Clinical trial NCT02325791
Conditions: Respiratory Syncytial Virus Infections
Sponsor: Regeneron Pharmaceuticals
Start date: 2015-07-21; Completion date: 2017-09-26
Enrollment: 1177 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate the efficacy, safety, pharmacokinetics (PK), and immunogenicity of suptavumab (REGN2222) in infants born no more than 35 weeks, 6 days gestational age who are no more than 6 months of age at the time of enrollment in their respective geographic location. In order to optimize the potential benefit in this vulnerable population, we conducted this study during the RSV season using dosing regimens that are expected to be effective.

Detailed description:
This study occurred in two parts: Part A and Part B.

Part A of the study was an open-label, PK evaluation of intramuscular (IM) administered suptavumab in preterm infants for whom palivizumab was not recommended to enable the selection of dosing regimens for Part B.

Part B of the study was randomized, double-blind, and placebo-controlled, designed to evaluate efficacy, safety, serum concentration and immunogenicity of IM administration of suptavumab in preterm infants for whom palivizumab was not recommended. The total duration of Part B was up to 265 days (includes a 28-day screening period, 57-day treatment period and 180-day follow-up period).

Up to 1515 subjects were planned to be included in Part B of the study. Participants were randomly assigned to 1 of 3 different groups, each with 505 infants; one group received one dose of suptavumab and one dose of placebo, the second group received two doses of suptavumab, and the third group received two doses of placebo.

There was a separate genetic testing sub study.

Arms: arm 1: None arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: Suptavumab 30 mg/kg intervention 2: Placebo Matched to Suptavumab intervention 3: Suptavumab 30 mg/kg- 1 Dose intervention 4: Suptavumab 30 mg/kg - 2 Doses
Intervention descriptions: intervention 1: Participants received single dose of suptavumab 30 milligram per kilogram (mg/kg) intramuscularly (IM) on Day 1. intervention 2: Participants received 2 IM doses of placebo matched to suptavumab: the first dose on Day 1 and the second dose on Day 57. intervention 3: Participants received single dose of suptavumab 30 mg/kg IM on Day 1 and single dose of placebo matched to suptavumab on Day 57. intervention 4: Participants received 2 doses of suptavumab 30 mg/kg IM: the first dose on Day 1 and the second dose on Day 57.

Protocol documents:
SAP_002.pdf: 
VV-RIM-00020534-1.0 Approved - 01 Aug 2017 GMT-5:00 
 
 
 
 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
 
NCT02325791 
 
 
 
STATISTICAL ANALYSIS PLAN 
VERSION: FINAL 
 
 
 
Clinical Study Protocol Title: 
 
A Phase 3, Randomized, Double-blind, Placebo-controlled Study Evaluating the Efficacy 
and Safety of a Human Monoclonal Antibody, REGN2222, for the Prevention of Medically 
attended RSV Infection in Preterm Infants 
 
Part B 
 
 
 
 
Compound: 
REGN2222 
 
Protocol Number: 
REGN2222-RSV-1332 
 
Clinical Phase: 
Phase 3 
 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician: 
Clinical Trial Manager: 
Study Medical Director: 
Version/Date: 
Original Statistical Analysis Plan / July 28, 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 


Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol: REGN2222-RSV-1332 
Date: July 28, 2017 
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APPROVAL PAGE 
 
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. 
 
 
 
Study Biostatistician 
 
See appended electronic signature page 
 
 
 
 
 
Study Clinical Pharmacologist 
 
See appended electronic signature page 
 
 
 
 
 
Study Bioanalytical Sciences Representative 
 
See appended electronic signature page 
 
 
 
 
 
Medical Director/Study Director 
 
See appended electronic signature page 
 
 
 
 
 
Head of Biostatics and Data Management or designee 
 
See appended electronic signature page 


Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol: REGN2222-RSV-1332 
Date: July 28, 2017 
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TABLE OF CONTENTS 
 
APPROVAL PAGE .........................................................................................................................2 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................................7 
 
1. 
OVERVIEW .................................................................................................................9 
 
1.1. 
Background/Rationale ..................................................................................................9 
 
1.2. 
Study Objectives ...........................................................................................................9 
 
1.2.1. 
Primary Objectives .......................................................................................................9 
 
1.2.2. 
Secondary Objectives .................................................................................................10 
 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol................................10 
 
1.2.4. 
Revision History for SAP Amendments .....................................................................10 
 
2. 
INVESTIGATION PLAN ..........................................................................................11 
 
2.1. 
Study Design and Randomization ..............................................................................11 
 
2.2. 
Sample Size and Power Considerations .....................................................................11 
 
2.3. 
Study Plan ...................................................................................................................12 
 
3. 
ANALYSIS POPULATIONS ....................................................................................15 
 
3.1. 
The Full Analysis Set (FAS).......................................................................................15 
 
3.2. 
The Safety Analysis Set (SAF) ...................................................................................15 
 
3.3. 
The Pharmacokinetic Analysis Set .............................................................................15 
 
3.4. 
The Anti-drug antibody (ADA) Analysis Set .............................................................15 
 
4. 
ANALYSIS VARIABLES .........................................................................................16 
 
4.1. 
Demographic and Baseline Characteristics ................................................................16 
 
4.2. 
Medical History ..........................................................................................................17 
 
4.3. 
Pre-Treatment / Concomitant Medication ..................................................................17 
 
4.4. 
Prohibited Medication During Study..........................................................................17 
 
4.5. 
Exposure to Study Drug and Compliance Variables ..................................................17 
 
4.6. 
Efficacy Variable ........................................................................................................18 
 
4.6.1. 
Primary Efficacy Variable ..........................................................................................18 
 
4.6.2. 
Secondary Efficacy Variable ......................................................................................21 
 
4.6.3. 
Exploratory Efficacy Variable(s)................................................................................22 
 
4.7. 
Safety Variables ..........................................................................................................24 
 
4.7.1. 
Adverse Events and Serious Adverse Events .............................................................24 
 
4.7.2. 
Adverse Events of Special Interest .............................................................................25 


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Date: July 28, 2017 
4.7.3. 
4.7.4. 
4.7.5. 
4.8. 
Laboratory Safety Variables .......................................................................................25 
Vital Signs ..................................................................................................................26 
Physical Examination Variables .................................................................................27 
Pharmacokinetic Variables and Anti-Drug Antibody Variables (ADA) ....................27 
 
 
 
4.8.1. 
Pharmacokinetic Variables .........................................................................................27 
 
4.8.2. 
Anti-Drug Antibody Variables ...................................................................................27 
 
4.9. 
Pharmacodynamic/Genomics Variables .....................................................................28 
 
4.10. 
RSV Subtyping ...........................................................................................................28 
 
4.11. 
RSV RT-PCR..............................................................................................................28 
 
4.12. 
Respiratory Pathogen Panel RT-PCR .........................................................................28 
 
5. 
STATISTICAL METHODS.......................................................................................29 
 
5.1. 
Demographics and Baseline Characteristics...............................................................29 
 
5.2. 
Medical History ..........................................................................................................29 
 
5.3. 
Prior/concomitant Illnesses and Medications .............................................................29 
 
5.4. 
Prohibited Medications ...............................................................................................29 
 
5.5. 
Subject Disposition .....................................................................................................29 
 
5.6. 
Extent of Study Treatment Exposure and Compliance...............................................30 
 
5.6.1. 
Exposure to Investigational product ...........................................................................30 
 
5.6.2. 
Measurement of Compliance ......................................................................................31 
 
5.7. 
Analyses of Efficacy Variables ..................................................................................31 
 
5.7.1. 
Analysis of Primary Efficacy Variable .......................................................................31 
 
5.7.1.1. 
Model Assumption Checks .........................................................................................33 
 
5.7.1.2. 
Supportive Analyses for the Primary Efficacy Endpoint ...........................................33 
 
5.7.1.3. 
Sensitivity to the Handling of Missing Data...............................................................34 
 
5.7.1.4. 
Individual Endpoints...................................................................................................35 
 
5.7.1.5. 
Sensitivity to GCP Non-compliance Site ...................................................................35 
 
5.7.1.6. 
Sensitivity to Stratification at Randomization ............................................................35 
 
5.7.1.7. 
Subgroup Analysis ......................................................................................................35 
 
5.7.2. 
Analysis of Secondary Efficacy Variable ...................................................................36 
 
5.7.3. 
Adjustment for Multiple Comparison.........................................................................36 
 
5.7.4. 
Analysis of Exploratory Efficacy Variables ...............................................................37 
 
5.7.5. 
Other Exploratory Analyses .......................................................................................38 
 
5.7.5.1. 
Potentially Pre-incubated RSV infection Prior to Study Treatment ...........................38 


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Date: July 28, 2017 
5.7.5.2. 
5.7.5.3. 
5.8. 
5.8.1. 
RSV Subtype Analysis ...............................................................................................38 
Non-RSV Medically Attended Respiratory Illness ....................................................39 
Analysis of Safety Data ..............................................................................................39 
Adverse Events ...........................................................................................................40 
 
 
 
5.8.2. 
Analysis of Adverse Events of Special Interest and Preferred Terms of 
Interest for Identification of Hypersensitivity ............................................................43 
 
5.8.3. 
Clinical Laboratory Measurements.............................................................................43 
 
5.8.4. 
Analysis of Vital Signs ...............................................................................................44 
 
5.8.5. 
Physical Exams ...........................................................................................................44 
 
5.9. 
Analysis of Pharmacokinetic and Antibody Data.......................................................45 
 
5.9.1. 
Analysis of Pharmacokinetic Data..............................................................................45 
 
5.9.2. 
Analysis of Anti-drug Antibody Variables .................................................................45 
 
5.10. 
Analysis of Pharmacodynamic/Genomics Variables..................................................45 
 
5.11. 
Analysis of RSV RT-PCR Data..................................................................................45 
 
5.12. 
Analysis of Multiplex Respiratory Pathogen RT-PCR Data ......................................45 
 
6. 
DATA CONVENTIONS ............................................................................................46 
 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................46 
 
6.2. 
Data Handling Convention for Efficacy Variables.....................................................46 
 
6.3. 
Data Handling Convention for Missing Data .............................................................46 
 
6.4. 
Visit Windows ............................................................................................................47 
 
6.5. 
Unscheduled Assessments ..........................................................................................47 
 
6.6. 
Pooling of Centers for Statistical Analyses ................................................................47 
 
6.7. 
Statistical Technical Issues .........................................................................................47 
 
7. 
INTERIM ANALYSIS ...............................................................................................48 
 
8. 
TIMING OF STATISTICAL ANALYSIS.................................................................48 
 
9. 
SOFTWARE ...............................................................................................................49 
 
10. 
REFERENCES ...........................................................................................................50 
 
11. 
APPENDIX.................................................................................................................51 
 
11.1. 
Summary of Statistical Analyses ................................................................................51 
 
11.2. 
Schedule of Time and Events .....................................................................................52 
 
11.3. 
Windows for Analysis Time Points ............................................................................54 
 
11.4. 
Criteria for Treatment-Emergent Potentially Clinically Significant Values 
(PCSV)........................................................................................................................55 


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Date: July 28, 2017 
 
 
 
11.5. 
Hypersensitivity PTs of interest per Carbonell-Estrany X et al. ................................57 
 
11.6. 
Hypersensitivity PTs of interest per Feltes TF et al. ..................................................58 
 
 
 
LIST OF FIGURES 
 
Figure 1: 
Part B: 30 mg/kg IM (1 Dose REGN2222 and 1 Dose Placebo), 30 mg/kg 
IM (2 Doses of REGN2222), or Placebo IM (2 Doses of Placebo) ...........................12 
 
Figure 2 
Flow diagram to depict the programmatic derivation of an observed primary 
endpoint event.............................................................................................................20 


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Date: July 28, 2017 
 
 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
ADA 
Anti-drug antibody 
 
AE 
Adverse event 
 
AESI 
Adverse event of special interest 
 
ALT 
Alanine aminotransferase 
 
AST 
Aspartate aminotransferase 
 
ATC 
Anatomical therapeutic chemical 
 
AUCinf 
Area under the concentration-time curve from time 0 to infinity 
 
CRF 
Case report form 
 
CTCAE 
Common terminology criteria for adverse events 
 
EOS 
End of study 
 
ET 
Early termination 
 
FDA 
Food and Drug Administration 
 
GA 
Gestational age 
 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
ICF 
Informed Consent Form 
IM 
Intramuscular 
 
IVRS 
Interactive voice response system 
IWRS 
Interactive web response system 
LLN 
Lower limit of normal 
LRTI 
Lower respiratory tract infection 
 
MedDRA 
Medical dictionary for regulatory activities 
 
PCSV 
Potentially clinically significant value 
 
PK 
Pharmacokinetic 
 
PT 
Preferred term 
 
Q 
Every 
 
RBC 
Red blood cell 
 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
RSV 
Respiratory syncytial virus 
SAE 
Serious adverse event 
 
SAF 
Safety set 
 
SAP 
Statistical analysis plan 


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Date: July 28, 2017 
 
 
 
SAS 
Statistical Analysis Software 
 
SOC 
System organ class 
 
TEAE 
Treatment emergent adverse event 
 
ULN 
Upper limit of normal 
 
WBC 
White blood cell 
 
WHODD 
World Health Organization Drug Dictionary 


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Statistical Analysis Plan 
Protocol: REGN2222-RSV-1332 
Date: July 28, 2017 
 
 
 
 
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 prior to database lock. 
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 REGN2222-RSV-1332 Part B only.  A separate 
SAP was prepared for Part A. 
 
This plan may be revised during the study to accommodate protocol amendments and to make 
changes to adapt to unexpected issues in study execution or data that affect planned analyses.  A 
final plan will be issued prior to database lock of Part B. 
 
1.1. 
Background/Rationale 
 
This phase 3 study of REGN2222 is designed to evaluate the efficacy, safety, pharmacokinetics 
(PK), and immunogenicity of REGN2222, a new human immunoglobulin G1 (IgG1) monoclonal 
antibody directed against the respiratory syncytial virus (RSV) fusion glycoprotein in infants 
born no more than 35 weeks 6 days gestational age (GA), who are no more than 6 months of age 
at the time of first dose of study drug. The study has 2 parts: 
 
Part A was an open-label PK study of REGN2222 to determine the PK in pre-term infants after a 
single dose to enable the selection of dosing regimens for Part B. It provided an initial evaluation 
of safety and tolerability in infants. A separate SAP was prepared for Part A. 
 
Part B is a randomized, double-blind, placebo-controlled, study designed to evaluate efficacy, 
safety, concentrations of REGN2222 in serum, and immunogenicity of IM administration of 
REGN2222 in preterm infants who are not eligible or recommended for, or who do not have 
access to, palivizumab. Up to 1515 subjects (1010 assigned to receive REGN2222 [505 subjects 
in each of the 2 arms] and 505 to receive placebo) are planned to be enrolled and randomized 
1:1:1 into 3 arms. The use of a placebo arm is justified because infants enrolled into the study 
would not receive less than standard of care for RSV prevention because only infants who are 
not eligible, recommended, nor is access available to receive palivizumab will be included in the 
study. 
 
1.2. 
Study Objectives 
 
1.2.1. 
Primary Objectives 
 
The primary objective of the study in Part B is to demonstrate the efficacy of REGN2222 in 
preventing medically attended RSV infections (subjects with either RSV-confirmed 
hospitalizations or outpatient lower respiratory tract infection [LRTI]). 


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Date: July 28, 2017 
 
 
 
1.2.2. 
Secondary Objectives 
 
The secondary objectives of the study in Part B are: 
 
• To evaluate safety and tolerability of REGN2222 
 
• To demonstrate the efficacy of REGN2222 in reducing RSV-confirmed 
hospitalizations, emergency room (ER), urgent care (UC), or pediatric clinic (PC) 
visits 
 
• To assess serum levels of different dosing regimens of REGN2222 
 
• To assess immunogenicity of REGN2222 
 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol 
 
None. 
 
1.2.4. 
Revision History for SAP Amendments 
 
This is the first version. 


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2. 
INVESTIGATION PLAN 
 
2.1. 
Study Design and Randomization 
 
This is a Phase 3 study that will be conducted in 2 parts. 
 
Part A was an open-label, single cohort, multicenter, PK study. 
 
Part B is a randomized, placebo-controlled, 3-arm, multicenter study.  In Part B, the sponsor 
(Regeneron Pharmaceuticals, Inc.) will provide permitted windows for prophylaxis of subjects in 
each geographical area based on historical data on the timing and duration of the RSV season.  A 
total of 3 treatment arms (1 dose of REGN2222 and 1 dose of placebo; 2 doses of REGN2222; 
and 2 doses of placebo) with a total of 1515 subjects are planned in Part B and will be 
randomized in a 1:1:1 ratio (505 subjects in each arm for a total of 1010 assigned to receive 
REGN2222 [505 subjects in each of the 2 REGN2222 arms] and 505 subjects to receive 
placebo). Randomization will be stratified by region (North America or rest of the world) and 
GA (≤31 weeks, 6 days GA or from 32 weeks, 0 days to 35 weeks, 6 days GA). 
 
2.2. 
Sample Size and Power Considerations 
 
Originally Planned Sample Size 
 
For Part B, the sample size estimation is based on the primary efficacy endpoint of medically 
attended RSV infection (hospitalization or outpatient LRTI).  Literature (Hall 2009, 
Ambrose 2014) show that the event rate in this endpoint is in the range of 12% to 22% in the 
studied infant populations.  The Hall data is population based and the majority of infants are 
full-term; the Ambrose publication of data from the RSV Respiratory Events Among Preterm 
Infants Outcomes and Risk Tracking (REPORT) study evaluated preterm infants of 32-35 weeks 
gestational age and less than 6 months of chronological, whom were not receiving RSV 
prophylaxis.  As the event rate may vary over RSV season or geographic region, a relatively 
conservative approach was taken to assume that event rate is 10% for the placebo group, and 
either dosing regimen of REGN2222 would reduce the event rate from placebo by 60% (event 
rate of 4%).  With 505 randomized subjects per arm or a total of 1515 randomized subjects, the 
study would have 90% power to demonstrate a 60% or greater reduction at 2-sided significance 
level α=0.025.  This originally planned sample size also incorporated a 5% early dropout rate. 
The sample size calculation was based on chi-square test with continuity correction and 
performed using nQuery version 7.0 (Statistical Solutions Ltd, Cork, Ireland). 
 
Based on the originally planned sample size and event rate assumption, we anticipated 
approximately 90 primary endpoint events. 
 
The blinded sample size re-estimation (as detailed in the study protocol Section 9.2.1) designed 
for the originally planned sample size has not been performed for this study. 
 
Power Calculation for Reduced Sample Size 
 
The sample size of the study has been reduced due to business considerations.  The intent of this 
power calculation is to understand the impact of the reduced sample size on the primary efficacy 
analysis. Specifically, to accommodate the reduced sample size, the overall Type I error for the 
pairwise comparisons of each REGN2222 dose regimen to placebo will be controlled using a 


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pre-specified hierarchical inferential approach (2-sided α=0.05 for each statistical test; see 
Section 5.7.3), as opposed to the originally planned Bonferroni adjustment (2-sided α=0.025 for 
each pairwise treatment comparison).  Therefore, assuming approximately 1200 subjects are 
administered study drug, the comparison of the REGN2222 2-dose regimen to placebo will have 
approximately 87% power to detect the previously planned 60% reduction in medically attended 
RSV infections with a 2-sided significance level of 0.05. 
 
2.3. 
Study Plan 
 
After the parent(s) or legal guardian(s) provide informed consent (obtained up to 28 days prior to 
randomization), subjects will be assessed for study eligibility for Part B at the screening visit. 
Subjects who continue to meet eligibility criteria at baseline will undergo Day 1 baseline 
assessments and will be randomly assigned in a 1:1:1 ratio to REGN2222 30 mg/kg single dose 
(1 dose REGN2222 and 1 dose placebo), REGN2222 30 mg/kg Q8 weeks (2 doses of 
REGN2222), or placebo (2 doses of placebo).  The study flow diagram for Part B is depicted in 
Figure 1. 
 
Figure 1: 
Part B: 30 mg/kg IM (1 Dose REGN2222 and 1 Dose Placebo), 30 mg/kg IM 
(2 Doses of REGN2222), or Placebo IM (2 Doses of Placebo) 
 
 
 
EOS = end of study; IM = intramuscular; Q8 = every 8 
Note: The screening visit occurs from Day -28 to Day -1. Black arrows denote dosing visits. Subjects will be 
monitored on site for at least1 hour after each dose of REGN2222 or placebo. Grey arrows denote study visits at 
which dosing does not occur. Visits 8, 9, and 10 will occur via phone call. In the event an AE is reported during a 
phone call visit, an unscheduled onsite visit may be required to follow-up, per investigator. 


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In Part B, assessment of the clinical efficacy endpoints will only occur during the 150 day study 
period (ie, through Visit 7).  Any RSV infection occurring after Day 150 visit will not be 
included in the efficacy evaluation.  If a primary endpoint is reached during the study period, 
ongoing assessments for other endpoints and measurements will continue until the end of the 
study period.  Subjects who reach the primary endpoint during the study period will not have 
additional study drug administered for the remainder of the RSV season because the risk of a 
second RSV infection is substantially (~70%) reduced for 6 months after the first infection 
(Ohuma 2012) and this practice is consistent with recommendations in the 2014 AAP guidelines 
for palivizumab.  Subjects who have reached the primary endpoint will continue to be monitored 
for additional medically attended acute respiratory infections that may occur during the study 
period. 
 
During the 150-day efficacy assessment period, data will be collected on subjects with any acute 
respiratory illness requiring medical attention. After enrollment of their infant into the study, 
parent(s) or guardian(s) taking their enrolled infant to a healthcare provider (inpatient or 
outpatient, including hospitalizations, ER, UC, or pediatric clinic) will be asked to contact the 
study staff immediately or soon after seeking medical attention for any of the following 
symptoms: fever, cough, earache, nasal congestion, rhinorrhea, vomiting after coughing, 
wheezing, or difficulty breathing (labored, rapid, or shallow). 
 
When the parent(s) or guardian(s) takes their child for medical attention for an acute respiratory 
infection, they will be instructed to take a Medical Information Packet with them for the treating 
clinician.  All infants who have a medically attended visit for a respiratory illness will be asked 
to have an unscheduled study visit as soon as possible or within 72 hours of discharge from the 
medical facility.  Study site personnel will evaluate the subject during an unscheduled visit, 
including a history of the acute illness and nose swab collections for viral detection will occur. 
All nose swabs will be tested using a reverse-transcriptase polymerase chain reaction (RT-PCR) 
assay for RSV, which will be conducted in a central laboratory.  All RSV isolates will be tested 
for their subtypes, specifically subtype A or subtype B.  If the unscheduled study visit following 
a medically attended respiratory infection occurs >72 hours but <14 days of discharge from the 
medical facility, all procedures (as appropriate), including nose swab collection, should occur 
despite being outside of the 72 hour window.  Unscheduled study visits for medically attended 
respiratory illness will be required through Day 150 even if a child has had a prior 
RSV-confirmed or other respiratory illness.  Unscheduled study visits for medically attended 
respiratory illness will not be required between the day after the Day 150 visit and Day 237 (end 
of study) visit for the purpose of nose swab collection. 
 
For infants who do not have an RSV RT-PCR assay for RSV infection done by the central 
laboratory, study site personnel will obtain and record information about all RSV RT-PCR assay 
done in a medical facility, including result(s), name of the assay(s) and whether the 
laboratory(ies) conducting the RT-PCR is a CLIA (Clinical Laboratory Improvement 
Amendments) certified (or equivalent) laboratory. 


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All subjects will be monitored for safety until the end of the study at Day 237.  Safety 
monitoring after Day 150 visit through Day 237 (end of study) visit will be made by telephone 
call, only to solicit information about concomitant medications and AEs.  In order to minimize 
total blood samples obtained throughout the study, a sparse blood collection schedule will be 
implemented based on a blood collection schedule that includes up to 3 total planned blood 
draws for each infant for safety laboratory tests, PK, and ADA assays from first visit through 
Day 150 visit. 
 
The schedules of events are provided in Appendix 11.2 . 


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3. 
ANALYSIS POPULATIONS 
 
In accordance with guidance from the International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (1998), the following populations of analysis will be used 
for all statistical analyses: 
 
3.1. 
The Full Analysis Set (FAS) 
 
FAS includes all randomized subjects (received a random number as assigned by the IVRS) who 
receive any study drug.  Efficacy analyses will be based on the treatment allocated by the IVRS 
at randomization (as randomized). 
 
FAS is the primary analysis set for all efficacy endpoints. 
 
3.2. 
The Safety Analysis Set (SAF) 
 
SAF includes all subjects (randomized or non-randomized) who receive any study drug.  For all 
safety variables, subjects will be analyzed as treated.  As-treated is defined as the actual number 
of REGN2222 doses received by a subject, ie, single dose of REGN2222, 2 doses of REGN2222, 
and placebo. 
 
3.3. 
The Pharmacokinetic Analysis Set 
 
The PK analysis set will contain subjects who receive at least 1 dose of the study drug 
(REGN2222 or placebo) and have at least 1 post-baseline non-missing concentration value. 
 
3.4. 
The Anti-drug antibody (ADA) Analysis Set 
 
The ADA analysis set will contain subjects who receive at least 1 dose of the study drug 
(REGN2222 or placebo) and have at least 1 post-baseline non-missing ADA result. 


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Date: July 28, 2017 
4. 
ANALYSIS VARIABLES 
 
 
 
4.1. 
Demographic and Baseline Characteristics 
 
The following demographic and baseline variables will be summarized: 
 
• Chronological age at the time of first dose (weeks) 
• Chronological age group 
− ≤ 3 months 
− > 3 months 
• Gestational age categories (per CRF) 
− ≤ 31 weeks 6 days 
− ≥ 32 weeks 0 days and ≤ 35 weeks 6 days 
• Sex (Male, Female) 
• Race (American Indian/Alaskan Native, Asian, Black, Native Hawaiian/Other Pacific 
Islander, White, and Other) 
• Ethnicity (Hispanic/Latino, not Hispanic/Latino) 
• Region (North America [US and Canada], Rest of World) (per CRF) 
• Baseline Weight (kg) 
• Mother employed (Yes, No, or not applicable) 
• Father employed (Yes, No, or not applicable) 
• Guardian employed (Yes, No, or not applicable) 
• Hemisphere (Northern, Southern) 
• Enrollment season (2015/2016 Northern Hemisphere, 2016 Southern Hemisphere, 
2016/2017 Northern Hemisphere) 
 
In addition, the following risk factor variables assessed at screening will be summarized: 
 
• Multiple births (Yes or No) 
• Infant small for gestational age (Yes or No) 
• Infant in child care (Yes or No) 
• Infant expected to be in a childcare setting in their first year of life (Yes or No) 
• Family history of Atopy (Yes or No) 
• Family history of Asthma (Yes or No) 
• Family history of Hay fever (Yes or No) 
• Family history of Eczema (Yes or No) 
• Smoker in the household (Yes or No) 
• Number of people currently living in household 
• Number of siblings 
• Children, 6 yrs or younger, currently living in household (Yes or No) 
• Children in household attending daycare or child care (Yes or No) 


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4.2. 
Medical History 
 
Medical history will be coded to a Preferred Term (PT) and associated primary System Organ 
Class (SOC) according to the Medical Dictionary for Regulatory Activities (MedDRA®) version 
in effect and available  at the time of the database lock. 
 
4.3. 
Pre-Treatment / Concomitant Medication 
 
Medications/Procedures will be recorded from the day of informed consent until the end of study 
(EOS) visit.  Medications will be coded to the ATC level 2 (therapeutic main group) and ATC 
level 4 (chemical/therapeutic subgroup), according to the version of WHO Drug Dictionary 
(WHODD) in effect and available at the time of database lock.  Note: a drug can be matched to 
more 1 ATC classification, ie, subjects can be counted in several categories for the same 
medication. 
 
Pre-treatment medications/procedures: medications that were started prior to the first dose of the 
study drug or procedures performed prior to the first dose of the study drug. 
 
Concomitant medications/procedures: medications taken (or continued to be taken) or procedures 
performed following the first dose of study drug through the end of the TEAE period 
(Section 4.7.1). 
 
4.4. 
Prohibited Medication During Study 
 
Definition of prohibited medications during the study is described in Section 5.6.1 of the study 
protocol. 
 
All pre-treatment/concomitant medications will be reviewed to determine if any of them are 
prohibited medications on an ongoing basis throughout the study, with the final list to be 
finalized before database lock. 
 
4.5. 
Exposure to Study Drug and Compliance Variables 
 
Exposure to study drug variables are listed below with the associated definitions: 
 
• The total number of study doses administered. 
 
• The calculated actual dose (in the unit of mg/kg) of each study treatment.  Actual 
dose is calculated as: (volume of dose × 150mg/mL) divided by body weight at 
dosing. 
 
• Number of injections received for each dose. 
 
• Length of observation period during the study is calculated as: (date of the last study 
visit - date of first dose of study drug) +1. 
 
Compliance will be assessed using the following variables with the associated definitions applied 
to both REGN2222 and placebo: 
 
• The compliance ratio (continuous) of actually administered dose (in the unit of 
mg/kg) vs. planned dose will be calculated for each dose received by a subject. 


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• The compliance ratio (categorical) defined above categorized into <0.8, 0.8 to <1.2, 
≥1.2, ≥1.5, and ≥2.0. 
 
4.6. 
Efficacy Variable 
 
Assessment of all efficacy variables will occur during the 150-day study period (ie, through the 
Day 150 visit).  Any RSV infection occurring after that period will not be included in the 
efficacy evaluation. 
 
For a subject who discontinued study treatment early (ie, not receiving the second dose), the 
subject will be followed to Day 150 visit for assessment of efficacy. 
 
4.6.1. 
Primary Efficacy Variable 
 
The primary efficacy variable is the proportion of FAS subjects with a medically attended RSV 
infection (hospitalization or outpatient LRTI) during the 150-day efficacy assessment period. 
The 150-day efficacy assessment period is defined as the first study drug administration through 
the Day 150 visit (defined as the protocol specified window which includes Study Day 155).  In 
the event that Day 150 visit occurs beyond the protocol specified window (ie, on or after Day 
156) and a respiratory AE is reported at that visit, that AE will only be considered for the 
primary endpoint if its start date is before Study Day 156. 
 
A medically attended RSV infection (hereafter referred to as a primary endpoint event) is defined 
as an infant with a positive RSV test by RT PCR with any of the following events: 
 
• Hospitalized (on the basis of the assessment of the admitting physician) for RSV 
infection. 
 
• Outpatient visit (emergency room [ER], urgent care [UC], or pediatric clinic [PC] for 
either a sick or well visit) with RSV LRTI. 
 
An RSV LRTI in an infant is defined as an RSV-proven respiratory infection (ie, 
positive RSV RT-PCR test) with parent(s)/guardian(s) report of cough or difficulty 
breathing, and with 1 of the following signs of LRTI, as assessed by a healthcare 
provider: 
 
− Lower chest wall indrawing 
 
− Hypoxemia (peripheral capillary oxygen saturation <95% breathing room air) 
 
− Wheezing or crackles 
 
The positive RSV RT-PCR test has to occur within a 14-day period since the start date of the 
adverse event (AE) corresponding to the medically attended respiratory illness (MARI), ie, the 
specimen collection date for RT-PCR - AE start date must be ≤ 14.  If multiple medical visits are 
made for the same episode of RSV illness, an RSV positive test by RT-PCR at any medical visit 
will label that episode as being RSV positive, and it will be counted toward the primary 
endpoint.  If there are multiple medically attended visits during an episode associated with an 
RSV positive test, then the most severe occurrence will be defined as the primary endpoint event, 
and events of decreasing severity will be defined in the following order: RSV positive 
hospitalization > RSV positive ER/UC LRTI > RSV positive pediatric clinic LRTI.  If a subject 
had multiple episodes of RSV infection, the first episode will be defined as the primary endpoint. 


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Only medically attended respiratory illness occurring during the 150-day efficacy assessment 
period will be considered for the primary endpoint.  If categorization of a MARI event as an 
endpoint is unclear, source documentation will be provided to a blinded adjudication committee 
for categorization prior to database lock. 
 
If an infant has a medically attended respiratory event but did not have an RT-PCR test 
conducted in the central laboratory within 14 days after onset of the episode of RSV illness, 
results from a RSV RT-PCR assay conducted in the local lab will be used to determine RSV 
infection if the RSV RT-PCR assay is reviewed by jurisdictional health authority and released 
for commercial distribution, or conducted in a laboratory that is currently certified for human 
diagnostic testing.  To that end, protocol has specified the following conditions for acceptable 
local lab RSV RT-PCR assays: 
 
• Assay is a FDA-cleared RSV RT-PCR assay or 
 
• Assay is an RSV RT-PCR assay that is not FDA-cleared but is conducted in a 
laboratory that is currently CLIA (or equivalent) certified. 
 
The algorithm to programmatically derive an observed primary endpoint event is depicted in 
Figure 2. 


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Figure 2 
Flow diagram to depict the programmatic derivation of an observed primary 
endpoint event 
 
 
 
Answers to questions (1) through (7) in the flow diagram are collected from the following 
electronic case report form (eCRF) pages and other source data: 
 
• Questions (1) and (3): eCRF page of “History of Medically-Attended Acute 
Respiratory Illness (MARI) Questionnaire”. 
• Question (2): eCRF page of “Hospitalization for Respiratory Illness Questionnaire”. 
• Question (4): eCRF page of “Lower Respiratory Infection (LRI) Questionnaire”. 
• Questions (5): eCRF page of “Central Laboratory” for nose swab collection and 
eCRF page of “History of Medically-Attended Acute Respiratory Illness (MARI) 
Questionnaire” for AE start date. 
• Question (6): Central lab RSV RT-PCR test results from Viracor. 
• Questions (7) and (8): eCRF page of “Unscheduled RSV RT-PCR (Local Lab)” 


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On the eCRFs, the MARI questionnaire, the LRI questionnaire, and the central (or local) lab 
RSV PCR test(s) are designated by the investigator to a corresponding medically-attended acute 
respiratory adverse event (AE).  Therefore, the corresponding AE serves as the key variable to 
programmatically merge information from the MARI and LRI pages with RSV PCR test(s) for 
each episode of illness. 
 
Missing Data Handling for the Primary Efficacy Endpoint 
 
For early termination (ET) subjects those who did not complete the 150-day efficacy assessment 
period, their primary endpoint will be handled according to the following rules in the primary 
analysis: 
 
• Early termination subjects who had a primary endpoint event during the 150-day 
efficacy assessment period (regardless of treatment status, ie, whether the subject 
received all study drug doses or discontinued dosing) will be used in the primary 
analysis and included as “event occurred”.  [Observed, thus no imputation] 
 
• Direct imputation of missing primary endpoint at Day 150 visit: 
 
− Subject deaths prior to Day 150 that are adjudicated to be RSV related will be 
included as “event occurred” at the onset date of the adverse event that led to 
death. 
 
− Remaining early termination subjects (including non-RSV deaths) across all 
treatment groups, will be imputed to the average placebo score (estimated placebo 
event rate). 
 
 Approach to estimating the placebo event rate is the Kaplan-Meier (KM) 
estimate at Day 150 based on all randomized subjects in the placebo group. 
Early termination subjects in the placebo group who had no primary 
endpoint event will be censored in the KM procedure at the last time point 
when their primary endpoint event is assessed (ie, at the last visit completed 
by the subject, scheduled or unscheduled, prior to Day 150 visit).  Placebo 
subjects who completed Day 150 visit with no primary endpoint event will 
be censored at the date of their Day 150 visit.  The derivation of study day is 
detailed in Appendix 11.3. 
 
• Imputed scores along with observed subject data will be utilized in the Cochran- 
Mantel-Haenszel (CMH) analysis. 
 
4.6.2. 
Secondary Efficacy Variable 
 
The secondary efficacy variable is the proportion of FAS subjects who have RSV-confirmed 
hospitalization, ER, UC, or pediatric clinic visits (for upper or lower respiratory infection) during 
the 150-day efficacy assessment period.  This secondary endpoint will be derived in the same 
way as the primary endpoint (including imputation for missing endpoint event) except that the 
RSV-confirmed outpatient visit (ER, UC, or pediatric clinic visits) can be for either upper or 
lower respiratory infection (ie, Question 4 in Figure 2 can have the answer of either YES or NO). 
For ET subjects who did not complete Day 150 visit, their secondary endpoint will be handled 
according to the same rule as specified for the primary endpoint, with secondary endpoint event 
in place of primary endpoint event in the rule. 


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4.6.3. 
Exploratory Efficacy Variable(s) 
 
Other secondary efficacy variables will be studied as exploratory endpoints and include the 
following measures during the 150-day efficacy assessment period: 
 
1) Number of days from first dose of study drug to first primary efficacy endpoint event. 
Subject deaths prior to Day 150 that are adjudicated to be RSV related will be included 
as event at the onset date of the adverse event that led to death.  For subjects who didn’t 
have a primary efficacy endpoint event, this endpoint will be defined as the number of 
days from the first dose of study drug to the last time point when their primary endpoint 
is assessed, ie, Day 150 visit or last visit completed for ET subjects. 
 
2) Number of days from first dose of study drug to first secondary efficacy endpoint event. 
Subject deaths prior to Day 150 that are adjudicated to be RSV related will be included 
as event at the onset date of the event that led to death.  For subjects who didn’t have a 
secondary efficacy endpoint event, this endpoint will be defined as the number of days 
from the first dose of study drug to the last time point when their secondary endpoint is 
assessed, ie, Day 150 visit or last visit completed for ET subjects. 
 
3) Proportion of FAS subjects with RSV-confirmed hospitalization. 
 
4) Total number of RSV-associated hospital visits (for upper or lower respiratory 
infection). 
 
5) Total number of RSV-associated ER visits (for upper or lower respiratory infection). 
 
6) Total number of RSV-associated UC visits (for upper or lower respiratory infection). 
 
7) Total number of RSV-associated pediatric clinic visits (for upper or lower respiratory 
infection) visits. 
 
8) Concomitant medications or procedures associated with RSV infection. 
 
9) Total number of all-cause respiratory illness-associated hospital visits (for upper or 
lower respiratory infection). 
 
10)  Total number of all-cause respiratory illness-associated ER visits (for upper or lower 
respiratory infection). 
 
11)  Total number of all-cause respiratory illness-associated UC visits (for upper or lower 
respiratory infection). 
 
12)  Total number of all-cause respiratory illness-associated pediatric clinic visits (for upper 
or lower respiratory infection). 
 
13)  Concomitant medications or procedures for all-cause respiratory illness. 
 
14)  Repeat items 9) through 13) above with the single exception to count the number of 
all-cause respiratory illness-associated visits after the initial episode of RSV illness. 
 
15)  Total number of days with RSV-associated mechanical ventilation for subjects with 
RSV-confirmed hospitalizations. 
 
16)  Total number of days with RSV-associated supplemental oxygen for subjects with 
RSV-confirmed hospitalizations. 


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17)  Total length of stay in hospital for subjects with RSV-confirmed hospitalizations. 
 
18)  Total number of missed days of work for parent(s) or guardian(s) associated with each 
medically attended RSV event. 
 
19)  Number and prevalence rate of other common respiratory pathogens identified by a RT- 
PCR multiplex respiratory panel for nose swab specimens determined to be negative for 
RSV (using the protocol specified Lyra RT-PCR assay [Quidel Molecular RSV/hMPV 
assay]). 
 
20)  Proportion of FAS subjects with the primary endpoint event, with the single exception of 
using an alternative definition for LRTI. 
 
Instead of the LRTI definition in Section 4.6.1, the following definition of LRTI will be 
used for medically attended RSV infection (hospitalization or outpatient LRTI) as 
agreed in the Pediatric Investigational Plan (PIP) : 
 
Infant with RSV-proven infection who presents with cough or difficulty breathing and 2 
of the following criteria: 
 
• Lower chest wall indrawing 
• Hypoxemia (peripheral capillary oxygen saturation <95% breathing room air) 
• Wheezing or crackles 
• Ventilatory failure (needing ventilator support in any form) 
• New onset apnea 
• Increased respiratory rate using WHO criteria for fast breathing for age 
(Wingerter 2012) as below: 
 
Age 
Increased Respiratory Rate 
(breaths/min) 
<  60 days 
≥ 60 
60 - 364 days 
≥ 50 
365 days - 5 years 
≥ 40 
Age in days = Onset date of the episode of RSV illness – birth date +1. 
 
21)  Proportion of FAS subjects with the primary endpoint event, with the single exception of 
the removal of RSV hospitalization non-LRTI. 
 
22)  Proportion of FAS subjects with the primary endpoint, with the single exception of 
accepting positive RSV detection results from the multiplex RT-PCR respiratory panel 
in deriving the primary endpoint event. 
 
23)  Proportion of FAS subjects with the secondary efficacy endpoint, with the single 
exception of accepting positive RSV detection results from the multiplex RT-PCR 
respiratory panel in deriving the secondary efficacy endpoint event. 
 
Note 1: For a RSV RT-PCR test to be considered positive for the analysis, the specimen 
collection has to occur within a 14 day period since the onset of the episode of RSV illness. 
 
Note 2: All-cause respiratory illness is defined as without consideration of RSV positivity or 
negativity. 


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4.7. 
Safety Variables 
 
Subject safety will be assessed through the collection of AEs, laboratory data (hematology, 
chemistry), vital signs, and physical exam (including weight).  For these measures, with the 
exception of the AEs, all measurements will be assigned to analysis windows for temporal 
summaries.  Unless otherwise noted (eg, AEs), baseline for these measures is defined as the last 
chronologically available valid assessment prior to the first dose of study drug. 
 
The period of safety observation starts from the time when the informed consent is given and 
continues into the following periods: 
 
• The PRE-TREATMENT period: defined as the day from the signed informed consent 
form (ICF) to before the first study drug injection. 
• The SAFETY TREATMENT period: defined as the day from the first study drug 
injection up to the day of the last study drug injection plus 180 days. 
• The POST-TREATMENT period: defined as starting the day after the end of the 
SAFETY TREATMENT period. 
4.7.1. 
Adverse Events and Serious Adverse Events 
The definitions for AEs and serious adverse events (SAEs) are described in Sections 7.1.1 and 
7.1.2 of the study protocol, respectively.  Additional information on determining whether 
abnormal laboratory or vital sign results should be considered as AEs is included in Section 7.2.6 
of the study protocol.  AEs and SAEs will be collected from the time of informed consent 
signature and then at each visit until the end of the study. 
 
The severity of AEs is graded using 1 of 2 severity scales.  The severity scale used is determined 
by the type of AE experienced by the subject; more detail is provided in Section 7.3.1 of the 
protocol. 
 
Adverse Event Observation Period 
 
• Pre-treatment AEs are AEs that developed or worsened or became serious during the 
pre-treatment period. 
 
• Treatment-emergent AEs (TEAEs) are defined as AEs that are not present at baseline 
or represent the exacerbation of a preexisting condition during the SAFETY 
TREATMENT period (TEAE period).  Therefore, referencing the protocol, TEAEs 
will be defined programmatically as any AE record with a start date/time on or after 
the first study drug administration (greater than or equal to study day 1), inclusive to 
the end of the TEAE period. 
 
• Post-treatment AEs are AEs that developed or worsened or became serious during the 
POST-TREATMENT period. 


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4.7.2. 
Adverse Events of Special Interest 
 
Adverse events of special interest (AESI) are AEs (serious or non-serious) required to be 
monitored, documented, and managed in a pre-specified manner as described in the protocol 
Section 7.2.4.2.  AESIs for this study are hypersensitivity reactions occurring within 48 hours 
after exposure to the study drug (including but not limited to urticaria, edema, respiratory 
distress, anaphylaxis, and allergic reactions).  Such treatment-emergent AESI are identified by 
investigator using a tick box on the eCRF AE page. 
 
Preferred Terms of Interest for Identification of Hypersensitivity 
 
As part of the safety assessment, in addition to evaluation of treatment-emergent AEs that are 
considered to be AESI by the investigator, the following sets of pre-defined PTs of interest for 
identification of treatment-emergent hypersensitivity AEs will also be monitored and 
summarized: 
 
1.   Modified narrow Standard MedDRA Query (SMQ [N]) for “hypersensitivity”.  The 
modification is to add PTs: pruritus, pruritus generalised, prurigo, flushing, erythema, 
generalised erythema, injection site erythema, rash papular, allergic oedema. 
 
2.   MedDRA query for all PTs under the high level term (HLT): injection site reactions. 
 
3.   Hypersensitivity PTs of interest per Carbonell-Estrany X. 2010 as listed in 
Appendix 11.5. 
 
4.   Hypersensitivity PTs of interest per Feltes TF 2011 as listed in Appendix 11.6. 
 
5.   Acute hypersensitivity reactions that occur within 2 days after dosing, classified in 
2 categories, per Shapiro 2010: 
 
a.   Urticarial Reactions which will be identified by search for PTs: urticaria, oedema; 
low level term (LLT): localized erythema. 
b.   Allergic Rash which will be identified by search for PTs: rash, dermatitis allergic, 
erythema annulare, erythema multiforme, rash maculo-papular.  For AEs coded to 
the PT of rash, a manual review of their verbatims will be conducted to identify 
AEs that are acute rash. 
 
4.7.3. 
Laboratory Safety Variables 
 
Clinical laboratory tests include hematology and blood chemistry.  Samples for laboratory testing 
will be collected at screening, a post-baseline visit according to assigned blood draw schedule 
(time points specified in the schedule of assessments [Appendix 11.2]), and at Visit 7 or at the 
time of ET if the subject discontinued prior to Visit 7. 
 
Clinical laboratory values will be in standard international (SI) units, including associated 
normal ranges provided by the central laboratory, and grouped by function in summary tables. 
Conventional unit may be provided.  There are no universally accepted normal ranges for 
preterm infants.  Therefore, the ranges provided by the central laboratory are associated with 
full-term infants and consequently, the ranges are to be used with caution in interpretation of 
results. 


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Clinical laboratory tests are provided below, sub-grouped by function.  Both actual test values 
and “change from baseline” values (defined as the post-baseline value minus the baseline value) 
will be used in central lab result summaries. Potentially clinically significant values (PCSV) 
ranges will be applied to central lab test values as applicable (see Appendix 11.4 for PCSV 
definitions). 
 
Blood Chemistry 
 
Electrolytes 
Liver function 
Metabolism 
Renal function 
Sodium 
AST 
Total protein, serum 
Blood Urea Nitrogen 
Potassium 
ALT 
Glucose 
Creatinine 
Chloride 
Alkaline phosphatase 
Albumin 
Uric acid 
Carbon dioxide 
Total bilirubin 
Creatine phosphokinase 
Calcium 
Indirect bilirubin 
Lactate dehydrogenase 
 
 
Hematology 
 
Red blood cells and platelets 
White blood cells 
Hemoglobin 
White blood cells (WBCs) 
Hematocrit 
Neutrophils 
Red blood cells (RBCs) 
Lymphocytes 
Red cell indices 
Monocytes 
Platelet count 
Basophils 
Eosinophils 
 
4.7.4. 
Vital Signs 
 
The following vital signs parameters will be collected at Visit 1 (screening visit), Visit 2 
(baseline visit), Visit 3, Visit 4, Visit 5, Visit 6, and Visit 7 or at the time of ET.  On the study 
drug dosing days, vital signs will be assessed prior to collection of blood sample, prior to 
injection of study drug, and at 1 hour [±10 minutes] after completion of the injection. 
 
• Respiration rate (breaths/min) 
 
• Pulse rate (beat/min) 
 
• Systolic and diastolic blood pressures (mmHg).  Blood pressure may be difficult to 
obtain in some infants because of size, therefore a systolic blood pressure alone can 
be recorded. 
 
• Temperature (°C / °F) 
 
Both actual values and “change from baseline” values (defined as the post-baseline value minus 
the baseline value) will be used in vital sign result summaries. Potentially clinically significant 
values (PCSV) ranges will be applied to vital sign values as applicable (see Appendix 11.4 for 
PCSV definitions). 


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4.7.5. 
Physical Examination Variables 
 
Subjects will have a physical examination (including weight) at Visit 1 (screening visit), Visit 2 
(baseline visit), Visit 3, Visit 4, Visit 5, and Visit 7 or at the time of ET.  On study drug-dosing 
days, physical examinations will be conducted predose and again postdose (excluding weight) 
prior to discharge.  The result for each body system is an outcome of normal or abnormal. 
 
4.8. 
Pharmacokinetic Variables and Anti-Drug Antibody Variables 
(ADA) 
 
4.8.1. 
Pharmacokinetic Variables 
 
Drug concentration in serum through Day 150 visit will be reported. 
 
4.8.2. 
Anti-Drug Antibody Variables 
 
Antidrug antibody variables include status and titer as follows.  If ADA collected at screening is 
missing, it will be considered as negative at baseline. 
 
• Total subjects with negative ADA assay response at all time points analyzed. 
 
• Pre-existing immunoreactivity - defined as either a baseline positive ADA assay 
response (assessed with the sample collected at screen visit) with all post-baseline 
ADA assay results negative, or a baseline positive assay response with all 
post-baseline ADA assay responses less than 4-fold over baseline titer levels. 
 
• Treatment-emergent - defined as any post-baseline positive ADA assay response after 
the initiation of study drug when the baseline ADA result is negative or missing. 
 
− Treatment-emergent will be further characterized: 
 
 persistent - defined as consecutive positive responses over at least a 12-week 
period 
 
 indeterminate - defined as positive only at the last sample analyzed 
 
 transient - defined as not persistent or indeterminate 
 
• Treatment-boosted - defined as any post-baseline positive ADA assay response that is 
greater than or equal to 4-fold over baseline titer level when baseline response is 
ADA positive in the ADA assay. 
 
• Titer values 
 
• Titer category 
 
− Low (titer <1000) 
 
− Moderate (1000 ≤ titer ≤ 10000) 
 
− High (titer >10000) 


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4.9. 
Pharmacodynamic/Genomics Variables 
 
 
An optional substudy, which requires separate informed consent, is being conducted to collect 
DNA from cheek swab samples for future use for the purpose of discovery of predictive 
biomarkers related to RSV infection and severity. 
 
4.10. 
RSV Subtyping 
 
RSV subtype analysis will be conducted by RSV-G gene sequencing of RNA derived from the 
nose swab samples in subjects who tested positive on the RSV Lyra RT-PCR assay. 
Classification to subtype A and subtype B categories will be performed based on the determined 
sequence. 
 
4.11. 
RSV RT-PCR 
 
Study site personnel should evaluate the subject during an unscheduled visit as soon as possible 
or within 72 hours after receipt of medical attention, including nose swab collections for viral 
detection.  All nose swabs will be tested using the RSV Lyra RT-PCR assay, which will be 
conducted in a central laboratory. 
 
The central laboratory reports a qualitative result of RSV positive or negative and a quantitative 
result of cycle threshold (Ct) levels.  Ct levels are inversely related to the amount of RSV RNA 
in the sample. 
 
For infants who do not have an RSV RT-PCR assay for RSV infection done by the central 
laboratory, study site personnel will obtain and record information about any RSV RT-PCR 
assays done in a medical facility, including result(s), name of the assay(s) and whether the 
laboratory(ies) conducting the RT-PCR is a CLIA (Clinical Laboratory Improvement 
Amendments) certified (or equivalent) laboratory. Type of specimen obtained (nasopharyngeal 
Swab, nasopharyngeal aspirate, or nasal swab) is collected for local laboratory RSV testing. 
 
4.12. 
Respiratory Pathogen Panel RT-PCR 
 
An RT-PCR multiplex respiratory panel that includes RSV detection along with detection and 
identification of other respiratory pathogens will be used as part of the assessment of nasal swab 
samples.  Only RSV negative samples on the RSV Lyra RT-PCR assay will be tested on the 
multiplex RT-PCR respiratory panel. 
 
The introduction of the use of a multiplex RT-PCR respiratory panel is to explore the alternative 
etiologies of RSV-negative respiratory tract infections per a comment received from the US FDA 
while the study was ongoing.  RSV test results from the multiplex RT-PCR respiratory panel will 
not be used to derive primary or secondary efficacy endpoints. All efficacy endpoints and RSV 
detection will be based on RSV Lyra RT-PCR assay as described in the protocol unless 
otherwise specified in this analysis plan. 


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5. 
STATISTICAL METHODS 
 
5.1. 
Demographics and Baseline Characteristics 
 
Demographic and baseline characteristics (including risk factors as listed in Section 4.1) will be 
summarized descriptively for all FAS subjects by treatment group (REGN2222 1 dose, 
REGN2222 2 doses, REGN2222 combined, and placebo), and for the study total.  Similar 
summaries will be made for subjects within each of the 2 stratification factors (ie, gestational age 
[GA] category and region) as recorded in IVRS/IWRS. 
 
For continuous variables, descriptive statistics will include the following: the number of subjects 
reflected in the calculation (n), mean, median, standard deviation (SD), minimum, the first and 
third quartiles (Q1 and Q3), and maximum.  For categorical or ordinal data, frequencies and 
percentages will be displayed for each category. 
 
Other safety baseline data such as vital signs and clinical laboratory measures will be presented 
collectively in the descriptive statistics summary tables containing respective post-baseline data. 
 
5.2. 
Medical History 
 
Medical history will be summarized descriptively based on the SAF population by treatment 
group (REGN2222 1 dose, REGN2222 2 doses, REGN2222 combined, and placebo), and for the 
study total.  Summaries will show subject counts (percentages) by primary SOC and PT.  The 
tables will be sorted by decreasing frequency of SOC in the combined REGN2222 group. 
Within each primary SOC, PTs will be sorted by decreasing frequency in the combined 
REGN2222 group. 
 
5.3. 
Prior/concomitant Illnesses and Medications 
 
Number and percentage of subjects taking concomitant medication will be summarized based on 
the SAF population by treatment group (REGN2222 1 dose, REGN2222 2 doses, REGN2222 
combined, and placebo), and for the study total.  The tables will be sorted by decreasing 
frequency of ATC Level 2,ATC Level 4, and preferred term in the combined REGN2222 group. 
Number and percentage of subjects taking prior medication will be summarized in a similar 
fashion to concomitant medication. 
 
5.4. 
Prohibited Medications 
 
Number and percentage of subjects taking prohibited medication will be summarized by 
treatment group (REGN2222 1 dose, REGN2222 2 doses, REGN2222 combined, and placebo) 
and for the study total, for the SAF population.  The tables will be sorted by decreasing 
frequency of ATC level 2, ATC level 4, and preferred term in the combined REGN2222 group. 
 
5.5. 
Subject Disposition 
 
Subject disposition includes the description of subject status at major milestone decisions in the 
study. 
 
Subject study status will be summarized by treatment group (REGN2222 1 dose, REGN2222 
2 doses, REGN2222 combined, and placebo) and for the study total unless otherwise specified. 


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Summaries will provide the frequency (and percentage as applicable) of subjects that met the 
criteria for the following variables: 
 
• Screened subjects (signed the ICF). 
 
• Screen failed subjects. 
 
• Subjects randomized. 
 
• Subjects randomized but not treated. 
 
• Subjects randomized and treated (SAF population). 
 
• Completed study (ie, Day 237 Visit) as collected on the End of Study eCRF page. 
 
• Completed efficacy assessment period (ie, Day 150 Visit) as collected on the End of 
Study eCRF page. 
 
• Did not complete study (ie, Day 237 Visit). 
 
− Did not complete efficacy evaluation period (ie, Day 150 Visit) on the End of 
Study eCRF page. 
 
• Subjects ongoing in the study (only applicable at the time of the first step analysis 
[see Section 8 for the definition of first step analysis]). 
 
• Primary reasons for discontinuation from study (ie, Day 237 Visit). 
 
• Primary reasons for discontinuation from study for subjects who did not complete 
efficacy evaluation period (ie, Day 150 visit). 
 
In addition, summary of the number (and percentage) of subjects in each analysis population (as 
defined in Section 3) will be presented by treatment group, and for the study total.  Percentages 
will be calculated using the number of randomized subjects as the denominator. 
 
The following listing will be provided: A listing of subject disposition including randomization 
date, dosing date(s), last visit date, completed efficacy evaluation period (ie, Day 150 Visit) or 
not with reason, completed study (ie, Day 237 Visit) or discontinued by reason; a listing of 
screening failures and reasons for all screen failed subjects. 
 
5.6. 
Extent of Study Treatment Exposure and Compliance 
 
5.6.1. 
Exposure to Investigational product 
 
Exposure to investigational product will be examined based on the SAF population.  Descriptive 
statistics including the number of subjects reflected in the calculation (n), mean, median, SD, 
minimum, Q1 and Q3, and maximum will be used to summarize the following variables: 
 
• The calculated actual dose (in the unit of mg/kg) of each study treatment. 
 
• Length of observation period. 
 
A tabulation of the number (and percentage) of subjects will be used to summarize the following 
variables: 
 
• The total number of study doses administered. 


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• 
• 
Number of injections received for each dose. 
The number (and percentage) of subjects having observation periods of specific 
lengths will be summarized according to time period breakdowns as follows: ≥1 to 
<27 days, ≥ 27 to <55 days, ≥ 55 to <80 days,  ≥ 80 to <108 days,  ≥ 108 to 
< 145 days,  ≥ 145 to <168 days,  ≥ 168 to <196 days,  ≥ 196 to <227 days, and 
≥ 227 days.  These categories are determined by the minimum number of days 
allowed by the protocol specified windows for scheduled visits. 
• The number (and percentage) of subjects having observation periods of at least 27, 
55, 80, 108, 145, 168, 196, and 227 days will be presented. 
5.6.2. 
Measurement of Compliance 
Study treatment compliance parameters will be examined based on the SAF population.  For the 
compliance ratio (categorical), the frequency (percentage) of subjects will be provided for each 
category. Descriptive statistics including the number of subjects reflected in the calculation (n), 
mean, median, SD, minimum, Q1 and Q3, and maximum will be used to summarize the 
compliance ratio (continuous). 
 
All major and minor protocol deviations potentially impacting efficacy analyses, randomization 
and drug-dispensing irregularities, as well as other deviations, have been collected and reviewed 
on an ongoing basis throughout the study as described in the Protocol Deviation Definitions 
Document (PDDD).  Both monitored and CRF derived protocol deviations will be summarized 
for subjects incurring any major deviation by count and percentage, and subjects incurring each 
type of major deviation by count and percentage.  A subject listing of all major and minor 
protocol deviations will be provided. 
 
5.7. 
Analyses of Efficacy Variables 
 
The null hypothesis of the primary efficacy variable is that the proportions of FAS subjects with 
medically attended RSV hospitalization or outpatient LRTI in the placebo group and in the 
REGN2222 group are the same (H0: p1 = p2). The alternative hypothesis is that the rate for each 
REGN2222 group is different from the rate for the placebo group (H1: p1 ≠ p2). 
 
5.7.1. 
Analysis of Primary Efficacy Variable 
 
The primary efficacy variable is the proportion of subjects with a medically attended RSV 
infection (hospitalization or outpatient LRTI) during the 150-day efficacy assessment period. 
Details regarding the derivation of observed primary endpoint event and imputation of missing 
primary endpoint at Day 150 visit are described in Section 4.6.1. 
 
The primary efficacy variable will be analyzed by CMH statistics with randomization stratum 
adjusted by the Mantel-Haenzel (MH) method to assess the pairwise comparisons of each 
REGN2222 treatment arm to placebo.  The stratification factors used in the CMH analysis are 
region and GA per IVRS/IWRS, which will give rise to the following 4 strata: 
 
• North America and ≤ 31 weeks 6 days GA. 
 
• North America and ≥ 32 weeks 0 days and < 35 weeks 6 days GA. 
 
• Rest of the world and ≤ 31 weeks 6 days GA. 


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ℎ
+
 
• Rest of the world and ≥ 32 weeks, 0 days and < 35 weeks 6 days GA. 
 
This stratum-adjusted difference (ie, absolute risk reduction) based on the MH method is 
weighted by the harmonic mean of sample size per treatment group for each stratum.  Point 
estimate, 95% confidence interval (CI), and p-value of the proportion difference between 
2 treatment groups will be calculated as follows: 
If ௭1ℎ  and ௭2ℎ   are the FAS sample sizes of the two treatment groups 1 and 2 in stratum ℎ, then 
the weight 
 
௭ℎ  = ௭ ௭1ℎ ௭2ℎ 
+ ௭ 
1ℎ 
2ℎ 
is used for stratum ℎ in calculating the overall difference.
 
Let ௭ℎ  = ௭1ℎ  − ௭2ℎ  be the treatment difference in the proportion of subjects with primary 
endpoint events in stratum ℎ, where ௭1ℎ  and ௭2ℎ  are calculated as: 
 
௭1ℎ  = 
௭1ℎ  + ௭ × ௭1ℎ
 
௭1ℎ 
, 
௭2ℎ  = 
௭2ℎ  + ௭ × ௭2ℎ
 
௭2ℎ 
 
with ௭1ℎ  and ௭2ℎ  being the number of subjects with observed primary endpoint event(s) in 
treatment groups 1 and 2, respectively (including ET subjects who had their primary endpoint 
missing but died prior to Day 150 due to causes adjudicated to be RSV related), ௭1ℎ  and ௭2ℎ 
being the number of early termination subjects missing the primary endpoint in treatment groups 
1 and 2, respectively, and ௭ being the KM estimate of the primary endpoint event rate in all 
subjects randomized to the placebo group (see Section 4.6.1).  Then the point estimate of 
stratum-adjusted proportion difference is 
 
 
The continuity-corrected variance of ௭ is 
∑ ௭ℎ ௭ℎ 
௭ = ∑ ௭ℎ
 
∗   (1 − ௭∗   )
 
௭∗   (1 − ௭∗   )
 
∑ ௭ 2( 
2 
௭1ℎ 
1ℎ 
௭1ℎ  + 1 
2ℎ ௭2ℎ 
2ℎ   ) 
+ 1 
where 
௭௭𝑑   
=
 
(∑ ௭ℎ )2
 
∗    = ௭1ℎ  + ௭ × ௭1ℎ  + 0.5 , 
௭∗     = ௭2ℎ  + ௭ × ௭2ℎ  + 0.5 
௭1ℎ 
௭1ℎ  + 1 
2ℎ 
௭2ℎ  + 1 
 
 
The 95% asymptotic CI of ௭ is [௭ − ௭௭0.975 ∗ ௭௭𝑑 ,  ௭ + ௭௭0.975 ∗ ௭௭𝑑 ] where  ௭௭0.9875  is the 
98.75th
 
percentile of the standard normal distribution.  The p-value will be computed from the 
z-score = ௭/௭௭𝑑 .  A SAS macro will be used to calculate all the above statistics.
 
In addition to the absolute risk difference, the stratum-adjusted relative risk of the primary 
efficacy variable will be provided for the pairwise comparisons of each REGN2222 treatment 
arm to placebo for descriptive purpose.  The number of subjects with primary endpoint event(s) 


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in each stratum will be rounded to its nearest integer for the calculation of relative risk. The 


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stratum-specific relative risks will be combined based on the MH method to compute the point 
estimate and asymptotic 95% CI of stratum-adjusted relative risk using the SAS FREQ 
procedure.  In the event that there are zero table cells in any strata, the exact CI for the relative 
risk may be computed in lieu of the asymptotic CI by specifying the RELRISK option in the 
EXACT statement of the SAS FREQ procedure. 
 
The statistical testing of the 2 pairwise comparisons of each REGN2222 treatment arm to 
placebo for the primary measure will be evaluated at a 2-sided significance level of 0.05 per 
pairwise comparison, adjusting for multiplicity through a hierarchical inferential approach.  In 
the hierarchy testing sequence, the comparison of REGN2222 2 doses arm to placebo is the first 
pairwise treatment comparison, and the comparison of REGN2222 1 dose arm to placebo is the 
second pairwise treatment comparison. 
 
5.7.1.1. 
Model Assumption Checks 
 
In order to check the homogeneity of treatment effect across strata, the treatment differences and 
corresponding 95% CI will be calculated and graphically presented for each stratum ℎ, following 
the same continuity correction method for variance as in the primary approach. 
 
5.7.1.2. 
Supportive Analyses for the Primary Efficacy Endpoint 
 
The following statistical analyses will be used to further assess the primary efficacy endpoint. 
As appropriate, p values will be provided for descriptive purpose only. 
 
Sensitivity to small event rate 
 
The adequacy of the CMH statistics may be of concern in the case of an unexpectedly very small 
event rate.  The Fisher’s exact test is valid regardless of the cell sizes and therefore will be 
employed as a supportive statistical approach to confirm the results from the primary approach. 
 
The Fisher’s exact test will be applied to the whole FAS for comparisons of each REGN2222 
arm to placebo. The number of subjects with primary endpoint event(s) will be (௭𝑖 + ௭ × ௭𝑖 ) 
rounded to its nearest integer, where ௭𝑖  is the number of subjects with observed primary 
endpoint event(s) in treatment group 𝑖 (including ET subjects who had their primary endpoint 
missing but died prior to Day 150 due to causes adjudicated to be RSV related), ௭𝑖   is the number 
of early termination subjects missing the primary endpoint in treatment group ௭௭, and ௭ is the 
KM 
estimate of the primary endpoint event rate in all subjects randomized to the placebo group. 
 
The Fisher’s exact test will also be applied to subgroups defined by stratification variables (ie, 
test in the subgroups of North America, rest of the world, ≤ 31 weeks 6 days GA, and GA ≥ 32 
weeks 0 days and < 35 weeks 6 days, respectively).  The number of subjects with primary 
endpoint event(s) in each of the subgroups will be calculated in the same fashion as for the whole 
FAS except that ௭𝑖  and ௭𝑖  will be stratified group specific. This analysis will only be performed 
if there are enough subjects in each stratification level. 
 
The SAS FREQ procedure with the option FISHER in the TABLE statement will be used to 
compute the 2-sided p-value of the Fisher’s exact test. 
 
In order to check the homogeneity of treatment effect across strata, the Fisher’s exact test will 
also be run for each stratum ℎ.
 


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Regression method adjusting for covariates 
 
The primary approach based on the CMH statistics tests for absolute difference in proportions 
between treatment groups. As a supportive approach, the logistic regression will use odds ratio 
to test for relative treatment effect of each REGN2222 arm over placebo on the primary efficacy 
variable.  The number of subjects with primary endpoint event(s) will be (௭𝑖ℎ  + ௭ × ௭𝑖ℎ ) 
rounded to its nearest integer for treatment group 𝑖 within each stratum ℎ (a total of 4 strata as 
defined in the primary approach).  The model for the logistic regression will include treatment 
group, region and gestational age category as factors.  The maximum likelihood (ML) estimates 
of the odds ratio, and asymptotic normality based 95% CIs and p-values will be computed using 
the SAS LOGISTIC procedure.  In the event that quasi-complete separation of data points occurs 
(ie, the outcome variable separates a predictor variable or a combination of predictor variable to 
an almost full degree), Firth’s penalized likelihood approach may be employed to reduce bias in 
logistic regression.  This approached will use the SAS LOGISTIC procedure with option=Firth. 
 
In order to check the homogeneity of treatment effect across strata, the terms of interaction 
between treatment and strata (ie, region and gestational age group) will be added to the logistic 
regression model to obtain p values for the interaction terms for descriptive purpose.  Stratum 
specific odds ratios and 95% CIs will also be reported. 
 
5.7.1.3. 
Sensitivity to the Handling of Missing Data 
 
The following analyses will be conducted to assess the results from the primary analysis with 
regards to the handling of missing data.  As appropriate, p values will be provided for descriptive 
purpose only. 
 
Observed-Case Analysis 
 
In the observed-case analysis, for each treatment group, the proportion of subjects considered to 
have primary endpoint event occurrence will be calculated with the numerator being the number 
of subjects with observed primary endpoint event(s) (including ET subjects who had their 
primary endpoint missing but died prior to Day 150 due to causes adjudicated to be RSV 
related), and the denominator being the number of subjects in the FAS.  The observed-case based 
proportion difference will be calculated for each stratum ℎ and then combinded across strata to 
generate the CMH statistics following the same method as in the primary approach. 
 
Tipping Point Analysis 
 
A tipping point analysis will be employed to explore the degree of shift from the placebo event 
rate used in the imputation of missing data in REGN2222 arms.  The tipping point analysis will 
include the following steps to impute missing primary endpoint at Day 150 visit: 
 
1.   Subject deaths prior to Day 150 that are adjudicated to be RSV related will be included as 
“event occurred”. 
 
2.   Remaining early termination subjects (including non-RSV deaths) in the placebo group 
will be imputed to the average placebo score (ie, the KM estimate of the primary 
endpoint event rate in all subjects randomized to the placebo group). 
 
3.   Remaining early termination subjects (including non-RSV deaths) in the REGN2222 arm 
will be imputed to 𝛿 × ௭ℎ௭ ௭௭௭௭௭𝑔௭ ௭௭௭௭௭௭௭ ௭௭௭௭௭, where 𝛿 = 2. (Note: 𝛿 = 1 is 
equivalent to the primary analysis) 


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4.   Repeat the step 3 with 𝛿 = 3, 4, 5, etc. until reaching the point that the treatment effect of 
REGN2222 will be lost (ie, the difference [REGN2222 – placebo] in the proportion of 
subjects with primary endpoint event[s] is ≥ 0). 
 
The tipping point analysis will be conducted for the pairwise comparisons of each REGN2222 
arm to placebo separately, using the same CMH statistics as in the primary approach. 
 
5.7.1.4. 
Individual Endpoints 
 
The primary efficacy variable can be considered as a composite endpoint comprising the 2 
individual endpoints: 
 
• Subjects hospitalized for RSV infection during the 150-day efficacy assessment 
period. 
 
• Subjects who had outpatient visit (ie, ER, UC, or PC visit) with RSV LRTI during the 
150-day efficacy assessment period. 
 
In order to examine which whether an individual endpoint will be driving the treatment difference 
observed for the primary efficacy variable, each of the 2 individual endpoints will be analyzed 
using the primary approach for the primary efficacy variable, including handling of missing data 
(Section 4.6.1) and the CMH statistics (Section 5.7.1).  In addition, Fisher’s exact test described 
in Section 5.7.1.2 will be performed for these 2 individual endpoints to confirm the results. 
 
5.7.1.5. 
Sensitivity to GCP Non-compliance Site 
 
To assess the impact of study data collected from an investigational study site that was not 
compliant with GCP standards, the primary efficacy analysis will be repeated excluding subject 
data from the non-compliant site. 
 
5.7.1.6. 
Sensitivity to Stratification at Randomization 
 
In order to assess the robustness of the primary analysis to stratification mistakes made at the 
time of randomization (ie, the stratum recorded in IVRS/IWRS differs from the actual stratum 
recorded in the eCRF), the primary efficacy analysis will be repeated replacing the IVRS/IWRS 
strata with the eCRF actual strata. 
 
5.7.1.7. 
Subgroup Analysis 
 
To assess the homogeneity of treatment effect across various subgroups, the primary efficacy 
variable will be analyzed using the same CMH method as in the primary approach for each 
subgroup of subjects defined by the following baseline characteristics, risk factors, geographic 
areas, or enrolment season: 
 
• Race (White, other) 
 
• Chronological age (≤ 3 months,  > 3 months) 
 
• Sex (Female , Male) 
 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino) 
 
• Region (NA, rest of the world) 


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• Gestational age (≤31 weeks 6 days GA, ≥ 32 weeks 0 days and < 35 weeks 6 days 
GA) 
 
• Hemisphere (Northern, Southern) 
 
• Enrollment season (2015-2016 Northern Hemisphere, 2016 Southern Hemisphere, 
2016-2017 Northern Hemisphere) 
 
• Study subjects in child care (Yes, No) 
 
• Children, 6 years or younger, live in study subject’s household (Yes, No) 
 
For ET subjects those who did not complete Day 150 visit, their primary endpoint will be 
handled according to the rules used in the primary analysis (Section 4.6.1) before conducting the 
CMH analysis for each subgroup. 
 
Point estimates and 95% CIs of the treatment effect will be calculated for each subgroup if that 
subgroup is of reasonable size to perform the evaluation.  Since the study sample size is not 
powered for subgroups, CIs are provided for descriptive purpose.  Results for treatment 
difference in the subgroups of subjects will be graphically displayed in the form of forest plots. 
 
In addition to the CMH statistics, logistic regression will be run with treatment, region, 
gestational age category, subgroup variable (eg, race), treatment-by-subgroup variable 
interaction term in the model.  The p value of the treatment-by-subgroup variable interaction 
term will be reported for descriptive purpose to assist the evaluation of treatment effect 
differentiation across the levels of a subgroup variable. 
 
As small cell size is more likely to occur in subgroup analyses, the Fisher’s exact test will be 
applied to the whole FAS within each subgroup in a similar fashion to the method described in 
Section 5.7.1.2 with the only difference being that ௭𝑖  and ௭𝑖  will be subgroup specific.
 
5.7.2. 
Analysis of Secondary Efficacy Variable 
 
The secondary efficacy variable is the proportion of subjects who have RSV-confirmed 
hospitalization, ER, UC, or pediatric clinic visits (for upper or lower respiratory infection) during 
the 150-day efficacy assessment period.  This secondary endpoint is different from the primary 
endpoint in the way that the RSV-confirmed outpatient visit (ER, UC, or pediatric clinic visits) 
for either upper or lower respiratory infection is included as the secondary endpoint event while 
only the RSV-confirmed outpatient visit for lower respiratory infection is included in the primary 
endpoint event.  The secondary endpoint will be analyzed by the same set of analyses as for the 
primary efficacy variable including the primary statistical approach, model assumption checks, 
supportive statistical approaches, individual endpoints, sensitivity analyses, and subgroup 
analyses. 
 
To understand if REGN2222 can provide any benefit in preventing upper respiratory RSV 
infection, the proportion of subjects who had observed secondary endpoint event(s) but no 
observed primary endpoint event(s) will be descriptively summarized for each treatment group. 
 
5.7.3. 
Adjustment for Multiple Comparison 
 
To control the 5% overall Type I error for the 2 pairwise comparisons in the primary analysis, 
the overall study α level will be controlled by the use of a hierarchical inferential approach. 


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Statistical significance of the first pairwise treatment comparison (REGN2222 2 doses arm to 
placebo) is required before drawing inferential conclusions about the second pairwise treatment 
comparison (REGN2222 1 dose arm to placebo) at the 0.05 alpha level. This fixed hierarchical 
approach will ensure a strong control of the overall Type I error rate at the 0.05 level for each 
REGN2222 dose regimen comparison. 
 
Further, in the case that the primary efficacy endpoint is statistically significant at 0.05 (2-sided) 
alpha level for both pairwise treatment group comparisons specified in the above paragraph, the 
secondary efficacy endpoint will be tested using the same hierarchical inferential approach as 
used for the primary efficacy endpoint. 
 
This multiple testing procedure ensures a strong control of the overall Type I error rate at the 
0.05 level.  No further adjustments will be made for other analyses for which p-values will be 
provided for descriptive purpose only. 
 
No adjustment will be made for the first step and second step statistical analyses (Section 8), 
since the primary and secondary efficacy endpoints will have been concluded at the time of the 
first step analysis. 
 
5.7.4. 
Analysis of Exploratory Efficacy Variables 
 
Time to event endpoints 
 
Number of days to the first efficacy endpoint event will be analyzed with stratified log-rank test. 
Different from the primary analysis, this time to event analysis will treat missing primary 
endpoint at Day 150 visit through a censoring method as described in Section 4.6.3. 
 
The SAS LIFETEST procedure will be used to run the stratified log-rank test by specifying 
region and gestational age category in the STRATA statement as 2 stratifying variables, and 
specifying treatment group in the GROUP= option.  In addition, for each treatment group, 
Kaplan-Meier curve will be used to graphically depict the proportion of subject who remained 
event free across time during the 150-day efficacy assessment period. Cox regression will be 
used to obtain hazard ratios and their confidence intervals.  The Cox regression model will 
include the fixed categorical effects of treatment group, region, and gestational age category. 
 
Continuous efficacy endpoints 
 
Descriptive statistics including the number of subjects reflected in the calculation (n), sum, mean, 
median, SD, minimum, Q1 and Q3, and maximum will be used to summarize the continuous 
exploratory endpoints (eg, total number of medical visit, length of stay in hospital, etc., as 
defined in Section 4.6.3) for each treatment group and their treatment difference between each 
REGN2222 arm and placebo.  For each exploratory endpoint, this descriptive summary will 
include only those subjects who had at least 1 endpoint specific event. 
 
To account for subjects who had no endpoint specific event, a separate analysis will be 
performed for each exploratory endpoint to include these subjects by treating their endpoint 
value as zero.  In this analysis, the event rate adjusted by subject-year of follow-up will be 
provided for each treatment group.  For each subject, the duration calculated as (end of efficacy 
evaluation - first dose date +1)/365.25 will be counted toward the subject-year of follow-up, 
except that for the endpoint of total number of respiratory illness-associated hospital, ER, UC, or 
PC visits after the initial episode of RSV illness, the duration will be (end of efficacy 


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evaluation - the day after the stop date of the initial episode of RSV illness + 1)/365.25.  The end 
of efficacy evaluation is the last visit completed by a subject, scheduled or unscheduled, up to 
Visit 7.  Negative binomial regression will be used to estimate the relative risk reduction 
associated with each REGN2222 arm as compared to placebo. 
 
Categorical efficacy endpoints 
 
RSV confirmed hospitalization, a component of the primary composite endpoint, will be 
explored using the same statistical methodology as the primary efficacy analysis. For this 
exploratory analysis, the two REGN2222 treatment groups will be combined for comparison to 
the placebo group, with the intent to evaluate the REGN2222 effect on subjects with RSV 
confirmed hospitalization. 
 
Number and percentage of subjects taking medications associated with RSV or respiratory illness 
will be summarized by treatment group. The denominator used to calculate percentage will be 
the number of subject in the FAS assigned to each treatment group. The tables will be sorted by 
alphabetical order of ATC level 2 followed by ATC level 4. 
 
The procedures associated with RSV or respiratory illness will only be listed for subjects in each 
treatment group. 
 
The same CMH statistics as used in the primary approach for the primary efficacy variable will 
used to analyze the following exploratory endpoints.  Missing data will be addressed using the 
same same rules as used in the primary analysis for the primary efficacy variable (Section 4.6.1). 
 
• Proportion of FAS subjects with the primary endpoint event, with the single 
exception of using an alternative definition for LRTI. 
• Proportion of subjects with the primary endpoint event, with the single exception of 
the removal of RSV hospitalization non-LRTI 
5.7.5. 
Other Exploratory Analyses 
 
5.7.5.1. 
Potentially Pre-incubated RSV infection Prior to Study Treatment 
 
Subjects who had their primary endpoint event occurrence by study day 7 (study day 1 being the 
day when the first dose of study drug was administered) could have potentially already 
contracted the RSV infection before receiving study drug.  To assess the sensitivity of efficacy 
results to those potentially pre-incubated RSV infections, such subjects will be considered as 
having no primary endpoint unless the subject had another primary endpoint event with onset 
more than 7 days after the first dose during the study (ie, on or after study day 8).  In this 
sensitivity analysis, for ET subjects who did not complete Day 150 visit, their missing endpoint 
will be handled according to the same rules as used in the primary analysis for the primary 
efficacy variable (Section 4.6.1), however, all primary endpoint event occurrences by study day 
7 will neither be included as events in the construction of KM estimate nor be considered as 
events in the analysis of treatment effect using the CMH statistics. 
 
5.7.5.2. 
RSV Subtype Analysis 
 
The primary endpoint and its component endpoints (as described in Section 5.7.1.4) will be 
summarized for each RSV subtype (ie, subtype A and subtype B, respectively) by treatment 


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group.  Only observed primary endpoint events with available RSV subtype information will be 
included as events in this analysis.  Treatment effect of each REGN2222 arm (over placebo) in 
prophylaxis against each RSV subtype will be assessed using CMH statistics with randomization 
stratum adjusted by the MH method previously described in 5.7.1.  Confidence intervals will be 
provided only for exploratory purpose. 
 
5.7.5.3. 
Non-RSV Medically Attended Respiratory Illness 
 
To evaluate the effect of REGN2222 on the non-RSV MARI, the proportion of subjects who had 
medically attended respiratory illness (hospitalization or outpatient LRTI) not confirmed to be 
related to RSV (either all negative RSV or missing RSV testing results within 14 days since AE 
onset) will be summarized for each treatment group.  If a subject had both non-RSV MARI and 
RSV MARI (ie, the primary endpoint event), they will not be included in the numerator when 
calculating the proportion. For this particular analysis, only observed events will be included as 
events.  Treatment difference in this proportion will be summarized using descriptive statistics. 
 
5.8. 
Analysis of Safety Data 
 
Safety and tolerability will be descriptively summarized, including AEs, clinical laboratory 
variables, physical exam, and vital signs for the SAF.  The summary of safety results will be 
presented for the treatment groups of combined REGN2222 dose arms with the intent to 
maximize efforts to detect potential safety signals.  The individual REGN22222 dose arms will 
also be presented with the intent to support the combined regimens.  No formal inferential testing 
will be performed.  Summaries will be descriptive in nature. 
 
All safety analyses will be performed, unless otherwise specified, using the following common 
rules: 
 
• The baseline value is defined as the last available value obtained up to the date and 
time of the first dose of study drug, unless otherwise specified. 
 
• For clinical laboratory, physical exam, and vital signs variables, all measurements, 
scheduled or unscheduled, will be assigned to analysis windows defined in 
Appendix 11.3 in order to provide an assessment for Visit 3 to Visit 7 time points. 
 
• For continuous safety parameters including central laboratory measurements and vital 
sign scores, descriptive statistics will be used to summarize results and change from 
baseline values by visit. 
 
• A treatment-emergent Potential Clinically Significant abnormal value (PCSV) is a 
laboratory value or vital sign that was: normal at baseline but abnormal after 
treatment with study drug during the TEAE period, or: abnormal at baseline and 
worsened after treatment with study drug during the TEAE period. Thresholds for 
treatment-emergent PCSV in laboratory variables and vital signs are defined in 
Appendix 11.4. Treatment-emergent PCSV criteria will determine which subjects had 
at least 1 treatment-emergent PCSV, taking into account all assessments including 
unscheduled assessments.  Subjects who had post-baseline PCSV during the TEAE 
period but missing baseline value will be regarded as having treatment-emergent 
PCSV.  There are no universally accepted normal ranges for preterm infants.  The 
ranges used to determine PCSV criteria are associated with full-term infants (except 


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for bilirubin) and consequently, the TEPCSV results are to be interpreted with 
caution. 
 
The summary of safety results will be presented by treatment group (REGN2222 1 dose, 
REGN2222 2 doses, REGN2222 combined, and placebo). 
 
5.8.1. 
Adverse Events 
 
The verbatim text, the PT, and the primary SOC will be listed in subject listings.  Summaries that 
include frequencies and proportions of subjects reporting AEs will include the PTs and the SOCs 
as appropriate. 
 
The focus of adverse event reporting in the clinical study report will be on TEAEs. 
Pre-treatment and post-treatment AEs will be provided separately. 
 
If an AE date/time of onset (occurrence, worsening, or becoming serious) is incomplete, an 
imputation algorithm will be used to classify the AE as pre-treatment, treatment-emergent, or 
post-treatment.  The algorithm for imputing date/time of onset will be conservative and will 
classify an AE as treatment-emergent unless there is definitive information to determine 
pre-treatment status.  For details on handling missing data and partial dates, see Section 6.3. 
Summaries of all TEAEs in each treatment group will include: 
• Overview of TEAEs, summarizing number and percentage of subjects with any 
− TEAEs. 
− Serious TEAEs. 
− TEAEs leading to death. 
− TEAEs leading to permanent treatment discontinuation. 
− TEAEs with severity of 3/4/5/Severe/Life-Threatening/Fatal (if multiple 
occurrences of an event for a subject, then worst severity is counted). 
− TEAEs that occurred within 2 days after either the first dose or the second dose 
(ie, post dose TEAE start date - dosing date ≤ 2). 
• All TEAEs by SOC and PT. 
• All TEAEs by SOC, PT, and severity. 
• All TEAEs by SOC, PT, and relationship (related, not related) to study drug. 
• All TEAEs by SOC, PT, and relationship (related, not related) to injection procedure. 
• TEAEs reported by ≥ 5% of subjects in any treatment group by PT ordered by 
decreasing subject frequency in the combined REGN2222 group. 
• TEAEs reported by ≥ 1% of subjects in any treatment group by PT ordered by 
decreasing subject frequency in the combined REGN2222 group. 
• Study drug-related TEAEs by SOC and PT. 
• Study drug-related TEAEs by SOC, PT, and severity. 
• Injection procedure-related TEAEs by SOC and PT. 
• Injection procedure-related TEAEs by SOC, PT, and severity. 


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• Serious adverse events: All, study drug-related, and injection procedure-related 
TEAEs by SOC and PT. 
• Death: All, study drug-related, and injection procedure-related TEAEs by SOC and 
PT.  TEAEs leading to death are TEAEs that led to death regardless of timing of 
death in relation to study drug injection (ie, death occurring in the TEAE period or 
during the post-treatment period) 
• Discontinuation of study drug: All, study drug-related, and injection procedure- 
related TEAEs by SOC and PT. 
• TEAEs with severity of 3/4/5/Severe/Life-Threatening/Fatal:  All, study drug-related, 
and injection procedure-related TEAEs by SOC and PT. 
• Non-serious study drug-related or injection procedure-related TEAEs by SOC and 
PT. 
• TEAEs according to time of occurrence in relation to dosing: 
− TEAEs that occurred after the first dose and before the second dose: All, study 
drug-related, and injection procedure-related TEAEs by SOC and PT.  For 
subjects who did not receive the second dose, only TEAEs that occurred up to 
Day 57 (Day 1 being the day when the first dose was administered) will be 
included. 
− TEAEs that occurred after the second dose in subjects who received the second 
dose: All, study drug-related, and injection procedure-related TEAEs by SOC and 
PT. 
− Serious TEAEs that occurred after the first dose and before the second dose: All, 
study drug-related, and injection procedure-related TEAEs by SOC and PT. For 
subjects who did not receive the second dose, only serious TEAEs that occurred 
up to Day 57 (Day 1 being the day when the first dose was administered) will be 
included. 
− Serious TEAEs that occurred after the second dose in subjects who received the 
second dose: All, study drug-related, and injection procedure-related TEAEs by 
SOC and PT. 
− TEAEs with severity of 3/4/5/Severe/Life-Threatening/Fatal that occurred after 
the first dose and before the second dose:  All, study drug-related, and injection 
procedure-related TEAEs by SOC and PT.  For subjects who did not receive the 
second dose, only relevant TEAEs that occurred up to Day 57 (Day 1 being the 
day when the first dose was administered) will be included. 
− TEAEs with severity of 3/4/5/Severe/Life-Threatening/Fatal that occurred after 
the second dose in subjects who received the second dose:  All, study 
drug-related, and injection procedure-related TEAEs by SOC and PT. 
− TEAEs that occurred within 2 days after either the first dose or the second dose 
(ie, post dose TEAE start date - dosing date ≤ 2): All, study drug-related, and 
injection procedure-related TEAEs by SOC and PT. 


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− TEAEs that occurred within 2 days after the first dose: All, study drug-related, 
and injection procedure-related TEAEs by SOC and PT. 
− TEAEs that occurred within 2 days after the second dose in subjects who received 
the second dose: All, study drug-related, and injection procedure-related TEAEs 
by SOC and PT. 
− TEAEs that occurred within 7 days after either the first dose or the second dose 
(ie, post dose TEAE start date - dosing date ≤ 7): All, study drug-related, and 
injection procedure-related TEAEs by SOC and PT. 
− TEAEs that occurred within 7 days after the first dose: All, study drug-related, 
and injection procedure-related TEAEs by SOC and PT. 
− TEAEs that occurred within 7 days after the second dose in subjects who received 
the second dose: All, study drug-related, and injection procedure-related TEAEs 
by SOC and PT. 
• T 
all
wo event rate estimations adjusted by subject year of follow-up will be provided for 
TEAEs by SOC and PT: 
− Total number of events divided by the total length of the TEAE period over all 
subjects in the SAF of each treatment group. 
− Total number of subjects with an event in question divided by the total length of 
the TEAE period.  For a subject with event, the time from first dose to the first 
event will be counted towards the denominator.  For a subject without event, the 
time from first dose to the end of the TEAE period will be counted towards the 
denominator. 
 
The above TEAE summaries will present the number (n) and percentage (%) of subjects 
experiencing an TEAE by SOC and PT.  Multiple occurrences of AEs of the same PT (or SOC) 
in the same subject will be counted only once for that PT (or SOC).  For tables presenting 
severity of events, the worst severity will be chosen for subjects with multiple instances of the 
same event.  Relatedness to study drug or injection procedure is according to investigator’s 
opinion. 
 
Primary SOCs will be sorted by decreasing frequency in the combined REGN2222 group. 
Within each primary SOC, PTs will be sorted by decreasing frequency in the combined 
REGN2222 group. 
 
The description of TEAEs reported by ≥ 5% of subjects in any treatment group will also be 
performed for demographic and baseline factors including: sex, chronological age (≤ 3 months, 
> 3 months), gestational age (≤ 31 weeks 6 days, ≥ 32 weeks 0 days and ≤ 35 weeks 6 days), and 
region. 
 
Subject listings for deaths, all serious TEAEs, TEAEs leading to permanent treatment 
discontinuation, TEAEs with severity of 3/4/5/Severe/Life-Threatening/Fatal, and 
treatment-emergent AESIs will be provided. 


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5.8.2. 
Analysis of Adverse Events of Special Interest and Preferred Terms of Interest 
for Identification of Hypersensitivity 
 
Treatment emergent AESIs and PTs of interest for identification of hypersensitivity (as defined 
in Section 4.7.2) will be presented by SOC and PT, or by PT alone. The summaries will be sorted 
by decreasing incidence of PT within each SOC in the combined REGN2222 group if presented 
by SOC and PT.  In addition, the following analyses will be performed to further characterize the 
safety profile in each treatment group: 
 
• TEAEs that are PTs under the HLT of injection site reaction will be summarized by: 
 
− Number (and percentage) of subjects who experienced 1 vs. >1 events of injection 
site reaction. 
 
− Number (and percentage) of subjects who experienced at least one event of 
injection site reaction by highest severity. 
 
− Descriptive statistics including number of subjects, mean, median, standard 
deviation, minimum, Q1, Q3, and maximum will be provided for the following 
measures: 
 
 Number of events divided by the number of study drug injections each 
subject received.  Note each dose of study drug can be administered via 
more than 1 injections according to the total volume of study drug 
determined by the subject’s body weight. 
 
 Mean duration of events.  The duration of an event is defined as (AE stop 
date - AE start date +1).  If an AE is ongoing at the end of the study, the last 
visit date will be used in lieu of AE stop date.  Mean duration is calculated 
as the duration averaged over all events experienced by a subject. 
 
 Number of days following the most recent study drug injection to the first 
event of injection site reaction. 
 
− Number of events and number (and percentage) of subjects with events that 
occurred within 2 days after dosing by PT.  For subjects who did not receive the 
second dose, only those events that occurred up to Day 57 (Day 1 being the day 
when the first dose was administered) will be included. 
 
- Number of events and number (and percentage) of subjects with events that 
occurred beyond 2 days after dosing by PT.  Only subjects who received the 
second dose will be included in this analysis. 
 
5.8.3. 
Clinical Laboratory Measurements 
 
Central laboratory measures for chemistry and hematology parameters will be explored through 
two methods: 
 
First, summaries will focus on study population changes with the intent of identifying deviations 
on a large scale across time. This approach for continuous variables summarizes both the actual 
results (at both baseline and post-baseline) and the change from baseline results at each 
post-baseline scheduled visit. Descriptive statistics include number of subjects, mean, median, 


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standard deviation, minimum, Q1, Q3, and maximum values for each of the 5 blood collection 
schedule group (Schedule I through M) by treatment group. 
 
Second, shift tables based on baseline categories of low/normal/high/total will be provided for 
each post-baseline visit by treatment group.   In addition, line plots of change from baseline in 
lab values over time will be presented with visit plotted on the x-axis and lab values on the y- 
axis, with treatment group side by side at each time point.  In addition to the shift analyses, 
number (and percentage) of subjects with lab values meeting the treatment-emergent PCSV 
criteria at least once during the TEAE period will be summarized.  These laboratory parameters 
will be presented by the biological functions defined in Section 4.7.3. Subject listings of 
laboratory measurements that meet treatment-emergent PCSV criteria will be provided. 
 
5.8.4. 
Analysis of Vital Signs 
 
All collected vital sign measures (pulse rate, respiratory rate, sitting blood pressures, and 
temperature) will be will be explored through summaries of both the actual measurements (at 
both baseline and post-baseline) and the change from baseline measurements at each 
post-baseline scheduled visit.  Descriptive statistics include number of subjects, mean, median, 
standard deviation, minimum, Q1, Q3, and maximum values for each treatment group.  In 
addition, body weight will be summarized in the same fashion. 
 
The obtainment of blood pressure in infants, without cause or suspicion of underlying 
abnormalities is not routinely done in the outpatient pediatric setting.  Specialized equipment, not 
routinely present in pediatric physician offices, is required.   As a result of the issues surrounding 
the accurate obtainment of blood pressures in the study’s infant population, the study protocol 
was revised to allow investigators to record that blood pressures are not able to be obtained.  In 
many instances blood pressure results are not available, and in instances where results have been 
obtained, the accuracy of the recordings can be questioned.  As a result, no shift table or 
treatment-emergent PCSV analyses will be performed on blood pressure measurements. 
 
The protocol allows for the measurement of subject temperature using different modalities, 
eg, temporal, axillary, rectal and tympanic.  Temperatures measured using different modalities 
are not equivalent and conversions are necessary to allow comparison.  Furthermore, as the child 
ages throughout their time participating in the study, elevations in temperature that would be of 
concern change.  Therefore due to the complexities to standardize reporting of temperatures and 
to accommodate changes reflecting the age of the child over time, no shift table or 
treatment-emergent PCSV analyses will be performed on temperature measurements. 
 
Only the number (and percentage) of subjects with pulse rate and respiratory rate values meeting 
the treatment-emergent PCSV criteria at least once during the TEAE period will be summarized. 
Subject listings of vital sign measurements that meet treatment-emergent PCSV criteria will be 
provided. 
 
5.8.5. 
Physical Exams 
 
The number (n) and percentage (%) of subjects with abnormal physical examination at baseline 
and each scheduled post-baseline assessment will be summarized for each treatment group. 


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5.9. 
Analysis of Pharmacokinetic and Antibody Data 
 
The analyses in this section will be performed by the Bioanalytical or Pharmacometrics groups. 
 
5.9.1. 
Analysis of Pharmacokinetic Data 
 
Concentration data will be summarized by descriptive statistics at each nominal time point. 
Pooled individual data and mean REGN2222 concentration-time plots will be produced. 
 
These data may be utilized in a population PK analysis. If conducted, results be reported 
separately. 
 
5.9.2. 
Analysis of Anti-drug Antibody Variables 
 
Listings of ADA positivity and titers will be presented by subject and time point.  Prevalence of 
ADA including treatment-emergent and treatment-boosted ADA will be assessed as absolute 
occurrence (n) and percent (%) of subjects. 
 
ADA titer levels and persistent ADA will also be evaluated. 
 
Possible correlation between changes in drug concentration and ADA assay response will be 
evaluated.  Additionally, possible correlation between ADA assay response and safety or 
efficacy will also be assessed. 
 
5.10. 
Analysis of Pharmacodynamic/Genomics Variables 
 
Pharmacogenomic analysis of subject genetic variants associated with adverse events or efficacy 
may also be performed. Statistical plan for subject genetic analysis will be described in a 
separate document. 
 
5.11. 
Analysis of RSV RT-PCR Data 
 
The number (and percentage) of subjects with at least one nose swab collected and of subjects 
with at least one RSV positive nose swab will be summarized respectively for the FAS by 
treatment group. 
 
A listing of local laboratory RSV RT-PCR assay results that were used to incur a primary 
endpoint event will be provided. 
 
5.12. 
Analysis of Multiplex Respiratory Pathogen RT-PCR Data 
 
Nose swab specimens tested negative on the RSV Lyra RT-PCR assay will be tested on the 
multiplex RT-PCR respiratory panel for alternative etiologies of RSV-negative respiratory tract 
infections. 
 
The number and percentage of subjects with non-RSV medically attended respiratory illness (as 
defined in Section 5.7.5.3) who tested positive for any and each type of non-RSV pathogen on 
the RT-PCR multiplex respiratory panel will be summarized by treatment group. The 
denominator used to calculate percentage will be the number of FAS subjects in each treatment 
group. 


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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 last 
chronologically available valid measurement taken prior to the administration of the first dose of 
study drug.  For most variables, Day 1 procedures and assessments are considered to be baseline. 
For variables such as ADA, samples collected at the screening visit will be considered to be 
baseline. 
 
6.2. 
Data Handling Convention for Efficacy Variables 
 
Rules for handling missing data for primary and secondary efficacy variables are described in 
Section 4.6.1 and Section 4.6.2. 
 
For other secondary variables, missing data will not be imputed, that is, only observed data will 
be included in the descriptive summaries. 
 
6.3. 
Data Handling Convention for Missing Data 
 
Adverse event 
 
If the severity/toxicity grade of a TEAE is missing, it will be classified as “severe” in the 
frequency tables by severity of TEAEs.  If the assessment of relationship of a TEAE to the study 
drug or injection procedure is missing, it will be classified as related to the study drug or 
injection procedure. 
 
Handling of medication missing/partial dates 
 
No imputation of medication start/end dates or times will be performed.  If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior, concomitant, and post-treatment medication. 
 
Handling of adverse events with missing or partial date/time of onset, worsening, seriousness 
 
Missing or partial AE dates and times will be imputed so that if the partial AE date/time 
information does not indicate that the AE started prior to treatment or after the TEAE period, the 
AE will be classified as treatment-emergent.  These data imputations are for categorization 
purpose only and will not be used in listings.  No imputation is planned for date/time of AE 
resolution. 
 
Baseline definition if “time” of the administration of study drug or time of assessment at Day1 
visit is missing 
 
If time of the administration of study drug or time of assessment at Day 1 visit is missing, then 
the baseline value is defined as the last available value obtained before or on the day of the study 
drug administration. 


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Laboratory Safety Variables 
 
For central laboratory data below the lower limit of quantification (LLOQ), half of the lower 
limit value (ie, LLOQ/2) will be used for quantitative analyses.  For central laboratory data 
above the upper limit of quantification (ULOQ), the upper limit value (ie, ULOQ) will be used 
for quantitative analyses. 
 
6.4. 
Visit Windows 
 
Visit windows will be programmatically imposed on those safety measures repeatedly collected 
over the course of the study. These visit windows are derived from the number of days in study, 
specifically assigning day ranges to mimic the study assessment schedule provided in the 
protocol. Data analyzed by time point (including laboratory safety data, vital signs, physical 
exam) will be summarized using the analysis windows given in Appendix 11.3. These analysis 
windows will be applicable for the aforementioned safety analyses, and they are defined to 
provide more homogeneous data for time point-specific analyses. If multiple valid values of a 
variable exist within an analysis window, the nearest from the targeted study day will be 
selected. If the difference is a tie, the value after the targeted study day will be used. If multiple 
valid values of a variable exist within the same day, then the first value of the day will be 
selected when time is available, or the scheduled visit will be selected. 
 
6.5. 
Unscheduled Assessments 
 
For safety laboratory data, vital signs, and physical exams, unscheduled visit measurements may 
be used to provide a measurement for a time point, a baseline, a last, or a worst value, if 
appropriate according to their definitions.  The measurements may also be used to determine 
abnormal values and treatment-emergent PCSVs. 
 
6.6. 
Pooling of Centers for Statistical Analyses 
 
The randomization scheme was not stratified by center because the RSV infection component of 
the primary efficacy variable is centrally assessed and expected not to be influenced by the 
center when other factors such as gestational age are already controlled.  Therefore, the center 
will not be added as a factor in the primary analysis model. 
 
6.7. 
Statistical Technical Issues 
 
Not applicable. 


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7. 
INTERIM ANALYSIS 
 
Sample size re-estimation based on the blinded and pooled event rate and hypothesized treatment 
effect was designed for the originally planned sample size and was allowed to be proposed at the 
end of each RSV season according to the study protocol Section 9.2.1.  This blinded sample size 
re-estimation has not been performed for this study. 
 
A study treatment unblinding interim efficacy analysis is not planned. 
 
 
8. 
TIMING OF STATISTICAL ANALYSIS 
 
Efficacy and safety analyses for this study will be performed in two steps, specifically for subject 
data collected up to the time the last subject completes efficacy assessments at Day 150 visit 
(step 1) and at the end of the study Day 237 visit (step 2).  No formal interim analysis for 
efficacy is planned since analyses of primary and secondary efficacy endpoints will be final at 
the time of first step analysis.  Therefore, no multiplicity adjustment for multiple analyses is 
needed (see Section 5.7.3).  The timing for subject data to be reported is defined below for each 
step: 
 
• First step: efficacy analyses through Day 150 visit and interim safety analysis 
 
− This analysis will be conducted on all randomized subjects when all subjects will 
have all their efficacy data up to Day 150 visit collected and validated. 
 
− The efficacy analyses will be performed up to Day 150 visit.  Analyses of 
endpoints up to Day 150 visit will correspond to the final analyses for these 
endpoints. 
 
− The safety analyses will be performed on all safety data collected up to the 
common cut-off date.  For this analysis, the common cut-off date is defined as 
date of the last Day 150 visit. 
 
• Second step: final safety analysis 
 
− This analysis will be conducted at the end of the study and will consist of the final 
safety analysis. 
 
Individuals involved in the first step analysis of the study will not be involved in the conduct of 
the study afterwards; individual subject identification will not be released to anyone who is 
directly involved in the conduct of the study.  The first step analysis process, the measures used 
to protect the blind and the integrity of the study, the communication plan, and the 
confidentiality agreement will be described in a separate document.  The results of the first 
analysis will not be used to change the conduct of the ongoing study in any aspect.  The first 
analysis will be used for planning the design of a separate efficacy study and communication 
with health authorities. 


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Analysis methods and conventions described in the other sections of this SAP will be applied for 
all analyses as applicable. The following additional rules will apply to analyses performed at first 
step analysis: 
 
• Any efficacy assessments up to Day 150 visit will be taken into account. 
 
• Subjects with EOS visit (ie, Day 237 visit) yet to be performed at the time of the 
cut-off date will be considered as ongoing and followed up to the cut-off date for the 
purpose of safety analyses. Therefore: 
 
− Subjects who did not complete Day 237/EOS (or early termination) visit at cut-off 
date will be analyzed as “ongoing” in the disposition summary. 
 
− Their TEAE period and on-study observation period will end at the cut-off date. 
 
− Their on-study observation period duration will be derived by considering date of 
cut-off as last study visit date. 
 
• AEs occurring, worsening or becoming serious after the cut-off date will not be 
included in the analyses.  However, any available outcome before database lock, 
regardless of timing in relation to the cut-off date, of an adverse event starting prior to 
the cut-off date will be taken into account.  Medications and deaths occurring after 
the cut-off date will not be included in the analyses. 
 
 
9.            SOFTWARE 
 
All clinical data analyses will be done using SAS Version 9.2 and above. 


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10. 
REFERENCES 
 
Ambrose CS, Anderson EJ, Simoes EA, et al. Respiratory syncytial virus in preterm infants in 
the U.S. born at 32-35 weeks gestation not receiving immunoprophylaxis. Pediatr Infect Dis J. 
2014;33(6):576-82. 
 
Carbonell-Estrany X, Simões EA, Dagan R, et al. Motavizumab for prophylaxis of respiratory 
syncytial virus in high-risk children: a noninferiority trial. Pediatrics. 2010; 125(1): e35-51. 
 
Hall CB, Weinberg GA, Iwane MK, et al. The burden of respiratory syncytial virus infection in 
young children. N Engl J Med. 2009;360(6):588-98. 
 
ICH. (1996, July 30). ICH Harmonized tripartite guideline: Structure and content of clinical 
study reports (E3). International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. 
 
ICH. (1997, July 17). ICH Harmonized tripartite guideline: General considerations for clinical 
trials (E8). International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. 
 
ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for clinical 
trials (E9). International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. 
 
Ohuma EO, Okiro EA, Ochoia R, et al. The natural history of respiratory syncytial virus in a 
birth cohort: the influence of age and previous infection on reinfection and disease. Am J 
Epidemiol. 2012;176(9):794-802. 
 
Feltes TF, Sondheimer HM, Tulloh RM, et al. A randomized controlled trial of motavizumab 
versus palivizumab for the prophylaxis of serious respiratory syncytial virus disease in children 
with hemodynamically significant congenital heart disease. Pediatr Res. 2011; 70(2): 186-91. 
 
Shapiro AM. FDA Core Presentations, (BLA) 125283, motavizumab, for the June 2, 2010 
Meeting of the Antiviral Drugs Advisory Committee. 
 
Wingerter S, Bachur R, Monuteaux M, et al. Application of the World Health Organization 
Criteria to Predict Radiographic Pneumonia in a US-based Pediatric Emergency Department. The 
Pediatric Infectious Disease Journal. 2012; 31(6):561-564. 


Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol: REGN2222-RSV-1332 
Date: July 28, 2017 
CONFIDENTIAL 
Page 51 of 58 
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11. 
APPENDIX 
 
11.1. 
Summary of Statistical Analyses 
 
Primary and Secondary Efficacy Analyses: 
 
Endpoint 
Analysis 
Populations 
Primary Analysis 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Primary Endpoint 
Proportion of subjects with a 
medically attended RSV 
infection (hospitalization or 
outpatient LRTI) during the 
150-day efficacy assessment 
period. 
FAS 
Proportion difference 
CMH statistics with 
randomization stratum 
adjusted by the Mantel- 
Haenzel (MH) method 
Yes 
Fisher’s exact test; 
Logistic regression; 
Time to first event; 
Missing data handling 
Yes 
Stratification; 
RSV LRTI; 
Alternative LRTI 
Definition 
Secondary Endpoint 
Proportion of subjects with a 
medically attended RSV 
infection (hospitalization or 
outpatient LRTI) during the 
150-day efficacy assessment 
period. 
FAS 
Proportion difference 
CMH statistics with 
randomization stratum 
adjusted by the Mantel- 
Haenzel (MH) method 
Yes 
Fisher’s exact test; 
Logistic regression; 
Time to first event; 
Missing data handling 
Yes 
Stratification 


CONFIDENTIAL 
Page 52 of 58 
VV-RIM-00020534-1.0 Approved - 01 Aug 2017 GMT-5:00 
Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol: REGN2222-RSV-1332 
Date: July 28, 2017 
 
 
 
 
11.2. 
Schedule of Time and Events 
 
Study Periods 
SV1 
BV 
Treatment Period 
Postdose Follow-Up 
Visit 
1 
2 
3 
4 
5 
6 
7/ET 
817 
917 
10/EOS17 
Day 
-28 to -1 
1 
29±2 
57±2 
85±5 
113±5 
150±5 
178±10 
206±10 
237±10 
Informed Consent18 
X 
Inclusion/Exclusion 
X 
X 
Medical History 
X 
Demographics 
X 
Randomization2 
X 
Dispense Medical Information Packet3 
X 
Administer Study Drug4 
X5 
X5 
Concomitant Medications and Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs6 
X 
X 
X 
X 
X 
X 
X 
Physical Examination (including weight) 
X 
X7 
X 
X7 
X 
X 
Adverse Events8 
X 
X9 
X9 
X9 
X9 
X9 
X9 
X9, 17 
X9, 17 
X9, 17 
Blood Sampling 
Hematology 
X10-14 
X10 
X11 
X12 
X13 
X10-14 
Blood Chemistry 
X10-14 
X10 
X11 
X12 
X13 
X10-14 
Pharmacokinetics 
X10 
X11 
X12 
X13 
X10-14 
Anti-REGN2222 (ADA) 
X10-14 
X10 
X11 
X\12 
X13 
X10-14 
Optional Substudy Informed Consent 
X 
Optional DNA Sample 
X15 
Pharmacoeconomic Information16 
X 
X 
X 
X 
X 
X 
ADA=antidrug antibody; BV=baseline visit, EOS/ET=end of study/early termination; IM=intramuscular; SV=screening visit; X=all subjects unless otherwise 
specified 
1. All safety assessments performed at screening must be normal and checked against the inclusion/exclusion criteria before REGN2222 administration on 
Day 1(baseline) 
2. Subject randomization and blood collection schedules are assigned using the interactive voice response system (or interactive web response system) at 
Visit 2. Depending on the availability of the study pharmacist or designee, subjects may be randomly assigned on Day -1 or Day 1. 


CONFIDENTIAL 
Page 53 of 58 
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Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol: REGN2222-RSV-1332 
Date: July 28, 2017 
 
 
 
3. When parent(s) or guardian(s) take their child for medical attention outside of the study site, the parents/guardians are instructed to take the Medical 
Information Packet with them for use by their healthcare provider. Data on medically attended RSV infections will be collecte d for all subjects until 
Day 150. 
4. Subjects randomly assigned to the 30 mg/kg Q8w arm will receive REGN2222 on Day 1 and Day 57. Subjects randomly assigned to the single 
30 mg/kg arm will receive REGN2222 on Day 1 and placebo on Day 57. Subjects randomly assigned to the placebo arm will receive placebo on Day 1 
and Day 57. 
5. No other vaccinations will be administered within 2 days before or after dosing of the study drug. Subjects who have reached the primary endpoint 
should not receive additional doses of study drug. The study staff will contact the parent(s) or legal guardian(s) by telepho ne at the end of each dosing 
day and daily over 48 hours following a dose to inquire about any change in the subject’s status. 
6. On study drug dosing days, vital signs when the child is calm (temperature, blood pressure, pulse, and respiration) will be a ssessed prior to blood sample 
collection, prior to injection of study drug, and 1 hour (±10 minutes) after completion of the injection. If a subject’s rectal temperature is 101°F (38.3°C) 
or greater on the day of a planned dose administration day, no dosing will occur (see Section 6.3.1.1 of protocol for temperature conversions). The 
subject will be re-evaluated within 48 hours and if the subject’s temperature is below 101°F (38.3°C) without the use of antipyretics during the previous 
48 hours, the schedule of assessments may be resumed. If the subject’s temperature is 101°F (38.3°C) or greater or the subject has received antipyretics 
in the previous 48 hours, dosing of the subject will be permanently discontinued. 
7. Physical examinations will be conducted before injection and after injection, prior to discharge, from the clinic at Visit 2 and Visit 4. Weight collection 
is not required post-injection. 
8. If the adverse event is considered a hypersensitivity or anaphylaxis reaction, then the adverse event will be assessed at as outlined in Protocol Table 4. 
9. If the adverse event is a hypersensitivity reaction that results in a rash, then a photo will be taken as part of the adverse event assessment (also see 
Protocol Table 4). 
10.  The subjects with Schedule M will have the following collected: hematology/chemistry samples at screening, Day 29, and Day 150/ET; PK samples at 
Day 29 and Day 150/ET; and ADA samples at screening, Day 29, and Day 150/ET. 
11.  The subjects with blood collection Schedule L will have the following collected: hematology/chemistry samples at screening, Day 57 (predose), and 
Day 150/ET; PK samples at Day 57 (predose) and Day 150/ET; and ADA samples at screening, Day 57 (predose), and Day 150/ET. 
12.  The subjects with blood collection Schedule K will have the following collected: hematology/chemistry samples at screening, Day 85, and Day 150/ET; 
PK samples at Day 85 and Day 150/ET; and ADA samples at screening, Day 85, and Day 150/ET. 
13.  The subjects with blood collection Schedule J will have the following collected: hematology/chemistry samples at screening, Day 113, and Day 150/ET; 
PK samples at Day 113 and Day 150/ET; and ADA samples at screening, Day 113, and Day 150/ET. 
14.  The subjects with blood collection Schedule I will have the following collected: hematology/chemistry samples at screening and Day 150/ET; PK 
samples at Day 150/ET; and ADA samples at screening and Day 150/ET. 
15.  After substudy consent, the cheek swab for DNA in the optional substudy can be obtained at any time during the study period, but preferably at baseline. 
16.  If the subject experiences a medically attended respiratory infection since the previous scheduled visit, then the parent(s) or guardian(s) will be asked to 
provide additional pharmacoeconomic information on the event. 
17.  Visits 8, 9, and 10 will be done by telephone contact. In the event an AE is reported during a phone call visit, an unscheduled onsite visit may be 
required to follow-up, per investigator. 
18.  Informed consent may be obtained from the parent(s) or legal guardian(s) up to 28 days prior to randomization. Consent can occur outside the screening 
visit or on the same day as the screening visit, but must occur prior to the screening visit. 


Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol: REGN2222-RSV-1332 
Date: July 28, 2017 
CONFIDENTIAL 
Page 54 of 58 
VV-RIM-00020534-1.0 Approved - 01 Aug 2017 GMT-5:00 
 
 
 
11.3. 
Windows for Analysis Time Points 
 
Below are the definitions for the visit windows programmatically imposed on measures 
repeatedly collected over the course of the study.  These visit windows reflect the study schedule 
of assessments as described in the protocol.  The visit windows are constructed using ranges 
applied to the number of days in study (study days) when the measure is collected.  Day 1 is 
defined as the date of the first study drug administration, and is labeled as baseline for most 
variables.  Since the protocol specifies that measurements be collected before study drug is 
administered on a given day, it is appropriate that baseline include Day 1.  For randomized but 
not treated subjects, Day 1 is the day of randomization. 
 
Time point 
Target Week 
Target study day 
Analysis window in study days 
Visit 3 (Day 29) 
Week 4 
29 
15 to 42 
Visit 4 (Day 57) 
Week 8 
57 
43 to 71 
Visit 5 (Day 85) 
Week 12 
85 
72 to 99 
Visit 6 (Day 113) 
Week 16 
113 
100 to 132 
Visit 7 (Day 150) 
Week 21 
150 
133 to 164 


Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol: REGN2222-RSV-1332 
Date: July 28, 2017 
CONFIDENTIAL 
Page 55 of 58 
VV-RIM-00020534-1.0 Approved - 01 Aug 2017 GMT-5:00 
 
 
 
11.4. 
Criteria for Treatment-Emergent Potentially Clinically Significant 
Values (PCSV) 
 
Parameter 
PCSV 
Comments 
Clinical chemistry 
PCSV based on criteria for infants born at term, except for total bilirubin where specific criteria are available for 
pre-term infants, considering Grade 3 Severe and above events as per the Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and Pediatric Adverse Events Version 2.0 November 2014). 
ALT, high 
≥ 5 ULN and baseline < 5 ULN 
Albumin, low 
< 20 g/L and baseline ≥ 20 g/L 
AST, high 
≥ 5 ULN and baseline < 5 ULN 
Alkaline 
Phosphatase, high 
≥ 5 ULN and baseline < 5 ULN 
Calcium, high 
Meeting the following PCSV criteria for at least one 
post-baseline measurement and no PCSV at baseline 
≥ 3.13 mmol/L for ≥ 7 days of age 
≥ 3.23 mmol/L for < 7 days of age 
Calcium, low 
Meeting the following PCSV criteria for at least one 
post-baseline measurement and no PCSV at baseline 
<1.75 mmol/L for ≥ 7 days of age 
<1.50 mmol/L for < 7 days of age 
Carbon Dioxide, 
low 
<11.0 mmol/L and baseline ≥ 11.0 mmol/L 
Creatinine, high 
> 1.8 ULN and baseline ≤ 1.8 ULN, or 
Increase of 1.5 x above baseline 
Total Bilirubin, 
high 
Meeting the following PCSV criteria for at least one 
post-baseline measurement and no PCSV at baseline 
≥ 307.8 µmol/L for ≥35 weeks gestational age and < 7 
days of age 
≥ 171 µmol/L for 32 to < 35 weeks gestational age 
and < 7 days of age* 
≥ 102.6 µmol/L for 28 to < 32 weeks gestational age 
and < 7 days of age* 
≥ 85.5 µmol/L for < 28 weeks gestational age and 
< 7 days of age* 
≥ 342 µmol/L for 7 to 28 days of age 
≥ 2.6 x ULN for > 28 days of age 
*Criteria are specific for preterm 
infants 
Glucose, high 
≥ 13.89 mmol/L and baseline < 13.89 mmol/L 
Glucose, low 
< 2.22 mmol/L and baseline ≥ 2.22 mmol/L 
Potassium, high 
≥ 6.5 mmol/L and baseline < 6.5 mmol/L 
Potassium, low 
< 2.5 mmol/L and baseline ≥ 2.5 mmol/L 


Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol: REGN2222-RSV-1332 
Date: July 28, 2017 
CONFIDENTIAL 
Page 56 of 58 
VV-RIM-00020534-1.0 Approved - 01 Aug 2017 GMT-5:00 
 
 
 
Parameter 
PCSV 
Comments 
Sodium, high 
≥ 154 mmol/L and baseline < 154 mmol/L 
Sodium, low 
< 125 mmol/L and baseline ≥ 125 mmol/L 
Uric acid, high 
≥ 0.71 mmol/L and baseline < 0.71 mmol/L 
Hematology 
PCSV based on criteria for infants born at term, considering Grade 3 Severe and above events as per the Division of 
AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events Version 2.0 November 2014). 
WBC, Decreased 
Meeting the following PCSV criteria for at least one 
post-baseline measurement and no PCSV at baseline 
≤ 1.499 x 109 cells/L for > 7 days of age 
≤ 3.999 x 109 cells/L for ≤ 7 days of age 
Neutrophils, low 
Meeting the following PCSV criteria for at least one 
post-baseline measurement and no PCSV at baseline 
< 0.600 x 109 cells/L for > 7 days of age 
< 1.000 x 109 cells/L for 2 to 7 days of age 
< 3.000 x 109 cells/L for ≤ 1day of age 
Hemoglobin, low 
Meeting the following PCSV criteria for at least one 
post-baseline measurement and no PCSV at baseline 
< 6.19 mmol/L (100 g/L) for ≤ 7 days of age 
< 5.57 mmol/L (90 g/L) for 8 to ≤ 21 days of age 
< 4.94 mmol/L (80 g/L) for 22 to 35 days of age 
< 4.32 mmol/L (70 g/L) for 36 to 56 days of age 
< 5.25 mmol/L (85 g/L) for ≥ 57 days of age 
Platelets, 
decreased 
< 50.000 x 109 cells/L and baseline ≥ 50.000 x 109 
cells/L 
Vital signs 
PCSV based on normal ranges in http://health.ny.gov/professionals/ems/pdf/assmttools.pdf 
Respiratory Rate 
< 30 breaths per minute and ≥ 30 breaths per minute 
at baseline 
> 60 breaths per minute and ≤ 60 breaths per minute 
at baseline 
Pulse Rate 
< 100 beats per minute and ≥ 100 beats per minute at 
baseline 
> 160 beats per minute and ≤ 160 beats per minute at 
baseline 


Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol: REGN2222-RSV-1332 
Date: July 28, 2017 
CONFIDENTIAL 
Page 57 of 58 
VV-RIM-00020534-1.0 Approved - 01 Aug 2017 GMT-5:00 
 
 
 
11.5. 
Hypersensitivity PTs of interest per Carbonell-Estrany X et al. 
 
Non-Specific PTs 
Specific PTs 
Erythema 
Anaphylactoid reaction 
Flushing 
Angioedema 
Pruritus 
Dermatitis allergic 
Rash 
Drug eruption 
Rash erythematous 
Drug hypersensitivity 
Rash macular 
Oedema 
Rash maculo-papular 
Erythema annulare 
Rash pruritic 
Erythema marginatum 
Erythema multiforme 
Eye swelling 
Eyelid oedema Face 
oedema 
Hypersensitivity 
Injection site erythema 
Laryngeal oedema 
Lip swelling 
Periorbital oedema 
Rash generalised 
Swelling 
Swelling face 
Tracheal oedema 
Urticaria 
  
Urticaria papular  
 
Note: The following terms listed in Carbonell-Estrany’s manuscript are LLTs that code into PTs as follows: 
LLT: Angioneurotic oedema codes to PT: Angioedema 
LLT: Exanthema codes to PT: Rash 
LLT: Urticaria generalised codes to PT: Urticaria. 


Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol: REGN2222-RSV-1332 
Date: July 28, 2017 
11.6. 
Hypersensitivity PTs of interest per Feltes TF et al. 
Non-Specific PTs 
Specific PTs 
VV-RIM-00020534-1.0 Approved - 01 Aug 2017 GMT-5:00 
 
 
Erythema 
Allergic oedema 
Fixed Drug Eruption 
Anaphylactoid reaction 
Generalised oedema 
Angioedema 
Pruritus 
Bronchial oedema 
Pruritus generalised 
Circumoral oedema 
Rash 
Dermatitis allergic 
Rash erythematous 
Drug eruption 
Rash macular 
Drug hypersensitivity 
Rash maculo-papular 
Erythema annulare 
Rash papular 
Erythema marginatum 
Rash pruritic 
Erythema multiforme 
Eye oedema 
Eye swelling 
Eyelid oedema 
Face oedema 
Flushing 
Generalised Erythema 
Hypersensitivity 
Laryngeal oedema 
Laryngotracheal oedema 
Lip oedema 
Lip swelling 
Oedema 
Oedema mouth 
Oropharyngeal swelling 
Periorbital oedema 
Pharyngeal oedema 
Pharyngeal ulceration 
Pruritus allergic 
Rash generalised 
Skin swelling 
Swelling 
Swelling face 
Swollen tongue 
Tongue oedema 
Tracheal oedema 
  
Urticaria  
 
Note: The following terms listed in Feltes TF’s manuscript are LLTs that code into PTs as follows: 
LLT: Angioneurotic oedema codes to PT: Angioedema 
LLT: Fixed Eruption codes to PT: Fixed Drug Eruption 
LLT: Urticaria generalised codes to PT: Urticaria 
 
 
 
 
CONFIDENTIAL 
Page 58 of 58 


VV-RIM-00020534-1.0 Approved - 01 Aug 2017 GMT-5:00 
 
 
 
 
 
Signatu re Page for VV-RIM-00020534 v 1.0 
 
 
Approval 
Approval 
Approval 
Approval 
Approval 
 
 
 
 
 
Signature Page for VV-RIM-00020534 vl.O Approved 

Prot_000.pdf: 
Clinical Study Protocol 
R2222-RSV-1332.04 
Regeneron Pharmaceuticals, Inc. 
Page 1 of 137 
CONFIDENTIAL 
VV-RIM-00012444-1.0 Approved - 11 Apr 2017 GMT-5:00 
 
 
 
 
IND Number 120003 
EudraCT Number: 2015-001714-96 
Regeneron Pharmaceuticals, Inc. 
NCT02325791 
 
Clinical Study Protocol 
 
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY 
EVALUATING THE EFFICACY AND SAFETY OF A HUMAN MONOCLONAL 
ANTIBODY, REGN2222, FOR THE PREVENTION OF MEDICALLY ATTENDED 
RSV INFECTION IN PRETERM INFANTS 
 
 
 
Compound: 
REGN2222 
 
Clinical Phase: 
3 
 
 
 
 
Protocol Number: 
R2222-RSV-1332 
 
Protocol Version: 
R2222-RSV-1332.04 
 
Amendment 4 Date of Issue: 
See appended electronic signature page 
 
Amendment 3 Date of Issue: 
16 MAR 2016 
 
Amendment 2 Date of Issue: 
8 JUL 2015 
 
Amendment 1 Date of Issue: 
21 APR 2015 
 
Original Date of Issue: 
18 DEC 2014 
 
 
 
 
Scientific/Medical Monitor: 
 
 
Senior Director, Clinical Sciences 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 


Clinical Study Protocol 
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Regeneron Pharmaceuticals, Inc. 
Page 2 of 137 
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VV-RIM-00012444-1.0 Approved - 11 Apr 2017 GMT-5:00 
 
 
 
 
 
 
 
 
Amendment 4 
AMENDMENT HISTORY 
 
The purpose of this amendment is: 
 
• To revise the approach of handling of missing data in the primary efficacy analysis 
. Specifically, the new statistical approach will directly 
impute missing data at Day 150 visit. For those subjects who died prior to Day 150 and 
the deaths are adjudicated to be RSV related, their missing primary endpoint will be 
imputed as “event occurred”. Remaining early termination subjects (including non-RSV 
deaths) across all treatment groups, will be imputed to the average placebo score 
(estimated placebo event rate). The approach to estimating the placebo event rate is the 
Kaplan-Meier estimate at Day 150. 
 
Rationale: To take into consideration the possibility of a study subject 
contracting RSV when addressing missing data in the primary efficacy analysis 
for a study subject that doesn’t complete Day 150 follow-up due to early 
termination. 
 
Enrollment into the study will end with the 2016-2017 RSV season in the Northern Hemisphere 
due to the Sponsor’s administrative decision.  The expected enrollment will be approximately 
1200 infants resulting in a smaller sample size for analysis.  The 2 following changes are a result: 
 
• Added power calculation for anticipated smaller sample size. 
 
Rationale:   To understand the impact of the reduced study enrollment on the 
primary efficacy analysis. 
 
• Revised statistical approach to controlling the overall type I error for the primary efficacy 
analysis. 
 
Rationale: To retain sufficient study power for the primary efficacy endpoint 
given the reduced sample size. 
 
Other Changes to the Statistical Plan include: 
 
• To remove complete and worst-case sensitivity analyses. 
 
Rationale: The complete analysis uses only data of a subset of subjects, thus 
results are not generalizable to the subject population. The worst-case analysis 
may unrealistically inflate the primary endpoint event rate above the expected 
small event rate in this subject population. 
 
• To clarify timing of statistical analyses. Specifically, the efficacy analysis will be 
conducted following completion of the 150-day efficacy assessment period by all 
subjects. This will represent the final analysis of all efficacy endpoints. 
 
Rationale: Due to the time sensitivity of future study initiation, this will support 
timely initiation of such studies and avoid long delays waiting for the start of a 
RSV season. 


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Page 3 of 137 
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VV-RIM-00012444-1.0 Approved - 11 Apr 2017 GMT-5:00 
 
 
 
 
Other changes include: 
 
• To add assessment of negative RSV nose swab specimens for other common respiratory 
pathogens. 
 
Rationale: 
to assess common respiratory 
pathogens, in addition to RSV, in clinical development. 
 
• To add text to clarify what is meant by “reached primary endpoint” when determining if 
the second dose of study drug should be administered, ie only those subjects who have 
had a positive RT-PCR test at the study central laboratory or at a CLIA-certified (or 
equivalent) laboratory after receipt of Dose #1 of study drug, but prior to receipt of Dose 
#2 should not receive Dose #2. 
 
Rationale: To clarify those subjects who should not receive a second dose of study 
drug at Visit 4, due to reduced potential for benefit. 
 
• To clarify that the symptom of chest wall indrawing used in the definition of the study 
primary endpoint is to be considered as lower chest wall indrawing. 
 
Rationale: To align the protocol with the eCRF and our communication with 
investigators, eg Investigator’s Meeting, on this topic. The Sponsor considers that 
chest wall indrawing and lower chest wall indrawing are implicitly the same; 
chest wall indrawing is the inward movement of the lower chest wall. 
 
• To clarify wording related to pediatric clinic visits. 
 
Rationale: To provide more explicit examples of the types of visits to be 
considered as "outpatient medically attended visits" or "pediatric clinic visits". 
This information has been collected in the eCRF, but clarifications are made in 
response to different interpretations noted by investigators as to how they are 
capturing data within the eCRF. 
 
• To clarify information collected during the Visit 2 (Baseline and First Dosing Visit, 
Day 1) to assess Risk Factors. 
 
Rationale: This information has always been collected at Visit 2 [per the EDC], 
but details are being added to clarify. 
 
• To clarify text related to follow up in the Study Enrollment and Assessment section. 
 
Rationale: To clarify that the follow up period for the occurrence of medically 
attended respiratory illnesses will continue only until the end of the 150-day study 
period. 
 
• To add text related to the Endpoint Adjudication Committee assessment of subject deaths 
after the first dose of study drug as RSV-related or not. 
 
Rationale: Text was added that any subject deaths that occur after the 
administration of the first dose of study drug and prior to Day 150 will be 
assessed to determine their association with RSV for purposes of determining 
handling in revised approach to missing data. 


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Page 4 of 137 
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VV-RIM-00012444-1.0 Approved - 11 Apr 2017 GMT-5:00 
 
 
 
 
• To clarify, in the Temperature/Safety Procedures Section, the specifics related to the 
restrictions to dosing of febrile subjects and use of antipyretics, including allowance for 
re-evaluation within 48 hours. 
 
Rationale: Provide clarity from previous versions of the protocol and to make 
consistent within all sections of the protocol. 
 
• To clarify, in Table 2, that two vital signs assessments (temperature, blood pressure, 
pulse, and respiration) will be performed on dosing days, before study drug 
administration (or blood draw, if applicable) and after. 
 
Rationale: Provide clarity from previous versions of the protocol. 
 
• To correct the definition of high titer to >10 000 in the Antidrug Antibody Section. 
 
Rationale: Correction of typographical error from previous versions of the 
protocol, which had omitted one "0". 
 
• To clarify that safety and tolerability will also be descriptively summarized in the 
combined REGN2222 treatment arms 
 
Rationale: Provide clarity from previous versions of the protocol. 
 
• To clarify wording in the Investigator Alert Notification Section that investigators will be 
notified in a blinded fashion of any SAE that possibly meets the relevant requirements for 
expedited reporting. 
 
Rationale: Updated wording to add that the notification will be blinded as per 
risk management and pharmacovigilance procedures. 
 
• To clarify wording in the Demographic and Baseline characteristics section related to 
pharmacoeconomics and risk factor assessment. 
 
Rationale: Provide clarity from previous versions of the protocol. 
 
• To update wording for the safety variables in Part B related to the definitions for the 3 
observation periods. 
 
The PRE-TREATMENT period is defined as the time from signing the ICF to 
before the first dose of study drug. 
 
The SAFETY-TREATMENT period is defined as the time from the first dose of 
study drug up to the day of the last dose of study drug + 180 days. 
 
The POST-TREATMENT period: defined as starting the day after the end of the 
TEAE period. 
 
Rationale: Provide clarity from previous versions of the protocol. 
 
• To clarify that the definition of treatment-emergent AEs in Part B are defined as those 
that are not present at baseline or represent the exacerbation of a preexisting condition 
during the SAFETY-TREATMENT period (TEAE period). 
 
Rationale: Provide clarity and consistency in language from previous versions of 
the protocol. 


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Page 5 of 137 
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VV-RIM-00012444-1.0 Approved - 11 Apr 2017 GMT-5:00 
 
 
 
 
• To clarify that the additional evaluation of TEAEs may be conducted for identification of 
hypersensitivity. 
 
Rationale: Added for safety evaluation. 
 
• To clarify that an unblinding interim efficacy analysis is not planned. 
 
Rationale: Provide clarity from the previous version. 
 
• To update the scientific/medical monitor 
 
Rationale: The name of the Scientific/Medical Monitor was updated due to 
organizational changes in scope of responsibilities. 
 
• To make minor edits and clarifications and remove redundancy 
 
Rationale: Editing purposes. 
 
The table that follows outlines both the changes described in the bullet points above and 
changes/clarifications made throughout the protocol and the affected sections. 
 
Change 
Sections Changed 
Changes in text related to the impact of early termination 
resulting in reduced sample size. 
Updated text related to multiplicity considerations. 
Section 9.2 Sample Size 
Section 9.5.2.4 Multiplicity Considerations 
Updated text to reflect the handling of missing data for 
efficacy analyses 
Removed complete and worst-case sensitivity analyses 
Clinical Study Protocol Synopsis 
Section 9.5.2.1 Primary Efficacy Analysis 
Clarify timing of statistical analyses and break down of 
statistical analysis into 2 steps. 
Clinical Study Protocol Synopsis 
Section 5.4.2.1 . Blinding 
Section 9.5.6 Timing of Statistical Analses 
Section 9.5.6.1 First Step: Efficacy and Safety Analysis 
Section 9.5.6.2 Second Step: Final Safety Analysis 
To clarify that the symptom chest wall indrawing refers 
to the lower chest wall that is indrawing. 
Clinical Study Protocol Synopsis 
Section 8.2 Primary Endpoints 
Section 9.5.2.1 Primary Efficacy Analysis 
Clarify that safety and tolerability will also be 
descriptively summarized in the comnined REGN2222 
treatment arms 
Section 9.5.3.2 Part B 
Section 9.5.3.5 Treatment Exposure 


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Change 
Sections Changed 
Clarify that the blinded sample size re-estimation was 
never performed during the study, nor is re-estimation 
planned during the remainder of the study since 
enrollment will end with the 2016/2017 RSV season in 
the Northern Hemisphere due to Sponsor’s 
administrative decision. 
Clarify that an unblinding interim efficacy analysis is 
not planned 
Clinical Study Protocol Synopsis 
Section 9.6.2 Part B 
Added a bullet : To detect and identify the presence of 
other common respiratory pathogens from RSV negative 
nose swab specimens collected from subjects. 
Added text to note that additional testing for other 
common respiratory pathogens is only conducted with 
RSV-negative swabs and will not be used in the primary 
analyses of the primary and secondary efficacy 
endpoints. 
Added an exploratory endpoint: Number and proportion 
of subjects with other common respiratory pathogens 
identified by a RT-PCR multiplex respiratory panel 
which is distinct from the RT-PCR assay being used to 
test for RSV for the study's efficacy endpoints. 
The multiplex evaluation will only be conducted on 
RSV negative swabs collected from subjects and will not 
be used in the primary analyses of the primary and 
secondary efficacy endpoints. 
Clinical Study Protocol Synopsis 
Section 2.3 Exploratory Objectives 
Section 8.4 Exploratory Endpoints 
Section 6.3.3.3 Virology Testing 
Section 9.5.2.3 Exploratory Analysis 
Clarified wording and added a footnote relating to 
pediatric clinic visits: “A pediatric clinic visit represents 
any outpatient medically attended visit that could 
include, but is not limited to, a pediatric clinic visit, a 
primary physician office visit, a family physician visit, 
or a study site visit” 
Clinical Study Protocol Synopsis 
Section 2.2 Secondary Objectives 
Section 6.2.3 Part B: Unscheduled Visit for Potential 
Respiratory Illness 
Section 6.5 Pharmacoeconomic Measurement 
Procedures 
Section 8.2 Primary Endpoints 
Section 8.3 Secondary Endpoints 
Section 8.4 Exploratory Endpoints 


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Change 
Sections Changed 
Added a bullet detailing the risk factor information that 
is collected during Visit 1. 
Minor edits and added text related to 
pharmacoeconomics data (risk factors). 
Details of risk factor information collected at Visit 1 was 
added to more completely describe current practice. 
Table 2 Part B: 30 mg/kg IM (Maximum 1 Dose 
REGN2222 and Maximum 1 Dose Placebo); 30 mg/kg 
IM (Maximum 2 Doses REGN2222); or Placebo IM 
(Maximum 2 Doses); for Subjects with Schedules I 
through M 
Section 6.2.2.2 Visit 2 (Baseline and First Dosing Visit, 
Day 1) 
Section 8.1 Demographic and Baseline Characteristics 
Clarified text related to the follow-up period as: 
The follow-up period for the occurrence of medically 
attended respiratory illnesses will continue until the end 
of the 150-day study period. 
Section 3.1.2.3 Study Enrollment and Assessments 
Added text related to the handling of any subject deaths 
occurring after the first dose of study drug by the 
Endpoint Adjudication Committee 
Section 3.3.3. Endpoint Adjudication Committee 
Temperature: Text was added to clarify that dosing may 
proceed only if the subject is afebrile without the use of 
antipyretics and that these subjects would be followed in 
the study for safety and efficacy if at least one dose of 
study drug was administered. 
Section 6.2.2.2 Visit 2 (Baseline and First Dosing Visit, 
Day 1) 
Section 6.2.2.4 Visit 4 (Second Dosing Visit, Day 57±2 
Days) 
Section 6.3.1.1 Temperature 
Table 2 Part B: 30 mg/kg IM (Maximum 1 Dose 
REGN2222 and Maximum 1 Dose Placebo); 30 mg/kg 
IM (Maximum 2 Doses REGN2222); or Placebo IM 
(Maximum 2 Doses); for Subjects with Schedules I 
through M, footnote #6 
Vital signs: The text related to taking vital signs before 
and after dosing was clarified. 
Section 6.2.2.2: Visit 2 (Baseline and First Dosing Visit, 
Day 1) 
Table 2 Part B: 30 mg/kg IM (Maximum 1 Dose 
REGN2222 and Maximum 1 Dose Placebo); 30 mg/kg 
IM (Maximum 2 Doses REGN2222); or Placebo IM 
(Maximum 2 Doses); for Subjects with Schedules I 
through M, footnote #6 
The definition for High ADA titer was corrected from 
>1000 to > 10000 
Section 8.5 Antidrug Antibody Variables 


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Change 
Sections Changed 
Updated to clarify that notification will be blinded as per 
risk management and pharmacovigilance procedures. 
Section 7.5 Investigator Alert Notification 
Any subject who has had a positive RT-PCR RSV nasal 
swab result, either at the study central laboratory or at an 
outside institution in a CLIA-certified (or equivalent) 
laboratory, should not receive a second dose of study 
drug and will be monitored. 
Clinical Study Protocol Synopsis 
Section 3.1.2.3 Study Enrollment and Assessments 
Table 2 Part B: 30 mg/kg IM (Maximum 1 Dose 
REGN2222 and Maximum 1 Dose Placebo); 30 mg/kg 
IM (Maximum 2 Doses REGN2222); or Placebo IM 
(Maximum 2 Doses); for Subjects with Schedules I 
through M, footnote #5 
Updated safety variables from 3 observation periods to 2 
observation periods in Part A 
For safety variables in Part B, added definitions for 3 
observation periods and treatment-emergent adverse 
events. 
Additional evaluation of TEAEs may be conducted for 
identification of hypersensitivity 
Included definition regarding TEAEs in Part B will be 
defined as those that are not present at baseline or 
represent the exacerbation of a pre-existing condition 
during the safety TEAE period. 
Section 9.5.3.3 Adverse Events 
Change “Part B” to “Part A” for the cohort that the 
subjects’ doses will be summarized in 
Section 9.5.3.5 Treatment Exposure 
Following the completion of Part A, subject data will be 
locked and reported. This will be done to confirm the 
dose to move forward with in Part B of the study. 
Section 9.6.1 Part A 
Added section to provide end of study definition 
Section 3.2.1 End of Study Definition 
Editorial and Administrative Changes/Updates 
Cover Page 
Section 3.2 Study Stopping Rules 
Section 4.2 Premature Withdrawal From the Study 
Table 2 Part B: 30 mg/kg IM (Maximum 1 Dose 
REGN2222 and Maximum 1 Dose Placebo); 30 mg/kg 
IM (Maximum 2 Doses REGN2222); or Placebo IM 
(Maximum 2 Doses); for Subjects with Schedules I 
through M, footnote #7 


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Amendment 3 
 
 
 
 
• To add 2 secondary endpoints to Part B 
 
− Rationale: The addition of secondary endpoints for PK and ADA titers are to 
align with agreed PIP. 
 
• To add RSV LRTI Analysis and Alternative LRTI Definition Analysis as sensitivity 
analyses to the primary endpoint 
 
− Rationale: To align with the EU protocol and requested by PDCO, respectively 
 
 
 
• To clarify language in Exclusion Criteria for the Mother 
 
− Rationale: To add that infants of mothers who are either 16 years or younger or 
of an age where they cannot legally provide informed consent in their 
state/country are excluded. 
 
The following additional changes were made: 
 
• To update the scientific/medical monitor 
 
• To clarify the window in Part B during which assessment of primary and secondary 
clinical endpoints will occur 
 
− Rationale: Although no change of the actual window in which primary and 
secondary endpoint acquisition was made, the change was to clarify that the 
windows end at different times during the study period. 
 
• To clarify that subjects who complete Day 150 may be eligible to enroll in a subsequent 
extension study 
 
• To change the screening period in Part B from 14 to 28 days 
 
− Rationale: Based on feedback from study PIs that a longer period from screening 
to enrollment is required if infants are enrolled in the hospital or neonatal 
intensive care unit but are enrolled in the study clinic. 
 
• To remove throat swab collection 
 
− Rationale: Based on feedback that because of high sensitivity of RT-PCR for 
diagnosis of RSV, a throat swab in addition to nose swab is not necessary and can 
be challenging to collect in some preterm infants. 
 
• To clarify phrasing of the target population definition and Exclusion Criterion #1 
 
− Rationale: The original phrase “eligible to receive palivizumab…” was meant to 
indicate that any infant who is eligible or can access palivizumab as standard of 
care is excluded from the study.  The phrasing was clarified indicate this. 


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• To add clarification to 2 exploratory endpoints 
 
− Rationale: Clarified that hospitalization is defined as a stay of 24 hours or 
longer.  Added “for RSV-associated illness” to clarify condition for length of stay 
in hospital. 
 
• To clarify language and exceptions in Exclusion Criterion #6 
 
− Rationale: Certain laboratory abnormalities are expected in preterm infants due 
to bone growth and physiological or breastfeeding jaundice and is not always 
considered an underlying medical disorder. Clarification is made to ensure that 
the upper limit of normal laboratory ranges are appropriate for preterm infants 
and for neonates, if applicable, as these ranges may be significantly different to 
full term infants. 
 
• To add details about sparse blood collection 
 
− Rationale: To add an explanation for the blood drawing schedule utilized in this 
study to minimize the total number of planned blood draws required during the 
study period 
 
• To add respiratory syncytial virus (RSV)-positive reverse-transcriptase polymerase chain 
reaction (RT-PCR) test result after receipt of first dose but prior to second dose as a 
reason for permanent discontinuation of study drug 
 
− Rationale: Although this was already in the protocol in section 3.1.2.3 
underlying Study Enrollment and Assessment, it should also be included in the 
section on Reasons for Study Discontinuation. 
 
• To add a new section to detail the temperature acquisition method and add a table of 
conversions for the different modalities of temperature measurement 
 
− Rationale:  Rectal temperatures are included in the DAIDS severity score table 
and is considered the most accurate method.  However, many sites indicated that 
rectal temperatures are not routinely measured in preterm infants.  A conversion 
of temperature using different modalities of temperature measurement is included 
to allow for standardized conversion into an equivalent rectal temperature. 
 
• To clarify when pharmacoeconomic information will be collected 
 
− Rationale: To clarify that pharmacoeconomic information will be collected only 
in infants who have had a medically attended respiratory visit. 
 
• To clarify, when a subject has a positive PCR RSV nasal swab result, that the subject 
should continue in the study and complete all assessments other than receiving the second 
of study drug and the postdose assessments 
 
− Rationale: To clarify what procedures still need to be done in infants who do not 
receive the second dose of study drug because of having a positive RSV test result 


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• To instruct study personnel how to record blood pressure if it is unable to be obtained 
 
− Rationale: Blood pressure may be difficult to obtain in some infants because of 
size and therefore this is to clarify that a systolic blood pressure alone can be 
recorded or if unable to obtain either systolic or diastolic pressures, “unable to 
obtain” should be recorded. 
 
• To add detailed instruction for blood redraw procedures 
 
− Rationale: Because of challenges of obtaining adequate blood volumes for 
screening blood tests, the clarification is to allow for blood redraw as long as the 
total volume is within the limits outlined by local or national guidelines on blood 
sampling limits in children. 
 
• To add detailed instruction for laboratory reference ranges for preterm infants 
 
− Rationale: Preterm reference ranges for laboratory tests may be different from 
full term reference ranges and because there is no standardized universal 
reference ranges available for preterm infants, the clarification is to provide 
standard guidance on preterm reference ranges using literature and advice from 
subject matter experts. 
 
• To add Version 2.0 of Division of AIDS (DAIDS) (Appendix F), a DAIDS Fever 
Grading Scale (Appendix G), and to clarify which DAIDS version should be used for 
evaluation of adverse event (AE) severity 
 
− Rationale:  The original DAIDS severity scale was version 2004 and was used in 
the original protocol. An updated scale was published in 2014.  Because there are 
some differences in definition of severity between 2004 and 2014 versions, the 
original 2004 version is maintained in the amendment with additions from the 
2014 version related specifically to preterm infants, such as total bilirubin. 
 
• To add detailed instructions for how information and test results are collected if an 
unscheduled visit associated with a medically attended respiratory infection does not 
occur within 14 days of discharge from a medical facility. 
 
• To update when sample size re-estimation occurs 
 
− Rationale: This study will be conducted in multiple hemispheres, therefore the 
team wanted to be more general about when this analysis will take place 
 
• To update when an interim analysis occurs 
 
− Rationale: This study will be conducted in multiple hemispheres, therefore the 
team wanted to be more general about when this analysis will take place 
 
To make minor clarifications to the text and correct spelling and grammatical errors 


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Amendment 2 
 
The purposes of this amendment are the following: 
 
• Extend the Part B Post-Dose Follow-up Period from 93 days to 180 days 
 
• Add a section describing the benefit/risk assessment 
 
• Update assessments to be performed at unscheduled visits 
 
• Update the study stopping rules 
 
• Clarify that some standard of care treatments are permitted 
 
• Include axillary temperature equivalents to rectal temperature 
 
• Add a section describing the sponsor’s reporting responsibilities 
 
• Add the last 5 pages to the severity grading scale provided in Appendix E 
 
• Make minor clarifications to the text 
 
Amendment 1 
 
The purposes of this amendment were the following: 
 
• To update the status of the FIH study by removing “ongoing” 
 
• To clarify the primary objective for Part B 
 
• To clarify the collection of days on supplemental oxygen 
 
• To clarify, in Part B, that the permitted windows for prophylaxis will be based on 
geographical area 
 
• To remove references to the study manual 
 
• To clarify, in Part A, the process of dosing for the 24 subjects 
 
• To clarify physical examination assessment time points, including the addition, in Part A 
and Part B, of a physical examination postdose 
 
• To clarify, in Part A, whether Visit 4 through Visit 6 will be at the clinic (if a blood draw 
is required) or will be conducted by telephone (if no blood draw is required) 
 
• To clarify IDMC review and recommendation to begin enrollment in Part B 
 
• To clarify Regeneron PK data review to confirm Part B dose and the addition of PK 
dosing adjustment rules 
 
• To change, in Part B, stratification from country to region 
 
• To clarify the gestational age categories as ≤31 weeks, 6 days GA or from 32 weeks, 0 
days to 35 weeks, 6 days GA 
 
• To clarify the Part B treatment arms 
 
• To update, in Part B, monitoring of the subject to 1 hour after dosing 
 
• To clarify, in Part B, the duration of subject participation 


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• To change the frequency of site contacts to weekly 
 
• To remove heel stick method of blood collection 
 
• To clarify information concerning the Medical Information Packet by changing the name, 
by updating the contents of the Medical Information Packet (including removal of swab 
samples), and by defining the time to the associated follow-up visit 
 
• To add the description of the Safety Monitoring Team 
 
• To describe the unscheduled visit for potential respiratory illness, including assessments 
 
• To remove, in Part B, the statement regarding availability of study staff by telephone 
7 days a week 
 
• To add study stopping rules 
 
• To clarify the countries and regions where study sites may be located 
 
• To clarify the study population age 
 
• To clarify that the parent(s) or legal guardian(s) must be legally able to provide informed 
consent 
 
• To update the window for subjects to not receive other vaccinations from within 7 days 
of dosing to within 2 days of dosing with study drug 
 
• To update the exclusion criteria for laboratory test results from >1.5 to >1.1 times the 
upper limit of normal 
 
• To clarify the exclusion criteria for excluded concomitant medications or other 
concurrent treatments 
 
• To update the exclusion criteria of previous reactions to agents or components 
 
• To update the exclusion criteria of the mother to younger than 16 years old 
 
• To clarify the discontinuation rules 
 
• To change the grading system for AEs of special interest 
 
• To clarify, in Part B, procedures relating to the unblinded study staff and their access to 
unblinded drug kit information 
 
• To clarify permitted medications and procedures 
 
• To clarify participation in optional substudy 
 
• To remove electrocardiogram 
 
• To remove urinalysis testing 
 
• To add unscheduled visit guidance for AEs considered hypersensitivity or anaphylaxis, 
including complete blood count with differential, liver function test, ADA, and a photo to 
assess hypersensitivity reactions that result in a rash 
 
• To change body temperature dosing criteria from 100.4°F to 101°F 


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• To remove from pharmacoeconomic measures the collection of sibling incidence of 
upper or lower tract respiratory infections 
 
• To remove socioeconomic measures 
 
• To clarify the definition of RSV LRTI 
 
• To remove the primary endpoint of new onset of RSV positive respiratory illness while 
already in the hospital 
 
• To remove the exploratory endpoint of RSV-associated symptoms 
 
• To clarify the statistical analysis, including updating the primary endpoint analysis 
 
• To clarify the final reporting of the results 
 
• To clarify initiation of Part B and protocol amendments 
 
• To modify the use of the toxicity grading scale 
 
• To clarify that the IVRS/IWRS will assign blood collection schedule 


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CLINICAL STUDY PROTOCOL SYNOPSIS 
 
Title 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study 
Evaluating the Efficacy and Safety of a Human Monoclonal Antibody, 
REGN2222, for the Prevention of Medically Attended RSV Infection in 
Preterm Infants 
 
Site Location 
 
Principal Investigator 
Global 
 
Primary Objectives 
Part A: 
 
• 
To determine the pharmacokinetics (PK) of intramuscular (IM) 
administrations of REGN2222 
 
Part B: 
 
• 
To demonstrate the efficacy of REGN2222 in preventing medically 
attended respiratory syncytial virus (RSV) infections (subjects with 
either RSV-confirmed hospitalizations or outpatient lower 
respiratory tract infection [LRTI]) 
 
Secondary Objectives 
Part A: 
 
• 
To evaluate safety, tolerability, and immunogenicity of REGN2222 
following IM administration 
 
Part B: 
 
• 
To evaluate safety and tolerability of REGN2222 
• 
To demonstrate the efficacy of REGN2222 in reducing 
RSV-confirmed hospitalizations, emergency room (ER), urgent care 
(UC), or pediatric clinic visitsa 
• 
To assess monthly serum levels of different dosing regimens of 
REGN2222 
• 
To assess the immunogenicity of REGN2222 
 
a  A pediatric clinic visit represents any outpatient medically attended visit 
that could include, but is not limited to, a pediatric office visit, a primary 
  
physician office visit, a family physician visit, or a study site visit.  
 


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Exploratory Objectives 
• 
To collect DNA for the prospective study of the association of host 
biomarkers with RSV infection and severity 
• 
To summarize the effect of REGN2222 on RSV-confirmed 
hospitalization, including the following: 
− 
Number of days on RSV mechanical ventilation 
− 
Number of days requiring supplemental oxygen 
• 
To assess the impact of REGN2222 on pharmacoeconomic 
outcomes (number of medical visits for RSV infection, total number 
of medical visits, associated medical interventions or treatments, 
number of missed days of work by the parent[s] or guardian[s] in 
association with each medically attended RSV event). 
• 
To detect and identify the presence of other common respiratory 
pathogens from RSV negative nose swab specimens collected from 
subjects. 
 
Study Design 
This is a Phase 3 study that will be conducted in 2 parts. Part A is an 
open-label, 1-cohort, multicenter PK study. Subjects in Part A may enroll 
anytime during the RSV season. Part B is a randomized, placebo-controlled, 
3-arm, multicenter study. In Part B, the sponsor (Regeneron 
Pharmaceuticals, Inc.) will provide permitted windows for prophylaxis of 
subjects in each geographical area based on historic data on the timing and 
duration of the RSV season. 
 
Part A will assess the PK of REGN2222. 
 
Subjects will be assigned open-label treatment with a single dose of 
REGN2222 30 mg/kg during the RSV season. Of the 24 subjects that are 
planned to be enrolled in Part A, the first 3 subjects will be dosed at least 
48 hours apart; safety data through at least Day 3 from the first 3 subjects 
will be reviewed by the investigators and the sponsor’s medical monitor 
prior to subsequent dosing. The remaining 21 subjects may be dosed with no 
more than 10 subjects dosed on the same day. 
 
After obtaining informed consent from the parent(s) or legal guardian(s), 
subjects will be assessed for study eligibility at the screening visit. Subjects 
will undergo screening within 14 days prior to baseline (Day 1). Subjects 
who continue to meet eligibility criteria at baseline will undergo Day 1 
baseline assessments and will receive REGN2222 30 mg/kg (maximum 
1 dose). Subjects will be monitored in the clinic for 3 hours after dosing, 
followed by discharge. An emergency phone number will be provided to 
parent(s) or guardian(s) who will also be given written and verbal 
instructions to call with any change in the subject’s status. In addition, the 
study staff will contact the parent(s) or legal guardian(s) at the end of Day 1 
to inquire about any change in the subject’s status, the subject will return to 
the study site on Day 2 for Visit 3, and the study staff will contact the 
  
parent(s) or legal guardian(s) on Day 3 to inquire about any change in the  
 


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subject’s status; this will provide at least daily contact for 48 hours after 
dosing. Any new signs or symptoms that have developed in the subject since 
the dose will be assessed by study staff to determine if there is a need for 
immediate medical attention and if that subject will also need to be seen 
within 24 hours by the study staff. The end of study will occur 150 days after 
REGN2222 dose. 
 
Dose Selection for Part B: Enrollment in Part B will only start following the 
recommendation to do so by the independent data monitoring committee 
(IDMC), after the IDMC has reviewed at a minimum the Day 3 safety data 
of the first 18 subjects who were enrolled in Part A and received a single 
dose of REGN2222. Regeneron will confirm the dose for Part B. The dose 
will remain the same as that in part A if the PK data up to Day 57 (from 
subjects enrolled in Part A) are consistent with the predicted concentrations, 
after age and body weight corrections. 
 
Part B will assess the efficacy, safety, and immunogenicity of REGN2222. 
 
Subjects (n=1515) will be randomly assigned in a 1:1:1 ratio to 1 of 3 arms 
(REGN2222 30 mg/kg single dose [maximum 1 dose REGN2222 and 1 dose 
placebo], REGN2222 30 mg/kg Q8 weeks [maximum 2 doses], or placebo 
[maximum 2 doses]) and stratified by region (North America or rest of the 
world) and gestational age (≤31 weeks, 6 days GA or from 32 weeks, 0 days 
to 35 weeks, 6 days GA) in a multicenter, double-blind study. 
 
Assessment of the primary and secondary clinical endpoints will only occur 
through Day 150. If a primary endpoint is reached during the study period, 
ongoing assessments will continue until the end of the study period. Any 
subject who has had a positive RT PCR RSV nasal swab result, either at the 
study central laboratory or at an outside institution in a CLIA-certified (or 
equivalent) laboratory, should not receive a second dose of study drug. The 
risk of a second RSV infection is reduced substantially (~70%) for 6 months 
after the first infection and this practice is also consistent with the 2014 
American Academy of Pediatrics recommendations for palivizumab 
(Synagis®) prophylaxis. Subjects who have a RSV infection (positive RT- 
PCR RSV nasal swab result) will continue to be monitored for additional 
medically attended acute respiratory infections that may occur during the 
study period. 
 
After the parent(s) or legal guardian(s) provide informed consent, the subject 
will be assessed for study eligibility at the screening visit. Subjects will 
undergo screening within 28 days prior to randomization. Subjects who 
continue to meet eligibility criteria at baseline will undergo Day 1 baseline 
assessments and will be randomly assigned to a treatment arm. Subjects will 
be monitored in the clinic for at least 1 hour after dosing, followed by 
discharge, when appropriate. 
 
The parent(s) or guardian(s) will be provided with an emergency phone 
  
number and will be given written and verbal instructions to call with any  
 


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change in the subject’s status. In addition, the study staff will contact 
parent(s) or legal guardian(s) at the end of the day and daily over 48 hours to 
inquire about any change in the subject’s status. Any new signs or symptoms 
that have developed in the subject since the last dose will be assessed by 
study staff to determine if there is a need for immediate medical attention 
and if that subject will also need to be seen within 24 hours by the study staff. 
The end of study will occur approximately 180 days after the last dose. 
 
During the study period, data will be collected on subjects with any acute 
respiratory illness requiring medical attention. After enrollment into the 
study, subjects taken by their parent(s) or guardian(s) to a healthcare 
provider (inpatient or outpatient, including emergency room [ER], urgent 
care [UC], or pediatric clinic visits) for any of the following symptoms will 
be asked to contact the study staff immediately or soon after seeking medical 
attention: fever, cough, earache, nasal congestion, rhinorrhea, vomiting after 
coughing, wheezing, and difficulty breathing (labored, rapid, or shallow). 
Study site personnel will evaluate the subject during an unscheduled visit 
within 72 hours or as soon as possible following discharge or the medical 
visit for respiratory infection. If the unscheduled study visit following a 
medically attended respiratory infection occurs more than 72 hours but 
within 14 days of discharge from the medical facility, all procedures, as 
appropriate, including nose swab collection should occur despite being 
outside of the 72 hour window. 
 
Evaluation will include a history of the acute illness. Nose swabs for viral 
detection will be conducted after the subject presents for medical attention 
(which may or may not be the study site). All nose swabs will be tested using 
reverse-transcriptase polymerase chain reaction (RT-PCR) assay for RSV, 
which will be conducted in a central laboratory. All RSV isolates will be 
subtyped. 
 
When the parent(s) or guardian(s) takes their child for medical attention for 
an acute respiratory infection, they will be instructed to take a Medical 
Information Packet with them for the treating clinician. For emergency and 
other visits to a medical facility other than the study site, medical records 
will be obtained by the investigator to gather information about treatments 
provided and use of concomitant medications or products. 
 
It is recommended that site personnel contact the parent(s) or legal 
guardian(s) weekly between routine study visits, to obtain information about 
medically attended acute respiratory events and to remind the parent(s) or 
legal guardian(s) about the next scheduled study visit. Parent(s) or 
guardian(s) will be instructed to contact study personnel to report any 
abnormalities, including any hospitalizations or doctor visits, during the 
intervals between study visits and to come to the study site if medical 
evaluation is needed and the urgency of the situation permits. The follow-up 
period for the occurrence of RSV-confirmed medical attention will continue 
  
through Day 150. Safety, laboratory, and other clinical assessments will be  
 


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performed at specified study visits, until end of study, as noted. 
 
Study Duration 
Part A 
 
This is a single dose study with a treatment and follow-up duration of 
150 days from baseline. The total duration of study will be up to 164 days 
(14-day screening period, single dose, and 150-day follow-up period). 
 
Part B: 
 
This is a repeat dose study with a treatment and follow-up duration of 
237 days. The total duration of study will be up to 265 days (28-day 
screening period, 57-day treatment period, and 180-day follow-up period). 
 
Sample Size: 
Target Population: 
Part A: Approximately 24 infants will be enrolled 
 
Part B: Approximately 1515 infants will be enrolled 
 
The study population will consist of healthy male and female infants who 
have a chronological age of ≤6 months at the time of first dose (ie, dosing on 
or before the subject’s 6-month birthday), who have a GA no more than 
35 weeks, 6 days, and who are not eligible, recommended for, nor have 
access to palivizumab by standard practice, local guidelines, or their 
healthcare provider. 
 
Treatments 
 
Study Drug Dose/Route/Schedule 
 
Formulation: 
 
 
 
Placebo 
 
 
Route: 
REGN2222 will be supplied as a lyophilized power in a 20 mL glass vial. 
Each vial contains 265 mg of REGN2222. Upon reconstitution with 1.4 mL 
of sterile water for IM injection, the composition of the drug product is 
150 mg/mL REGN2222. 
 
Placebo product will be supplied in vials that match the REGN2222 vial, but 
without the active protein. 
 
IM injection 
 
Treatment Dose Schedule: 
Part A: 
• 
Approximately 24 subjects will receive REGN2222 30 mg/kg 
(maximum 1 dose) 
 
Part B: 
• 
Approximately 505 subjects will receive REGN2222 30 mg/kg on 
Day 1 (maximum 1 dose) and placebo on Day 57 (maximum 
1 dose) 
• 
Approximately 505 subjects will receive REGN2222 30 mg/kg 
(Q8 weeks) on Day 1 and Day 57 (maximum 2 doses) 
• 
Approximately 505 subjects will receive placebo on Day 1 and 
Day 57 (maximum 2 doses) 


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Endpoints 
 
Primary: 
The primary endpoints are: 
 
Part A: 
• 
Serum  concentration  of  REGN2222  over  time  and  other  PK 
parameters 
 
Part B: 
• 
Proportion of subjects with a medically attended RSV infection 
(hospitalization or outpatient LRTI) during the study period. A 
medically attended RSV infection is defined as an infant with a 
positive RSV test by RT-PCR with any of the following events: 
− 
Hospitalized (on the basis of the assessment of the admitting 
physician) for RSV infection 
− 
Outpatient visit (ER, UC, or pediatric clinic visita [for either a 
sick or well visit]) with RSV LRTI 
a   A pediatric clinic visit represents any outpatient medically 
attended visit that could include, but is not limited to, a 
pediatric clinic visit, a primary physician office visit, a 
family physician visit, or a study site visit 
• 
An RSV LRTI in an infant is defined as an RSV-proven respiratory 
infection (ie, positive RSV RT-PCR test) with parent(s)/ 
guardian(s) report of cough or difficulty breathing, and with 1 of the 
following signs of LRTI, as assessed by a healthcare provider: 
− 
Lower chest wall indrawing 
− 
Hypoxemia (peripheral capillary oxygen saturation 
<95% breathing room air) 
− 
Wheezing or crackles 
 
Secondary: 
The secondary endpoints are: 
 
Part A: 
• 
Incidence and severity of treatment-emergent adverse events 
(TEAEs) 
• 
Presence and titer of anti-REGN2222 antibodies 
 
Part B: 
• 
Proportion of subjects who have RSV-confirmed hospitalization, 
ER, UC, or pediatric clinic visitsa (for upper or lower tract 
infections) during the study period. 
• 
PK parameters using sparse sampling 
• 
Presence and titer of anti-REGN2222 antibodies 
 
a A pediatric clinic visit represents any outpatient medically 
attended visit that could include, but is not limited to, a pediatric 


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clinic visit, a primary physician office visit, a family physician 
visit, or a study site visit 
Exploratory: 
The exploratory endpoints are: 
 
• 
Total number of RSV-associated medical visits (hospital, ER, UC, 
or pediatric visitsa) for each subject and associated treatments or 
procedures at these visits 
 
• 
Total  number  of  medical  visits  (hospital,  ER,  UC,  or  pediatric 
visitsa) for each subject and associated treatments or procedures at 
these   visits,   during   the   study   period   excluding   the   initial 
RSV-associated medical visits. 
 
a   A pediatric clinic visit represents any outpatient medically 
attended visit that could include, but is not limited to, a pediatric 
clinic visit, a primary physician office visit, a family physician 
visit, or a study site visit. 
• 
Number of RSV-confirmed hospitalizations (defined as stay in 
hospital [or its ER] for 24 hours or longer) 
• 
Number of days with RSV-associated mechanical ventilation 
 
• 
Number of days with RSV-associated supplemental oxygen 
 
• 
Length of stay in hospital for RSV-associated illness 
 
• 
Number of missed days of work for parent(s) or guardian(s) 
associated with each medically attended RSV event 
 
• 
Number and proportion of subjects with other common 
respiratory pathogens identified by a RT-PCR multiplex 
respiratory panel which is distinct from the RT-PCR assay 
being used to test for RSV in the primary analyses of the 
primary and secondary efficacy endpoints. 
 
Note: Only nose swab specimens determined to be negative for 
RSV using the RT-PCR assay being utilized for evaluation of 
the study's efficacy endpoints will be evaluated by the RT-PCR 
multiplex respiratory panel. RSV positive samples identified by 
the RT-PCR multiplex respiratory panel will not be taken into 
account in the primary analyses of the primary and secondary 
efficacy endpoints. 
 
Procedures and Assessments 
Safety Procedures (Part A and Part B) 
 
The safety of REGN2222 will be assessed by evaluating TEAEs, detailed 
medical history, physical examinations, vital signs, and clinical laboratory 
testing, as indicated. Concomitant medications and procedures will be 
collected from time of informed consent to the end of the study. Safety data 
  
will be reviewed on an ongoing basis by the sponsor. An independent data  
 


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monitoring committee will be established before study initiation and periodic 
review and recommendations will be provided to the sponsor regarding 
safety as specified in the charter. Blood samples will be collected for 
REGN2222 drug concentrations and antidrug antibody (ADA) levels at 
predetermined time points. Research samples and samples for exploratory 
biomarker analyses will also be collected from any remaining PK and ADA 
samples and will not require a separate blood draw or visit. 
 
Efficacy Procedures (Part B only): 
 
During the study period, efficacy data will be collected by recording all 
acute respiratory tract infections requiring medical attention that are 
RSV-confirmed. An RSV LRTI event in an infant is defined as an 
RSV-proven respiratory infection (ie, positive RSV RT-PCR test) with 
parent(s)/ guardian(s) report of cough or difficulty breathing, and with 1 of 
the following signs of LRTI, as assessed by a healthcare provider: lower 
chest wall indrawing, hypoxemia (peripheral capillary oxygen saturation 
<95% breathing room air), and/or wheezing or crackles. The RSV LRTI 
definition is used to assess the occurrence of outpatient or hospitalized visits 
for RSV that is attributable to RSV LRTIs. Data will be collected on all 
medical visits for RSV and any associated medications, treatments, or 
procedures associated with that visit. 
 
Statistical Plan 
Sample Size 
 
For Part A: The goal is to confirm infant PK and therefore no formal 
sample size calculation will be conducted. A total of 24 subjects will receive 
REGN2222 in Part A as this is considered a sufficient number of subjects to 
confirm PK parameters. 
 
For Part B: A total of 1515 subjects are planned to enroll in Part B. Subjects 
will be randomly assigned in a 1:1:1 ratio (505 subjects in each arm for a 
total of 1010 assigned to receive REGN2222 [505 subjects in each of the 
2 REGN2222 arms] and 505 subjects to receive placebo). 
 
There will be at least 90% power to detect the difference between either dose 
of REGN2222 and placebo using a chi-square test with continuity correction 
at 2-sided test alpha=0.025 for each comparison between treatment group 
and placebo assuming the following: a placebo incidence rate of the primary 
endpoint of 10% and an efficacy of REGN2222 of at least 60% in reducing 
the rate of the primary endpoint compared with placebo and 5% early 
dropout rate. 
 
Sample size may be re-estimated at the end of each RSV season. If the study 
is fully enrolled at that time, then the sample size will be re-estimated before 
database lock. Sample size re-estimation will be based on the blinded and 
pooled event rate and hypothesized treatment effect. The hypothesized 
treatment effect for each arm of REGN2222 will be a 60% reduction in event 
  
rates compared with the placebo arm. The blinded sample size re-estimation  
 


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does not affect type I error materially for binomially distributed data. The 
objective of this sample size re-estimation is to ensure that the study is 
adequately powered in case of a milder-than-expected RSV season, leading 
to low medically attended visits for RSV infection. 
 
Statistical Analysis 
 
Primary Efficacy Analyses for Part B: The primary endpoint will be 
analyzed using Mantel-Haenszel methods to assess the differences in the 
proportions between each REGN2222 treatment and placebo, stratifying by 
region (North America or rest of the world) and GA (≤31 weeks, 6 days GA 
or from 32 weeks, 0 days to 35 weeks, 6 days GA). 
 
Safety Analyses: Safety and tolerability will be descriptively summarized by 
treatment arms, including TEAEs, laboratory variables, vital signs, and 
physical examination. 
 
For Part B, the analysis will be conducted in 2 steps. The first step analysis 
will be conducted as soon as the last randomized subject has completed the 
end of the 150-day efficacy assessment period and all the data have been 
collected and validated; this will consist of the final analysis of all efficacy 
endpoints. The safety analyses will be performed on all safety data collected 
and validated at the time of the first step analysis. The results of the first step 
analysis will not be used to change the conduct of the ongoing study in any 
aspect. Since all the efficacy measure data collection will have been 
concluded at the time of this first step analysis, the significance level for the 
study remains at 2-sided 0.05. 
 
The second step analysis will be performed at the end of the study and will 
consist of the final analysis of the safety measures. 


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TABLE OF CONTENTS 
 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................15 
 
1. 
INTRODUCTION AND RATIONALE.....................................................................34 
 
1.1. 
Introduction.................................................................................................................34 
 
1.2. 
Rationale .....................................................................................................................35 
 
1.2.1. 
Rationale for Study Design.........................................................................................35 
 
1.2.2. 
Rationale for Dose Selection ......................................................................................35 
 
1.2.2.1. 
Part A: Pharmacokinetics and Safety of REGN2222 .................................................35 
 
1.2.2.2. 
Part B: Safety, Efficacy, and Immunogenicity of 2 Dosing Regimens of 
REGN2222 .................................................................................................................36 
 
1.3. 
Benefit/Risk Assessment ............................................................................................36 
 
2. 
STUDY OBJECTIVES ..............................................................................................37 
 
2.1. 
Primary Objectives .....................................................................................................37 
 
2.2. 
Secondary Objectives .................................................................................................37 
 
2.3. 
Exploratory Objectives ...............................................................................................38 
 
3. 
STUDY DESIGN .......................................................................................................38 
 
3.1. 
Study Description and Duration .................................................................................38 
 
3.1.1. 
Part A: Pharmacokinetics and Safety of 1 Dose Regimen of REGN2222 .................38 
 
3.1.2. 
Part B: Efficacy, Safety, and Immunogenicity of 2 Dose Regimens of 
REGN2222 .................................................................................................................40 
 
3.1.2.1. 
Randomization and Stratification for Part B ..............................................................40 
 
3.1.2.2. 
Dose Selection for Part B ...........................................................................................41 
 
3.1.2.3. 
Study Enrollment and Assessments ............................................................................41 
 
3.1.2.4. 
Onstudy Potential Respiratory Illness and the Medical Information Packet ..............42 
 
3.1.2.5. 
Optional Substudy ......................................................................................................43 
 
3.2. 
Study Stopping Rules .................................................................................................44 
 
3.2.1. 
End of Study Definition ..............................................................................................44 
 
3.3. 
Study Committees.......................................................................................................44 
 
3.3.1. 
Independent Data Monitoring Committee ..................................................................44 
 
3.3.2. 
Safety Monitoring Team .............................................................................................44 
 
3.3.3. 
Endpoint Adjudication Committee .............................................................................45 
 
4. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF SUBJECTS..............45 
 
4.1. 
Number of Subjects Planned ......................................................................................45 


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4.1.1. 
Inclusion Criteria ........................................................................................................45 
 
4.1.2. 
Exclusion Criteria .......................................................................................................46 
 
4.1.2.1. 
Exclusion Criteria for the Infant .................................................................................46 
 
4.1.2.2. 
Exclusion Criteria for the Mother ...............................................................................47 
 
4.2. 
Premature Withdrawal From the Study ......................................................................47 
 
4.3. 
Replacement of Subjects.............................................................................................48 
 
5. 
STUDY TREATMENTS............................................................................................48 
 
5.1. 
Investigational and Reference Treatments..................................................................48 
 
5.2. 
Dose Modification and Study Drug Discontinuation Rules .......................................48 
 
5.2.1. 
Dose Modification ......................................................................................................48 
 
5.2.2. 
Study Drug Discontinuation .......................................................................................48 
 
5.2.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................48 
 
5.2.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................49 
 
5.3. 
Management of Injection Site Reactions ....................................................................49 
 
5.3.1. 
Acute Systemic Injection Reactions ...........................................................................49 
 
5.3.2. 
Delayed Onset Reactions ............................................................................................49 
 
5.3.3. 
Hypersensitivity Reactions .........................................................................................50 
 
5.3.4. 
Local Injection Site Reactions ....................................................................................50 
 
5.4. 
Method of Treatment Assignment ..............................................................................50 
 
5.4.1. 
Part A: Open-label Treatment with 30 mg/kg IM (Maximum 1 Dose) ......................50 
 
5.4.2. 
Part B: Randomized Treatment with 30 mg/kg (1 Dose REGN2222 and 
1 Dose Placebo); or 30 mg/kg IM (2 Doses REGN2222); or Placebo IM 
(Maximum 2 Doses) ...................................................................................................50 
 
5.4.2.1. 
Blinding ......................................................................................................................50 
 
5.4.2.2. 
Emergency Unblinding ...............................................................................................51 
 
5.5. 
Treatment Logistics and Accountability.....................................................................52 
 
5.5.1. 
Packaging, Labeling, and Storage ..............................................................................52 
 
5.5.2. 
Supply and Disposition of Treatments .......................................................................52 
 
5.5.3. 
Treatment Accountability ...........................................................................................52 
 
5.5.4. 
Treatment Compliance................................................................................................52 
 
5.6. 
Concomitant Medications and Procedures .................................................................52 
 
5.6.1. 
Prohibited Medications and Procedures .....................................................................52 
 
5.6.2. 
Permitted Medications and Procedures ......................................................................53 


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6. 
STUDY SCHEDULE OF EVENTS AND VISIT DESCRIPTIONS.........................53 
 
6.1. 
Schedule of Events .....................................................................................................53 
 
6.2. 
Study Procedures ........................................................................................................60 
 
6.2.1. 
Part A: 30 mg/kg IM (Maximum 1 Dose) ..................................................................60 
 
6.2.1.1. 
Visit 1 (Screening, Day -14 to Day -1) .......................................................................60 
 
6.2.1.2. 
Visit 2 (Baseline and Dosing Visit, Day 1) ................................................................61 
 
6.2.1.3. 
Visit 3 (Day 2) ............................................................................................................62 
 
6.2.1.4. 
Visit 4 (Day 8) ............................................................................................................62 
 
6.2.1.5. 
Visit 5 (Day 15) ..........................................................................................................63 
 
6.2.1.6. 
Visit 6 (Day 22) ..........................................................................................................63 
 
6.2.1.7. 
Visit 7 (Day 29) ..........................................................................................................64 
 
6.2.1.8. 
Visit 8 (Day 57±5 Days) .............................................................................................64 
 
6.2.1.9. 
Visit 9 (Day 85±5 Days) .............................................................................................65 
 
6.2.1.10. 
Visit 10 (Day 113±5 Days) .........................................................................................65 
 
6.2.1.11. 
Visit 11 (Day 150±5 Days), End of Study or Early Termination ...............................65 
 
6.2.2. 
Part B: 30 mg/kg (1 Dose REGN2222 and 1 Dose Placebo); or 30 mg/kg IM 
(2 Doses REGN2222); or Placebo IM (Maximum 2 Doses) ......................................66 
 
6.2.2.1. 
Visit 1 (Screening, Day -28 to Day -1) .......................................................................66 
 
6.2.2.2. 
Visit 2 (Baseline and First Dosing Visit, Day 1) ........................................................67 
 
6.2.2.3. 
Visit 3 (Day 29±2 Days) .............................................................................................68 
 
6.2.2.4. 
Visit 4 (Second Dosing Visit, Day 57±2 Days)..........................................................68 
 
6.2.2.5. 
Visit 5 (Day 85±5 Days) .............................................................................................70 
 
6.2.2.6. 
Visit 6 (Day 113±5 Days) ...........................................................................................70 
 
6.2.2.7. 
Visit 7 (Day 150±5 Days), or Early Termination .......................................................71 
 
6.2.2.8. 
Visit 8 (Day 178±10 Days) .........................................................................................71 
 
6.2.2.9. 
Visit 9 (Day 206±10 Days) .........................................................................................71 
 
6.2.2.10. 
Visit 10 (Day 237±10 Days)/End of Study.................................................................71 
 
6.2.3. 
Part B: Unscheduled Visit for Potential Respiratory Illness ......................................72 
 
6.2.4. 
Part A and Part B: Unscheduled Visit Following Any Adverse Event 
(Including Suspected Hypersensitivities) ...................................................................73 
 
6.3. 
Safety Procedures .......................................................................................................74 
 
6.3.1. 
Vital Signs ..................................................................................................................74 
 
6.3.1.1. 
Temperature ................................................................................................................74 


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6.3.1.2. 
Blood Pressure ............................................................................................................75 
 
6.3.2. 
Physical Examination .................................................................................................75 
 
6.3.3. 
Laboratory Testing......................................................................................................75 
 
6.3.3.1. 
Blood Chemistry .........................................................................................................76 
 
6.3.3.2. 
Hematology.................................................................................................................77 
 
6.3.3.3. 
Virology Testing .........................................................................................................77 
 
6.3.3.4. 
Abnormal Laboratory Values and Laboratory Adverse Events .................................77 
 
6.4. 
Pharmacokinetic and Antibody Procedures ................................................................77 
 
6.4.1. 
REGN2222-Concentration Measurements and Samples ............................................77 
 
6.4.2. 
Antidrug Antibody Measurements and Samples ........................................................77 
 
6.4.3. 
Research Samples .......................................................................................................78 
 
6.4.4. 
Substudy - Optional ....................................................................................................78 
 
6.5. 
Pharmacoeconomic Measurement Procedures ...........................................................78 
 
7. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................79 
 
7.1. 
Definitions ..................................................................................................................79 
 
7.1.1. 
Adverse Event.............................................................................................................79 
 
7.1.2. 
Serious Adverse Event................................................................................................79 
 
7.2. 
Recording and Reporting Adverse Events..................................................................80 
 
7.2.1. 
Adverse Events ...........................................................................................................80 
 
7.2.2. 
Serious Adverse Events ..............................................................................................80 
 
7.2.3. 
Sponsor’s Responsibility ............................................................................................80 
 
7.2.4. 
Other Events that Require Accelerated Reporting......................................................81 
 
7.2.4.1. 
Symptomatic Overdose of Study Drug .......................................................................81 
 
7.2.4.2. 
Adverse Events of Special Interest .............................................................................81 
 
7.2.5. 
Reporting Adverse Events Leading to Withdrawal From the Study ..........................81 
 
7.2.6. 
Abnormal Laboratory or Vital Sign Results ...............................................................81 
 
7.2.7. 
Adverse Event Follow-up ...........................................................................................82 
 
7.3. 
Evaluation of Severity and Causality .........................................................................82 
 
7.3.1. 
Evaluation of Severity ................................................................................................82 
 
7.3.2. 
Evaluation of Causality...............................................................................................83 
 
7.3.2.1. 
Relationship of AEs to Study Drug ............................................................................83 
 
7.3.2.2. 
Relationship of AEs to Injection Procedure ...............................................................83 


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7.4. 
Safety Monitoring .......................................................................................................84 
 
7.5. 
Investigator Alert Notification....................................................................................84 
 
8. 
STUDY VARIABLES................................................................................................84 
 
8.1. 
Demographic and Baseline Characteristics ................................................................84 
 
8.2. 
Primary Endpoints ......................................................................................................85 
 
8.3. 
Secondary Endpoints ..................................................................................................86 
 
8.4. 
Exploratory Endpoints ................................................................................................86 
 
8.5. 
Antidrug Antibody Variables .....................................................................................87 
 
9. 
STATISTICAL PLAN................................................................................................88 
 
9.1. 
Statistical Hypothesis..................................................................................................88 
 
9.2. 
Sample Size ................................................................................................................88 
 
9.2.1. 
Blinded Sample Size Re-estimation ...........................................................................89 
 
9.3. 
Analysis Sets...............................................................................................................89 
 
9.3.1. 
Part A ..........................................................................................................................89 
 
9.3.2. 
Part B ..........................................................................................................................89 
 
9.4. 
Subject Disposition .....................................................................................................90 
 
9.4.1. 
Part A ..........................................................................................................................90 
 
9.4.2. 
Part B ..........................................................................................................................90 
 
9.5. 
Statistical Methods......................................................................................................90 
 
9.5.1. 
Demography and Baseline Characteristics .................................................................90 
 
9.5.2. 
Efficacy Analysis ........................................................................................................90 
 
9.5.2.1. 
Primary Efficacy Analysis ..........................................................................................91 
 
9.5.2.2. 
Secondary Efficacy Analysis ......................................................................................92 
 
9.5.2.3. 
Exploratory Analysis ..................................................................................................92 
 
9.5.2.4. 
Multiplicity Considerations ........................................................................................93 
 
9.5.3. 
Safety Analysis ...........................................................................................................93 
 
9.5.3.1. 
Part A ..........................................................................................................................93 
 
9.5.3.2. 
Part B ..........................................................................................................................93 
 
9.5.3.3. 
Adverse Events ...........................................................................................................93 
 
9.5.3.4. 
Other Safety ................................................................................................................94 
 
9.5.3.5. 
Treatment Exposure ....................................................................................................95 
 
9.5.3.6. 
Treatment Compliance................................................................................................95 


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9.5.4. 
Pharmacokinetic Analysis ..........................................................................................96 
 
9.5.4.1. 
Part A ..........................................................................................................................96 
 
9.5.4.2. 
Part B ..........................................................................................................................96 
 
9.5.5. 
Analysis of Antidrug Antibody Data ..........................................................................96 
 
9.5.5.1. 
Part A ..........................................................................................................................96 
 
9.5.5.2. 
Part B ..........................................................................................................................96 
 
9.5.5.3. 
Part A and Part B: .......................................................................................................96 
 
9.5.6. 
Timing of Statistical Analyses ....................................................................................96 
 
9.5.6.1. 
First Step:  Efficacy and Safety Analysis ...................................................................97 
 
9.5.6.2. 
Second Step:  Final Safety Analysis ...........................................................................97 
 
9.6. 
Interim Analysis..........................................................................................................97 
 
9.6.1. 
Part A ..........................................................................................................................97 
 
9.6.2. 
Part B ..........................................................................................................................97 
 
9.7. 
Final Reporting ...........................................................................................................97 
 
9.8. 
Additional Statistical Data Handling Conventions .....................................................98 
 
9.8.1. 
Definition of Baseline .................................................................................................98 
 
9.8.2. 
General Rules for Handling Missing Data..................................................................98 
 
9.8.3. 
Visit Windows ............................................................................................................98 
 
9.8.4. 
Unscheduled Assessments ..........................................................................................98 
 
9.9. 
Statistical Considerations Surrounding the Premature Termination of a Study .........98 
 
10. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS .....................................99 
 
10.1. 
Data Management .......................................................................................................99 
 
10.2. 
Electronic Systems......................................................................................................99 
 
10.2.1. 
Interactive Voice or Web Response System...............................................................99 
 
11. 
STUDY MONITORING ..........................................................................................100 
 
11.1. 
Monitoring of Study Sites.........................................................................................100 
 
11.2. 
Source Document Requirements ..............................................................................100 
 
11.3. 
Case Report Form Requirements ..............................................................................100 
 
12. 
AUDITS AND INSPECTIONS ...............................................................................101 
 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................102 
 
13.1. 
Good Clinical Practice Statement .............................................................................102 
 
13.2. 
Informed Consent .....................................................................................................102 


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13.3. 
Subject Confidentiality and Data Protection ............................................................102 
 
13.4. 
Institutional Review Board/Ethics Committee .........................................................103 
 
14. 
PROTOCOL AMENDMENTS ................................................................................104 
 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A SITE 
..........................................................................................................................105 
 
15.1. 
Premature Termination of the Study.........................................................................105 
 
15.2. 
Close Out of a Site ....................................................................................................105 
 
15.2.1. 
Investigator’s Decision to Close Out Site.................................................................105 
 
15.2.2. 
Sponsor’s Decision to Close Out Site.......................................................................105 
 
16. 
STUDY DOCUMENTATION .................................................................................106 
 
16.1. 
Certification of Accuracy of Data.............................................................................106 
 
16.2. 
Retention of Records ................................................................................................106 
 
17. 
CONFIDENTIALITY ..............................................................................................106 
 
18. 
FINANCING AND INSURANCE...........................................................................106 
 
19. 
PUBLICATION POLICY ........................................................................................106 
 
20. 
REFERENCES .........................................................................................................107 
 
21. 
APPENDICES ..........................................................................................................109 
 
Signature of Sponsor’s Responsible Officers ..............................................................................137 


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LIST OF TABLES 
 
Table 1: 
Part A: 30 mg/kg IM (Maximum 1 Dose REGN2222); for Subjects with 
Schedules A through H ...............................................................................................54 
 
Table 2: 
Part B: 30 mg/kg IM (Maximum 1 Dose REGN2222 and Maximum 1 Dose 
Placebo); 30 mg/kg IM (Maximum 2 Doses REGN2222); or Placebo IM 
(Maximum 2 Doses); for Subjects with Schedules I through M ................................56 
 
Table 3: 
Part B: Unscheduled Visit for Potential Respiratory Illness - All Dose 
Regimens ....................................................................................................................59 
 
Table 4: 
Part A and Part B: Unscheduled Visit Following Any Adverse Events 
(Including Suspected Hypersensitivities) - All Dose Regimens.................................60 
 
Table 5: 
Conversion of Axillary/Temporal Temperatures to Rectal /Tympanic 
Temperatures in Infants by Age .................................................................................75 
 
Table 6: 
DAIDS Fever Grading Scale ......................................................................................83 
 
 
 
LIST OF FIGURES 
 
Figure 1: 
Part A: 30 mg/kg Single Dose (Maximum 1 Dose REGN2222) ................................40 
 
Figure 2: 
Part B: 30 mg/kg IM (Maximum 1 Dose REGN2222 and 1 Dose Placebo), 
30 mg/kg IM (Maximum 2 Doses), or Placebo IM (Maximum 2 Doses) ..................41 
 
 
LIST OF APPENDICES 
 
Appendix A. Investigator’s Agreement 
 
Appendix B. Part B Dose Selection based on Pharmacokinetics Process 
 
Appendix C. Factors to Consider in Assessing the Relationship of Adverse Events to 
Study Drug Injection Procedure 
 
Appendix D. Toxicity Grading Scale for grading Allergic Reactions and 
Anaphylaxis - Common Terminology Criterial for Adverse Events (CTCAE; 
Version 4.0, published 28 May 2009; v4.03, 14 June 2010) 
 
Appendix E. Toxicity Grading Scale - Modified from Division of AIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events (Version 1.0, 
December 2004; Clarification August 2009) 
 
Appendix F. Toxicity Grading Scale - Modified from Division of AIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events (Version 2.0, 
November 2014) 
 
Appendix G. Preterm Upper Limit of Normal (ULN) Values Specified in Exclusion 
Criterion 6 and the 1.1 Times ULN Cut-off Limit for These Values Above 
Which Subjects Would Be Excluded From Study Entry 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
AAP 
American Academy of Pediatrics 
 
AE 
Adverse event 
 
AESI 
Adverse event of special interest 
 
ADA 
Antidrug antibody 
 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
CLD 
Chronic lung disease 
CLIA 
Clinical Laboratory Improvement Amendments 
 
CRF 
Case report form (electronic) 
 
CTCAE 
Common Terminology Criteria for Adverse Events 
 
ED 
Effective dose 
 
ER 
Emergency room 
 
ERC 
Ethics review committee 
 
FIH 
First-in-human 
 
GA 
Gestational age 
 
GCP 
Good Clinical Practice 
 
ICF 
Informed consent form 
 
ICH 
International Council on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IM 
Intramuscular 
IRB 
Institutional Review Board 
 
IV 
Intravenous 
 
IVRS 
Interactive voice response system 


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IWRS 
Interactive web response system 
 
LRTI 
Lower respiratory tract infection 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
PCSV 
Potential clinical significant value 
 
PK 
Pharmacokinetic 
 
PT 
Preferred term 
 
Q 
every 
 
RBC 
Red blood cell 
 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
RSV 
Respiratory syncytial virus 
RT-PCR 
Reverse-transcriptase polymerase chain reaction 
 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SMT 
Safety monitoring team 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
 
UC 
Urgent care 
 
URTI 
Upper respiratory tract infection 
 
US 
United States 
 
WBC 
White blood cell 


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1. 
INTRODUCTION AND RATIONALE 
 
1.1. 
Introduction 
 
Globally, respiratory syncytial virus (RSV) is the second leading cause of mortality in infants 
1 month to 1 year of age and the most common viral cause of acute lower respiratory tract 
infection (LRTI) in children under 5 years of age (Lapillonne 2013). Respiratory syncytial virus 
illness can range from mild upper respiratory tract infection (URTI) to severe LRTI, including 
bronchiolitis and pneumonia. In the United States (US), compared with influenza, RSV is 
associated with a 9-fold greater risk for hospitalization (Iwane 2004) and approximately 9-fold 
higher mortality rate in infants less than 1 year of age (Thompson 2003). Furthermore, RSV 
disease in early infancy may also predispose children to reactive airway disease in early 
childhood (American Academy of Pediatrics 2009, Ambrose 2014, Blanken 2013, 
Yoshihara 2013). 
 
Passive immunoprophylaxis with an RSV neutralizing antibody is a safe and effective approach 
for reducing RSV-related hospitalizations in infants and has been in use for almost 2 decades. 
Palivizumab (commercially available as Synagis®), a humanized monoclonal antibody, is the 
only RSV preventive agent currently available. When given monthly for 5 months during the 
RSV season, Synagis resulted in a 55% reduction in RSV-related hospitalizations in premature 
infants with and without chronic lung disease (CLD) compared with placebo 
(Palivizumab 1998). 
 
Despite the efficacy and excellent safety record of palivizumab, the majority of infants at risk for 
severe RSV do not receive palivizumab (Hall 2013). While palivizumab is indicated for the 
broader population of high-risk children for the prevention of serious RSV lower respiratory tract 
disease, the American Academy of Pediatrics (AAP) and other pediatric society position 
statements recommends restricting its use to only infants at the highest-risk category due to the 
high cost of palivizumab (Hall 2013, Robinson 2011). In the US, these highest-risk infants 
include premature infants who are less than 29 weeks gestational age (GA) and infants with CLD 
or congenital heart disease during their first year of life (AAPCID 2014). However, infants who 
are at least 29 weeks GA, including full-term infants, are also at high risk for severe RSV 
infection (Hall 2013). This burden of RSV infection in all young infants has kept RSV vaccine 
development a high priority for the past 50 years, although there is still no licensed RSV vaccine 
available. There remain many challenges in the development of a RSV vaccine for use in infants, 
including an immature immune system (Anderson 2013, American Academy of Pediatrics 2009). 
 
The purpose of this study is to demonstrate the safety, efficacy, pharmacokinetics (PK), and 
immunogenicity of REGN2222, a new fully human immunoglobulin G1 (IgG1) monoclonal 
antibody directed against the RSV fusion glycoprotein in infants born no more than 
35 weeks 6 days GA, who are no more than 6 months of age during the RSV season in their 
respective geographic location. In order to optimize the potential benefit in this vulnerable 
population, we will conduct this study during the RSV season using dosing regimens that are 
expected to be effective. 
 
In a first-in-human (FIH) study (R2222-HV-1326) in 132 healthy adults 110 adults were 
evaluated for safety and tolerability of REGN2222 delivered intravenously and intramuscularly 


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compared to placebo. The doses studied in the FIH study included a 3 mg/kg intravenous (IV) 
(maximum 1 dose), 10 mg/kg IV (maximum 1 dose), 30 mg/kg IV Q4 (every 4) weeks 
(maximum 2 doses), 3 mg/kg intramuscular (IM) Q4 weeks (maximum 2 doses), and 10 mg/kg 
IM Q4 weeks (maximum 2 doses). REGN2222 was generally well-tolerated at all evaluated 
doses. There were no serious adverse events (SAEs) or dose-limiting toxicities. The observed 
treatment-emergent immunogenicity (antidrug antibody [ADA] formation) in 2 subjects was 
transient and not associated with any adverse events (AEs). 
 
1.2. 
Rationale 
 
1.2.1. 
Rationale for Study Design 
 
This is a 2-part study. 
 
Part A is an open-label PK study of REGN2222 to determine the PK in preterm infants after a 
single dose to enable the selection of dosing regimens for Part B. It will also provide initial 
evaluation of safety and tolerability in infants. Because the primary goal of Part A is to 
determine the PK in infants for REGN2222 and not for efficacy, a placebo cohort and blinding of 
treatment are not required. At a dose of 30 mg/kg of REGN2222, it is expected that protection 
will be provided to the majority of infants during the RSV season. 
 
Part B is a randomized, double-blind, placebo-controlled, study designed to evaluate efficacy, 
safety, monthly serum concentration of REGN2222, and immunogenicity of IM administration 
of REGN2222 in preterm infants who are not eligible, recommended, nor is access to 
palivizumab available. Up to 1515 subjects (1010 assigned to receive REGN2222 [505 subjects 
in each of the 2 arms] and 505 to receive placebo) are planned to be enrolled and randomized 
1:1:1 into 3 arms. The study design is optimal for evaluating safety, efficacy, PK, and 
immunogenicity of 2 different dosing regimens of REGN2222 (sample size is further described 
in Section 9.2). The use of a placebo arm is justified because infants enrolled into the study 
would not receive less than standard of care for RSV prevention because only infants who are 
not eligible, recommended, nor is access available to receive palivizumab will be included in the 
study. 
 
1.2.2. 
Rationale for Dose Selection 
 
1.2.2.1. 
Part A: Pharmacokinetics and Safety of REGN2222 
 
The study drug REGN2222 will be administered as a single dose of 30 mg/kg IM (Figure 1). 
This dose has been selected based on the safety profile established in nonclinical safety studies 
and results from the FIH study (R2222-HV-1326) in normal healthy adult subjects. 
 
Nonclinical safety studies in cynomolgus monkeys have shown REGN2222 to be well tolerated at 
IV, IM, and subcutaneous doses up to 100 mg/kg every week with no observed adverse effect 
level for 10 weeks. In the FIH study, single and multiple administration of REGN2222 with up to 
30 mg/kg for IV doses and 10 mg/kg for IM doses have been well tolerated in a healthy 
population of adults (132 total; 110 exposed to REGN2222) with no study drug-associated SAEs 
or drug-limiting toxicities. 


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For the FIH adult study, PK analyses indicate linear dose proportional kinetics with a relatively 
long half-life (mean up to 36 days) in healthy adult volunteers. It is expected that dosing 
regimens of REGN2222 at 30 mg/kg IM dosed Q8 weeks or a 30 mg/kg IM single dose will 
maintain serum levels similar to the serum levels of REGN2222 in cotton rat experiments that 
were associated with a 2-log (or 99%) reduction in RSV viral titer in the lung for subtype A 
(5 µg/mL) and subtype B (27 µg/mL) for most of the RSV season. This serum level is attained at 
an effective dose (ED) to attain a 99% reduction in lung RSV viral titer, hereafter referred to as 
ED99. Final dose regimens used in Part B will be informed based on additional safety and PK 
data from Part A of this study. Alternative dose regimens for Part B may be selected if the PK 
parameters of REGN2222 observed in infants are significantly different than the one estimated 
from adult PK data. A dose higher than 30 mg/kg is not included in this study because, as 
currently formulated, it would require more than 2 simultaneous IM injections in some larger 
infants. 
 
1.2.2.2. 
Part B: Safety, Efficacy, and Immunogenicity of 2 Dosing Regimens of 
REGN2222 
 
Two dosing regimens will be assessed in Part B. The planned regimens are REGN2222 30 mg/kg 
single dose (maximum 1 dose) and REGN2222 30 mg/kg, Q8 weeks (maximum 2 doses) 
(Figure 2). However, following evaluation of the PK data from infants studied in Part A, an 
adjustment to dose level may be implemented (Appendix B). 
 
The currently proposed dose (30 mg/kg) for Part B is proposed based on modeling of available 
PK data from adults to predict exposure in infants. The prediction will be re-evaluated when 
complete data are available from the adult study and initial data are available from infants in 
Part A. If the PK parameters indicate exposure significantly exceeds prediction from the model, a 
lower dose (eg, 20 mg/kg) will be used in Part B instead of 30 mg/kg. 
 
1.3. 
Benefit/Risk Assessment 
 
REGN2222, a human IgG1 monoclonal antibody targeting RSV-F, is being developed for use as 
passive immunization for the prevention of LRTI caused by RSV in infants. REGN2222 may 
provide a more convenient dosing regimen (less frequent than monthly dosing of palivizumab) to 
justify use in the larger population of at-risk infants including late preterm and full-term infants, 
who are not eligible, recommended, nor is access available to prophylaxis according to local 
standard of care. 
 
There are no identified risks for REGN2222 based on clinical experience to date. 
 
 
 
 
 
The following list of potential risks considered was based on known risks associated with other 
monoclonal antibodies with a similar mechanism of action, preclinical/toxicology data, as well as 
risks associated with monoclonal antibody therapies in general, such as changes in salivation, 
hypersensitivity reactions, and immunogenicity (antidrug antibody formation). The 
treatment-emergent adverse events (TEAEs) in the FIH adult study described above that were 
associated with the potential risks of changes in salivation or hypersensitivity reactions were 


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generally mild and easily manageable. In the IM cohorts, no acute systemic injection reaction 
TEAEs and no local injection site reaction TEAEs were observed. The observed 
treatment-emergent immunogenicity (ADA formation) in 2 subjects was transient, and not 
associated with any AEs. The complete description of previous human experience, potential 
risks, and monitoring and mitigation strategies for those risks is found in the Investigator’s 
Brochure. 
 
In the current infant study, appropriate exclusion criteria, close monitoring of the subjects, and 
periodic review of safety data will be performed to minimize and manage the potential risks to 
the infants. An Independent Data Monitoring Committee (IDMC) is in place to further support 
the protection of subjects.  The safety data available to date and safety precautions that will be 
taken by the sponsor support the potential benefit of REGN2222 in these infants and continued 
development of this compound. 
 
2. 
STUDY OBJECTIVES 
 
2.1. 
Primary Objectives 
 
Part A: 
 
 
 
Part B: 
 
• To determine the PK of IM administration of REGN2222 
 
 
 
• To demonstrate the efficacy of REGN2222 in preventing medically attended RSV 
infections (subjects with either RSV-confirmed hospitalizations or outpatient LRTI) 
 
2.2. 
Secondary Objectives 
 
Part A: 
 
 
 
 
Part B: 
 
• To evaluate safety, tolerability, and immunogenicity of REGN2222 following IM 
administration 
 
 
 
• To evaluate safety and tolerability of REGN2222 
 
• To demonstrate the efficacy of REGN2222 in reducing RSV-confirmed 
hospitalizations, emergency room (ER), urgent care (UC), or pediatric clinic visitsa 
 
• To assess monthly serum levels of different dosing regimens of REGN2222 
 
• To assess immunogenicity of REGN2222 
 
a   A pediatric clinic visit represents any outpatient medically attended visit that could include, but is 
not limited to, a pediatric clinic visit, a primary physician office visit, a family physician visit, or a 
study site visit. 


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2.3. 
Exploratory Objectives 
 
The following items were considered exploratory objectives: 
 
• To collect DNA for the prospective study of the association of host biomarkers with RSV 
infection and severity 
 
• To summarize the effect of REGN2222 on RSV-confirmed hospitalization, including the 
following: 
 
− Number of days on RSV mechanical ventilation 
 
− Number of days requiring supplemental oxygen 
 
• To assess the impact of REGN2222 on pharmacoeconomic outcomes (number of medical 
visits for RSV infection, total number of medical visits, associated medical interventions 
or treatments, number of missed days of work by the parent[s] or guardian[s] in 
association with each medically attended RSV event). 
 
• To detect and identify the presence of other common respiratory pathogens from RSV 
negative nose swab specimens collected from subjects. 
 
 
3. 
STUDY DESIGN 
 
3.1. 
Study Description and Duration 
 
This is a Phase 3 study that will be conducted in 2 parts. 
 
Part A is an open-label, single cohort, multicenter, PK study. Subjects in Part A may enroll any 
time during the RSV season. 
 
Part B is a randomized, placebo-controlled, 3-arm, multicenter study. In Part B, the sponsor 
(Regeneron Pharmaceuticals, Inc.) will provide permitted windows for prophylaxis of subjects in 
each geographical area based on historical data on the timing and duration of the RSV season. 
 
Subjects who complete this study may be eligible to enroll in a subsequent extension study in 
which they will be monitored for medically attended episodes of wheezing over a 12 month 
period. 
 
3.1.1. 
Part A: Pharmacokinetics and Safety of 1 Dose Regimen of REGN2222 
 
Part A will assess the PK as well as initial safety and tolerability of REGN2222 in infants. Blood 
will be drawn for the purpose of determining the PK or REGN2222. 
 
Subjects will be assigned open-label treatment with a single dose of REGN2222 30 mg/kg during 
the RSV season. Of the 24 subjects that are planned to be enrolled in Part A, the first 3 subjects 
will be dosed at least 48 hours apart; safety data through at least Day 3 from the first 3 subjects 
will be reviewed by the investigators and the sponsor’s medical monitor prior to subsequent 
dosing. After this review, the remaining 21 subjects may be dosed with no more than 10 subjects 
dosed on the same day. Subjects will have maximum study duration of 150 days from baseline. 


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After the parent(s) or legal guardian(s) provide informed consent, subjects will be assessed for 
study eligibility at the screening visit. In Part A, subjects will complete screening within 14 days 
prior to baseline (Day 1). Subjects who continue to meet eligibility criteria at baseline will 
undergo Day 1 baseline assessments and will receive a single dose of REGN2222 30 mg/kg IM 
(maximum 1 dose). Subjects will be monitored in the clinic for 3 hours after dosing, followed by 
a physical examination, and when appropriate, discharge. 
 
The parent(s) or guardian(s) will be provided with an emergency phone number and will be 
given written and verbal instructions to call with any change in the subject’s status. In addition, 
the study staff will contact the parent(s) or legal guardian(s) at the end of Day 1 to inquire about 
any change in the subject’s status, the subject will return to the study site on Day 2 for Visit 3, 
and the study staff will contact the parent(s) or legal guardian(s) on Day 3 to inquire about any 
change in the subject’s status; this will provide at least daily contact for 48 hours after dosing. 
Any new signs or symptoms that have developed in the subject since being dosed will be 
assessed by study staff to determine if there is a need for immediate medical attention and if that 
subject will also need to be seen within 24 hours by the study staff. 
 
The total duration of the study will be up to 164 days (14-day screening period, a single dose 
treatment period, and 150-day follow-up period). An interim PK analysis will be conducted on 
the first 18 infants after at least 1 blood sample is collected for determination of drug 
concentration following administration of study drug. At study completion, a final PK analysis 
will be conducted on all infants enrolled in Part A, who have at least 1 blood sample collected. 
Serious adverse event collection may extend for 30 days past the EOS, as described in 
Section 7.2.2. 
 
An optional substudy, which requires separate informed consent, is being conducted to collect 
DNA from cheek swab samples for future use for the purpose of discovery of predictive 
biomarkers related to RSV infection and severity. 
 
See Section 6.1 for a schedule of study assessments. 


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The dose cohort for Part A is depicted in Figure 1 for REGN2222 30 mg/kg. 
 
Figure 1: 
Part A: 30 mg/kg Single Dose (Maximum 1 Dose REGN2222) 
 
 
 
EOS=end of study; ET=early termination; IM=intramuscular 
Note: The screening visit will occur from Day -14 to Day -1. Black arrow denotes dosing visit. At Visit 2, subjects 
will be monitored on site for 3 hours after dosing. Grey arrows denote study visits at which dosing does not occur. If 
a subject does not have a blood draw scheduled at Visit 4, Visit 5, or Visit 6, then the visit will be conducted by 
telephone. Serious adverse event collection may extend for 30 days past the EOS, as described in Section 7.2.2 
 
3.1.2. 
Part B: Efficacy, Safety, and Immunogenicity of 2 Dose Regimens of REGN2222 
 
Enrollment of Part B will only start following the recommendation to do so by the IDMC, after 
the IDMC has reviewed, at a minimum, the Day 3 safety data of the first 18 subjects who were 
enrolled in Part A and received a single dose of REGN2222. 
 
Regeneron will confirm the dose for Part B. The dose will remain the same as that in part A if 
the PK data up to Day 57 (from subjects enrolled in Part A) are consistent with the predicted 
concentrations, after age and body weight corrections, as defined in Appendix B. 
 
The decision to proceed from Part A to Part B, along with the confirmation of the dose regimens 
to be used in Part B, will be communicated in writing to the investigators, Ethics Committees 
and the competent authorities (Section 13.4) by the sponsor. Part B will be initiated based on the 
written communication prior to formally amending the protocol for the purpose of altering the 
dose, if applicable. 
 
3.1.2.1. 
Randomization and Stratification for Part B 
 
A total of 3 treatment arms (1 dose of REGN2222 and 1 dose of placebo; 2 doses of REGN2222; 
and 2 doses of placebo) with a total of 1515 subjects are planned in Part B randomized in a 
1:1:1 ratio (505 subjects in each arm for a total of 1010 assigned to receive REGN2222 
[505 subjects in each of the 2 REGN2222 arms] and 505 subjects to receive placebo). 
Randomization will be stratified by region (North America or rest of the world) and GA 
(≤31 weeks, 6 days GA or from 32 weeks, 0 days to 35 weeks, 6 days GA). 


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3.1.2.2. 
Dose Selection for Part B 
 
Two dosing regimens of REGN2222 will be assessed in Part B (Section 1.2.2.2). The treatment 
arms for Part B are depicted in Figure 2. The placebo arm will include a maximum of 2 doses of 
placebo. 
 
Figure 2: 
Part B: 30 mg/kg IM (Maximum 1 Dose REGN2222 and 1 Dose Placebo), 
30 mg/kg IM (Maximum 2 Doses), or Placebo IM (Maximum 2 Doses) 
 
 
 
EOS = end of study; IM = intramuscular; Q8 = every 8 
Note: The screening visit occurs from Day -28 to Day -1. Black arrows denote dosing visits. Subjects will be 
monitored on site for at least1 hour after each dose of REGN2222 or placebo. Grey arrows denote study visits at 
which dosing does not occur. Visits 8, 9, and 10 will occur via phone call. In the event an AE is reported during a 
phone call visit, an unscheduled onsite visit may be required to follow-up, per investigator. 
 
3.1.2.3. 
Study Enrollment and Assessments 
 
After the parent(s) or legal guardian(s) provide informed consent (obtained up to 28 days prior to 
randomization), subjects will be assessed for study eligibility at the screening visit. Subjects will 
undergo screening within 28 days prior to randomization. Subjects who continue to meet 
eligibility criteria at baseline will undergo Day 1 baseline assessments and will be randomly 
assigned in a 1:1:1 ratio to REGN2222 30 mg/kg single dose (maximum 1 dose REGN2222 and 
1 dose placebo), REGN2222 30 mg/kg Q8 weeks (maximum 2 doses of REGN2222), or placebo 
(maximum 2 doses of placebo). Subjects will be monitored in the clinic for at least 1 hour after 
dosing, followed by discharge, when appropriate. 
 
The parent(s) or guardian(s) will be provided with an emergency phone number and will be 
given written and verbal instructions to call with any change in the subject’s status. In addition, 
the study staff will contact the parent(s) or legal guardian(s) at the end of the day and daily over 


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48 hours to inquire about any change in the subject’s status. Any new signs or symptoms that 
have developed in the subject since the last dose will be assessed by study staff to determine if 
there is a need for immediate medical attention and if that subject will also need to be seen 
within 24 hours by the study staff. 
 
It is recommended that site personnel contact the parent(s) or legal guardian(s) weekly between 
routine study visits, to obtain information about medically attended acute respiratory events and 
to remind the parent(s) or legal guardian(s) about the next scheduled study visit. Parent(s) or 
guardian(s) will be instructed to contact study personnel to report any abnormalities, including 
any hospitalizations or doctor visits, during the intervals between study visits and to come to the 
study site if medical evaluation is needed and the urgency of the situation permits. The follow-up 
period for the occurrence of RSV-confirmed medical attention will continue until the end of the 
150 day study period. 
 
In Part B, assessment of the primary and secondary clinical endpoints (Section 8.2 and 
Section 8.3 for endpoints) will only occur during the 150 day study period. Any RSV infection 
occurring after Day 150 will not be included in the efficacy evaluation. If a primary endpoint is 
reached during the study period (Section 8.2), ongoing assessments for other endpoints and 
measurements will continue until the end of the study period. Any subject who has had a positive 
RT-PCR RSV nasal swab result, either at the study central laboratory or at an outside institution 
in a Clinical Laboratory Improvement Amendments (CLIA)-certified (or equivalent) laboratory, 
should not receive a second dose of study drug. The risk of a second RSV infection is 
substantially (~70%) reduced for 6 months after the first infection and this practice is consistent 
with recommendations in the 2014 AAP guidelines for palivizumab prophylaxis (Ohuma 2012). 
Subjects who have reached the primary endpoint will continue to be monitored for additional 
medically attended acute respiratory infections that may occur during the study period. 
 
All subjects will be monitored for safety until the end of the study at Day 237. Safety monitoring 
after Day 150 through Day 237 (end of study) will be made by telephone call, only to solicit 
information about concomitant medications and AEs. In order to minimize total blood samples 
obtained throughout the study, a sparse blood collection schedule will be implemented based on 
a blood collection schedule that includes up to 3 total planned blood draws for each infant for 
safety laboratory tests, PK, and ADA assays. The schedules of events are provided in 
Section 6.1. Subjects who complete Day 150 may be eligible to enroll in a subsequent extension 
study in which they will be monitored for medically attended episodes of wheezing over a 
12-month period. 
 
The end of study will be approximately 180 days after the last dose or approximately 237 days 
after the first dose, whichever is longer. 
 
3.1.2.4. 
Onstudy Potential Respiratory Illness and the Medical Information Packet 
 
During the 150-day efficacy assessment period, data will be collected on subjects with any acute 
respiratory illness requiring medical attention. After enrollment into the study, subjects taken by 
their parent(s) or guardian(s) to a healthcare provider (inpatient or outpatient, including 
hospitalizations, ER, UC, or pediatric clinic) for any of the following symptoms will be asked to 
contact the study staff immediately or soon after seeking medical attention: fever, cough, 


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earache, nasal congestion, rhinorrhea, vomiting after coughing, wheezing, and difficulty 
breathing (labored, rapid, or shallow). 
 
When the parent(s) or guardian(s) takes their child for medical attention for an acute respiratory 
infection, they will be instructed to take a Medical Information Packet with them for the treating 
clinician. The Medical Information Packet will include important information regarding a 
potential acute respiratory infection, including information about this clinical trial and a checklist 
to provide guidance for the healthcare provider in documenting specific signs and symptoms 
related to the respiratory illness into the medical chart. The Medical Information Packet will be 
provided to the parents at randomization (Visit 2) (Table 2). 
 
All infants who have a medically attended visit for a respiratory illness will be asked to have an 
unscheduled study visit (Section 6.2.3) as soon as possible or within 72 hours of discharge from 
the medical facility. Parents/guardians will be instructed to provide the Medical Informational 
Packet containing the contact information of the treating healthcare provider to study staff during 
the unscheduled visit. Medical records will be obtained by the investigator to gather information 
about LRTI symptoms, as outlined in the checklist; treatments provided; and concomitant 
medications or products. 
 
Study site personnel will evaluate the subject during an unscheduled visit as soon as possible or 
within 72 hours after receipt of medical attention. Evaluation will include a history of the acute 
illness and nose swab collections for viral detection will occur. All nose swabs will be tested 
using a reverse-transcriptase polymerase chain reaction (RT-PCR) assay for RSV, which will be 
conducted in a central laboratory. All RSV isolates will be subtyped. If the unscheduled study 
visit following a medically attended respiratory infection occurs >72 hours but <14 days of 
discharge from the medical facility, all procedures (as appropriate), including nose swab 
collection, should occur despite being outside of the 72 hour window. If the child has had an 
RSV-confirmed medically attended visit, nose swab collection will be required at the 
unscheduled study visit. Unscheduled study visits for medically attended respiratory illness will 
be required through Day 150 even if a child has had a prior RSV-confirmed or other respiratory 
illness. Unscheduled study visits for medically attended respiratory illness will not be required 
between Day 151 and Day 237 (end of study) for the purpose of nose swab collection. 
 
A new Medical Information Packet will be provided to the parent(s) or guardian(s) following 
each potential medically attended respiratory illness visit. 
 
For infants who do not have an RSV RT-PCR assay for RSV infection done by the central 
laboratory, study site personnel will obtain and record information about all RSV RT-PCR assay 
done in a medical facility, including result(s), name of the assay(s) and whether the 
laboratory(ies) conducting the RT-PCR is a CLIA (Clinical Laboratory Improvement 
Amendments) certified (or equivalent) laboratory. 
 
3.1.2.5. 
Optional Substudy 
 
An optional substudy is to collect a cheek swab from subjects for DNA for future use for the 
purpose of discovery of predictive biomarkers. See Section 6.1 for a schedule of study 
assessments. 


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3.2. 
Study Stopping Rules 
 
If the following are observed, the study will be temporarily halted (screening, randomization, 
dosing of study drug) by the sponsor: 
 
• Two similar (by preferred term [PT]) treatment-related Grade 3 SAEs that are not 
generally reported in the preterm population; or 
 
• One treatment-related Grade 4 SAE that is not generally reported in the preterm 
population. 
 
In order to assess whether these SAEs are in the treatment arms, only unblinded study members 
and/or the IDMC will make the assessment for the need to halt the study. The sponsor will 
follow the relevant regulatory requirements for reporting of SAEs to regulatory authorities and 
ethics committees and the data will be submitted to the appropriate authorities as required. A full 
evaluation will be conducted to determine if it is appropriate to continue the study. In the event 
the study will be restarted, local regulatory procedures will apply. 
 
Generally reported AEs in the preterm population include but are not limited to:  hypothermia, 
hypoglycemia, respiratory distress, apnea (with or without bradycardia), hyperbilirubinemia, 
feeding difficulties, poor weight gain, dehydration, respiratory disorders (including 
bronchiolitis), gastrointestinal disorders, and sudden infant death syndrome. 
 
3.2.1. 
End of Study Definition 
 
The end of study will be approximately 180 days after the last dose or approximately 237 days 
after the first dose, whichever is longer. 
 
3.3. 
Study Committees 
 
3.3.1. 
Independent Data Monitoring Committee 
 
An IDMC, composed of members who are independent from the sponsor and the investigators, 
will monitor subject safety by conducting formal reviews of accumulated safety data that will be 
blinded by treatment group; if requested, the IDMC may have access to the treatment allocation 
code or any other requested data for the purposes of a risk-benefit assessment. 
 
The IDMC will provide the sponsor with appropriate recommendations on the conduct of the 
clinical study to ensure the protection and safety of the subjects enrolled in the study. The IDMC 
will also recommend any measures that may be required for ensuring the integrity of the study 
results during the study execution. 
 
All activities and responsibilities of the IDMC are described in the IDMC charter. 
 
3.3.2. 
Safety Monitoring Team 
 
A cross-functional safety monitoring team (SMT) at Regeneron Pharmaceuticals, Inc. 
(Regeneron) will meet periodically to review blinded safety data. These data will include, but 
may not be limited to: 
 
• TEAEs that result in an early study withdrawal 


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• SAEs 
 
• Selected laboratory test results 
 
• Additional AEs of interest, as determined by the SMT 
 
Any signals identified through this review will be investigated and monitored. The SMT will 
propose risk management/mitigation activities as needed and will monitor their impact. 
 
3.3.3. 
Endpoint Adjudication Committee 
 
An adjudication committee will be formed before database lock, to address any categorization of 
a medically attended respiratory illness event as an endpoint that is unclear. Source 
documentation will be provided to a blinded adjudication committee for categorization. In 
addition, any subject deaths occurring after the administration of the first dose of study drug and 
prior to Day 150 will be assessed to determine their association with RSV. 
 
4. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
SUBJECTS 
 
4.1. 
Number of Subjects Planned 
 
A total of 1539 subjects are planned to be enrolled, as follows: 
 
• Part A: Single cohort study with approximately 24 subjects planned to receive 
REGN2222 
 
• Part B: 3-arm study with approximately 505 subjects planned in each of the 3 
treatment arms for a total of 1515 subjects (1010 to receive REGN2222 [505 subjects 
in each of the 2 REGN2222 arms]; 505 to receive placebo) 
 
This study will be conducted at multiple sites in the US, Canada, Australia, and New Zealand, as 
well as several countries in Europe. Additional countries/regions may be added. 
 
The study population will consist of healthy male and female infants who have a chronological 
age of ≤6 months at the time of first dose (ie, dosing on or before the subject’s 6-month 
birthday), who have a GA no more than 35 weeks, 6 days, and who are not eligible, 
recommended, nor have access to receive palivizumab by standard practice, local guidelines, or 
their healthcare provider. 
 
4.1.1. 
Inclusion Criteria 
 
A subject must meet the following criteria to be eligible for inclusion in the study: 
 
1.   Preterm, otherwise healthy male or female infant who has a chronological age of 
≤6 months of age at the time of the first dose (ie, infant must receive the first dose on or 
before the subject’s 6-month birthday) 
 
2.   Gestational age at birth is no more than 35 weeks, 6 days 
 
3.   Parent(s) or legal guardian(s) of the infant is able to understand the study requirements, 
willing to provide informed consent, and legally able to provide informed consent. 


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4.1.2. 
Exclusion Criteria 
 
4.1.2.1. 
Exclusion Criteria for the Infant 
 
An infant who meets any of the following criteria will be excluded from the study: 
 
1.   Eligible, recommended, and have access to receive palivizumab per AAP or other local 
guidelines, standard practice, or by their healthcare provider 
 
2.   Diagnosis of CLD defined as requirement of supplemental oxygen for at least 28 days 
(cumulative) after birth; exceptions are infants who have received supplemental oxygen 
as standard of care for reasons other than CLD. 
 
3.   Known hemodynamically significant congenital heart disease 
 
4.   Known immunodeficiency, neuromuscular disease, or congenital abnormalities of the 
airway 
 
5.   Known renal or hepatic dysfunction 
 
6.   Serum creatinine, bilirubin, alkaline phosphatase hepatic enzymes (aspartate 
aminotransferase [AST] and alanine aminotransferase [ALT]) total that is >1.1 times the 
upper limit of normal for gestational age and chronological age (Appendix G). 
Exceptions are if the investigator has evidence that increased alkaline phosphatase 
corresponds to normal bone growth of preterm infancy, if the investigator has evidence 
that increased indirect bilirubin corresponds to a Gilbert’s-type syndrome, or that it 
corresponds to an increase in bilirubin due to physiological jaundice, breastfeeding 
jaundice, or other conditions commonly found in otherwise healthy preterm infants and 
neonates). 
 
7.   Any other laboratory findings showing evidence of organ dysfunction or any clinically 
significant deviation from the normal range for gestational age and chronological age, as 
decided by the investigator at the screening visit 
 
8.   Use of any concomitant medications within 30 days of the screening visit, including 
prescription medications (exceptions are those used as standard of care, such as 
antibiotics, topical analgesic for blood draws [not to be used for IM injections, including 
vaccines], nutritional supplements, medications for gastroesophageal reflux, topical 
medications, and eye drops), and over-the-counter medications (except for vitamin 
supplements, ibuprofen, acetaminophen, or topical creams) 
 
9.   Vaccine or other IM drug administration within 2 days before or after dosing of the study 
drug 
 
10. History of hospitalization prior to screening; exceptions include hospitalization for 
delivery and the subsequent stay for preterm infants; uncomplicated or elective surgeries 
(eg, circumcision, repairs of uncomplicated hernia without sequelae). 
 
11. Life expectancy of <6 months 
 
12. Major congenital malformations, including congenital cleft palate, cytogenetic 
abnormalities, or serious chronic disorders 
 
13. Known or suspected impairment of immunological functions or autoimmune diseases 


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14. History of anaphylaxis 
 
15. History of a seizure disorder 
 
16. Previously received palivizumab, IV gamma globulin, or any other investigational RSV 
prophylaxis or vaccine product 
 
17. Previous allergic reaction to IV immunoglobulin, blood products or other foreign 
proteins, such as vaccines and monoclonal antibodies, or any of the components of the 
investigational product formulation 
 
18. Participation in any clinical research study evaluating another investigational drug or 
therapy that is inconsistent with current standard of care within at least 5 half-lives of the 
investigational drug prior to the screening visit 
 
4.1.2.2. 
Exclusion Criteria for the Mother 
 
An infant will be excluded from the study if the biological mother meets any of the following 
criteria: 
 
1.   Is younger than 16 years old or is unable to legally provide informed consent at the time 
of screening of the infant 
 
2.   Has self-reported history of illicit drug or alcohol abuse during pregnancy with the infant 
 
3.   Has self-reported or confirmed history of human immunodeficiency virus or hepatitis B 
 
4.   Has self-reported history of receiving an investigational RSV vaccine 
 
4.2. 
Premature Withdrawal From the Study 
 
The parent(s) or legal guardian(s) of a subject has the right to withdraw the subject from the 
study at any time, for any reason, and without repercussions to their future medical care by the 
investigator or at the study site. Every effort should be made to keep subjects in the study. The 
reason for subjects not completing the study will be recorded by the investigator on the relevant 
page of the case report form (CRF). 
 
The investigator and sponsor have the right to withdraw a subject from the study in the event of 
an intercurrent illness, AE, treatment failure, protocol violation, and for administrative or other 
reasons. An excessive rate of withdrawals would render the study uninterpretable; therefore, 
unnecessary withdrawal of subjects should be avoided. 
 
For subjects who fail to return for assessments, the study site will make every attempt to contact 
the parent(s) or legal guardian(s) to have them comply with the protocol. A minimum of 
3 telephone call attempts should be documented on different days over the course of 14 days 
following a missed assessment. 
 
A subject who withdraws from the study with an ongoing AE or SAE must be followed until it is 
resolved or deemed stable. In every case, efforts must be made to undertake protocol-specified 
safety follow-up procedures. All study assessments are specified in the schedule of study 
assessments, Section 6.1. 


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4.3. 
Replacement of Subjects 
 
Subjects prematurely discontinued from the study will not be replaced. 
 
5. 
STUDY TREATMENTS 
 
5.1. 
Investigational and Reference Treatments 
 
REGN2222 drug product will be supplied as a lyophilized powder in a 20 mL glass vial. Each 
vial contains 265 mg of REGN2222. Upon reconstitution with 1.4 mL of sterile water for IM 
injection, the composition of the drug product is 150 mg/mL REGN2222. 
 
Placebo product will be supplied in vials that match the REGN2222 drug product, but will not 
contain the active protein. Instructions on dosing preparation are provided in the pharmacy 
manual. 
 
During the screening period, the subject will be evaluated within 2 weeks (from Day -14 to 
Day -1) in Part A and within 4 weeks (from Day -28 to Day -1) in Part B, prior to receiving any 
study drug. On Day 1 (baseline), all subjects will be assigned and administered the first dose of 
study drug. 
 
• In Part A, subjects will be open-label assigned to a single cohort (Section 5.4.1) 
 
• In Part B, subjects will be randomly assigned to 1 of 3 treatment arms (Section 5.4.2) 
 
5.2. 
Dose Modification and Study Drug Discontinuation Rules 
 
5.2.1. 
Dose Modification 
 
Dose modification for an individual subject is not allowed in Part A or Part B. 
 
5.2.2. 
Study Drug Discontinuation 
 
For Part A or Part B, subjects 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. 
 
Subjects who withdraw from the study will be asked to complete study assessments, as specified 
in Section 6.1. 
 
5.2.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
 
Part A consists of only 1 dose. 
 
Part B: Study drug dosing in individual subjects will be permanently stopped for any of the 
following reasons: 
 
• The infant experiences acute systemic injection reactions with AEs including, but not 
limited to, anaphylaxis, laryngeal/pharyngeal edema, severe bronchospasm, seizure, 
or severe hypotension 
 
• The infant experiences a Grade 3 or greater drug-related AE 


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• The infant has an RSV-positive RT-PCR result at the study central laboratory or a 
CLIA (or equivalent) certified laboratory after receipt of the first dose of study drug, 
but prior to the second dose of study drug. 
 
• The parent(s) or legal guardian(s) of a subject withdraws consent 
 
• A decision is made by the sponsor to stop treating an individual subject with study 
drug 
 
• A decision is made by the sponsor to stop the study (Section 3.2) 
 
5.2.2.2. 
Reasons for Temporary Discontinuation of Study Drug 
 
For Part B only: The investigator may temporarily discontinue study drug dosing at any time, 
even without consultation with the medical monitor, if the urgency of the situation requires 
immediate action and if this is determined to be in the subject’s best interest. However, the 
medical monitor should be contacted as soon as possible in any case of temporary or permanent 
study drug discontinuation. Resumption of study drug requires consultation and agreement 
between the investigator and the medical monitor. 
 
5.3. 
Management of Injection Site Reactions 
 
In both Part A and Part B, injection site reactions will be managed according to the type of 
reaction. 
 
5.3.1. 
Acute Systemic Injection Reactions 
 
Acute systemic injection reactions are AEs that occur during the IM injection of study drug or 
within 2 hours after the injection is completed. Emergency equipment and medication for the 
treatment of these potential AEs (eg, antihistamines, bronchodilators, IV saline, corticosteroids, 
acetaminophen, and/or epinephrine) must be available for immediate use. Study personnel must 
be trained to recognize and treat anaphylaxis. If generalized urticaria, wheezing, hypotension, or 
anaphylaxis occurs, dosing should be discontinued immediately, and treatment will be given for 
severe symptoms as medically indicated in an appropriate timeframe based on symptom severity. 
 
An acute systemic reaction after injection must be reported as an AE of special interest (AESI) 
and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.0 criteria for grading allergic reactions and anaphylaxis (Appendix D). Management of 
acute hypersensitivity reactions is addressed in Section 5.3.3. 
 
5.3.2. 
Delayed Onset Reactions 
 
A delayed onset reaction (defined as a reaction that occurs from 2 hours to 48 hours after IM 
injection), which is considered an allergic or hypersensitivity reaction, must be reported as an 
AESI (Section 7.2.4.2) and graded according to the CTCAE Version 4.0 criteria for grading 
allergic reactions and anaphylaxis (Appendix D), if the AE is considered to be allergic in nature. 
 
Management of delayed hypersensitivity reactions is addressed in Section 5.3.3. 
 
For delayed injection site reactions that are not considered to be allergic or hypersensitivity 
reactions, refer to Section 5.3.4. 


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5.3.3. 
Hypersensitivity Reactions 
 
Hypersensitivity reactions must be reported as AESIs (Section 7.2.4.2) and graded according to 
the CTCAE Version 4.0 criteria for grading allergic reactions and anaphylaxis (Appendix D). 
 
Any reaction that is suspected to be a hypersensitivity reaction requires a complete AE work-up 
and the following additional procedures (Table 4): 
 
• Complete blood count with differential 
 
• Liver function test 
 
• ADA testing 
 
• Photographic documentation of the rash, if present 
 
5.3.4. 
Local Injection Site Reactions 
 
Local injection site reactions must be reported as AEs and graded according to the Modified 
Toxicity Grading Scale from Division of AIDS for Grading the Severity of Adult and Pediatric 
Adverse Events (Version 2.0, December 2014; Division of AIDS). 
 
5.4. 
Method of Treatment Assignment 
 
5.4.1. 
Part A: Open-label Treatment with 30 mg/kg IM (Maximum 1 Dose) 
 
In Part A, subjects will be assigned through the interactive voice response system (IVRS; or 
interactive web response system [IWRS]) to receive a single dose of open-label REGN2222. 
 
Part A is open-label and there will be no blinding. 
 
5.4.2. 
Part B: Randomized Treatment with 30 mg/kg (1 Dose REGN2222 and 1 Dose 
Placebo); or 30 mg/kg IM (2 Doses REGN2222); or Placebo IM (Maximum 
2 Doses) 
 
In Part B, a total 1515 subjects will be randomly assigned in a 1:1:1 ratio through the 
IVRS/IWRS to 2 dosing regimens or placebo (505 subjects in each arm for a total of 
1010 subjects assigned to receive REGN2222 [505 subjects in each of the 2 REGN2222 arms] 
and 505 subjects to receive placebo). Randomization in Part B will be stratified by region (North 
America or rest of the world) and GA (≤31 weeks, 6 days GA or from 32 weeks, 0 days to 
35 weeks, 6 days GA). 
 
An independent randomization team will create the actual randomization schedule and deliver it 
to the IVRS/IWRS. The randomization schedule is computer-generated using block 
randomization, stratified by region (North America or rest of the world) and GA (≤31 weeks, 
6 days GA or from 32 weeks, 0 days to 35 weeks, 6 days GA). 
 
5.4.2.1. 
Blinding 
 
The parent(s) or guardian(s) of study subjects, the principal investigators, and study site 
personnel will remain blinded to all subject assignments throughout the study. The sponsor’s 
study director, medical monitor, study monitor, and any other sponsor and contract research 


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organization personnel who are in regular contact with the study site will remain blinded to all 
subject assignments. 
 
For Part B, a pharmacist (or other qualified individual) will be unblinded at each site. All 
unblinded personnel must be appropriately trained to ensure they understand their 
responsibilities to maintain the blind. 
 
Selected individuals not involved in the conduct of the study may have access to unblinded data 
as needed for safety review or other data review. 
 
Unblinded (open-label) study drug will be prepared and blinded by the study 
pharmacist(s)/designee according to the pharmacy manual. 
 
Antidrug antibody results will not be communicated to the sites, and the sponsor’s operational 
team will not have access to results associated with subject identification until after the final 
database lock. 
 
No study personnel involved in the day-to-day conduct of the study will have access to 
unblinded data before the database is locked for this study. 
 
While the study is ongoing, it is anticipated that unblinded data, after the first step analysis 
(Section 9.5.6.1), may be submitted to health authorities.  Sponsor representatives who will 
conduct and review such data analyses for submission to the health authorities will not be part of 
the study operational team from that point forward, and subject level results will not be provided 
to the study sites.  The analysis process, the measures used to protect the blind and the integrity 
of the study, and a communication plan and confidentially agreement will be described in a 
separate document. 
 
5.4.2.2. 
Emergency Unblinding 
 
Unblinding of treatment assignment for a subject may be necessary due to a medical emergency 
and other significant medical event or for expedited reporting. 
 
If unblinding is required at the site: 
 
• Only the investigator will make the decision to unblind the treatment assignment. 
 
• Only the affected subject will be unblinded. 
 
• The designated study pharmacist(s) (designee) at the study site will provide the 
treatment assignment to the investigator. If there is no study pharmacist (or designee) 
available, the investigator for the site will unblind the subject, using the IVRS/IWRS. 
 
• The investigator will notify the sponsor (designee) before unblinding the subject, 
whenever possible. 
 
The treatment assignment is not to be provided to site personnel, including the investigator, at 
any time during the conduct of the study, except in the case of a true emergency. 
 
For individual cases, serious, related (as assessed by investigator and/or company) and unlisted 
events, pharmacovigilance (designee) will unblind the treatment assignment before reporting to 
the health authorities. Based on Section 3.3, Section 7.4, and the IDMC charter, the IDMC may 
also be unblinded as part of the safety review. 


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5.5. 
Treatment Logistics and Accountability 
 
5.5.1. 
Packaging, Labeling, and Storage 
 
A medication numbering system will be used in labeling unblinded investigational study drug. 
Lists linking medication numbers with product lot numbers will be maintained by the groups (or 
companies) responsible for study drug packaging. In order to maintain the blind, these lists will 
not be accessible to individuals involved in study conduct. 
 
Study drug will be stored at the site 
; storage instructions will be 
provided in the pharmacy manual. 
 
5.5.2. 
Supply and Disposition of Treatments 
 
Study drug will be shipped 
to the investigator (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 returned to 
the sponsor (designee). 
 
5.5.3. 
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, study medication dispensed to each subject, and whether 
disposed of at the site or returned to the sponsor (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. 
 
5.5.4. 
Treatment Compliance 
 
All drug compliance records must be kept current and must be made available for inspection by 
the sponsor and regulatory agency inspectors. 
 
5.6. 
Concomitant Medications and Procedures 
 
Any treatment administered from the time of the first dose of study drug to the end of study/early 
termination visit will be considered concomitant medication. This includes medications that were 
started before the study and are ongoing during the study. Medication considered necessary for 
the subject’s safety and well-being may be given at the discretion of the investigator and 
recorded. For all concomitant medications, the date, reason given, and dose will be recorded in 
the CRF. 
 
5.6.1. 
Prohibited Medications and Procedures 
 
The use of any concomitant medications within 30 days of the screening visit, including 
prescription medications (except those used as standard of care, such as antibiotics, topical 
analgesic for blood draws [not to be used for IM injections, including vaccines], nutritional 
supplements, medications for gastroesophageal reflux, topical medications, and eye drops) and 


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over-the-counter medications (except for vitamin supplements, ibuprofen, acetaminophen, and 
topical creams) is prohibited. No vaccinations will be administered within 2 days before or after 
dosing of the study drug. 
 
5.6.2. 
Permitted Medications and Procedures 
 
Nutritional supplements (including over-the-counter vitamin supplements), standard of care 
treatments such as antibiotics, medicines for gastroesophageal reflux, eye drops, ibuprofen, 
acetaminophen, topical analgesic for blood draws (not to be used for IM injections, including 
vaccines), topical medications, and topical creams, are permitted. 
 
Routine vaccinations will be allowed. For further information regarding vaccination criteria, see 
Section 4.1.2.1, exclusion criteria # 9. 
 
6. 
STUDY SCHEDULE OF EVENTS AND VISIT DESCRIPTIONS 
 
6.1. 
Schedule of Events 
 
The schedules of events are provided as follows: 
 
• Part A: 30 mg/kg IM single dose (maximum 1 dose REGN2222) in Table 1 
 
• Part B: 
 
− 30 mg/kg IM single dose (maximum 1 dose of REGN2222 [Day 1] and maximum 
1 dose of placebo [Day 57]); or 
 
− 30 mg/kg IM Q8 weeks (maximum 2 doses of REGN2222); or 
 
− IM placebo (maximum 2 doses placebo) in Table 2 
 
• Part B: Unscheduled respiratory illness visit for all dosing regimens in Table 3 
 
• Part A and Part B: Unscheduled visits for AEs, including potential hypersensitivity 
reactions in Table 4 


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Table 1: 
Part A: 30 mg/kg IM (Maximum 1 Dose REGN2222); for Subjects with Schedules A through H 
Study Periods 
SV1 
BV 
Postdose Follow-Up 
Visit 
1 
2 
3 
42 
52 
62 
7 
8 
9 
10 
11EOS/ET 
Day 
-14 to -1 1 
2 
8 
15 
22 
29 
57±5 
85±5 
113±5 
150±5 
Informed Consent 
X 
Inclusion/Exclusion 
X 
X 
Medical History 
X 
Demographics 
X 
IVRS/IWRS Assigned Blood Collection 
Schedule3 
X 
Administer Study Drug 
X4 
Concomitant Medications and Procedures 
X 
X 
X 
X2 
X2 
X2 
X 
X 
X 
X 
X 
Vital Signs5 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination (including weight) 
X 
X6 
X 
X 
X 
Adverse Events7 
X 
X 
X 
X2 
X2 
X2 
X 
X 
X 
X 
X 
Hematology 
X8-15 
X8 
X9 
X10 
X11 
X12 
X13 
X14 
X15 
X8-15 
Blood Chemistry 
X8-15 
X8 
X9 
X10 
X11 
X12 
X13 
X14 
X15 
X8-15 
Pharmacokinetics 
X8 
X9 
X10 
X11 
X12 
X13 
X14 
X15 
X8-15 
Anti-REGN2222 (ADA) 
X8-15 
X11 
X12 
X13 
X14 
X15 
X8-15 
Optional Sub-study Informed Consent 
X 
Optional DNA Sample 
X16 
ADA=antidrug antibody; BV=baseline visit, EOS/ET=end of study/early termination; IVRS=interactive voice response system; IWRS=interactive web response 
system; SV=screening visit; X=all subjects unless otherwise specified 


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1.   All safety assessments performed at screening must be normal and checked against the inclusion/exclusion criteria before REGN2222 administration on 
Day 1(baseline) 
2.   Visit 4, Visit 5, and Visit 6 will be conducted by telephone to collect concomitant medication and adverse event information for all subjects, unless subjects 
are required by dosing schedule (Schedule C, Schedule D, and Schedule E) to undergo a PK/ADA and hematology/chemistry blood d raw. Those subjects 
assigned to Schedule C (Footnote 11), Schedule D (Footnote 10), and Schedule E (Footnote 9) will have an onsite visit. 
3.   Subject blood collection schedules are assigned using the IVRS/IWRS. 
4.   No other vaccinations will be administered within 2 days before or after dosing of the study drug. The study staff will contact the parent(s) or legal 
guardian(s) at the end of Day 1 and on Day 3 by telephone to inquire about any change in the subject’s status. 
5.   On the study drug dosing day, vital signs (temperature, blood pressure, pulse, and respiration) will be assessed prior to injection of study drug and 1, 2, and 
3 hours (±10 minutes) after completion of the injection. If a subject’s rectal temperature is 101°F/38.3°C (equivalent to axillary temperature of 
100.6°F/38.1°C for infants <4 weeks of age or 99.2°F/ 37.3°C for infants ≥4 weeks of age) or greater on the day of a planned dose administration day, no 
dosing will occur. The subject will be re-evaluated within 48 hours and if the subject’s temperature is below 101°F (38.3°C) without the use of antipyretics 
during the previous 48 hours, the schedule of assessments may be resumed. If the subject’s temperature is 101°F (38.3°C) or g reater or the subject has 
received antipyretics in the previous 48 hours, dosing of the subject will be permanently discontinued. 
6.   Physical examination will be conducted before injection and after injection, prior to discharge from the clinic, at Visit 2. 
7.   If the adverse event is considered a hypersensitivity or anaphylaxis reaction, then the adverse event will be assessed as outlined in (Table 4). If the adverse 
event is a hypersensitivity reaction that results in a rash, then a photo will be taken as part of the adverse event assessment as outlined in (Table 4). 
8.   The subjects with blood collection Schedule F will have the following collected: hematology/chemistry samples at screening, Day 2, and EOS/ET; PK 
samples on Day 2 and EOS/ET; and ADA samples at screening and EOS/ET. 
9.   The subjects with blood collection Schedule E will have the following collected: hematology/chemistry samples at screening, Day 8, and EOS/ET; PK 
samples on Day 8 and EOS/ET; and ADA samples at screening and EOS/ET. 
10. The subjects with blood collection Schedule D will have the following collected: hematology/chemistry samples at screening, Day 15, and EOS/ET; PK 
samples on Day 15 and EOS/ET; and ADA samples at screening and EOS/ET. 
11. The subjects with blood collection Schedule C will have the following collected: hematology/chemistry samples at screening, Day 22, and EOS/ET; PK 
samples drawn on Day 22 and EOS/ET; and ADA samples drawn at screening, Day 22, and EOS/ET. 
12. The subjects with blood collection Schedule B will have the following collected: hematology/chemistry samples at screening, Day 29, and EOS/ET; PK 
samples on Day 29 and EOS/ET; and ADA samples at screening, Day 29, and EOS/ET. 
13. The subjects with blood collection Schedule A will have the following collected: hematology/chemistry samples at screening, Day 57, and EOS/ET; PK 
samples on Day 57 and EOS/ET; and ADA samples at screening, Day 57, and EOS/ET. 
14. The subjects with blood collection Schedule G will have the following collected: hematology/chemistry samples at screening, Day 85, and EOS/ET; PK 
samples on Day 85 and EOS/ET; and ADA samples at screening, Day 85, and EOS/ET. 
15. The subjects with blood collection Schedule H will have the following collected: hematology/chemistry samples at screening, Day 113, and EOS/ET; PK 
samples on Day 113 and EOS/ET; and ADA samples at screening, Day 113, and EOS/ET. 
16. After substudy consent, a cheek swab for DNA in the optional substudy can be obtained at any time during the study period, but preferably at baseline. 


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Table 2: 
Part B: 30 mg/kg IM (Maximum 1 Dose REGN2222 and Maximum 1 Dose Placebo); 30 mg/kg IM (Maximum 
2 Doses REGN2222); or Placebo IM (Maximum 2 Doses); for Subjects with Schedules I through M 
 
Study Periods 
SV1 
BV 
Treatment Period 
Postdose Follow-Up 
Visit 
1 
2 
3 
4 
5 
6 
7/ET 
817 
917 
10/EOS17 
Day 
-28 to -1 
1 
29±2 
57±2 
85±5 
113±5 
150±5 
178±10 
206±10 
237±10 
Informed Consent18 
X 
Inclusion/Exclusion 
X 
X 
Medical History 
X 
Demographics 
X 
Randomization2 
X 
Dispense Medical Information Packet3 
X 
Administer Study Drug4 
X5 
X5 
Concomitant Medications and Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs6 
X 
X 
X 
X 
X 
X 
X 
Physical Examination (including weight) 
X 
X7 
X 
X7 
X 
X 
Adverse Events8 
X 
X9 
X9 
X9 
X9 
X9 
X9 
X9, 17 
X9, 17 
X9, 17 
Blood Sampling 
Hematology 
X10-14 
X10 
X11 
X12 
X13 
X10-14 
Blood Chemistry 
X10-14 
X10 
X11 
X12 
X13 
X10-14 
Pharmacokinetics 
X10 
X11 
X12 
X13 
X10-14 
Anti-REGN2222 (ADA) 
X10-14 
X10 
X11 
X\12 
X13 
X10-14 


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Study Periods 
SV1 
BV 
Treatment Period 
Postdose Follow-Up 
Visit 
1 
2 
3 
4 
5 
6 
7/ET 
817 
917 
10/EOS17 
Day 
-28 to -1 
1 
29±2 
57±2 
85±5 
113±5 
150±5 
178±10 
206±10 
237±10 
Optional Substudy Informed Consent 
X 
Optional DNA Sample 
X15 
Pharmacoeconomic Information16 
X 
X 
X 
X 
X 
X 
Risk Factors Assessment 
X 
ADA=antidrug antibody; BV=baseline visit, EOS/ET=end of study/early termination; IM=intramuscular; SV=screening visit; X=all subjects unless otherwise 
specified 
1. All safety assessments performed at screening must be normal and checked against the inclusion/exclusion criteria before REGN2222 administration on 
Day 1(baseline) 
2. Subject randomization and blood collection schedules are assigned using the interactive voice response system (or interactive web response system) at 
Visit 2. Depending on the availability of the study pharmacist or designee, subjects may be randomly assigned on Day -1 or Day 1. 
3. When parent(s) or guardian(s) take their child for medical attention outside of the study site, the parents/guardians are instructed to take the Medical 
Information Packet with them for use by their healthcare provider. Data on medically attended RSV infections will be collected for all subjects until 
Day 150. 
4. Subjects randomly assigned to the 30 mg/kg Q8w arm will receive REGN2222 on Day 1 and Day 57. Subjects randomly assigned to t he single 30 
mg/kg arm will receive REGN2222 on Day 1 and placebo on Day 57. Subjects randomly assigned to the placebo arm will receive placebo on Day 1 and 
Day 57. 
5. No other vaccinations will be administered within 2 days before or after dosing of the study drug. Any subject who has had a positive RT -PCR RSV 
nasal swab result, either at the study central laboratory or at an outside institution in a CLIA-certified (or equivalent) laboratory, should not receive a 
second dose of study drug nor have postdose assessments completed on the day of dosing. The subject should, however, co ntinue in the study and have 
all other assessments completed during subsequent visits. If the subject has had a positive RSV test using non-PCR assays or any RSV positive test 
including a RT-PCR test in laboratories that are not CLIA-certified (or equivalent), they should receive the second dose as planned. The study staff will 
contact the parent(s) or legal guardian(s) by telephone at the end of each dosing day and daily over 48 hours following a dos e to inquire about any 
change in the subject’s status. 
6. On study drug dosing days, two vital signs assessments (temperature, blood pressure, pulse, and respiration) will be performed when the child is calm: 
once prior to blood sample collection (if applicable) and injection of study drug, and again 1 hour (±10 minutes) after completion of the injection. 
Dosing may only proceed if the subject is afebrile (rectal temperature ≤101°F (38.3°C) without the use of antipyretics in the preceeding 48 hours. If a 
subject’s rectal temperature is ≥101°F (38.3°C) on a dose administration day then no dosing will occur (see Section 6.3.1.1 for temperature 
conversions). The subject will then be re-evaluated within 48 hours; if the subject’s temperature is ≤101°F (38.3°C) without the use of antipyretics 
during the previous 48 hours then the schedule of assessments may be resumed. Conversely, if the subject’s temperature is still ≥101°F (38.3°C) or the 
subject has received antipyretics in the previous 48 hours, then dosing of the subject will be permanently discontinued. 
7. Physical examinations will be conducted before injection and after injection, and prior to discharge from the clinic at Visit 2 and Visit 4. Weight 
collection is not required post-injection. 


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8. If the adverse event is considered a hypersensitivity or anaphylaxis reaction, then the adverse event will be assessed at as outlined in Table 4. 
9. If the adverse event is a hypersensitivity reaction that results in a rash, then a photo will be taken as part of the adverse event assessment (also see 
Table 4). 
10.  The subjects with Schedule M will have the following collected: hematology/chemistry samples at screening, Day 29, and Day 150/ET; PK samples at 
Day 29 and Day 150/ET; and ADA samples at screening, Day 29, and Day 150/ET. 
11.  The subjects with blood collection Schedule L will have the following collected: hematology/chemistry samples at screening, Day 57 (predose), and 
Day 150/ET; PK samples at Day 57 (predose) and Day 150/ET; and ADA samples at screening, Day 57 (predose), and Day 150/ET. 
12.  The subjects with blood collection Schedule K will have the following collected: hematology/chemistry samples at screening, Day 85, and Day 150/ET; 
PK samples at Day 85 and Day 150/ET; and ADA samples at screening, Day 85, and Day 150/ET. 
13.  The subjects with blood collection Schedule J will have the following collected: hematology/chemistry samples at screening, Day 113, and Day 150/ET; 
PK samples at Day 113 and Day 150/ET; and ADA samples at screening, Day 113, and Day 150/ET. 
14.  The subjects with blood collection Schedule I will have the following collected: hematology/chemistry samples at screening and Day 150/ET; PK 
samples at Day 150/ET; and ADA samples at screening and Day 150/ET. 
15.  After substudy consent, the cheek swab for DNA in the optional substudy can be obtained at any time during the study period, but preferably at baseline. 
16.  If the subject experiences a medically attended respiratory infection since the previous scheduled visit, then the parent(s) or guardian(s) will be asked to 
provide additional pharmacoeconomic information on the event. 
17.  Visits 8, 9, and 10 will be done by telephone contact. In the event an AE is reported during a phone call visit, an unscheduled onsite visit may be 
required to follow-up, per investigator. 
18.  Informed consent may be obtained from the parent(s) or legal guardian(s) up to 28 days prior to randomization. Consent can occur outside the screening 
visit or on the same day as the screening visit, but must occur prior to the screening visit. 


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Table 3: 
Part  B:  Unscheduled  Visit  for  Potential  Respiratory  Illness - All  Dose 
Regimens 
 
Visit 
Unscheduled Visit 
Within 72 hours of discharge from medical facility 
where medical attention was provided (including for 
an acute respiratory illness1) 
Concomitant Medications and Procedures 
X 
Adverse Events 
X 
History of Acute Illness (including any 
treatments or interventions received) 
X 
LRTI Checklist (included in Medical 
Information Packet and completed using 
medical records obtained by site from treating 
healthcare provider) 
X2 
Nose Swab for RT-PCR if Subject Has Acute 
Respiratory Tract Symptoms3 
X 
Dispense New Medical Information Packet4 
X 
LRTI=lower respiratory tract infection; RSV=respiratory syncytial virus; RT-PCR=Reverse-transcriptase 
polymerase chain reaction 
Note: Adverse events that require unscheduled visits include medically attended events for potential respiratory 
illness (Table 3) and for acute injection reactions or suspected hypersensitivity reactions, with or without rash 
(Table 4) 
1. If an unscheduled visit associated with a medically attended respiratory infection occurs >72 hours but 
within 14 days of discharge from a medical facility, all procedures (as appropriate), including nose swab 
collection, should occur despite being outside of the 72-hour window. 
If the unscheduled visit associated with a recent medically attended respiratory infection occurs 
> 14 days of discharge from a medical facility, site must obtain information about any RSV test 
conducted at that facility. Information will include: Name of assay, type of assay (RT-PCR, 
antigen test, other), result of assay, date of assay result, and documentation as to whether the 
laboratory performing the assay is CLIA (clinical laboratory improvement amendments) certified 
(or equivalent), date of CLIA certification (or equivalent). 
2. The LRTI check list  is in the Medical Information Packet and should be given by the parent(s) or 
guardian(s) to study staff with the contact information of the treating healthcare provider. The site will 
obtain medical records for all inpatient and outpatient respiratory visits from the treating facility. 
3. Acute Respiratory Tract Symptoms are described in Section 6.2.3. 
4. A Medical Information Packet will be dispensed to all parent(s) or guardian(s) at randomization. When 
parent(s) or guardian(s) take their child for medical attention outside of the study site catchment areas, they 
will be instructed to take the Medical Information Packet with them for use by their healthcare provider. A 
new Medical Information Packet should be dispensed to parent(s) or guardian(s) at every unscheduled visit 
which is to occur at the clinical site following discharge from a medical facility for an acute respiratory 
infection. 


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Table 4: 
Part A and Part B: Unscheduled Visit Following Any Adverse Events 
(Including Suspected Hypersensitivities) - All Dose Regimens 
 
Visit 
Unscheduled Visit following Adverse Event 
(including suspected hypersensitivities) 
Concomitant Medications and Procedures 
X 
Vital Signs 
X 
Physical Examination (including weight) 
X 
Adverse Events 
X 
Photograph of Rash (if Present) 
X1 
Complete Blood Count With Differential 
X2 
Liver Function Test 
X2 
Blood Anti-REGN2222 Antibody (ADA) 
X2 
History of Present Illness (including any treatments 
or interventions received) 
X 
ADA=antidrug antibody; AE=adverse event 
Note: Adverse events that require unscheduled visits include medically attended events for potential respiratory 
illness (Table 3) and for acute injection reactions or suspected hypersensitivity reactions, with or without rash 
(Table 4). Other AEs may require unscheduled visits based on the investigator decision and as warranted. 
1. 
If the AE includes a suspected hypersensitivity rash, then a photo will be taken as part of the AE assessment. 
2. 
Only AEs that are suspected to be hypersensitivity reactions require additional tests. Other AEs do not require these 
procedures. 
 
6.2. 
Study Procedures 
 
6.2.1. 
Part A: 30 mg/kg IM (Maximum 1 Dose) 
 
6.2.1.1. 
Visit 1 (Screening, Day -14 to Day -1) 
 
After the subject’s parent(s) or legal guardian(s) have provided informed consent (with or 
without optional substudy informed consent), the following information will be collected 
(Table 1): 
 
• Inclusion/exclusion criteria 
 
• Medical history 
 
• Demographics 


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The following procedures and assessments will be conducted: 
 
• Concomitant medications and procedures 
 
• AEs 
 
• Vital signs (including temperature, blood pressure, pulse, and respiration rate) prior to 
scheduled collection of blood sample 
 
• Physical examination (including weight) 
 
• Hematology (all subjects [blood collection Schedule A through Schedule H]) 
 
• Blood chemistry (all subjects [blood collection Schedule A through Schedule H]) 
 
• ADA sampling (all subjects [blood collection Schedule A through Schedule H]) 
 
6.2.1.2. 
Visit 2 (Baseline and Dosing Visit, Day 1) 
 
The following procedures and assessments will be conducted prior to administration of study 
drug, unless specified otherwise: 
 
• Confirm inclusion/exclusion criteria 
 
• Retrieve IVRS/IWRS-assigned subject blood collection schedule and study drug kit 
number 
 
• AEs 
 
• Concomitant medications and procedures 
 
• Physical examination (including weight) 
 
• Vital signs (including temperature, blood pressure, pulse and respiration rate) 
 
− If a subject’s rectal temperature is101°F (38.3°C) (equivalent to axillary 
temperature of 100.6°F [38.1°C] for infants <4 weeks of age or 99.2°F [37.3°C] 
for infants ≥4 weeks of age) or greater on the day of a planned dose 
administration day, no dosing will occur. The subject will be re-evaluated within 
48 hours and if the subject’s temperature is below 101°F (38.3°C) without the use 
of antipyretics during the previous 48 hours, the schedule of assessments may be 
resumed. If the subject’s temperature is 101°F (38.3°C) or greater or the subject 
has received antipyretics in the previous 48 hours, dosing of the subject will be 
permanently discontinued. 
 
• If consented, then optional substudy DNA collection (cheek swab to be collected at 
any time during the study period, but preferably at baseline) 


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A single dose of REGN2222 30 mg/kg IM will be administered. Subjects will be monitored in 
the clinic for 3 hours after dosing, followed by discharge, if appropriate. After study drug 
administration, the following information will be collected, and the following procedures and 
assessments will be conducted: 
 
• AEs 
 
• Vital signs, including temperature, blood pressure, pulse and respiration rate, assessed 
at 1, 2, and 3 hours (±10 minutes) after completion of the injection 
 
• Physical examination (including weight) post dose 
 
No vaccinations will be administered within 2 days of dosing of the study drug (Section 4.1.2.1, 
exclusion criterion #9). An emergency phone number will be provided to parent(s) or 
guardian(s); they will also be given written and verbal instructions to call with any change in the 
subject’s status. In addition, the study staff will contact parent(s) or legal guardian(s) at the end 
of Day 1, the subject will return to the study site on Day 2 for Visit 3, and the study staff will 
contact the parent(s) or legal guardian(s) on Day 3 to inquire about any change in the subject’s 
status; this will provide at least daily contact for 48 hours after dosing. Any new signs or 
symptoms that have developed in the subject since dosing will be assessed by study staff to 
determine if there is a need for immediate medical attention and if that subject will also need to 
be seen within 24 hours by the study staff. 
 
6.2.1.3. 
Visit 3 (Day 2) 
 
The parent(s) or guardian(s) will bring the subject to the study site on Day 2 for Visit 3 
evaluations. The following information will be collected, and the following procedures and 
assessments will be conducted during the visit: 
 
• Concomitant medications and procedures 
 
• Vital signs (including temperature, blood pressure, pulse, and respiration rate) prior to 
any scheduled collection of blood sample 
 
• Physical examination (including weight) 
 
• AEs 
 
• Hematology (subjects with blood collection Schedule F only) 
 
• Blood chemistry (subjects with blood collection Schedule F only) 
 
• PK sampling (subjects with blood collection Schedule F only) 
 
The study staff will contact the parent(s) or legal guardian(s) on Day 3 to inquire about any 
change in the subject’s status. 
 
6.2.1.4. 
Visit 4 (Day 8) 
 
This visit may take place by telephone for all subjects except those with blood collection 
Schedule E, who will be required to have an onsite visit. 


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For all subjects (telephone or onsite visit), the following information will be collected, and the 
following procedures and assessments will be conducted during the visit: 
 
• Concomitant medications and procedures 
 
• AEs 
 
For subjects that have an onsite visit (subjects with blood collection Schedule E only), the 
following information will be collected, and the following procedures and assessments will be 
conducted during the visit: 
 
• Hematology (subjects with blood collection Schedule E only) 
 
• Blood chemistry (subjects with blood collection Schedule E only) 
 
• PK sampling (subjects with blood collection Schedule E only) 
 
6.2.1.5. 
Visit 5 (Day 15) 
 
This visit may take place by telephone for all subjects except those with blood collection 
Schedule D, who will be required to have an onsite visit. 
 
For all subjects (telephone or onsite visit), the following information will be collected, and the 
following procedures and assessments will be conducted during the visit: 
 
• Concomitant medications and procedures 
 
• AEs 
 
For subjects that have an onsite visit (subjects with blood collection Schedule D only), the 
following information will be collected, and the following procedures and assessments will be 
conducted during the visit: 
 
• Hematology (subjects with blood collection Schedule D only) 
 
• Blood chemistry (subjects with blood collection Schedule D only) 
 
• PK sampling (subjects with blood collection Schedule D only) 
 
6.2.1.6. 
Visit 6 (Day 22) 
 
This visit may take place by telephone for all subjects except those with blood collection 
Schedule C, who will be required to have an onsite visit. 


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For all subjects (a telephone or onsite visit), the following information will be collected, and the 
following procedures and assessments will be conducted during the visit: 
 
• Concomitant medications and procedures 
 
• AEs 
 
For all subjects that have an onsite visit (subjects with blood collection Schedule C only), the 
following information will be collected, and the following procedures and assessments will be 
conducted during the visit: 
 
• Hematology (subjects with blood collection Schedule C only) 
 
• Blood chemistry (subjects with blood collection Schedule C only) 
 
• PK sampling (subjects with blood collection Schedule C only) 
 
• ADA sampling (subjects with blood collection Schedule C only) 
 
6.2.1.7. 
Visit 7 (Day 29) 
 
All subjects will be required to attend an onsite visit. 
 
The following information will be collected, and the following procedures and assessments will 
be conducted: 
 
• Concomitant medications and procedures 
 
• Vital signs (including temperature, blood pressure, pulse, and respiration rate) prior to 
any scheduled collection of blood sample 
 
• AEs 
 
• Hematology (subjects with blood collection Schedule B only) 
 
• Blood chemistry (subjects with blood collection Schedule B only) 
 
• PK sampling (subjects with blood collection Schedule B only) 
 
• ADA sampling (subjects with blood collection Schedule B only) 
 
6.2.1.8. 
Visit 8 (Day 57±5 Days) 
 
All subjects will have an onsite visit. 
 
The following information will be collected, and the following procedures and assessments will 
be conducted: 
 
• Concomitant medications and procedures 
 
• Vital signs (including temperature, blood pressure, pulse, and respiration rate) prior to 
any scheduled collection of blood sample 
 
• Physical examination (including weight) 
 
• AEs 
 
• Hematology (subjects with blood collection Schedule A only) 


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• Blood chemistry (subjects with blood collection Schedule A only) 
 
• PK sampling (subjects with blood collection Schedule A only) 
 
• ADA sampling (subjects with blood collection Schedule A only) 
 
6.2.1.9. 
Visit 9 (Day 85±5 Days) 
 
All subjects will have an onsite visit. 
 
The following information will be collected, and the following procedures and assessments will 
be conducted: 
 
• Concomitant medications and procedures 
 
• Vital signs (including temperature, blood pressure, pulse, and respiration rate) prior to 
any scheduled collection of blood sample 
 
• AEs 
 
• Hematology (subjects with blood collection Schedule G only) 
 
• Blood chemistry (subjects with blood collection Schedule G only) 
 
• PK sampling (subjects with blood collection Schedule G only) 
 
• ADA sampling (subjects with blood collection Schedule G only) 
 
6.2.1.10. Visit 10 (Day 113±5 Days) 
 
All subjects will have an onsite visit. 
 
The following information will be collected, and the following procedures and assessments will 
be conducted: 
 
• Concomitant medications and procedures 
 
• Vital signs (including temperature, blood pressure, pulse, and respiration rate) prior to 
any scheduled collection of blood sample 
 
• AEs 
 
• Hematology (subjects with blood collection Schedule H only) 
 
• Blood chemistry (subjects with blood collection Schedule H only) 
 
• PK sampling (subjects with blood collection Schedule H only) 
 
• ADA sampling (subjects with blood collection Schedule H only) 
 
6.2.1.11. Visit 11 (Day 150±5 Days), End of Study or Early Termination 
 
All subjects will have an onsite visit. 
 
Subjects will return to the clinic for an end of study assessment. Subjects who are withdrawn 
from the study will be asked to return to the clinic for early termination assessments. 
 
The end of study will occur 150 days after the first dose. 


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The following information will be collected, and the following procedures and assessments will 
be conducted: 
 
• Concomitant medications and procedures 
 
• Vital signs (including temperature, blood pressure, pulse, and respiration rate) prior to 
any scheduled collection of blood sample 
 
• Physical examination (including weight) 
 
• AEs 
 
• Hematology (all subjects [blood collection Schedule A through Schedule H]) 
 
• Blood chemistry (all subjects [blood collection Schedule A through Schedule H]) 
 
• PK sampling (all subjects [blood collection Schedule A through Schedule H]) 
 
• ADA sampling (all subjects [blood collection Schedule A through Schedule H]) 
 
6.2.2. 
Part B: 30 mg/kg (1 Dose REGN2222 and 1 Dose Placebo); or 30 mg/kg IM 
(2 Doses REGN2222); or Placebo IM (Maximum 2 Doses) 
 
Informed consent may be obtained from the parent(s) or legal guardian(s) up to 28 days prior to 
randomization. 
 
6.2.2.1. 
Visit 1 (Screening, Day -28 to Day -1) 
 
After the subject’s parent(s) or legal guardian(s) has provided informed consent (with or without 
optional substudy informed consent), the following information will be collected: 
 
• Inclusion/exclusion criteria 
 
• Medical history 
 
• Demographics 
 
The following procedures and assessments will be conducted: 
 
• Concomitant medications and procedures 
 
• AEs 
 
• Vital signs taken when the child is calm (including temperature, blood pressure, 
pulse, and respiration rate) prior to any scheduled collection of blood sample. Rectal, 
axillary, temporal, and tympanic temperature acquisitions are permitted. 
 
• Physical examination (including weight) 
 
• Blood sampling 
 
− Hematology (all subjects [blood collection Schedule I through Schedule M]) 
 
− Blood chemistry (all subjects [blood collection Schedule I through Schedule M]) 
 
− ADA sampling (all subjects [blood collection Schedule I through Schedule M]) 


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• Please see Section 6.3.3 regarding guidance on interpreting abnormal screening 
laboratory values and redrawing blood samples due to insufficient volumes or 
hemolyzed samples. 
 
6.2.2.2. 
Visit 2 (Baseline and First Dosing Visit, Day 1) 
 
The following procedures and assessments will be conducted prior to administration of study 
drug, unless specified otherwise: 
 
• Confirm inclusion/exclusion criteria 
 
• IVRS/IWRS-assigned subject blood collection schedule 
 
• Randomization to REGN2222 or placebo 
 
• AEs 
 
• Physical examination (including weight) 
 
• Vital signs (including temperature, blood pressure, pulse and respiration rate) 
 
− On study drug dosing days, vital signs assessments (temperature, blood pressure, 
pulse, and respiration) will be performed twice when the child is calm: once prior 
to blood sample collection (if applicable) and injection of study drug, and again 
1 hour (±10 minutes) after completion of the injection. Dosing may only proceed 
if the subject is afebrile (rectal temperature ≤101°F (38.3°C)) without the use of 
antipyretics in the preceeding 48 hours. If a subject's rectal temperature is ≥101°F 
(38.3°C) on a dose administration day then no dosing will occur (see Section 
6.3.1.1 for temperature conversions). The subject will then be re-evaluated within 
48 hours. If the subject's temperature is ≤101°F (38.3°C) without the use of 
antipyretics during the previous 48 hours, then the schedule of assessments may 
be resumed. Conversely, if the subject's temperature is still ≥101°F (38.3°C) or 
the subject has received antipyretics in the previous 48 hours then dosing of the 
subject will be permanently discontinued. 
 
− Table 5 provides the equivalents for Celsius and Fahrenheit temperatures. 
 
• Risk factor assessment (geographic region, multiple births, small for gestational age, 
child care status, family history of atopy, asthma, hay fever, or eczema, number of 
people in the household, including siblings, number of individuals 6 years or younger 
in the household,  parent smoking status and parent work status). 
 
• Dispense Medical Information Packet 
 
• If consented, optional substudy DNA collection (cheek swab to be collected at any 
time during the study period, but preferably at baseline) 
 
• Concomitant medications and procedures 
 
• Pharmacoeconomic information on subjects who have experienced a medically 
attended respiratory event since last visit 


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The first study drug will be administered (REGN2222 or Placebo). Subjects will be monitored in 
the clinic for at least 1 hour after dosing, followed by discharge, when appropriate. 
 
After randomization and study drug administration, the following information will be collected, 
and the following procedures and assessments will be conducted: 
 
• AEs 
 
• Vital signs, including temperature, blood pressure, pulse and respiration rate assessed 
1 hour (±10 minutes) after completion of the injection 
 
• Physical examination, (excluding weight) post dose 
 
No other vaccinations will be administered within 2 days of dosing of the study drug (Section 
4.1.2.1, exclusion criterion #9). An emergency phone number will be provided to parent(s) or 
guardian(s) and they will also be given written and verbal instructions to call with any change 
in the subject’s status. In addition, the study staff will contact parent(s) or legal guardian(s) at 
the end of the day and daily over 48 hours to inquire about any change in the subject’s status. 
Any new signs or symptoms that have developed in the subject since the last dose will be 
assessed by study staff to determine if there is a need for immediate medical attention and if 
that subject will also need to be seen within 24 hours by the study staff. 
 
6.2.2.3. 
Visit 3 (Day 29±2 Days) 
 
The following information will be collected, and the following procedures and assessments will 
be conducted: 
 
• Concomitant medications and procedures 
 
• Vital signs (including temperature, blood pressure, pulse, and respiration rate) prior to 
any scheduled collection of blood sample 
 
• AEs 
 
• Physical examination (including weight) 
 
• Blood sampling 
 
− Hematology (subjects with blood collection Schedule M only) 
 
− Blood chemistry (subjects with blood collection Schedule M only) 
 
− PK sampling (subjects with blood collection Schedule M only) 
 
− ADA sampling (subjects with blood collection Schedule M only) 
 
• Pharmacoeconomic information on subjects who have experienced a medically 
attended respiratory event since last visit 
 
6.2.2.4. 
Visit 4 (Second Dosing Visit, Day 57±2 Days) 
 
Note: Any subject who has had a positive PCR RSV nasal swab result, either at the study central 
laboratory or at an outside institution in a CLIA-certified (or equivalent) laboratory, should not 
receive a second dose of study drug or have postdose assessments completed. The infant should, 
however, continue in the study and have all other assessments completed during subsequent 


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visits. If the subject has had a positive RSV test using non-PCR assays or in laboratories that are 
not CLIA-certified (or equivalent), they should receive the second dose as planned. 
 
The following procedures and assessments will be conducted prior to administration of study 
drug, unless specified otherwise: 
 
• Physical examination (including weight) 
• Vital signs (including temperature, blood pressure, pulse, and respiration rate) 
Dosing may only proceed if the subject is afebrile (rectal temperature <101°F 
(38.3°C) without the use of antipyretics in the preceeding 48 hours. If a subject's 
rectal temperature is ≥101°F (38.3°C) on a dose administration day then no dosing 
will occur (see Section 6.3.1.1 for temperature conversions). The subject will be then 
be re-evaluated within 48 hours; if the subject's temperature is ≤101°F (38.3°C) 
without the use of antipyretics during the previous 48 hours, then the schedule of 
assessments may be resumed. Conversely, if the subject's temperature is still ≥101°F 
(38.3°C) or the subject has received antipyretics in the previous 48 hours then dosing 
of the subject will be permanently discontinued. 
 
− Table 5 provides the equivalents for Celsius and Fahrenheit temperatures. 
 
• Concomitant medications 
 
• AEs 
 
• Blood sampling 
 
− Hematology (subjects with blood collection Schedule L only) 
 
− Blood chemistry (subjects with blood collection Schedule L only) 
 
− PK sampling (subjects with blood collection Schedule L only) 
 
− ADA sampling (subjects with blood collection Schedule L only) 
 
• Pharmacoeconomic information on subjects who have experienced a medically 
attended respiratory event since last visit. 
 
The second study drug dose will be administered (REGN2222 or Placebo). Subjects will be 
monitored in the clinic for at least 1 hour after dosing, followed by discharge, when appropriate. 
 
• Vital signs, including temperature, blood pressure, pulse, and respiration rate assessed 
1 hour (±10 minutes) after completion of the injection 
 
• Physical examination (excluding weight) post dose 
 
No other vaccinations will be administered within 2 days of dosing of the study drug (Section 
4.1.2.1, exclusion criterion #9). An emergency phone number will be provided to parent(s) or 
guardian(s) will also be given written and verbal instructions to call with any change in the 
subject’s status. In addition, the study staff will contact parent(s) or legal guardian(s) at the end 
of the day and daily over 48 hours to inquire about any change in the subject’s status. Any new 
signs or symptoms that have developed in the subject since the last dose will be assessed by 


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study staff to determine if there is a need for immediate medical attention and that subject will 
also be seen within 24 hours by the study staff. 
 
6.2.2.5. 
Visit 5 (Day 85±5 Days) 
 
The following information will be collected, and the following procedures and assessments will 
be conducted: 
 
• Concomitant medications and procedures 
 
• Vital signs taken when the child is calm (including temperature, blood pressure, 
pulse, and respiration rate) 
 
• Physical examination (including weight) 
 
• AEs 
 
• Blood sampling 
 
− Hematology (subjects with blood collection Schedule K only) 
 
− Blood chemistry (subjects with blood collection Schedule K only) 
 
− PK sampling (subjects with blood collection Schedule K only) 
 
− ADA sampling (subjects with blood collection Schedule K only) 
 
• Pharmacoeconomic information on subjects who have experienced a medically 
attended respiratory event since last visit 
 
6.2.2.6. 
Visit 6 (Day 113±5 Days) 
 
The following information will be collected, and the following procedures and assessments will 
be conducted: 
 
• Concomitant medications and procedures 
 
• Vital signs taken when the child is calm (including temperature, blood pressure, 
pulse, and respiration rate) 
 
• AEs 
 
• Blood sampling 
 
− Hematology (subjects with blood collection Schedule J only) 
 
− Blood chemistry (subjects with blood collection Schedule J only) 
 
− PK sampling (subjects with blood collection Schedule J only) 
 
− ADA sampling (subjects with blood collection Schedule J only) 
 
• Pharmacoeconomic information on subjects who have experienced a medically 
attended respiratory event since last visit 


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6.2.2.7. 
Visit 7 (Day 150±5 Days), or Early Termination 
 
Subjects will return to the clinic for Visit 7 assessment. Subjects who are withdrawn from the 
study at any point prior to Visit 7/Day 150 will be asked to return to the clinic for early 
termination assessments. 
 
The following information will be collected, and the following procedures and assessments will 
be conducted: 
 
• Concomitant medications and procedures 
 
• Vital signs taken when the child is calm (including temperature, blood pressure, 
pulse, and respiration rate) 
 
• Physical examination (including weight) 
 
• AEs 
 
• Blood sampling 
 
− Hematology (all subjects [blood collection Schedule I through Schedule M]) 
 
− Blood chemistry (all subjects [blood collection Schedule I through Schedule M]) 
 
− PK sampling (all subjects [blood collection Schedule I through Schedule M]) 
 
− ADA sampling (all subjects [blood collection Schedule I through Schedule M]) 
 
• Pharmacoeconomic information on subjects who have experienced a medically 
attended respiratory event since last visit 
 
6.2.2.8. 
Visit 8 (Day 178±10 Days) 
 
The following information will be collected during a telephone visit; subjects will not be 
required to come to the site unless deemed necessary to follow-up on an AE 
 
• Concomitant medications and procedures 
 
• AEs 
 
6.2.2.9. 
Visit 9 (Day 206±10 Days) 
 
The following information will be collected during a telephone visit; subjects will not be 
required to come to the site unless deemed necessary to follow-up on an AE 
 
• Concomitant medications and procedures 
 
• AEs 
 
6.2.2.10. Visit 10 (Day 237±10 Days)/End of Study 
 
The following information will be collected during a telephone visit; subjects will not be 
required to come to the site unless deemed necessary to follow-up on an AE 
 
• Concomitant medications and procedures 
 
• AEs 


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6.2.3. 
Part B: Unscheduled Visit for Potential Respiratory Illness 
 
During the study, data will be collected from subjects with any respiratory illness requiring 
medical attention (inpatient and outpatient incidences). After enrollment into the study, any 
subject taken by their parent(s) or guardian(s) to a healthcare provider (inpatient or outpatient, 
including ER, UC, or pediatric clinic visitsa) will be asked to contact the study staff immediately 
after seeking medical attention for any of the following symptoms: 
 
• Fever 
 
• Cough 
 
• Earache 
 
• Nasal congestion 
 
• Rhinorrhea 
 
• Vomiting after coughing 
 
• Wheezing 
 
• Difficulty breathing (labored, rapid, or shallow). 
 
a A pediatric clinic visit represents any outpatient medically attended visit that could include, but is not limited to, a 
pediatric clinic visit, a primary physician office visit, a family physician visit, or a study site visit 
Unscheduled visits are required by the protocol in the event of a potential respiratory illness 
(Table 3). Other unscheduled visits (Section 6.2.4) may be necessary to repeat testing following 
abnormal laboratory results, for follow-up of AEs, for acute injection reactions, or for any other 
reason. 
 
Unscheduled visits for potential respiratory illness should occur within 72 hours of discharge 
from a medical facility where medical attention was provided (including that for an acute 
respiratory illness). If an unscheduled visit associated with a medically attended respiratory 
infection occurs more than 72 hours but within 14 days of discharge from a medical facility, all 
procedures (as appropriate), including nose swab collection, should occur despite being outside 
of the 72 hour window. 
 
If an unscheduled visit associated with a medically attended respiratory infection does not occur 
within 14 days of discharge from the medical facility, a nose swab for RSV RT-PCR testing does 
not need to be sent to the central laboratory. Instead, site personnel should obtain results of all 
RSV RT-PCR tests conducted during that illness at outside laboratories, including information 
on the result of the test, name of the RT-PCR assay used, and whether the laboratory conducting 
the RT-PCR is a CLIA-certified (or equivalent) laboratory. If an RSV RT-PCR was not 
conducted but other types of RSV assays were conducted (ie, rapid antigen test), the information 
outlined above does not need to be collected. 


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The following information will be collected, and the following procedures and assessments will 
be conducted for unscheduled visits in the event of a respiratory illness: 
 
• Concomitant medications and procedures 
 
• AEs 
 
• History of acute illness (including any treatments or interventions received) 
 
• LRTI checklist from the Medical Information Packet should be given by the parent(s) 
or guardian(s) to study staff with the contact information of the treating healthcare 
provider. The site will obtain medical records for all inpatient and/or outpatient 
respiratory visits from the treating facility. 
 
• Nose swabs for infants with acute respiratory tract symptoms 
 
− All nose swabs will be tested using a Food and Drug Administration-cleared and 
CE (Conformité Européenne)-marked RT-PCR assay for RSV, which will be 
conducted in a central laboratory. Any subject with an acute respiratory illness 
who tests positive for RSV by RT-PCR will also have testing of samples to 
identify the RSV subtype. The RSV subtyping will not require an additional 
sample or study visit. 
 
• Dispense new Medical Information Packet to the parent(s) or guardian(s) at every 
unscheduled visit following discharge from a medical facility for an acute respiratory 
infection 
6.2.4. 
Part A and Part B: Unscheduled Visit Following Any Adverse Event (Including 
Suspected Hypersensitivities) 
Other unscheduled visits may be necessary to repeat testing following abnormal laboratory 
results, for follow-up of AEs, for acute injection reactions or suspected hypersensitivity reactions 
(with or without rash), or for any other reason, as warranted (Table 4). Other AEs that require 
unscheduled visits include medically attended events for potential respiratory illness (Table 3, 
Section 6.2.3). 
 
The following information will be collected, and the following procedures and assessments will 
be conducted for unscheduled visits: 
 
•  Concomitant medications and procedures 
 
•  Vital signs taken when child is calm (including temperature, blood pressure, pulse, 
and respiration rate) 
 
•  Physical examination (including weight) 
 
•  AEs 
 
•  History of present illness (including any treatments or interventions received) 


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If the AE is a suspected hypersensitivity reaction, then additional tests are required and include 
the following (Table 4): 
 
• Complete blood count with differential 
 
• Liver function test 
 
• ADA sampling 
 
• Photograph of suspected hypersensitivity rash, if present 
 
6.3. 
Safety Procedures 
 
6.3.1. 
Vital Signs 
 
Vital signs (including temperature, blood pressure, pulse, and respiration rate) will be collected 
before dosing at time points specified in the schedule of assessments (Section 6.1). On the study 
drug dosing days, vital signs will be assessed prior to collection of blood sample, prior to 
injection of study drug, and after completion of the injection (Part A at 1, 2, and 3 hours 
[±10 minutes] after completion of the injection and Part B at 1 hour [±10 minutes] after 
completion of the injection). 
 
6.3.1.1. 
Temperature 
 
Dosing may only proceed if the subject is afebrile (rectal temperature <101°F (38.3°C) without 
the use of antipyretics in the preceeding 48 hours. If a subject's rectal temperature is ≥101°F 
(38.3°C) on a dose administration day then no dosing will occur (see Section 6.3.1.1 for 
temperature conversions). The subject will be then be re-evaluated within 48 hours; if the 
subject's temperature is ≤101°F (38.3°C) without the use of antipyretics during the previous 48 
hours, then the schedule of assessments may be resumed. Conversely, if the subject's temperature 
is still ≥101°F (38.3°C) or the subject has received antipyretics in the previous 48 hours, dosing 
of the subject will be permanently discontinued, but the subject will continue to be followed for 
safety and efficacy, if at least 1 dose of study drug was administered. 
 
Table 5 below provides the equivalents for Celsius and Fahrenheit temperatures. 
 
Temperature acquisition method: It is acknowledged that the method for temperature acquisition 
is not standard across all sites. Therefore, rectal as well as axillary, temporal, and tympanic 
measurements will be permitted. There is a recognized difference between temperatures obtained 
using different modalities and the following conversions (Table 5) must be used when assessing 
pre-dose temperature to hold dosing. 


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Table 5: 
Conversion of Axillary/Temporal Temperatures to Rectal /Tympanic 
Temperatures in Infants by Age 
 
Infants <4 Weeks Chronological Age 
Infants ≥4 Weeks Chronological Age 
Axillary/Temporal 
Temperature 
Rectal/Tympanic 
(0.2°C+axillary) 
Axillary/Temporal 
Temperature 
Rectal/Tympanic 
(1.0°C+axillary) 
°C 
°F 
°C 
°F 
°C 
°F 
°C 
°ₒF 
37.8 
100.0 
38.0 
100.4 
37.0 
98.6 
38.0 
100.4 
38.1 
100.5 
38.3 
100.9 
37.3 
99.1 
38.3 
100.9 
38.8 
101.8 
39.0 
102.2 
38.0 
100.4 
39.0 
102.2 
39.8 
103.6 
40.0 
104.0 
39.0 
102.2 
40.0 
104.0 
40.8 
105.4 
41.0 
105.8 
40.0 
104.0 
41.0 
105.8 
41.8 
107.2 
42.0 
107.6 
41.0 
105.8 
42.0 
107.6 
Note: Boldface values in the table indicate a cut-off. At temperatures equal to or greater than those in boldface, no 
dosing should occur. 
Table adapted from Shann F 1996. 
 
6.3.1.2. 
Blood Pressure 
 
Blood pressure may be difficult to obtain in some infants because of size, therefore a systolic 
blood pressure alone can be recorded. If site personnel are unable to obtain either systolic or 
diastolic pressures, “unable to obtain” should be recorded. 
 
6.3.2. 
Physical Examination 
 
A thorough and complete physical examination, including weighing the subject, will be 
performed at time points specified in the schedule of assessments (Section 6.1). Care should be 
taken to examine and assess any abnormalities that may be present, as indicated by the subject’s 
medical history. On study drug-dosing days, physical examinations will be conducted predose 
and again postdose (excluding weight) prior to discharge. 
 
6.3.3. 
Laboratory Testing 
 
Hematology and blood chemistry testing samples will be analyzed by a central laboratory. 
Detailed instructions for blood sample collection are in the laboratory manual provided to study 
sites. 
 
Samples for laboratory testing will be collected at time points specified in the schedule of 
assessments (Section 6.1) and during unscheduled visits (Section 6.2.3). 


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Blood redraw: 
 
If screening laboratory test results are unavailable due to hemolysis or insufficient specimen 
volume, redraw of screening blood samples are acceptable if the blood volume withdrawn from 
the infant does not surpass the ethical and safety recommendations for such procedures 
according to the informed consent and the site pediatric guidelines (local or national) on total 
blood volume allowable for blood tests. If specimens are redrawn, it is advised that the redraw 
occur in a timely manner to allow for rapid enrollment decision and dosing. Visits for blood 
redraws should be conducted as an unscheduled visit. 
 
Laboratory reference ranges for preterm infants: 
 
Clinical laboratory reference ranges for preterm infants are not standardized therefore the 
reference ranges currently used in the central laboratory are based on values observed in 
full-term infants. Because there are no standardized reference ranges for preterm infants the 
following guidance to Principal Investigators to consider for infants for whom levels creatinine, 
alkaline phosphatase, AST, or total bilirubin are >1.1 times the central laboratory reported upper 
limit of normal is provided. The subject may be considered for inclusion into the study if the 
Principal Investigator concludes the following: 
 
•  There is no evidence that the elevated levels are associated with a possible underlying 
medical condition leading to clinical concern or the need to carry out additional 
workup or treatment. 
 
•  In particular, for renal status, there is no evidence of renal disease which may be 
manifested by creatinine >1.5 mg/dL (133 μmol/L) along with signs including, but not 
limited to, a decrease in urine output or abnormal urinalysis. 
 
•  For liver status, there is no evidence of liver disease which may be manifested by a 
total bilirubin level that is >12 mg/dL (205 μmol/L) along with abnormal liver 
enzymes including but not limited to, ALT >45 U/L, AST >150 U/L (0 to10 days 
chronological age), AST >80 U/L (10 days to 12 months chronological age), and 
alkaline phosphatase >700 U/L. 
 
Please refer to Appendix G for laboratory cut-off values to be considered for Exclusion 
Criterion #6. 
 
6.3.3.1. 
Blood Chemistry 
 
Tests will include the following: 
 
• 
Sodium 
• Total protein, serum 
• Total bilirubin 
• 
Potassium 
• Creatinine 
• Indirect bilirubin 
• 
Chloride 
• Blood urea nitrogen 
• Uric acid 
• 
Carbon dioxide 
• AST 
• Creatine phosphokinase 
• 
Calcium 
• ALT 
• 
Glucose 
• Alkaline phosphatase 
• 
Albumin 
• Lactate dehydrogenase 


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6.3.3.2. 
Hematology 
 
Tests will include the following: 
 
• 
Hemoglobin 
• 
Differential: 
• 
Hematocrit 
− Neutrophils 
• 
• 
Red blood cells (RBCs) 
White blood cells (WBCs) 
− 
− 
Lymphocytes 
Monocytes 
• 
• 
Red cell indices 
Platelet count 
− 
− 
Basophils 
Eosinophils 
 
6.3.3.3. 
Virology Testing 
 
Nose swabs collected from respiratory unscheduled visits (Section 6.2.3) will be tested at a 
central laboratory for RSV by RT-PCR. Positive samples will be sequenced for viral subtyping 
and resistance monitoring. Further details will be provided in the study manual. 
 
In addition, nose swab specimens negative for RSV using the RT-PCR assay utilized for 
determination of primary endpoint cases will be evaluated using a second and distinctly different 
RT-PCR multiplex respiratory panel. The multiplex assay will be performed to determine the 
presence of other common respiratory pathogens in nose swabs. This multiplex evaluation will 
only be conducted on RSV negative swabs collected from subjects and will not be used in the 
primary analyses of the primary and secondary efficacy endpoints. 
 
6.3.3.4. 
Abnormal Laboratory Values and Laboratory Adverse Events 
All laboratory values must be reviewed by the investigator or authorized designee. 
Significantly abnormal tests 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 monitor 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 7.2.6. 
 
6.4. 
Pharmacokinetic and Antibody Procedures 
 
6.4.1. 
REGN2222-Concentration Measurements and Samples 
 
Serum samples for REGN2222-concentration measurements will be collected at the time points 
specified in the schedule of assessments (Section 6.1). 
 
6.4.2. 
Antidrug Antibody Measurements and Samples 
 
Serum samples for ADA assessment will be collected at the time points specified in the schedule 
of assessments (Section 6.1). 


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6.4.3. 
Research Samples 
 
Any remaining serum samples collected for PK and ADA measurements may be banked and 
used for exploratory research. The samples maybe used to study the effects of the study drug, on 
prediction of medically attended RSV infection, or severity of RSV infection and resultant 
long-term sequelae of infection, such as recurrent wheezing or reactive airway disease. The 
analysis may include, but is not limited to, RSV microneutralization and inflammatory markers. 
 
6.4.4. 
Substudy - Optional 
 
Parent(s) or legal guardian(s) of subjects who agree to allow their infant to participate in the 
substudy will be required to sign a separate substudy informed consent form (ICF) before 
collection of the samples. Subjects are not required to participate in the substudy in order to 
enroll in the primary study. Cheek swab for DNA extraction may be collected at any time during 
the study period but preferably at baseline. 
 
DNA samples for the substudy will be double-coded as defined by the International Council on 
Harmonisation (ICH) guideline E15. Substudy samples may be stored for up to 15 years after the 
date of the final database lock and may be used for research purposes. 
 
 
 
 
Analyses may include sequence determination or single 
nucleotide polymorphism studies of candidate genes and surrounding genomic regions. 
 
 
 
 
 
6.5. 
Pharmacoeconomic Measurement Procedures 
 
Pharmacoeconomic information will only be collected during Part B. At each scheduled visit 
(Table 2), the parent(s) or guardian(s) will be asked if the subject had experienced a respiratory 
infection. Only if the subject had experienced a medically attended respiratory infection, 
including an RSV infection, would the parent(s) or guardian(s) will be asked to provide 
additional pharmacoeconomic information. 
 
At each scheduled visit (Table 2), health care resource utilization and respiratory symptoms will 
be asked of the parent(s) or guardian(s) or the hospital staff (nurse or treating physician) where 
treatment was received. This will include the number of RSV and non-RSV-associated medical 
visits (hospital, ER, UC, or pediatric visitsa); length of stay in hospital, ER, or UC; and 
treatments or procedures (including number of days) for each visit. In addition, the parent(s) or 
guardian(s) will be asked to provide information of the number of missed days from work for 
each medically attended respiratory event. The specific questions will be provided in the study 
manual. 
 
a A pediatric clinic visit represents an outpatient medically attended visit that could include, but 
is not limited to, a pediatric clinic visit, a primary physician office visit, a family physician 
visit, or a study site visit. 


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7. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
 
7.1. 
Definitions 
 
7.1.1. 
Adverse Event 
 
An AE is any untoward medical occurrence in a subject 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. 
 
An AE also includes any 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. 
 
7.1.2. 
Serious Adverse Event 
 
An SAE is any untoward medical occurrence that occurs at any dose and includes the following: 
 
• Results in death – includes all deaths, even those that appear to be completely 
unrelated to study drug (eg, a car accident in which a subject is a passenger). 
 
• Is life threatening – in the view of the investigator, the subject 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 inpatient hospitalization or prolongation of existing hospitalization. 
Inpatient hospitalization is defined as admission to a hospital or an ER 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 subject or 
may require intervention to prevent 1 of the other serious outcomes listed above (eg, 
intensive treatment in an ER or at home for allergic bronchospasm; blood dyscrasias 
or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse). 


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7.2. 
Recording and Reporting Adverse Events 
 
7.2.1. 
Adverse Events 
 
The investigator (designee) will record all AEs that occur from the time the ICF is signed until 
the end of study. Refer to the study manual for the procedures to be followed. 
 
Information on follow-up for AEs is provided in Section 7.2.7. Laboratory test results or vital 
signs are to be recorded as AEs as outlined in Section 7.2.6. 
 
7.2.2. 
Serious Adverse Events 
 
All SAEs, regardless of assessment of causal relationship to study drug must be reported to the 
sponsor (designee) within 24 hours. Refer to the study manual for the procedure to be followed. 
 
Information not available at the time of the initial report must be documented in a follow-up 
report. Substantiating data such as relevant hospital or medical records and diagnostic test reports 
may also be requested. 
 
The investigator must promptly report to the Institutional Review Board/Ethics Review 
Committee (IRB/ERC) all unanticipated problems involving risks to subjects. This includes 
death from any cause and all SAEs related to the use of the study drug. It is recommended that 
all SAEs be reported to the IRB/ERC, regardless of assessed causality. 
 
In the event the investigator is informed of an SAE after the subject completes the study, the 
following will apply: 
 
• SAE with an onset within 30 days of the end of study/early termination visit - the 
SAE will be reported to the sponsor. The investigator should make every effort to 
obtain follow-up information on the outcome until the event is considered chronic 
and/or stable. 
• SAE with an onset day greater than 30 days from the end of study/early termination 
visit - only fatal SAEs and those deemed by the investigator to be drug-related SAEs 
will be reported to the sponsor. The investigator will make every effort to obtain 
follow-up information on the outcome of a drug-related SAE until the event is 
considered chronic and/or stable. 
7.2.3. 
Sponsor’s Responsibility 
During the course of the study, the sponsor will report in an expedited manner all SAEs that are 
both unexpected and at least reasonably related to the study drug (Suspected Unexpected Serious 
Adverse Reaction), to the Health Authorities, ERCs/IRBs as appropriate and to the investigators. 
 
In addition, the sponsor will report in an expedited manner all SAEs that are expected and at 
least reasonably related to the study drug to the Health Authorities, according to local 
regulations. 
 
Any other AE not listed as an expected event in the Investigator’s Brochure or in this protocol 
will be considered as unexpected. 


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The sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report to Health Authorities and ERCs/IRB as appropriate. 
 
7.2.4. 
Other Events that Require Accelerated Reporting 
 
The events of symptomatic drug overdose and AESI will be reported to the sponsor (designee) 
within 24 hours of learning of the event. Refer to the study manual for definitions and procedures 
to be followed. 
 
7.2.4.1. 
Symptomatic Overdose of Study Drug 
 
Symptomatic overdose is defined in this study as accidental or intentional overdose of at least 
2 times the intended dose of study drug within the intended therapeutic window and if associated 
with an AE. 
 
7.2.4.2. 
Adverse Events of Special Interest 
 
Adverse events of special interest must be reported to the sponsor (designee) within 24 hours of 
identification. Adverse events of special interest for this study are hypersensitivity reactions 
occurring within 48 hours after exposure to the study drug (including but not limited to urticaria, 
edema, respiratory distress, anaphylaxis, and allergic reactions). The severity of AESIs will be 
graded according to the CTCAE Version 4.0 criteria for grading allergic reactions and 
anaphylaxis (Appendix D). 
 
7.2.5. 
Reporting Adverse Events Leading to Withdrawal From the Study 
 
All AEs that lead to a subject withdrawing from the study must be reported to the sponsor’s 
medical monitor within 30 days. Refer to the study manual for the procedures to be followed. 
 
7.2.6. 
Abnormal Laboratory or Vital Sign Results 
 
The criteria for determining whether an abnormal objective test finding will be reported as an AE 
include any of the following: 
 
• The test result is associated with accompanying symptoms, 
 
• The test result requires additional diagnostic testing or medical/surgical intervention, 
 
• The test result leads discontinuation from the study treatment, discontinuation from 
the study, significant additional concomitant drug treatment, or other therapy, 
 
• Grade 3 or higher laboratory test result abnormalities 
 
The investigator will contact the medical monitor in the event the investigator feels that an 
abnormal test finding should be reported as an AE, although it does not meet any of the above 
criteria. 
 
Repeating an abnormal test, in the absence of any of the above conditions will not constitute an 
AE. Any abnormal test result that is determined to be an error will not require reporting as an 
AE. 
 
Evaluation of severity of laboratory abnormalities will be assessed according to the scale 
outlined in Section 7.3.1. 


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7.2.7. 
Adverse Event Follow-up 
 
Adverse event information will be collected until the subject’s last study visit. 
 
Serious adverse event information will be collected until the event has resolved or is considered 
chronic and/or stable. 
 
7.3. 
Evaluation of Severity and Causality 
 
7.3.1. 
Evaluation of Severity 
 
The severity of the AE will be graded using 1 of 2 severity scales, and the severity scale used 
will be determined by the type of AE experienced by the subject. 
 
The severity of AEs related to allergic or anaphylactic reactions (including AESIs) will be 
graded according to the CTCAE Version 4.0 criteria for grading allergic reactions and 
anaphylaxis (Appendix D). 
 
The severity of AEs related to other events (excluding allergic or anaphylactic reactions) will be 
graded according to the Modified Toxicity Grading Scale from Division of AIDS for Grading the 
Severity of Adult and Pediatric Adverse Events. Two versions are in use for this protocol: 
Version 1.0, December, 2004; Clarification August 2009 (Appendix E) and Version 2.0, 
November 2014 (Appendix F, only applicable pages are included). 
 
Notes: Version 2.0 is to be used for grading AEs associated with total bilirubin and hemoglobin. 
For all other AEs (excluding allergic or anaphylactic reactions) Version 1.0 with the August 
2009 clarification should be used. 
 
1.   For AEs not identified elsewhere in Appendix E, the AE should be graded using the row 
describing Estimating Severity Grade. 
 
2.   For AEs associated with abnormal glucose and calcium values, a footnote is present in 
Version 1.0 of the Division of AIDS (DAIDS) scale indicating that the values are 
associated with full-term infants. This footnote has been removed from Version 2.0 of the 
DAIDS scale with no resultant changes to the grading cut-off values. Therefore, for the 
purposes of this protocol, the values present in Version 1.0 of the DAIDS scale are 
appropriate to use. 
 
3.   Any occurrence of fever must be graded according to the scale provided in Version 1.0 of 
the DAIDS scale. The DAIDS scale specifies a non-axillary temperature range in degrees 
Celsius. Please refer to Table 6 below for temperature conversion to degrees Fahrenheit 
and for a breakdown by age of infant. 


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Table 6: 
DAIDS Fever Grading Scale 
 
Infants <4 Weeks Chronological Age 
Infants ≥4 Weeks Chronological Age 
Axillary/Temporal 
Temperature 
Rectal/Tympanic 
(0.2°C+axillary) 
Axillary/Temporal 
Temperature 
Rectal/Tympanic 
(1.0°C+axillary) 
°C 
°F 
°C 
°F 
Severity 
°C 
°F 
°C 
°F 
37.5- 
38.4 
99.5- 
101.2 
37.7- 
38.6 
99.8- 
101.5 
Grade 1 
36.7- 
37.5 
98.1- 
99.5 
37.7- 
38.6 
99.8- 
101.5 
38.5- 
39.1 
101.3- 
102.4 
38.7- 
39.3 
101.6- 
102.8 
Grade 2 
37.7- 
38.3 
99.8- 
100.9 
38.7- 
39.3 
101.6- 
102.8 
39.2- 
40.3 
102.5- 
104.5 
39.4- 
40.5 
102.9- 
104.9 
Grade 3 
38.4- 
39.5 
101.2- 
103.1 
39.4- 
40.5 
102.9- 
104.9 
>40.3 
>104.5 
>40.5 
>104.9 
Grade 4 
>39.5 
>103.1 
>40.5 
>104.9 
Note: The grading scale and rectal temperatures in this table are from Division of AIDS 2004. The conversions to 
axillary/temporal temperature were created using information from Shann F 1996. 
 
If a laboratory value is considered an AE, its severity will be based on the degree of 
physiological impairment the value indicates. 
 
7.3.2. 
Evaluation of Causality 
 
7.3.2.1. 
Relationship of AEs to Study Drug 
 
The relationship of AEs to study drug will be assessed by the investigator, and will be a clinical 
decision based on all available information. The following question will be addressed: 
 
Is there a reasonable possibility that the AE may have been caused by the study drug? 
The possible answers are: 
• Not Related: There is no reasonable possibility that the event may have been caused 
by the study drug 
 
• Related: There is a reasonable possibility that the event may have been caused by the 
study drug (ie, a causal relationship cannot reasonably be ruled out) 
 
A list of factors to be considered in assessing the relationship of AEs to study drug are available 
in Appendix C. 
 
The sponsor will request information to justify the causality assessment of SAEs, as needed. 
 
7.3.2.2. 
Relationship of AEs to Injection Procedure 
 
The relationship of AEs to injection procedure will be assessed by the investigator, and will be a 
clinical decision based on all available information. The following question will be addressed: 
 
Is there a reasonable possibility that the AE may have been caused by the injection procedure? 


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The possible answers are: 
 
• Not Related: There is no reasonable possibility that the event may have been caused 
by the injection procedure 
 
• Related: There is a reasonable possibility that the event may have been caused by the 
injection procedure 
 
For a list of factors to consider in assessing the relationship of AEs to injection procedure, see 
Appendix C. 
 
The sponsor will request information to justify the causality assessment of SAEs, as needed. 
 
7.4. 
Safety Monitoring 
 
The investigator will monitor the safety of study subjects 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 monitor will have primary responsibility for 
the emerging safety profile of the compound. The study monitor will be supported by other 
departments (eg, Pharmacovigilance and 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. 
 
An IDMC will monitor subject safety during the course of the study. The composition and 
activities of the IDMC are described in Section 3.3 and the IDMC charter, composed of members 
who are independent from the sponsor and the investigators, by conducting formal reviews of 
accumulated safety data that will be blinded by treatment group; if requested, the IDMC may 
have access to the treatment allocation code or any other requested data for the purposes of a 
risk-benefit assessment. 
 
7.5. 
Investigator Alert Notification 
 
Sponsor (designee) will inform all investigators participating in this clinical trial, as well as in 
any other clinical trial using the same investigational drug, of any SAE that possibly meets the 
relevant requirements for expedited reporting (an AE that is serious, unexpected based on the 
investigator’s brochure, and has a reasonable suspected causal relationship to the study drug) in a 
blinded fashion. 
 
8. 
STUDY VARIABLES 
 
8.1. 
Demographic and Baseline Characteristics 
 
Demographics and baseline characteristics will include standard demography (eg, age, race, 
weight, length), disease characteristics (including medical history and GA at birth, family 
history, medication history for each subject), pharmacoeconomics (eg, parent employment status 
[mother and father], full or part-time, unemployed) and risk factor assessment (eg, infant care 
provided at home or daycare center, number of siblings at home [including age and school 
status], parent smoking status.) 


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8.2. 
Primary Endpoints 
The primary endpoints are the following: 
Part A: 
 
 
 
Part B: 
• Serum concentration of REGN2222 over time and other PK parameters 
 
•  Proportion of subjects with a medically attended RSV infection (hospitalization or 
outpatient LRTI) during the study period. A medically attended RSV infection is 
defined as an infant with a positive RSV test by RT-PCR with any of the following 
events: 
 
− Hospitalized (on the basis of the assessment of the admitting physician) for RSV 
infection 
 
− Outpatient visit (ER, UC, or pediatric clinica [for either a sick or well visit]) with 
RSV LRTI. 
 
a A pediatric clinic visit represents any outpatient medically attended visit that could 
include, but is not limited to, a pediatric clinic visit, a primary physician office visit, a 
family physician visit, or a study site visit. 
 
•  An RSV LRTI in an infant is defined as an RSV-proven respiratory infection (ie, 
positive RSV RT-PCR test) with parent(s)/guardian(s) report of cough or difficulty 
breathing, and with 1 of the following signs of LRTI, as assessed by a healthcare 
provider: 
 
− Lower chest wall indrawing 
 
− Hypoxemia (peripheral capillary oxygen saturation <95% breathing room air) 
 
− Wheezing or crackles 
 
An episode of RSV infection will be defined as any medically attended respiratory illness 
associated with a positive RSV RT-PCR test occurring within a 14-day period. If multiple 
medical visits (events) are made for the same episode of RSV illness, an RSV positive test by 
RT-PCR at any medical visit (event) will label that episode as being RSV positive, and it will be 
counted toward the primary endpoint. If there are multiple events during an episode associated 
with an RSV positive test, then the most severe event will be defined as the primary endpoint 
event, and events of decreasing severity will be defined in the following order: RSV positive 
hospitalization > RSV positive ER/UC LRTI > RSV positive pediatric clinic LRTI. If 
categorization of a medically attended respiratory illness event as an endpoint is unclear, source 
documentation will be provided to a blinded adjudication committee for categorization. 


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If an infant has a medically attended respiratory event but did not have an RT-PCR test 
conducted in the central laboratory within 14 days of the event, the missing result will be 
imputed using results from an RSV RT-PCR assay if it meets the following conditions: 
 
• Assay is a FDA-cleared RSV RT-PCR assay or 
 
• Assay is an RSV RT-PCR assay that is not FDA-cleared but is conducted in a laboratory 
that is currently CLIA certified. 
 
Results from non-RT-PCR RSV assays will not be collected. Only medically attended 
respiratory visits occurring during the first 150-day period will be counted toward the primary 
endpoint. 
 
8.3. 
Secondary Endpoints 
The secondary endpoints are the following: 
Part A: 
 
 
 
 
 
Part B: 
• Incidence and severity of TEAEs 
 
• Presence and titer of anti-REGN2222 antibodies 
 
 
 
• Proportion of subjects who have RSV-confirmed hospitalization, ER,UC, or pediatric 
clinic visitsa (for upper or lower respiratory infection) during the study period 
 
• PK parameters using sparse sampling 
 
• Presence and titer of anti-REGN2222 antibodies 
 
a A pediatric clinic visit represents any outpatient medically attended visit that could 
include, but is not limited to, a pediatric clinic visit, a primary physician office visit, a 
family physician visit, or a study site visit. 
 
8.4. 
Exploratory Endpoints 
The exploratory endpoints are the following:Total number of RSV-associated medical visits 
(hospital, ER, UC, or pediatric visitsa) for each subject and associated treatments or procedures at 
these visits 
 
•  Total number of medical visits (hospital, ER, UC, or pediatric visitsa) for each subject 
and associated treatments or procedures at these visits, during the study period 
excluding the initial RSV–associated medical visits. 
 
•  Number of RSV-confirmed hospitalizations (defined as stay in hospital [or its ER] for 
24 hours or longer) 
 
− Number of days with RSV-associated mechanical ventilation 
 
− Number of days with RSV-associated supplemental oxygen 
 
• Length of stay in hospital for RSV-associated illness 


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• Number of missed days of work for parent(s) or guardian(s) associated with each 
medically attended RSV event 
 
• Number and proportion of subjects with other common respiratory pathogens 
identified by a RT-PCR multiplex respiratory panel which is distinct from the RT-PCR 
assay being used to test for RSV for the study's efficacy endpoints. 
 
Note: Only nose swab specimens determined to be negative for RSV using the RT-PCR 
assay being utilized for evaluation of the study's efficacy endpoints will be evaluated by 
the RT-PCR multiplex respiratory panel. RSV positive samples identified by the RT-PCR 
multiplex respiratory panel will not be taken into account for the purpose of the analysis of 
the study's efficacy endpoints. 
 
a A pediatric clinic visit represents any outpatient medically attended visit that could 
include, but is not limited to, a pediatric clinic visit, a primary physician office visit, a 
family physician visit, or a study site visit. 
 
8.5. 
Antidrug Antibody Variables 
 
Antidrug antibody variables include status (positive or negative) and titer as follows: 
 
• Total ADA-positive subjects at any time 
 
• Pre-existing immune reactivity - defined as either an ADA positive response at 
baseline with all posttreatment ADA results negative, or a positive response at 
baseline with all posttreatment ADA responses less than 4-fold over baseline titer 
levels. 
 
• Treatment-emergent - defined as either an ADA positive response after treatment 
when baseline results are negative, or if any posttreatment ADA-positive response is 
greater than or equal to 4-fold over baseline titer levels. The treatment-emergent 
responses will be further characterized into Persistent and Transient. 
 
− Persistent Response - treatment-emergent ADA positive response with two or 
more ADA-positive sampling time points during the treatment period (and 
follow-up phase if any) such that the first and last ADA-positive sample (with no 
ADA-negative samples in between) is separated by at least a 12-week period or 
only the last collected sample is ADA-positive. 
 
− Transient Response - Any treatment-emergent ADA-positive response that is not 
considered persistent 
 
• Titer values 
 
• Titer category 
 
− Low (titer <1000) 
 
− Moderate (1000 ≤ titer ≤ 10 000) 
 
− High (titer >10 000) 


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9. 
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. 
 
Primary and secondary endpoints are listed in Section 8.2 and Section 8.3, respectively. 
Results from Part A and Part B of this study will be analyzed separately. 
 
9.1. 
Statistical Hypothesis 
 
The null hypothesis of the study is that the proportions of medically attended RSV 
hospitalization or outpatient LRTI in the placebo group and in the REGN2222 groups are the 
same (H0: p1 = p2). The alternative hypothesis is that the rate for each REGN2222 group is 
different from the rate for the placebo group (H1: p1 ≠ p2). 
 
9.2. 
Sample Size 
 
For Part A, the goal of the study is to study infant PK, and therefore no formal sample size 
calculation will be conducted. 
 
For Part B, the sample size estimation is based on the primary efficacy endpoint of medically 
attended RSV infection (hospitalization or outpatient LRTI). Literature (Hall 2009, 
Ambrose 2014) show that the event rate in this endpoint is in the range of 12% to 22% in the 
studied infant populations. As the event rate may vary over RSV season or geographic region, it 
is assumed that event rate is 10% for the placebo group, and either dose of RENG2222 would 
reduce the event rate from placebo by 60% (event rate of 4%). With 505 randomized subjects per 
arm or a total of 1515 randomized subjects, the study has 90% power to demonstrate a 60% or 
greater reduction at 2-sided significance level α=0.025. This sample size also incorporated a 
5% early dropout rate. The sample size calculation is based chi-square test with continuity 
correction and performed using nQuery version 7.0 (Statistical Solutions Ltd, Cork, Ireland). 
 
The significant level of 2-sided 0.025 is set in consideration of multiplicity of 2 comparisons 
between each of the 2 REGN2222 dose arms with placebo. 
 
With a total of 1515 randomized subjects and 1:1:1 randomization ratio, it is expected 
1010 subjects to receive REGN2222 (505 subjects in each of the 2 REGN2222 arms) and 
505 subjects to receive placebo and in total, an approximate of 90 primary endpoint events. Also, 
with 1010 subjects exposed to REGN2222, the regulatory requirement for safety assessment will 
be met. 
 
Impact of Early Termination on Sample Size and Power 
 
Acknowledging the study enrollment is planned to be terminated with the 2016-2017 RSV 
season and final enrollment of approximately 1200 subjects, the comparison of the REGN2222 
2-dose regimen to placebo will have approximately 87% power to detect the previously planned 
60% reduction in medically attended RSV infections with a 2-sided significance level of 0.05. 
The overall type I error for the pairwise comparisons of each REGN2222 dose regimen to 
placebo will be controlled using a pre-specified hierarchical inferential approach (2-sided α 


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=00.05 for each statistical test) as opposed to the originally planned Bonferroni adjustment (two- 
sided α = 0.025 for each pairwise treatment comparison). (See Section 9.5.2.4). 
 
9.2.1. 
Blinded Sample Size Re-estimation 
 
Sample size may be re-estimated at the end of each RSV season. If the study is fully enrolled at 
that time, then the sample size will be re-estimated before database lock. Sample size 
re-estimation will be based on the blinded and pooled event rate and hypothesized treatment 
effect. The hypothesized treatment effect for each arm of REGN2222 will be a 60% reduction in 
event rates compared with the placebo arm. As stated by Gould and Shih (Gould 1998), the 
blinded sample size re-estimation does not affect type I error materially for binomially 
distributed data. The objective of this sample size re-estimation is to ensure the study will be 
adequately powered in case of a milder-than-expected RSV season, leading to low medically 
attended visits for RSV infection. Sample size re-estimation will be done using the formula from 
Gould (Gould 1992). If the re-estimated sample size is less than 1665 subjects, or 1.10 times of 
planned sample size, the study will proceed as is, with no change in planned sample size (the 
study will have approximately 86% or more power with planed sample size). If the re-estimated 
sample size is between 1665 and 2200, the study sample size will be increased to the 
re-estimated sample size. If the re-estimated sample size is greater than 2200 subjects, the 
sponsor will make an administrative decision to either increase the sample size to 2200 subjects, 
or keep the planed sample size unchanged. 
 
9.3. 
Analysis Sets 
 
9.3.1. 
Part A 
 
The safety analyses will be based on enrolled subjects who receive any study drug. The PK 
analysis set contains subjects who received a single dose of REGN2222 and have at least 
1 measurable serum concentration of REGN2222. 
 
9.3.2. 
Part B 
 
The efficacy analyses will be based on the full analysis set defined as all randomized subjects 
who receive any study drug. For all efficacy analyses, subjects will be analyzed as randomized. 
 
The safety analysis set contains all randomized subjects who received at least 1 dose of the study 
medication. For all safety analyses, subjects will be summarized as treated. 
 
The PK analysis set contains all subjects who received at least 1 dose of REGN2222 and have at 
least 1 measurable serum concentration of REGN2222. 


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9.4. 
Subject Disposition 
 
9.4.1. 
Part A 
 
The following will be provided: 
 
• The total number of screened subjects: parent(s) or legal guardian(s) who signed the 
ICF 
• The total number of subjects in the safety analysis set and PK analysis set 
• The total number of subjects who discontinued the study, and the reasons for 
discontinuation 
• A listing of subjects prematurely discontinued from treatment, and the reasons for 
discontinuation 
9.4.2. 
Part B 
The following will be provided: 
• The total number of screened subjects: parent(s) or legal guardian(s) who signed the 
ICF 
• The total number of randomized subjects: received a randomization number (subject 
identification) 
• The total number of subjects in the safety analysis set and PK analysis set 
• The total number of subjects who discontinued the study, and the reasons for 
discontinuation 
• A listing of subjects prematurely discontinued from treatment, and the reasons for 
discontinuation 
9.5. 
Statistical Methods 
Part A and Part B: For continuous variables, descriptive statistics will include the following: the 
number of subjects reflected in the calculation, mean, median, standard deviation, minimum, and 
maximum. 
 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
 
9.5.1. 
Demography and Baseline Characteristics 
 
Demographic and baseline characteristics will be summarized descriptively for Part A and by 
treatment arm for Part B of the study. 
 
9.5.2. 
Efficacy Analysis 
 
Efficacy analyses apply to Part B and not Part A. 


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9.5.2.1. 
Primary Efficacy Analysis 
 
Part B 
 
The primary endpoint will be analyzed using Mantel-Haenszel methods to assess the differences 
in the proportions between each REGN2222 treatment and placebo, stratifying by region (North 
America or rest of the world) and GA (≤31 weeks, 6 days GA or from 32 weeks, 0 days to 
35 weeks, 6 days GA). 
 
The proportion of primary endpoint events for primary analysis will be calculated as number of 
subjects with a medically attended RSV infection (hospitalization or outpatient RSV LRTI) 
during the 150-day efficacy assessment period divided by total number of subjects assigned to 
each treatment group from the full analysis set. 
 
For a subject who discontinued study treatment early (see Section 5.2.2.1), the subject will be 
followed to Day 150 for assessment of primary endpoint events. The event observed after the 
early termination of study treatment will be counted as an event and will be included in the 
primary analysis. 
 
For early termination subjects (ie, those who did not complete Day 150 visit), the primary 
endpoint will be handled according to the following rules in the primary analysis: 
 
• Early termination subjects who had a primary endpoint event during the 150-day efficacy 
assessment period (regardless of treatment status, ie, whether the subject received all 
study drug doses or discontinued dosing) will be used in the primary analysis and 
included as “event occurred”.  [No imputation] 
 
• Direct imputation of missing primary endpoint at Day 150 visit: 
 
o Subject deaths prior to Day 150 that are adjudicated to be RSV related will be 
included as “event occurred”. 
 
o Remaining early termination subjects (including non-RSV deaths) across all 
treatment groups, will be imputed to the average placebo score (estimated placebo 
event rate). The approach to estimating the placebo event rate is the Kaplan-Meier 
estimate at Day 150. 
 
• Imputed scores along with observed subject data will be utilized in the Cochran-Mantel- 
Haenszel analysis. Imputed scores along with observed subject data will be utilized in the 
Cochran-Mantel-Haenszel (CMH) analysis (with stratum adjusted by Mantel-Haenszel 
method). 
 
As a sensitivity analysis to the primary endpoint, the following analyses will be performed: 
 
RSV LRTI analysis: For the proportion of subjects with a medically attended RSV infection, 
only those RSV hospitalizations meeting the protocol-specified definition of LRTI (a subset 
of all RSV hospitalizations) will be counted towards the hospitalization component; the 
outpatient component will remain as described for the primary analysis. 
 
Alternative LRTI Definition Analysis: Comparing the proportion of subjects with a 
medically attended RSV-confirmed infection (hospitalization or outpatient lower respiratory 
tract infection) during the study period (Day 150) as compared to placebo; using the 
following definition of LRTI: 


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• Infant with RSV-proven infection who presents with cough or difficulty breathing 
and 2 of the following criteria: 
 
− Lower chest wall indrawing 
 
− Hypoxemia (peripheral capillary oxygen saturation <95% breathing room air) 
 
− Wheezing or crackles 
 
− Ventilatory failure (needing ventilator support in any form) 
 
− New onset apnea 
 
− Increased respiratory rate using WHO criteria for fast breathing for age 
 
The primary endpoint events of medically attended RSV infection (hospitalization or outpatient 
LRTI) will also be analyzed by stratified logistic regression and by stratified log-rank test and 
presented using a Kaplan-Meier curve. For the log-rank test and Kaplan-Meier curve, time to the 
first primary endpoint event will be analyzed; subjects who do not have a primary endpoint event 
will be censored at the last time point when the primary endpoint event is assessed. 
 
Additional sensitivity analyses are planned to support the primary analysis, including exact test 
method (Fisher’s), etc. All sensitivity analyses with associated details will be described in the 
SAP. 
 
9.5.2.2. 
Secondary Efficacy Analysis 
 
The proportion of subjects who have RSV-confirmed hospitalization, ER, UC, or pediatric visits 
during the 150-day efficacy assessment period will be analyzed using the same methods 
described in the analysis of the primary endpoint. 
 
9.5.2.3. 
Exploratory Analysis 
 
Pharmacoeconomic variables will be summarized descriptively for Part B. 
 
Respiratory syncytial virus confirmed hospitalization, a component of the primary composite 
endpoint,  will  be  explored  using  the  same  statistical  methodology  as  the  primary  efficacy 
analysis. For this exploratory analysis, the 2 REGN2222 treatment groups will be combined for 
comparison to the placebo group, with the intent to evaluate the REGN2222 effect on subjects 
with RSV confirmed hospitalization. 
 
Pharmacoeconomic variables and proportion of subjects with other common respiratory 
pathogens identified by a RT-PCR multiplex respiratory panel will be summarized descriptively 
for Part B.  Only nose swab specimens determined to be negative for RSV using the RT-PCR 
assay being utilized for evaluation of the study's efficacy endpoints will be evaluated by the RT- 
PCR multiplex respiratory panel. 


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9.5.2.4. 
Multiplicity Considerations 
 
To control the 5% overall type I error for the 2 pairwise comparisons in the primary analysis, the 
overall study α level will be controlled by the use of a hierarchical inferential approach. 
Statistical significance of the first pairwise treatment comparison (REGN2222 2 doses arm to 
placebo) is required before drawing inferential conclusions about the second pairwise treatment 
comparison (REGN2222 1 dose arm to placebo) at the 0.05 alpha level. This fixed hierarchical 
approach will ensure a strong control of the overall type I error rate at the 0.05 level for each 
REGN2222 dose regimen comparison. 
 
Further, in the case that the primary efficacy endpoint is statistically significant at 0.05 (2-sided) 
alpha level for both pairwise treatment group comparisons specified in the above paragraph, the 
secondary efficacy endpoint will be tested using the same hierarchical inferential approach as 
used for the primary efficacy endpoint. 
 
This multiple testing procedure ensures a strong control of the overall type I error rate at the 0.05 
level. No further adjustments will be made for other analyses for which p-values will be provided 
for descriptive purpose only. 
 
No adjustment will be made for the first step and second step statistical analyses (Section 9.5.6), 
since the primary and secondary efficacy endpoints will have been concluded at the time of the 
first step analysis. 
 
9.5.3. 
Safety Analysis 
 
9.5.3.1. 
Part A 
 
Safety and tolerability will be descriptively summarized, including TEAEs, laboratory variables, 
vital signs, and physical examination. 
 
9.5.3.2. 
Part B 
 
Safety and tolerability will be descriptively summarized by treatment arm and the combined 
REGN2222 treatment arms, including TEAEs, laboratory variables, vital signs, and physical 
examination. 
 
Safety evaluations will be performed on the safety analysis set; no formal comparisons and 
testing against the placebo group or between different treatment arms are planned. 
 
9.5.3.3. 
Adverse Events 
 
Definitions 
 
For safety variables in Part A, 2 observation periods are defined: 
 
• The pre-treatment period is defined as the time from signing the ICF to before the 
first dose of study drug. 
 
• The treatment period is defined as the days from the first dose of study drug to the 
Day 150 visit. 


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Treatment-emergent AEs in Part A are defined as those that are not present at baseline or 
represent the exacerbation of a preexisting condition during the treatment period. 
 
For safety variables in Part B, 3 observation periods are defined: 
 
• The pre-treatment period is defined as the time from signing the ICF to before the 
first dose of study drug. 
 
• The safety treatment period is defined as the time from the first dose of study drug up 
to the day of the last dose of study drug + 180 days. 
 
• The post-treatment period: defined as starting the day after the end of the TEAE 
period. 
 
Treatment-emergent adverse event in Part B are defined as those that are not present at baseline 
or represent the exacerbation of a pre-existing condition during the safety treatment period 
(TEAE 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 PT, and the primary system organ class (SOC) will be listed. 
 
Summaries of all TEAEs by treatment group (dose cohort in Part A or treatment arm in Part B) 
will include: 
 
• The number (n) and percentage (%) of subjects with at least 1 TEAE by SOC and PT 
 
• TEAEs by severity (according to the grading scale outlined in Section 7.3.1), 
presented by SOC and PT 
• TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
Deaths, AESIs, and other SAEs will be listed and summarized by dose cohort for Part A and by 
treatment arm for Part B of the study. 
 
Treatment-emergent AEs leading to permanent treatment discontinuation will be listed and 
summarized by dose cohort for Part A and by treatment arm for Part B of study. 
 
Additional evaluation of TEAEs may be conducted for identification of hypersensitivity. 
 
9.5.3.4. 
Other Safety 
 
Vital Signs 
 
Vital signs (temperature, pulse, blood pressure, and respiration rate) will be summarized by 
baseline and change from baseline to each scheduled assessment time with descriptive statistics. 
 
Number and percentage of subjects with treatment-emergent potential clinical significant value 
(PCSV) will be summarized for each vital sign variable. The definition of treatment-emergent 
PCSV will be defined in the SAP. 


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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 subject with a treatment-emergent PCSV will be summarized for each 
clinical laboratory test. The definition of treatment-emergent PCSV will be defined in the SAP. 
 
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. 
 
9.5.3.5. 
Treatment Exposure 
 
Part A: 
 
The observation period (defined as the time between the date of the first study drug 
administration and the date of the end of study or the last visit), rather than the treatment 
exposure, will be presented by dose cohort. The number of doses each subject receives will also 
be summarized by dose cohort for Part A. 
 
Part B: 
 
The number (%) of subjects randomly assigned and exposed to double-blind study drug will be 
presented by specific time periods for each treatment group and the combined REGN2222 
treatment arms. The time periods of interest will be specified in the SAP. 
 
In addition, duration of exposure during the study will be summarized for each treatment group 
and the combined REGN2222 treatment arms using number of subjects, means, standard 
deviation, minimums, medians, and maximums. A summary of the number of doses by treatment 
group will also be provided. 
 
9.5.3.6. 
Treatment Compliance 
 
The compliance with study treatment will be calculated as follows: 
 
 
 
 
Treatment Compliance = 
(Number of study drug injections during exposure 
period) 
 
(Number of study drug injections expected during 
exposure period) 
 
 
 
× 100%. 
 
The treatment compliance will be presented by specific ranges for each treatment group. The 
ranges of interest will be specified in the SAP. 


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9.5.4. 
Pharmacokinetic Analysis 
 
9.5.4.1. 
Part A 
 
The PK of REGN2222 will be characterized using a population modeling approach. Data from 
Part A may be combined with data from an additional study in healthy adult volunteers. The 
details of the population PK analysis will be described in a separate PK analysis plan. 
 
The structural model will contain absorption rate constant, clearance, and volume of distribution 
as fixed-effect parameters. The intersubject variability of the PK parameter estimates and the 
random residual error in the data will be estimated with appropriate error models. The best base 
model will be identified based on standard goodness-of-fit criteria and the covariates that have a 
significant impact on PK of REGN2222 will be identified, if appropriate. The final population 
PK model will be evaluated using bootstrapping and visual predictive check. 
 
Individual post hoc PK parameters such as absorption rate constant, clearance, and volume of 
distribution of REGN2222 will be estimated. Pharmacokinetic simulations will be performed 
using the final PK model developed in Part A to assist with selection of REGN2222 dosage 
regimen for Part B. 
 
9.5.4.2. 
Part B 
 
PK data from Part A will be combined with PK data from Part B and the population PK model 
developed from Part A data will be refined using the similar approach described in Part A. Data 
from healthy adult volunteers in the previous study may also be included. Pharmacokinetic 
simulations using the revised final PK model may be performed to provide insight into any 
dosage adjustment in infants. 
 
9.5.5. 
Analysis of Antidrug Antibody Data 
 
9.5.5.1. 
Part A 
 
Listings of ADA positivity and titers will be presented by subject and time point. Prevalence of 
ADA will be assessed as absolute occurrence (n) and percent (%) of subjects, grouped by 
single cohort and ADA-titer level. 
 
9.5.5.2. 
Part B 
 
Listings of ADA positivity and titers will be presented by subject, time point, and treatment arm. 
Prevalence of ADA will be assessed as absolute occurrence (n) and percent (%) of subjects, 
grouped by treatment arms and ADA-titer level. 
 
9.5.5.3. 
Part A and Part B: 
 
Plots of drug concentrations will be examined, and the influence of ADAs on individual 
PK profiles will be evaluated. An assessment of impact of ADA on safety may be provided. 
 
9.5.6. 
Timing of Statistical Analyses 
 
The analysis for Part B will be conducted in 2 steps. 


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9.5.6.1. 
First Step:  Efficacy and Safety Analysis 
 
The first step analysis will be conducted as soon as the last randomized subject has completed 
the end of the 150-day efficacy assessment period visit and all the data have been collected and 
validated; this will consist of the final analysis of all efficacy endpoints. The safety analyses will 
be performed on all safety data collected through the common cut-off date. For this analysis, the 
common cut-off date is  the date that the last subject completes the day 150 visit (Part B Visit 7; 
end of 150-day efficacy assessment period). 
 
The results of the first step analysis will not be used to change the conduct of the ongoing study 
in any aspect. Since all the efficacy measure data collection will have been concluded at the time 
of this first step analysis, the significance level for the study remains at 2-sided 0.05. This first 
step analysis may be used for submission to health authorities or other interested parties. 
 
Sponsor personnel involved in the first step analysis of the study will not be involved in the 
conduct of the study afterwards; individual study subject identification will not be released to 
anyone who is directly involved in the conduct of the study. The first step analysis process, the 
measures used to protect the blind and the integrity of the study, the communication plan, and the 
confidentiality agreement will be described in a separate document. 
 
9.5.6.2. 
Second Step:  Final Safety Analysis 
 
The second step analysis will be performed at the end of the study and will consist of the final 
analysis of the safety measures. 
 
9.6. 
Interim Analysis 
 
9.6.1. 
Part A 
 
An interim PK analysis will be conducted on the first 18 infants after at least one postdose blood 
sample is collected for determination of drug concentration following administration of study 
drug. Following the completion of Part A, subject data will be locked and reported.  This will be 
done to confirm the dose to move forward with in Part B of the study. 
 
9.6.2. 
Part B 
 
If the sample size of 1515 infants is not achieved via enrollment in the Northern Hemisphere, the 
study will continue to enroll in subsequent RSV seasons. A study-treatment blinded sample size 
re-assessment (as detailed in Section 9.2.1) may be proposed at the end of any RSV season. This 
blinded sample size re-estimation was never performed during the study, nor is re-estimation 
planned during the remainder of the study since enrollment will end with the 2016/2017 RSV 
season in the Northern Hemisphere due to Sponsor’s administrative decision. 
 
An unblinded interim efficacy analysis is not planned. 
 
9.7. 
Final Reporting 
The results from Part A and Part B of this study will be summarized separately. The results from 
Part A of the study will be summarized after its completion. The final report will be written after 
completion of both Part A and Part B of the study. 


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9.8. 
Additional Statistical Data Handling Conventions 
 
9.8.1. 
Definition of Baseline 
 
Unless otherwise specified, the baseline assessment for all measurements will be the latest 
available valid measurement taken prior to the administration of the study drug. For most 
variables, Day 1 procedures and assessments are considered to be baseline. 
 
9.8.2. 
General Rules for Handling Missing Data 
 
If the start date of an AE or concomitant medication is incomplete or missing, it will be assumed 
to have occurred on or after the intake of study medication, except if an incomplete date (eg, 
month and year) clearly indicates that the event started prior to treatment. If the partial date 
indicates the same month or year of the intake of the study medication date, then the start date by 
the study medication intake date will be imputed; otherwise, the missing day or month by the 
first day or the first month will be imputed. 
 
No imputations for missing laboratory data, vital sign data, or physical examination data will be 
made. 
 
9.8.3. 
Visit Windows 
 
Assessments taken outside of protocol allowable windows will be displayed according to the 
CRF assessment recorded by the investigator. 
 
9.8.4. 
Unscheduled Assessments 
 
Extra assessments (laboratory data or vital signs associated with nonprotocol clinical visits or 
obtained in the course of investigating or managing AEs) will be included in listings, but not 
summarized by study visit. If more than 1 laboratory value is available for a given visit, the first 
observation will be used in summaries and all observations will be presented in listings. 
 
9.9. 
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. The investigator and 
Sponsor responsibilities surrounding the premature termination of a study are presented in 
Section 15.1. 


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10. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
 
10.1. 
Data Management 
 
A data management plan specifying all relevant aspects of data processing for the study 
(including data validation, cleaning, correcting, releasing) will be maintained and stored at 
sponsor. 
 
A medical coding plan will specify the processes and the dictionary used for coding. All data 
coding (eg, AEs, baseline findings, medication, medical history/surgical history) will be done 
using internationally recognized and accepted dictionaries. 
 
The CRF data for this study will be collected with an electronic data capture tool (Medidata rave) 
 
10.2. 
Electronic Systems 
 
Electronic systems that may be used to process and/or collect data in this study include the 
following: 
 
• IVRS/IWRS system – assignment of subject identification number, blood collection 
schedule, randomization (Part B only), study drug supply 
 
• Electronic data capture system – data capture 
 
• SAS software – statistical review and analysis 
 
10.2.1. 
Interactive Voice or Web Response System 
 
An IVRS/IWRS will be used for the assignment of the subject identification number, including 
order of blood sampling, randomization to a treatment arm (in Part B only), and assignment of 
study drug kits (Part A: open-label with 1 cohort; Part B: randomized with 3 arms). A subject 
will be considered to be enrolled in the study upon receipt from the IVRS/IWRS of the subject’s 
blood collection schedule and assignment of study drug kit from the site supply. 


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11. 
STUDY MONITORING 
 
11.1. 
Monitoring of Study Sites 
 
The study monitor (designee, eg, contract research organization’s monitor) will visit each site 
prior to enrollment of the first subject, and periodically during the study. In accordance with ICH 
guidelines, the monitor will compare the CRF entries with the appropriate source documents. 
Additional review may include, but is not limited to, subject ICFs, documentation of subject 
recruitment and follow-up, AEs, SAEs, and concomitant therapy, as well as records of study 
drug dispensing, compliance, and accountability. A copy of the drug dispensing log must be 
provided to the sponsor upon request. 
 
11.2. 
Source Document Requirements 
 
Investigators are required to prepare and maintain adequate and accurate subject records (source 
documents). 
 
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. 
 
11.3. 
Case Report Form Requirements 
 
Study data obtained in the course of the clinical study will be recorded on electronic CRFs by 
trained site personnel. A CRF must be completed for each and every subject enrolled in the 
study. After review of the clinical data for each subject, the investigator must provide an 
electronic signature. A copy of each CRF page 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 system. For corrections made 
via data queries, a reason for any alteration must be provided. 


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12. 
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/ERC 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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13. 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
13.1. 
Good Clinical Practice Statement 
 
It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable 
regulatory requirements. 
 
13.2. 
Informed Consent 
 
The principles of informed consent are described in the 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/ERC. A copy of the IRB/ERC-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 (designee; if acceptable by local regulations) to obtain 
written informed consent from each subject's parent(s) or legal guardian(s) prior to the subject’s 
participation in the study and after the aims, methods, objectives, and potential hazards of the 
study have been explained to fullest possible extent in language that the parent(s) or legal 
guardian(s) can understand. The ICF will be signed and dated by the subject’s parent(s) or legal 
guardian(s) and the same investigator (designee) who explained the ICF. 
 
Local law must be observed in deciding whether the consent of 1 or both parent(s) or legal 
guardian(s) is required. If only 1 parent or guardian signs the ICF, the investigator must 
document the reason the other parent or guardian did not sign. The subject’s parent(s) or legal 
guardian(s) may also be required to sign and date the ICF, as determined by the IRB/ERC and in 
accordance with the local regulations and requirements. 
 
If the subject’s parent(s) or legal guardian(s) can write but cannot read, the assent form will be 
read to them before writing their name on the form. If the subject’s parent(s) or legal guardian(s) 
can understand but can neither write nor read, the ICF will be 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 subject's study record, and a 
copy of the signed ICF must be given to the subject’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 parent(s) or legal guardian(s) of study subjects 
must be informed of the new information and provide their written consent if they wish the 
subject to continue in the study. The original signed revised ICF must be maintained in the 
subject’s study record and a copy must be given to the subject’s parent(s) or legal guardian(s). 
 
13.3. 
Subject Confidentiality and Data Protection 
 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
subject will be maintained. Subjects will be identified by their initials and a subject identification 


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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 subject'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 will take all 
appropriate measures to safeguard and prevent access to these data by any unauthorized third 
party. 
 
13.4. 
Institutional Review Board/Ethics Committee 
 
An appropriately constituted IRB/ERC, as described in the ICH guidelines for GCP, must review 
and approve: 
 
• The protocol, ICF, and any other materials to be provided to the subjects’ parent(s) or 
legal guardian(s) (eg, advertising) before any subject 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 subjects, in 
which case the IRB/ERC will be informed as soon as possible 
 
• Continuation of study from Part A to Part B with confirmation of the dose regimens 
to be used in Part B 
• Ongoing studies on an annual basis or at intervals appropriate to the degree of risk. 
In addition, the IRB/ERC will be informed of any event likely to affect the safety of subjects or 
the continued conduct of the clinical study. 
 
A copy of the IRB/ERC approval letter with a current list of the IRB/ERC members and their 
functions must be received by the sponsor prior to shipment of drug supplies to the investigator. 
The approval letter will include the study number and title, the documents reviewed, and the date 
of the review. 
 
Records of the IRB/ERC review and approval of all study documents (including approval of 
ongoing studies) must be kept on file by the investigator. 


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14. 
PROTOCOL AMENDMENTS 
 
The sponsor may initiate Part B based on the written communication to investigators, ethics 
committees and competent authorities prior to formally amending the protocol for the purpose of 
altering the dose, if applicable. The sponsor may not implement a change in the design of the 
protocol or ICF without an IRB/ERC-approved amendment. All substantial protocol 
amendments will be approved by the competent authorities before changes are implemented 
according to national regulations. 


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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. 
 
15.2.1. 
Investigator’s Decision to Close Out Site 
 
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 will be made through mutual agreement with the 
sponsor. Both parties will arrange the close-out procedures after review and consultation. 
 
15.2.2. 
Sponsor’s Decision to Close Out Site 
 
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 subject 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 subjects required for the study is enrolled earlier than expected. 
In all cases, the appropriate IRB/ERC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection 
of the subjects’ interests. 


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16. 
STUDY DOCUMENTATION 
 
16.1. 
Certification of Accuracy of Data 
 
A declaration assuring the accuracy and content of the data recorded on the CRFs must be signed 
by the investigator. This certification form accompanies each set of CRFs. The signed form will 
be provided to the sponsor with the final set of CRFs for each subject. 
 
16.2. 
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 consult with the sponsor before discarding or 
destroying any essential study documents 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 and the relevant records will be transferred to a mutually 
agreed-upon destination. 
 
17. 
CONFIDENTIALITY 
 
Confidentiality of information is provided as a separate agreement. 
 
18. 
FINANCING AND INSURANCE 
 
Financing and insurance information is provided as a separate agreement. 
 
19. 
PUBLICATION POLICY 
 
The publication policy is provided as a separate agreement. 


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20. 
REFERENCES 
 
Ambrose CS, Anderson EJ, Simoes EA, et al. Respiratory syncytial virus in preterm infants in 
the U.S. born at 32-35 weeks gestation not receiving immunoprophylaxis. Pediatr Infect Dis J. 
2014;33(6):576-82. 
 
American Academy of Pediatrics Committee on Infectious Diseases (AAPCID). American 
Academy of Pediatrics Bronchiolitis Guideline Committee Updated guidance for palivizumab 
prophylaxis among infants and young children at increased risk of hospitalization for respiratory 
syncytial virus infection. Pediatrics. 2014;134(2):415-20. 
 
American Academy of Pediatrics. Respiratory syncytial virus. In: Pickering LK BC, Kimberlin 
DW, Long SS, ed. Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk 
Grove Village (IL). 2009. 
 
Anderson LJ, Dormitzer PR, Nokes DJ, et al. Strategic priorities for respiratory syncytial virus 
(RSV) vaccine development. Vaccine. 2013;31(suppl 2):B209-15. 
 
Blanken MO, Rovers MM, Molenaar JM, et al. Respiratory syncytial virus and recurrent wheeze 
in healthy preterm infants. N Engl J Med. 2013;368(19):1791-9. 
 
Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 
1.0. National Institute of Allergy and Infectious Diseases website. 
http://www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/documents/daidsaegradingta 
ble.pdf. Published December, 2004. Accessed 8 December 2014. 
 
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Version 2.0. US Department of Health and Human Services, National Institutes of 
Health, National Institute of Allery and Infectious Diseases. Available from: 
http://rsc.tech-res.com/Document/safetyandpharmacovigilance/DAIDS_AE_GRADING_TABL 
E_v2_NOV2014.pdf. Published November, 2014. 
 
Gould AL, Shih WJ. Modifying the design of ongoing trials without unblinding. Stat Med. 
1998;17(1):89-100. 
 
Gould AL, Shih WJ. Sample size re-estimation without unblinding for normally distributed 
outcomes with unknown variance. Commun Statists: Theory and Methods. 1992;21(10):2833-53. 
 
Hall CB, Weinberg GA, Iwane MK, et al. The burden of respiratory syncytial virus infection in 
young children. N Engl J Med. 2009;360(6):588-98. 
 
Hall CB, Weinberg GA, Blumkin AK, et al. Respiratory syncytial virus-associated 
hospitalizations among children less than 24 months of age. Pediatrics. 2013;132(2):e341-8. 
 
Iwane MK, Edwards KM, Szilagyi PG, et al. Population-based surveillance for hospitalizations 
associated with respiratory syncytial virus, influenza virus, and parainfluenza viruses among 
young children. Pediatrics. 2004;113(6):1758-64. 
 
Lapillonne A, Regnault A, Gournay V, et al. Development of a questionnaire to assess the 
impact on parents of their infant's bronchiolitis hospitalization. BMC Health Serv Res. 2013; 
13:272. 


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Ohuma EO, Okiro EA, Ochoia R, et al. The natural history of respiratory syncytial virus in a 
birth cohort: the influence of age and previous infection on reinfection and disease. Am J 
Epidemiol. 2012;176(9):794-802. 
 
Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces 
hospitalization from respiratory syncytial virus infection in high-risk infants. The IMpact-RSV 
Study Group. Pediatrics. 1998;102(3 Pt 1):531-537. 
 
Robinson J. Preventing respiratory syncytial virus infections. Paediatr Child Health. 
2011;16(8):487-90. 
 
Shann F, Mackenzie A. Comparison of rectal, axillary, and forehead temperatures. Arch Pediatr 
Adolesc Med. 1996;150(1):74-8. 
 
Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and 
respiratory syncytial virus in the United States. JAMA. 2003;289(2):179-86. 
 
Yoshihara S, Kusuda S, Mochizuki H, et al. Effect of palivizumab prophylaxis on subsequent 
recurrent wheezing in preterm infants. Pediatrics. 2013;132(5):811-8. 


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21. 
APPENDICES 


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APPENDIX A. INVESTIGATOR’S AGREEMENT 
 
I have read the attached protocol, A Phase 3, Randomized, Double-Blind, Placebo-Controlled 
Study Evaluating the Efficacy and Safety of a Human Monoclonal Antibody, REGN2222, for the 
Prevention of Medically Attended RSV Infection in Preterm Infants, Amendment 4, and agree to 
abide by all provisions set forth therein. 
 
I agree to comply with the current International Council on 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/ERC. 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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APPENDIX B. PART B DOSE SELECTION BASED ON 
PHARMACOKINETICS PROCESS 
 
The following process will be used to select the dose for Part B. 
 
1.   Run individual simulations based on subjects’ specific body weights and ages (post-natal 
age and gestational age), estimate the concentration at each sampling time point (Days 2, 
8, 15, 22, 29, and 57)*, and calculate the corresponding 90% prediction interval. 
 
2.   Compare the observed with 90% prediction interval: 
 
• If 16 or more (>88%) of observed values are above the 90% prediction interval; 
re-estimate the PK model and reduce dose accordingly to achieve target 
concentration** 
 
• If 16 or more (>88%) of observed values are below the 90% prediction interval; re-
estimate the PK model and evaluate the probability (P) that the target 
concentration** will be achieved in >40% of subjects; and if (P) <20%, then revise 
the dose frequency. 
 
• Otherwise continue the study as planned 
 
*Note: There will be data for 18 patients [1 sample per patient; 3 patients per time point] 
 
**Pharmacokinetic target for subtype A (5 µg/mL) and subtype B (27 µg/mL). 


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APPENDIX C. FACTORS TO CONSIDER IN ASSESSING THE 
RELATIONSHIP OF ADVERSE EVENTS TO STUDY 
DRUG INJECTION PROCEDURE 
 
Is there a reasonable possibility that the event may have been caused by the study drug injection 
procedure? 
 
No: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes: 
 
• Due to external causes such as environmental factors or other treatment/s being 
administered 
 
• Due to the patient’s/subject’s disease state or clinical condition 
 
• Does not follow a reasonable temporal sequence following the time of administration 
of the dose of study drug injection procedure 
 
• Does not reappear or worsen when dosing with study drug injection procedure is 
resumed 
 
• Is not known to be a response to the study drug injection procedure based upon 
pre-clinical data or prior clinical data 
 
 
 
• Could not be explained by environmental factors or other treatment/s being 
administered 
 
• Could not be explained by the patient’s/subject’s disease state or clinical condition 
 
• Follows a reasonable temporal sequence following the time of administration of the 
dose of study drug injection procedure 
 
• Resolves or improves after discontinuation of study drug injection procedure 
 
• Reappears or worsens when dosing with study drug injection procedure is resumed 
 
• Is known to be a response to the study drug injection procedure based upon pre- 
clinical data or prior clinical data 
 
NOTE: This list is not exhaustive. 


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APPENDIX D. TOXICITY GRADING SCALE FOR GRADING 
ALLERGIC REACTIONS AND 
ANAPHYLAXIS - COMMON TERMINOLOGY 
CRITERIAL FOR ADVERSE EVENTS (CTCAE; 
VERSION 4.0, PUBLISHED 28 MAY 2009; V4.03, 
14 JUNE 2010) 
 
The CTCAE descriptive terminology will be utilized for reporting AEs of allergic reactions and 
anaphylaxis. A grading (severity) scale is provided for each AE term. 
 
Adverse Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Allergic reaction 
Transient 
flushing or 
rash, drug fever 
<38 degrees C 
(<100.4 degrees 
F); intervention 
not indicated 
Intervention or 
infusion 
interruption 
indicated; responds 
promptly to 
symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDS, 
narcotics); 
prophylactic 
medications 
indicated for 
≤24 hours 
Prolonged (e.g., not 
rapidly responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion); recurrence 
of symptoms 
following initial 
improvement; 
hospitalization 
indicated for clinical 
sequelae (e.g., renal 
impairment, 
pulmonary 
infiltrates) 
Life- 
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by an adverse local or general response from exposure to an allergen 
Anaphylaxis 
– 
– 
Symptomatic 
bronchospasm, with 
or without urticaria; 
parenteral 
intervention 
indicated; 
allergy-related 
edema/angioedema; 
hypotension 
Life- 
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of histamine and 
histamine-like substances from mast cells, causing a hypersensitivity immune response. Clinically, it presents with 
breathing difficulty, dizziness, hypotension, cyanosis and loss of consciousness and may lead to death. 


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APPENDIX E. TOXICITY GRADING SCALE - MODIFIED FROM 
DIVISION OF AIDS TABLE FOR GRADING THE 
SEVERITY OF ADULT AND PEDIATRIC ADVERSE 
EVENTS (VERSION 1.0, DECEMBER 2004; 
CLARIFICATION AUGUST 2009) 
 
The following modification was made: removal of acute systemic allergic reaction. 
(Division of AIDS 2004) 
 
Parameter 
Grade 1 
MILD 
Grade 2 
MODERATE 
Grade 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
ESTIMATING SEVERITY GRADE 
Clinical adverse event 
NOT identified elsewhere 
in this DAIDS AE 
Grading Table 
Symptoms causing no 
or minimal 
interference with usual 
social & functional 
activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms 
causing inability 
to perform usual 
social & 
functional 
activities 
Symptoms causing 
inability to perform 
basic self-care 
functions or 
medical or 
operative 
intervention 
indicated to 
prevent permanent 
impairment, 
persistent 
disability, or death 
SYSTEMIC 
Chills 
Symptoms causing no 
or minimal 
interference with usual 
social & functional 
activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms 
causing inability 
to perform usual 
social & 
functional 
activities 
NA 
Fatigue 
Malaise 
Symptoms causing no 
or minimal 
interference with usual 
social & functional 
activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms 
causing inability 
to perform usual 
social & 
functional 
activities 
Incapacitating 
fatigue/ malaise 
symptoms causing 
inability to perform 
basic self-care 
functions 
Fever (nonaxillary) 
37.7°C - 38.6°C 
38.7°C - 39.3°C 
39.4°C - 40.5°C 
>40.5°C 


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Parameter 
Grade 1 
MILD 
Grade 2 
MODERATE 
Grade 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Pain (indicate body site) 
DO NOT use for pain 
due to injection (See 
Injection Site Reactions: 
Injection site pain) 
See also Headache, 
Arthralgia, and Myalgia 
Pain causing no or 
minimal interference 
with usual social & 
functional activities 
Pain causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Pain causing 
inability to 
perform usual 
social & 
functional 
activities 
Disabling pain 
causing inability to 
perform basic 
self-care functions 
or hospitalization 
(other than 
emergency room 
visit) indicated 
Unintentional weight 
loss 
NA 
5% - 9% loss in body 
weight from baseline 
10% - 19% loss in 
body weight from 
baseline 
≥20% loss in body 
weight from 
baseline or 
aggressive 
intervention 
indicated (eg, tube 
feeding or total 
parenteral 
nutrition) 
INFECTION 
Infection 
Localized, no 
systemic 
antimicrobial 
treatment indicated 
and symptoms 
causing no or 
minimal interference 
with usual social & 
functional activities 
Systemic 
antimicrobial 
treatment indicated or 
symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Systemic 
antimicrobial 
treatment 
indicated and 
symptoms causing 
inability to 
perform usual 
social & functional 
activities or 
operative 
intervention (other 
than simple 
incision and 
drainage) 
indicated 
Life-threatening 
consequences (eg, 
septic shock) 


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Parameter 
Grade 1 
MILD 
Grade 2 
MODERATE 
Grade 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
INJECTION SITE REACTIONS 
Injection site pain (pain 
without touching) 
or Tenderness (pain 
when area is touched) 
Pain/tenderness 
causing no or 
minimal limitation of 
use of limb 
Pain/tenderness 
limiting use of limb 
or pain/tenderness 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Pain/tenderness 
causing inability 
to perform usual 
social & 
functional 
activities 
Pain/tenderness 
causing inability to 
perform basic 
self-care function 
or hospitalization 
(other than 
emergency room 
visit) indicated for 
management of 
pain/tenderness 
Injection site reaction (localized) 
Pediatric ≤15 years 
Erythema or 
induration or edema 
present but ≤2.5 cm 
diameter 
Erythema or 
induration or edema 
>2.5 cm diameter but 
<50% surface area of 
the extremity 
segment (eg, upper 
arm/thigh) 
Erythema or 
induration or 
edema involving 
≥50% surface area 
of the extremity 
segment (eg, upper 
arm/thigh) or 
ulceration or 
secondary 
infection or 
phlebitis or sterile 
abscess or 
drainage 
Necrosis (involving 
dermis and deeper 
tissue) 
Pruritus associated with 
injection 
See also Skin: Pruritus 
(itching - no skin 
lesions) 
Itching localized to 
injection site and 
relieved 
spontaneously or with 
<48 hours treatment 
Itching beyond the 
injection site but not 
generalized or itching 
localized to injection 
site requiring 
≥48 hours treatment 
Generalized 
itching causing 
inability to 
perform usual 
social & 
functional 
activities 
NA 


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Parameter 
Grade 1 
MILD 
Grade 2 
MODERATE 
Grade 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
SKIN – DERMATOLOGICAL 
Cutaneous reaction – 
rash 
Localized macular 
rash 
Diffuse macular, 
maculopapular, or 
morbilliform rash or 
target lesions 
Diffuse macular, 
maculopapular, or 
morbilliform rash 
with vesicles or 
limited number of 
bullae or 
superficial 
ulcerations of 
mucous 
membrane limited 
to 1 site 
Extensive or 
generalized bullous 
lesions or 
Stevens-Johnson 
syndrome or 
ulceration of 
mucous membrane 
involving 2 or 
more distinct 
mucosal sites or 
toxic epidermal 
necrolysis 
Hyperpigmentation 
Slight or localized 
Marked or 
generalized 
NA 
NA 
Hypopigmentation 
Slight or localized 
Marked or 
generalized 
NA 
NA 
Pruritus (itching – no 
skin lesions) 
(See also Injection Site 
Reactions: Pruritus 
associated with 
injection) 
Itching causing no or 
minimal interference 
with usual social & 
functional activities 
Itching causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Itching causing 
inability to 
perform usual 
social & 
functional 
activities 
NA 
CARDIOVASCULAR 
Cardiac arrhythmia 
(general) 
(By ECG or physical 
examination) 
Asymptomatic and no 
intervention indicated 
Asymptomatic and 
nonurgent medical 
intervention indicated 
Symptomatic, 
nonlife- 
threatening and 
non-urgent 
medical 
intervention 
indicated 
Life-threatening 
arrhythmia or 
urgent intervention 
indicated 
Cardiac- 
ischemia/infarction 
NA 
NA 
Symptomatic 
ischemia (stable 
angina) or testing 
consistent with 
ischemia 
Unstable angina or 
acute myocardial 
infarction 


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Parameter 
Grade 1 
MILD 
Grade 2 
MODERATE 
Grade 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Hemorrhage (significant 
acute blood loss) 
NA 
Symptomatic and no 
transfusion indicated 
Symptomatic and 
transfusion of 
≤2 units packed 
RBCs (for 
children 
≤10 cc/kg) 
indicated 
Life-threatening 
hypotension or 
Transfusion of 
>2 units packed 
RBCs (for children 
>10 cc/kg) 
indicated 
Hypertension 
Pediatric ≤17 years 
(with repeat testing at 
same visit) 
NA 
91st - 94th percentile 
adjusted for age, 
height, and gender 
(systolic and/or 
diastolic) 
≥95th percentile 
adjusted for age, 
height, and gender 
(systolic and/or 
diastolic) 
Life-threatening 
consequences (eg, 
malignant 
hypertension) or 
hospitalization 
indicated (other 
than emergency 
room visit) 
Hypotension 
NA 
Symptomatic, 
corrected with oral 
fluid replacement 
Symptomatic, IV 
fluids indicated 
Shock requiring use 
of vasopressors or 
mechanical 
assistance to 
maintain blood 
pressure 
Pericardial effusion 
Asymptomatic, small 
effusion requiring no 
intervention 
Asymptomatic, 
moderate or larger 
effusion requiring no 
intervention 
Effusion with non-
life threatening 
physiologic 
consequences or 
effusion with non- 
urgent 
intervention 
indicated 
Life-threatening 
consequences (eg, 
tamponade) or 
urgent intervention 
indicated 
Prolonged PR Interval - 
Pediatric ≤16 years 
first-degree AV block 
(PR > normal for age 
and rate) 
Type I second-degree 
AV block 
Type II second- 
degree AV block 
Complete AV 
block 


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Parameter 
Grade 1 
MILD 
Grade 2 
MODERATE 
Grade 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Prolonged QTc - 
Pediatric ≤16 years 
Asymptomatic, QTc 
interval 0.450 - 
0.464 sec 
Asymptomatic, QTc 
interval 0.465 - 
0.479 sec 
Asymptomatic, 
QTc interval 
≥0.480 sec 
Life-threatening 
consequences, eg, 
torsade de pointes 
or other associated 
serious ventricular 
dysrhythmia 
Thrombosis/ embolism 
NA 
Deep vein thrombosis 
and No intervention 
indicated (eg, 
anticoagulation, lysis 
filter, invasive 
procedure) 
Deep vein 
thrombosis and 
Intervention 
indicated (eg, 
anticoagulation, 
lysis filter, 
invasive 
procedure) 
Embolic event (eg, 
pulmonary 
embolism, 
life-threatening 
thrombus) 
Vasovagal episode 
(associated with a 
procedure of any kind) 
Present without loss 
of consciousness 
Present with transient 
loss of consciousness 
NA 
NA 
Ventricular dysfunction 
(congestive heart failure) 
NA 
Asymptomatic 
diagnostic finding 
and intervention 
indicated 
New onset with 
symptoms or 
worsening 
symptomatic 
congestive heart 
failure 
Life-threatening 
congestive heart 
failure 
GASTROINTESTINAL 
Anorexia 
Loss of appetite 
without decreased 
oral intake 
Loss of appetite 
associated with 
decreased oral intake 
without significant 
weight loss 
Loss of appetite 
associated with 
significant weight 
loss 
Life-threatening 
consequences or 
aggressive 
intervention 
indicated (eg, tube 
feeding or total 
parenteral 
nutrition) 
Comment: Please note that, while the grading scale provided for Unintentional Weight Loss may be used as a 
guideline when grading anorexia, this is not a requirement and should not be used as a substitute for clinical judgment. 


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Parameter 
Grade 1 
MILD 
Grade 2 
MODERATE 
Grade 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Diarrhea 
Adult and Pediatric 
≥1 year 
Transient or 
intermittent episodes 
of unformed stools or 
increase of ≤3 stools 
over baseline per 
24-hour period 
Persistent episodes of 
unformed to watery 
stools or increase of 
4 - 6 stools over 
baseline per 24-hour 
period 
Bloody diarrhea or 
increase of ≥7 
stools per 24-hour 
period or IV fluid 
replacement 
indicated 
Life-threatening 
consequences (eg, 
hypotensive shock) 
Pediatric <1 year 
Liquid stools (more 
unformed than usual) 
but usual number of 
stools 
Liquid stools with 
increased number of 
stools or mild 
dehydration 
Liquid stools with 
moderate 
dehydration 
Liquid stools 
resulting in severe 
dehydration with 
aggressive 
rehydration 
indicated or 
hypotensive shock 
Dysphagia-Odynophagia 
Symptomatic but able 
to eat usual diet 
Symptoms causing 
altered dietary intake 
without medical 
intervention indicated 
Symptoms 
causing severely 
altered dietary 
intake with 
medical 
intervention 
indicated 
Life-threatening 
reduction in oral 
intake 
Nausea 
Transient (<24 hours) 
or intermittent nausea 
with no or minimal 
interference with oral 
intake 
Persistent nausea 
resulting in decreased 
oral intake for 24 – 
48 hours 
Persistent nausea 
resulting in 
minimal oral 
intake for 
>48 hours or 
aggressive 
rehydration 
indicated (eg, IV 
fluids) 
Life-threatening 
consequences (eg, 
hypotensive shock 
Pancreatitis 
NA 
Symptomatic and 
hospitalization not 
indicated (other than 
emergency room visit 
Symptomatic and 
hospitalization 
indicated (other 
than emergency 
room visit) 
Life-threatening 
consequences (eg, 
circulatory failure, 
hemorrhage, 
sepsis) 


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Parameter 
Grade 1 
MILD 
Grade 2 
MODERATE 
Grade 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Vomiting 
Transient or 
intermittent vomiting 
with no or minimal 
interference with oral 
intake 
Frequent episodes of 
vomiting with no or 
mild dehydration 
Persistent 
vomiting resulting 
in orthostatic 
hypotension or 
aggressive 
rehydration 
indicated (eg, IV 
fluids) 
Life-threatening 
consequences (eg, 
hypotensive shock) 
NEUROLOGIC 
Alteration in personality- 
behavior or in mood (eg, 
agitation, anxiety, 
depression, mania, 
psychosis) 
Alteration causing no 
or minimal 
interference with 
usual social & 
functional activities 
Alteration causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Alteration causing 
inability to 
perform usual 
social & functional 
activities 
Behavior 
potentially harmful 
to self or others 
(eg, suicidal and 
homicidal ideation 
or attempt, acute 
psychosis) or 
causing inability to 
perform basic 
self-care functions 
Altered Mental Status 
For Dementia, see 
Cognitive and 
behavioral/attentional 
disturbance (including 
dementia and attention 
deficit disorder) 
Changes causing no 
or minimal 
interference with 
usual social & 
functional activities 
Mild lethargy or 
somnolence causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Confusion, 
memory 
impairment, 
lethargy, or 
somnolence 
causing inability 
to perform usual 
social & 
functional 
activities 
Delirium or 
obtundation, or 
Coma 
Ataxia 
Asymptomatic ataxia 
detectable on 
examination or 
Minimal ataxia 
causing no or 
minimal interference 
with usual social & 
functional activities 
Symptomatic ataxia 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Symptomatic 
ataxia causing 
inability to 
perform usual 
social & 
functional 
activities 
Disabling ataxia 
causing inability to 
perform basic 
self-care functions 


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Parameter 
Grade 1 
MILD 
Grade 2 
MODERATE 
Grade 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Cognitive and 
behavioral/ attentional 
disturbance (including 
dementia and attention 
deficit disorder) 
Disability causing no 
or minimal 
interference with 
usual social & 
functional activities 
or specialized 
resources not 
indicated 
Disability causing 
greater than minimal 
interference with 
usual social & 
functional activities 
or Specialized 
resources on 
part-time basis 
indicated 
Disability causing 
inability to 
perform usual 
social & 
functional 
activities or 
Specialized 
resources on a 
full-time basis 
indicated 
Disability causing 
inability to perform 
basic self-care 
functions or 
Institutionalization 
indicated 
CNS ischemia 
(acute) 
NA 
NA 
Transient 
ischemic attack 
Cerebral vascular 
accident (CVA, 
stroke) with 
neurological deficit 
Developmental delay – 
Pediatric ≤16 years 
Mild developmental 
delay, either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Moderate 
developmental delay, 
either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Severe 
developmental 
delay, either 
motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Developmental 
regression, either 
motor or cognitive, 
as determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Headache 
Symptoms causing no 
or minimal 
interference with usual 
social & functional 
activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms 
causing inability 
to perform usual 
social & 
functional 
activities 
Symptoms causing 
inability to perform 
basic self-care 
functions or 
hospitalization 
indicated (other 
than emergency 
room visit) or 
headache with 
significant 
impairment of 
alertness or other 
neurologic function 


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Parameter 
Grade 1 
MILD 
Grade 2 
MODERATE 
Grade 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Insomnia 
NA 
Difficulty sleeping 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Difficulty 
sleeping causing 
inability to 
perform usual 
social & 
functional 
activities 
Disabling insomnia 
causing inability to 
perform basic 
self-care functions 
Neuromuscular 
weakness 
(including myopathy & 
neuropathy) 
Asymptomatic with 
decreased strength on 
examination or 
minimal muscle 
weakness causing no 
or minimal 
interference with 
usual social & 
functional activities 
Muscle weakness 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Muscle weakness 
causing inability 
to perform usual 
social & 
functional 
activities 
Disabling muscle 
weakness causing 
inability to perform 
basic self-care 
functions or 
respiratory muscle 
weakness 
impairing 
ventilation 
Neurosensory alteration 
(including paresthesia 
and painful neuropathy) 
Asymptomatic with 
sensory alteration on 
examination or 
minimal paresthesia 
causing no or 
minimal interference 
with usual social & 
functional activities 
Sensory alteration or 
paresthesia causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Sensory alteration 
or paresthesia 
causing inability 
to perform usual 
social & 
functional 
activities 
Disabling sensory 
alteration or 
paresthesia causing 
inability to perform 
basic self-care 
functions 
Seizure 
– Pediatric <18 years 
Seizure, generalized 
onset with or without 
secondary 
generalization, lasting 
<5 minutes with 
<24 hours postictal 
state 
Seizure, generalized 
onset with or without 
secondary 
generalization, 
lasting 5 to 
20 minutes with 
<24 hours postictal 
state 
Seizure, 
generalized onset 
with or without 
secondary 
generalization, 
lasting 
>20 minutes 
Seizure, 
generalized onset 
with or without 
secondary 
generalization, 
requiring 
intubation and 
sedation 
Syncope (not associated 
with a procedure) 
NA 
Present 
NA 
NA 
Vertigo 
Vertigo causing no or 
minimal interference 
with usual social & 
functional activities 
Vertigo causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Vertigo causing 
inability to 
perform usual 
social & 
functional 
activities 
Disabling vertigo 
causing inability to 
perform basic self- 
care functions 


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Parameter 
Grade 1 
MILD 
Grade 2 
MODERATE 
Grade 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
RESPIRATORY 
Bronchospasm (acute) 
FEV1 or peak flow 
reduced to 
70% - 80% 
FEV1 or peak flow 
50% - 69% 
FEV1 or peak 
flow 
25% - 49% 
Cyanosis OR FEV1 
or peak flow 
<25% or Intubation 
Dyspnea or respiratory 
distress - Pediatric 
<14 years 
Wheezing or minimal 
increase in respiratory 
rate for age 
Nasal flaring or 
Intercostal retractions 
or Pulse oximetry 
90% - 95% 
Dyspnea at rest 
causing inability 
to perform usual 
social & 
functional 
activities or Pulse 
oximetry <90% 
Respiratory failure 
with ventilatory 
support indicated 
MUSCULOSKELETAL 
Arthralgia 
Joint pain causing no 
or minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
inability to 
perform usual 
social & 
functional 
activities 
Disabling joint pain 
causing inability to 
perform basic self-
care functions 
OCULAR/VISUAL 
Uveitis 
Asymptomatic but 
detectable on 
examination 
Symptomatic anterior 
uveitis or medical 
intervention indicated 
Posterior or 
pan-uveitis or 
operative 
intervention 
indicated 
Disabling visual 
loss in affected 
eye(s) 
Visual changes (from 
baseline) 
Visual changes 
causing no or 
minimal interference 
with usual social & 
functional activities 
Visual changes 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Visual changes 
causing inability 
to perform usual 
social & 
functional 
activities 
Disabling visual 
loss in affected 
eye(s) 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and 
feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (eg, feeding self with 
culturally appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, 
shopping, cooking, use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (eg, social 
interactions, play activities, learning tasks, etc.). 
ENDOCRINE/METABOLIC 


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Parameter 
Grade 1 
MILD 
Grade 2 
MODERATE 
Grade 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Abnormal fat 
accumulation 
(eg, back of neck, 
breasts, abdomen) 
Detectable by study 
participant (or by 
caregiver for young 
children and disabled 
adults) 
Detectable on 
physical 
exam by health care 
provider 
Disfiguring OR 
Obvious 
changes on casual 
visual inspection 
NA 
Diabetes mellitus 
NA 
New onset without 
need to initiate 
medication OR 
Modification of 
current medications 
to regain glucose 
control 
New onset with 
initiation of 
medication 
indicated OR 
Diabetes 
uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (eg, 
ketoacidosis, 
hyperosmolar non- 
ketotic coma) 
Gynecomastia 
Detectable by study 
participant or 
caregiver (for young 
children and disabled 
adults) 
Detectable on 
physical exam by 
health care provider 
Disfiguring OR 
Obvious on casual 
visual inspection 
NA 
Hyperthyroidism 
Asymptomatic 
Symptomatic causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
suppression therapy 
indicated 
Symptoms 
causing inability 
to perform usual 
social & 
functional 
activities OR 
Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (eg, 
thyroid storm) 
Hypothyroidism 
Asymptomatic 
Symptomatic causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
replacement therapy 
indicated 
Symptoms 
causing inability 
to perform usual 
social & 
functional 
activities OR 
Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (eg, 
myxedema coma) 


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Parameter 
Grade 1 
MILD 
Grade 2 
MODERATE 
Grade 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Lipoatrophy (eg, fat loss 
from the face, 
extremities, buttocks) 
Detectable by study 
participant (or by 
caregiver for young 
children and disabled 
adults) 
Detectable on 
physical exam by 
health care provider 
Disfiguring OR 
Obvious on casual 
visual inspection 
NA 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and 
feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self 
with culturally appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, 
shopping, cooking, use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., 
social interactions, play activities, learning tasks, etc.). 
HEMATOLOGY Standard International Units are listed in italics 
Absolute CD4+ count – 
Adult and Pediatric > 
13 years (HIV 
NEGATIVE ONLY) 
300 – 400/mm 3 
300 - 400/μL 
200 – 299/mm3 
200 – 299/μL 
100 – 199/mm3 
100 – 199/μL 
<100/mm3 
<100/μL 
Absolute lymphocyte 
count – Adult and 
Pediatric > 13 years 
(HIV NEGATIVE 
ONLY) 
600 – 650/mm3 0.600 
x 109 – 
0.650 x 109/L 
500 – 599/mm3 
0.500 x 109 – 
0.599 x 109/L 
350 – 499/mm3 
0.350 x 109 – 
0.499 x 109/L 
<350/mm3 <0.350 
x 109/L 
Comment: Values in children ≤ 13 years are not given for the two parameters above because the absolute counts are 
variable. 
Absolute neutrophil count (ANC) 
Adult and Pediatric, >7 
days 
1,000 – 1,300/mm3 
1.000 x 109 – 
1.300 x 109/L 
750 – 999/mm3 
0.750 x 109 – 
0.999 x 109/L 
500 – 749/mm3 
0.500 x 109 – 
0.749 x 109/L 
<500/mm3 
<0.500 x 109/L 
Infant∗† , 2 – ≤ 7 days
 
1,250 – 1,500/mm3 
1.250 x 109 – 
1.500 x 109/L 
1,000 – 1,249/mm3 
1.000 x 109 – 
1.249 x 109/L 
750 – 999/mm3 
0.750 x 109 – 
0.999 x 109/L 
<750/mm3 
<0.750 x 109/L 
Infant∗† , ≤1 day
 
4,000 – 5,000/mm3 
4.000 x 109 – 
5.000 x 109/L 
3,000 – 3,999/mm3 
3.000 x 109 – 
3.999 x109/L 
1,500 – 
2,999/mm3 
1.500 x 109 – 
2.999 x 109/L 
<1,500/mm3 
<1.500 x 109/L 
Comment: Parameter changed from “Infant, < 1 day” to “Infant, ≤1 day” 
∗ Values are for term infants. Preterm infants should be assessed using local normal ranges. 
† Use age and sex appropriate values (eg, bilirubin). 


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Parameter 
Grade 1 
MILD 
Grade 2 
MODERATE 
Grade 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Fibrinogen, decreased 
100 – 200 mg/dL 
1.00 – 2.00 g/L 
OR 
0.75 – 0.99 x LLN 
75 – 99 mg/dL 
0.75 – 0.99 g/L 
OR 
0.50 – 0.74 x LLN 
50 – 74 mg/dL 
0.50 – 0.74 g/L 
OR 
0.25 – 0.49 x LLN 
<50 mg/dL <0.50 
g/L 
OR 
<0.25 x LLN 
OR 
Associated with 
gross bleeding 
Hemoglobin (Hgb) 
Comment: The Hgb values in mmol/L have changed because the conversion factor used to convert g/dL to mmol/L 
has been changed from 0.155 to 0.6206 (the most commonly used conversion factor). For grading Hgb results obtained 
by an analytic method with a conversion factor other than 0.6206, the result must be converted to g/dL using 
the appropriate conversion factor for that lab. 
Adult and Pediatric 
≥57 days (HIV 
POSITIVE ONLY) 
8.5 – 10.0 g/dL 
5.24 – 6.23 mmol/L 
7.5 – 8.4 g/dL 
4.62–5.23 mmol/L 
6.50 – 7.4 g/dL 
4.03–4.61 mmol/L 
< 6.5 g/dL 
<4.03 mmol/L 
Adult and Pediatric 
≥57 days (HIV 
NEGATIVE ONLY) 
10.0 – 10.9 g/dL 
6.18 – 6.79 mmol/L 
OR 
Any decrease 2.5 – 
3.4 g/dL 
1.58 – 2.13 mmol/L 
9.0 – 9.9 g/dL 
5.55 - 6.17 mmol/L 
OR 
Any decrease 3.5 – 
4.4 g/dL 
2.14 – 2.78 mmol/L 
7.0 – 8.9 g/dL 4.34 
- 5.54 mmol/L 
OR 
Any decrease ≥4.5 
g/dL 
>2.79 mmol/L 
< 7.0 g/dL 
<4.34 mmol/L 
Comment: The decrease is a decrease from baseline 
Infant∗†, 36 – 56 days 
(HIV POSITIVE OR 
NEGATIVE) 
8.5 – 9.4 g/dL 
5.24 – 5.86 mmol/L 
7.0 – 8.4 g/dL 
4.31 – 5.23 mmol/L 
6.0 – 6.9 g/dL 3.72 
– 4.30 mmol/L 
< 6.00 g/dL 
<3.72 mmol/L 
Infant∗†, 22 – 35 days 
(HIV POSITIVE OR 
NEGATIVE) 
9.5 – 10.5 g/dL 
5.87 - 6.54 mmol/L 
8.0 – 9.4 g/dL 
4.93 – 5.86 mmol/L 
7.0 – 7.9 g/dL 4.34 
– 4.92 mmol/L 
< 7.00 g/dL 
<4.34 mmol/L 
Infant∗† , ≤ 21 days 
(HIV POSITIVE OR 
NEGATIVE) 
12.0 – 13.0 g/dL 
7.42 – 8.09 mmol/L 
10.0 – 11.9 g/dL 
6.18 – 7.41 mmol/L 
9.0 – 9.9 g/dL 
5.59- 6.17 mmol/L 
< 9.0 g/dL 
<5.59 mmol/L 
Correction: Parameter changed from “Infant < 21 days” to “Infant ≤ 21 days” 
∗ Values are for term infants. Preterm infants should be assessed using local normal ranges. 
† Use age and sex appropriate values (eg, bilirubin). 
International Normalized 
Ratio of prothrombin 
time (INR) 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 3.0 x ULN 
> 3.0 x ULN 
Methemoglobin 
5.0 – 10.0% 
10.1 – 15.0% 
15.1 – 20.0% 
> 20.0% 
Prothrombin Time (PT) 
1.1 – 1.25 x ULN 
1.26 – 1.50 x ULN 
1.51 – 3.00 x ULN 
> 3.00 x ULN 


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Parameter 
Grade 1 
MILD 
Grade 2 
MODERATE 
Grade 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Partial Thromboplastin 
Time (PTT) 
1.1 – 1.66 x ULN 
1.67 – 2.33 x ULN 
2.34 – 3.00 x 
ULN 
> 3.00 x ULN 
Platelets, decreased 
100,000 – 
124,999/mm3 
100.000 x 109 – 
124.999 x 109/L 
50,000 – 
99,999/mm3 
50.000 x 109 – 
99.999 x 109/L 
25,000 – 
49,999/mm3 
25.000 x 109 – 
49.999 x 109/L 
< 25,000/mm3 
< 25.000 x 109/L 
WBC, decreased 
2,000 – 2,500/mm3 
2.000 x 109 – 
2.500 x 109/L 
1,500 – 1,999/mm3 
1.500 x 109 – 
1.999 x 109/L 
1,000 – 
1,499/mm3 
1.000 x 109 – 
1.499 x 109/L 
< 1,000/mm3 
<1.000 x 109/L 
CHEMISTRIES Standard International Units are listed in italics 
Acidosis 
NA 
pH < normal, but 
≥ 7.3 
pH < 7.3 without 
life-threatening 
consequences 
pH < 7.3 with life- 
threatening 
consequences 
Albumin, serum, low 
3.0 g/dL – < LLN 
30 g/L – < LLN 
2.0 – 2.9 g/dL 
20 - 29 g/L 
< 2.0 g/dL 
< 20 g/L 
NA 
Alkaline Phosphatase 
1.25 – 2.5 x ULN† 
2.6 – 5.0 x ULN† 
5.1 – 10.0 x 
ULN† 
> 10.0 x ULN† 
Alkalosis 
NA 
pH > normal, but 
≤ 7.5 
pH > 7.5 without 
life-threatening 
consequences 
pH > 7.5 with life- 
threatening 
consequences 
ALT (SGPT) 
1.25 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10.0 x ULN 
> 10.0 x ULN 
AST (SGOT) 
1.25 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10.0 x ULN 
> 10.0 x ULN 
Bicarbonate, serum, low 
16.0 mEq/L – < LLN 
16.0 mmol/L – < 
LLN 
11.0 – 15.9 mEq/L 
11.0 – 15.9 mmol/L 
8.0 – 10.9 mEq/L 
8.0 – 10.9 
mmol/L 
< 8.0 mEq/L 
< 8.0 mmol/L 
Comment: Some laboratories will report this value as Bicarbonate (HCO3) and others as Total Carbon Dioxide (CO2). 
These are the same tests; values should be graded according to the ranges for Bicarbonate as listed above. 
Bilirubin (Total) 
Adult and Pediatric > 
14 days 
1.1 – 1.5 x ULN 
1.6 – 2.5 x ULN 
2.6 – 5.0 x ULN 
> 5.0 x ULN 
Infant∗† , ≤ 14 days 
(non-hemolytic) 
NA 
20.0 – 25.0 mg/dL 
342 – 428 μmol/L 
25.1 – 30.0 mg/dL 
429 – 513 μmol/L 
> 30.0 mg/dL 
>513.0 μmol/L 
Infant∗† , ≤ 14 days 
(hemolytic) 
NA 
NA 
20.0 – 25.0 mg/dL 
342 – 428 μmol/L 
> 25.0 mg/dL 
> 428 μmol/L 
Calcium, serum, high 
Adult and Pediatric ≥ 7 
days 
10.6 – 11.5 mg/dL 
2.65 – 2.88 mmol/L 
11.6 – 12.5 mg/dL 
2.89 – 3.13 mmol/L 
12.6 – 13.5 mg/dL 
3.14 – 3.38 mmol/L 
> 13.5 mg/dL 
> 3.38 mmol/L 
∗ Values are for term infants. Preterm infants should be assessed using local normal ranges. 
† Use age and sex appropriate values (eg, bilirubin). 


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Parameter 
Grade 1 
MILD 
Grade 2 
MODERATE 
Grade 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Infant∗†, < 7 days 
11.5 – 12.4 mg/dL 
2.88 – 3.10 mmol/L 
12.5 – 12.9 mg/dL 
3.11 – 3.23 mmol/L 
13.0 – 13.5 mg/dL 
3.245 – 3.38 
mmol/L 
> 13.5 mg/dL 
>3.38 mmol/L 
Calcium, serum, low 
Adult and Pediatric ≥ 7 
days 
7.8 – 8.4 mg/dL 
1.95 – 2.10 mmol/L 
7.0 – 7.7 mg/dL 
1.75 – 1.94 mmol/L 
6.1 – 6.9 mg/dL 
1.53 – 1.74 mmol/L 
< 6.1 mg/dL 
<1.53 mmol/L 
Infant∗†, < 7 days
 
6.5 – 7.5 mg/dL 
1.63 – 1.88 mmol/L 
6.0 – 6.4 mg/dL 
1.50 – 1.62 mmol/L 
5.50 – 5.90 mg/dL 
1.38 – 1.51 mmol/L 
< 5.50 mg/dL 
<1.38 mmol/L 
Comment: Do not adjust Calcium, serum, low or Calcium, serum, high for albumin 
∗ Values are for term infants. Preterm infants should be assessed using local normal ranges. 
† Use age and sex appropriate values (e.g., bilirubin). 
Cardiac troponin I (cTnI) 
NA 
NA 
NA 
Levels consistent 
with myocardial 
infarction or 
unstable angina 
as defined by the 
manufacturer 
Cardiac troponin T 
(cTnT) 
NA 
NA 
NA 
≥ 0.20 ng/mL OR 
Levels consistent 
with myocardial 
infarction or 
unstable angina 
as defined by the 
manufacturer 
Cholesterol (fasting) 
Adult ≥ 18 years 
200 – 239 mg/dL 
5.18 – 6.19 mmol/L 
240 – 300 mg/dL 
6.20 – 7.77 mmol/L 
> 300 mg/dL 
> 7.77 mmol/L 
NA 
Pediatric < 18 years 
170 – 199 mg/dL 
4.40 – 5.15 mmol/L 
200 – 300 mg/dL 
5.16 – 7.77 mmol/L 
> 300 mg/dL 
>7.77 mmol/L 
NA 
Creatine Kinase 
3.0 – 5.9 x ULN† 
6.0 – 9.9 x ULN† 
10.0 – 19.9 x 
ULN† 
≥ 20.0 x ULN† 
Creatinine 
1.1 – 1.3 x ULN† 
1.4 – 1.8 x ULN† 
1.9 – 3.4 x ULN† 
≥ 3.5 x ULN† 
Glucose, serum, high 
Nonfasting 
116 – 160 mg/dL 
6.44 – 8.88 mmol/L 
161 – 250 mg/dL 
8.89 – 13.88 mmol/L 
251 – 500 mg/dL 
13.89 – 27.75 
mmol/L 
> 500 mg/dL 
> 27.75 mmol/L 
Fasting 
110 – 125 mg/dL 
6.11 – 6.94 mmol/L 
126 – 250 mg/dL 
6.95 – 13.88 mmol/L 
251 – 500 mg/dL 
13.89 – 27.75 
mmol/L 
> 500 mg/dL 
>27.75 mmol/L 
Glucose, serum, low 


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Parameter 
Grade 1 
MILD 
Grade 2 
MODERATE 
Grade 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Adult and Pediatric ≥ 1 
month 
55 – 64 mg/dL 
3.05 – 3.55 mmol/L 
40 – 54 mg/dL 
2.22 – 3.06 mmol/L 
30 – 39 mg/dL 
1.67 – 2.23 
mmol/L 
< 30 mg/dL 
<1.67 mmol/L 
Infant∗†, < 1 month
 
50 – 54 mg/dL 
2.78 – 3.00 mmol/L 
40 – 49 mg/dL 
2.22 – 2.77 mmol/L 
30 – 39 mg/dL 
1.67 – 2.21 
mmol/L 
< 30 mg/dL 
<1.67 mmol/L 
∗ Values are for term infants. Preterm infants should be assessed using local normal ranges. 
† Use age and sex appropriate values (eg, bilirubin). 
Lactate 
ULN - < 2.0 x ULN 
without acidosis 
≥ 2.0 x ULN without 
acidosis 
Increased lactate 
with pH < 7.3 
without life- 
threatening 
consequences 
Increased lactate 
with pH < 7.3 with 
life-threatening 
consequences 
LDL cholesterol (fasting) 
Adult ≥ 18 years 
130 – 159 mg/dL 
3.37 – 4.12 mmol/L 
160 – 190 mg/dL 
4.13 – 4.90 mmol/L 
≥ 190 mg/dL 
≥4.91 mmol/L 
NA 
Pediatric > 2 - < 18 
years 
110 – 129 mg/dL 
2.85 – 3.34 mmol/L 
130 – 189 mg/dL 
3.35 – 4.90 mmol/L 
≥ 190 mg/dL 
≥ 4.91 mmol/L 
NA 
Lipase 
1.1 – 1.5 x ULN 
1.6 – 3.0 x ULN 
3.1 – 5.0 x ULN 
> 5.0 x ULN 
Magnesium, serum, low 
1.2 – 1.4 mEq/L 0.60 
– 0.70 mmol/L 
0.9 – 1.1 mEq/L 
0.45 – 0.59 mmol/L 
0.6 – 0.8 mEq/L 
0.30 – 0.44 
mmol/L 
< 0.60 mEq/L 
< 0.30 mmol/L 
Pancreatic amylase 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 5.0 x ULN 
> 5.0 x ULN 
Phosphate, serum, low 
Adult and Pediatric > 
14 years 
2.5 mg/dL – < LLN 
0.81 mmol/L – < 
LLN 
2.0 – 2.4 mg/dL 
0.65 – 0.80 mmol/L 
1.0 – 1.9 mg/dL 
0.32 – 0.64 mmol/L 
< 1.00 mg/dL 
< 0.32 mmol/L 
Pediatric 1 year – 14 
years 
3.0 – 3.5 mg/dL 0.97 
– 1.13 mmol/L 
2.5 – 2.9 mg/dL 
0.81 – 0.96 mmol/L 
1.5 – 2.4 mg/dL 
0.48 – 0.80 mmol/L 
< 1.50 mg/dL 
<0.48 mmol/L 
Pediatric < 1 year 
3.5 – 4.5 mg/dL 1.13 
– 1.45 mmol/L 
2.5 – 3.4 mg/dL 
0.81 – 1.12 mmol/L 
1.5 – 2.4 mg/dL 
0.48 – 0.80 mmol/L 
< 1.50 mg/dL 
< 0.48 mmol/L 
Potassium, serum, high 
5.6 – 6.0 mEq/L 
5.6 – 6.0 mmol/L 
6.1 – 6.5 mEq/L 
6.1 – 6.5 mmol/L 
6.6 – 7.0 mEq/L 6.6 
– 7.0 mmol/L 
> 7.0 mEq/L 
> 7.0 mmol/L 
Potassium, serum, low 
3.0 – 3.4 mEq/L 
3.0 – 3.4 mmol/L 
2.5 – 2.9 mEq/L 
2.5 – 2.9 mmol/L 
2.0 – 2.4 mEq/L 2.0 
– 2.4 mmol/L 
< 2.0 mEq/L < 
2.0 mmol/L 
Sodium, serum, high 
146 – 150 mEq/L 146 
– 150 mmol/L 
151 – 154 mEq/L 
151 – 154 mmol/L 
155 – 159 mEq/L 
155 – 159 mmol/L 
≥ 160 mEq/L 
≥ 160 mmol/L 
Sodium, serum, low 
130 – 135 mEq/L 130 
– 135 mmol/L 
125 – 129 mEq/L 
125 – 129 mmol/L 
121 – 124 mEq/L 
121 – 124 mmol/L 
≤ 120 mEq/L 
≤ 120 mmol/L 


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Parameter 
Grade 1 
MILD 
Grade 2 
MODERATE 
Grade 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Triglycerides (fasting) 
NA 
500 – 750 mg/dL 
5.65 – 8.48 mmol/L 
751 – 1,200 
mg/dL 
8.49 – 13.56 
mmol/L 
> 1,200 mg/dL 
> 13.56 mmol/L 
Uric acid 
7.5 – 10.0 mg/dL 
0.45 – 0.59 mmol/L 
10.1 – 12.0 mg/dL 
0.60 – 0.71 mmol/L 
12.1 – 15.0 mg/dL 
0.72 – 0.89 
mmol/L 
> 15.0 mg/dL 
> 0.89 mmol/L 
URINALYSIS Standard International Units are listed in italics 
Hematuria (microscopic) 
6 – 10 RBC/HPF 
> 10 RBC/HPF 
Gross, with or 
without clots OR 
with RBC casts 
Transfusion 
indicated 
Proteinuria, random 
collection 
1 + 
2 – 3 + 
4 + 
NA 
Proteinuria, 24 hour collection 
Adult and Pediatric ≥ 
10 years 
200 – 999 mg/24 h 
0.200 – 0.999 g/d 
1,000 – 1,999 mg/24 
h 1.000 – 1.999 g/d 
2,000 – 3,500 
mg/24 h 
2.000 – 3.500 g/d 
> 3,500 mg/24 h > 
3.500 g/d 
Pediatric > 3 mo - < 10 
years 
201 – 499 
mg/m2/24 h 
0.201 – 0.499 g/d 
500 – 799 mg/m2/24 
h 0.500 – 0.799 g/d 
800 – 1,000 
mg/m2/24 h 
0.800 – 1.000 g/d 
> 1,000 mg/ m2/24 
h 
> 1.000 g/d 
∗ Values are for term infants. Preterm infants should be assessed using local normal ranges. 
† Use age and sex appropriate values (eg, bilirubin). 
AE=adverse event; AV=atrioventricular; CNS=central nervous system; CVA=cerebral vascular accident; ECG=electrocardiogram; FEV1= 
forced expiratory volume in the first second; IV=intravenous; NA=not applicable; QTc=corrected QT interval; RBC=red blood cells 
 
Modified from:  28 Dec-04/Clarification Aug 09 
Version 1.0/Clarification 1 


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Hematology1 
Parameter 
Grade 1 
MILD 
Grade 2 
MODERATE 
Grade 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Absolute CD4+ 
Count, Low 
(cell/mm3; cells/L) 
>5 years of age 
(not HIV infected) 
300 to <400 
300 to <400 
200 to <300 
200 to <300 
100 to <200 
100 to <200 
<100 
<100 
Absolute 
Lymphocyte Count, 
Low 
(cell/mm3; cells/L) 
>5 years of age 
(not HIV infected) 
600 to <650 
9 
9 
500 to <600 
9 
9 
350 to <500 
9 
9 
<350 
<0.350 x 109 
Absolute Neutrophil 
Count (ANC), Low 
(cells/mm3; cells/L) 
>7 days of age 
800 to 1,000 
9 
9 
600 to 799 
9 
9 
400 to 599 
9 
9 
<400 
<0.400 x 109 
2 to 7 days of age 
1,250 to 1,500 
1.250 x 109 to 
1.500 x 109 
1,000 to 1,249 
1.000 x 109 to 
1.249 x 109 
750 to 999 
0.750 x 109 to 
0.999 x 109 
<750 
<0.750 x 109 
≤1 day of age 
4,000 to ,5000 
4.000 x 109 to 
5.000 x 109 
3,000 to 3,999 
3.000 x 109 to 
3.999 x 109 
1,500 to 2,999 
1.500 x 109 to 
2.999 x 109 
<1,500 
<1.500 x 109 
Fibrinogen, 
Decreased 
(mg/dL; g/L) 
100 to <200 
1.00 to <2.00 
OR 
0.75 to <1.00 x 
LLN 
75 to <100 
0.75 to <1.00 
OR 
≥0.50 to <0.75 x 
LLN 
50 to <75 
0.50 to <0.75 
OR 
0.25 to <0.50 x 
LLN 
<50 
<0.50 
OR 
<0.25 x LLN 
OR Associated 
with gross 
bleeding 
 
 
 
APPENDIX F. TOXICITY GRADING SCALE - MODIFIED FROM 
DIVISION OF AIDS TABLE FOR GRADING THE 
SEVERITY OF ADULT AND PEDIATRIC ADVERSE 
EVENTS (VERSION 2.0, NOVEMBER 2014) 
 
The following tables are reproduced from selected pages of Division of AIDS, November 2014. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0.600 x 10  to 
0.500 x 10  to 
0.500 x 10  to 
<0.650  x 10 
<0.600 x 10 
<0.500 x 10 
 
 
 
 
0.800 x 10  to 
1.000 x 10 
0.600 x 10  to 
0.799 x 10 
0.400 x 10  to 
0.599 x 10 


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Hematology1 
Parameter 
Grade 1 
MILD 
Grade 2 
MODERATE 
Grade 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Hemoglobin2, Low 
(g/dL; mmol/L)3 
≥13 years of age 
(male only) 
10.0 to 10.9 
6.19 to 6.76 
9.0 to <10.0 
5.57 to <6.19 
7.0 to <9.0 
4.34 to <5.57 
<7.0 
<4.34 
≥13 years of age 
(female only) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to <9.5 
5.25 to <5.88 
6.5 to <8.5 
4.03 to <5.25 
<6.5 
<4.03 
57 days of age to <13 
years of age 
(male and female) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to <9.5 
5.25 to <5.88 
6.5 to <8.5 
4.03 to <5.25 
<6.5 
4.03 
36 to 56 days of age 
(male and female) 
8.5 to 9.6 
5.26 to 5.99 
7.0 to <8.5 
4.32 to <5.26 
6.0 to <7.0 
3.72 to <4.32 
<6.0 
<3.72 
22 to 35 days of age 
(male and female) 
9.5 to 11.0 
5.88 to 6.86 
8.0 to <9.5 
4.94 to <5.88 
6.7 to <8.0 
4.15 to <4.94 
<6.7 
<4.15 
8 to ≤21 days of age 
(male and female) 
11.0 to 13.0 
6.81 to 8.10 
9.0 to <11.0 
5.57 to <6.81 
8.0 to <9.0 
4.96 to <5.57 
<8.0 
<4.96 
≤7 days of age 
(male and female) 
13.0 to 14.0 
8.05 to 8.72 
10.0 to <13.0 
6.19 to <8.05 
9.0 to <10.0 
5.59 to <6.19 
<9.0 
<5.59 
INR, High (not 
on 
anticoagulation 
therapy) 
1.1 to <1.5 x ULN 
1.5 to <2.0 ULN 
2.0 to 3.0 x 
ULN 
≥3.0 x ULN 
Methemoglobin 
(% hemoglobin) 
5.0 to <10.0% 
10.0 to <15.0% 
15.0 to <20.0% 
≥20.0% 
PTT, High (not 
on 
anticoagulation 
therapy) 
1.1 to <1.66 x 
ULN 
1.66 to <2.33 x 
ULN 
2.33 to <3.00 x 
ULN 
≥3.00 x ULN 
Platelets, Decreased 
(cells/mm3; cells/L) 
100,000 to 
<124,999 
100.000 x 109 to 
<124.999 x 109 
50,000 to 
<100,000 
50.000 x 109 to 
<100,000 x 109 
25,000 to 
<50,000 
25.000 x 109 to 
<50.000 x 109 
<25,000 
<25.000 x 109 


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Hematology1 
Parameter 
Grade 1 
MILD 
Grade 2 
MODERATE 
Grade 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
PT, High (not 
on 
anticoagulation 
therapy) 
1.1 to <1.25 x 
ULN 
1.25 to <1.50 x 
ULN 
1.50 to <3.00 x 
ULN 
≥3.00 x ULN 
WBC, Decreased 
(cells/mm3; cells/L) 
>7 days of age 
2,000 to 2,499 
2.000 x 109 to 
2,499 x 109 
1,500 to 1,999 
1.500 x 109 to 
1.999 x 109 
1,000 to 1,499 
1.000 x 109 to 
1.499 x 109 
<1,000 
<1.000 x 109 
≤7 days of age 
5,500 to 6,999 
5.500 x 109 to 
6.999 x 109 
4,000 to 5,499 
4.000 x 109 to 
5.499 x 109 
2,500 to 3,999 
2,500 x 109 to 
3.999 x 109 
<2,500 
<2.500 x 109 
INR=international normalized ratio; LLN=lower limit of normal; PT=prothrombin time; PTT=partial 
thromboplastin time; ULN=upper limit of normal; WBC=white blood cells 
1. DAIDS AE Grading Table Version 2.0, November 2014, pages 27 and 28. 
2. Male and female sex are defined as sex at birth. 
3. The conversion factor used to convert g/dL to mmol/L is 0.6206 and is the most commonly used conversion 
factor. For grading hemoglobin results obtained by an analytic method with a conversion factor other than 0.6206, 
the result must be converted to g/dL using the appropriate conversion factor for the particular laboratory. 
 
 
 
Total Bilirubin for Term and Preterm Neonates1 
Parameter 
Grade 1 
MILD 
Grade 2 
MODERATE 
Grade 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Total Bilirubin2, 
High 
(mg/dL; μmol/L)3 
Term Neonate4 
<24 hours of age 
4 to <7 
68.4 to <119.7 
7 to <10 
119.7 to <171 
10 to <17 
171 to <290.7 
≥17 
≥290.7 
24 to <48 hours of 
age 
5 to <8 
85.5 to <136.8 
8 to <12 
136.8 to <205.2 
12 to <19 
205.2 to <324.9 
≥19 
≥324.9 
48 to <72 hours of 
age 
8.5 to <13 
145.35 to <222.3 
13 to <15 
222.3 to <256.5 
15 to <22 
256.5 to <376.2 
≥22 
≥376.2 
72 hours to <7 days 
of age 
11 to <16 
188.1 to <273.6 
16 to <18 
273.6 to <307.8 
18 to <24 
307.8 to <410.4 
≥24 
≥410.4 
7 to 28 days of age 
(breastfeeding) 
5 to <10 
85.5 to <171 
10 to <20 
171 to <342 
20 to <25 
342 to <427.5 
≥25 
≥427.5 


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Total Bilirubin for Term and Preterm Neonates1 
Parameter 
Grade 1 
MILD 
Grade 2 
MODERATE 
Grade 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
7 to 28 days of age 
(not breast feeding) 
1.1 to <1.6 x ULN 
1.6 to <2.6 x ULN 
2.6 to <5.0 x 
ULN 
≥5.0 x ULN 
Preterm Neonate4 
35 to <37 weeks 
gestational age 
Same as for Total 
Bilirubin, High, 
Term Neonate 
(based on days of 
age). 
Same as for Total 
Bilirubin, High, 
Term Neonate 
(based on days of 
age). 
Same as for 
Total Bilirubin, 
High, Term 
Neonate (based 
on days of age). 
Same as for Total 
Bilirubin, High, 
Term Neonate 
(based on days of 
age). 
32 to <35 weeks 
gestational age and 
<7 days of age 
NA 
NA 
10 to <14 
171 to <239.4 
≥14 
≥239.4 
28 to <32 weeks 
gestational age and 
<7 days of age 
NA 
NA 
6 to <10 
102.6 to <171 
≥10 
≥171 
<28 weeks 
gestational age and 
<7 days of age 
NA 
NA 
5 to <8 
85.5 to <136.8 
≥8 
≥136.8 
7 to 28 days of age 
(breastfeeding) 
5 to <10 
85.5 to <171 
10 to <20 
171 to <342 
20 to <25 
342 to <427.5 
≥25 
≥427.5 
7 to 28 days of age 
(not breast feeding) 
1.1 to 1.6 x ULN 
1.6 to <2.6 ULN 
2.6 to <5.0 
ULN 
≥5.0 x ULN 
NA=not applicable ULN=upper limit of normal 
1. DAIDS AE Grading Table Version 2.0, November 2014, page 30. 
2. Severity grading for total bilirubin in neonates is complex because of rapidly changing total bilirubin normal 
ranges in the first week of life followed by the benign phenomenon of breast milk jaundice after the first week of 
life. Severity grading in this appendix corresponds approximately to cut-offs for phototherapy at grade 3 and for 
exchange transfusion at grade 4. 
3. A laboratory value of 1 mg/dL is equivalent to 17.1 μmol/L. 
4. Definitions: Term is defined as ≥37 weeks gestational age; near-term, as ≥35 weeks gestational age; preterm, as 
<35 weeks gestational age; and neonate, as 0 to 28 days of age. 


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Regeneron Pharmaceuticals, Inc. 
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APPENDIX G.  PRETERM UPPER LIMIT OF NORMAL (ULN) VALUES 
SPECIFIED IN EXCLUSION CRITERION 6 AND THE 
1.1 TIMES ULN CUT-OFF LIMIT FOR THESE VALUES 
ABOVE WHICH SUBJECTS WOULD BE EXCLUDED 
FROM STUDY ENTRY 
 
Parameter 
Conventional Unit 
SI Unit 
ULN 
>1.1 x ULN 
ULN 
>1.1 x ULN 
Creatinine 
1.5 mg/dL 
1.65 mg/dL 
133 µmol/L 
146.3 µmol/L 
Total Bilirubin 
12 mg/dL 
13.2 mg/dL 
205 µmol/L 
225.5 µmol/L 
ALT 
45 U/L 
49.5 U/L 
45 U/L 
49.5 U/L 
AST 
0 to10 days of 
age 
150 U/L 
165 U/L 
150 U/L 
165 U/L 
10 days to 
< 12 months 
of age 
80 U/L 
88 U/L 
80 U/L 
88 U/L 
Alkaline Phosphatase 
700 U/L 
770 U/L 
700 U/L 
770 U/L 
ALT = alanine aminotransferase, AST = aspartate aminotransferase, SI = International System of Units, 
ULN = upper limit of normal 


Clinical Study Protocol 
R2222-RSV-1332.04 
VV-RIM-00012444-1.0 Approved - 11 Apr 2017 GMT-5:00 
 
 
 
 
 
Signature of Sponsor’s Responsible Officers 
 
(Scientific/Medical Monitor, 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: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study 
Evaluating the Efficacy and Safety of a Human Monoclonal Antibody, 
REGN2222, for the Prevention of Medically Attended RSV Infection in 
Preterm Infants 
 
Protocol Number: 
R2222-RSV-1332 
 
 
 
See appended electronic signature page 
 
Sponsor’s Responsible Scientific/Medical Monitor 
 
 
 
 
 
See appended electronic signature page 
 
Sponsor’s Responsible Regulatory Representative 
 
 
 
 
 
See appended electronic signature page 
 
Sponsor’s Responsible Clinical Study Team Lead 
 
 
 
 
 
See appended electronic signature page 
 
Sponsor’s Responsible Biostatistician 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Regeneron Pharmaceuticals, Inc. 
 
 
CONFIDENTIAL 
Page 137 of 137 


VV-RIM-00012444-1.0 Approved  - 1 1 Apr 2017 GMT-5:00 
 
 
 
 
 
 
 
 
 
 
Approval 
Approval 
Approval 
Signatu re Page for VV-RIM-00012444 v l.O 
 
 
 
 
 
Signature Page for VV-RIM-00012444 vl.O Approved 

SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
vsv00061899-1.0 Approved - 12 Aug 2016 GMT-5:00 
 
 
 
NCT02325791 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
VERSION: FINAL 
 
 
 
 
 
Clinical Study Protocol Title: 
 
A Phase 3, Randomized, Double-blind, Placebo-controlled Study Evaluating the Efficacy 
and Safety of a Human Monoclonal Antibody, REGN2222, for the Prevention of Medically 
attended RSV Infection in Preterm Infants 
 
Part A 
 
 
 
 
 
Compound: 
REGN2222 
 
Protocol Number: 
R2222-RSV-1332 
 
Clinical Phase: 
Phase 3 
 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician: 
Clinical Trial Manager: 
Study Medical Director: 
Version/Date: 
Original Statistical Analysis Plan / Aug 9, 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 


Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
CONFIDENTIAL 
Page 2 of 34 
vsv00061899-1.0 Approved - 12 Aug 2016 GMT-5:00 
 
 
 
 
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. 
 
Study Biostatistician 
(Author) 
 
 
 
Print Name 
Signature 
Date 
 
 
Study Clinical Pharmacologist (Author) 
 
 
 
 
 
Print Name 
Signature 
Date 
 
 
Study Bioanalytical Sciences 
Representative 
(Author) 
 
 
 
Print Name 
Signature 
Date 
 
 
Medical Director/Study 
Director 
(Approver) 
 
 
 
Print Name 
Signature 
Date 
 
 
Senior Director, Clinical 
Pharmacology 
(Approver) 
 
 
 
Print Name 
Signature 
Date 
 
 
Head of Biostatics and Data 
Management or designee 
(Approver) 
 
 
 
Print Name 
Signature 
Date 


CONFIDENTIAL 
Page 3 of 34 
vsv00061899-1.0 Approved - 12 Aug 2016 GMT-5:00 
Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol: R2222-RSV-1332 
Date: Aug 9, 2016 
 
 
 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................................5 
 
1. 
OVERVIEW .................................................................................................................7 
 
1.1. 
Background/Rationale ..................................................................................................7 
 
1.2. 
Study Objectives ...........................................................................................................7 
 
1.2.1. 
Primary Objective .........................................................................................................7 
 
1.2.2. 
Secondary Objective .....................................................................................................7 
 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol..................................8 
 
1.2.4. 
Modifications from the Approved Statistical Analysis Plan ........................................8 
 
2. 
INVESTIGATING PLAN ............................................................................................9 
 
2.1. 
Study Design and Randomization ................................................................................9 
 
2.2. 
Sample Size and Power Considerations .......................................................................9 
 
2.3. 
Study Plan .....................................................................................................................9 
 
3. 
ANALYSIS POPULATIONS ....................................................................................11 
 
3.1. 
The Safety Analysis Set (SAF) ...................................................................................11 
 
3.2. 
The Pharmacokinetic Analysis Set .............................................................................11 
 
3.3. 
The Anti-drug antibody (ADA) Analysis Set .............................................................11 
 
4. 
ANALYSIS VARIABLES .........................................................................................12 
 
4.1. 
Demographic and Baseline Characteristics ................................................................12 
 
4.2. 
Medical History ..........................................................................................................12 
 
4.3. 
Prior / Concomitant Medications ................................................................................12 
 
4.4. 
Efficacy Variables ......................................................................................................12 
 
4.5. 
Safety Variables ..........................................................................................................13 
 
4.5.1. 
Adverse Events and Serious Adverse Events .............................................................13 
 
4.5.2. 
Adverse Events of Special Interest .............................................................................13 
 
4.5.3. 
Laboratory Safety Variables .......................................................................................14 
 
4.5.4. 
Vital Signs ..................................................................................................................15 
 
4.5.5. 
Physical Examination .................................................................................................15 
 
4.6. 
Pharmacokinetic Variables and Anti-Drug Antibody Variables (ADA) ....................16 
 
5. 
STATISTICAL METHODS.......................................................................................17 
 
5.1. 
Demographics and Baseline Characteristics...............................................................17 
 
5.2. 
Medical History ..........................................................................................................17 


CONFIDENTIAL 
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vsv00061899-1.0 Approved - 12 Aug 2016 GMT-5:00 
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Statistical Analysis Plan 
Protocol: R2222-RSV-1332 
Date: Aug 9, 2016 
 
 
 
5.3. 
Prior / Concomitant Medications ................................................................................17 
 
5.4. 
Subject Disposition .....................................................................................................17 
 
5.5. 
Treatment Compliance and Observation Period .........................................................18 
 
5.6. 
Analysis of Safety Data ..............................................................................................18 
 
5.6.1. 
Adverse Events ...........................................................................................................19 
 
5.6.2. 
Clinical Laboratory Measurements.............................................................................21 
 
5.6.3. 
Vital Signs ..................................................................................................................21 
 
5.6.4. 
Physical Examination .................................................................................................22 
 
5.7. 
Analysis of Pharmacokinetics and Anti-Drug Antibody Data ...................................22 
 
6. 
DATA CONVENTIONS ............................................................................................24 
 
6.1. 
Definition of Baseline for Safety Variables................................................................24 
 
6.2. 
Data Handling Convention for Missing Data .............................................................24 
 
6.3. 
Visit Windows ............................................................................................................25 
 
6.4. 
Unscheduled Assessments ..........................................................................................25 
 
7. 
INTERIM ANALYSIS ...............................................................................................26 
 
8. 
SOFTWARE ...............................................................................................................27 
 
9. 
REFERENCES ...........................................................................................................28 
 
10. 
APPENDIX.................................................................................................................29 
 
10.1. 
Schedule of Time and Events .....................................................................................29 
 
10.2. 
Hypersensitivity PTs of interest per Carbonell-Estrany X 2010. ...............................31 
 
10.3. 
Hypersensitivity PTs of interest per Feltes TF 2011. .................................................32 
 
10.4. 
Criteria for Treatment-Emergent Potentially Clinically Significant Values 
(PCSV)........................................................................................................................33 
 
 
 
LIST OF FIGURES 
 
Figure 1:.... Part A: 30 mg/kg Single Dose ....................................................................................10 


CONFIDENTIAL 
Page 5 of 34 
vsv00061899-1.0 Approved - 12 Aug 2016 GMT-5:00 
Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol: R2222-RSV-1332 
Date: Aug 9, 2016 
 
 
 
 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
ADA 
Anti-drug antibody 
 
AE 
Adverse event 
 
AESI 
Adverse event of special interest 
 
ALT 
Alanine aminotransferase 
 
AST 
Aspartate aminotransferase 
 
ATC 
Anatomical therapeutic chemical 
 
AUCinf 
Area under the concentration-time curve from time 0 to infinity 
 
CRF 
Case report form 
 
CTCAE 
Common terminology criteria for adverse events 
 
EOS 
End of study 
 
ET 
Early termination 
 
FDA 
Food and Drug Administration 
 
GA 
Gestational age 
 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
ICF 
Informed Consent Form 
IM 
Intramuscular 
 
IVRS 
Interactive voice response system 
IWRS 
Interactive web response system 
LLN 
Lower limit of normal 
MedDRA 
Medical dictionary for regulatory activities 
 
PCSV 
Potentially clinically significant value 
 
PK 
Pharmacokinetic 
 
PT 
Preferred term 
 
Q 
Every 
 
RBC 
Red blood cell 
 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
RSV 
Respiratory syncytial virus 
SAE 
Serious adverse event 
 
SAF 
Safety set 
 
SAP 
Statistical analysis plan 


CONFIDENTIAL 
Page 6 of 34 
vsv00061899-1.0 Approved - 12 Aug 2016 GMT-5:00 
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Statistical Analysis Plan 
Protocol: R2222-RSV-1332 
Date: Aug 9, 2016 
 
 
 
 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
SAS 
Statistical Analysis Software 
 
SOC 
System organ class 
 
TEAE 
Treatment emergent adverse event 
 
ULN 
Upper limit of normal 
 
WBC 
White blood cell 
 
WHODD 
World Health Organization Drug Dictionary 


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Statistical Analysis Plan 
Protocol: R2222-RSV-1332 
Date: Aug 9, 2016 
 
 
 
 
 
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 analyses prior to database lock.  The SAP is 
intended to be a comprehensive and detailed description of strategy and statistical technique to 
be used to realize the analyses of data for study R2222-RSV-1332 Part A only.  A separate SAP 
is prepared for Part B. 
 
This plan may be revised during the study to accommodate protocol amendments and to make 
changes to adapt to unexpected issues in study execution or data that affect planned analyses.  A 
final plan will be issued prior to database lock of Part A. 
 
1.1. 
Background/Rationale 
 
This phase 3 study of REGN2222 is designed to evaluate the safety, efficacy, pharmacokinetics 
(PK), and immunogenicity of REGN2222, a new fully human immunoglobulin G1 (IgG1) 
monoclonal antibody directed against the respiratory syncytial virus (RSV) fusion glycoprotein 
in infants born no more than 35 weeks 6 days gestational age (GA), who are no more than 6 
months of age at the time of study enrollment.  The study has 2 parts: 
 
Part A is an open-label PK study of REGN2222 to determine the PK in pre-term infants after a 
single dose to enable the selection of dosing regimens for Part B.  It will also provide initial 
evaluation of safety and tolerability in infants.  A sparse PK sampling scheme is used to reduce 
the volume of blood collected in infants.  Based on observed PK data from R2222-HV-1326, a 
FIH healthy adult study, a population PK model was developed and scaled to the infant 
population following age and body weight correction, using the scaling approach adopted by 
Robbie 2012.  A Bayesisan feedback analysis will be used to determine the concordance of 
observed REGN2222 serum concentration in infants of Part A with model predicted 
concentrations after administration of a single 30 mg/kg IM dose of REWGN2222.  Pre-specified 
criteria in the protocol will be used to qualify the dosing regimens selected a priori in Part B. 
 
Part B is a randomized, double-blind, placebo-controlled, study designed to evaluate efficacy, 
safety, monthly concentrations of REGN2222 in serum, and immunogenicity of IM 
administration of REGN2222 in preterm infants who are not eligible or recommended for, or 
who do not have access to, palivizumab. 
 
1.2. 
Study Objectives 
 
1.2.1. 
Primary Objective 
 
The primary objective of the study in Part A is to determine the PK of Intramuscular (IM) 
administration of REGN2222. 
 
1.2.2. 
Secondary Objective 
 
The secondary objective of the study in Part A is to evaluate safety, tolerability, and 
immunogenicity of REGN2222 following IM administration. 


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Statistical Analysis Plan 
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Date: Aug 9, 2016 
 
 
 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol 
 
Analyses of Preferred Terms (PTs) of interest for hypersensitivity are added to assist safety 
evaluation. 
 
1.2.4. 
Modifications from the Approved Statistical Analysis Plan 
 
This is the first version. 


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Statistical Analysis Plan 
Protocol: R2222-RSV-1332 
Date: Aug 9, 2016 
 
 
 
 
 
2. 
INVESTIGATING PLAN 
 
2.1. 
Study Design and Randomization 
 
This is a Phase 3 study that will be conducted in 2 parts. 
 
Part A is an open-label, single cohort, multicenter, PK study.  Subjects in Part A may enroll any 
time during the RSV season.  Subjects will be assigned open-label treatment with a single dose 
of REGN2222 30 mg/kg during the RSV season. 
 
Part B is a randomized, placebo-controlled, 3-arm, multicenter study.  A separate SAP is 
prepared for Part B. 
 
2.2. 
Sample Size and Power Considerations 
 
For Part A, the goal of the study is to study infant PK, and therefore no formal sample size 
calculation was conducted.  Twenty-four subjects were planned to be enrolled in Part A. 
 
2.3. 
Study Plan 
 
After the parent(s) or legal guardian(s) provide informed consent, subjects will be assessed for 
study eligibility at the screening visit.  In Part A, subjects will complete screening within 14 days 
prior to baseline (Day 1).  Subjects who continue to meet eligibility criteria at baseline will 
undergo Day 1 baseline assessments and will receive a single dose of REGN2222 30 mg/kg IM. 
Subjects will be monitored in the clinic for 3 hours after dosing, followed by a physical 
examination, and if appropriate, discharge.  The study staff will contact the parent(s) or legal 
guardian(s) at the end of Day 1 to inquire about any change in the subject’s status, the subject 
will return to the study site on Day 2 for Visit 3, and the study staff will contact the parent(s) or 
legal guardian(s) on Day 3 to inquire about any change in the subject’s status.  The study flow 
diagram for Part A is depicted in Figure 1. 
 
The total duration of the study will be up to 164 days (14-day screening period, a single dose 
treatment period, and 150-day follow-up period).  An interim PK analysis will be conducted on 
the first 18 infants after at least 1 blood sample is collected for determination of drug 
concentration following administration of study drug.  At study completion, a final PK analysis 
will be conducted on all infants enrolled in Part A, who have at least 1 blood sample collected. 


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Statistical Analysis Plan 
Protocol: R2222-RSV-1332 
Date: Aug 9, 2016 
 
 
 
Figure 1: 
Part A: 30 mg/kg Single Dose 
 
 
 
EOS=end of study; ET=early termination; IM=intramuscular 
Note: The screening visit will occur from Day -14 to Day -1. Black arrow denotes dosing visit. At Visit 2, subjects 
will be monitored on site for 3 hours after dosing. Grey arrows denote study visits at which dosing does not occur. If 
a subject does not have a blood draw scheduled at Visit 4, Visit 5, or Visit 6, then the visit will be conducted by 
telephone. 
 
The study schedule of events is presented in Appendix 10.1.  As shown in Appendix 10.1, PK 
samples will be collected at clinical study day 2,8,15,22,29,57,85,113 and 150 (EOS).  A sparse 
sampling strategy is used to reduce the volume of blood collected from infants; there will be 3 
PK samples (one provided by each of 3 infants) per each nominal time point, except Day 150, at 
which all 23 enrolled infants will have a serum sample collected for determination of REGN2222 
concentration. 


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Statistical Analysis Plan 
Protocol: R2222-RSV-1332 
Date: Aug 9, 2016 
 
 
 
 
 
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 (1998), the following population of analysis will be used 
for all statistical analysis: 
 
3.1. 
The Safety Analysis Set (SAF) 
 
The safety analyses will be based on enrolled subjects who receive any dose of REGN2222. 
 
3.2. 
The Pharmacokinetic Analysis Set 
 
The PK analysis set will contain subjects who receive a single dose of REGN2222 and have at 
least 1 measurable concentration of REGN2222 in serum. 
 
3.3. 
The Anti-drug antibody (ADA) Analysis Set 
 
The ADA analysis set contains subjects who received a single dose of REGN2222 and have at 
least 1 post-treatment ADA result. 


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Statistical Analysis Plan 
Protocol: R2222-RSV-1332 
Date: Aug 9, 2016 
 
 
 
 
 
4. 
ANALYSIS VARIABLES 
 
4.1. 
Demographic and Baseline Characteristics 
 
The following demographic and baseline variables will be summarized: 
 
• Age at screening (weeks) 
 
• Gestational age categories 
 
− ≤31 weeks 6 days 
 
− ≥32 weeks 0 days and ≤35 weeks 6 days 
 
• Sex (Male, Female) 
 
• Race (American Indian/Alaskan Native, Asian, Black, Native Hawaiian/Other Pacific 
Islander, White, and Other) 
 
• Ethnicity (Hispanic/Latino, not Hispanic/Latino) 
 
• Baseline Weight (kg) 
 
• Country 
 
• Region (North America [United States and Canada], Rest of the world) 
 
4.2. 
Medical History 
 
Medical history will be coded to a Preferred Term (PT) and associated primary System Organ 
Class (SOC) according to the Medical Dictionary for Regulatory Activities (MedDRA®) version 
17.1. 
 
4.3. 
Prior / Concomitant Medications 
 
Medications/Procedures will be recorded from the day of informed consent until the end of study 
(EOS) visit or early termination (ET) visit, whichever is applicable.  Medications will be coded 
to the anatomical therapeutic chemical (ATC) classification level 2 (therapeutic main group) and 
ATC level 4 (chemical/therapeutic subgroup), according to the latest available version of WHO 
Drug Dictionary (WHODD).  Subjects will be counted once in all ATC categories linked to the 
medication. 
 
Pre-treatment medications/procedures: medications taken or procedures performed prior to 
administration of REGN2222. 
 
Concomitant medications/procedures: medications taken or procedures performed following the 
dose of REGN2222 through the EOS visit or early termination (ET) visit, whichever is 
applicable. 
 
4.4. 
Efficacy Variables 
 
Clinical efficacy variables analyses are not applicable for Part A. 


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Statistical Analysis Plan 
Protocol: R2222-RSV-1332 
Date: Aug 9, 2016 
 
 
 
4.5. 
Safety Variables 
 
Subject safety will be assessed through the collection of adverse events (AEs), laboratory data 
(hematology, chemistry), vital signs, and physical exam (including weight).  For these measures, 
with the exception of the AEs, the eCRF visit label will be used for temporal summaries.  Unless 
otherwise noted (example: AEs), baseline for these measures is defined as the last 
chronologically available valid assessment prior to the dose of REGN2222. 
 
For safety variables, 2 observation periods are defined for Part A: 
 
• The pretreatment period is defined as the time from signing the informed consent 
form (ICF) to before the first dose of REGN2222. 
• The treatment period is defined as the days from the first dose of REGN2222 to the 
last study visit (ie, Day 150 EOS visit or ET visit, whichever is applicable). 
4.5.1. 
Adverse Events and Serious Adverse Events 
The definitions for AEs and serious adverse events (SAEs) are described in Sections 7.1.1 and 
7.1.2 of the study protocol, respectively.  Additional information on determining whether 
abnormal laboratory or vital sign results should be considered as AEs is included in Section7.2.6 
of the study protocol.  AEs and SAEs will be collected from the time of informed consent 
signature and then at each visit until the end of the study.  All AEs are to be coded to a PT and 
associated primary SOC according to the MedDRA version 17.1. 
 
Treatment-emergent AEs (TEAEs) are defined as AEs that are not present at baseline or 
represent an exacerbation of a preexisting condition during the treatment period.  Therefore, 
referencing the protocol, TEAEs will be defined programmatically as any AE record with a start 
date/time on or after the first study treatment administration (greater than or equal to study 
day 1), inclusive to the end of the study (specifically the EOS visit or ET visit). 
 
The severity of AEs is graded using 1 of 2 severity scales.  The severity scale used is determined 
by the type of AE experienced by the subject; more detail is provided in Section 7.3.1 of the 
protocol. 
 
4.5.2. 
Adverse Events of Special Interest 
 
Adverse events of special interest (AESI) for this study are hypersensitivity reactions occurring 
within 48 hours after exposure to the study drug (including but not limited to urticaria, edema, 
respiratory distress, anaphylaxis, and allergic reactions). Such treatment-emergent AESI are 
identified by investigator using a tick box on the eCRF AE page. 
 
As part of the safety assessment, in addition to evaluation of treatment-emergent AEs that are 
considered to be AESI by the investigator, the following sets of pre-defined PTs of interest of 
treatment-emergent hypersensitivity AEs will also be monitored and summarized: 
 
1.   Modified narrow Standard MedDRA Query (SMQ [N]) for “hypersensitivity”.  The 
modification is to add PTs: pruritus, pruritus generalised, prurigo, flushing, erythema, 
generalised erythema, injection site erythema, rash papular, allergic oedema. 
 
2.   MedDRA query for all PTs under the high level term (HLT): injection site reaction. 


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Statistical Analysis Plan 
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Date: Aug 9, 2016 
 
 
 
3.   Hypersensitivity PTs of interest per Carbonell-Estrany X 2010 as listed in Appendix 10.2. 
 
4.   Hypersensitivity PTs of interest per Feltes TF 2011 as listed in Appendix 10.3 . 
 
5.   Acute hypersensitivity reactions that occur within 48 hours after dosing, classified in 2 
categories, per Shapiro 2010: 
 
a. Urticarial Reactions which will be identified by search for PTs: urticaria, oedema; 
low level term (LLT): localized erythema. 
b. Allergic Rash which will be identified by search for PTs: rash, dermatitis allergic, 
erythema annulare, erythema multiforme, rash maculo-papular.  For AEs with the PT 
of rash, a manual review of their verbatims will be conducted to specifically identify 
4.5.3. 
AEs that are acute rash. 
Laboratory Safety Variables 
Clinical laboratory tests include hematology and blood chemistry.  Samples for laboratory testing 
will be collected at screening, a post-baseline visit according to assigned blood draw schedule 
(time points specified in the schedule of assessments [Appendix 10.1]), and at EOS or at the time 
of early termination (ET). 
 
Clinical laboratory values will be in standard international (SI) units, including associated 
normal ranges provided by the central laboratory, and grouped by function in summary tables. 
Conventional unit may be provided.  Clinical laboratory tests are provided below, sub-grouped 
by function: 


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Statistical Analysis Plan 
Protocol: R2222-RSV-1332 
Date: Aug 9, 2016 
 
 
 
Blood Chemistry 
 
Electrolytes 
Liver function 
Metabolism 
Renal function 
Sodium 
AST 
Total protein, serum 
Blood Urea Nitrogen 
Potassium 
ALT 
Glucose 
Creatinine 
Chloride 
Alkaline phosphatase 
Albumin 
Uric acid 
Carbon dioxide 
Blood urea nitrogen 
Creatine phosphokinase 
Calcium 
Total bilirubin 
Indirect bilirubin 
Lactate dehydrogenase 
 
 
Hematology 
 
Red blood cells and platelets 
White blood cells 
Hemoglobin 
White blood cells (WBCs) 
Hematocrit 
Neutrophils 
Red blood cells (RBCs) 
Lymphocytes 
Red cell indices 
Monocytes 
Platelet count 
Basophils 
Eosinophils 
 
4.5.4. 
Vital Signs 
 
The following vital signs parameters will be collected at visit 1, visit 2, visit 3, visit 7, visit 8, 
visit 9, visit 10, and at EOS or at the time of ET.  On the study drug dosing days, vital signs will 
be assessed prior to collection of blood sample, prior to injection of study drug, and after 
completion of the injection (Part A at 1, 2, and 3 hours [±10 minutes] after completion of the 
injection. 
 
• Respiration rate (breaths/min) 
• Pulse rate (beat/min) 
• Systolic and diastolic blood pressures (mmHg).  Blood pressure may be difficult to
obtain in some infants because of size, therefore a systolic blood pressure alone can
be recorded. 
• Temperature (oC/ oF) 
4.5.5. 
Physical Examination 
Subjects will have a physical examination (including weight) at visit 1, visit 2, visit 3, visit 8, 
and at EOS or at the time of ET.  On study drug-dosing days, physical examinations will be 
conducted predose and again postdose (excluding weight) prior to discharge.  The result for each 
body system is an outcome of normal or abnormal. 


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Statistical Analysis Plan 
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Date: Aug 9, 2016 
 
 
 
4.6. 
Pharmacokinetic Variables and Anti-Drug Antibody Variables 
(ADA) 
 
Drug concentration in serum at Day 150 will be reported for each infant, however because of the 
pooled sampling scheme and sparseness of the data, non-compartmental analysis on observed 
individual concentration-time profiles will not be performed. 
 
Because of the pooled sampling scheme, not all infants will have ADA measurements at the 
same time. 
 
Antidrug antibody variables include status (positive or negative) and titer as follows: 
 
• Total subjects with negative ADA assay response at all times. 
 
• Total subjects with positive ADA assay response at any time. 
 
• Pre-existing immunoreactivity - defined as either a positive ADA assay response at 
baseline with all post-treatment ADA assay results negative, or a positive assay 
response at baseline with all post-treatment ADA assay responses less than 4-fold 
over baseline titer levels. 
 
• Treatment-emergent - defined as any post-treatment positive ADA assay response 
when the baseline ADA result is negative or missing. 
 
• Treatment-boosted - defined as any post-treatment positive ADA assay response that 
is greater than or equal to 4-fold over baseline titer level when baseline is ADA 
positive in the ADA assay. 
 
• Titer values 
 
• Titer category 
 
− Low (titer <1000) 
 
− Moderate (1000 ≤ titer ≤ 10000) 
 
− High (titer >10000) 


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Statistical Analysis Plan 
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Date: Aug 9, 2016 
 
 
 
 
 
5. 
STATISTICAL METHODS 
 
Part A is a single cohort PK study, therefore there is no statistical testing and all summaries will 
be descriptive in nature. 
 
For continuous variables, descriptive statistics will include the following: the number of subjects 
reflected in the calculation (n), mean, median, standard deviation, minimum, the first and third 
quartiles (Q1 and Q3), and maximum.  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 based on the SAF. 
Other safety baseline data is presented collectively in the descriptive statistics summary tables 
containing respective post-baseline data.  Listing of demographics and baseline characteristics 
will be presented. 
 
5.2. 
Medical History 
 
Medical history will be summarized by primary SOC and PT based on the SAF. Summaries will 
show subject counts (percentages).  The tables will be sorted by SOC in alphabetical order. 
Within each primary SOC, PTs will be sorted by decreasing frequency of the counts in the study 
total.  A listing for medical history will also be provided. 
 
5.3. 
Prior / Concomitant Medications 
 
The number and percentage of subjects taking concomitant medication will be summarized, 
sorted by decreasing frequency of ATC Level 2 and ATC level 4 based on the SAF.  The tables 
will be sorted by alphabetical order of ATC level 2 and ATC level 4 followed by descending 
order of frequency of preferred name.  Number and percentage of subjects taking prior 
medication will be summarized in a similar fashion to concomitant medication. 
 
Listings of concomitant medications will include generic name and ATC levels 2 and 4, 
indication, start date, end date, dose, frequency, and route.  To separate prior and concomitant 
medications in the listing, a flag will be added for prior medication.  A flag will also be added to 
the listing to denote a concomitant medication administered to treat an AE. 
 
5.4. 
Subject Disposition 
 
The following summaries will be provided for subject disposition status. For all categories, 
percentages will be calculated using the number of enrolled subjects as the denominator except 
for the screened and screen failure categories, where denominator will be the number of screen 
subjects. 
 
• Screened subjects (signed the ICF). 
 
• Screen failed subjects and reasons for screen failure. 
 
• Subjects enrolled (received a drug kit assignment in IVRS/IWRS) 


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Date: Aug 9, 2016 
 
 
 
• Subjects treated (SAF population) 
 
• Completed study (from the EOS eCRF) 
 
• Did not complete study (from the EOS eCRF) 
 
• Primary reasons for study discontinuation (from the EOS eCRF) 
 
Study completers are defined as subjects who complete the EOS visit.  The following listing will 
be provided for all enrolled subjects: A listing of subject disposition including dosing date(s), 
last visit date, completed study or discontinued by reason; a listing of screening failures and 
reasons. 
 
5.5.         Treatment Compliance and Observation Period 
 
As Part A is a single-dose study, treatment compliance is not applicable.  The observation period, 
rather than the treatment exposure, will be presented. 
 
Duration of observation period during the study is calculated as: 
 
(Date of the last study visit – date of the first dose of REGN2222) +1. 
 
The duration of the observation period will be summarized using the number of subjects, mean, 
median, SD, minimum, Q1, Q3, and maximum. 
 
The number (%) of subjects having observation periods of specific lengths will be summarized 
according to time period breakdowns as follows:   ≥1 to <8 days,  ≥ 8 to <15 days,  ≥ 15 to <22 
days, ≥ 22 to <29 days, ≥ 29 to <57 days, ≥ 57 to <85 days,  ≥ 85 to <113 days,  ≥ 113 to < 145 
days, and ≥ 145 days. 
 
5.6.         Analysis of Safety Data 
 
Safety and tolerability will be descriptively summarized, including AEs, clinical laboratory 
variables, physical exam, and vital signs for the SAF (as defined in Section 3.1). 
 
All safety analyses will be performed, unless otherwise specified, using the following common 
rules: 
 
• The baseline value is defined as the last available value obtained up to the date and 
time of the first dose of REGN2222, except otherwise specified. 
 
• Supplemental assessment is defined in the case of more than 1 assessment collected at 
a scheduled visit, specifically the later assessment in the visit window will be marked 
as supplemental assessment.  Supplemental measurements will not be included by- 
visit summaries, therefore the earliest assessment at the visit will be used in 
summaries and all observations will be presented in listings. 
 
• Assessments repeatedly collected during the study will be defined by the eCRF visit 
label for temporal summaries and subject listings. 
 
• All data points of safety parameters including central laboratory measurements, vital 
signs, physical exams, adverse events will be presented by subject in listings. 


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• For continuous safety parameters including central laboratory measurements (for 
selected chemistry parameters) and vital sign scores, descriptive statistics will be used 
to summarize results and change from baseline values by visit. 
• A treatment-emergent Potential Clinically Significant abnormal value (PCSV) is a 
laboratory value or vital sign that was: normal at baseline but abnormal after 
treatment with study drug, or: abnormal at baseline and worsened after treatment with 
study drug.  Thresholds for treatment-emergent PCSV in laboratory variables and 
vital signs are defined in Section 10.4.  Treatment-emergent PCSV criteria will 
determine which subjects had at least 1 treatment-emergent PCSV during the 
post-baseline observation period, taking into account all assessments including 
unscheduled or supplemental assessments.  Subjects who had post-baseline PCSV but 
missing baseline value will be regarded as having treatment-emergent PCSV. 
5.6.1. 
Adverse Events 
The verbatim text, the PT, and the primary SOC will be listed in subject listings.  Summaries that 
include frequencies and proportions of subjects reporting AEs will include the PTs and the 
SOCs. 
 
If an AE date/time of onset (occurrence, worsening, or becoming serious) is incomplete, an 
imputation algorithm will be used to classify the AE as pre-treatment or treatment-emergent. 
The algorithm for imputing date/time of onset will be conservative and will classify an AE as 
treatment-emergent unless there is definitive information to determine pre-treatment status. 
Details on classification of AEs with missing or partial onset dates are provided in Section 6.2. 
 
Summaries of all TEAEs will include: 
 
• Overview of TEAEs, summarizing number and percentage of subjects with any 
 
− TEAEs. 
 
− Serious TEAEs. 
 
− TEAEs leading to death. 
 
− TEAEs leading to permanent treatment discontinuation. 
 
− TEAEs with severity of 3/4/5/Severe/Life-Threatening/Fatal. 
 
− TEAEs that occurred within 2 days after study drug administration. 
 
• All TEAEs by SOC and PT. 
 
• All TEAEs by SOC, PT, and severity. 
 
• All TEAEs by SOC, PT, and relationship (related, not related) to study drug. 
 
• All TEAEs by SOC, PT, and relationship (related, not related) to injection procedure. 
 
• All TEAEs by PT ordered by decreasing subject frequency. 
 
• Study drug-related TEAEs by SOC and PT. 


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• Study drug-related TEAEs by SOC, PT, and severity (this output will not be produced 
if there is no study drug-related TEAEs). 
 
• Injection procedure-related TEAEs by SOC and PT. 
 
• Injection procedure-related TEAEs by SOC, PT, and severity (this output will not be 
produced if there is no injection procedure-related TEAEs). 
 
• Summaries of TEAEs of special interest (as defined in Section 4.5.2): 
 
− TEAEs of special interest (as flagged by the investigator on the eCRF) by SOC 
and PT. 
 
− TEAEs that are PTs of interest of hypersensitivity from modified SMQ(N) for 
hypersensitivity by PT. 
 
− TEAEs that are PTs of interest of hypersensitivity from MedDRA query for all 
PTs under the HLT of injection site reaction by PT. This analysis will also be 
performed for subgroups of subjects administered with 1 and 2 injections 
respectively. 
 
− TEAEs that are hypersensitivity PTs of interest per Carbonell-Estrany X 2010. by 
PT. 
 
− TEAEs that are hypersensitivity PTs of interest per Feltes TF 2011. by PT. 
 
− TEAEs that are acute hypersensitivity reactions per Shapiro 2010 by PT (or LLT 
where appropriate). 
 
− The above TEAEs of special interest may also be presented by PT and severity. 
 
• TEAEs with severity of 3/4/5/Severe/Life-Threatening/Fatal by SOC, PT, and 
severity 
 
• Study drug-related TEAEs with severity of  3/4/5/Severe/Life-Threatening/Fatal by 
SOC, PT, and severity (this output will not be produced if there is no study drug- 
related TEAEs). 
 
• Injection procedure-related TEAEs with severity of 3/4/5/Severe/Life- 
Threatening/Fatal by SOC, PT, and severity (this output will not be produced if there 
is no injection procedure-related TEAEs). 
 
• Serious TEAEs by SOC and PT. 
 
• Study drug-related serious TEAEs by SOC and PT (this output will not be produced if 
there is no serious TEAEs). 
 
• Injection procedure-related serious TEAEs by SOC and PT (this output will not be 
produced if there is no serious TEAEs). 
 
• TEAEs leading to death by SOC and PT. 
 
• Non-serious study drug-related TEAEs by SOC and PT. 
 
• Non-serious injection procedure-related TEAEs by SOC and PT. 


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The above TEAE summaries will present the number (n) and percentage (%) of subjects 
experiencing an AE by SOC and PT.  Multiple occurrences of AEs of the same PT (or SOC) in 
the same subject will be counted only once for that PT (or SOC).  For tables presenting severity 
of events, the worst severity will be chosen for subjects with multiple instances of the same 
event.  Relatedness to study drug or injection procedure is according to investigator’s opinion. 
 
Primary SOCs will be sorted by alphabetical order.  Within each primary SOC, PTs will be 
sorted by decreasing frequency of the counts for study total. 
 
Subject listings for deaths, all serious TEAEs, TEAEs leading to permanent treatment 
discontinuation, TEAEs with severity of 3/4/5/Severe/Life-Threatening/Fatal, and AESIs will be 
provided. 
 
5.6.2. 
Clinical Laboratory Measurements 
 
Central laboratory measures for chemistry and hematology parameters will be explored through 
two methods: 
 
First summaries will focus on study population changes with the intent of identifying deviations 
on a large scale across time.  This approach for continuous variables summarizes both the actual 
scores (at both baseline and post-baseline) and the change from baseline scores at each 
post-baseline scheduled visit.  Descriptive statistics include number of subjects, mean, median, 
standard deviation, minimum, Q1, Q3, and maximum values for each of the 8 blood collection 
schedule group (Schedule A through H) and for study total (at baseline and EOS visits only). 
Unscheduled or supplemental measurements will not be included in this summary. 
 
Second, shift tables based on baseline categories of low/normal/high/total will be provided for 
each post-baseline visit.  Numerical shift in lab values (from baseline to post-baseline) will also 
be visually displayed by graphical plots.  Scatter-box plots of lab values over time will be 
presented with visit plotted on the x-axis and lab values on the y-axis. Unscheduled or 
supplemental measurements will not be included in these summaries.  In addition to the shift 
analyses, number (and percentage) of subjects with lab values meeting the treatment-emergent 
PCSV criteria at least once during the post-baseline observation period will be summarized. 
These laboratory parameters will be presented by the biological functions defined in 
Section 4.5.3.  Subject listings of laboratory measurements with a flag to indicate those meeting 
the treatment-emergent PCSV criteria will be provided. 
 
Local laboratory measures will only be listed separately. 
 
5.6.3. 
Vital Signs 
 
All collected vital sign measures (pulse rate, respiratory rate, sitting blood pressures, and 
temperature) will be explored through summaries of both the actual scores (at both baseline and 
post-baseline) and the change from baseline scores at each post-baseline scheduled visit. 
Descriptive statistics include number of subjects, mean, median, standard deviation, minimum, 
Q1, Q3, and maximum values for study total.  In addition, body weight will be summarized in 
the same fashion. 
 
The obtainment of blood pressure in infants, without cause or suspicion of underlying 
abnormalities is not routinely done in the outpatient pediatric setting.  Specialized equipment, not 


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Statistical Analysis Plan 
Protocol: R2222-RSV-1332 
Date: Aug 9, 2016 
 
 
 
routinely present in physician offices, is required.  As a result of the issues surrounding the 
accurate obtainment of blood pressures in the study’s infant population, the study protocol was 
revised to allow investigators to mark that blood pressures are not able to be obtained.  In many 
instances blood pressure results are not available, and in instances where results have been 
obtained, the accuracy of the recordings can be questioned.  As a result, no shift table or 
treatment-emergent PCSV analyses will be performed on blood pressure measurements. 
 
The protocol allows for the measurement of subject temperature using different modalities, eg, 
temporal, axillary, rectal and tympanic.  Temperatures measured using different modalities are 
not equivalent and conversions are necessary to allow comparison.  Furthermore, as the child 
ages throughout their time participating in the study, elevations in temperature that would be of 
concern change.  Therefore due to the complexities to standardize reporting of temperatures and 
to accommodate changes reflecting the age of the child over time, no shift table or 
treatment-emergent PCSV analyses will be performed on temperature measurements. 
 
Only the number (and percentage) of subjects with pulse rate and respiratory rate values meeting 
the treatment-emergent PCSV criteria at least once during the post-baseline observation period 
will be summarized. 
 
Subject listings of vital sign measurements with a flag to indicate those meeting the 
treatment-emergent PCSV criteria will be provided. 
 
5.6.4. 
Physical Examination 
 
The number (n) and percentage (%) of subjects with abnormal physical examination at baseline 
and each scheduled post-baseline assessment will be summarized for study total. 
 
5.7. 
Analysis of Pharmacokinetics and Anti-Drug Antibody Data 
 
The analysis in this section will be done by PK/Bioanalytical group and results will be provided 
in a separate report. 
 
Pooled individual scatter and mean concentration-time plots will be produced and descriptive 
statistics will be calculated for each time point at day 2, 8, 15, 22, 29, 57, 85, 113 and 150. 
 
Predicted drug concentrations from a previously developed PK model based on REGN2222 adult 
PK data from the FIH study (REGN-HV-1326) will be compared with observed drug 
concentration data from Part A using a Bayesian Feedback approach.  In this approach, observed 
REGN2222 drug concentration data is superimposed on the 90% prediction interval generated 
from the population PK model to confirm a priori PK model estimates and provide a Bayesian 
estimate of REGN2222 half-life in infants.  Given the sparse nature of the drug concentration 
sampling scheme and the limited number of subjects in part A (N=23), post hoc individual PK 
estimates will not be determined from part A data.  A final population analysis with parameter 
estimation will be conducted at the end of Part B of the study and will combine both Part A and 
Part B data.  Post hoc PK parameters may be determined from the mean integrated drug 
concentration time profile using a non-compartmental approach.  Given that only a single 
concentration time profile of the mean data will be available, descriptive satisicis for any PK 
parameter calculated will not be determined. 


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Statistical Analysis Plan 
Protocol: R2222-RSV-1332 
Date: Aug 9, 2016 
 
 
 
Listings of ADA positivity and titers will be presented by subject and time point.  Prevalence of 
ADA, including treatment-emergent and treatment-boosted ADA, will be assessed as absolute 
occurrence (n) and percent (%) of subjects, grouped by single cohort and ADA titer level. 
 
Possible correlation between changes in PK profile and treatment-emergent positive responses in 
the ADA assay will be evaluated to identify a potential impact of anti-REGN2222 antibodies on 
drug exposure.  The impact of treatment-emergent ADA assay response may be evaluated 
separately for subjects with missing baseline ADA results. 


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Statistical Analysis Plan 
Protocol: R2222-RSV-1332 
Date: Aug 9, 2016 
 
 
 
 
 
6. 
DATA CONVENTIONS 
 
The following analysis conventions will be used in the statistical analysis. 
 
6.1. 
Definition of Baseline for Safety Variables 
 
Unless otherwise specified, the baseline assessment for all measurements will be the last 
chronologically available valid measurement taken prior to the administration of the study drug. 
For most variables, Day 1 procedures and assessments are considered to be baseline. 
 
6.2. 
Data Handling Convention for Missing Data 
 
Adverse event 
 
If the severity/toxicity grade of a TEAE is missing, it will be classified as “severe” in the 
frequency tables by severity of TEAEs.  If the assessment of relationship of a TEAE to the study 
drug or injection procedure is missing, it will be classified as related to the study drug or 
injection procedure. 
 
Missing date 
 
Every effort will be made to collect the start date/time of all AEs and concomitant medications. 
However, in the case the start date/time of an AE or concomitant medication is incomplete or 
missing, it will be assumed to have occurred on or after the first dose of study drug, except if an 
incomplete date (eg, month and year) or an indicator variable clearly indicates that the event 
started prior to treatment.  If the partial date indicates the same year (when only year is available) 
or the same month/year (when both month and year are available) of the first dose of study drug 
date, then the start date of the first dose will be imputed, otherwise, the missing day or month by 
the first day or the first month will be imputed.  No imputation is planned for date/time of AE 
resolution. 
 
No imputations for missing laboratory data, vital sign data, or physical examination data will be 
made. 
 
Baseline definition if “time” of the administration of study drug or time of assessment at Day1 
visit is missing 
 
If time of the administration of study drug or time of assessment at Day 1 visit is missing, then 
the baseline value is defined as the last available value obtained before or on the day of the study 
drug administration. 
 
Laboratory Safety Variables 
 
For central laboratory data below the lower limit of quantification (LLOQ), half of the lower 
limit value (ie, LLOQ/2) will be used for quantitative analyses.  For central laboratory data 
above the upper limit of quantification (ULOQ), the upper limit value (ie, ULOQ) will be used 
for quantitative analyses. 


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Statistical Analysis Plan 
Protocol: R2222-RSV-1332 
Date: Aug 9, 2016 
 
 
 
6.3. 
Visit Windows 
 
Assessments repeatedly collected during the study (including those taken outside of protocol 
allowable windows) will be displayed according to their eCRF visit label for temporal 
summaries and subject listings.  Drug concentration data obtained outside study visit window 
will be included in the analysis accounting for the actual time elapsed since dosing. 
 
6.4. 
Unscheduled Assessments 
 
Extra assessments (laboratory data or vital signs associated with unscheduled clinical visits or 
obtained in the course of investigating or managing AEs) will be included in listings and may 
also be used to determine treatment-emergent PCSVs., but not in by visit summaries of 
parameters with descriptive statistics for study population changes.  If more than 1 laboratory 
value is available for a given visit, the first observation will be used in summaries and all 
observations will be presented in listings. 


CONFIDENTIAL 
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Statistical Analysis Plan 
Protocol: R2222-RSV-1332 
Date: Aug 9, 2016 
 
 
 
 
 
7. 
INTERIM ANALYSIS 
 
An interim population PK analysis using a Bayesian Feedback approach will be conducted on the 
first 18 infants after at least one postdose blood sample is collected for determination of drug 
concentration following administration of study drug.  Dose assessment and selection criteria are 
described in the protocol. The a prior selected dosing regimens in Part B will remain unchanged, 
if the PK data up to Day 57 (from subjects enrolled in Part A) demonstrates that the individual 
PK observations are consistent with the  model predicted concentrations, following age and body 
weight corrections. 


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Statistical Analysis Plan 
Protocol: R2222-RSV-1332 
Date: Aug 9, 2016 
 
 
 
 
 
8. 
SOFTWARE 
 
All analyses will be done using SAS Version 9.2 or above. 


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Statistical Analysis Plan 
Protocol: R2222-RSV-1332 
Date: Aug 9, 2016 
 
 
 
 
 
9. 
REFERENCES 
 
Carbonell-Estrany X, Simões EA, Dagan R, et al. Motavizumab for prophylaxis of respiratory 
syncytial virus in high-risk children: a noninferiority trial. Pediatrics. 2010; 125(1): e35-51. 
 
Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 
1.0. National Institute of Allergy and Infectious Diseases website. 
http://www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/documents/daidsaegradingta 
ble.pdf. Published December, 2004. Accessed 8 December 2014. 
 
Feltes TF, Sondheimer HM, Tulloh RM, et al. A randomized controlled trial of motavizumab 
versus palivizumab for the prophylaxis of serious respiratory syncytial virus disease in children 
with hemodynamically significant congenital heart disease. Pediatr Res. 2011; 70(2): 186-91. 
 
ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for clinical 
trials (E9). International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. 
 
Robbie GJ, Zhao L, Mondick J, et al. Population pharmacokinetics of palivizumab, a humanized 
anti-respiratory syncytial virus monoclonal antibody, in adults and children. Antimicrob Agents 
Chemother. 2012;56(9):4927-36. 
 
Shapiro AM. FDA Core Presentations, (BLA) 125283, motavizumab, for the June 2, 2010 
Meeting of the Antiviral Drugs Advisory Committee. 


Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol: R2222-RSV-1332 
Date: Aug 9, 2016 
CONFIDENTIAL 
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10. 
APPENDIX 
 
10.1. 
Schedule of Time and Events 
 
Part A: 30 mg/kg IM (Maximum 1 Dose REGN2222); for Subjects with Schedules A through H 
 
Study Periods 
SV1 
BV 
Postdose Follow-Up 
Visit 
1 
2 
3 
42 
52 
62 
7 
8 
9 
10 
11EOS/ET 
Day 
-14 to -1 1 
2 
8 
15 
22 
29 
57±5 
85±5 
113±5 
150±5 
Informed Consent 
X 
Inclusion/Exclusion 
X 
X 
Medical History 
X 
Demographics 
X 
IVRS/IWRS Assigned Blood Collection 
Schedule3 
X 
Administer Study Drug 
X4 
Concomitant Medications and Procedures 
X 
X 
X 
X2 
X2 
X2 
X 
X 
X 
X 
X 
Vital Signs5 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination (including weight) 
X 
X6 
X 
X 
X 
Adverse Events7 
X 
X 
X 
X2 
X2 
X2 
X 
X 
X 
X 
X 
Hematology 
X8-15 
X8 
X9 
X10 
X11 
X12 
X13 
X14 
X15 
X8-15 
Blood Chemistry 
X8-15 
X8 
X9 
X10 
X11 
X12 
X13 
X14 
X15 
X8-15 
Pharmacokinetics 
X8 
X9 
X10 
X11 
X12 
X13 
X14 
X15 
X8-15 
Anti-REGN2222 (ADA) 
X8-15 
X11 
X12 
X13 
X14 
X15 
X8-15 
Optional Sub-study Informed Consent 
X 
Optional DNA Sample 
X16 


Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol: R2222-RSV-1332 
Date: Aug 9, 2016 
CONFIDENTIAL 
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ADA=antidrug antibody; BV=baseline visit, EOS/ET=end of study/early termination; IVRS=interactive voice response system; IWRS=interactive web response 
system; SV=screening visit; X=all subjects unless otherwise specified 
1  All safety assessments performed at screening must be normal and checked against the inclusion/exclusion criteria before REGN2222 administration on 
Day 1(baseline) 
2  Visit 4, Visit 5, and Visit 6 will be conducted by telephone to collect concomitant medication and adverse event information for all subjects, unless subjects are 
required by dosing schedule (Schedule C, Schedule D, and Schedule E) to undergo a PK/ADA and hematology/chemistry blood draw. Those subjects assigned 
to Schedule C (Footnote 11), Schedule D (Footnote 10), and Schedule E (Footnote 9) will have an onsite visit. 
3  Subject blood collection schedules are assigned using the IVRS/IWRS. 
4  No other vaccinations will be administered within 2 days before or after dosing of the study drug. The study staff will contact the parent(s) or legal guardian(s) 
at the end of Day 1 and on Day 3 by telephone to inquire about any change in the subject’s status. 
5  On the study drug dosing day, vital signs (temperature, blood pressure, pulse, and respiration) will be assessed prior to injection of study drug and 1, 2, and 
3 hours (±10 minutes) after completion of the injection. If a subject’s rectal temperature is 101°F/38.3°C (equivalent to axillary temperature of 100.6°F/38.1°C 
for infants <4 weeks of age or 99.2°F/ 37.3°C for infants ≥4 weeks of age) or greater on the day of a planned dose administration day, no dosing will occur. The 
subject will be re-evaluated within 48 hours and if the subject’s temperature is below 101°F (38.3°C) without the use of antipyretics during the previous 48 
hours, the schedule of assessments may be resumed. If the subject’s temperature is 101°F (38.3°C) or greater or the subject h as received antipyretics in the 
previous 48 hours, dosing of the subject will be permanently discontinued. 
6  Physical examination will be conducted before injection and after injection, prior to discharge from the clinic, at Visit 2. 
7  If the adverse event is considered a hypersensitivity or anaphylaxis reaction, then the adverse event will be assessed as outlined in Protocol Table 4. If the 
adverse event is a hypersensitivity reaction that results in a rash, then a photo will be taken as part of the adverse event assessment as outlined in Protocol Table 
4. 
8  The subjects with blood collection Schedule F will have the following collected: hematology/chemistry samples at screening, Day 2, and EOS/ET; PK samples 
on Day 2 and EOS/ET; and ADA samples at screening and EOS/ET. 
9  The subjects with blood collection Schedule E will have the following collected: hematology/chemistry samples at screening, Day 8, and EOS/ET; PK samples 
on Day 8 and EOS/ET; and ADA samples at screening and EOS/ET. 
10 The subjects with blood collection Schedule D will have the following collected: hematology/chemistry samples at screening, Day 15, and EOS/ET; PK samples 
on Day 15 and EOS/ET; and ADA samples at screening and EOS/ET. 
11 The subjects with blood collection Schedule C will have the following collected: hematology/chemistry samples at screening, Day 22, and EOS/ET; PK samples 
drawn on Day 22 and EOS/ET; and ADA samples drawn at screening, Day 22, and EOS/ET. 
12   The subjects with blood collection Schedule B will have the following collected: hematology/chemistry samples at screening, Day 29, and EOS/ET; PK 
samples on Day 29 and EOS/ET; and ADA samples at screening, Day 29, and EOS/ET. 
13   The subjects with blood collection Schedule A will have the following collected: hematology/chemistry samples at screening, Day 57, and EOS/ET; PK 
samples on Day 57 and EOS/ET; and ADA samples at screening, Day 57, and EOS/ET. 
14   The subjects with blood collection Schedule G will have the following collected: hematology/chemistry samples at screening, Day 85, and EOS/ET; PK 
samples on Day 85 and EOS/ET; and ADA samples at screening, Day 85, and EOS/ET. 
15   The subjects with blood collection Schedule H will have the following collected: hematology/chemistry samples at screening, Day 113, and EOS/ET; PK 
samples on Day 113 and EOS/ET; and ADA samples at screening, Day 113, and EOS/ET. 
16   After substudy consent, a cheek swab for DNA in the optional substudy can be obtained at any time during the study period, but preferably at baseline. 


Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol: R2222-RSV-1332 
Date: Aug 9, 2016 
CONFIDENTIAL 
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10.2.  
Hypersensitivity PTs of interest per Carbonell-Estrany X 2010. 
Non-Specific PTs 
Specific PTs 
Erythema 
Anaphylactoid reaction 
Flushing 
Angioedema 
Pruritus 
Dermatitis allergic 
Rash 
Drug eruption 
Rash erythematous 
Drug hypersensitivity 
Rash macular 
Oedema 
Rash maculo-papular 
Erythema annulare 
Rash pruritic 
Erythema marginatum 
Erythema multiforme 
Eye swelling 
Eyelid oedema Face 
oedema 
Hypersensitivity 
Injection site erythema 
Laryngeal oedema 
Lip swelling 
Periorbital oedema 
Rash generalised 
Swelling 
Swelling face 
Tracheal oedema 
Urticaria 
Urticaria papular 
Note: The following terms listed in Carbonell-Estrany’s manuscript are LLTs that code into PTs as follows: 
LLT: Angioneurotic oedema codes to PT: Angioedema 
LLT: Exanthema codes to PT: Rash 
LLT: Urticaria generalized codes to PT: Urticaria. 


Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol: R2222-RSV-1332 
Date: Aug 9, 2016 
CONFIDENTIAL 
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10.3.       Hypersensitivity PTs of interest per Feltes TF 2011. 
Non-Specific PTs 
Specific PTs 
Erythema 
Allergic oedema 
Fixed Drug Eruption 
Anaphylactoid reaction 
Generalised oedema 
Angioedema 
Pruritus 
Bronchial oedema 
Pruritus generalized 
Circumoral oedema 
Rash 
Dermatitis allergic 
Rash erythematous 
Drug eruption 
Rash macular 
Drug hypersensitivity 
Erythema annulare 
Erythema marginatum 
Erythema multiforme 
Eye oedema 
Eye swelling 
Eyelid oedema 
Face oedema 
Flushing 
Generalized Erythema 
Hypersensitivity 
Laryngeal oedema 
Laryngotracheal oedema 
Lip oedema 
Lip swelling 
Oedema 
Oedema mouth 
Oropharyngeal swelling 
Periorbital oedema 
Pharyngeal oedema 
Pharyngeal ulceration 
Pruritus allergic 
Rash generalized 
Skin swelling 
Swelling 
Swelling face 
Swollen tongue 
Tongue oedema 
Tracheal oedema 
Urticaria 
Note: The following terms listed in Feltes TF’s manuscript are LLTs that code into PTs as follows: 
LLT: Angioneurotic oedema codes to PT: Angioedema 
LLT: Fixed Eruption codes to PT: Fixed Drug Eruption 
LLT: Urticaria generalized codes to PT: Urticaria 


Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol: R2222-RSV-1332 
Date: Aug 9, 2016 
CONFIDENTIAL 
Page 33 of 34 
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10.4. 
Criteria for Treatment-Emergent Potentially Clinically Significant 
Values (PCSV) 
Parameter 
PCSV 
Comments 
Clinical chemistry 
PCSV based on criteria for infants born at term, except for total bilirubin where specific criteria are 
available for pre-term infants, considering Grade 3 Severe and above events as per the Division of AIDS 
(DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events Version 2.0 November 
2014). 
ALT, high 
≥ 5 ULN and baseline < 5 ULN 
Albumin, low 
< 20 g/L and baseline ≥ 20 g/L 
AST, high 
≥ 5 ULN and baseline < 5 ULN 
Alkaline 
Phosphatase, 
high 
≥ 5 ULN and baseline < 5 ULN 
Calcium, high 
Meeting the following PCSV criteria for at least 
one post-baseline measurement and no PCSV at 
baseline 
≥ 3.13 mmol/L for ≥ 7 days of age 
≥ 3.23 mmol/L for < 7 days of age 
Calcium, low 
Meeting the following PCSV criteria for at least 
one post-baseline measurement and no PCSV at 
baseline 
<1.75 mmol/L for ≥ 7 days of age 
<1.50 mmol/L for < 7 days of age 
Carbon 
Dioxide, low 
<11.0 mmol/L and baseline ≥ 11.0 mmol/L 
Creatinine, high 
> 1.8 ULN and baseline ≤ 1.8 ULN, or 
Increase of 1.5 x above baseline 
Total Bilirubin, 
high 
Meeting the following PCSV criteria for at least 
one post-baseline measurement and no PCSV at 
baseline 
≥ 171 µmol/L for 32 to < 35 weeks gestational 
age and < 7 days of age* 
≥ 102.6 µmol/L for 28 to < 32 weeks gestational 
age and < 7 days of age* 
≥ 85.5 µmol/L for < 28 weeks gestational age 
and < 7 days of age* 
≥ 342 µmol/L for 7 to 28 days of age* 
≥ 2.6 x ULN for > 28 days of age 
*Criteria are specific for preterm 
infants 
Glucose, high 
≥ 13.89 mmol/L and baseline < 13.89 mmol/L 
Glucose, low 
< 2.22 mmol/L and baseline ≥ 2.22 mmol/L 
Potassium, high 
≥ 6.5 mmol/L and baseline < 6.5 mmol/L 


Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol: R2222-RSV-1332 
Date: Aug 9, 2016 
vsv00061899-1.0 Approved - 12 Aug 2016 GMT-5:00 
 
 
 
Parameter 
PCSV 
Comments 
Potassium, low 
< 2.5 mmol/L and baseline ≥ 2.5 mmol/L 
Sodium, high 
≥ 154 mmol/L and baseline < 154 mmol/L 
Sodium, low 
< 125 mmol/L and baseline ≥ 125 mmol/L 
Uric acid, high 
≥ 0.71 mmol/L and baseline < 0.71 mmol/L 
Hematology 
PCSV based on criteria for infants born at term, considering Grade 3 Severe and above events as per the 
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
Version 2.0 November 2014). 
WBC, 
Decreased 
Meeting the following PCSV criteria for at least 
one post-baseline measurement and no PCSV at 
baseline 
≤ 1.499 x 109 cells/L for > 7 days of age 
≤ 3.999 x 109 cells/L for ≤ 7 days of age 
Neutrophils, 
low 
Meeting the following PCSV criteria for at least 
one post-baseline measurement and no PCSV at 
baseline 
< 0.600 x 109 cells/L for > 7 days of age 
< 1.000 x 109 cells/L for 2 to 7 days of age 
< 3.000 x 109 cells/L for ≤ 1day of age 
Hemoglobin, 
low 
Meeting the following PCSV criteria for at least 
one post-baseline measurement and no PCSV at 
baseline 
< 6.19 mmol/L for ≤ 7 days of age 
< 5.57 mmol/L for 8 to ≤ 21 days of age 
< 4.94 mmol/L for 22 to 35 days of age 
< 4.32 mmol/L for 36 to 56 days of age 
< 5.25 mmol/L for ≥ 57 days of age 
Platelets, 
decreased 
< 50.000 x 109 cells/L and baseline ≥ 50.000 x 
109 cells/L 
Vital signs 
PCSV based on normal ranges in http://health.ny.gov/professionals/ems/pdf/assmttools.pdf 
Respiratory 
Rate 
< 30 breaths per minute and ≥ 30 breaths per 
minute at baseline 
> 60 breaths per minute and ≤ 60 breaths per 
minute at baseline 
Pulse Rate 
< 100 beats per minute and ≥ 100 beats per 
minute at baseline 
> 160 beats per minute and ≤ 160 beats per 
minute at baseline 
 
 
 
 
 
 
CONFIDENTIAL 
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