manifests as a familial form of protein-losing enteropathy (PLE) caused 
by primary intestinal lymphangiectasia (PIL) or Waldmann’s disease that is frequently severe and 
can be accompanied by lethal systemic manifestations. CD55 is a glycophosphatidylinositol (GPI)-
anchored membrane protein that inhibits the enzymatic activity of C3b and C4b, thus preventing 
the formation of C3 and C5 convertases that lead ultimately to the assembly of the membrane-
attack complex (C5b–C9). Thus, the absence of CD55 causes overactivation of the complement 
system, causing the production of various complement products including anaphylatoxins and the 
membrane-attack complex. When absent due to somatic mutation of the PIGA gene (required for 
the biosynthesis of GPI anchors) in hematopoietic stem cells, CD55 loss, as well as CD59 loss, is 
specific to hematopoietic cells (CD59 is another GPI-linked complement regulatory protein). The 
resultant complement-mediated lysis of red cells and platelets gives rise to intravascular hemolysis 
and thrombosis, in a disease termed PNH. In CD55-deficient PLE, isolated germ line loss of CD55 
expression in all tissues manifests in the GI tract, as primary intestinal lymphangiectasia, which 
causes PLE. The majority of patients suffer from early-onset GI manifestations, including bloody 
diarrhea, vomiting, and abdominal pain, and occasionally develop partial or complete intestinal 
obstruction and intestinal failure. The loss of proteins through the GI tract leads to 
hypoalbuminemia and subsequent peripheral and facial edema and ascites, as well as 
hypogammaglobulinemia which predisposes to repeat infections. Due to loss of nutrients in the 
intestinal lumen, a malabsorption syndrome ensues, leading to vitamin and micronutrient 
deficiencies and severely impaired growth. As for PNH and other examples of complement 
disorders, atypical hemolytic uremic syndrome (aHUS), and transplant thrombotic 
microangiopathy, CD55-deficient PLE patients are susceptible to thrombosis, particularly in 
mesenteric and hepatic veins, and it is the thrombotic manifestation that leads to intestinal and 
hepatic failure, and most frequently leads to early mortality. Patients with CD55 deficiency 
frequently manifest with thrombocytosis. 
Following its discovery in 2017, CD55-deficient PLE/CHAPLE disease has to date been described 
in 14 patients (Kurolap, 2017) (Ozen, 2017b). Age of onset in these 14 patients was less than 1 year 
in three, 1 year of age in five, 2-3 years in three, and 4 to 10 years in three. Severity ranges from 
subclinical PLE (described in 3 relatives of 14 published patients) to early fatality (in 3 of the 
14 published patients). A hallmark of CD55-deficient PLE disease, and PLE in general, is a 
decrease in serum proteins: all described patients demonstrate hypoalbuminemia and 
hypogammaglobulinemia. While a proportion of patients with CD55-deficient PLE display 
features of inflammatory bowel disease (IBD) and receive IBD medications (to which they are 
generally refractory), a greater percentage present with symptoms attributable to 
hypoalbuminemia, namely, edema. A typical case is a child with infantile onset of facial and 
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extremity edema in relation to hypoalbuminemia, with or without diarrhea, who requires frequent 
hospital admissions to receive albumin infusion. Due to malabsorption, these patients commonly 
show growth failure, and some have delay in pubertal development. The more severely affected 
cases develop mesenteric venous thrombosis that is frequently associated with retrograde 
extension and cardiac involvement, as well as embolic complications. It appears that once the 
thrombotic complications develop, the patients follow a chronic course of increasing debilitation, 
eventually leading to premature death. Treatment has typically included corticosteroids, IVIg or 
SCIg, intravenous (IV) albumin, biologic immunomodulators (anti-tumor necrosis factor [TNF], 
vedolizumab), small molecule immunomodulators (e.g. azathioprine, mesalazine), micronutrients, 
enteral or parenteral feeding, anti-coagulants (low-molecular-weight heparin, aspirin), antibiotics, 
anticoagulants, and anti-platelet agents (Kurolap, 2017). In spite of these therapies, the long-term 
morbidity and risk of mortality remains high. In keeping with the role of CD55 absence in 
pathogenesis, eculizumab, which is a humanized monoclonal antibody directed against the 
terminal complement protein C5, alleviates disease, with an immediate recovery of PLE and in 
children, improved growth, with the cessation of other medications. Eculizumab has been made 
available to some patients through a compassionate use program but is not currently approved for 
the treatment of CD55-deficient PLE/CHAPLE disease nor, based on a search of public records, 
does there appear to be an ongoing development program.  
Regeneron Pharmaceuticals, Inc. intends to develop pozelimab for the treatment of CD55-deficient 
PLE/CHAPLE. Pozelimab is a fully human, monoclonal immunoglobulin G4P (IgG4P) antibody 
directed against the terminal complement protein C5 that inhibits terminal complement activation 
by blocking cleavage of C5 into C5a (anaphylatoxin) and C5b, thereby blocking the formation of 
the membrane-attack complex (C5b-C9, a structure-mediating cell lysis. Pozelimab is being 
developed for the treatment of PNH and other diseases in which tissue damage is mediated by the 
terminal complement pathway activity. Pozelimab can be administered by IV or subcutaneous 
(SC) administration. Additionally, pozelimab binds to polymorphic variations in C5 that are not 
recognized by eculizumab. 
Additional background information on the study drug and development program can be found in 
the Investigator’s Brochure. 
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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of the study is to determine the effect of pozelimab on active CD55-deficient 
protein-losing enteropathy (PLE; CHAPLE), as measured by:  
1. Normalization of serum albumin, and  
2. Improvement in the following clinical outcomes that are evaluable for improvement at 
baseline, without worsening of the others, after 24 weeks of treatment (assessed at 
week 24): 
• Daily bowel movement frequency  
• The presence and severity of facial or peripheral edema  
• The patient/caregiver assessment of abdominal pain frequency 
2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To evaluate the safety and tolerability of pozelimab in patients with CD55-deficient 
PLE disease 
• To evaluate the effect of pozelimab on CD55-deficient PLE (both patients with active 
disease at baseline and those with inactive disease on eculizumab, switching to 
pozelimab)  
• To determine the effects of pozelimab on albumin and other serum proteins (total 
protein, immunoglobulins) 
• To determine the effects of pozelimab on ascites 
• To determine the effects of pozelimab on stool consistency 
• To determine the effect of pozelimab on health-related quality of life 
• To determine the effect of pozelimab on lab abnormalities observed in CD55-deficient 
PLE such as hypertriglyceridemia, thrombocytosis, and hypovitaminosis B12 
• To describe the effects of pozelimab on the sparing of concomitant medications and 
reduction in hospitalization days 
• To determine the effects of pozelimab on growth 
• To characterize the concentration of pozelimab in patients with CD55-deficient PLE 
• To assess the incidence of treatment-emergent ADA for pozelimab in patients with 
CD55-deficient PLE disease 
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2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
• To characterize the effect of pozelimab on the incidence of new thromboembolic events 
and the extension of existing thromboses 
• To assess the effect of pozelimab on sexual maturation 
• To assess the effect of pozelimab on complement pathway activity 
• To assess the effect of pozelimab on inflammation and thrombosis markers 
• To determine the effects of pozelimab on patient/caregiver assessment of change and 
severity of disease 
• To determine the effects of pozelimab on physician assessment of change and severity 
of disease 
• To explore the effect of pozelimab on gastrointestinal (GI) symptoms (nausea and 
vomiting and diarrhea) and on caregiver quality of life/burden 
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3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypothesis 
Pozelimab treatment will result in normalization of serum albumin and improvement in clinical 
signs and symptoms in CD55-deficient PLE/CHAPLE disease. 
3.2. 
Rationale 
3.2.1. 
Rationale for Study Design 
CD55-deficient PLE is a life-threatening, ultra-orphan disease of infants, children, adolescents, 
and young adults with no current approved therapy. There are approximately 40 patients across 
the world known to have this disease as of December 2018. R3918-PLE-1878 is an open-label 
study to evaluate the safety and efficacy of pozelimab in 4 to 20 patients with CD55-deficient PLE, 
as an addition to standard-of-care therapies (excluding eculizumab). The rationale for an open-
label study is that the disease is too severe for patients to be allocated to a placebo group, and that 
there are no suitable active comparator therapies available. There are reports of cases that suggest 
that a similar anti-C5 monoclonal antibody drug, eculizumab, significantly improves the clinical 
condition of patients with CD55-deficient PLE and there is a very high likelihood, given the similar 
mechanism of action of eculizumab and pozelimab, that pozelimab will have a similar effect. 
CD55-deficient PLE is a serious condition for which patients may experience disease progression 
over the period of the study if they do not receive active treatment. The expected effect of treatment 
is expected to be large enough to distinguish the effect of treatment with pozelimab from the 
underlying disease progression accounting for its variability over time. The intent of this study is 
to generate the first efficacy and safety data from a clinical study for the anti-C5 therapeutic class 
in this indication, and to support licensure for the treatment of CD55-deficient PLE with 
pozelimab. The study population has been designed (based on an analysis of data obtained from 
13 patients prior to and after eculizumab treatment) to maximize the inclusion of patients from 
among the known global patient population (which currently stands at 23 individuals, of which 17 
are known to be on eculizumab treatment and in remission). The following types of patients may 
be included: 
• Patients with active PLE who are naïve to eculizumab therapy. Active PLE is defined 
as: hypoalbuminemia of less than or equal to 3.2 g/dL within the screening period; and, 
within the last 6 months, at least 7 days (which do not have to be consecutive) of 1 or 
more of the following symptoms or signs: diarrhea, vomiting, abdominal pain, 
peripheral or facial edema, or an episode of infection with concomitant 
hypogammaglobulinemia, or a new thrombotic event. 
• Patients with active PLE who were previously taking eculizumab, and stopped it 
because of access issues, or because their physician withdrew it in the expectation that 
they would remain inactive, or because they were refractory to it due to the Arg885His 
variant in the C5 gene (which is unable to bind to eculizumab).  
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• Patients on treatment with eculizumab, with inactive or controlled disease, who elect 
to switch from an IV to an SC anti-C5 treatment. These patients will switch from 
eculizumab to pozelimab without an interruption of anti-C5 treatment to limit the risk 
of loss of disease control. In these patients, eculizumab should be discontinued during 
the screening period, and pozelimab started at the time that the next scheduled 
eculizumab dose would have taken place. These patients will not contribute data 
towards the primary endpoint but will provide supportive safety and efficacy data. 
The definition of inactive PLE is any case of PLE which fails to meet the definition of active 
disease as per definition above. This should not include patients whose future access to eculizumab 
would be compromised, ie, those on the Alexion compassionate use program, with no likelihood 
of finding alternative reimbursement for eculizumab. Regeneron will not provide for patients to 
be treated with eculizumab at any time during or after the study. 
Rationale for a study in pediatric patients: CD55-deficient PLE is a life-threatening, ultra-
orphan disease with no current approved therapy. Pozelimab was well-tolerated in toxicology 
studies in adolescent (13-week study) and adult (26-week study) cynomolgus monkeys at doses 
up to 100 mg/kg/week via IV administration for up to 26 weeks. The no observable adverse effect 
level (NOAEL) based on the results of these toxicology studies was determined to be 100 mg/kg, 
the highest dose tested. To date, toxicology studies in juvenile animals have not been conducted 
for pozelimab. Available adult safety data, known target biology, and the lack of target organs 
identified in nonclinical toxicology (13- and 26-week) studies are expected to support dosing in 
the proposed patient population. Enhanced pre- and post-natal development (ePPND) data 
generation will run in parallel and is expected to be supportive of marketing authorization/BLA in 
pediatric patients. The safety and effectiveness of Soliris® for the treatment of aHUS have been 
established in pediatric patients and supported by evidence from 4 adequate and well-controlled 
clinical studies (Soliris package insert, 2019). To mitigate the potential risk in very young patients, 
the first 2 patients recruited into the trial should be 6 years of age or older and safety through 
week 12 will be assessed before inclusion of pediatric patients 1 year and older. Exceptions to this 
rule will be made if patients younger than 6 years of age present with life-threatening disease prior 
to the availability of 12 weeks of data in 2 patients aged 6 years or older. Examples of life-
threatening disease include, but are not limited to: hemodynamic compromise from severe edema 
or from evolving thrombosis, bowel intussusception or ileus. The decision to allow exceptions will 
be made in conjunction with the medical director, steering committee, and will require approval 
from senior Regeneron medical staff and Ethics Committee (EC)/Institutional Review Board 
(IRB). Depending on local policy, input from health authority may be sought before proceeding. 
As of 13 March 2020, 1 patient (aged greater than 6 years) has been recruited. There is a patient 
aged 5 years and 5 months with severe edema and serum albumin as low as 1.0 g/dL, requiring 
high dose intermittent steroids and intermittent albumin infusions, daily at their most frequent. 
Intravenous access is unreliable and when not available the edema has progressed to life-
threatening hemodynamic compromise. An expedited request for EC approval to enroll this patient 
is currently in progress. 
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Evidence of pozelimab efficacy will be based on (a) an induction and maintenance of response 
with respect to normalization of serum albumin in active patients and (b) improvement in a clinical 
endpoint in active patients, as the 2 components of the primary endpoint (Section 5.1). 
Maintenance of response in switch patients will be measured and reported as supportive evidence. 
Given the ultra-rare nature of this condition and very small size of the study, the albumin endpoint 
has been designed to capture both induction and maintenance, and maintenance alone, so that it 
can be applied to every patient. Namely, that albumin measured between week 12 (allowing time 
for both the active patients to respond, and the switch patients to wash-out residual eculizumab) 
and week 24 (allowing for time to demonstrate maintenance of effect) is normalized. Sustained 
normalization of albumin as a primary endpoint is objective and stringent and has never been 
achieved through the use of existing standard of care prior to the advent of anti-C5 therapy in all 
known patients. Serum albumin also has clinical meaning: Facial and peripheral edema and GI 
symptoms are directly correlated with the albumin level, since they are caused by a decrease in the 
oncotic pressure that is maintained by albumin. Furthermore, IV albumin infusions are an 
established standard therapy in PLE and temporarily improve these clinical manifestations, in 
parallel with a temporary increase in the albumin level. The decision to treat with albumin is made 
based on monitoring of the albumin level. Taken together, these factors argue that the albumin 
level is clinically meaningful. The first component of the primary endpoint is: the proportion of 
patients with at least 70% of albumin measurements within the normal range between week 12 
(allowing time for both the active patients to respond, and the switch patients to wash-out residual 
eculizumab) and week 24 (allowing a full 3 months to demonstrate maintenance). Albumin normal 
range varies little between labs and is typically 3.5 to 5.5 g/dL. The upper limit for active PLE 
patients was set at 3.2 g/dL based on a review of data from 7 Turkish and 3 Israeli patients (Ozen 
unpublished data; Baris-Feldman unpublished data). In up to 15 years of pre-eculizumab follow-
up in these patients, the albumin never went above 3.2 g/dL nor showed a short-term increase of 
1 g/dL (absent having received an albumin infusion). Following eculizumab treatment, all 
10 patients showed a normalization of the mean albumin level using measurements taken between 
weeks 12 and 24, and all 10 patients showed an increase from baseline of at least 1 g/dL on at least 
1 occasion between weeks 12 and 24. We will collect all available pre-study albumin (as well as 
other relevant laboratory and clinical) data on all patients. A patient who receives an albumin 
infusion between weeks 12 and 24  will be considered a non-responder: in the historical data set, 
no patient required any albumin infusion while on treatment with eculizumab.  Patients will also 
be considered a non-responder if any single albumin value is <2.5 g/dL after between weeks 12 
and 24 . 
An improvement in clinical endpoints will be the second component of the primary endpoint. A 
range of clinical endpoints have been designed to capture patient benefit, due to the paucity of 
quantitative data regarding the clinical effect of eculizumab, and due to variability of clinical 
manifestations: there is no single clinical manifestation that occurs in every patient. Some of the 
clinical endpoints are included within the primary endpoint; others are included as secondary. Four 
clinical endpoints were selected for inclusion in the primary endpoint on the basis of: a relatively 
higher prevalence in the patient population, a relatively stronger face validity for meaningfulness, 
and a relatively greater degree of objective quantification. Frequent bowel movements emerged as 
commonly experienced by patients with the disease. In an analysis of data from 13 patients prior 
to and following eculizumab treatment, 8/13 patients had average daily bowel movements 
(measured over a week) of 3 or more. Of these 8 patients, 7 showed a reduction of at least 50%. 
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Only 4/13 patients had bowel movements of more than 4 times a day, and all 4 patients showed an 
improvement of at least 50%. Based on published literature and discussions with physicians with 
experience treating patients with CD55-deficient PLE, abdominal pain was also identified as a 
prevalent aspect of disease. Frequency of abdominal pain is quantifiable using an existing patient 
reported outcome measure, the PedsQL GI Symptoms Scales' Stomach Pain and Hurt Subscale 
(Varni, 2012). The definition of a responder, ie, a 25-point change on the transformed score, 
reflects a 1-category change on the raw score scale. The scores at which patients will be considered 
evaluable for improvement is 70 or less because the average score on the subscale tended to be 
less than 70 for patients with GI diseases (range: 63.8 to 71.9) (Varni, 2015b) (Varni, 2015c) 
(Varni, 2016). Facial and peripheral edema was also a prevalent aspect of disease but due to a lack 
of suitable existing measurement tools (with nothing available for children and for facial edema), 
we have developed Likert scales for the physician to grade the severity of edema. For the peripheral 
edema scale we have adopted response options from an existing developed clinician-reported 
outcome assessment (Brodovicz, 2009). 
To mitigate the risk that our pre-defined responder thresholds do not perform adequately, we will 
use anchor-based methods using the patient/caregiver globals as anchors to assess the responder 
definition for the individual endpoints. Concept elicitation interviews conducted during the 
screening period will also be used to elicit each patient’s most bothersome sign/symptom from 
amongst those included in the core sign/symptom concepts of disease. Exit interviews will also be 
conducted on the date the primary endpoints will be assessed. The qualitative data from the exit 
interviews will also be used to interpret trial results and to further understand whether the observed 
changes were meaningful from the perspective of the patient/caregiver. 
3.2.2. 
Rationale for Dose Selection 
Following an IV loading dose of 30 mg/kg, pozelimab will be administered SC weekly at doses 
depending on body weight (BW) as follows:   
• For BW < 10 kg: 125 mg 
• For BW ≥10 kg and <20 kg: 200 mg 
• For BW ≥20 kg and <40 kg: 350 mg 
• For BW ≥40 kg and <60 kg: 500 mg 
• For BW ≥60 kg: 800 mg 
These doses were selected to achieve, in modeling, similar peak and trough pozelimab 
concentrations in serum as those shown to completely inhibit C5 activity (as assessed by 
suppression of ex vivo hemolysis through the CH50 assay) in healthy adult subjects. These are the 
doses chosen for the study of adult PNH patients (30 mg/kg IV loading dose followed by a weekly 
dose of 800 mg SC) in study R3918-PNH-1852. The predicted peak concentrations of 600 to 
700 mg/L have been observed in study R3918-HV-1659 in healthy volunteers and have been 
shown to be well tolerated; the predicted trough concentration of 400 mg/L is above the 
concentration considered minimally necessary to achieve maximal suppression of C5 activity for 
all patients, and allows for the variability and uncertainty in pharmacokinetics/ pharmacodynamics 
(PK/PD). There is a theoretical consideration that increased enteric protein loss very early in 
treatment might require an upwards correction of the loading dose. However, the published data 
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on eculizumab-treated patients report that free C5 concentrations fall to the lower limit of 
quantification within 3 days of first infusion, along with clinical improvement in all 3 patients 
within the first 12 hours of treatment, using a standard IV dose of eculizumab (ie, the maintenance 
dose tiered by body weight according to the label for pediatric patients with atypical hemolytic 
uremic syndrome, in which there is no enteric protein loss) (Kurolap, 2017) (Soliris package insert, 
2019). These data suggest that increased enteric protein loss early in treatment is unlikely to result 
in a pharmacologically meaningful reduction in therapeutic monoclonal antibody concentration. 
Pozelimab has been evaluated in a randomized, placebo-controlled double-blind study 
(R3918-HV-1659) in 56 healthy subjects in 7 dose cohorts (N=8, randomized 6:2 
pozelimab:placebo for each cohort). Pozelimab was found to be generally well tolerated in 
ascending single doses of 1, 3, 10, and 30 mg/kg IV and 300 and 600 mg SC. The seventh cohort, 
a multiple-dose cohort of 4 weekly SC doses of 400 mg following a 15 mg/kg IV loading dose, 
resulted in one resolved serious adverse event (SAE) in the study, an episode of salpingitis of 
undetermined etiology. The range of concentrations of pozelimab observed in study R3918-HV-
1659 encompasses the predicted concentrations expected in pediatric patients at the proposed 
dosing regimen. In all 4 IV dosing cohorts, suppression of hemolysis was observed as early as 
15 minutes post-injection. Transient, complete suppression of hemolysis was achieved with 
≥ 3 mg/kg dosing. At 30 mg/kg, complete suppression of hemolysis was maintained for 4 weeks, 
consistent with observed, prolonged pozelimab exposure following this dose. In the multiple-dose 
cohort 5, complete suppression of CH50 was observed over the 4-week dosing period and up to 
2 weeks after the last SC dosing. 
Pozelimab was well-tolerated in toxicology studies in adolescent (13-week study) and adult 
(26-week study) cynomolgus monkeys at doses up to 100 mg/kg/week via IV administration for 
up to 26 weeks. The NOAEL based on the results of these toxicology studies was determined to 
be 100 mg/kg, the highest dose tested. To date, toxicology studies in juvenile animals have not 
been conducted for pozelimab. Juvenile toxicology data are not expected to be required to initiate 
trials in a limited number of pediatric (<12 years of age) patients with life-threatening, ultra-orphan 
condition and no approved therapy. Available adult safety data, known target biology, and the lack 
of target organs identified in nonclinical toxicology (13- and 26-week) studies are expected to 
support dosing in the proposed patient population. Enhanced pre- and post-natal development 
(ePPND) data generation will run in parallel and is expected to be supportive of marketing 
authorization/BLA in pediatric patients. 
Additional background information can be found in the Investigator’s Brochure. 
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3.2.3. 
Risk-Benefit Assessment 
CD55-deficient PLE is a life-threatening, ultra-orphan disease with no current approved therapy. 
Current treatments typically include: corticosteroids, IVIg or SCIg, IV albumin, biologic 
immunomodulators 
(anti-TNF, 
vedolizumab), 
small 
molecule 
immunomodulators 
(e.g. azathioprine, mesalazine), micronutrients, enteral or parenteral feeding, anti-coagulants 
(low-molecular-weight heparin, aspirin), antibiotics, and anti-coagulants (Kurolap, 2017). In spite 
of these therapies, the long-term morbidity and risk of mortality remains. 
The benefit of blocking C5 complement activity in PLE is supported from reports of eculizumab, 
which alleviates disease, with an immediate recovery of signs and symptoms of PLE and in 
children, improved growth, along with the cessation of other medications (Kurolap, 2017). 
Pozelimab offers potential additional benefits of better control by providing maximal and durable 
inhibition of C5 throughout the dosing interval, improving the dosing regimen, binding to the 
polymorphic variant C5 protein which renders eculizumab ineffective, and development of a SC 
formulation. 
An established risk of blocking C5 complement activity is an increased susceptibility to infections, 
specifically to encapsulated organisms, the most potentially severe of which is infection with 
Neisseria meningitidis (Figueroa, 1991). Experience with eculizumab suggests that pretreatment 
with appropriate vaccinations covering multiple serotypes and concurrent therapy with oral 
antibiotics are effective at mitigating this risk (Hill, 2013)(Soliris package insert, 2019). Current 
treatment guidelines for PNH and the eculizumab package insert recommend such vaccination 
prior to dosing. 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 encapsulated organisms including N. meningitidis (Gaston, 1986) 
(Wedzicha, 2008). 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. Therefore, vaccination prior to administration (or at the time of administration, based on 
local practice, per Section 8.3.1) will sufficiently mitigate the risks of single and multiple doses of 
pozelimab in patients to a level that has been considered acceptable in other anti-C5 clinical 
development programs. In addition, concurrent therapy with oral antibiotics should be considered 
according to local practice (Section 8.3.2). 
Recently, serious infections with Neisseria species (other than N. meningitidis), including 
disseminated gonococcal infections, have been reported during eculizumab treatment 
(Soliris package insert, 2019). Counseling about Neisseria gonorrhea prevention, testing, and 
treatment is to be performed in accordance with local practice/national guidelines (see 
Section 8.4). 
There is a potential risk of immune complex formation when switching from eculizumab to 
pozelimab. SKY59, a humanized antibody against C5, is being administered in a clinical trial to 
7 patients with PNH who had been on eculizumab for at least 3 months (Röth, 2018). SKY59 is 
administered as IV loading dose 2 weeks after the last dose of eculizumab, and then 1 week later 
patients receive SC administration either weekly, every 2 weeks, or every 4 weeks. In 2 out of 
7 patients, mild to moderate, non-serious, likely drug-target-drug complex-mediated reactions 
with clinical manifestations similar to serum sickness were observed in the initial post-switch 
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period (days 9 and 10, respectively). These manifestations were treated with topical steroids and 
resolved by day 21 with no interruption in study treatment. The authors noted that in patients 
switching from eculizumab to SKY59, the formation of drug-target-drug complex composed of 
SKY59, C5, and eculizumab is expected due to the different binding epitopes of the 2 antibodies. 
Therefore, during the transition of therapy in patients currently being treated with eculizumab and 
who switch to pozelimab treatment, immune complex formation comprising eculizumab, C5, and 
pozelimab may occur. Although the consequences of this hypothetical complex formation are 
unknown, a potential risk includes immune adverse events (AEs). To mitigate this risk, the 
investigator will maintain heightened awareness, and appropriate safety monitoring during this 
early phase will be included. Also, the loading dose of pozelimab has been designed to generate 
an excess of pozelimab over eculizumab, a measure intended to avoid the equimolar stoichiometric 
conditions (Regeneron data; report in preparation) that may give rise to higher-order immune 
complexes. Guidance on the management of a suspected immune AE due to drug-target-drug 
immune complex formations of eculizumab-C5-pozelimab is provided in Section 8.5. 
A risk-benefit statement for pozelimab is provided in the Investigator’s Brochure. 
3.2.3.1. 
Study Conduct in Response to COVID-19 
Recognizing that the “Coronavirus Disease 2019” (COVID-19) pandemic will have an impact on 
the conduct of clinical trials, the sponsor does not intend to screen any subjects 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 subjects 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. 
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4. 
STUDY VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
Baseline characteristics (as allowed to be collected per local regulations) will include standard 
demographic information (eg, age, race, weight, height, etc.), disease characteristics, medical 
history, and medication history for each patient. 
4.2. 
Outcome Variables 
The outcome variables include albumin and albumin infusion, protein, immunoglobulins, 
micronutrients, laboratory markers, α-1 trypsin, AEs, vital signs, frequency of bowel movements 
and diarrhea, gastrointestinal symptoms, health-related quality of life, clinician assessment of 
disease activity (current and change), assessment of edema and ascites, use of concomitant 
medications to treat PLE, outcome assessments, hospitalization days, and height and weight. A list 
and details of outcome variables can be found in Sections 9.2.2 (Efficacy Procedures) and 9.2.4 
(Safety Procedures). 
4.3. 
Pharmacokinetic Variables 
The PK variable is the concentration of total pozelimab at time points shown in Table 1. 
4.4. 
Immunogenicity Variables 
The immunogenicity variables are ADA status, titer, status of neutralizing antibodies (NAbs), and 
time point/visit. Samples in this study will be collected at the clinic visits specified in Table 1. 
Samples positive in the ADA assay will be further characterized for NAbs. 
4.5. 
Exploratory Biomarker Variables 
Exploratory variables may include but are not limited to:  
• Markers of thrombosis: D-dimer, and N terminal prothrombin fragments [F1+2]  
• Levels of total C5 protein 
• Markers of complement pathway activation: soluble C5b-9 
• A sample for additional exploratory biomarkers (PD, predictive, and prognostic) 
potentially related to pozelimab treatment exposure, clinical activity, or underlying 
disease may be collected and archived. 
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5. 
PRIMARY AND SECONDARY OUTCOMES 
5.1. 
Primary Outcome 
The primary endpoint at week 24 is the proportion of patients with active disease at baseline 
achieving both of the following: 
• Normalization of serum albumin, defined as 
− serum albumin within the normal range at at least 70% of measurements between 
week 12 and week 24, and 
− no single albumin measurement of <2.5 g/dL between week 12 and week 24, and 
− no requirement for albumin infusion between week 12 and week 24 
• Improvement in the following clinical outcomes that were evaluable for improvement 
at baseline, with no worsening of the others (ie, those not evaluable for improvement) 
at week 24: 
− The number of bowel movements per day, based on a 1-week average, captured by 
e-diary. Improvement is defined as a reduction of 50% or more in the number of 
daily bowel movements based on a 1-week average. Patients evaluable for 
improvement are defined as those with an average of 3 or more bowel movements 
per day at baseline. Worsening is defined as an increase of 30% or more. 
− Physician assessment of facial edema (based on a 5-point Likert scale). 
Improvement is defined as a reduction of 2 points or more. Patients evaluable for 
improvement are defined as those with a severity of at least 3 points out of 5 at 
baseline. Worsening is defined as an increase of 2 points or more. 
− Physician assessment of peripheral edema (based on a 5-point Likert scale). 
Improvement is defined as a reduction of 2 points or more. Patients evaluable for 
improvement are defined as those with a severity of at least 3 points out of 5 at 
baseline. Worsening is defined as an increase of 2 points or more.  
− Patient/caregiver assessment of abdominal pain frequency as assessed by the 
Stomach pain and hurt sub-scale of the PedsQL™ GI Symptom Scale. 
Improvement is defined as an increase of 25 points or more (on the 0 to 
100 transformed total subscale score where lower scores indicate worse GI stomach 
pain and hurt). Patients evaluable for improvement are defined as those with a score 
of 70 points or less at baseline. Worsening is defined as a decrease of 25 points or 
more. 
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5.2. 
Secondary Outcomes 
The secondary endpoints are:  
• Incidence and severity of treatment-emergent adverse events (TEAEs) and other safety 
variables from baseline to week 144 
• Improvement in each patient’s most bothersome sign/symptom at week 24, as 
determined prior to baseline using a semi-structured concept elicitation interview, from 
amongst the ‘core’ clinical endpoints of frequency of bowel movements, peripheral 
edema, facial edema, abdominal pain frequency (as described in Section 5.1), nausea, 
vomiting, and stool consistency: 
− Improvement in nausea and vomiting will be defined as an increase of 25 points or 
more on the 0 to 100 transformed nausea and vomiting subscale of the PedsQL GI 
Symptom Scale score where lower scores indicate worse nausea and vomiting. 
Patients will be evaluable for improvement in nausea and vomiting if they have a 
score ≤75 on the nausea and vomiting subscale at baseline 
− Improvement in stool consistency will be defined as a reduction of ≥50% in the 
number of days per week that the patient has a bowel movement of loose/watery 
consistency. A bowel movement is considered to be loose/watery if it corresponds 
to 3 images of loose or watery stools on the Brussels Infant and Toddler Stool Scale 
(BITSS), the images and descriptors for categories 4 or 5 on the modified Bristol 
Stool Form Scale for Children (mBSFS-C), and the images and descriptors for 
categories 6 or 7 of the Bristol Stool Form Scale (BSFS). To be evaluable for 
improvement in stool consistency, patients must have a bowel movement of 
loose/watery stool consistency for ≥2 days/week at baseline 
• The proportion of patients with active disease at baseline who maintain disease control 
in these time periods (in weeks) 12-48, 12-144, 24-48, 48-96, 96-144 as defined by: 
− Normalization of serum albumin, defined as serum albumin within the normal 
range at at least 70% of measurements and no single albumin measurement of 
<2.5 g/dL and no requirement for albumin infusion 
− No worsening (definitions in parentheses) from the beginning of the stated time 
period, at any single visit during the stated time period, of: facial or peripheral 
edema (≥2-point increase); or stomach pain and hurt sub-scale (≥25-point 
decrease); or diarrhea subscale of the PedsQL GI Symptom Scale (≥25-point 
decrease) 
− No increase in dose of permitted concomitant medication for the treatment of PLE 
at any time, no re-introduction of any permitted concomitant medication once 
withdrawn, where permitted concomitant medication is as follows: corticosteroids, 
IV or SC immunoglobulin, IV albumin, biologic immunomodulators (anti-TNF, 
vedolizumab), small molecule immunomodulators (eg, azathioprine, mesalazine), 
micronutrients, enteral or parenteral supplementation 
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• The proportion of patients with inactive disease on eculizumab at baseline who 
maintain disease control in these time periods (in weeks) 12-48, 12-144, 24-48, 48-96, 
96-144 as defined by: 
− Normalization of serum albumin, defined as serum albumin within the normal 
range at at least 70% of measurements and no single albumin measurement of 
<2.5 g/dL and no requirement for albumin infusion  
− No worsening (definitions in parentheses), from the beginning of the stated time 
period, at any single visit during the stated time period, of: facial or peripheral 
edema (≥2-point increase); or stomach pain and hurt sub-scale (≥25-point 
decrease); or diarrhea subscale of the PedsQL GI Symptom Scale (≥25-point 
decrease) 
− No increase in dose of permitted concomitant medication for the treatment of PLE 
at any time, no re-introduction of any permitted concomitant medication once 
withdrawn, where permitted concomitant medication is as follows: corticosteroids, 
IV or SC immunoglobulin, IV albumin, biologic immunomodulators (anti-TNF, 
vedolizumab), small molecule immunomodulators (eg, azathioprine, mesalazine), 
micronutrients, enteral or parenteral supplementation 
• The number of bowel movements per day, based on a 1-week average, captured by 
e-diary from baseline to week 24 
• The number of days/week with ≥1 bowel movement of loose/watery stool consistency, 
as measured by BSFS for patients who are 18 years of age and older, mBSFS-C for 
patients who are toilet-trained and less than 18 years of age, or the BITSS who are not 
toilet-trained, and captured by e-diary from baseline to week 24 
• Physician assessment of facial edema (based on a 5-point Likert scale) from baseline 
to week 144 
• Physician assessment of peripheral edema (based on a 5-point Likert scale) from 
baseline to week 144 
• Change in abdominal symptoms, as assessed by the PedsQL™ GI Symptom Scale 
stomach pain and hurt sub-scale and food and drink limits sub-scale from baseline to 
week 144 
• Health-related quality of life as assessed by the PedsQL™ Generic Core Scales from 
baseline to week 144; additionally, the following sub-scales will be reported separately:  
− About my work/studies and school functioning sub-scale 
− Physical functioning sub-scale 
• Assessment of abdominal ascites (assessed by measurement of abdominal 
circumference) from baseline to week 24 
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• Frequency of albumin infusions up to week 144, expressed as number per half-year. 
Albumin infusions are permitted during the treatment phase in the event that the 
albumin level is below 3.0 g/dL at 2 consecutive visits with accompanying symptoms 
of facial or peripheral edema or ascites. Any albumin infusions between week 12 and 
week 24 will render the patient a non-responder for the primary endpoint. 
• Total albumin, protein, total Ig, IgG, IgM, IgA, expressed as:  
− Absolute value at every scheduled time point including week 24 
− Absolute and percent change from baseline over time 
− Time to first normalization 
• Vitamin B12, folate, iron, iron binding capacity, ferritin, magnesium, fasting 
cholesterol/triglycerides, expressed as:  
− Absolute value at every scheduled time point including week 24 
− Change from baseline over time 
− Time to first normalization 
• Alpha-1 antitrypsin levels in blood and stool, and change from baseline to week 12 and 
week 24 
• Use and dose/frequency from baseline to week 144 of: corticosteroids, IV or SC 
immunoglobulin, IV albumin, biologic immunomodulators (anti-TNF, vedolizumab), 
small molecule immunomodulators (eg, azathioprine, mesalazine), micronutrients, 
enteral or parenteral supplementation, anti-coagulants (eg, low-molecular-weight 
heparin), antibiotics (with the exception of those used for the purpose of Neisserial 
prophylaxis), anti-platelet agents (eg, low-dose aspirin) 
• Hospitalization days (percentage of days hospitalized) over time 
• Body weight and height (expressed as z scores) over time  
• Concentrations of total pozelimab in serum assessed throughout the study 
• Incidence of treatment-emergent anti-drug antibodies (ADA) to pozelimab in patients 
over time 
• Change and percent change from baseline of total complement activity CH50 over time 
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5.3. 
Exploratory Outcomes 
• Total C5 concentrations in plasma over time 
• Markers of thrombosis: D-dimer, and N terminal prothrombin fragments (F1+2)  
• Complement assays : sC5b-9 
• Change in GI symptoms (Diarrhea sub-scale and Nausea and vomiting sub-scale) as 
measured by the Pediatric Quality of Life Inventory (PedsQL™) GI Symptoms Scales 
from baseline over time 
• Change in caregiver well-being and burden as measured by the PedsQL™ Family 
Impact Module from baseline over time 
• Clinician global impression of change (CGIC) from baseline to week 144 
• Clinician global impression of severity (CGIS) from baseline to week 144 
• Patient/caregiver global impression of change (PGIC/CareGIC) from baseline to 
week 144 
• Patient/caregiver global impression of severity (PGIS/CareGIS) from baseline to 
week 144 
• If appropriate to age and stage of sexual maturation, the Tanner pubertal stage 
• Whole exome sequencing (if not already done) 
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6. 
STUDY DESIGN 
6.1. 
Study Description and Duration 
R3918-PLE-1878 is an open-label, single-arm, 144-week treatment study in patients aged 1 year 
and older with active clinical signs and symptoms of CD55-deficient PLE/CHAPLE disease, and 
a CD55 loss-of-function mutation detected by genotype analysis (frameshift, nonsense mutations). 
In the case of missense or suspected splice site mutations, CD55-deficient PLE is to be confirmed 
by flow cytometry of peripheral blood cells. The first 2 patients enrolled will be of age 6 or older 
(exception will be made for patients under 6 years of age with life-threatening disease, see 
Section 3.2.1). 
A minimum of 6 patients with active PLE will be enrolled, up to approximately 20 patients. The 
primary analysis will occur when approximately 6 patients with active PLE have received 
24 weeks of treatment. Subsequent analyses will occur 1 and 2 years after the first dose in the last 
patient enrolled. 
Patients will be given a single loading dose of pozelimab 30 mg/kg IV on day 1, then fixed doses 
SC (based on body weight) QW (±2 days) over the treatment period (Section 3.2.2).  
The study consists of a screening period (up to 4 weeks [or up to 10 weeks for patients with 
extenuating circumstances, Section 9.2.1]) followed by a 144-week treatment period (from week 0 
to week 144, with last dose at week 143), and a follow-up period (from week 145 to week 164;  
Figure 1).  
Active PLE is defined as hypoalbuminemia of less than or equal to 3.2 g/dL within the screening 
period, and within the last 6 months, at least 7 days (which do not have to be consecutive) of one 
or more of the following symptoms or signs: diarrhea, vomiting, abdominal pain, peripheral or 
facial edema, or an episode of infection with concomitant hypogammaglobulinemia, or a new 
thrombotic event. Active patients should not be on current therapy with eculizumab.  
As part of risk mitigation for this study, patients should receive updated meningococcal, 
Haemophilus influenzae type B, and pneumococcal vaccinations (Section 8.3.1) and are 
recommended to receive daily oral antibiotic prophylaxis (Section 8.3.2) as well as counselling 
regarding risk of Neisseria gonorrhea (Section 8.4), as applicable. Subsequent to the first 
2 patients, in addition to the active patient population heretofore described, patients who are well-
controlled on eculizumab may consider switching to pozelimab to avoid IV infusion. Patients 
switching to pozelimab from eculizumab will be switched with no wash-out, due to the risk of 
thrombosis with a return to active disease. In this case, eculizumab should be discontinued at the 
baseline visit, which should be scheduled within the window for the next eculizumab dose. 
Pozelimab should be started at the time that the next scheduled eculizumab dose would have taken 
place (the dosing interval for eculizumab is typically 2 weeks). The first pozelimab dose will be 
administered instead of eculizumab. Due to a theoretical risk of formation of higher order 
complexes of pozelimab/C5/eculizumab in these patients in the initial weeks of active treatment, 
the protocol contains guidance for investigators to create awareness of the symptoms and signs of 
type III hypersensitivity reactions and provides for clinical management of such reactions 
(Section 8.5). 
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Figure 1: 
Study Flow Diagram 
 
 
1. Screening period may be extended to approximately 10 weeks for patients with extenuating circumstances, 
as described in Section 9.2.1. 
2. Patients will receive an IV loading dose of pozelimab on week 0/day 1 and then receive SC pozelimab 
weekly until week 143 for a total treatment duration of 144 weeks. 
After the first administration of pozelimab at the study site, subsequent administrations may either 
be continued at the clinical site, or by the site personnel or another healthcare professional at 
patient’s home (if possible) or local clinic, or self-administered/administered by the patient or 
designated person, respectively. 
6.1.1. 
Study Stopping Rules 
6.1.1.1. 
Individual Patient Stopping Rules 
If a patient experiences 1 SAE, or 2 AEs of severe intensity (in either case possibly or definitely 
attributable to pozelimab) (Section 10.2.5), or 1 of the reasons for discontinuation outlined in 
Section 8.6.2, a meeting of the Steering Committee (Section 6.3.1) will take place to review the 
event and make recommendations as to whether the patient may continue treatment.  
6.1.1.2. 
Study Stopping Criteria 
Decisions to discontinue or suspend the study will be made by the Steering Committee 
(Section 6.3.1).  
Enrollment of new patients will be paused should the following occur: 
• Two or more patients experience 1 or more SAEs judged to be possibly or definitely 
attributable to pozelimab 
Following the review of all available safety data by the Steering Committee, a consensus opinion 
that the totality of the data suggests that this event is unlikely to be related to pozelimab will lead 
to resumption of study enrollment. Conversely, an unfavorable benefit-risk assessment will lead 
to a recommendation to terminate the study. Any recommendation to terminate the study made by 
the Steering Committee must be approved by the Regeneron Safety Oversight Committee (RSOC), 
which includes senior clinical, regulatory, and pharmacovigilance leaders at Regeneron. 
6.1.2. 
End of Study Definition 
The end of study is defined as the last visit of the last patient.  
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6.2. 
Planned Interim Analysis 
There will not be a formal interim analysis of efficacy data for an early stopping of the study. 
6.3. 
Study Committees 
6.3.1. 
Steering Committee 
There will be a Steering Committee comprised of key investigators and individuals representing 
the sponsor (including representatives from clinical, safety, and statistics) who will meet regularly 
to review available data throughout the study, and ad hoc triggered by individual or study stopping 
rules. Impartial input will be provided by committee members who are not directly involved in the 
conduct of the study, including at least 1 physician experienced in treating patients with PLE and 
at least 1 member experienced in pediatric rare diseases and/or pediatric ethics. If 1 individual is 
identified with both these areas of expertise, there will be only 1 additional member. The Steering 
Committee may recommend to continue, discontinue, suspend, or alter the study on the basis of 
accumulating efficacy and safety information.  
The composition and meeting schedule for this committee will be described further in a charter.  
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7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
7.1. 
Number of Patients Planned 
A minimum of 6 patients with active PLE will be enrolled, up to approximately 20 patients. 
Eligible patients with inactive disease may also be enrolled, but their data will not contribute to 
the primary analysis.  
Selected sites are those in Turkey, Israel, and the USA that have diagnosed and provided care for 
these patients. Other countries (including those in the EU) may be added depending on patient 
availability, without amending this protocol. Patients may attend some visits at a site in a country 
other than their country of residence on a case-by-case basis. 
7.2. 
Study Population 
Patients aged 1 year and older with a clinical diagnosis of CD55-deficient PLE disease, with CD55 
loss-of-function mutation determined by genetic analysis (frameshift, nonsense mutations) and 
confirmed (only necessary in the case of missense or suspected splice site mutations) by flow 
cytometry or western blotting CD55 on peripheral blood cells. The first 2 patients must be aged 
6 years or older, except in a case whereby severity of disease is life-threatening (Section 3.2.1). 
7.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Male or female aged 1 year and older. The first 2 patients recruited must be aged 6 years 
or older (exception will be made for patients under 6 years of age with life-threatening 
disease, see Section 3.2.1). 
2. Clinical diagnosis of CD55-deficient PLE/CHAPLE disease (based on a history of PLE), 
confirmed by biallelic CD55 loss-of-function mutation detected by genotype analysis 
(frameshift, nonsense mutations). In the case of missense or suspected splice site mutations, 
CD55-deficient PLE is to have been confirmed by flow cytometry of peripheral blood cells 
or western blot. These diagnostic tests can be performed as part of the study screening 
procedures, or as part of standard clinical evaluation prior to screening.  
3. Patient either has:  
a. Active disease, defined as:   
i 
Hypoalbuminemia of less than or equal to 3.2 g/dL within the screening period, 
and 
ii Within the last 6 months and attributable to CD55-deficient PLE, at least 7 days 
(which do not have to be consecutive) of at least one of the following symptoms or 
signs: diarrhea, vomiting, abdominal pain, peripheral or facial edema, or an episode 
of infection with concomitant hypogammaglobulinemia, or a new thromboembolic 
event 
NOTE: The first 2 patients enrolled in the study must fall into inclusion criterion 3a. 
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b. Inactive disease on eculizumab therapy (and whose treating physician has the 
expectation of future access to renewed eculizumab treatment should this be required), 
and is willing to discontinue eculizumab during screening and start pozelimab at 
baseline with no eculizumab wash-out. 
4. Willing and able to comply with clinic visits and study-related procedures. 
5. Written informed consent from parent/guardian for minor patients. 
6. Written assent from minor patients as appropriate (eg, above the age of 6 years or the 
applicable age per local regulatory requirements). 
7. Patient either alone or with the help of their parents/legal guardians, as required, must be 
able to understand and complete study-related questionnaires. 
7.2.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. History of meningococcal infection. 
2. No documented meningococcal vaccination within 3 years prior to screening and patient 
unwilling to undergo vaccination during the study (if fully available according to local 
practice). Refer to Section 8.3.1 for further details. 
3. No documented vaccination for Haemophilus influenzae and Streptococcus pneumoniae if 
applicable based on local practice or guidelines prior to screening and patient unwilling to 
undergo vaccination during the study if required per local practice or guidelines. Refer to 
Section 8.3.1 for further details. 
4. Presence of a concomitant disease that leads to hypoproteinemia at the time of starting 
pozelimab, including a urinary protein loss or a hepatic disease that affects production of 
proteins by liver. 
5. A concomitant disease that leads to secondary intestinal lymphangiectasia such as a fontan 
procedure for congenital heart disease. 
6. Recent infection requiring systemic treatment with antibiotics, antivirals, or antifungals 
(within 2 weeks of screening or during the screening period). If the patient is appropriately 
treated, the patient may be rescreened. 
7. PLE previously refractory to eculizumab, with the exception of patients with the 
Arg885His variant in the C5 gene. 
8. Known hereditary complement deficiency other than CD55 deficiency. 
9. Documented history of active, ongoing systemic autoimmune diseases. 
10. Known or suspected infectious colitis at screening. Once this has resolved, patient may be 
rescreened. 
11. Patients with an estimated glomerular filtration rate (eGFR) of <30 mL/min/1.73 m2 
(according to Chronic Kidney Disease - Epidemiology Collaboration equation 2009 
[adults] or creatinine-based Schwartz equation [pediatric patients]). 
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12. Recent, unstable medical conditions, excluding PLE and related complications, within the 
past 3 months prior to screening visit. Option to rescreen after 3 months has elapsed. 
13. Known sensitivity to any of the components of the pozelimab formulation or drug 
product. 
14. Any clinically significant abnormality identified at the time of screening that, in the 
judgment of the investigator or any sub-investigator, would preclude safe completion of 
the study or constrain endpoints assessment, such as major systemic diseases, including a 
medical history of hepatitis B or C. Patients known to have had hepatitis B or C in the past 
can enroll only if these diseases are no longer active, as demonstrated by negative hepatitis 
B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), hepatitis B virus DNA, and 
negative hepatitis C virus RNA (HCV RNA), respectively. 
Note: Testing for hepatitis B and C is not mandatory for enrollment in the trial but may 
be performed at the discretion of the investigator.  
15. Participation in another interventional clinical study 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 complement inhibitors (see Section 7.2.1) 
16. Considered by the investigator or any sub-investigator as inappropriate for this study for 
any reason, eg: 
• Deemed unable to meet specific protocol requirements, such as scheduled visits and/or 
• Deemed unable to tolerate long-term injections as per the patient, the investigator, sub-
investigator, pharmacist, study coordinator, other study staff, or relative thereof directly 
involved in the conduct of the study, etc. and/or 
• 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 
17. Patients who are committed to an institution by virtue of an order issued either by the 
judicial or the administrative authorities 
18. Women who are pregnant, breastfeeding, or who have a positive pregnancy test at 
screening visit or day 1 
19. Pregnant or breastfeeding women 
20. Women of childbearing potential* and girls beyond menarche (and not sexually 
abstinent) who are unwilling to practice highly effective contraception prior to the initial 
dose/start of the first treatment, during the study, and for at least 21 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) 
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c. Bilateral tubal ligation 
d. Vasectomized partner 
e. And/or sexual abstinence†, ‡. 
* 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 or tubal ligation. 
† 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 treatments. 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 patient. 
‡ Periodic 
abstinence 
(calendar, 
symptothermal, 
post-ovulation 
methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea 
method (LAM) are not acceptable methods of contraception. Female condom and 
male condom should not be used together.  
21. Intentionally left blank  
22. Documented history of unresolved tuberculosis (TB), or evidence of active or latent 
tuberculosis infection (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. 
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. 
Patients who are withdrawn prematurely from the study will be asked to complete study 
assessments, as described in Section 9.1.2. 
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 8.6.2. 
7.4. 
Replacement of Patients 
Patients prematurely discontinued from study will not be replaced. 
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8. 
STUDY TREATMENTS 
8.1. 
Investigational Treatment 
Pozelimab drug product will be provided in a sterile, single-use glass vial for either IV or SC 
administration and will be supplied by the sponsor. 
Pozelimab drug product will be initially provided in lyophilized form in a sterile, single use glass 
vial for IV or SC administration that requires reconstitution with sterile water for injection, and 
then transitioned to a sterile, single-use glass vial or pre-filled syringe containing a liquid 
200 mg/mL pozelimab formulation for IV or SC administration that will not require reconstitution. 
The compositions of the lyophilized and liquid formulations differ, mainly as a result of the 
inclusion of a viscosity reducer in the high concentration liquid formulation. 
Study drug will be supplied by the sponsor. The admixture solutions needed for delivery of the 
lyophilized or liquid drug product for IV administration will be sourced locally, or may be supplied 
by the sponsor, as necessary. Detailed information about the drug product and dose preparation is 
provided in the pharmacy manual. Detailed information about the drug product and dose 
preparation is provided in the pharmacy manual. 
8.2. 
Drug Administration 
Patients will be given a single loading dose of pozelimab 30 mg/kg IV on day 1, then SC dosing 
QW (±2 days) over the treatment period based on body weight. The last dose of study drug is 
administered at week 143. 
Dose regimen: 
• For BW < 10 kg: 125 mg. 
• For BW ≥10 kg and < 20 kg: 200 mg. 
• For BW ≥20 kg and < 40 kg: 350 mg. 
• For BW ≥40 kg and < 60 kg: 500 mg. 
• For BW ≥60 kg: 800 mg. 
The location and administration options for SC route of administration will depend on the 
preference of the investigator and patient (eg, abdomen, thigh, or upper arm), the availability of 
clinical supply, and home healthcare visiting professional. Clinic visits for SC administration may 
or may not be needed. 
If self-administration/administration by patient/designated person is allowed locally, then 
sufficient injection training at the scheduled injection with pozelimab 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. Once this observation is 
considered satisfactory, then the study drug can be subsequently administered independently by 
patient/designated person for the remainder of the study. 
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In addition, a patient diary will be provided prior to initiation of self-administration (ie, day 29). 
The diary should be completed upon each study drug administration. A study drug kit will be 
dispensed at the clinical site visit, using a direct-to-patient (DTP) service provider, or transported 
by a healthcare professional, as applicable. 
Detailed information about the study drug administration is provided in the pharmacy manual. 
8.3. 
Pretreatments 
Enrolled patients will require evidence of meningococcal immunization or administration of 
vaccination during the screening period, and oral antibiotics are recommended during the treatment 
period, according to local or national practice and investigator’s assessment. 
8.3.1. 
Vaccinations 
Enrolled patients will require immunization with meningococcal vaccinations. Administration of 
vaccination should occur preferably at least 2 weeks prior to initiation of pozelimab, or at another 
time point according to local practice or national guidelines. It is suggested that patients undergo 
vaccination for serotypes A, C, Y, W, and, if available, serotype B. Patients who have had previous, 
documented vaccination for meningococcus will be re-immunized based on local practice. Patients 
should be closely monitored for early signs and symptoms of meningococcal infection and 
evaluated immediately if an infection is suspected. Patients will be provided with a patient safety 
card describing signs and symptoms of meningococcal infection, along with instructions in case 
of a potential meningococcal infection, as well as information for the non-investigator healthcare 
provider.  
In addition, patients are also required to have evidence of Haemophilus influenzae and 
pneumococcal immunizations, unless the patient has a medical contraindication. If adequate 
documentation of prior administration is not available or if the patient is not up-to-date with the 
recommended administration, the vaccines will be administered prior to the initiation of treatment 
with the study drug, according to local practice, guidelines, and availability. 
The vaccinations will be sourced locally by the investigator or designee and reimbursed by the 
sponsor. 
8.3.2. 
Oral Antibiotics 
Daily, oral antibiotic prophylaxis may commence on the day of first dosing, unless the risks 
outweigh the benefits, or it is inconsistent with local practice, and continue for the duration of the 
study. It is recommended that patients who prematurely discontinue pozelimab receive at least 
21 weeks of oral antibiotic prophylaxis after discontinuing pozelimab, or a duration consistent with 
local guidelines, whichever is longer (Section 9.1.2). For adults, it is suggested that antibiotic 
prophylaxis be penicillin V 500 mg twice a day (BID), and in the case of penicillin allergy, 
erythromycin 500 mg BID may be used at the discretion of the investigator. For pediatric patients, 
it is suggested that antibiotic prophylaxis be penicillin VK 125 mg orally BID in patients who are 
< 5 years of age, and 250 mg BID if ≥ 5 years of age. If pediatric patients are penicillin-allergic, 
then erythromycin 125 mg orally BID in patients who are < 3 years of age and 250 mg orally BID 
in patients who are ≥ 3 years of age. Ultimately, the decision to administer prophylaxis with oral 
antibiotics, the duration of prophylaxis, the choice and dosage regimen of oral antibiotics will be 
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at the discretion of the investigator. The oral antibiotics will be sourced locally by the investigator 
or designee and reimbursed by the sponsor. 
8.4. 
Risk Management of Neisseria Gonorrhea 
Patients should be counseled about Neisseria gonorrhea prevention and regular testing should be 
advised for at-risk patients, as applicable. 
A risk factor 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 healthcare 
provider) to determine if the patient is at risk, which would lead to further management on 
prevention, testing, and treatment of Neisseria gonorrhea. 
Testing and treatment should be in accordance with local practice/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. 
8.5. 
Risk Management of Immune Complex Formation 
During the transition of therapy from eculizumab to pozelimab, investigators should have 
heightened awareness for possible immune AEs as a result of the risk of drug-target-drug immune 
complex formations of eculizumab-C5-pozelimab. Patients may present with a variety of signs and 
symptoms such as fever, malaise, rash, and polyarthralgia. Less common manifestations include 
edema, neuropathy, GI complaints, nephropathy (including systemic hypertension), and vasculitis. 
If a rash does develop, the site may consider taking pictures of the skin lesions, as allowed based 
on local requirements. If photos are obtained, then copies should be kept as source documents, 
which may later be collected by the Sponsor. Laboratory tests should include an unscheduled CBC, 
ESR, CRP, chemistry, C3, C4, and urinalysis. Hematuria of ++ or more on urinalysis should be 
followed up with urine microscopy for red blood cell (RBC) and white blood cell (WBC) 
quantification. Proteinuria of ++ or more should be followed up with a protein:creatinine ratio 
from a spot urine sample. Further investigations are at the discretion of the investigator. 
Investigators should consider treatment with an additional dose of SC pozelimab. This dose should 
be in accordance with the tiered, weight-based regimen and be administered 3 to 4 days prior to 
the next scheduled dose. This additional dose will establish conditions of pozelimab excess in the 
circulation and minimize the risk of further formation of immune complexes. In addition, further 
management should be based on clinical experience with type III hypersensitivity reactions (ie, 
serum sickness) which include antihistamines, non-steroidal anti-inflammatory drugs, topical 
corticosteroids for localized skin rash, and systemic corticosteroids for generalized skin rash, 
internal organs, or systemic manifestations. 
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8.6. 
Dose Modification and Study Treatment Discontinuation Rules 
8.6.1. 
Dose Modification 
Dose regimen modification/reduction is not allowed for an individual patient.  
• Patients will increase dose as specified by the dose regimen in the event that they move 
into a higher BW bracket. For the purposes of these dose increases, body weight will 
be measured at the study visits as specified in the schedule of assessments (Table 1) 
and not at each weekly administration. Pozelimab will be supplied initially in vials as 
lyophilized powder for reconstitution, so a single presentation will support all the 
weight-based dosing regimen The correct number of vials and volume for SC injection 
drawn up will be administered by a healthcare practitioner (not necessarily a doctor) at 
the study site, during a visit, or at a local primary healthcare clinic in between visits or 
at home; self-administration/administration by patient/designated person may also be 
allowed (Section 8.2). Each SC dose may be administered by more than one injection 
if necessary; each injection should not exceed a 2 mL volume. Further details will be 
described in the Pharmacy Manual. 
8.6.2. 
Study Drug Discontinuation 
Patients who permanently discontinue from study drug and who 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 
may be asked to complete study assessments, per Section 9.1.2. 
8.6.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
Study drug dosing will be permanently stopped in the event of: 
• Serious or severe allergic reactions considered related to study drug 
• Liver impairment as evidenced by one or more of the following criteria occurring 
without evidence of another etiology:  
− Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 8 x ULN 
or 
− ALT or AST > 5 x ULN for more than 2 weeks or 
− ALT or AST > 3 x ULN and total bilirubin > 2 x ULN (or international normalized 
ratio [INR] > 1.5) and no other reason can be found to explain the combination of 
increased AST/ALT and total bilirubin, such as viral hepatitis A, B, or C; 
preexisting or acute liver disease; or another drug capable of causing the observed 
injury 
• Patient withdraws consent 
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• Patient noncompliance (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 
Note: Evidence of pregnancy is not considered an automatic reason for permanent discontinuation 
and should be discussed with the medical monitor. Pregnancy may be a reason for permanent 
discontinuation if the benefit-risk assessment of continuing treatment with pozelimab is deemed 
unfavorable. 
8.6.2.2. 
Reasons for Temporary Discontinuation of Study Drug 
Temporary discontinuation may be considered by the investigator because of suspected AEs. The 
investigator can reinitiate treatment with study drug under close and appropriate clinical and/or 
laboratory monitoring once the investigator will have considered, according to his/her best medical 
judgment, that the responsibility of the study drug in the occurrence of the concerned event was 
unlikely. 
8.7. 
Management of Acute Reactions 
8.7.1. 
Acute Intravenous Infusion Reactions 
Patients should be observed for 30 minutes after the infusion. 
Emergency equipment and medication for the treatment of infusion reactions must be available 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. 
8.7.1.1. 
Interruption of the Intravenous Infusion 
The infusion should be interrupted if any of the following AEs are observed: 
• 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 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. 
8.7.1.2. 
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) 
8.7.2. 
Acute Injection Reactions 
8.7.2.1. 
Systemic Injection Reactions 
Patients should be observed for 30 minutes after the first SC injection. 
Emergency equipment and medication for the treatment of systemic reactions must be available 
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 SC injection of study drug should be treated using clinical 
judgment to determine the appropriate response according to typical clinical practice.  
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8.7.2.2. 
Local Injection Site Reactions 
Local injection site reactions must be reported as AEs and graded according to the Food and Drug 
Administration (FDA) September 2007 Guidance for Industry, Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (see also 
Section 10.2.5). 
8.8. 
Method of Treatment Assignment 
All patients who sign the informed consent form (ICF) will be assigned a patient number. 
Treatment assignment will be performed in an unblinded fashion. To demonstrate a clear effect of 
pozelimab as early as possible, the first 2 patients recruited should have active PLE. 
8.8.1. 
Blinding 
This is an open-label study. 
8.9. 
Treatment Logistics and Accountability 
8.9.1. 
Packaging, Labeling, and Storage 
Pozelimab for injection will be provided as open-label supplies packaged in carton boxes. Each 
carton box will contain 1 labeled vial. Carton box and vial label will indicate the protocol number, 
product identity and strength, medication/reference number, batch number, directions for use, 
route of administration, expiry date, sponsor information, and storage conditions, and will 
correspond to all regulatory requirements. 
If provided by sponsor, diluent for pozelimab for IV and SC injections will be provided as open-
label supplies packaged in carton boxes. Each carton box will contain 1 labeled vial. Carton box 
and vial label will indicate the protocol number, product identity and strength, 
medication/reference number, batch number, directions for use, route of administration, expiry 
date, and sponsor. 
Study drug will be stored at the site at a temperature of 2ºC to 8ºC; storage instructions will be 
provided in the pharmacy manual. 
8.9.2. 
Supply and Disposition of Treatments 
Study drug 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 study drug will be destroyed on site or at a destruction 
depot after accountability and reconciliation. 
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8.9.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug. 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. 
8.9.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the sponsor 
and regulatory agency inspectors. 
8.10. 
Concomitant Medications 
Any treatment administered from the time of informed consent to the end of the final study visit 
will be considered concomitant medication. This includes medications that were started before the 
study and are ongoing during the study. 
8.10.1. 
Prohibited Medications 
The following medications are prohibited, with the exception of those listed in Section 8.10.2, as 
described below: 
• Within 24 hours prior to each clinic visit when blood is drawn, patients should not 
consume any alcohol. 
• Beginning on day 1 and continuing throughout the study, while the patient is continuing 
pozelimab, the patient should not take eculizumab. 
• Add any experimental therapy, including complement inhibitors even if they become 
approved during study conduct. 
• No Vitamin B12 supplementation during the first 4 weeks of pozelimab treatment (ie, 
cannot be initiated prior to week 4 visit) 
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8.10.2. 
Permitted Medications 
Permitted medication is any medication that is not prohibited. The following medications and 
procedures will be permitted, under the following conditions: 
• Albumin infusions are permitted during screening for disease of life-threatening 
severity only, and after start of study drug in the event that the albumin level is below 
3.0 g/dL with accompanying symptoms of facial or peripheral edema or ascites. This 
limitation only applies to albumin infusions given specifically for the PLE. 
• Any medication required to treat an AE, including non-steroidal anti-inflammatory 
drugs, antihistamines, or topical or systemic corticosteroids, at the discretion of the 
investigator 
• Meningococcal vaccination, as described in Section 8.3.1  
• Oral antibiotic prophylaxis, as described in Section 8.3.2  
• Medications for treatment of type III hypersensitivity reactions as described in 
Section 8.5 
• Oral contraceptives or hormone replacement therapy may continue or be started during 
the study 
• Acetaminophen/paracetamol, aspirin, or ibuprofen at the recommended dose per the 
local label 
• Immunosuppressive drugs, biologic therapies, immunoglobulins, corticosteroids, iron 
supplements, vitamins, and enteral and parenteral feeding are permitted and considered 
treatments of PLE. Any changes to these concomitant medications will be at the 
discretion of the investigator. Weaning and/or withdrawal of any of these medications 
is permitted at the discretion of the investigator, in the context of response in the 
underlying disease to treatment with pozelimab. Anti-thrombotic agents, 
anticoagulants, antibiotics are permitted. 
• Any medication required for the treatment of patient’s background medical conditions 
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9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
9.1. 
Schedule of Events 
Study assessment and procedures are presented by study period and visit in Table 1. 
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. 
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Table 1: 
Schedule of Events  
Study Procedure 
Screening 29 
Baseline 
Treatment Period1 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Day  
-28 
1 
2 
8±3 
15±3 
22±3 
29±3 
43±3 
57±3 
71±3 
85±3 
Week 
-4 
0 
 
1 
2 
3 
4 
6 
8 
10 
12 
Screening/Baseline: 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion2 
X 
X 
 
 
 
 
 
 
 
 
 
Genetic testing (if needed)2 
X 
 
 
 
 
 
 
 
 
 
 
Medical History3 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Prior Medications4 
X 
 
 
 
 
 
 
 
 
 
 
Lab Parameter History5 
X 
 
 
 
 
 
 
 
 
 
 
Vaccination History6 
X 
X 
 
 
 
 
 
 
 
 
 
Risk assessment for Neisseria gonorrhea 
(as applicable)7 
X 
 
 
 
 
 
 
 
 
 
 
Hepatitis/TB history and assessment8 
X 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
Concept Elicitation Interview9 
X 
 
 
 
 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
Administer Study Drug10 
 
X11 
 
X12 
Patient Diary (for self-admin) 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Concomitant Meds and Interventions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy: 
 
 
 
 
 
 
 
 
 
 
 
Tanner Staging13 
 
X 
 
 
 
 
 
 
 
 
X 
e-Diary  
X14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BSFS, mBSFS-C, or BITSS 
X14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGIS 
 
X 
 
X 
X 
X 
X 
 
X 
 
X  
CGIC 
 
 
 
X 
X 
X 
X 
 
X 
 
X  
Physician Assessment of Facial Edema15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physician Assessment of Peripheral 
Edema15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abdominal Circumference15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body Weight with z Score 
X16 
X 
 
 
 
 
X 
 
X 
 
X 
Height with z Score 
X16 
X 
 
 
 
 
X 
 
X 
 
X 
PedsQL Generic Core Scales 
 
X 
 
X 
X 
X 
X 
 
X 
 
X 
PedsQL GI Symptom Scales 
 
X 
 
X 
X 
X 
X 
 
X 
 
X 
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Study Procedure 
Screening 29 
Baseline 
Treatment Period1 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Day  
-28 
1 
2 
8±3 
15±3 
22±3 
29±3 
43±3 
57±3 
71±3 
85±3 
Week 
-4 
0 
 
1 
2 
3 
4 
6 
8 
10 
12 
PedsQL Family Impact Module 
 
X 
 
X 
X 
X 
X 
 
X 
 
X 
PGIS/CareGIS 
 
X 
 
X 
X 
X 
X 
 
X 
 
X 
PGIC/CareGIC 
 
 
 
X 
X 
X 
X 
 
X 
 
X 
Hospitalization Days 
X17 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety: 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing and Biomarkers: 
 
 
 
 
 
 
 
 
 
 
Blood Chemistry Panel19 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Micronutrients and Lipid Panel20 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Blood Immunoglobulin Panel21 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Alpha-1 Antitrypsin (fecal and serum) 
 
X 
 
  
 
 
  
 
 
 
X 
Pregnancy Test22 
X 
X 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
X 
X 
X 
X 
 
 
 
X 
Hematology 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
Coagulation Panel (APTT/PT) 
X 
 
 
X 
 
 
X 
 
 
 
X 
Complement Hemolytic Assay (CH50)23 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Total C523 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Total Complement C3 and C4 Levels 
X 
 
 
 
 
 
 
 
 
 
 
Thrombosis Biomarkers24 
 
X 
 
X 
 
 
X 
 
 
 
X 
sC5b-9 (plasma) 23 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
Buccal Swab for DNA Isolation 
(optional)25 
 
X 
 
 
 
 
 
 
 
 
 
Future biomedical research (optional, 
weight >20 kg only) 
 
X 
 
 
 
 
X 
 
X 
 
X 
Drug Concentration and ADA Samples:  
 
 
 
 
 
 
 
 
 
Drug Conc. Sample 23, 27 
 
X 
 
X 
X 
 
X 
X 
X 
 
X 
ADA Sample 23,  27, 28 
 
X 
 
 
 
 
 
 
 
 
X 
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Table 1 
Schedule of Events (contd) 
Study Procedure 
Treatment Period1 
Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of TX 
Analysis 
End of 
Study 
Early 
Term 
Visit Number 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
 
Day  
99 
±3 
113 
±3 
127 
±3 
141 
±3 
155 
±3 
169 
±3 
253 
±3 
337 
±3 
421 
±3 
505 
±3 
589 
±3 
673 
±3 
1009 
±3 
1149 
±3 
 
Week 
14 
16 
18 
20 
22 
24 
36 
48 
60 
72 
84 
96 
144 
164 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer Study Drug10 
X12 
 
 
 
Patient Diary (self-admin) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant Meds and Interventions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tanner Staging13 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
E-Diary  
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
BSFS, mBSFS-C, or BITSS 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
CGIS 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
CGIC 
 
X 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
Physician Assessment of Facial Edema15 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Physician Assessment of Peripheral Edema15 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Abdominal Circumference15 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Body Weight with z Score16 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Height with z Score16 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
PedsQL Generic Core Scales 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
PedsQL GI Symptom Scales 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
PedsQL Family Impact Module 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
PGIS/CareGIS 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
PGIC/CareGIC 
 
X 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
Exit interview9 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Hospitalization Days 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Physical Examination 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse Events18 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Study Procedure 
Treatment Period1 
Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of TX 
Analysis 
End of 
Study 
Early 
Term 
Visit Number 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
 
Day  
99 
±3 
113 
±3 
127 
±3 
141 
±3 
155 
±3 
169 
±3 
253 
±3 
337 
±3 
421 
±3 
505 
±3 
589 
±3 
673 
±3 
1009 
±3 
1149 
±3 
 
Week 
14 
16 
18 
20 
22 
24 
36 
48 
60 
72 
84 
96 
144 
164 
 
Laboratory Testing and Biomarkers: 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Chemistry Panel19 
X26 
X 
X26 
X 
X26 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Micronutrients and Lipid Panel20 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
X 
Blood Immunoglobulin Panel21 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Alpha 1-Antitrypsin (fecal and serum) 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test22 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
Hematology 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
 
Coagulation Panel (APTT/PT) 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
Complement Hemolytic Assay (CH50) 23 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
 
Total C523 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
 
Total Complement C3 and C4 Levels 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thrombosis Biomarkers24 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
sC5b-9 (plasma) 23 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
Buccal Swab for DNA Isolation (optional) 25 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Future biomedical research (optional, body 
weight >20 kg only) 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
Drug Concentration and ADA Samples:  
 
 
 
 
 
 
 
 
 
 
 
 
Drug Conc. Sample 23, 27 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
ADA Sample 23, 27 
 
 
 
 
 
X 
 
X 
 
 
 
 X 
X  
X 
X 
 
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9.1.1. 
Footnotes for the Schedule of Events Table 
1. Treatment period is from week 0 to week 144, with first dose given on day 1 [week 0] and 
last dose at week 143. All visits in the Schedule of Events table are mandatory in-clinic 
visits, and do not reflect the dosing schedule, which is weekly (±2 days). Study procedures 
within each visit may be conducted on different days, within the stated visit window. 
2. Including history of CD55 gene mutation analysis and if necessary CD55 protein analysis, 
confirmed by flow cytometry or western blot, respectively. If this data is unavailable, a 
blood sample may be collected, as needed, for analysis. Refer to Section 9.2.1 for details. 
3. Including history of albumin infusions and prior thromboembolic events since birth 
4. Including eculizumab administration history 
5. Albumin, total protein, total immunoglobulin data including everything available from the 
patient’s birth onwards  
6. All patients require meningococcal, pneumococcal, and Haemophilus influenzae 
vaccination, either prior to the study or during screening, according to local availability 
and practice guidelines. Refer to Section 8.3.1 for details. 
7. Risk assessment for Neisseria gonorrhea is described in Section 8.4. 
8. 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. 
Optional hepatitis B/C testing may be performed at the discretion of the investigator. 
9. Patients (and caregivers, as appropriate) will be undergo a concept elicitation interview at 
screening and an exit interview at the time point of the primary endpoint as part of clinical 
outcomes evaluation. Details are described in Section 9.2.3.3. 
10. Meningococcal vaccination is required and daily oral antibiotic prophylaxis is 
recommended as described in Section 8.3. 
11. IV loading dose  
12. Subcutaneous dosing to be administered weekly either at study site or in local community 
healthcare setting close to patient or at home. Weekly dosing is not noted as visits on this 
SOE table. The last dose of study drug is administered at week 143. 
13. Only for patients between ages 8 to 20 years 
14. Patients to begin completion of e-diary recording bowel movements and consistency at 
least 7 days prior to the baseline visit 
15. In the presence of facial or peripheral edema or ascites, assessment should be always 
accompanied by clinical photography. 
16. Including all available historical height and weight data from birth 
17. Collect all available information pertaining to previous hospitalization dates since birth. 
18. Including new thromboses and extension of existing thromboses 
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19. Total protein and albumin are tested in this panel (see blood chemistry panel in 
Section 9.2.4.4 Laboratory Testing). Testing will use either adult or small-volume pediatric 
kits as specified in a manual or kit instruction. If patient receives IV albumin infusion, this 
panel should be drawn either prior to the infusion or 2 weeks after the infusion. 
20. See Micronutrients Panel and Lipids Panel in Section 9.2.4.4 Laboratory Testing. 
21. See Blood Immunoglobulin Panel in Section 9.2.4.4 Laboratory Testing. 
22. A pregnancy test is mandatory at screening and baseline for all women of childbearing 
potential (as defined in exclusion criterion #20). According to local practice in the study 
country, pregnancy testing (serum or urine) after enrollment is mandatory for all females 
from the age of sexual maturity, or for married females and, at the discretion of the 
investigator, for non-married females from the age of sexual maturity. 
23. Intensity of blood sampling for these analytes will be reduced if necessary to comply with 
local body weight-specific limitations on blood withdrawal volume. The blood draw 
schedule in Table 1 is designed for patients with body weight equal or greater than 20 kg. 
It is expected that patients below 20 kg in weight will require reduction in blood-draw 
intensity. A separate blood draw schedule will be provided for patients with body weight 
between 10 kg and 20 kg in the sample handling manual. For patients with body weight 
less than 10 kg, an order of priority of blood draws will be provided in the sample handling 
manual or kit instruction, and samples should be drawn in this order until the volume limit 
is reached. The chemistry panel will have highest priority followed by full blood count and 
drug concentration. 
24. Includes D-dimer, and F(1+2). Refer to lab manual for procedure. 
25. Sample should be collected at baseline visit but may be collected at any time. 
26. Kits may be provided locally so that the chemistry panel may be taken locally to the 
patient without needing a site visit. 
27. Drug concentration and ADA samples are to be collected prior to study drug 
administration. In the event of any SAE or any AESI of anaphylactic reactions or systemic 
allergic reactions that are related to study drug and require treatment, or severe injection 
site reaction lasting longer than 24 hours, drug concentration and ADA samples will be 
collected at or near the onset of the event for any additional analysis.  
28. In the event a patient sample is positive in the pozelimab ADA assay at week 12 or the first 
time point analyzed, the week 4 PK sample may be analyzed in the ADA assay, provided 
there is sufficient volume. 
29. The screening period may be extended to approximately 10 weeks for patients with 
extenuating circumstances as described in Section 9.2.1. 
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9.1.2. 
Early Termination Visit  
Patients who discontinue treatment and do not withdraw from study should continue all study visits 
as scheduled. If the week 164 visit does not include at least 21 weeks of follow-up, then patient 
should continue with site visits until 21 weeks after last dose of study drug. 
Patients who discontinue treatment and study should be requested to have an early termination 
visit consisting of assessments listed for end of treatment visit (Table 1). If the patient agrees to a 
follow-up safety phone visit, then a follow-up phone call will be scheduled for 21 weeks after last 
dose of study drug. 
Patients who discontinue study treatment after completing the treatment period should have a 
follow-up visit 21 weeks after last dose of study drug. This visit will consist of the safety 
assessments including laboratory tests (Section 9.2.4.4) listed for the week 144 visit in Table 1. 
Patients who are withdrawn from the study before the primary endpoint visit (week 24) will be 
asked to return to the clinic for 2 visits: once for an early termination visit consisting of the end of 
study assessments described in Table 1, and again at the primary endpoint visit (week 24, 
day 169/visit 17). Patients who are withdrawn from the study after the primary endpoint visit will 
be asked to return to the clinic for early termination assessments, only. 
In all instances, every attempt will be made to conduct a safety follow-up at 21 weeks after the last 
dose of study drug. 
9.1.3. 
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. 
9.2. 
Study Procedures 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed for the sole purpose of determining study eligibility 
or characterizing the baseline population:  
• Medical history, including demonstration of CD55 gene loss of function (and absence 
of CD55 protein, if necessary) and collection of all available genetic sequencing data. 
All available genetic sequencing data and flow cytometry data are to be collected in its 
entirety. If at the time of screening, the patient does not have documentation of what 
mutation he/she carries or it cannot be retrieved, then the study site staff should collect 
a blood sample for genetic testing by the investigator to determine the mutation type 
prior to randomization. This testing will be performed on an as needed basis.  
• History of albumin infusions and prior thromboembolic events since birth 
• Demographics 
• Prior medications including eculizumab 
• Hospitalizations including dates, since birth if available 
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• Historical laboratory parameters, including albumin, total protein, and total 
immunoglobulins, since birth if available 
• Vaccination history 
• Risk assessment for Neisseria gonorrhea, as applicable. See Section 8.4  
• 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 
• Optional hepatitis B/C testing may be performed at the discretion of the investigator 
and may include: HBsAg, HBeAg, hepatitis B virus DNA, or HCV RNA 
• ECG as described in Section 9.2.4.3  
• Concept elicitation interview as described in Section 9.2.3.3 
For screening purposes, multiple retest of laboratory testing is permitted for non-clinically 
significant abnormality. Additionally, patients who are appropriately treated for an intercurrent 
illness (eg, after a successful resolution of an infection) may be rescreened.  
The screening period may be extended to approximately 10 weeks for patients who meet any of 
the following criteria: 
• Patient requires additional time to complete meningococcal vaccinations  
• Patient must physically relocate to the vicinity of a study center 
• Patient is pending his/her screening laboratory results (Note: Samples for screening 
must be collected within 6 weeks of baseline) 
• Patient has another requirement, which will be evaluated on a case by case basis after 
a discussion between the sponsor and investigator 
9.2.2. 
Study Drug Administration 
Study drug will be administered as described in Section 8.2. Immunization with meningococcal, 
Haemophilus influenzae, and pneumococcal vaccines are to be performed according to local 
practice (Section 8.3.1). Daily oral antibiotic prophylaxis is recommended (Section 8.3.2). 
Compliance with study drug administration may be monitored with a patient diary according to 
Table 1. 
9.2.3. 
Efficacy Procedures 
9.2.3.1. 
Serum Albumin, Total Protein, and Immunoglobulin 
Samples will be collected at visits according to Table 1, and tested in the blood chemistry or 
immunoglobin panel (see Section 9.2.4.4) at a central lab. 
9.2.3.2. 
Physician Assessment of Edema and Ascites 
Physicians will assess peripheral edema as follows*: Following a general inspection and palpation 
of all 4 limbs, the investigator will rate the overall severity of peripheral edema, taking into account 
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both degree and distribution, on a 5-point rating scale: 1) no edema; 2) mild edema: slight pitting, 
no visible change in the shape of the extremity; 3) moderate edema: definite pitting, slight change 
in the shape of the extremity; 4) severe edema: deep pitting, swollen extremity; and 5) very severe 
edema: very deep pitting, very swollen, distorted extremity.  
Physicians will assess facial edema as follows*: Following a general inspection of the face, the 
investigator will rate the overall severity of facial edema, taking into account both degree and 
distribution, on a 5-point rating scale: 1) no edema, 2) mild edema, slight puffiness around the eyes 
with some flattening of superficial creases, 3) moderate edema, definite periorbital swelling with 
some flattening of deep creases with or without puffiness of the cheeks, 4) severe edema, marked 
periorbital swelling with loss of deep periorbital creases and definite swelling of the cheeks, 
5) very severe edema, marked swelling of the entire face, eyes can only open to slit-like apertures.  
Ascites severity will be assessed by measurement of abdominal circumference, as follows*: 
1. Palpate for the lower rib margin (costal margin) and mark with a short horizontal line. 
2. Palpate for the iliac crest and mark with a short horizontal line. 
3. Using the tape measure, measure the mid-distance between the two horizontal lines and 
mark this with another short horizontal line in the middle. 
4. Ask the patient to cross their arms across their chest so that you have access to the waist. 
Instruct them to stand relaxed and look straight ahead. Try to make sure that they don’t 
deliberately hold themselves in or out. 
5. Pass the tape around the waist, making sure it is level and that it is positioned at the mid-
distance mark on both sides. 
6. Make sure the tape is not pulled too tight. It should rest on the skin but not indent it. 
7. Make the measurement at the end of expiration. 
8. Measure to the nearest 0.1 cm (1 mm). 
9. Make 3 measurements of waist circumference. 
10. Record all three measurements and the mean (average) by adding the values together and 
dividing by 3. 
* In case of abnormal findings, assessments of facial edema, peripheral edema, and ascites should 
be accompanied by clinical photography. All physician assessments for a patient should be 
performed by the same investigator until at least week 24. In addition, for consistency, a single 
independent physician blinded to the time point at which the photograph was taken will be 
performing an evaluation of the clinical photographs obtained. 
9.2.3.3. 
Clinical Outcome Assessments 
Daily e-Diary 
The daily e-diary, developed specifically for this study, will capture frequency of bowel 
movements as well as stool consistency for each bowel movement. The e-diary will be completed 
by the patients themselves if 12 years of age and older, and by caregiver otherwise (with input 
from the patient). When the caregiver is not with their child, bowel movement data will be 
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collected by the patient (patient ages 8 to 11) or by an alternate caregiver (patients <8 years) such 
as a nanny, teacher, or daycare provider. Once reunited with their child, the caregiver will be 
responsible for entering the data on bowel movements in the e-diary. 
Modified Bristol Stool Form Scale 
Stool consistency for patients who have been toilet-trained and who are less than 18 years of age 
will be assessed using the mBSFS-C. The BSFS was developed as a clinical assessment of 
intestinal transit time in patients with diseases of the bowel (O'Donnell, 1990) and has been 
modified for use in children (Lane, 2011). The mBSFS-C categorizes the form of human feces into 
5 categories using drawings of different stool forms and consistencies: 1) separate hard lumps, like 
nuts; 2) sausage-shaped but lumpy; 3) like a sausage or snake, smooth and soft; 4) fluffy pieces 
with ragged edges, a mushy stool; 5) watery, no solid pieces. The patient or caregiver will be asked 
to select the picture that best corresponds to each bowel movement. The mBSFS-C has been 
demonstrated to be reliable and valid for use by children; 8 is the minimum age limit for use of 
this scale without descriptors being read (Lane, 2011).  
Bristol Stool Form Scale 
Stool consistency for patients who have been toilet-trained and are 18 years of age and older will 
be assessed using the BSFS. The BSFS was developed as a clinical assessment of intestinal transit 
time in patients with diseases of the bowel (O'Donnell, 1990). The BSFS categorizes the form of 
human feces into 7 categories using drawings of different stool forms and consistencies: 
1) separate hard lumps; 2) lumpy and sausage-like; 3) like a sausage with cracks on the surface; 
4) like a smooth, soft sausage or snake; 5) soft blobs; 6) fluffy, mushy stool; 7) entirely liquid. The 
patient or caregiver will be asked to select the picture that best corresponds to each bowel 
movement. The BSFS is widely used to treat and study bowel disorders in clinical and research 
settings and has demonstrated validity and reliability (Blake, 2016). The BSFS is the measure 
recommended by the Rome Foundation (Lacy, 2016) and is considered appropriate by the FDA to 
assess stool consistency in irritable bowel syndrome (IBS)(FDA, 2012). 
Brussels Infant and Toddler Stool Scale 
Stool consistency for patients who are not toilet-trained will be assessed using the BITSS. The 
BITSS was developed with input from physicians, nurses, and parents to specifically assess stool 
consistency in infants and young children who use diapers (Vandenplas, 2017). The instrument 
consists of 7 photographs of different stool forms and consistencies: 1) hard stools; 2) formed 
stools; 3) loose stools; and 4) watery stools. The caregiver will be asked to select the picture that 
best corresponds to each bowel movement. BITSS is a reliable assessment of stool consistency for 
children in diapers and has good agreement with the BSFS. 
Pediatric Quality of Life Inventory™ Generic Core Scales 
The PedsQL™ 4.0 Generic Core Scales is a measure assessing health-related quality of life 
(HRQoL) in children and adolescents. The PedsQL™ Generic Score Scales for patients ages 
2 years and above is a 23-item measure that assesses physical functioning, emotional functioning, 
social functioning, and school/work/studies functioning. Different forms of the PedsQL™ Generic 
Core Scales allow the instrument to be self-administered in older patients and allow for parent 
proxy report for younger patients. The items for each of the forms for patients ages 2 to 18 years 
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are essentially identical, differing primarily in the use of developmentally appropriate language, 
or first- or third-person tense. The PedsQL™ Generic Core Scales for patients ages 13 to 
24 months is a 45-item measure assessing physical functioning, physical symptoms, emotional 
functioning, social functioning, and cognitive functioning from the perspective of the parent. The 
instructions for all PedsQL™ Generic Core Scales forms ask how much of a problem each item 
has been over the past 7 days on a 5-point response scale, ranging from never a problem (0) to 
almost always a problem (4). The measure will be a self-administered patient-reported outcome 
(PRO) for patients ages 12 years and older, using the child report (age 12 years), teen report (ages 
13 to 17 years), young adult report (ages 18 to 25 years), and adult report (>25 years) forms. For 
patients 1 to 11 years of age, it will be an observer reporter outcome (ObsRO) measure using 
different forms for patients 8 to 11 years (parent report for children), 5 to 7 years (parent report for 
young children), >2 years to 4 years (parent report for toddlers), and 13 to 24 months (parent report 
for infants). Items are reverse-scored and linearly transformed to a 0 to 100 scale so that higher 
scores indicate better HRQoL. The total scale score is computed as the sum of all the items over 
the number of items answered on individual scales. The PedsQL™ Generic Core Scales was 
developed using focus groups, cognitive interviews, pre-testing, and field-testing measurement 
development protocols (Varni, 2001) (Varni, 1999) and has demonstrated validity, reliability, 
ability to detect change, and responsiveness (Desai, 2014) (Varni, 2003) (Varni, 2011) 
(Varni, 2002) (Varni, 2001). This measure has also been used to evaluate HRQoL in patients with 
functional and organic gastrointestinal disorders, which tends to be lower compared to healthy 
controls (Kunz, 2010) (Varni, 2015a). 
Pediatric Quality of Life Inventory™ Gastrointestinal Symptoms Scales 
The PedsQL™ GI Symptoms Scales is a 74-item measure assessing gastrointestinal disease-
specific HRQoL in children, adolescents, and adults. The PedsQL™ Gastrointestinal Symptoms 
Scales is a multidimensional instrument comprising of 14 individual scales which can be 
administered and scored individually. Only the following 4 scales (23 items) will be administered: 
stomach pain and hurt (6 items), food and drink limitations (6 items), nausea and vomiting 
(4 items), and diarrhea (7 items). The format, instructions, Likert response scale, and scoring 
method for the PedsQL™ Gastrointestinal Symptoms Scales are identical to the PedsQL™ 4.0 
Generic Core Scales.  
As with the PedsQL™ Generic Core Scales, different forms of the PedsQL™ Gastrointestinal 
Symptoms Scales allow the instrument to be self-administered in older patients and also allow for 
parent proxy report for younger patients. There is no PedsQL™ Gastrointestinal Symptoms Scales 
form to assess gastrointestinal symptoms in patients younger than 2 years of age. The items for 
each of the forms for patients ages 2 to 25 years are essentially identical, differing primarily in the 
use of developmentally appropriate language, or first- or third-person tense. The instructions for 
all PedsQL™ Gastrointestinal Symptoms Scales forms ask how much of a problem each item has 
been over the past 7 days on a 5-point response scale, ranging from never a problem (0) to almost 
always a problem (4). The PedsQL™ Gastrointestinal Symptoms Scales will be a self-
administered, PRO measure for patients age 12 years (child report), 13 to 18 years (teen report), 
and 18 years of age and older (young adult report). For patients 2 to 11 years of age, the PedsQL™ 
Gastrointestinal Symptoms Scales will be an ObsRO measure using different forms for patients 8 
to 11 years (parent report for children), 5 to 7 years (parent report for young children), and 2 to 
4 years (parent report for toddlers). Items are reverse-scored and linearly transformed to a 0 to 
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100 scale so that higher scores indicate better HRQoL. The measure was developed by consulting 
the literature, interviewing pediatric gastroenterologists with clinical experience in treating 
gastrointestinal disorders, and by conducting focus groups, concept elicitation, and cognitive 
debriefing (Varni, 2012). The PedsQL™ Gastrointestinal Symptoms Scales has demonstrated 
validity and reliability (Varni, 2014) (Varni, 2016). 
PedsQL™ Quality of Life Inventory - Family Impact Module 
The PedsQL™ Family Impact Module Scales is a 36-item, self-administered PRO measure 
assessing the impact of pediatric acute and chronic health conditions on parents and the family. 
The measure will be administered to parent and non-parent caregivers. Additional instructions for 
the caregiver to think of the person they care for rather than the child to which the questionnaire 
refers will be included for non-parent caregivers. The PedsQL™ Family Impact Module assesses 
the parent’s physical functioning, emotional functioning, social functioning, cognitive functioning, 
communication, and worry as well as family functioning in terms of ability to perform daily 
activities and maintain family relationships. The instructions ask how much of a problem each 
item has been for the parent (for physical functioning, emotional functioning, social functioning, 
cognitive functioning, communication, and worry) or the family (for daily activities and family 
relationships) over the past 7 days, as a result of their child’s health, on a 5-point response scale 
ranging from never a problem (0) to almost always a problem (4). Items are reverse-scored and 
linearly transformed to a 0 to 100 scale so that higher scores indicate less negative impact. The 
total scale score is computed as the sum of all the items over the number of items answered on 
individual scales. The measure was developed using focus groups, cognitive interviews, and pre-
testing measurement development protocols, and informed by prior research and clinical 
experiences with children with chronic health conditions and their families (Varni, 2004). The 
PedsQL™ Quality of Life Inventory – Family Impact Module has demonstrated reliability and 
validity among families caring for a child with complex chronic health conditions such as severe 
cerebral palsy and birth defects (Varni, 2004).  
Patient/Caregiver Global Impression of Severity 
The PGIS/CareGIS items are self-administered PRO questions for patients ages 12 and above, and 
self-administered ObsRO questions for patients aged less than 12 years. The PGIS/CareGIS 
questions will be used to assess the patient’s current overall severity of disease and of specific 
symptoms from the perspective of the patient or caregiver. 
Patient/Caregiver Global Impression of Change 
The PGIC/CareGIC items are self-administered PRO questions for patients ages 12 and above, 
and self-administered ObsRO questions for patients aged less than 12 years. The PGIC/CareGIC 
questions will be used to assess the change in overall severity of disease and in specific symptoms 
compared to the start of the study, from the perspective of the patient or caregiver. 
Clinical Global Impression of Severity 
The CGIS items are self-administered clinical-reported outcome (ClinRO) questions assessing the 
patient’s overall disease activity or symptom severity from the perspective of the treating clinician. 
Over the course of the study, the treating clinician will rate the patient’s current disease activity 
and symptom severity. 
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Clinical Global Impression of Change 
The CGIC items are self-administered ClinRO questions assessing the change in a patient’s overall 
disease activity or symptom severity compared to the start of the study. Over the course of the 
study, the treating clinician will rate the change in the patient’s disease activity and symptom 
severity. 
Concept Elicitation Interview  
Eligible patients and, when appropriate, their caregivers will participate in a face-to-face concept 
elicitation interview at screening. Concept elicitation is designed to identify/confirm, describe, and 
substantiate important and relevant concepts of interest from the perspective of patients and their 
caregivers. Patients and, when appropriate, their caregivers will be asked questions related to their 
experience or their child’s experience with CD55-deficient PLE in terms of the signs/symptoms 
of disease, how bothersome each sign/symptom is and which is the most bothersome, as well as 
the ways in which the disease has impacted his/her life. Each interview will last approximately 
60 minutes and will be conducted by a trained internal or external interviewer following a semi-
structured interview guide. Further details will be provided in a separate study manual. 
Exit Interview  
At the time point of the primary endpoint, patients and, when appropriate, their caregivers will be 
interviewed to more fully explore the experiences of trial patients on treatment. Patients and their 
caregivers, where appropriate, will be asked questions to better understand the change in 
signs/symptoms (including the sign/symptom identified as most bothersome during the concept 
elicitation interview), and impact on quality of life. Results from exit interviews will be used to 
contextualize findings on the clinical outcome assessments (COAs) and other clinical endpoints. 
Each interview will last approximately 60 minutes and will be conducted by a trained internal or 
external interviewer following a semi-structured interview guide.  
9.2.3.4. 
Tanner Stages 
The Tanner stages will be assessed throughout the study for patients between the ages of 8 and 
20 years, in whom pubertal development is not complete (in the assessment of the investigator at 
specified time points shown in Table 1). If possible, for each adolescent patient, the Tanner stages 
assessment should be performed by the same investigator or designee trained to assess pubertal 
development. 
9.2.4. 
Safety Procedures 
9.2.4.1. 
Vital Signs 
Vital signs, including temperature, sitting blood pressure, and pulse will be collected predose at 
time points according to Table 1. 
Vital signs will be obtained after patient has been sitting quietly for at least approximately 
5 minutes. At the first visit, blood pressure should be measured from both arms. The arm with the 
higher diastolic pressure will be selected for measurement throughout the study. 
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9.2.4.2. 
Physical Examination, Height, and Body Weight 
A thorough and complete physical examination will be performed at time points according to 
Table 1. Each physical examination will include an evaluation of 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. Additionally, for patients switching 
from eculizumab, risk assessment of immune complex formation is described in Section 8.5. 
Height and body weight will be measured at time points according to Table 1. Body weight should 
be obtained with the patient wearing undergarments or very light clothing and no shoes (should be 
the same each time). A calibrated scale should be used. 
9.2.4.3. 
Electrocardiogram 
A standard 12-lead electrocardiogram (ECG) will be performed at time points according to 
Table 1.  
Twelve-lead ECGs will be systematically recorded after the patient has been in the supine position 
for at least 10 minutes.  
The ECG will be interpreted locally by the investigator and a consultation with the sponsor may 
occur. Any new and/or clinically significant changes in ECG parameters should be immediately 
rechecked for confirmation before making any decision for the concerned patient. Any clinically 
significant abnormality should be documented as an AE/SAE as applicable. 
Heart rate will be recorded from the ventricular rate, and the PR/PQ, QRS, RR, QT intervals, and 
QTcF will be recorded. The ECG strips or reports will be retained with the source. 
9.2.4.4. 
Laboratory Testing 
Samples for laboratory testing will be collected at visits according to Table 1.  
Hematology, chemistry (except total C5, CH50 sC5b-9), urinalysis, and pregnancy testing samples 
may be analyzed by a local/central laboratory. 
Other testing will be done by a local, central or specialized laboratory. 
Detailed instructions for blood sample collection are provided to study sites. 
Blood Chemistry 
Sodium 
Total protein, serum albumin 
Total bilirubin* 
Potassium 
Creatinine (eGFR) 
Total cholesterol** 
Chloride 
Blood urea nitrogen (BUN) / Urea 
Triglycerides 
Calcium 
Aspartate aminotransferase (AST) 
Uric acid 
Glucose 
Alanine aminotransferase (ALT) 
Creatine kinase (CK) 
Albumin 
Alkaline phosphatase 
C-reactive protein (CRP) 
Magnesium 
Lactate dehydrogenase (LDH) 
 
 
* If the total bilirubin is above the upper limit of normal, the bilirubin should be fractionated 
**(low-density lipoprotein [LDL] and high-density lipoprotein [HDL]) 
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Fasting lipids and glucose should be obtained at the baseline visit and visits at weeks 12 and 24, if possible. 
 
Lipid Panel (fasting) 
Total cholesterol (LDL and HDL) 
Triglycerides 
Blood Immunoglobin Panel  
Total Ig, IgG, IgM, IgA 
Micronutrient Panel  
Vitamin B12, folate, iron, iron-binding capacity, ferritin  
Hematology Panel  
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
Reticulocyte count 
 
Coagulation Panel 
PT/aPTT 
Urinalysis 
Glucose 
 
Protein 
Note: If protein is ++ or more then reflex to urinary protein creatinine ratio  
Blood 
Note: if blood is ++ or more then reflex to microscopy 
Other Laboratory Tests 
Other laboratory tests may include: 
• Complement hemolytic assay (CH50) 
• Alpha-1 antitrypsin 
• Pregnancy testing: serum human chorionic gonadotropin pregnancy testing or urine 
pregnancy testing according to local practice 
• Sample collection is described separately for drug concentration (Section 9.2.5), 
ADA (Section 9.2.6), and exploratory biomarkers (Section 9.2.7) 
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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 10.2.5. 
9.2.5. 
Drug Concentration and Measurements 
Samples for drug concentration will be collected prior to drug administration at visits listed in 
Table 1. The exact sampling time must be recorded, as allowed per local regulation. 
Any unused samples may be used for exploratory biomarker research.  
9.2.6. 
Anti-Drug Antibody Measurements and Samples 
Blood samples for ADA assessment in serum will be collected prior to drug administration at visits 
listed in Table 1. Samples positive in the ADA assay may be stored and analyzed in the NAb assay 
at a later time once the NAb assay is available. 
Detailed instructions for blood sample collection are included in the laboratory manual provided 
to study sites. 
Any unused samples may be used for exploratory research, as allowed per local regulation. 
9.2.7. 
Pharmacodynamic and Exploratory Biomarker Procedures 
Samples will be collected at time points according to Table 1, and tested in a central lab or a 
specialty lab.  
Biomarker measurements will be performed in specified matrix to determine effects of pozelimab 
on relevant physiological and pathogenic processes. 
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. 
Biomarkers studied may include but need not be limited to: 
• Thrombosis biomarkers  
• Total C5 
• sC5b-9  
• Others as described in Section 4.5 
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9.2.7.1. 
Future Biomedical Research (Optional) 
Patients who have a body weight >20 kg and agree to participate in the future biomedical research 
sub-study will be required to assent/consent to this optional sub-study before collection of the 
serum and plasma samples. The unused 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. The unused samples may be utilized for future biomedical research of pozelimab, the 
complement pathway, PLE, and related diseases. Additional samples will be collected for future 
biomedical research according to the Schedule of Events in Table 1. After 15 years, any residual 
samples will be destroyed. The results of these future biomedical research analyses will not be 
presented in the clinical study report. 
9.2.7.2. 
Genomics Sub-Study (Optional) 
Patients who agree to participate in the genomics sub-study will be required to assent/consent to 
this optional sub-study before collection of the samples. This genomics sub-study will not be 
available in countries where a separate ethics committee (EC) approval is required for such studies, 
and where such an approval is not in place. 
Buccal swab samples for DNA extraction should be collected on day 1 (predose) but can be 
collected at a later study visit. 
DNA samples will be collected for pharmacogenomics analyses. These samples will be single-
coded as defined by the International Council on Harmonisation (ICH) guideline E15. Samples 
will be stored for up to 15 years after the final date of the database lock. If there are specific site 
or country requirements involving the pharmacogenomic analyses with which the sponsor is 
unable to comply, samples will not be collected at those sites. 
The purpose of the pharmacogenomic analyses is to identify genomic associations with clinical 
(safety or efficacy) or biomarker response to pozelimab, the complement pathway, PLE, and 
related complement-mediated diseases, clinical outcome measures, and possible AEs. In addition, 
associations between genomic variants and prognosis or progression of PLE and related 
complement-mediated 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 PLE 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, transcriptome sequencing 
(or other methods for quantitating RNA expression), and methods for quantifying epigenetic 
modifications 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 clinical events occurring during the study data collection 
period (see Section 10.1.2). 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 follow-up/post 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. 
• Adverse Events of Special Interest (AESI; serious and nonserious): Adverse events 
of special interest for this study include the following:  
− Moderate or severe infusion reactions 
− Confirmed Neisseria infection 
− Any thrombotic or embolic event 
• 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  or female partner of a male, during 
the study or within 21 weeks of the last dose of study drug. Any complication of 
pregnancy affecting a female study patient or female partner of a male 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. Also see 
Section 8.6.2.1. 
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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. In-
patient hospitalization is defined as admission to a hospital or an emergency room for 
longer than 24 hours. Prolongation of existing hospitalization is defined as a hospital 
stay that is longer than was originally 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. Depending on the nature of the 
event, rapid communication by the trial sponsor to other parties (eg, regulators) might also be 
warranted (Section 10.1.3). 
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10.2.4. 
Infusion Reactions 
Infusion reactions are defined as any relevant AE that occurs during the infusion or within 2 hours 
(up to 24 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’s 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 patient’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. 
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 
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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: 
− 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 
(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. 
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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 (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, 
Pharmacovigilance; Risk Management; 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 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), as 
appropriate 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 IRB/EC unless delegated to the sponsor. 
Event expectedness for study drug (pozelimab) is assessed against the Reference Safety 
Information section of the current Investigator’s Brochure. 
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 the basis for the statistical analysis plan (SAP) for the study. The SAP may 
be revised during the study to accommodate amendments to the clinical study protocol and to make 
changes to adapt to unexpected issues in study execution and data that may affect the planned 
analyses. The final SAP will be issued before the database is locked. 
Analysis variables are listed in Section 4. 
11.1. 
Statistical Hypothesis 
The primary objective of the study is to determine the effect of pozelimab on active CD55-deficient 
PLE/CHAPLE disease in patients with active disease at baseline. The primary outcome at week 24 
is achievement of both of the following: 
• Normalization of serum albumin, defined as 
− serum albumin within the normal range at at least 70% of measurements between 
week 12 and week 24, and 
− no single albumin measurement of <2.5 g/dL between week 12 and week 24, and 
− no requirement for albumin infusion between week 12 and 24  
• Improvement at week 24 in clinical outcomes listed in Section 5.1 that were evaluable 
for improvement at baseline, with no worsening of the others.  
The primary endpoint is the proportion of patients achieving the primary outcome. 
11.2. 
Justification of Sample Size 
The study is regarded as successful if at least 4 of 6 evaluable patients achieve the primary 
endpoint. Unpublished patient-level data of 14 patients treated with eculizumab (Kurolap, 2017) 
(Kurolap, 2019) (Ozen, 2017a) were made available to the study sponsor (Ozen unpublished data, 
Baris-Feldman unpublished data). In the historical control period before initiating eculizumab, 0 
of 14 patients met the primary endpoint (90% exact confidence interval (CI): [0.00, 0.19]). If 4 of 
6 patients treated with pozelimab achieve the primary endpoint, the 90% exact CI for the 
probability of achieving the primary endpoint is (0.27, 0.94), with the lower limit of 0.27 clearly 
greater than the upper limit of 0.19 for the historical control period of the 14 patients. By a 
Bayesian analysis, a comparison between 4 of 6 pozelimab-treated patients achieving the primary 
endpoint and 0 of 14 in the historical data by a Beta-Binomial analysis with the Jefferys prior of 
Beta(0.5, 0.5) would conclude that there is a >99% posterior probability that pozelimab has a 
greater response rate than untreated patients. There would also be a 90% posterior probability that 
the response rate with pozelimab is at least 0.37 higher than that of untreated patients. Thus, the 
study success criterion of observing at least 4 of 6 evaluable patients achieving the primary 
endpoint provides strong evidence of effectiveness. 
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All of the 14 eculizumab-treated patients achieved a normalized serum albumin level by 12 weeks 
of treatment and required no albumin infusions subsequent to treatment initiation (90% exact CI: 
[0.81, 1.00]) (Kurolap, 2017) (Kurolap, 2019) (Ozen, 2017a). If the true rate of achieving the 
primary endpoint for patients on pozelimab is 0.81 (the lower limit of the CI for eculizumab), then 
a sample size of 6 gives a probability of 91% for achieving the study success criterion.  
11.3. 
Analysis Sets 
11.3.1. 
Efficacy Analysis Set 
The full analysis set (FAS) includes all enrolled patients who received any study drug. Efficacy 
endpoints will be analyzed using the FAS analysis set unless otherwise specified. 
11.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all enrolled patients who received any study drug. 
Treatment compliance/administration and all clinical safety variables will be analyzed using the 
SAF. 
11.3.3. 
Pharmacokinetic Analysis Set 
The PK analysis set includes all patients who received any study drug and who had at least 1 non-
missing result for concentration of pozelimab following the first dose of study drug. 
11.3.4. 
Immunogenicity Analysis Sets 
The ADA analysis set will consist of all patients who received any study drug and who had at least 
one non-missing ADA result after first dose of the study drug.  
The NAb analysis set includes all patients who received any study drug and who are negative in 
the ADA assay or 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. 
Exploratory Analysis Sets 
11.3.5.1. Exploratory Biomarker Endpoint Analysis Set 
The PD analysis populations include all patients who received any study drug and who had at least 
1 non-missing analyte measurement following the first dose of study drug. 
11.3.5.2. Exploratory Clinical Outcome Assessment Analysis Set 
The clinical outcome assessment (COA) analysis populations include all patients who received 
any study drug and who had at least 1 non-missing COA measurement following the first dose of 
study drug. 
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11.4. 
Statistical Methods 
For continuous variables, descriptive statistics will include the following information: the number 
of patients reflected in the calculation (n), mean, median, standard deviation, minimum, and 
maximum.  
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
In addition to summary statistics, data will be plotted whenever needed. 
11.4.1. 
Patient Disposition 
The following will be provided: 
• The total number of screened patients: met the inclusion criteria regarding the target 
indication and signed the ICF 
• The total number of enrolled patients 
• The total number of patients in each analysis set (eg, provided in Section 11.3) 
• The total number of patients who discontinued the study, and the reasons for 
discontinuation 
• A listing of patients enrolled but not treated 
• A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation 
11.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively.  
11.4.3. 
Efficacy Analyses 
11.4.3.1. Primary Efficacy Analysis 
The subset of the FAS with patients having active PLE at baseline will provide the data for the 
primary efficacy analysis. The percentage of patients achieving normalization of albumin and 
achieving improvement in the prespecified evaluable clinical outcomes listed in Section 5.1 will 
be calculated and its 90% CI will be reported.  
There are 7 planned albumin measurements between week 12 and week 24, inclusive. Patients will 
be considered non-evaluable for the primary analysis if there are fewer than 5 available albumin 
measurements between week 12 and week 24. Albumin measurements outside of the visit 
windows and/or carried out at local laboratories will be considered as valid measurements. To be 
considered responders, at least 70% of available measurements must be normal (≥3.5 g/dL). Thus, 
patients with the minimum of 5 available measurements must have 4 out of 5 normal. Patients with 
the planned number of 7 measurements must have at least 5 normal. Patients who have more than 
7 available measurements (due to unplanned albumin measurement in local labs) must have at least 
70% of all available measurements normal.  Non-responder imputation for patients with fewer 
than 5 available albumin measurements between week 12 and week 24 will be carried out as a 
sensitivity analysis. The mean changes from baseline in albumin over time and the mean number 
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of albumin infusions per half-year will also be estimated. Patient profiles of albumin over time 
will be plotted.  
There are 4 clinical outcomes that can contribute to the clinical improvement component of the 
primary endpoint. Patients are evaluable for improvement in each of these based on activity at 
baseline, as defined in Section 5.1. Patients evaluable for only 1 of the 4 clinical outcomes must 
show improvement in that clinical outcome and no worsening in the other 3. Patients evaluable for 
more than 1 clinical outcome must show improvement (as defined) for all of their evaluable 
outcomes and no worsening in any non-evaluable outcomes.  
For facial and peripheral edema, the primary analysis will be performed using the investigating 
physician’s report. Clinical photographs will be rated by a single, central reader blinded to the time 
point at which the photograph was taken. The correlation of central read to physician’s assessment 
will be described. The central read will be used as a sensitivity analysis on the primary endpoint. 
For the primary endpoint, the definitions of baseline for the component variables are: 
• Albumin - The measurement at the baseline visit will be used 
• PedsQL GI Symptoms Scales’ Stomach Pain and Hurt Subscale - The baseline visit 
score will be used 
• Bowel movement frequency - The daily average from the e-diary from the last 7 days 
pre-baseline will be used 
• Facial edema - The baseline value will be used 
• Peripheral edema - The baseline value will be used 
11.4.3.2. Secondary Efficacy Analysis 
For the responder outcomes for maintenance of effect at week 48 and 144, there are 9 planned 
albumin measurements between week 12 and week 48 inclusive. Patients will be considered non-
evaluable for the secondary analysis if there are fewer than 6 available albumin measurements 
between week 12 and week 48. Non-responder imputation for patients with fewer than 6 available 
albumin measurements between week 12 and week 48 will be carried out as a sensitivity analysis. 
There are 14 planned albumin measurements between week 12 and week 144 inclusive. Patients 
will be considered non-evaluable for the secondary analysis if there are fewer than 10 available 
albumin measurements between week 12 and week 144. There are 3 planned albumin 
measurements between week 24 and week 48 inclusive. Patients will be considered non-evaluable 
for this secondary analysis if there are fewer than 2 available albumin measurements between 
week 24 and week 48. There are 5 planned albumin measurements between week 48 and week 96 
inclusive. Patients will be considered non-evaluable for this secondary analysis if there are fewer 
than 3 available albumin measurements between week 48 and week 96. There are 2 planned 
albumin measurements between week 96 and week 144 inclusive. Patients will be considered non-
evaluable for this secondary analysis if there are fewer than 2 available albumin measurements 
between week 96 and week 144. Albumin measurements outside of the visit windows and/or 
carried out at local laboratories will be considered as valid measurements. Non-responder 
imputation for patients with fewer than 10 available albumin measurements between week 12 and 
week 144 will be carried out as a sensitivity analysis. The mean changes from baseline in albumin 
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over time and the mean number of albumin infusions per half-year will also be estimated. Patient 
profiles of albumin over time will be plotted.  
Prior to baseline, concept elicitation interviews will seek to identify each patient’s most 
bothersome sign/symptom from the ‘core’ clinical manifestations. The identification of the most 
bothersome sign/symptom following the interview and its translation into English may take place 
after the baseline visit, by expert individuals with no access to post-baseline clinical data. For 
continuous secondary outcomes, including total protein, total Ig, and weight, patient profiles over 
time will be tabularly and graphically presented. Changes from baseline in the outcome measures 
over time will be summarized with mean, 90% CI, and other summary statistics.  
For count secondary outcomes, including number of bowel movements per day, frequency of 
albumin infusions and hospitalization days, counts by day or periods of time will be summarized.  
For categorical secondary outcomes, including AEs and physician assessment of disease inactivity, 
percentages of patients in categories will be summarized.  
For time-to-event secondary outcomes, including time to first normalization of serum albumin, 
survival analysis of data with censoring through time will be conducted.  
11.4.4. 
Safety Analysis 
11.4.4.1. Adverse Events 
Definitions 
For safety variables, 3 observation periods are defined: 
• The pretreatment period is defined as the time from signing the ICF to before the first 
dose of study drug. 
• The treatment period is defined as either the first dose of study drug to last dose of 
study drug +21 weeks. 
• The posttreatment period is defined as the time after the treatment period. 
Treatment-emergent adverse events are defined as those that are not present at baseline or represent 
the exacerbation of a pre-existing condition during the on-treatment period. 
Analysis 
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®). Coding will be to lowest-level terms. The 
verbatim text, the preferred term (PT), and the primary system organ class (SOC) will be listed. 
Summaries of all TEAEs by treatment group will include: 
• The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
• TEAEs by severity (according to the grading scale outlined in Section 10.2.5), 
presented by SOC and PT 
• TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
• Treatment-emergent AESIs (defined with a PT or a prespecified grouping) 
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Deaths and other SAEs will be listed and summarized by treatment group. 
Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized by treatment group. 
11.4.4.2. Other Safety 
Vital Signs 
Vital signs (temperature, blood pressure, and pulse rate) 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.  
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. 
Listings will be provided with flags indicating the out-of-laboratory range values. 
11.4.4.3. Treatment Exposure 
The observation period (defined as the time between the date of first study drug administration and 
the date of the end of study visit for the patient), rather than the treatment exposure, will be 
presented. 
11.4.4.4. Treatment Compliance 
Analysis of treatment compliance will be described in the SAP. 
11.4.5. 
Pharmacokinetics 
11.4.5.1. Analysis of Drug Concentration Data 
The PK endpoint is concentration of total pozelimab in serum over time. 
Summary of total drug concentrations and total C5 will be presented by nominal time point (ie, the 
time points specified in the protocol). Individual data will be presented by actual time. Plots of the 
concentrations of pozelimab and total C5 will be presented over time (linear and log scales). When 
the scale is linear, concentrations below the lower limit of quantification (LLOQ) will be set to 
zero. In the log-scaled figures, concentrations below the LLOQ will be imputed as LLOQ/2. 
Summary statistics of concentrations of total pozelimab and total C5 may include, but are not 
limited to, arithmetic mean, standard deviation, standard error of the mean, coefficient of variation 
(in %), minimum, Q1, median, Q3, and maximum. 
No formal statistical analysis will be performed. 
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11.4.6. 
Analysis of Immunogenicity Data 
Anti-drug antibodies will be characterized by the type and level of the observed response. Samples 
positive in the ADA assay will be further characterized for NAbs and ADA titers. 
Anti-drug antibodies response categories and titer categories that will be assessed are as follows: 
• Preexisting immunoreactivity: defined as a positive ADA assay response at baseline 
with all ADA results negative after the first dose of study drug, or a positive assay 
response at baseline with all ADA assay responses less than 9-fold over baseline titer 
levels after the first dose of study drug 
• Treatment-emergent response: defined as any positive ADA assay response after the 
first dose of study drug when the baseline results are negative or missing 
• Treatment-boosted response: defined as any positive ADA assay response after the first 
dose of study drug that is 9-fold over baseline titer levels when baseline is positive in 
the ADA assay 
Treatment-emergent ADA responses may be further characterized into persistent, transient and 
indeterminate responses.  
Titer value category (titer range): 
− Low (titer <1,000) 
− Moderate (1,000 ≤ titer ≤10,000) 
− High (tier >10,000) 
Listings of pre-existing, treatment-boosted, and treatment-emergent ADA responses, ADA titers, 
and NAb positivity presented by patient and time point will be provided. Incidence of treatment-
emergent, persistent and NAb responses will be assessed as absolute occurrence (N) and percent 
of patients (%), grouped by ADA titer level. 
Plots of drug concentrations will be examined and the influence of ADA responses on individual 
PK profiles evaluated. Assessment of impact of ADA responses on safety and efficacy may be 
provided. 
11.4.7. 
Analysis of Exploratory Pharmacodynamic and Biomarker Data 
Analysis of biomarker data is defined in the SAP. 
11.4.8. 
Analysis of Exploratory Clinical Outcome Assessment Data 
Analysis of COA data is defined in the SAP. 
11.5. 
Interim Analysis 
There will not be a formal interim analysis of the efficacy data for an early stopping of the study. 
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11.6. 
Timing of Analyses 
Database locks and analyses prior to the final database lock are planned for the following times 
for the stated purposes:  
• First database lock for reporting on the primary efficacy endpoint takes place at 
24 weeks from the first dose in the sixth active patient (may be more patients depending 
on the rate of patient accrual) 
• Second database lock and reporting of longer-term effects takes place at 1 year from 
first dose in the last patient 
• Third database lock and reporting of longer-term effects takes place at 2 years from 
first dose in the last patient 
11.7. 
Statistical Considerations Surrounding the Premature Termination 
of a Study 
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities 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) will be done using internationally 
recognized and accepted dictionaries. 
The case report form (CRF) data for this study will be collected with an electronic data capture 
(EDC) tool. 
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 
• Statistical Analysis System (SAS) – statistical review and analysis 
• Pharmacovigilance safety database 
• eCOA system – capture COA 
12.2. 
Study Monitoring 
12.2.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, contract research organization [CRO] monitor) will visit 
each site prior to enrollment of the first patient, and periodically during the study. This study will 
use the principles of risk-based monitoring (ICH E6 R2). This means that the number of visits for 
any given site may vary based on site risk indicators. The investigator must allow study-related 
monitoring. 
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 
accordance with the current, approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements. 
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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 eCRFs 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, 
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. 
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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 CRF/eCRF must be 
signed electronically by the investigator. This signed declaration accompanies each set of patient 
final CRFs/eCRFs 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 
13.2.1. 
Adult Patients 
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 the 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, 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. 
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13.2.2. 
Pediatric Patients 
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 and his/her parent(s) or legal guardian(s) prior to the 
patient’s participation in the study and after the aims, methods, objectives, and potential hazards 
of the study have been explained to the fullest possible extent in language that the patient and the 
parent(s) or legal guardian(s) can understand. The ICF should be signed and dated by the patient’s 
parent(s) or legal guardian(s) and the same investigator or designee who explained the ICF. 
Local law must be observed in deciding whether 1 or both parents’/guardians’ consent is required. 
If only 1 parent or guardian signs the consent form, the investigator must document the reason the 
other parent or guardian did not sign. The patient may also be required to sign and date the ICF, 
as determined by the IRB/EC and in accordance with the local regulations and requirements. 
• Patients who can write but cannot read will have the assent form read to them before 
writing their name on the form. 
• Patients who can understand but who can neither write nor read will have the ICF read 
to them in the 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’s parent(s) or legal guardian(s). 
If new safety information results in significant changes in the risk-benefit assessment, the ICF 
must be reviewed and updated appropriately. All study patients and their parent(s) or legal 
guardian(s) must be informed of the new information and provide their written consent if they wish 
the patient 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’s parent(s) or legal guardian(s). 
13.3. 
Patient 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 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. 
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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 CLOSE-
OUT 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. 
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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. 
REFERENCES 
Blake MR, Raker JM, Whelan K. Validity and reliability of the Bristol Stool Form Scale in healthy 
adults and patients with diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol 
Ther 2016; 44(7):693-703. 
Brodovicz KG, McNaughton K, Uemura N, Meininger G, Girman CJ, Yale SH. Reliability and 
feasibility of methods to quantitatively assess peripheral edema. Clin Med Res 2009; 7(1-2):21-
31. 
Desai AD, Zhou C, Stanford S, Haaland W, Varni JW, Mangione-Smith RM. Validity and 
responsiveness of the pediatric quality of life inventory (PedsQL) 4.0 generic core scales in the 
pediatric inpatient setting. JAMA Pediatr 2014; 168(12):1114-21. 
FDA. 2012 Guidance for Industry: Irritable Bowel Syndrome -- Clinical Evaluation of Drugs for 
Treatment, https://www.fda.gov/downloads/Drugs/Guidances/UCM205269.pdf. 
Figueroa JE, Densen P. Infectious diseases associated with complement deficiencies. Clin 
Microbiol Rev 1991; 4(3):359-95. 
Gaston MH, Verter JI, Woods G, Pegelow C, Kelleher J, Presbury G, et al. Prophylaxis with oral 
penicillin in children with sickle cell anemia. A randomized trial. N Engl J Med 1986; 
314(25):1593-9. 
Hill A, Kelly RJ, Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood 2013; 
121(25):4985-96; quiz 5105. 
Kunz JH, Hommel KA, Greenley RN. Health-related quality of life of youth with inflammatory 
bowel disease: a comparison with published data using the PedsQL 4.0 generic core scales. 
Inflamm Bowel Dis 2010; 16(6):939-46. 
Kurolap A, Eshach-Adiv O, Hershkovitz T, Paperna T, Mory A, Oz-Levi D, et al. Loss of CD55 
in Eculizumab-Responsive Protein-Losing Enteropathy. N Engl J Med 2017; 377(1):87-9. 
Kurolap A, Eshach Adiv O, Hershkovitz T, Tabib A, Karbian N, Paperna T, et al. Eculizumab Is 
Safe and Effective as a Long-term Treatment for Protein-losing Enteropathy Due to CD55 
Deficiency. J Pediatr Gastroenterol Nutr 2019; 68(3):325-33. 
Lacy BE, Mearin F, Chang L, Chey WD, Lembo AJ, Simren M, et al. Bowel Disorders. 
Gastroenterology 2016; 150(6):1393-407.e5. 
Lane MM, Czyzewski DI, Chumpitazi BP, Shulman RJ. Reliability and validity of a modified 
Bristol Stool Form Scale for children. J Pediatr 2011; 159(3):437-41 e1. 
O'Donnell LJ, Virjee J, Heaton KW. Detection of pseudodiarrhoea by simple clinical assessment 
of intestinal transit rate. BMJ 1990; 300(6722):439-40. 
Ozen A, Comrie WA, Ardy RC, Dominguez Conde C, Dalgic B, Beser OF, et al. CD55 Deficiency, 
Early-Onset Protein-Losing Enteropathy, and Thrombosis. N Engl J Med 2017a; 377(1):52-61. 
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Ozen A, Comrie WA, Lenardo MJ. CD55 Deficiency and Protein-Losing Enteropathy. N Engl J 
Med 2017b; 377(15):1499-500. 
Röth A, Egyed M, Ichikawa S, Kim JS, Nagy Z, Gaàl Weisinger J, et al. The SMART Anti-hC5 
Antibody (SKY59/RO7112689) Shows Good Safety and Efficacy in Patients with Paroxysmal 
Nocturnal Hemoglobinuria (PNH). Blood 2018; 132(Suppl 1):535. 
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: summary report--second 
National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
symposium. Ann Emerg Med 2006; 47(4):373-80. 
Soliris package insert. 2019 Prescribing information for eculizumab. Alexion Pharmaceuticals I, 
editor, Boston, MA. 
Vandenplas Y, Szajewska H, Benninga M, Di Lorenzo C, Dupont C, Faure C, et al. Development 
of the Brussels Infant and Toddler Stool Scale ('BITSS'): protocol of the study. BMJ Open 2017; 
7(3):e014620. 
Varni JW, Bendo CB, Denham J, Shulman RJ, Self MM, Neigut DA, et al. PedsQL gastrointestinal 
symptoms module: feasibility, reliability, and validity. J Pediatr Gastroenterol Nutr 2014; 
59(3):347-55. 
Varni JW, Bendo CB, Nurko S, Shulman RJ, Self MM, Franciosi JP, et al. Health-related quality 
of life in pediatric patients with functional and organic gastrointestinal diseases. J Pediatr 2015a; 
166(1):85-90. 
Varni JW, Bendo CB, Shulman RJ, Self MM, Nurko S, Franciosi JP, et al. Interpretability of the 
PedsQL Gastrointestinal Symptoms Scales and Gastrointestinal Worry Scales in Pediatric Patients 
With Functional and Organic Gastrointestinal Diseases. J Pediatr Psychol 2015b; 40(6):591-601. 
Varni JW, Burwinkle TM, Seid M, Skarr D. The PedsQL 4.0 as a pediatric population health 
measure: feasibility, reliability, and validity. Ambul Pediatr 2003; 3(6):329-41. 
Varni JW, Franciosi JP, Shulman RJ, Saeed S, Nurko S, Neigut DA, et al. PedsQL gastrointestinal 
symptoms scales and gastrointestinal worry scales in pediatric patients with inflammatory bowel 
disease in comparison with healthy controls. Inflamm Bowel Dis 2015c; 21(5):1115-24. 
Varni JW, Kay MT, Limbers CA, Franciosi JP, Pohl JF. PedsQL gastrointestinal symptoms 
module item development: qualitative methods. J Pediatr Gastroenterol Nutr 2012; 54(5):664-71. 
Varni JW, Limbers CA, Neighbors K, Schulz K, Lieu JE, Heffer RW, et al. The PedsQL Infant 
Scales: feasibility, internal consistency reliability, and validity in healthy and ill infants. Qual Life 
Res 2011; 20(1):45-55. 
Varni JW, Seid M, Knight TS, Uzark K, Szer IS. The PedsQL 4.0 Generic Core Scales: sensitivity, 
responsiveness, and impact on clinical decision-making. J Behav Med 2002; 25(2):175-93. 
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Varni JW, Seid M, Kurtin PS. PedsQL 4.0: reliability and validity of the Pediatric Quality of Life 
Inventory version 4.0 generic core scales in healthy and patient populations. Med Care 2001; 
39(8):800-12. 
Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the pediatric quality of life 
inventory. Med Care 1999; 37(2):126-39. 
Varni JW, Sherman SA, Burwinkle TM, Dickinson PE, Dixon P. The PedsQL Family Impact 
Module: preliminary reliability and validity. Health Qual Life Outcomes 2004; 2(55. 
Varni JW, Shulman RJ, Self MM, Saeed SA, Patel AS, Nurko S, et al. Gastrointestinal Symptoms 
Predictors of Health-Related Quality of Life in Patients With Inflammatory Bowel Disease. J 
Pediatr Gastroenterol Nutr 2016; 63(6):e186-e92. 
Wedzicha JA. Antibiotics at COPD exacerbations: the debate continues. Thorax 2008; 63(11):940-
2. 
 
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20. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: An Open-Label Efficacy and Safety Study of Pozelimab in 
Patients with CD55-Deficient Protein-Losing Enteropathy (CHAPLE Disease) 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 Team Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the conduct of the study. 
Study Title: 
AN OPEN-LABEL EFFICACY AND SAFETY STUDY OF 
POZELIMAB IN PATIENTS WITH CD55-DEFICIENT PROTEIN-LOSING 
ENTEROPATHY (CHAPLE DISEASE). 
Protocol Number: 
R3918-PLE-1878 
Protocol Version:  
R3918-PLE-1878 Amendment 6 
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 Team Lead 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
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Signature Page for VV-RIM-00158650 v1.0
Signature Page for VV-RIM-00158650 v1.0 Approved
Approval/eSignature
2022 23:23:51 GMT+0000
Approval/eSignature
22 00:20:46 GMT+0000
Approval/eSignature
-2022 00:27:04 GMT+0000
Approval/eSignature
00
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SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
Regeneron Pharmaceuticals, Inc. 
Page 1 of 67 
CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN 
VERSION: 4.0 
Clinical Study Protocol Title: 
AN OPEN-LABEL EFFICACY AND SAFETY STUDY 
OF POZELIMAB IN PATIENTS WITH CD55-
DEFICIENT PROTEIN-LOSING ENTEROPATHY 
(CHAPLE DISEASE). 
Compound: 
REGN3918 
Protocol Number: 
R3918-PLE-1878 
Clinical Phase:  
Phase 2/3 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician: 
 
Clinical Trial Manager: 
 
Study Medical Director: 
 
Version/Date: 
Version 4.0 / 20 June 2022 
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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 
 
 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................6 
1. 
OVERVIEW .................................................................................................................8 
1.1. 
Background/Rationale for Study Design ......................................................................8 
1.2. 
Revision History for SAP Amendments .......................................................................9 
1.3. 
Study Objectives .........................................................................................................11 
1.3.1. 
Primary Objective .......................................................................................................11 
1.3.2. 
Secondary Objectives .................................................................................................11 
1.3.3. 
Exploratory Objectives ...............................................................................................12 
1.3.4. 
Modifications from the Statistical Section in the Final Protocol ................................12 
2. 
INVESTIGATION PLAN ..........................................................................................13 
2.1. 
Study Design ...............................................................................................................13 
2.2. 
Success Criteria, Sample Size and Power Considerations ..........................................13 
2.3. 
Study Plan ...................................................................................................................14 
3. 
ANALYSIS POPULATIONS ....................................................................................15 
3.1. 
The Full Analysis Set (FAS) .......................................................................................15 
3.2. 
The Per Protocol Set (PPS) .........................................................................................15 
3.3. 
The Safety Analysis Set (SAF) ...................................................................................15 
3.4. 
The Pharmacokinetic Analysis Set (PKAS) ...............................................................15 
3.5. 
Anti-drug Antibody Analysis Set (AAS) ....................................................................15 
3.6. 
Exploratory Biomarker Endpoint Analysis Set ..........................................................15 
3.7. 
Clinical Outcome Assessment Analysis Set ...............................................................16 
4. 
ANALYSIS VARIABLES .........................................................................................17 
4.1. 
Demographic and Baseline Characteristics ................................................................17 
4.2. 
Medical History ..........................................................................................................17 
4.3. 
Prior/Concomitant Medication and Procedures ..........................................................18 
4.4. 
Prohibited Medication During Study ..........................................................................18 
4.5. 
Efficacy Variables ......................................................................................................19 
4.5.1. 
Primary Efficacy Variable ..........................................................................................19 
4.5.2. 
Secondary Efficacy Variables .....................................................................................20 
4.5.3. 
Exploratory Efficacy Variables ..................................................................................23 
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4.6. 
Safety Variables ..........................................................................................................23 
4.6.1. 
Adverse Events and Serious Adverse Events .............................................................23 
4.6.2. 
Adverse Events of Special Interest .............................................................................24 
4.6.3. 
Laboratory Safety Variables .......................................................................................25 
4.6.4. 
Vital Signs ..................................................................................................................25 
4.6.5. 
12-Lead Electrocardiography (ECG) ..........................................................................25 
4.6.6. 
Physical Examination Variables .................................................................................25 
4.7. 
Pharmacokinetic Variables .........................................................................................25 
4.8. 
Immunogenicity Variables ..........................................................................................25 
4.9. 
Exploratory Biomarker Endpoint Variables ...............................................................26 
4.10. 
Clinical Outcome Assessments (COAs) .....................................................................26 
5. 
STATISTICAL METHODS .......................................................................................31 
5.1. 
Demographics and Baseline Characteristics ...............................................................31 
5.2. 
Medical History ..........................................................................................................31 
5.3. 
Prior/concomitant Medications ...................................................................................31 
5.4. 
Prohibited Medications ...............................................................................................31 
5.5. 
Patient Disposition ......................................................................................................32 
5.6. 
Extent of Study Treatment Exposure and Compliance ...............................................32 
5.6.1. 
Measurement of Compliance ......................................................................................32 
5.6.2. 
Exposure to Investigational Product ...........................................................................32 
5.7. 
Analyses of Efficacy Variables ..................................................................................33 
5.7.1. 
Analysis of Primary Efficacy Variable .......................................................................33 
5.7.2. 
Analysis of Secondary Efficacy Variables .................................................................35 
5.7.3. 
Analysis of Exploratory Efficacy Variables ...............................................................37 
5.8. 
Analysis of Safety Data ..............................................................................................38 
5.8.1. 
Adverse Events ...........................................................................................................38 
5.8.2. 
Analysis of Adverse Events of Special Interest ..........................................................39 
5.8.3. 
Clinical Laboratory Measurements.............................................................................39 
5.8.4. 
Analysis of Vital Signs ...............................................................................................40 
5.8.5. 
Analysis of 12-Lead ECG ...........................................................................................40 
5.9. 
Analysis of Pharmacokinetic and Immunogenicity Data ...........................................40 
5.9.1. 
Analysis of Pharmacokinetic Data ..............................................................................40 
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5.9.2. 
Analysis of Immunogenicity Data ..............................................................................40 
5.9.2.1. 
Analysis of ADA Data ................................................................................................40 
5.9.3. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................41 
5.9.3.1. 
Immunogenicity and Exposure ...................................................................................41 
5.9.3.2. 
Immunogenicity and Safety and Efficacy ...................................................................42 
5.10. 
Analysis of Pharmacodynamics and Biomarkers .......................................................42 
6. 
DATA CONVENTIONS ............................................................................................43 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................43 
6.2. 
Data Handling Convention for Efficacy Variables .....................................................43 
6.3. 
Data Handling Convention for Missing Data .............................................................43 
6.3.1. 
Adverse events ............................................................................................................43 
6.3.2. 
PCSV ..........................................................................................................................45 
6.3.3. 
Date of first / last study drug administration ..............................................................45 
6.4. 
Visit Windows ............................................................................................................46 
6.5. 
Unscheduled Assessments ..........................................................................................46 
7. 
INTERIM ANALYSIS ...............................................................................................47 
8. 
SOFTWARE ...............................................................................................................48 
9. 
REFERENCES ...........................................................................................................49 
10. 
APPENDIX.................................................................................................................50 
10.1. 
Summary of Statistical Analyses ................................................................................50 
10.2. 
Schedule of Events .....................................................................................................51 
10.2.1. 
Footnotes for the Schedule of Events Table ...............................................................56 
10.3. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................58 
10.4. 
History of R3918-PLE-1878 Protocol and Statistical Analysis Plan 
Amendments ...............................................................................................................65 
 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................51 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical 
BID 
Twice daily 
BITSS 
Brussels infant and toddler stool scale 
BSFS 
Bristol Stool Form Scale 
CareGIC 
Caregiver global impression of change 
CareGIS 
Caregiver global impression of severity 
CGIC 
Clinical global impression of change 
CGIS 
Clinical global impression of severity 
CHAPLE 
CD55 deficiency with hyperactivation of complement, angiopathic 
thrombosis, and protein-losing enteropathy 
COA 
Clinical Outcome Assessment 
CRF 
Case report form (electronic or paper) 
CRP 
C-reactive protein 
ECG 
Electrocardiogram 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FPFD 
First patient first dose 
GI 
Gastrointestinal 
HBeAg 
Hepatitis B e antigen 
HBsAG 
Hepatitis B surface antigen 
HCV RNA 
Hepatitis C virus RNA 
HRQoL 
Health-related quality of life 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IV 
Intravenous 
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mBSFS-C 
modified Bristol Stool Form Scale for Children 
MedDRA® 
Medical Dictionary for Regulatory Activities 
MID 
Minimum important difference 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamics 
PedsQL™ 
Pediatric Quality of Life Inventory™ 
PGIC 
Patient global impression of change 
PGIS 
Patient global impression of severity 
PK 
Pharmacokinetic 
PLE 
Protein-losing enteropathy 
PT 
Preferred term 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SOC 
System organ class 
TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 
TFPI 
Tissue factor pathway inhibitor 
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 ensure the credibility of the study results 
by pre-specifying the statistical approaches for the analysis of study data. SAP version 1 was 
finalized prior to first patient first dose, per health authority recommendations, as the study is 
designed as an open-label single-arm trial. SAP version 2 was finalized after protocol amendment 
3 to incorporate changes to the study. SAP version 3, was finalized after protocol amendment 5 to 
incorporate changes made to the protocol and health authority guidance up to and including 
6AUG2020.  The current version of the SAP, version 4, was finalized after protocol amendment 6 
to incorporate changes made to the protocol. The SAP is intended to be a comprehensive and 
detailed description of the strategy and statistical methods to be used in the analysis of data for this 
study. 
1.1. 
Background/Rationale for Study Design 
CD55-deficient protein losing enteropathy (PLE), also known as CD55 deficiency with 
hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy 
(CHAPLE), is a life-threatening, ultra-orphan disease of infants, children, adolescents, and young 
adults with no current approved therapy (Ozen, 2017).  R3918-PLE-1878 is an open-label study 
to evaluate the safety and efficacy of pozelimab in 6 to 20 patients with active CD55-deficient 
PLE, as an addition to standard-of-care therapies (excluding eculizumab). The hypothesis is that 
pozelimab treatment will result in normalization of serum albumin and improvement in clinical 
signs and symptoms in CD55-deficient PLE/CHAPLE disease. 
The intent of this study is to generate efficacy and safety data from a clinical study for pozelimab 
in this indication, and to support licensure for the treatment of CD55-deficient PLE with 
pozelimab.  This study does not include a randomized, concurrent placebo control group. The 
rationale for this is that there is some prior evidence that therapeutic inhibition of C5, with 
eculizumab, can resolve serious manifestations of the disease and likely prevent irreversible harm. 
This evidence comes in the form of two uncontrolled case series of the use of eculizumab in a 
small number (total 14) of patients (Ozen, 2017) (Kurolap, 2019). Therefore, a trial design 
involving the withholding of active therapy from some trial subjects, as a control group, is not 
considered acceptable. These eculizumab data have been used to provide an external control to 
enable interpretation of the results from our open-label study, as per guidance in 21CFR 314.126. 
Specifically, the eculizumab data were utilized to determine a quantitative threshold for a treatment 
effect that would be sufficiently large to distinguish it from variability over the course of disease. 
We were able to identify a definition of a treatment effect (the normalization of albumin level over 
a 12-week period, along with improvement in clinical signs and symptoms) that was manifest in 
no historical cohort patients (over an observation period of several months to years) prior to 
eculizumab and in all of these patients after eculizumab, within the first six months of treatment. 
Based on recurring FDA advice provided to us on 19Mar2019, 19Aug2019, 05Sept2019 and 
07Apr2021, a second external control has been designed into the R3918-PLE-1878 study. Namely, 
the collection of data from study patients’ charts over six months to several years, prior to baseline. 
These data are expected to provide further evidence that the improvement in clinical signs and 
symptoms and in albumin levels after pozelimab treatment is of an effect size that clearly exceeds 
the variability of the natural course of disease. Taken together, these considerations make a trial 
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design that uses external controls a scientifically reliable means to assess the effect of pozelimab. 
Further discussion may be found in Section 3.2.1 of the protocol. 
1.2. 
Revision History for SAP Amendments 
Summary of Changes from Version 1 to Version 2 
Change and Rationale for Change 
Sections changed 
Details of most bothersome signs/symptoms 
analysis, bowel movement frequency and 
stool consistency, and facial and peripheral 
edema.  Revisions made to address health 
authority recommendation.  
Section 4.5.2  
Section 4.10  
Section 5.7.1  
Additional supportive analyses included for 
time periods 24-48 weeks and 48-104 weeks 
to assess maintenance of efficacy.  Revisions 
made to address health authority 
recommendation. 
Section 5.7.2  
An additional database lock included at 
week 12. 
Section 7  
Summary of Changes from Version 2 to Version 3 
Change and Rationale for Change 
Sections changed 
Edits and additions, due to amendments and 
interactions with FDA,  and for added clarity. 
Section 1   
Section 1.1  
Moved summary of changes to Section 1.2. 
Section 1.2   
Minor changes to design details, due to 
amendments and interactions with FDA. 
Section 2.1   
Section 2.2  
Changes to efficacy variables, due to 
amendments and interactions with FDA. 
Section 4.5   
Re-arrangement: Moved part of 5.9.2.1 text to 
4.8 and added some details. Removed details 
of NAb assay in the immunogenicity sections. 
Section 3.6  
Section 4.8  
Section 5.9.2  
Section 5.9.3  
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COAs: Additional detail for variable 
descriptions. 
Section 4.10  
Additional details and changes to efficacy 
analyses due to amendments. 
Section 5.7  
Added statements about COVID-19 data 
considerations. 
Section 6.3  
Changes in SOE due to amendments and 
interactions with FDA. 
Section 10.3  
History of R3918-PLE-1878 Protocol and 
Statistical Analysis Plan Amendments added. 
Section 10.4  
Summary of Changes from Version 3 to Version 4 
Change and Rationale for Change 
Sections changed 
Edits and additions, due to amendments and 
for added clarity. 
Section 1   
Section 1.1  
Due to extension of study duration, updated 
endpoints and study design language with 
previous wording of week 104 to include full 
144-week study treatment period 
Section 1.3.2 
Section 2.1 
Section 4.5.2, 4.5.3 
Section 4.6 
Section 4.10 
Section 5.7.2 
Treatment duration timepoints updated to 
match visit schedule study days and 144-week 
study treatment period   
Section 5.6.2 
Removal of reference to open label extension 
Section 5.8.1 
Schedule of events updated to reflect protocol 
amendment 6 
Section 10.2 
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1.3. 
Study Objectives  
1.3.1. 
Primary Objective 
The primary objective of the study is to determine the effect of pozelimab on active CD55-deficient 
protein-losing enteropathy (PLE; CHAPLE), as measured by:  
1. Normalization of serum albumin between weeks 12 and 24, and  
2. Improvement in the following clinical outcomes that were evaluable for improvement at 
baseline, without worsening of the others, after 24 weeks of treatment (assessed at 
week 24): 
• Daily bowel movement frequency 
• The presence and severity of facial or peripheral edema 
• The patient/caregiver assessment of abdominal pain frequency 
1.3.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To evaluate the safety and tolerability of pozelimab in patients with CD55-deficient 
PLE disease 
• To evaluate the effect of pozelimab on CD55-deficient PLE (both patients with active 
disease at baseline and those with inactive disease on eculizumab, switching to 
pozelimab) 
• To determine the effects of pozelimab on albumin and other serum proteins (total 
protein, immunoglobulins) 
• To determine the effects of pozelimab on ascites 
• To determine the effects of pozelimab on stool consistency 
• To determine the effect of pozelimab on health-related quality of life 
• To determine the effect of pozelimab on lab abnormalities observed in 
CD55-deficient PLE such as hypertriglyceridemia, thrombocytosis, and 
hypovitaminosis B12 
• To describe the effects of pozelimab on the sparing of concomitant medications and 
reduction in hospitalization days 
• To determine the effects of pozelimab on growth 
• To characterize the concentration of pozelimab in patients with CD55-deficient PLE 
• To assess the incidence of treatment-emergent ADA for pozelimab in patients with 
CD55-deficient PLE disease 
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1.3.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
• To characterize the effect of pozelimab on the incidence of new thromboembolic 
events and the extension of existing thromboses 
• To assess the effect of pozelimab on sexual maturation 
• To assess the effect of pozelimab on complement pathway activity 
• To assess the effect of pozelimab on inflammation and thrombosis markers 
• To determine the effects of pozelimab on patient/caregiver assessment of change and 
severity of disease 
• To determine the effects of pozelimab on physician assessment of change and 
severity of disease 
• To explore the effect of pozelimab on gastrointestinal (GI) symptoms (nausea and 
vomiting and diarrhea) and on caregiver quality of life/burden 
1.3.4. 
Modifications from the Statistical Section in the Final Protocol 
There are no modifications from the statistical section of the protocol. 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design 
R3918-PLE-1878 is an open-label, single-arm, 144-week treatment study in patients aged 1 year 
and older with active clinical signs and symptoms of CD55-deficient PLE/CHAPLE disease, and 
a CD55 loss-of-function mutation detected by genotype analysis (frameshift, nonsense mutations).  
In the case of missense or suspected splice site mutations, CD55-deficient PLE is to be confirmed 
by flow cytometry of peripheral blood cells. The first 2 patients enrolled will be of age 6 or older 
(exception will be made for patients under 6 years of age with life-threatening disease). 
A minimum of 6 patients with active PLE will be enrolled, up to approximately 20 patients. The 
primary analysis will occur when approximately 6 patients with active PLE have received 
24 weeks of treatment.  Subsequent analyses will occur 1 and 2 years after the first dose in the last 
patient enrolled. 
Patients will be given a single loading dose of pozelimab 30 mg/kg IV on day 1, then fixed doses 
SC (based on body weight) QW (±2 days) over the treatment period.   
The study consists of a screening period (up to 4 weeks [or up to 10 weeks for patients with 
extenuating circumstances]) followed by a 144-week treatment period (from week 0 to week 144, 
with with final dose at week 143), and a follow-up period to week 164. 
Active PLE is defined as hypoalbuminemia of less than or equal to 3.2 g/dL within the screening 
period, and at least 7 days (which do not have to be consecutive) of one or more of the following 
symptoms or signs within the 6 months prior to enrolment:  diarrhea, vomiting, abdominal pain, 
peripheral or facial edema, or an episode of infection with concomitant hypogammaglobulinemia, 
or a new thrombotic event.  Active patients should not be on current therapy with eculizumab.   
As part of risk mitigation for this study, patients should receive updated meningococcal, 
Haemophilus influenzae type B, and pneumococcal vaccinations and are recommended to receive 
daily oral antibiotic prophylaxis and counselling regarding risk of Neisseria gonorrhea, as 
applicable.  Subsequent to the first 2 patients, in addition to the active patient population heretofore 
described, patients who are well-controlled on eculizumab will be provided an option of switching 
to pozelimab to avoid IV infusion.   
2.2. 
Success Criteria, Sample Size and Power Considerations 
A minimum of 6 patients will be enrolled, up to approximately 20 patients. Eligible patients with 
inactive PLE may also be enrolled, but their data will not be included in the primary analysis. 
The study is regarded as successful if at least 4 of 6 evaluable patients with active PLE achieve the 
primary endpoint. Patient-level data of 14 patients treated with eculizumab were made available 
to the study sponsor (Ozen, 2021) (Kurolap, 2019). In the historical control period before initiating 
eculizumab, 0 of 14 patients met the primary endpoint (90% exact confidence interval (CI): [0.00, 
0.19]). If 4 of 6 patients treated with pozelimab achieve the primary endpoint, the 90% exact CI 
for the probability of achieving the primary endpoint is (0.27, 0.94), with the lower limit of 0.27 
clearly greater than the upper limit of 0.19 for the historical control period of the 14 patients. By a 
Bayesian analysis, a comparison between 4 of 6 pozelimab-treated patients achieving the primary 
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endpoint and 0 of 14 in the historical data by a Beta-Binomial analysis with the Jefferys prior of 
Beta(0.5, 0.5) would conclude that there is a >99% posterior probability that pozelimab has a 
greater response rate than untreated patients. There would also be a 90% posterior probability that 
the response rate with pozelimab is at least 0.37 higher than that of untreated patients. Thus, the 
study success criterion of observing at least 4 of 6 evaluable patients with active PLE achieving 
the primary endpoint provides strong evidence of effectiveness. 
All of the aforementioned 14 historically eculizumab-treated patients achieved a normalized serum 
albumin level by 12 weeks of treatment and required no albumin infusions subsequent to treatment 
initiation (90% exact CI: [0.81, 1.00]). If the true rate of achieving the primary endpoint for patients 
on pozelimab is 0.81 (the lower limit of the CI for eculizumab), then a sample size of 6 gives a 
probability of 91% for achieving the study success criterion. 
2.3. 
Study Plan 
The study event table is presented in Section 10.2. 
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3. 
ANALYSIS POPULATIONS 
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. 
The Full Analysis Set (FAS) 
The full analysis set (FAS) includes all enrolled patients who received any study drug. Efficacy 
endpoints will be analyzed using the FAS analysis set unless otherwise specified.    
3.2. 
The Per Protocol Set (PPS) 
The per protocol (PPS) includes those patients in the FAS who did not discontinue study drug early 
and who had no major protocol deviations that potentially affected efficacy. 
3.3. 
The Safety Analysis Set (SAF) 
The safety analysis set (SAF) includes all enrolled patients who received any study drug.  
Treatment compliance/administration and all clinical safety variables will be analyzed using the 
SAF. 
3.4. 
The Pharmacokinetic Analysis Set (PKAS) 
The pharmacokinetic (PK) analysis set includes all patients who received any study drug and who 
had at least 1 non-missing result for concentration of pozelimab following the first dose of study 
drug. 
3.5. 
Anti-drug Antibody Analysis Set (AAS) 
The anti-drug antibody (ADA) analysis set will consist of all patients who received any study drug 
and had at least one non-missing ADA result following the first dose of the study drug. 
3.6. 
Exploratory Biomarker Endpoint Analysis Set 
The exploratory biomarker endpoint (PD) analysis population includes all patients who received 
any study drug and who had at least 1 non-missing analyte measurement following the first dose 
of study drug. 
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3.7. 
Clinical Outcome Assessment Analysis Set 
The clinical outcome assessment (COA) analysis populations include all patients who received 
any study drug and who had a baseline assessment and at least 1 non-missing COA measurement 
following the first dose of study drug. In addition,  
• For the bowel movement e-diary, data will be considered missing for a given week if 
bowel movement or consistency data have not been entered in the diary for >3 days in 
that week 
• For the total score of the PedsQL™ Generic Core Scales and Family Impact Scale as 
well as the dimensions of the PedsQL™ Generic Core Scales, GI Symptoms Scales, 
and Family Impact Module, data will be considered missing if more than 50% of the 
items in the scale or dimension are missing 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
The following demographic variables will be summarized:  
• Age at screening (years) 
• Sex (Male, Female) 
• Race (American Indian/Alaskan Native, Asian, Black/African American, Native 
Hawaiian/Other Pacific Islander, White and Other) 
• Baseline Weight 
• Baseline Weight (z-score) 
• Baseline Height 
• Baseline Height (z-score) 
• Baseline Body Mass Index (BMI) calculated from weight and height 
4.2. 
Medical History 
Medical history will be coded to a Preferred Term (PT) and associated primary System Organ 
Class (SOC) according to the latest available version of Medical Dictionary for Regulatory 
Activities (MedDRA®).   
A detailed chart review will be undertaken on all subjects focusing on the 6 to 12 months prior to 
baseline, recording evidence of the severity of clinical signs and symptoms, with an emphasis on 
the core disease features of abdominal pain, diarrhea (bowel movement frequency and 
loose/watery stool consistency), facial and peripheral edema, nausea and vomiting. In addition, the 
following historical data will be summarized: 
• All available albumin, total protein and total immunoglobulin data from birth 
• Neisseria meningitidis vaccination history 
• Other vaccination history 
• All available history of hospitalizations from birth 
• All available history of body weight and height from birth 
• All available history of albumin infusions and prior thromboembolic events from 
birth 
• Tuberculosis history 
• Demonstration of CD55 gene loss of function (and absence of CD55 protein, if 
necessary) 
• All available genetic sequencing data 
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4.3. 
Prior/Concomitant Medication and Procedures 
Medications will be recorded from the day of informed consent until the end-of-study (EOS) visit. 
Medications will be coded to the Anatomical Therapeutic Chemical (ATC) level 2 (therapeutic 
main group) and ATC level 4 (chemical/therapeutic subgroup), according to the latest available 
version of World Health Organization Drug Dictionary (WHODD). Patients will be counted once 
in all ATC categories linked to the medication. 
Prior medications are medications taken prior to administration of the first dose of study drug. 
Concomitant medications are medications taken between the first dose of study drug and the EOS 
visit. 
Prior/concomitant medications, including meningococcal vaccinations and oral antibiotic 
prophylaxes, will be summarized. 
Prior/concomitant procedures will be recorded.  Prior procedures are procedures performed prior 
to administration of the first dose of study drug.  Concomitant procedures are procedures 
performed between the first dose of study drug and the EOS visit. 
Eculizumab administration history will be included in a listing. 
Historical prednisolone usage and albumin infusions will be collected in detail. 
4.4. 
Prohibited Medication During Study 
The following medications are prohibited, with the exception of those listed in Section 8.10.2 of 
the protocol as described below: 
• Within 24 hours prior to each clinic visit when blood is drawn, patients should not 
consume any alcohol. 
• Beginning on day 1 and continuing throughout the study, while the patient is 
continuing pozelimab, the patient should not take eculizumab. 
• Add any experimental therapy, including complement inhibitors even if they become 
approved during study conduct. 
•  Albumin infusions are permitted during screening for disease of life-threatening 
severity only, and after start of study drug in the event that the albumin level is below 
3.0 g/dL with accompanying symptoms of facial or peripheral edema or ascites. This 
limitation only applies to albumin infusions given specifically for the PLE. 
• No Vitamin B12 supplementation during the first 4 weeks of pozelimab treatment 
(i.e., cannot be initiated prior to week 4 visit) 
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4.5. 
Efficacy Variables 
4.5.1. 
Primary Efficacy Variable 
The primary efficacy variable is the proportion of patients with active disease at baseline achieving 
both of the following: 
• Normalization of serum albumin, defined as 
− serum albumin within the normal range at at least 70% of measurements between 
week 12 and week 24, and 
− no single albumin measurement of <2.5 g/dL between week 12 and week 24, and 
− no requirement for albumin infusion between week 12 and week 24 
• Improvement in the following clinical signs/symptoms that were evaluable for 
improvement at baseline, with no worsening of the others (i.e. those not evaluable for 
improvement) at week 24: 
− The number of bowel movements per day, based on a 1-week average, captured 
by e-diary. Improvement is defined as a reduction of 50% or more in the number 
of daily bowel movements based on a 1-week average. Patients evaluable for 
improvement are defined as those with an average of 3 or more bowel movements 
per day at baseline (daily average from the e-diary from the last 7 days pre-
baseline). Worsening is defined as an increase of 30% or more 
− Physician assessment of facial edema (based on a 5-point Likert scale). 
Improvement is defined as a reduction of 2 points or more. Patients evaluable for 
improvement are defined as those with a severity of at least 3 points out of 5 at 
baseline (baseline visit value). Worsening is defined as an increase of 2 points or 
more. 
− Physician assessment of peripheral edema (based on a 5-point Likert scale). 
Improvement is defined as a reduction of 2 points or more. Patients evaluable for 
improvement are defined as those with a severity of at least 3 points out of 5 at 
baseline (baseline visit value). Worsening is defined as an increase of 2 points or 
more.  
− Patient/caregiver assessment of abdominal pain frequency as assessed by the 
Stomach pain and hurt sub-scale of the PedsQL™ GI Symptoms Scales. 
Improvement is defined as an increase of 25 points or more (on the 0 to 
100 transformed total subscale score where lower scores indicate worse GI 
stomach pain and hurt). Patients evaluable for improvement are defined as those 
with a score of 70 points or less at baseline (baseline visit score). Worsening is 
defined as a decrease of 25 points or more. 
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4.5.2. 
Secondary Efficacy Variables 
The secondary efficacy endpoints are:  
• Improvement in each patient’s most bothersome sign/symptom at week 24, as 
determined prior to baseline using a semi-structured concept elicitation interview, 
from amongst the ‘core’ clinical endpoints of frequency of bowel movements, 
peripheral edema, facial edema, frequency of problematic abdominal pain (as 
described in Section 4.5.1), nausea and vomiting, and stool consistency 
- Improvement in nausea and vomiting will be defined as an increase of 25 points 
or more on the 0 to 100 transformed nausea and vomiting subscale of the PedsQL 
GI Symptoms Scales score where lower scores indicate worse nausea and 
vomiting. Patients will be evaluable for improvement in nausea and vomiting if 
they have a score ≤75 on the nausea and vomiting subscale at baseline 
- Improvement in stool consistency will be defined as a reduction of ≥50% in the 
number of days per week that the patient has a bowel movement of loose/watery 
consistency. A bowel movement is considered to be loose/watery if it corresponds 
to 3 images of loose or watery stools on the Brussels Infant and Toddler Stool 
Scale (BITSS), the images and descriptors for categories 4 or 5 on the modified 
Bristol Stool Form Scale for Children (mBSFS-C), and the images and descriptors 
for categories 6 or 7 of the Bristol Stool Form Scale (BSFS). To be evaluable for 
improvement in stool consistency, patients must have a bowel movement of 
loose/watery stool consistency for ≥2 days/week at baseline 
• The proportion of patients with active disease at baseline who maintain disease 
control in these time periods (in weeks): 12-48, 12-144, 24-48, 48-144 as defined by: 
− Normalization of serum albumin, defined as serum albumin within the normal 
range at at least 70% of measurements and no single albumin measurement of 
<2.5 g/dL and no requirement for albumin infusion. 
− No worsening (definitions in parentheses), from the beginning of the stated time 
period, at any single visit during the stated time period, of: facial or peripheral 
edema (≥2-point increase); or frequency of problematic abdominal pain (≥25 
point decrease on the Stomach Pain and Hurt subscale of the PedsQL GI 
Symptoms Scales)  or diarrhea subscale of the PedsQL GI Symptoms Scales 
(≥25-point decrease) 
− No increase in dose of permitted concomitant medication for the treatment of PLE 
at any time, no re-introduction of any permitted concomitant medication once 
withdrawn, where permitted concomitant medication is as follows: 
corticosteroids, IV or SC immunoglobulin, IV albumin, biologic 
immunomodulators (anti-TNF, vedolizumab), small molecule immunomodulators 
(e.g., azathioprine, mesalazine), micronutrients, enteral or parenteral 
supplementation 
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• The proportion of patients with inactive disease on eculizumab at baseline who 
maintain disease control in these time periods (in weeks): 12-48, 12-144, 24-48, 48-
144 as defined by: 
− Normalization of serum albumin, defined as serum albumin within the normal 
range at at least 70% of measurements and no single albumin measurement of 
<2.5 g/dL and no requirement for albumin infusion and 
- No worsening (definitions in parentheses), from the beginning of the stated time 
period, at any single visit during the stated time period, of: facial or peripheral 
edema (≥2-point increase); or frequency of problematic abdominal pain (≥25-
point decrease on the PedsQL GI Symptoms Scales’ stomach pain and hurt sub-
scale); or frequency of problems with diarrhea (≥25-point  decrease on the 
PedsQL GI Symptoms Scales’ diarrhea subscale)  
− No increase in dose of permitted concomitant medication for the treatment of PLE 
at any time, no re-introduction of any permitted concomitant medication once 
withdrawn, where permitted concomitant medication is as follows: 
corticosteroids, IV or SC immunoglobulin, IV albumin, biologic 
immunomodulators (anti-TNF, vedolizumab), small molecule immunomodulators 
(e.g., azathioprine, mesalazine), micronutrients, enteral or parenteral 
supplementation 
• The number of bowel movements per day, based on a 1-week average, captured by 
e-diary from baseline to week 24 
• The number of days/week with ≥1 bowel movement of loose/watery stool 
consistency, as measured by BSFS for patients who are 18 years of age and older, 
mBSFS-C for patients who are toilet-trained and less than 18 years of age, or the 
BITSS for patients who are not toilet-trained, and captured by e-diary from baseline 
to week 24 
• Physician assessment of facial edema (based on a 5-point Likert scale) from baseline 
to week 144 
• Physician assessment of peripheral edema (based on a 5-point Likert scale) from 
baseline to week 144 
• 
Change in abdominal symptoms, as assessed by the PedsQL™ GI Symptoms Scales 
stomach pain and hurt sub-scale and food and drink limits sub-scale from baseline to 
week 144 
• Health-related quality of life as assessed by the PedsQL™ Generic Core Scales from 
baseline to week 144; additionally, the following sub-scales will be reported 
separately:  
− About my work/studies and school functioning sub-scale 
− Physical functioning sub-scale 
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• Assessment of abdominal ascites (assessed by measurement of abdominal 
circumference) from baseline to week 24 
• Frequency of albumin infusions up to week 144, expressed as number per half-year. 
Albumin infusions are permitted during the treatment phase in the event that the 
albumin level is below 3.0 g/dL at 2 consecutive visits with accompanying symptoms 
of facial or peripheral edema or ascites. Any albumin infusions after week 12 will 
render the patient a non-responder for the primary endpoint. 
• Total albumin, protein, total Ig, IgG, IgM, IgA, expressed as:  
− Absolute value at every scheduled time point including week 24 
− Absolute and percent change from baseline over time 
− Time to first normalization 
• Vitamin B12, folate, iron, iron binding capacity, ferritin, magnesium, fasting 
cholesterol/triglycerides, expressed as:  
− Absolute value at every scheduled time point including week 24 
− Change from baseline over time 
− Time to first normalization 
• Alpha-1 antitrypsin levels in blood and stool, and change from baseline to week 12 
and week 24 
• Use and dose/frequency from baseline to week 144 of: corticosteroids, IV or SC 
immunoglobulin, IV albumin, biologic immunomodulators (anti-TNF, vedolizumab), 
small molecule immunomodulators (e.g., azathioprine, mesalazine), micronutrients, 
enteral or parenteral supplementation, anti-coagulants (e.g., low-molecular-weight 
heparin), antibiotics (with the exception of those used for the purpose of Neisserial 
prophylaxis), anti-platelet agents (e.g., low-dose aspirin) 
• Hospitalization days (per 24-week period) over time 
• Body weight and height (expressed as z-scores) over time  
• Concentrations of total pozelimab in serum assessed throughout the study 
• Incidence of treatment-emergent anti-drug antibodies to pozelimab in patients over 
time 
• Change and percent change from baseline of total complement activity CH50 over 
time 
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4.5.3. 
Exploratory Efficacy Variables 
• Total C5 concentrations in plasma over time 
• Markers of thrombosis: D-dimer, and N terminal prothrombin fragments (F1+2)  
• Complement assays: sC5b-9 
• Change in GI symptoms of problematic diarrhea and nausea/vomiting as measured by 
the PedsQL™ GI Symptoms Scales' diarrhea sub-scale and nausea and vomiting sub-
scale from baseline over time 
• Change in caregiver well-being and burden as measured by the PedsQL™ Family 
Impact Module from baseline over time 
• Clinician global impression of change (CGIC) from baseline to week 144 
• Clinician global impression of severity (CGIS) from baseline to week 144 
• Patient/caregiver global impression of change (PGIC/CareGIC) from baseline to 
week 144 
• Patient/caregiver global impression of severity (PGIS/CareGIS) from baseline to 
week 144 
• If appropriate to age and stage of sexual maturation, the Tanner pubertal stage 
• Whole exome sequencing (if not already done) 
• Radiographic features of PLE as captured by unscheduled abdominal imaging 
assessments taken as part of standard clinical care over time 
4.6. 
Safety Variables 
“Incidence and severity of treatment-emergent adverse events (TEAEs) and other safety variables 
from baseline to week 144” is listed in the protocol as a secondary endpoint. 
4.6.1. 
Adverse Events and Serious Adverse Events 
Adverse events and serious adverse events will be collected from the time of informed consent 
signature and then at each visit until the end of study. All adverse events are to be coded to a PT 
and associated primary SOC according to the Medical Dictionary for Regulatory Activities 
(MedDRA, the Version 10 or the latest current available version). 
An Adverse Event is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. 
A Serious Adverse Event is an adverse event (AE) that is classified as serious according to the 
criteria specified in the protocol. 
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Local injection site reactions must be reported as AEs and graded according to the Food and Drug 
Administration (FDA) September 2007 Guidance for Industry, Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. 
The severity of AEs that are not infusion reactions, or are not covered in the Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, 
will be graded according to the following scale:  
• Mild: Does not interfere in a significant manner with the patient’s 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 patient’s health. Treatment for symptom may be given and/or 
patient hospitalized.  
Laboratory results, vital signs, or ECG abnormalities are to be recorded as AEs if they are 
medically relevant: symptomatic, requiring corrective therapy, leading to treatment 
discontinuation and/or fulfilling a seriousness criterion. 
4.6.2. 
Adverse Events of Special Interest 
Adverse events of special interest (AESIs) are AEs (serious or non-serious) required to be 
monitored, documented, and managed in a pre-specified manner as described in the protocol. The 
following are the AESIs in this study (as provided in the protocol), along with the approach for 
summarizing them: 
• Moderate or severe infusion reactions (use SMQ “Infusion related reactions”) 
• Confirmed Neisseria infection (use preferred term) 
• Any thrombotic or embolic event (use SMQ “Embolic and thrombotic events”) 
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4.6.3. 
Laboratory Safety Variables 
Clinical laboratory values will be converted to standard international (SI) units and grouped by 
function in summary tables. Conventional units will be provided. The following laboratory tests 
are given in the table in Section 10.2, with details in the footnotes: 
• Blood Chemistry Panel 
• Lipid Panel 
• Blood Immunoglobulin Panel 
• Micronutrient Panel 
• Hematology 
• Coagulation Panel 
• Urinalysis 
• Other Laboratory Tests 
4.6.4. 
Vital Signs 
Vital signs variables include temperature, sitting blood pressure, and pulse, collected predose at 
time points according to the table in Section 10.2. 
4.6.5. 
12-Lead Electrocardiography (ECG) 
Twelve-lead ECG parameters include ventricular rate, heart rate and the PR/PQ, QRS, RR, QT, 
and QTcF intervals. 
4.6.6. 
Physical Examination Variables 
Physical examination variables include results of evaluations of head and neck, lungs, heart, 
abdomen, extremities, and skin, as well as height and body weight. 
4.7. 
Pharmacokinetic Variables   
The PK variable is the concentration of total pozelimab, total C5, and time shown in Section 10.2. 
4.8. 
Immunogenicity Variables  
The immunogenicity variables are anti-drug antibody (ADA) status, titer at nominal time 
point/visit. Samples in this study will be collected at the clinic visits specified in Section 10.2.  PK 
sample at Week 4 may be analyzed for ADA in patients positive for ADA at week 12 or the first 
time point analyzed, provided there is sufficient volume. 
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4.9. 
Exploratory Biomarker Endpoint Variables 
Exploratory variables may include but are not limited to:  
• Markers of thrombosis: D-dimer, and N terminal prothrombin fragments [F1+2)] 
• Markers of complement pathway activation: soluble C5b-9 
• A sample for additional exploratory biomarkers (PD, predictive, and prognostic) 
potentially related to pozelimab treatment exposure, clinical activity, or underlying 
disease may be collected and archived. 
4.10. 
Clinical Outcome Assessments (COAs) 
The following clinical outcome assessments (COAs) will be included: 
• The number of bowel movements per day, based on a one-week average, captured by 
e-diary from baseline to week 24 will be assessed through daily completion of an e-
diary. 
Notes: The daily e-diary, developed specifically for this study, will capture frequency 
of bowel movements over a 24-hour period. The e-diary will be completed by the 
patient if 12 years of age and older, and by caregiver otherwise (with input from the 
patient). When the caregiver is not with their child, bowel movement data will be 
collected by the patient (patient ages 8 to 11) or by an alternate caregiver (patients 
<8 years) such as a nanny, teacher, or daycare provider. Once reunited with their 
child, the caregiver will be responsible for entering the data on bowel movements in 
the e-diary. The number of bowel movements per day will be calculated each week of 
the study. It will be based on a one-week average and calculated as the sum of the 
number of bowel movements in a given week divided by the number of days with 
non-missing bowel movement frequency data. If more than 3 days of bowel 
movement data is missing in a given week, bowel movement frequency data will be 
considered missing for that week. Bowel movement frequency data will be 
summarized overall and by respondent type.  
• The number of days/week with ≥1 bowel movement with loose/watery stool 
consistency as measured by the Bristol Stool Form Scale (BSFS) for patients who are 
18 years of age and older, modified Bristol Stool Form Scale for Children (mBSFS-
C) for patients who are toilet-trained and less than 18 years of age, or the BITTS for 
patients who are not toilet-trained, and captured by e-diary from baseline to week 24. 
Notes: The consistency of each bowel movement will be captured using the daily 
e-diary which will be completed by the patient if aged 12 years of age and older or 
completed by the caregiver if the patient is less than 12 years of age (with input from 
the patient). Stool consistency will be evaluated using the BITTS for patients who are 
not toilet-trained, the mBSFS-C for patients <18 years of age, and the BSFS for 
patients ages 18 years of age and older. The BITTS, mBSFS-C, and BSFS each have 
a unique set of images and text-based descriptors as response options.  The BITTS 
consists of 7 photographs of different stool forms and consistencies: 1) hard stools 
(3 images); 2) formed stools (1 image); 3) loose stools (2 images); and 4) watery 
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stools (1 image). The mBSFS-C categorizes the form of stool into 5 categories using 
drawings with written descriptors: 1) separate hard lumps, like nuts; 2) sausage-
shaped but lumpy; 3) like a sausage or snake, smooth and soft; 4) fluffy pieces with 
ragged edges, a mushy stool; 5) watery, no solid pieces. The BSFS categorizes the 
form of human feces into 7 categories using drawings and written descriptions: 
1) separate hard lumps; 2) lumpy and sausage-like; 3) like a sausage with cracks on 
the surface; 4) like a smooth, soft sausage or snake; 5) soft blobs; 6) fluffy, mushy 
stool; 7) entirely liquid. Loose/watery stool consistency will be defined as the three 
images of loose or watery stools on the BITTS, the images and descriptors for 
categories 4 or 5 on the mBSFS-C, and the images and descriptors for categories 6 or 
7 on the BSFS. The number of days/week with ≥1 loose/watery bowel movement, 
calculated each week of the study as the sum of the number of days with ≥1 
loose/watery bowel movement in a given week divided by the number of days with 
non-missing stool consistency data and then multiplied by 7, will be presented. If 
more than 3 days of stool consistency data are missing in a given week, stool 
consistency data will be considered missing for that week. Stool consistency data will 
be summarized overall and by respondent type.  
• Frequency of problematic abdominal signs and symptoms, as assessed by the 
PedsQL™ GI Symptoms Scales' stomach pain and hurt sub-scale, food and drink 
limits sub-scale and diarrhea subscale from baseline to week 144. 
Notes: The Stomach Pain and Hurt, the Food and Drink Limits, and the Diarrhea 
subscales of the PedsQL™ GI Symptom Scale ask the patient (if age >=12 years) or 
caregiver (if patient <12 years) to rate how much of a problem each item concept has 
been over the past 7 days on a 5-point response scale, ranging from never (0) to 
almost always (4). Items are reverse-scored and linearly transformed to a 0 to 100 
scale so that higher scores indicate less frequency of problems with abdominal signs 
and symptoms. To reverse score, the 0-4 scale items will be transformed to 0-100 as 
follows: 0=100, 1=75, 2=50, 3=25, 4=0. The mean score is estimated as the sum of 
the items over the number of items answered. If more than 50% of the items in the 
scale are missing, the Scale Score will not be calculated. Scores on the PedsQL(TM) 
subscales will be summarized overall and by respondent type. 
• Health-related quality of life as assessed by the PedsQL™ Generic Core Scales from 
baseline to week 144; additionally, the following sub-scales will be reported 
separately:  
− About my work/studies and school functioning sub-scale 
− Physical functioning sub-scale 
Notes: In the PedsQL Generic Core Scales, the patient (if age >=12 years) or 
caregiver (if patient age <12 years) rates how much of a problem each item concept 
has been over the past 7 days on a 5-point response scale, ranging from never (0) to 
almost always (4). For patients >2 years of age there are 8 items assessing physical 
functioning, 5 items assessing emotional functioning, 5 items assessing social 
functioning, and 5 items assessing school/work functioning. For patients 13 months to 
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24 months, there are 9 items assessing physical functioning, 10 items assessing 
physical symptoms, 12 items assessing emotional functioning, 5 items assessing 
social functioning, and 9 items assessing cognitive functioning. Items are reverse-
scored and linearly transformed to a 0 to 100 scale so that higher scores indicate 
better HRQoL. To reverse score, the 0-4 scale items are transformed to 0-100 as 
follows: 0=100, 1=75, 2=50, 3=25, 4=0. The mean score for the physical functioning 
and work/school functioning subscales for patients ages 2 years of age and older will 
be estimated as the sum of the items over the number of items answered in that scale. 
For patients ages 13 to 24 months, the Physical Health Summary Score will be 
calculated as the sum of the items in the physical functioning and physical symptoms 
scales divided by the number of items answered in those scales. If more than 50% of 
the items in the scale are missing, the scale scores will not be calculated. The total 
score will be calculated as the sum of all the items over the number of items answered 
on all the scales. The PedsQL(TM) Generic Core Scales Total and Physical Health 
Summary Scores will be reported separately for patients 13 to 24 months.  Total and 
subscale scores for patients >2 years will be summarized overall and by respondent 
type. 
• GI signs and symptoms (Diarrhea sub-scale and Nausea and vomiting sub-scale) as 
measured by the (PedsQL™ GI Symptoms Scales from baseline over time. 
Notes: The Diarrhea as well as the Nausea and Vomiting subscales of the PedsQL™ 
GI Symptom Scale have 7 and 4 items, respectively, in which the patient (if age 
>=12 years) or caregiver (if patient age <12 years) rates how much of a problem each 
item concept has been over the past 7 days on a 5-point response scale, ranging from 
never (0) to almost always (4). Items are reverse-scored and linearly transformed to a 
0 to 100 scale so that higher scores indicate less frequency of problems with 
abdominal signs and symptoms. To reverse score, the 0-4 scale items will be 
transformed to 0-100 as follows: 0=100, 1=75, 2=50, 3=25, 4=0. The mean score is 
estimated as the sum of the items over the number of items answered. If more than 
50% of the items in the scale are missing, the Scale Score will not be calculated. The 
subscale scores will be summarized overall and by respondent type. 
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• Caregiver well-being and burden as measured by the PedsQL™ Family Impact 
Module from baseline over time. 
Notes: In the PedsQL™(TM) Family Impact Module, the caregiver rates how much 
of a problem each item concept  has been for the caregiver (physical functioning, 
emotional functioning, social functioning, cognitive functioning, communication, and 
worry) or the family (for daily activities and family relationships) over the past 
7 days, as a result of their child’s health, on a 5-point scale ranging from never (0) to 
almost always (4). There are 6 items assessing physical functioning, 5 items assessing 
emotional functioning, 5 items assessing social functioning, 5 items assessing 
cognitive functioning, 3 assessing communication, 5 assessing worry, 3 assessing 
daily activities, and 5 assessing family relationships. Items are reverse-scored and 
linearly transformed to a 0 to 100 scale so that higher scores indicate better HRQoL 
for the caregiver and family of patients. To reverse score, the 0-4 scale items are 
transformed to 0-100 as follows: 0=100, 1=75, 2=50, 3=25, 4=0. The mean score for 
the physical functioning and work/school functioning subscales will be estimated as 
the sum of the items over the number of items answered in that scale. If more than 
50% of the items in the scale are missing, the scale scores will not be calculated. The 
Parent Health-Related Quality of Life Summary Score (20 items) is the sum of the 
items divided by the number of items in the physical functioning, emotional 
functioning, social functioning, and cognitive functioning scales. The Family 
Functioning Summary Score (8 items) is computed as the sum of the items divided by 
the number of items answered in the Daily Activities and Family Relationship scales. 
The total score and the Parent Health-Related Quality of Life Summary Score will be 
reported. 
• Clinician global impression of change (CGIC) over time to week 144. 
Notes: The CGIC is a question which asks the treating physician to rate the change in 
the severity of disease over the course of the study on a 7-point response scale 
ranging from much worse (-3) to no change (0) to much better (3).  
• Clinician global impression of severity (CGIS) from baseline to week 144. 
Notes: The CGIS is a question which asks the treating physician to rate the severity of 
signs and symptoms of disease on a 5-point response scale ranging from no 
sign/symptoms (0) to very severe (4).  
• Patient/caregiver global impression of change (PGIC/CareGIC) over time to week 
144. 
Notes: The PGIC consists of 6 questions and the CareGIC consists of 5 questions 
which assess from the perspective of the patient (if age >=12 years) or caregiver (if 
age <12 years), respectively, the change in overall disease severity, diarrhea, stomach 
pain (PGIC only), impact of disease on school/work, impact of disease on physical 
functioning, and impact of disease on food and drink limitations since the patient 
started the study medication. Patients or caregivers will rate the change of the 
sign/symptom or impact on a 7-point response scale ranging from much worse (-3) to 
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no change (0) to much better (3).  Responses on the PGIC and CareGIC scores will be 
reported overall and stratified by respondent type.  
• Patient/caregiver global impression of severity (PGIS/CareGIS) from baseline to 
week 144. 
Notes: The PGIS consist of 6 questions which assess, from the perspective of the 
patient (if age >=12 years), overall disease severity, diarrhea, stomach pain, impact of 
disease on school/work, impact of disease on physical functioning, and impact of 
disease on food and drink limitations. Patients will rate the severity of the 
sign/symptom or impact on a 5-point response scale ranging from absent (0) to very 
severe (4) for overall disease severity and sign/symptoms or from not at all (0) to very 
much (4) for the disease impacts. The CareGIS consist of 5 questions which assess, 
from the perspective of the caregiver (if patient age <12 years), overall disease 
severity, diarrhea, impact of disease on school/work, impact of disease on physical 
functioning, and impact of disease on food and drink limitations. Caregivers will rate 
the severity of the sign or impact on a 5-point response scale ranging from absent (0) 
to very severe (4) for overall disease severity and signs or from not at all (0) to very 
much (4) for the disease impacts. PGIS and CareGIS will be reported overall and 
stratified by respondent type. 
• If appropriate to age and stage of sexual maturation, the Tanner pubertal stage 
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5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, median, standard deviation, minimum, and maximum. For 
longitudinal data, changes and/or percentage changes will be summarized as appropriate. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
5.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively.  Continuous data will 
be summarized using the number of patients with data, mean, median, standard deviation, Q1, Q3, 
minimum and maximum.  Categorical and ordinal data will be summarized using the number and 
percentage of patients. 
5.2. 
Medical History 
Medical history will be descriptively summarized overall for the study in safety population. 
All reported patient medical history will be presented by primary SOC and PT.  The tables will be 
presented by SOC sorted alphabetically and decreasing patient frequency of PT.  In addition, all 
medical history of specific interest, as described in Section 4.2, will be summarized by patient 
incidence and percentage. 
5.3. 
Prior/concomitant Medications  
All prior medications, dictionary coded by WHODD, will be descriptively summarized for the 
study, for patients in the safety set. Summaries will present patient counts (and percentages) for 
all prior medications, by decreasing frequency of the overall incidence of ATC followed by 
therapeutic class.  In the case of equal frequency across anatomic or therapeutic categories, 
alphabetical order will be used. Patients will be counted once in each ATC category (anatomic or 
therapeutic) linked to the medication but may be counted again for a different category if the same 
medication falls under multiple categories.   
All concomitant medications during the treatment period, dictionary coded by WHODD, will be 
descriptively summarized for patients in the safety set.  In the case of equal frequency across 
anatomic or therapeutic categories, alphabetical order will be used. Patients will be counted once 
in each ATC category (anatomic or therapeutic) linked to the medication, and hence may be 
counted again for a different category if the same medication falls under multiple categories. 
For the follow-up period, medications will be dictionary coded by WHODD and will be 
descriptively summarized as described for the treatment period.  Summaries will present patient 
counts (and percentages). 
5.4. 
Prohibited Medications 
A listing of prohibited medications, found in Section 4.4, will be provided for the patients in the 
safety analysis set for the treatment period and follow-up period. 
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5.5. 
Patient Disposition 
The following displays will be provided: 
• The total number of screened patients:  signed the ICF 
• The total number of enrolled patients 
• The total number of patients in each analysis set 
• The total number of patients who discontinued the study, and the reasons for 
discontinuation 
5.6. 
Extent of Study Treatment Exposure and Compliance 
5.6.1. 
Measurement of Compliance 
Compliance with protocol-defined investigational product will be calculated as follows: 
Treatment Compliance = (Number of investigational product doses taken during study 
period)/(Number of investigational product doses prescribed to be taken during period) x 
100%, 
where temporary dose discontinuation is ignored.  IV and SC doses will be analyzed separately 
and combined for this compliance analysis. 
The percentage of patients who have <60%, 60-80%, 80-100%, and >100% compliance will be 
summarized. 
5.6.2. 
Exposure to Investigational Product 
Exposure to investigational product will be examined for each patient. 
The total number of complete and incomplete injections administered will be summarized for 
infusions and SCs combined and also separately. SC injection location will also be summarized. 
In addition, duration of treatment will be calculated as: [last dose day] – [first dose day] + 1. The 
number of patients exposed to the investigational product will be presented by specific time 
periods. Time periods of interest are as follows:   
• ≥ Day 29  
• ≥ Day 57 
• ≥ Day 85 
• ≥ Day 169 
• ≥ Day 337 
• ≥ Day 1,002 
In addition, frequencies and percentages of SC injections by location will be presented. 
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5.7. 
Analyses of Efficacy Variables 
5.7.1. 
Analysis of Primary Efficacy Variable 
The subset of the FAS with patients having active PLE at baseline will provide the data for the 
primary efficacy analysis. The percentage of patients achieving normalization of albumin (defined 
in Section 4.5.1) and achieving improvement in the prespecified clinical outcomes listed in 
Section 4.5.1 will be calculated and its 90% exact CI will be reported.   
There are 7 planned albumin measurements between week 12 and week 24 inclusive. Patients will 
be considered not evaluable for the primary analysis if there are fewer than 5 available albumin 
measurements between week 12 and week 24. Albumin measurements will be carried out at local 
laboratories and those within the 12 week visit to 24 visit range but outside of the visit windows 
will be considered as valid measurements. To be considered responders, at least 70% of available 
measurements, although not necessarily consecutive, must be normal (≥ 3.5 g/dL). Thus, patients 
with the minimum of 5 available measurements must have 4 out of 5 normal. Patients with the 
planned number of 7 measurements must have at least 5 normal. Patients who have more than 7 
available measurements (due to unplanned albumin measurement) must have at least 70% of all 
available measurements normal.  The mean changes from baseline in albumin over time will also 
be estimated and plotted.   
There are 4 clinical outcomes that can contribute to the clinical improvement component of the 
primary endpoint. Patients are evaluable for improvement in each of these based on activity at 
baseline, as defined in Section 4.5.1. Patients evaluable for only 1 of the 4 clinical outcomes must 
show improvement as defined in Section 4.5.1 in that clinical outcome and no worsening in the 
other 3. Patients evaluable for more than 1 clinical outcome must show improvement (as defined) 
for all of their evaluable outcomes and no worsening in any non-evaluable outcomes.  
For facial and peripheral edema, the primary analysis will be performed using the investigating 
physicians report. Clinical photographs will be rated by a single, central reader blinded to the 
timepoint at which the photograph was taken. The correlation of central read to physician’s 
assessment will be described. The central read will be used as a sensitivity analysis on the primary 
endpoint. 
For the primary endpoint, the definitions of baseline for the component variables are: 
• Albumin - The measurement at the baseline visit will be used; if missing, the 
screening measurement will be used 
• PedsQL GI Symptoms Scales’ Stomach Pain and Hurt Subscale - The baseline visit 
score will be used 
• Bowel movement frequency - The daily average from the e-diary from the last 7 days 
pre-baseline will be used 
• Facial edema - The baseline visit value will be used 
• Peripheral edema - The baseline visit value will be used 
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For the clinical outcome assessments, the rules for missing post-baseline data are as follows: 
• Facial edema and peripheral edema: A measure is required at Week 20 and/or 
Week 24 (and the last observed measure will be used) 
• Bowel movement frequency: At least one valid week of measurements (defined as at 
least 4 of 7 days with measurements) is required in Weeks 20 through 24 (and the last 
week of observation will be used) 
• Stomach Pain and Hurt sub-scale: A valid score at Week 24, or a calculable score at a 
non-scheduled assessment in weeks 20 through 24, is required 
A patient is not evaluable for the primary endpoint if any of these rules for missing data fail to be 
met. 
Regardless of assessability status with respect to missing data for albumin and the above clinical 
measures, a patient will be considered a non-responder if at least one of the following holds: 
• The patient discontinues due to lack of efficacy 
• The patient discontinues due to an adverse event 
• The patient fails to achieve an albumin measure in the normal range at any visit 
• The patient experiences no clinical improvement as defined in Section 4.5.1 at any 
visit 
Sensitivity and subset analyses for the primary endpoint:  
• Repeat of the primary analysis using non-responder imputation for patients with 
fewer than 5 available albumin measurements between week 12 and week 24; in this 
analysis, patients with fewer than 5 albumin measurements will be included in the 
analysis as non-responders 
• Repeat of the primary analysis in which patients with baseline albumin >2.9 g/dL are 
non-evaluable, unless no such patients are recruited 
• Repeat of the primary analysis, using the central reads of facial and peripheral edema, 
rather than the investigators’ reads 
• Per protocol analysis of the primary efficacy endpoint 
Supportive analyses for the primary endpoint:  
• Responder analysis based on improvement in clinical outcomes only 
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5.7.2. 
Analysis of Secondary Efficacy Variables 
For the composite responder efficacy variables for maintenance of effect at week 48 and 144, there 
are 9 planned albumin measurements between week 12 and week 48 inclusive. Patients will be 
considered non-evaluable for the secondary analysis if there are fewer than 6 available albumin 
measurements between week 12 and week 48. Non-responder imputation for patients with fewer 
than 6 available albumin measurements between week 12 and week 48 will be carried out as a 
sensitivity analysis. There are 14 planned albumin measurements between week 12 and week 144 
inclusive. Patients will be considered non-evaluable for the secondary analysis if there are fewer 
than 10 available albumin measurements between week 12 and week 144. There are 3 planned 
albumin measurements between week 24 and week 48 inclusive. Patients will be considered non-
evaluable for this secondary analysis if there are fewer than 2 available albumin measurements 
between week 24 and week 48. There are 6 planned albumin measurements between week 48 and 
week 144 inclusive. Patients will be considered non-evaluable for this secondary analysis if there 
are fewer than 4 available albumin measurements between week 48 and week 144. Within the 
range of weeks of interest, albumin measurements outside of the visit windows and/or carried out 
at local laboratories will be considered as valid measurements. Non-responder imputation for 
patients with fewer than 10 available albumin measurements between week 12 and week 144 will 
be carried out as a sensitivity analysis. The mean changes from baseline in albumin over time and 
the mean number of albumin infusions per half-year will also be estimated. Patient profiles of 
albumin over time will be plotted. 
In addition, a repeat of the primary analysis, defining albumin normalization as having all available 
measurements in the normal range, will be performed. 
For the above responder efficacy variables, the estimate and 90% exact confidence interval for the 
proportion responding will be presented. 
The baseline measure for analyses of secondary efficacy variables will be the measure at the 
baseline visit (or the screening visit’s value if the baseline value is missing), with the following 
exceptions: 
• Week 12, 24 and 48 clinical outcomes are used as baseline for measures of 
maintenance of effect 
• The bowel movement frequency efficacy variable will be assessed using the diarrhea 
sub-scale of the PedsQL™ GI Symptoms Scales 
For continuous secondary outcomes, patient profiles over time will be tabularly and graphically 
presented.  Changes (and/or percentage changes, as appropriate) from baseline in these outcome 
measures over time will be summarized with mean and 90% CI.  There are 3 basic types of 
endpoints that are considered continuous: (1) Labs or other measurements, (2) Single item scales 
with 5 to 7 levels, and (3) Scales based in multiple items, each with several levels. 
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Labs or other measurements: 
• Assessment of abdominal ascites (assessed by measurement of abdominal 
circumference) from baseline to week 24 
• Total albumin, protein, total Ig, IgG, IgM, IgA, expressed as:   
− Absolute value at every scheduled time point including week 24 
- Absolute and percent change from baseline over time 
- Time to first normalization 
• Vitamin B12, folate, iron, iron binding capacity, ferritin, magnesium, fasting 
cholesterol/triglycerides, expressed as:   
− Absolute value at every scheduled time point including week 24 
- Change from baseline over time 
- Time to first normalization 
• Alpha-1 antitrypsin levels in blood and stool, and stool to blood ratio, and change 
from baseline to week 12 and week 24 
• Body weight and height, (expressed as z-scores) over time; plots of raw values over 
time separately will be given for individual patients 
• Absolute value and percent change from baseline of total complement CH50 assay 
over time 
(2) Single item scales: 
• Physician assessment of facial edema (based on a 5-point Likert scale) from baseline 
to week 144 
• Physician assessment of peripheral edema (based on a 5-point Likert scale) from 
baseline to week 144 
(3) Scales based on multiple items: 
• 
Change in abdominal symptoms, as assessed by the PedsQL™ GI Symptoms Scales 
stomach pain and hurt sub-scale, food and drink limits, and diarrhea sub-scales from 
baseline to week 144 
• Health-related quality of life as assessed by the PedsQL™ Generic Core Scales from 
baseline to week 144; additionally, the following sub-scales will be reported separately:  
- About my work/studies and school functioning sub-scale 
- Physical functioning sub-scale 
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For count secondary outcomes, counts per day or per other period of time will be summarized: 
• Number of hospitalization days per 24-week period in the following time periods: -
24 weeks to baseline, baseline to 24 weeks, 24 to 48 weeks, 48 to 72 weeks and 72 to 
96 weeks. 
• The number of bowel movements per day, based on a one-week average, captured by 
e-diary from baseline to week 24 
• Frequency of albumin infusions expressed as number per 24-week period in the 
following time periods: -24 weeks to baseline, baseline to 24 weeks, 24 to 48 weeks, 
48 to 72 weeks and 72 to 96 weeks.  
• Cumulative dose of corticosteroids (in hydrocortisone equivalents) divided into the 
following time periods: -24 weeks to baseline, baseline to 24 weeks, 24 to 48 weeks, 
48 to 72 weeks and 72 to 96 weeks.  
• IV or SC immunoglobulin, biologic immunomodulators (anti-TNF, vedolizumab), 
small molecule immunomodulators (e.g., azathioprine, mesalazine), micronutrients, 
enteral or parenteral supplementation, anti-coagulants (e.g., low-molecular-weight 
heparin), antibiotics (with the exception of those used for the purpose of Neisserial 
prophylaxis), anti-platelet agents (e.g., low-dose aspirin) will be listed. 
• Stool consistency is measured by the Bristol Stool Form Scale (BSFS) for patients 
who are 18 years of age and older, modified Bristol Stool Form Scale for Children 
(mBSFS-C)for patients who are toilet-trained and less than 18 years of age, or the 
BITTS for patients who are not toilet-trained, and captured by e-diary from baseline 
to week 24.  The number of days/week with ≥1 loose/watery bowel movement, 
calculated each week of the study as the sum of the number of days with ≥1 
loose/watery bowel movement in a given week divided by the number of days with 
non-missing stool consistency data, multiplied by 7, will be presented. 
For time-to-event secondary outcomes, including time to first normalization of serum albumin and 
other tests listed above, times for patients will be summarized using Kaplan-Meier methods. 
For the assessment of response for the most bothersome symptom, a patient will be considered a 
responder if he/she meets the a priori pre-defined threshold for response as defined in Section 4.5.2 
for his/her most bothersome symptom.  
5.7.3. 
Analysis of Exploratory Efficacy Variables 
If the Tanner pubertal stages are performed, the information will be presented in a listing.  All 
other exploratory efficacy variables will be summarized in the same manner as the continuous 
secondary efficacy variables.  
With a few exceptions, the baseline measure for analysis of exploratory efficacy variables will be 
the measure at the baseline visit (or the screening visit’s value if the baseline value is missing).  
Exceptions: There is no baseline measure for CGIC or PGIC/CareGIC. 
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5.8. 
Analysis of Safety Data 
The analysis of safety and tolerance will be performed on the SAF, as defined in Section 3.3. 
The safety analysis will be based on the reported AEs and other safety information (clinical 
laboratory evaluations, vital signs and 12-lead ECG).  
Thresholds for Potential Clinically Significant Values (PCSV) in laboratory variables, vital signs 
and ECG are defined in Section 10.3. 
The summary of safety results will be presented for each treatment group. 
5.8.1. 
Adverse Events  
Summaries that include frequencies and proportions of patients reporting AEs will include the PTs 
and the SOCs. 
Day 1 is the first day of investigational product dosing, Day –1 is the day before, and there is no 
Day 0. 
Pre-treatment AEs are defined as AEs that developed or worsened during the pre-treatment 
period. The pre-treatment period is defined as the time between when the patient gives informed 
consent and just before the start of investigational product dosing. 
Treatment-emergent AEs (TEAEs) are defined as AEs that developed or worsened during the 
on-treatment period. The on-treatment period is defined as the time from first dose of 
investigational product up to 21 weeks after the last dose of investigational product. 
Post-treatment AEs are AEs that developed or worsened during the post-treatment period. 
The focus of adverse event summaries in the clinical study report will be on TEAEs. 
For details on handling missing data and partial dates, see Section 6. 
Summaries of all TEAEs will include: 
• The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
• TEAEs by severity (according to the grading scale outlined in Section 4.6.1), 
presented by SOC and PT 
• Treatment related TEAEs, presented by SOC and PT 
• Treatment-emergent AESIs (defined by experiencing a prespecified PT or 
prespecified grouping of PTs, or by being put in a grouping specified in the CRF) 
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Deaths and all SAEs will be summarized. 
Treatment-emergent adverse events leading to permanent treatment discontinuation will be  
summarized. 
Summaries of all TEAEs will include: 
• All TEAEs by SOC and PT 
• Related TEAEs by SOC and PT 
• Serious adverse events: All TEAEs by SOC and PT 
• Death: All fatal TEAEs by SOC and PT 
• Discontinuation: All TEAEs by SOC and PT 
• Non-serious related TEAEs by SOC and PT 
Counts will be provided according to treatment group for each PT within each SOC. Percentages 
will be calculated using the number of patients from the safety population in each treatment group. 
Primary SOCs will be sorted according to the order described in the Guideline on summary of 
product characteristics (December 1999, European commission), with the total overall classes 
coming first and labeled “Any class”. Within each primary SOC, PTs will be sorted by decreasing 
frequency of investigational product. 
A second type of table with counts of each primary SOC in decreasing order of frequency will be 
provided.  A third type of table with counts of each PT in decreasing order of frequency will also 
be provided.  
5.8.2. 
Analysis of Adverse Events of Special Interest 
Treatment emergent adverse events of special interest (listed in Section 4.6.2) will be presented by 
SOC and PT (when selection is based on the e-CRF tick box).  The summaries will be sorted by 
decreasing incidence of PT within each SOC. 
5.8.3. 
Clinical Laboratory Measurements  
A treatment-emergent Potential Clinically Significant abnormal value (PCSV) is a laboratory value 
that was normal at Screening and Baseline but abnormal after treatment with investigational 
product, or a laboratory value that was abnormal at Baseline and exacerbates after treatment with 
investigational product.  “Exacerbations” will be identified by the Medical Monitor using clinical 
judgment.  
Baseline clinical laboratory analytes and change from Baseline in clinical laboratory analytes to 
each scheduled assessment time will be summarized with descriptive statistics.  
For categorical urinalysis variables, counts and percentages will be presented.  
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5.8.4. 
Analysis of Vital Signs 
Vital signs (pulse, sitting blood pressures, and temperature) will be summarized by Baseline and 
change from Baseline to each scheduled assessment time with descriptive statistics.   The graphs 
of mean (or median) value of some vital sign parameter vs. visit will also be plotted.  
5.8.5. 
Analysis of 12-Lead ECG 
ECG parameters (PR interval, QT interval, QTcF interval, QRS interval, and heart rate [from 
ventricular rate]) will be summarized by visit and change from Baseline to each scheduled and 
collected assessment time.  
ECG status (i.e. normal, abnormal) will be reported. Shift tables will be provided to present the 
post-baseline status according to the baseline status (normal or missing / abnormal).  
5.9. 
Analysis of Pharmacokinetic and Immunogenicity Data 
5.9.1. 
Analysis of Pharmacokinetic Data 
Descriptive statistics of concentrations of total pozelimab and total C5 will be presented. Mean 
concentrations of each analyte will be tabulated by visit and treatment group, with concentrations 
below the LLOQ set to zero. 
Plots of the mean concentrations will be presented by nominal sampling time. Plots of the 
individual concentrations will be presented by actual sampling time. In the linear-scaled plots, 
concentrations below the LLOQ will be set to zero; in the log-scaled plots, concentrations below 
the LLOQ will be imputed as LLOQ/2. 
5.9.2. 
Analysis of Immunogenicity Data 
5.9.2.1. 
Analysis of ADA Data 
Immunogenicity variables described in Section 4.8 will be summarized using descriptive statistics. 
Immunogenicity will be characterized by ADA status, ADA category and maximum titer observed 
in patients in the ADA analysis set. 
The ADA status of each patient 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 9-fold the baseline titer value 
• Negative - If all samples are found to be negative in the ADA assay. 
The ADA category of each positive patient is classified as: 
• Treatment-boosted - A positive result at baseline in the ADA assay with at least one 
post baseline titer result ≥9-fold 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.  
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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 a 16-week post baseline period [based 
on nominal sampling time], with no ADA-negative results in-between, regardless 
of any missing samples 
− Transient - Not persistent or indeterminate, 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 
The maximum titer of each patient is classified as: 
• Low (titer <1,000) 
• Moderate (1,000 ≤ titer ≤ 10,000) 
• High (titer >10,000) 
The following analysis will be provided: 
• Number (n) and percent (%) of pre-existing patients 
• Number (n) and percent (%) of ADA-negative patients  
• Number (n) and percent (%) of treatment-emergent ADA positive patients  
− Number (n) and percent (%) of persistent treatment-emergent ADA positive 
patients 
− Number (n) and percent (%) of indeterminate treatment-emergent ADA positive 
patients 
− Number (n) and percent (%) of transient treatment-emergent ADA positive 
patients 
• Number (n) and percent (%) of treatment-boosted ADA positive patients   
A listing of all ADA titer levels will be provided for patients with pre-existing, treatment-emergent 
and treatment-boosted ADA response. 
5.9.3. 
Association of Immunogenicity with Exposure, Safety and Efficacy  
5.9.3.1. 
Immunogenicity and Exposure 
Potential association between immunogenicity and systemic exposure to pozelimab will be 
explored by treatment. Plots of individual pozelimab concentration time profiles may be provided 
to examine the potential impact of ADA category and maximum titer on these profiles. 
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5.9.3.2. 
Immunogenicity and Safety and Efficacy 
Potential association between immunogenicity variables and safety may be explored with a 
primary focus on the following safety events during the TEAE period:  
• Injection site reaction (serious or severe and lasting 24 hours or longer) 
• Hypersensitivity (SMQ: Hypersensitivity [Narrow]) 
• Anaphylaxis (SMQ: Anaphylaxis [Narrow]) 
Potential association between immunogenicity variables and efficacy endpoints may be explored 
(e.g. scatter plot or spaghetti plot).  
The safety and efficacy analyses mentioned above will be conducted using the following 
categories: 
• ADA positive  
− Treatment-emergent 
− Treatment-boosted  
• Maximum post-first dose titer in treatment-emergent or treatment-boosted ADA 
positive patients:  
− Low (titer <1,000) 
− Moderate (1,000 ≤ titer ≤ 10,000) 
− High (titer >10,000) 
5.10. 
Analysis of Pharmacodynamics and Biomarkers 
For the thrombosis and complement activation biomarker variables described in Section 4.9, 
descriptive statistics (means and mean changes) will be presented by visit.  Where applicable, plots 
of means and mean changes will be presented by visit. 
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis.  
6.1. 
Definition of Baseline for Efficacy/Safety Variables 
Unless otherwise specified, the Baseline assessment for all measurements will be the latest 
available valid measurement taken prior to the administration of investigational product. If the 
scheduled Baseline Day 1 measurements are not available, screening assessments may be used; 
when scores are used, this rule applies to scores, not individual variables. 
6.2. 
Data Handling Convention for Efficacy Variables 
In Section 4.10, COAs are discussed.  The rules for number of missing items necessary for a scale 
to be missing are given, as well as the number of days in a week with no counts necessary for a 
weekly count to be missing. 
In Section 5.7.1, the primary analysis and sensitivity and supportive analyses are discussed.  The 
rules for number of missing measures necessary for a patient to be non-evaluable or a non-
responder, depending on the analysis, are given. 
In Section 5.7.2, similar rules are given for secondary efficacy responder analyses. 
6.3. 
Data Handling Convention for Missing Data 
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. 
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. For analysis purposes, these data will be treated the 
same as data collected under normal circumstances. 
6.3.1. 
Adverse events 
If the severity of a TEAE is missing, it will be classified as “severe” in the frequency tables by 
severity of TEAE. If the measurement of relationship of a TEAE to the investigational product is 
missing, it will be classified as “related” in the frequency tables by relation to the investigational 
product. 
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Adverse event start date  
AE start date will be used for AE classification and analysis of AESIs. If AE start date is not 
complete, then the character variable will keep the original incomplete date, the numerical date 
variable will be imputed, and an imputation flag will indicate which date component is missing. 
If AE start day is missing, and AE start month and year are not missing: If AE start year is the 
same as first dose year and the AE start month is the same as the first dose month then impute AE 
start day using the day of first dose. If this leads to a date after the AE end date, use AE end date 
instead. Otherwise impute the AE start day using the first day of the month. If this leads to a date 
before informed consent, the informed consent date will be used. Imputation flag is ‘D’. 
If AE start month is missing, and AE start year is not missing: If AE start year is less than the first 
dose year, use the informed consent day and month. If AE start year is equal to the first dose year, 
use the first dose day and month. If this leads to a date after the AE end date, use AE end date 
instead. If AE start year is after the first dose year, use 01 January. Imputation flag is ‘M’. 
If AE start year is missing: Impute AE start date using the day of first dose. If this leads to a date 
after the AE end date, use AE end date instead. Imputation flag is ‘Y’. 
Adverse event end date 
The general recommendation is not to impute AE end date. However, since AE end date will be 
used for AE starting date imputation, in order to carry through the logic for programming, the 
following intermediate step will be used. Afterwards, only the original character/numeric date 
recorded in CRF will be kept in the final analysis dataset. 
If AE end day is missing, and AE end month and year are not missing: Impute AE end date using 
the last day of the month. If this leads to a date after end of study follow up date, use the last study 
visit date instead. 
If AE end month is missing, and AE end year is not missing: Impute AE end date using 
31 December as the day and month. If this leads to a date after end of study follow up date, use 
the last study visit date instead. 
If AE end year is missing: Impute AE end date using the end of follow up date. 
Medication start and end date missing 
To determine whether a medication is pre-treatment medication or concomitant medication or 
both, the missing medication start date is estimated as early as possible, and the missing medication 
end date is estimated as late as possible. If the medication start date is missing, the onset day will 
not be calculated in medication listings. 
Prior medication start date  
If start day is missing, and start month and year are not missing: Impute the start day using the first 
day of the month. Imputation flag is ‘D’; 
If start month is missing, and start year is not missing: Impute the day and month using 01 January. 
Imputation flag is ‘M’. 
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If start year is missing: Impute start date using 2 years before informed consent date. Imputation 
flag is ‘Y’. 
A special note: for start date with year missing, the general principle is not to impute. However, in 
order to simplify the programming flow, the imputation is proposed to align with the protocol 
which specifies to collect up to 2 years prior medication. Since the start date of prior medication 
will not be used in any analysis, the rule will not impact the analysis result.  
Prior medication end date 
If end day is missing, and end month and year are not missing: Impute end date using the last day 
of the month. If this leads to a date on or after first dose intake date, use first dose intake date -1 
instead. Imputation flag is ‘D’. 
If end month is missing, and end year is not missing: Impute end date using 31 December as the 
day and month. If this leads to a date on or after first dose intake date, use first dose intake date -
1 instead. Imputation flag is ‘M’ 
If end year is missing: Impute end date using the first dose intake date –1. Imputation flag is ‘Y’. 
Concomitant medication start date 
The imputation rule for concomitant medication start date is the same as AE start date. 
Concomitant medication end date 
If end day is missing, and end month and year are not missing: Impute end date using the last day 
of the month. If this leads to a date after end of study follow up date, use the last visit study date 
instead. Imputation flag is ‘D’. 
If end month is missing, and end year is not missing: Impute end date using 31 December as the 
day and month. If this leads to a date after end of study follow up date, use the last study visit date 
instead. Imputation flag is ‘M’. 
If end year is missing: Impute date using the end of last study visit date. Imputation flag is ‘Y’. 
Medication coding 
Medications whose ATC level 4 cannot be coded will be summarized by setting ATC4=ATC2 in 
the table programs. However, these uncoded ATC level 4 records still need to be confirmed with 
study DM and study MD. 
6.3.2. 
PCSV 
Patients who had post-baseline PCSV, but missing baseline value will be regarded as having 
treatment emergent PCSV. 
6.3.3. 
Date of first / last study drug administration 
Date of first study drug administration is the first non-missing start date of dosing filled in the CRF 
“Investigational Product” module. 
If a patient’s date of the last dose is totally missing or unknown, his/her last visit date will be 
substituted.  
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6.4. 
Visit Windows 
Data analyzed by visit (including efficacy, laboratory data, visit sign, ECG) will be summarized 
by the study scheduled visits described in Section 10.2 (Schedule of Time and Events). Analysis 
visit windows will be constructed using ranges applied to the number of days in study (study days) 
when the measure is collected, with the general rule of windows being half-way between 
consecutive visits’ target days.  There will be no gaps, so that all available values obtained from 
unscheduled visits, early termination visit (ETV) and end of treatment (EOT)/end of study (EOS) 
have the potential to be summarized. Analysis visit windows will not be applied to study scheduled 
visits. 
6.5. 
Unscheduled Assessments 
The determination of baselines and values at the end of treatment for both efficacy and safety 
variables will be based on scheduled available assessments and unscheduled available 
assessments.  
Extra assessments (laboratory data or vital signs associated with non-protocol clinical visits or 
obtained in the course of investigating or managing adverse events) will be included in listings, 
but not summaries, except for the endpoint determination.  If more than one laboratory value is 
available for a given visit, the first observation will be used in summaries and all observations will 
be presented in listings. 
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CONFIDENTIAL 
7. 
INTERIM ANALYSIS 
Database locks and analyses prior to the final database lock are planned for the following times 
for the stated purposes:   
• The first database lock takes place at 12 weeks from the first dose in the fourth active 
patient, for an FDA meeting 
• The second database lock for reporting on the primary efficacy endpoint takes place 
at 24 weeks from the first dose in the eighth active patient  
• The third database lock and reporting of longer-term effects takes place at 1 year from 
first dose in the last patient 
• The fourth database lock and reporting of longer-term effects takes place at 2 years 
from first dose in the last patient 
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CONFIDENTIAL 
8. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or higher. 
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CONFIDENTIAL 
9. 
REFERENCES 
ICH. E9 Statistical Principles for Clinical Trials (ICH Harmoised Tripartite Guideline).  1998; 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. 
Kurolap A, Eshach-Adiv O, Hershkovitz T, Paperna T, Mory A, Oz-Levi D, et al. Loss of CD55 
in Eculizumab-Responsive Protein-Losing Enteropathy. N Engl J Med 2017; 377(1):87-89. 
Kurolap A, Eshach Adiv O, Hershkovitz T, Tabib A, Karbian N, Paperna T, et al. Eculizumab Is 
Safe and Effective as a Long-term Treatment for Protein-losing Enteropathy Due to CD55 
Deficiency. J Pediatr Gastroenterol Nutr 2019; 68(3):325-333. 
Ozen A, Comrie WA, Ardy RC, Dominguez Conde C, Dalgic B, Beser OF, et al. CD55 Deficiency, 
Early-Onset Protein-Losing Enteropathy, and Thrombosis. N Engl J Med 2017; 377(1):52-61. 
Ozen A, Kasap N, Vujkovic-Cvijin I, Apps R, Cheung F, Karakoc-Aydiner E, et al. Broadly 
effective metabolic and immune recovery with C5 inhibition in CHAPLE disease. Nat Immunol 
2021; 22(2):128-139. 
 
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CONFIDENTIAL 
10. 
APPENDIX 
10.1. 
Summary of Statistical Analyses 
 
Analysis 
Statistical 
Supportive 
Subgroup 
Other 
Endpoint 
Populations 
Method 
Analysis 
Analysis 
Analyses 
 
 
 
 
 
 
Efficacy analysis 
FAS 
Confidence intervals 
No  
Yes 
Yes 
Adverse Events 
SAF 
Descriptive Statistics 
No 
No 
No 
Laboratory Measures 
SAF 
Descriptive Statistics 
No 
No 
No 
Vital sign 
SAF 
Descriptive Statistics 
No 
No 
No 
ECG 
SAF 
Descriptive Statistics 
No 
No 
No 
 
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CONFIDENTIAL 
10.2. 
Schedule of Events 
Table 1: 
Schedule of Events 
Study Procedure 
Screening 29 
Baseline 
Treatment Period1 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Day  
-28 
1 
2 
8±3 
15±3 
22±3 
29±3 
43±3 
57±3 
71±3 
85±3 
Week 
-4 
0 
 
1 
2 
3 
4 
6 
8 
10 
12 
Screening/Baseline: 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion2 
X 
X 
 
 
 
 
 
 
 
 
 
Genetic testing (if needed)2 
X 
 
 
 
 
 
 
 
 
 
 
Medical History3 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Prior Medications4 
X 
 
 
 
 
 
 
 
 
 
 
Lab Parameter History5 
X 
 
 
 
 
 
 
 
 
 
 
Vaccination History6 
X 
X 
 
 
 
 
 
 
 
 
 
Risk assessment for Neisseria gonorrhea 
(as applicable)7 
X 
 
 
 
 
 
 
 
 
 
 
Hepatitis/TB history and assessment8 
X 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
Concept Elicitation Interview9 
X 
 
 
 
 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
Administer Study Drug10 
 
X11 
 
X12 
Patient Diary (for self-admin) 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Concomitant Meds and Interventions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy: 
 
 
 
 
 
 
 
 
 
 
 
Tanner Staging13 
 
X 
 
 
 
 
 
 
 
 
X 
e-Diary  
X14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BSFS, mBSFS-C, or BITSS 
X14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGIS 
 
X 
 
X 
X 
X 
X 
 
X 
 
X  
CGIC 
 
 
 
X 
X 
X 
X 
 
X 
 
X  
Physician Assessment of Facial Edema15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physician Assessment of Peripheral 
Edema15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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CONFIDENTIAL 
Study Procedure 
Screening 29 
Baseline 
Treatment Period1 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Day  
-28 
1 
2 
8±3 
15±3 
22±3 
29±3 
43±3 
57±3 
71±3 
85±3 
Week 
-4 
0 
 
1 
2 
3 
4 
6 
8 
10 
12 
Abdominal Circumference15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body Weight with z Score 
X16 
X 
 
 
 
 
X 
 
X 
 
X 
Height with z Score 
X16 
X 
 
 
 
 
X 
 
X 
 
X 
PedsQL Generic Core Scales 
 
X 
 
X 
X 
X 
X 
 
X 
 
X 
PedsQL GI Symptom Scales 
 
X 
 
X 
X 
X 
X 
 
X 
 
X 
PedsQL Family Impact Module 
 
X 
 
X 
X 
X 
X 
 
X 
 
X 
PGIS/CareGIS 
 
X 
 
X 
X 
X 
X 
 
X 
 
X 
PGIC/CareGIC 
 
 
 
X 
X 
X 
X 
 
X 
 
X 
Hospitalization Days 
X17 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety: 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing and Biomarkers: 
 
 
 
 
 
 
 
 
 
 
Blood Chemistry Panel19 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Micronutrients and Lipid Panel20 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Blood Immunoglobulin Panel21 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Alpha-1 Antitrypsin (fecal and serum) 
 
X 
 
  
 
 
  
 
 
 
X 
Pregnancy Test22 
X 
X 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
X 
X 
X 
X 
 
 
 
X 
Hematology 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
Coagulation Panel (APTT/PT) 
X 
 
 
X 
 
 
X 
 
 
 
X 
Complement Hemolytic Assay (CH50)23 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Total C523 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Total Complement C3 and C4 Levels 
X 
 
 
 
 
 
 
 
 
 
 
Thrombosis Biomarkers24 
 
X 
 
X 
 
 
X 
 
 
 
X 
sC5b-9 (plasma) 23 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
Buccal Swab for DNA Isolation 
(optional)25 
 
X 
 
 
 
 
 
 
 
 
 
Future biomedical research (optional, 
weight >20 kg only) 
 
X 
 
 
 
 
X 
 
X 
 
X 
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CONFIDENTIAL 
Study Procedure 
Screening 29 
Baseline 
Treatment Period1 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Day  
-28 
1 
2 
8±3 
15±3 
22±3 
29±3 
43±3 
57±3 
71±3 
85±3 
Week 
-4 
0 
 
1 
2 
3 
4 
6 
8 
10 
12 
Drug Concentration and ADA Samples:  
 
 
 
 
 
 
 
 
 
Drug Conc. Sample 23, 27 
 
X 
 
X 
X 
 
X 
X 
X 
 
X 
ADA Sample 23,  27, 28 
 
X 
 
 
 
 
 
 
 
 
X 
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CONFIDENTIAL 
Table 1 
Schedule of Events (contd) 
Study Procedure 
Treatment Period1 
Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of TX 
Analysis 
End of 
Study 
Early 
Term 
Visit Number 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
 
Day  
99 
±3 
113 
±3 
127 
±3 
141 
±3 
155 
±3 
169 
±3 
253 
±3 
337 
±3 
421 
±3 
505 
±3 
589 
±3 
673 
±3 
1009 
±3 
1149 
±3 
 
Week 
14 
16 
18 
20 
22 
24 
36 
48 
60 
72 
84 
96 
144 
164 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer Study Drug10 
X12 
 
 
 
Patient Diary (self-admin) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant Meds and Interventions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tanner Staging13 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
E-Diary  
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
BSFS, mBSFS-C, or BITSS 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
CGIS 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
CGIC 
 
X 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
Physician Assessment of Facial Edema15 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Physician Assessment of Peripheral Edema15 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Abdominal Circumference15 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Body Weight with z Score16 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Height with z Score16 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
PedsQL Generic Core Scales 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
PedsQL GI Symptom Scales 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
PedsQL Family Impact Module 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
PGIS/CareGIS 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
PGIC/CareGIC 
 
X 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
Exit interview9 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Hospitalization Days 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Physical Examination 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse Events18 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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CONFIDENTIAL 
Study Procedure 
Treatment Period1 
Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of TX 
Analysis 
End of 
Study 
Early 
Term 
Visit Number 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
 
Day  
99 
±3 
113 
±3 
127 
±3 
141 
±3 
155 
±3 
169 
±3 
253 
±3 
337 
±3 
421 
±3 
505 
±3 
589 
±3 
673 
±3 
1009 
±3 
1149 
±3 
 
Week 
14 
16 
18 
20 
22 
24 
36 
48 
60 
72 
84 
96 
144 
164 
 
Laboratory Testing and Biomarkers: 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Chemistry Panel19 
X26 
X 
X26 
X 
X26 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Micronutrients and Lipid Panel20 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
X 
Blood Immunoglobulin Panel21 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Alpha 1-Antitrypsin (fecal and serum) 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test22 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
Hematology 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
 
Coagulation Panel (APTT/PT) 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
Complement Hemolytic Assay (CH50) 23 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
 
Total C523 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
 
Total Complement C3 and C4 Levels 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thrombosis Biomarkers24 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
sC5b-9 (plasma) 23 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
Buccal Swab for DNA Isolation (optional) 25 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Future biomedical research (optional, body 
weight >20 kg only) 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
Drug Concentration and ADA Samples:  
 
 
 
 
 
 
 
 
 
 
 
 
Drug Conc. Sample 23, 27 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
ADA Sample 23, 27 
 
 
 
 
 
X 
 
X 
 
 
 
 X 
X  
X 
X 
 
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10.2.1. 
Footnotes for the Schedule of Events Table 
1. Treatment period is from week 0 to week 144, with first dose given on day 1 [week 0] and 
last dose at week 143. All visits in the Schedule of Events table are mandatory in-clinic 
visits, and do not reflect the dosing schedule, which is weekly (±2 days). Study procedures 
within each visit may be conducted on different days, within the stated visit window. 
2. Including history of CD55 gene mutation analysis and if necessary CD55 protein analysis, 
confirmed by flow cytometry or western blot, respectively. If this data is unavailable, a 
blood sample may be collected, as needed, for analysis. Refer to Protocol Section 9.2.1 for 
details. 
3. Including history of albumin infusions and prior thromboembolic events since birth 
4. Including eculizumab administration history 
5. Albumin, total protein, total immunoglobulin data including everything available from the 
patient’s birth onwards  
6. All patients require meningococcal, pneumococcal, and Haemophilus influenzae 
vaccination, either prior to the study or during screening, according to local availability 
and practice guidelines. Refer to Protocol Section 8.3.1 for details. 
7. Risk assessment for Neisseria gonorrhea is described in Protocol Section 8.4. 
8. 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. 
Optional hepatitis B/C testing may be performed at the discretion of the investigator. 
9. Patients (and caregivers, as appropriate) will be undergo a concept elicitation interview at 
screening and an exit interview at the time point of the primary endpoint as part of clinical 
outcomes evaluation. Details are described in Protocol Section 9.2.3.3. 
10. Meningococcal vaccination is required and daily oral antibiotic prophylaxis is 
recommended as described in Protocol Section 8.3. 
11. IV loading dose  
12. Subcutaneous dosing to be administered weekly either at study site or in local community 
healthcare setting close to patient or at home. Weekly dosing is not noted as visits on this 
SOE table. The last dose of study drug is administered at week 143. 
13. Only for patients between ages 8 to 20 years 
14. Patients to begin completion of e-diary recording bowel movements and consistency at 
least 7 days prior to the baseline visit 
15. In the presence of facial or peripheral edema or ascites, assessment should be always 
accompanied by clinical photography. 
16. Including all available historical height and weight data from birth 
17. Collect all available information pertaining to previous hospitalization dates since birth. 
18. Including new thromboses and extension of existing thromboses 
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19. Total protein and albumin are tested in this panel (see blood chemistry panel in Protocol 
Section 9.2.4.4 Laboratory Testing). Testing will use either adult or small-volume pediatric 
kits as specified in a manual or kit instruction. If patient receives IV albumin infusion, this 
panel should be drawn either prior to the infusion or 2 weeks after the infusion. 
20. See Micronutrients Panel and Lipids Panel in Protocol Section 9.2.4.4 Laboratory 
Testing. 
21. See Blood Immunoglobulin Panel in Protocol Section 9.2.4.4  Laboratory Testing. 
22. A pregnancy test is mandatory at screening and baseline for all women of childbearing 
potential (as defined in exclusion criterion #20). According to local practice in the study 
country, pregnancy testing (serum or urine) after enrollment is mandatory for all females 
from the age of sexual maturity, or for married females and, at the discretion of the 
investigator, for non-married females from the age of sexual maturity. 
23. Intensity of blood sampling for these analytes will be reduced if necessary to comply with 
local body weight-specific limitations on blood withdrawal volume. The blood draw 
schedule in Table 1 is designed for patients with body weight equal or greater than 20 kg. 
It is expected that patients below 20 kg in weight will require reduction in blood-draw 
intensity. A separate blood draw schedule will be provided for patients with body weight 
between 10 kg and 20 kg in the sample handling manual. For patients with body weight 
less than 10 kg, an order of priority of blood draws will be provided in the sample handling 
manual or kit instruction, and samples should be drawn in this order until the volume limit 
is reached. The chemistry panel will have highest priority followed by full blood count and 
drug concentration. 
24. Includes D-dimer, and F(1+2). Refer to lab manual for procedure. 
25. Sample should be collected at baseline visit but may be collected at any time. 
26. Kits may be provided locally so that the chemistry panel may be taken locally to the 
patient without needing a site visit. 
27. Drug concentration and ADA samples are to be collected prior to study drug 
administration. In the event of any SAE or any AESI of anaphylactic reactions or systemic 
allergic reactions that are related to study drug and require treatment, or severe injection 
site reaction lasting longer than 24 hours, drug concentration and ADA samples will be 
collected at or near the onset of the event for any additional analysis.  
28. In the event a patient sample is positive in the pozelimab ADA assay at week 12 or the first 
time point analyzed, the week 4 PK sample may be analyzed in the ADA assay, provided 
there is sufficient volume. 
29. The screening period may be extended to approximately 10 weeks for patients with 
extenuating circumstances as described in Protocol Section 9.2.1. 
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CONFIDENTIAL 
10.3. 
Criteria for Potentially Clinically Significant Values (PCSV) 
Parameter 
PCSV 
Comments 
Clinical chemistry 
ALT 
By distribution analysis: 
> 3 ULN 
> 5 ULN 
> 10 ULN 
> 20 ULN 
FDA DILI Guidance July 2009 
 
AST 
By distribution analysis: 
> 3 ULN 
> 5 ULN 
> 10 ULN 
> 20 ULN 
FDA DILI Guidance July 2009 
 
Alkaline Phosphatase 
> 1.5 ULN 
FDA DILI Guidance July 2009 
Total Bilirubin 
≥1.3 ULN (Under 18 yrs) 
> 1.5 ULN (18 yrs +) 
> 2 ULN (18 yrs +) 
FDA DILI Guidance July 2009 
 
ALT and Total Bilirubin 
ALT > 3 ULN and Total Bilirubin > 2 ULN (under 18 yrs) 
ALT > 3 ULN and Total Bilirubin > 2 ULN (18 yrs +) 
FDA DILI Guidance July 2009 
 
CPK 
> 3 ULN 
>10 ULN 
FDA Feb 2005 
Am J Cardiol April 2006 
Categories are cumulative 
First row is mandatory.  
Creatinine 
 30% increase from baseline 
 60% increase from baseline 
Benichou C., 1994 
 
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CONFIDENTIAL 
Parameter 
PCSV 
Comments 
Sodium 
129 mmol/L (Under 18 yrs) 
 150 mmol/L (Under 18 yrs) 
129 mmol/L (18 yrs +) 
 160 mmol/L (18 yrs +) 
Must also be outside the normal range. 
 
Potassium 
≤3.5 mmol/L or 3.5 mEq/L (Under 2 yrs) 
≥6.0 mmol/L or 6.0 mEq/L (Under 2 yrs) 
≤3.5 mmol/L or 3.5 mEq/L (2 to 17 yrs) 
≥5.5 mmol/L or 5.5 mEq/L ( 2 to 17 yrs) 
< 3  mmol/L (18 yrs +) 
 5.5 mmol/L (18 yrs +) 
FDA Feb 2005 
Must also be outside the normal range. 
 
Total Cholesterol 
>6.20 mmol/L (Under 18 yrs) 
>7.74 mmol/L (18 yrs +) 
Must also be outside the normal range. 
 
Triglycerides 
> 4.0 mmol/L 
Must also be outside the normal range. 
Glucose 
  
  
Hypoglycaemia <2.7 mmol/L or 50 mg/dL (Under 18 yrs) 
Hyperglycaemia ≥7 mmol/L or 120 mg/dL (fasted after >12 hours 
of fast); ≥10.0 mmol/L or 180 mg/dL (unfasted) (Under 18 yrs) 
≤3.9 mmol/L and <LLN (18 yrs +) 
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) 
ADA May 2005, Jan 2008 
Must also be outside the normal range. 
 
 
 
 
CRP 
>10 mg/L 
FDA Sept 2005 
                                        VV-RIM-00202459-1.0 Approved - 23 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PLE-1878 
Statistical Analysis Plan 
 
Date: June 20, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 60 of 67 
 
CONFIDENTIAL 
Parameter 
PCSV 
Comments 
Hematology 
WBC 
<4.0 GIGA/L or 4,000 /mm3 (Under 2 yrs) 
>20.0 GIGA/L or 20,000 /mm3 (Under 2 yrs) 
<3.0 GIGA/L or 3,000 /mm3 (2 to 5 yrs) 
>16.0 GIGA/L or 16,000 /mm3 (2 to 5 yrs) 
<5.0 GIGA/L or 5,000 /mm3 (6 to 11 yrs) 
>17.0 GIGA/L or 17,000 /mm3 (6 to 11 yrs) 
<4.5 GIGA/L or 5,000 /mm3 (12 to 17 yrs) 
>13.5 GIGA/L or 17,000 /mm3 (12 to 17 yrs) 
< 3.0 Giga/L (3000/mm3) (Non-Black 18 yrs +) 
< 2.0 Giga/L (2000/mm3) (Black 18 yrs +) 
≥ 16.0 Giga/L (18 yrs +) 
Must also be outside the normal range. 
 
Neutrophils 
<1.2 GIGA/L or 1,200 /mm3 (Under 2 yrs) 
> 1 ULN (Under 2 yrs) 
<1.2 GIGA/L or 1,200 /mm3 (2 to 17 yrs) 
> 1 ULN (2 to 17 yrs) 
< 1.5 Giga/L (1,500/mm3) (Non-Black 18 yrs +) 
< 1.0 Giga/L (1,000/mm3) (Black 18 yrs +) 
Must also be outside the normal range. 
 
Eosinophils 
>0.5 GIGA/L or 500 /mm3  
Or >ULN if ULN >0.5 GIGA/L or 500 /mm3 (Under 18 yrs) 
>0.5 Giga/L or >ULN (if ULN≥0.5 Giga/L) (18 yrs +) 
Harrisson 17th Ed, 2008. 
                                        VV-RIM-00202459-1.0 Approved - 23 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PLE-1878 
Statistical Analysis Plan 
 
Date: June 20, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 61 of 67 
 
CONFIDENTIAL 
Parameter 
PCSV 
Comments 
Hemoglobin 
< 1.40 mmol/L or 9.0 g/dL or any decrease > 0.31 mmol/L or 2 g/dL 
(Under 2 yrs) 
< 1.55 mmol/L or10.0 g/dL or any decrease > 0.31 mmol/L or 2 
g/dL (2 to 17 yrs) 
≤115 g/L (Male 18 yrs +) 
≤95 g/L (Female 18 yrs +) 
≥185 g/L (Male 18 yrs +) 
≥165 g/L (Female 18 yrs +) 
Decrease from Baseline ≥20 g/L (18 yrs +) 
Must also be outside the normal range. 
 
Platelets 
<100 GIGA/L or 100,000 /mm3 (Under 18 yrs) 
> 700 GIGA/L or 700,000 /mm3 (Under 18 yrs) 
< 100 Giga/L (100,000/mm3) 
> 700 Giga/L (100,000/mm3) 
Must also be outside the normal range. 
 
Vital Signs 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
 
SBP 
≤70 mmHg and decrease from baseline ≥20 mmHg (Under 2 yrs) 
≥98 mmHg and increase from baseline ≥20 mmHg (Under 2 yrs) 
≤70 mmHg and decrease from baseline ≥20 mmHg (2 to 5 yrs) 
≥101 mmHg and increase from baseline ≥20 mmHg (2 to 5 yrs) 
≤80 mmHg and decrease from baseline ≥20 mmHg (6 to 11 yrs) 
≥108 mmHg and increase from baseline ≥20 mmHg (6 to 11 yrs) 
≤90 mmHg and decrease from baseline ≥20 mmHg (12 to 17 yrs) 
≥119 mmHg and increase from baseline ≥20 mmHg (12 to 17 yrs) 
 95 mmHg and decrease from baseline  20 mmHg (18 yrs +) 
 160 mmHg and increase from baseline  20 mmHg (18 yrs +) 
 
                                        VV-RIM-00202459-1.0 Approved - 23 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PLE-1878 
Statistical Analysis Plan 
 
Date: June 20, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 62 of 67 
 
CONFIDENTIAL 
Parameter 
PCSV 
Comments 
DBP 
≤34 mmHg and decrease from baseline ≥10 mmHg (under 2 yrs) 
≥54mHg and increase from baseline ≥10 mmHg (Under 2 yrs) 
≤34 mmHg and decrease from baseline ≥10 mmHg (2 to 5 yrs) 
≥59mHg and increase from baseline ≥10 mmHg (2 to 5 yrs) 
≤48 mmHg and decrease from baseline ≥10 mmHg (6 to 11 yrs) 
≥72mHg and increase from baseline ≥10 mmHg (6 to 11 yrs) 
≤54 mmHg and decrease from baseline ≥10 mmHg (12 to 17 yrs) 
≥78 mmHg and increase from baseline ≥10 mmHg (12 to 17 yrs) 
 45 mmHg and decrease from baseline  10 mmHg (18 yrs +) 
 110 mmHg and increase from baseline  10 mmHg (18 yrs +) 
 
 
Weight 
 5% decrease versus baseline 
FDA Feb 2007  
ECG parameters 
 Ref. : Rijnbeek P.R. et al., Eur Heart J 2001; Davignon 
A. et al., Ped Cardiol 1979/1980; Semizel E.et al., 
Cardiol Young 2008; Mulberg AE et al. Pediatric Drug 
Development Concepts and applications. John Wiley & 
sons, Inc. 2009 
HR 
≤80 bpm and decrease from baseline ≥20 bpm (Under 2 yrs) 
≥175 bpm and increase from baseline ≥20 bpm (Under 2 yrs) 
≤75 bpm and decrease from baseline ≥20 bpm  
(2 to 5 yrs) 
≥140 bpm and increase from baseline ≥20 bpm (2 to 5 yrs) 
 50 bpm and decrease from baseline  20 bpm (Age 6 to 11 yrs) 
 120 bpm and increase from baseline  20 bpm (Age 6 to 11 yrs) 
≤50 bpm and decrease from baseline ≥20 bpm (12 to 17) 
≥120 bpm and increase from baseline ≥20 bpm (12 to 17) 
≤50 bpm and decrease from baseline ≥20 bpm (18 yrs +) 
≥120 bpm and increase from baseline≥20 bpm (18 yrs +) 
 
                                        VV-RIM-00202459-1.0 Approved - 23 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PLE-1878 
Statistical Analysis Plan 
 
Date: June 20, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 63 of 67 
 
CONFIDENTIAL 
Parameter 
PCSV 
Comments 
PR 
≥ 140 ms (Under 2 yrs) 
≥ 160 ms (2 to 5 yrs) 
 170 ms (6 to 11 yrs) 
 180 ms (12 to 17 yrs) 
>200 ms and increase from baseline ≥25% (18 yrs +) 
>220 ms and increase from baseline ≥25%(18 yrs +) 
>240 ms and increase from baseline ≥25% (18 yrs +) 
 
QRS 
≥85 ms (Under 2 yrs) 
≥95 ms (2 to 5 yrs) 
 100 ms (6 to 11 yrs) 
 110 ms (12 to 17 yrs) 
>110 ms and increase from baseline ≥25% (18 yrs +) 
>120 ms and increase from baseline ≥25% (18 yrs +) 
 
                                        VV-RIM-00202459-1.0 Approved - 23 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PLE-1878 
Statistical Analysis Plan 
 
Date: June 20, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 64 of 67 
 
CONFIDENTIAL 
Parameter 
PCSV 
Comments 
QTc 
Borderline 
Prolonged* 
Additional 
Absolute values (ms)  
Borderline: 431-450 ms 
Prolonged*: >450 ms 
Additional: ≥500 ms 
AND 
Increase from baseline 
Borderline: Increase from baseline 30-60 ms 
Prolonged*: Increase from baseline >60 ms (Under 12 yrs) 
 
Borderline: 431-450 ms (Boys); 451-470 ms (Girls) 
Prolonged*: >450 ms (Boys); >470 ms (Girls) 
Additional: ≥500 ms 
AND 
Increase from baseline 
Borderline: Increase from baseline 30-60 ms 
Prolonged*: Increase from baseline >60 ms  
(12 to 17 yrs) 
 
>450 ms 
>480 ms 
>500 ms 
AND 
Increase from baseline [30-60] ms 
Increase from baseline >60 ms  
(18 yrs +) 
To be applied to QTcF correction formulas  
 
 
 
                                        VV-RIM-00202459-1.0 Approved - 23 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PLE-1878 
Statistical Analysis Plan 
 
Date: June 20, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 65 of 67 
 
CONFIDENTIAL 
10.4. 
History of R3918-PLE-1878 Protocol and Statistical Analysis Plan 
Amendments 
The original Statistical Analysis Plan (SAP) was submitted to the FDA on 03Jan2020 prior to the 
first patient being screened in the R3918-PLE-1878 study on 24Feb2020.  The study had been 
designated as safe to proceed on 5Sep2019 following an Investigation New Drug (IND) 
application submission.   
Five amendments to the study R3918-PLE-1878 protocol and one amendment to the SAP have 
been submitted to the FDA, based on feedback received from the Agency.  A second amendment 
to the SAP (the current document, Version 3.0) consistent with the final protocol amendment has 
been authored and will be submitted to the Agency.  All protocol amendments have not required 
an amendment to the SAP.   
This Appendix provides a brief summary of sequence of protocol and SAP amendments as 
related primarily to key study design requirements from the Agency.   
On 02Jan2019, the Sponsor approved a protocol for the R3918-PLE-1878 study, for discussion 
with the Agency at a pre-IND meeting on 19Mar2019. The FDA advised the Sponsor to ensure 
that sufficient historical data are collected on each trial patient in order to be able to interpret 
changes from baseline in the context of disease variability prior to baseline and to show that 
treatment effect size is clearly greater than that due to disease variability. Additionally, the 
Agency request the Sponsor to make several changes to the protocol. In accordance with this 
advice, Amendment 1 of the protocol was approved by the Sponsor on 08May2019, with the 
following changes, as requested by the Agency: 
• Primary endpoint altered from normalization of albumin, to a combination of 
normalization of albumin along with improvement of one or more amongst a core set 
of signs and symptoms (bowel movement frequency, abdominal pain, peripheral and 
facial edema). However, clear threshold definitions of activity, improvement and 
worsening were not provided in the amended protocol. 
• Primary analysis to include only patients active at baseline, and not well-controlled 
patients switching from eculizumab, and a minimum of 6 active patients from 4. 
In response to this amendment, further advice was received from the Agency on 19Aug2019. 
The Agency reiterated its advice to ensure that sufficient historical data should be collected on 
each trial patient. The Agency further advised the Sponsorto construct a primary clinical 
endpoint that ensures relevance to core symptoms of disease, as perceived by patient and 
caregiver, if necessary, by individualization. Furthermore, the Sponsor is to establish clear 
clinically meaningful threshold definitions for evaluable disease activity for improvement and 
worsening. Following this advice from the Agency, Amendment 2 of the protocol was approved 
on16Dec2019, with the following changes: 
• Provision of clear threshold definitions of activity, improvement and worsening for 
the four core domains of signs and symptoms. 
• Adoption of an individualized endpoint of response of ‘most bothersome symptom’ 
based on concept elicitation interview during screening, as a key secondary endpoint. 
                                        VV-RIM-00202459-1.0 Approved - 23 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PLE-1878 
Statistical Analysis Plan 
 
Date: June 20, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 66 of 67 
 
CONFIDENTIAL 
On 5Sep2019, following an IND application submission, the Agency granted a Study May 
Proceed letter, along with further advice (in addition to advice on 19Aug2019). The Agency 
advised the Sponsor to increase the stringency of the primary albumin responder definition (to 
“between Weeks 13 to 24, patients will have serum albumin within the normal range (≥3.5 g/dL) 
for at least 8 of the 12 weeks, no value <2.5 g/dL, and will not require albumin infusion for any 
threshold”). Further, the Sponsor is to decrease the tolerance for missing values between weeks 
12 and 24. Furthermore, the Agency requested details regarding how baseline clinical scores 
would be captured. Clear success criteria for the study were to be include in a protocol 
amendment and a SAP. The Agency indicated that the success criteria should be based on the 
upper limit of the 90% confidence interval (CI) for the historical controls. The Agency reiterated 
the importance of pre-baseline data, specifying key laboratory parameters graphically plotted 
over time (from the time of initial presentation until study enrollment), a summary of the key 
signs/symptoms that were reported at each clinical visit during that time (focusing on the items 
selected for inclusion in the endpoint, such as abdominal pain, diarrhea, and edema) as examples 
of useful pre-baseline data. Finally, the Agency advised that the edema rating scales have more 
detailed severity descriptors for each point on the scale.  
On 3Jan2020, the original SAP was provided to the Agency, containing clear success criteria 
based on the lower limit of the 90% CI for the treated patients being larger than the upper limit 
of the CI for the historical controls. On 24Feb2020, the first subject was enrolled, in Istanbul, 
Turkey.  
On 17Mar2020, the Sponsor approved Amendment 3, the purpose of which was to permit the 
enrollment of children under 6 in the early part of the trial, if disease is life-threatening, and to 
permit albumin infusions during the screening period for life-threatening disease. 
Also, on 17Mar2020, the Sponsor received further Agency advice, in response to the SAP. The 
Agency recommended to limit enrollment of active patients to those with albumin below 
2.9 g/dL (not 3.2 g/dL as in the protocol). The Sponsor has not modified the protocol in this 
regard because all patients recruited in the trial have met the Agency requirement of albumin less 
than 2.9 g/dL at baseline. The Agency advised that all patients to be included in the primary 
analysis should show sufficiently severe symptoms (meeting the criteria for active disease) that 
fulfill the “evaluable” criteria for at least one of the four core symptoms as defined in the 
primary endpoint. Furthermore, the Agency requested that the threshold for meaningful change 
on the PedsQL scales be increased from 6 points to 25 points, since the latter reflects a one-
category change on the raw scales. Accordingly, Amendment 1 of the SAP was finalized on 
15Apr2020 and submitted to the Agency. 
On 09Jun2020, protocol amendment 4 was approved by the Sponsor. This amendment allowed 
for flexibility in data collection in light of the SARS-CoV-2 pandemic. This amendment also 
provided revised threshold definitions for nausea and vomiting and for stool consistency scales. 
On 26Aug2020, after review of protocol amendment 4 and the SAP amendment 1, follow-up 
advice was received from the Agency. This advice reiterated that all patients to be included in 
the primary analysis should show sufficiently severe symptoms and the threshold for meaningful 
change on the PedsQL scales be increased. As a result, on 18Feb2021, Amendment 5 was 
approved by the Sponsor. In this amendment, to meet the Agency’s requests, patients without 
evaluable disease activity in any of the four core symptoms comprising the primary endpoint are 
                                        VV-RIM-00202459-1.0 Approved - 23 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PLE-1878 
Statistical Analysis Plan 
 
Date: June 20, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 67 of 67 
 
CONFIDENTIAL 
excluded from the primary analysis (note: all of the 9 active patients recruited into the trial as of 
24May2021 have evaluable disease activity in at least one of the four core symptom areas). 
Secondly, the threshold for meaningful change on the PedsQL GI Symptoms Scales' problematic 
frequency of abdominal pain, nausea and vomiting, and diarrhea sub-scales was increased from 6 
to 25 points. These latest changes are reflected in this current SAP (amendment 2, version 3). 
On 07Apr2021, a discussion was held with the Agency regarding potential for Breakthrough 
Designation. Data from the first 4 subjects recruited in R3918-PLE-1878, with at least 6 weeks 
of post baseline data, were provided. External control data were provided in the form of albumin 
levels on these subjects preceding baseline for a period of 793 to 2210 days. As observed for the 
historical patient cohort, none of the subjects achieved a normalization of albumin for 12 weeks 
(or even for more than 3 days) over this pre-baseline period. In contrast, the pozelimab treatment 
period saw an on-going normalization of albumin in all 4 patients lasting between 5 and 
21 weeks. The Agency reiterated its advice to collect pre-baseline data (6-12 months prior 
enrollment), from chart review, on the core signs and symptoms of disease, to be able to interpret 
post dosing changes in the context of pre-dosing variability. 
                                        VV-RIM-00202459-1.0 Approved - 23 Jun 2022 GMT-5:00


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