A Randomized, Double-blind, Multicenter, Multiple-dose Study of ALX-0171 Versus Placebo Along With Standard of Care in Japanese Infants and Young Children Hospitalized for Respiratory Syncytial Virus Lower Respiratory Tract Infection
Phase: PHASE2
Conditions: Respiratory Syncytial Virus Lower Respiratory Tract Infection
Sponsor: Ablynx, a Sanofi company

 
 
 
 
 
CLINICAL STUDY PROTOCOL  
 
ALX0171-C203 
 
 
A randomized, double-blind, multicenter, multiple-dose study of 
ALX-0171 versus placebo along with standard of care in Japanese 
infants and young children hospitalized for respiratory syncytial 
virus lower respiratory tract infection 
 
 
 
Short Title: 
Evaluation of ALX-0171 in Japanese children 
hospitalized for RSV lower respiratory tract infection 
Investigational Product: 
ALX-0171 nebulizer solution 
Sponsor Protocol Code: 
ALX0171-C203 
Sponsor: 
Ablynx NV  
Technologiepark 21 
9052 Zwijnaarde, Belgium 
Phase of Development: 
Phase 2 
Indication: 
Treatment of RSV lower respiratory tract infection 
Study Center: 
Multicenter 
Protocol Date: 
13 November 2017 
Protocol Version: 
Version 3.0 
Protocol Status: 
Final 
 
This study will be performed in compliance with the Clinical Study Protocol, the principles of 
Japan - and International Council on Harmonization - Good Clinical Practice (ICH-GCP), and 
the applicable regulatory requirement(s). 
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Ablynx NV 
 
Clinical Study Protocol ALX0171-C203 
  
 
Final Version 3.0 
 
13 November 2017 
CONFIDENTIAL 
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CONFIDENTIALITY STATEMENT 
 
The information contained in this document, especially unpublished data, is the property of 
Ablynx NV (or under its control), and therefore provided to you in confidence as an 
Investigator, potential Investigator, or consultant, for review by you, your study staff, and 
applicable Institutional Review Board (IRB). It is understood that this information will not be 
disclosed to others without written authorization from Ablynx NV, except to the extent 
necessary to obtain informed consent from the parent(s)/legal guardian(s) of the persons to 
whom the study drug may be administered. 
 
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Clinical Study Protocol ALX0171-C203 
  
 
Final Version 3.0 
 
13 November 2017 
CONFIDENTIAL 
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APPROVAL OF CLINICAL STUDY PROTOCOL 
 
The Sponsor and the Investigator(s) agree to conduct the study as outlined in this Clinical 
Study Protocol. Any modification of the Clinical Study Protocol must be agreed upon by the 
Sponsor and the Investigator(s), and must be documented in writing. 
 
 
 
Sponsor: 
 
Name: 
 
Function: Senior Medical Director 
 
Signature – Date: See signature page at the end of the document 
 
 
 
 
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Clinical Study Protocol ALX0171-C203 
  
 
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13 November 2017 
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Investigator:  
 
 
 
 
 
 
I have read Clinical Study Protocol ALX0171-C203 and agree to personally 
conduct or supervise the clinical study in accordance with this Clinical 
Study Protocol, with the terms of the clinical trial agreement and with any 
other study procedures and documents provided by Ablynx NV. 
 
I agree to ensure that all associates, colleagues, and employees assisting 
in the conduct of the study are informed about their obligations. 
Mechanisms are in place to ensure that site staff receives the appropriate 
information throughout the study. 
 
I confirm that the study team and I will not implement any deviations from 
this Clinical Study Protocol without agreement of Ablynx NV, except where 
necessary to eliminate an immediate hazard to the patients. 
 
I confirm that I am thoroughly familiar with the appropriate use of the 
study drug, as described in this Clinical Study Protocol and any other 
information provided by Ablynx NV. 
 
I confirm that I am aware of and will comply with Japan- and ICH-GCP and 
all applicable national and regional regulations/guidelines.  
 
Hence, I agree to supply Ablynx NV with any necessary information 
regarding the ownership interest and financial ties, to promptly update this 
information if any relevant changes occur during the course of the study 
and for one year following completion of the study, and that Ablynx NV 
may disclose any available information about such ownership interest and 
financial ties to regulatory authorities. 
 
Principal Investigator Name: 
 
 
 
Site details/Address: 
 
 
 
Signature – Date: 
 
 
 
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13 November 2017 
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SERIOUS ADVERSE EVENT CONTACT 
INFORMATION 
 
Contact details of the Sponsor and third parties are available in the “Investigator Site File”.  
 
 
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TABLE OF CONTENTS 
CONFIDENTIALITY STATEMENT .............................................................................. 2 
APPROVAL OF CLINICAL STUDY PROTOCOL ........................................................... 3 
SERIOUS ADVERSE EVENT CONTACT INFORMATION .............................................. 5 
TABLE OF CONTENTS .............................................................................................. 6 
LIST OF TABLES ..................................................................................................... 9 
LIST OF FIGURES ................................................................................................... 9 
LIST OF ABBREVIATIONS AND DEFINITIONS ........................................................10 
CHANGES COMPARED TO PREVIOUS VERSION(S) .................................................12 
PROTOCOL SYNOPSIS ...........................................................................................13 
SCHEDULE OF ASSESSMENTS ................................................................................24 
1. 
INTRODUCTION .............................................................................................27 
1.1. TREATMENT OF RSV LRTI ............................................................................27 
1.2. ALX-0171 ....................................................................................................27 
1.2.1. 
Pharmaceutical Properties .................................................................... 28 
1.2.2. 
Nonclinical Studies .............................................................................. 29 
1.2.3. 
Effects in Humans ............................................................................... 30 
1.3. SAFETY PROFILE AND BENEFIT-RISK ASSESSMENT ....................................32 
1.3.1. 
Nonclinical Results .............................................................................. 32 
1.3.2. 
Clinical Safety Results ......................................................................... 33 
1.3.3. 
Potential Risks .................................................................................... 33 
1.3.4. 
Potential Benefits ................................................................................ 35 
1.3.5. 
Conclusion ......................................................................................... 36 
2. 
OBJECTIVES ...................................................................................................37 
3. 
STUDY DESIGN ..............................................................................................37 
3.1. OVERALL STUDY DESIGN .............................................................................37 
3.1.1. 
Study Overview .................................................................................. 37 
3.1.2. 
Study Rationale and Discussion of Study Design ..................................... 40 
3.1.3. 
Blinding ............................................................................................. 44 
3.2. SELECTION OF STUDY POPULATION ............................................................45 
3.2.1. 
Inclusion Criteria ................................................................................ 45 
3.2.2. 
Exclusion Criteria ................................................................................ 46 
3.3. TREATMENT OF SUBJECTS ...........................................................................48 
3.3.1. 
Overview of Treatments Administered ................................................... 48 
3.3.2. 
Selection of Doses in the Study ............................................................ 49 
3.3.3. 
Identity of Study Drug ......................................................................... 51 
3.3.4. 
Study Drug Administration ................................................................... 53 
3.3.5. 
Drug Accountability ............................................................................. 56 
3.3.6. 
Study Drug Handling ........................................................................... 57 
3.3.7. 
Concomitant Therapy .......................................................................... 58 
3.3.8. 
Treatment Compliance ......................................................................... 59 
3.4. WITHDRAWAL AND DISCONTINUATION CRITERIA .....................................60 
3.4.1. 
Withdrawal from the Study .................................................................. 60 
3.4.2. 
Discontinuation of Study Drug .............................................................. 60 
3.5. STUDY TERMINATION .................................................................................61 
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3.6. STUDY ASSESSMENTS ..................................................................................62 
3.6.1. 
Timing of Assessments ........................................................................ 62 
3.6.2. 
Baseline Characteristics ....................................................................... 65 
3.6.3. 
Safety Assessments ............................................................................ 66 
3.6.4. 
Pharmacokinetic Assessments .............................................................. 70 
3.6.5. 
Antiviral Effect Assessments ................................................................. 70 
3.6.6. 
Clinical Activity Assessments ................................................................ 72 
3.6.7. 
Parent/Caregiver Assessments ............................................................. 73 
3.6.8. 
Immunogenicity Assessments ............................................................... 73 
3.6.9. 
Pharmacodynamic Assessments ............................................................ 74 
3.6.10. 
Total Blood Volume ............................................................................. 74 
3.6.11. 
Appropriateness and Timing of Measurements ........................................ 76 
4. 
ADVERSE EVENT EVALUATION AND REPORTING ............................................77 
4.1. ADVERSE EVENTS ........................................................................................77 
4.1.1. 
Definitions ......................................................................................... 77 
4.1.2. 
Recording of Adverse Events ................................................................ 79 
4.1.3. 
AE Assessments .................................................................................. 80 
4.1.4. 
Recording of SAEs ............................................................................... 82 
4.1.5. 
Notification of SAEs to Sponsor ............................................................. 83 
4.1.6. 
SUSAR Notification Process .................................................................. 84 
4.2. OTHER REPORTABLE INFORMATION............................................................85 
4.2.1. 
Medication Errors ................................................................................ 85 
4.2.2. 
Medical Device Issues .......................................................................... 85 
5. 
STATISTICS ...................................................................................................86 
5.1. STUDY POPULATIONS ..................................................................................86 
5.2. STATISTICAL AND ANALYTICAL PLAN .........................................................86 
5.3. DEMOGRAPHICS AND BASELINE CHARACTERISTICS ...................................86 
5.4. EVALUATION OF SAFETY .............................................................................87 
5.5. EVALUATION OF PK .....................................................................................87 
5.6. EVALUATION OF ANTIVIRAL EFFECT ...........................................................88 
5.7. EVALUATION OF CLINICAL ACTIVITY ..........................................................88 
5.8. EVALUATION OF IMMUNOGENICITY ............................................................89 
5.9. EVALUATION OF PD .....................................................................................89 
6. 
DATA QUALITY ASSURANCE AND DIRECT ACCESS TO SOURCE 
DATA/DOCUMENTS ........................................................................................90 
7. 
DATA PROTECTION ........................................................................................91 
8. 
ETHICS ..........................................................................................................92 
8.1. ETHICAL APPROVAL ....................................................................................92 
8.2. ETHICAL CONDUCT OF THE STUDY ..............................................................92 
8.3. SUBJECT INFORMATION AND CONSENT ......................................................93 
8.4. PRIVACY ......................................................................................................94 
9. 
DATA HANDLING AND RECORD KEEPING .......................................................96 
9.1. DISTRIBUTION OF ACTIVITIES ...................................................................96 
9.2. DOCUMENTATION ........................................................................................96 
9.2.1. 
Case Report Form Completion .............................................................. 96 
9.2.2. 
Source Documentation ........................................................................ 96 
9.2.3. 
Record Retention ................................................................................ 97 
9.2.4. 
Monitoring ......................................................................................... 97 
10. FINANCING AND INSURANCE ........................................................................99 
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11. USE OF INFORMATION, REPORTING, AND PUBLICATION ............................100 
12. REFERENCES ................................................................................................101 
13. APPENDICES ................................................................................................103 
13.1. 
APPENDIX 1: RDAI AND RACS ........................................................103 
13.2. 
APPENDIX 2: GLOBAL SEVERITY SCORE.........................................104 
 
 
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LIST OF TABLES 
Table 1: 
Study drug nebulizer filling volumes and nebulization times by dose ......... 54 
Table 2: 
Timing, priority and estimated volume of scheduled blood draws .............. 75 
 
 
LIST OF FIGURES 
Figure 1: 
Schematic representation of ALX-0171 Nanobody ................................... 28 
Figure 2: 
ALX0171-C203 – Study Design ............................................................. 38 
Figure 3: 
ALX0171-C203 - Study Flow ................................................................. 39 
Figure 4: 
Comparison of observed and extrapolated ALX-0171 plasma concentration in 
pediatric population with adult observed Cmax at 200 mg QD and 105 mg BID 
repeated dose .................................................................................... 50 
Figure 5: 
Overview of the FOX-Flamingo inhalation system .................................... 52 
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LIST OF ABBREVIATIONS AND 
DEFINITIONS 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
AR 
Adverse reaction 
ATC 
Anatomical therapeutic chemical 
AUC 
Area under the curve 
BID 
Twice a day (bis in die) 
BQL 
Below the limit of quantification 
CE 
Conformité Européene 
CL/F 
Apparent clearance 
Cmax 
peak plasma concentration 
cPAP 
Continuous positive airway pressure 
CRO 
Contract research organization 
CSR 
Clinical Study Report 
DAP 
Data analysis plan 
DIN 
Deutsches Institut für Normung (German Institute For Standardization) 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EOS 
End of Study 
F protein 
Fusion protein 
FDA 
Food and Drug Administration 
FU 
Follow-up 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HFOT 
High-flow oxygen therapy 
HIV 
Human immunodeficiency virus 
i.v. 
Intravenous 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council on Harmonization 
ICU 
Intensive care unit 
ID 
Identification 
IDMC 
Independent Data Monitoring Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
IWRS/IVRS 
Interactive web/voice response system  
KL-6 
Krebs von den Lungen-6 
LBA 
Ligand binding assay 
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Legal guardian(s) Authorized representative(s) for the subject, according to local 
legislation 
LRTI 
Lower respiratory tract infection 
LSLV 
Last visit of the last subject 
LTRA(s) 
Leukotriene Receptor Antagonist(s) 
mAb 
Monoclonal antibody 
MD 
Doctor of Medicine 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHLW 
Ministry of Health, Labour and Welfare 
mITT 
Modified Intent-to-treat  
mRNA 
Messenger ribonucleic acid 
N 
Number of subjects 
NAb 
Neutralizing anti-drug antibodies 
PBPK 
physiologically based pharmacokinetic (model) 
pCO2 
partial pressure of carbon dioxide 
PCR 
Polymerase Chain Reaction 
PD 
Pharmacodynamic 
PFU 
Plaque forming unit  
PK 
Pharmacokinetic(s) 
PMDA 
Pharmaceuticals and Medical Devices Agency 
Pre-Ab 
Pre-existing antibodies 
QD 
once a day (quaque die) 
qPCR 
quantitative polymerase chain reaction 
RACS 
Respiratory Assessment Change Score 
RDAI 
Respiratory Distress Assessment Instrument 
RNA 
Ribonucleic acid 
RSV 
Respiratory syncytial virus 
RT-qPCR 
real-time (quantitative) polymerase chain reaction 
SAE 
Serious adverse event 
SAINT 
Sophia anatomical infant nose-throat 
SAP 
Statistical analysis plan 
SAR 
Serious Adverse Reaction 
SmPC 
Summary of Product Characteristics 
SpO2 
Peripheral capillary oxygen saturation 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TE 
Treatment-emergent 
TE ADA 
Treatment-emergent anti-drug antibodies 
TEAE(s) 
Treatment-emergent adverse event(s) 
VAS 
Visual Analogue Scale 
WHO 
World Health Organization 
 
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CHANGES COMPARED TO PREVIOUS 
VERSION(S) 
 
Protocol version 1.0 was not submitted for approval to any Regulatory Authority or 
Institutional Review Board (IRB)/Ethics Committee. Version 1.0 was provided to potential 
Investigators and clinical sites for initial review and feasibility evaluation only. Minor 
corrections were made in protocol version 2.0.   
 
Global Version 3.0 (dated 13 November 2017) compared to Global Version 2.0 (dated 5 September 
2017). This amendment is considered substantial as new exclusion criteria and screening assessments 
were added to the study following the request of the Pharmaceuticals and Medical Device Agency 
(PMDA) Japan. 
Version n° and date were adapted throughout the document (including headers and footers). The Table of Contents 
was updated. The section “Changes Compared to Previous Version(s)” was updated with the changes of the current 
amendment, use of abbreviations and the abbreviations list had minor updates stemming from the amendment 
changes.  
Section affected 
Change/ Rationale 
Schedule of 
Assessments;  
Section 3.6.1.2. 
The Schedule of Assessments underwent the following change: 
12-lead ECG was added as an additional screening assessment. 
As such this was also added to assessments performed at screening. 
Synopsis, Exclusion 
criteria 
Section 3.2.2. 
There was an exclusion criterion added to perform and assess a 12-lead ECG at screening 
for any clinically significant abnormalities that would not allow the subject to be included 
according to the Investigators’ judgement.  
An additional criterion was added to exclude subjects considered ineligible for participating 
in the trial for safety reasons or any other concerns of the Investigator. 
Section 4.1.6. 
Added reporting deadlines for SUSAR expedited reporting to PMDA, IRB and Investigator.  
 
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PROTOCOL SYNOPSIS 
 
Protocol title 
  
A randomized, double-blind, multicenter, multiple-dose study of ALX-0171 versus placebo 
along with standard of care in Japanese infants and young children hospitalized for 
respiratory syncytial virus lower respiratory tract infection 
 
 
Protocol short title 
  
Evaluation of ALX-0171 in Japanese children hospitalized for respiratory syncytial virus 
(RSV) lower respiratory tract infection 
 
 
Investigational product 
  
ALX-0171 nebulizer solution 
 
The active pharmaceutical ingredient is ALX-0171 Nanobody, a therapeutic protein directed 
against the fusion protein of the human RSV. 
 
 
Sponsor Protocol Code 
  
ALX0171-C203 
 
 
Sponsor 
  
Ablynx NV  
Technologiepark 21 
9052 Zwijnaarde, Belgium 
 
 
Phase of Development 
  
Phase 2 
 
 
Indication 
  
Treatment of RSV lower respiratory tract infection 
 
 
Study centre 
  
Multicenter 
 
 
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Objectives 
 
 To evaluate the safety, tolerability and systemic pharmacokinetics (PK) of different doses 
of inhaled ALX-0171 in Japanese infants and young children hospitalized for RSV LRTI. 
 To evaluate the antiviral effect, clinical activity, immunogenicity, and pharmacodynamics 
(PD) of different doses of inhaled ALX-0171 in Japanese infants and young children 
hospitalized for RSV LRTI. 
 
 
Study Design 
 
This is a randomized, double-blind, multicenter, multiple-dose study of ALX-0171 versus 
placebo along with standard of care. The study population will consist of 60 Japanese infants 
and young children aged 28 days to <2 years with a gestational age ≥ 33 weeks who are 
hospitalized for and diagnosed with RSV LRTI. Four dose levels are planned to be evaluated 
in four consecutive cohorts: 
 
 Dose level 1: target dose of 1.5 mg/kg 
 Dose level 2: target dose of 3.0 mg/kg 
 Dose level 3: target dose of 6.0 mg/kg 
 Dose level 4: target dose of 9.0 mg/kg 
 
Each dose level has the potential to be of benefit to the subjects. The study will provide 
information on safety, tolerability, PK, antiviral effect, clinical activity, immunogenicity, and 
PD across a relevant range, and is intended to support selection of an optimal dose of 
ALX-0171 for further clinical development, taking ethnicity into consideration.  
 
 The starting dose level is the same dose level evaluated in the first-in-infant study, 
ALX0171-C104, which was conducted outside of Japan. In total, 53 infants and young 
children hospitalized for RSV LRTI were enrolled. The results of study ALX0171-C104 
indicated that this dose was well tolerated in all age groups (28 days to 24 months). 
Reductions in nasal viral load (obtained from nasal swabs) were noted, confirming that 
ALX-0171 exhibits antiviral activity. 
 Dose levels 2, 3 and 4 are the same as those currently being evaluated in the Phase 2b 
dose-ranging study ALX0171-C201, which is being conducted outside of Japan (N=180 
infants and young children hospitalized for RSV LRTI).  
 
Each cohort will consist of 15 subjects enrolled and randomly assigned to receive ALX-0171 
or placebo, in an allocation ratio of 4:1 (N=12 active versus N=3 placebo per dose level). 
Study drug will be administered once daily for 3 consecutive days and will be given along 
with standard of care treatment, which will be determined by the Investigator according to 
institutional practice (taking into account the prohibited medications listed in section 3.3.7). 
The 3-day treatment period is expected to bridge the time needed for the body to mount an 
effective immune response. 
 
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IDMC=Independent Data Monitoring Committee 
 
 
After the last subject in a cohort has completed his/her treatment period or has 
discontinued study drug, an Independent Data Monitoring Committee (IDMC) consisting of 
an independent group of clinical experts, will review the cumulative unblinded safety data 
(i.e., all available data for all included subjects, including preceding cohorts) and advise the 
Sponsor on proceeding to the subsequent cohort (i.e., the next higher dose). The 
participants, objectives, and roles and responsibilities of the IDMC will be described in an 
IDMC Charter. Recruitment will be paused while the IDMC reviews the data of each cohort. 
Serious adverse event (SAE) information will be communicated to the IDMC in real time 
throughout the study, as per the IDMC Charter. An ad-hoc meeting can be requested by the 
IDMC members at any time. 
 
In addition to the individual discontinuation criteria (see section 3.4), criteria for stopping or 
pausing recruitment in each cohort and criteria to stop dose escalation will apply (see 
section 3.1.1).  
 
 
Study Flow 
 
Upon signing of the Informed Consent Form by the parent or legal guardian, subjects will be 
screened as soon as possible after arrival at the hospital/emergency unit. 
 
 After completion of the screening assessments and confirmation of subject’s eligibility, 
randomization should follow as soon as possible but not longer than 24 hours after arrival 
at the hospital/emergency unit.  
 Subjects will receive once-daily doses of study drug on 3 consecutive days. Study drug 
administration should start as soon as possible after randomization with a maximum time 
interval of 3 hours following randomization. Subsequent doses of study drug will be 
administered at 24-hour intervals (±4 hours) relative to the first dose. No pre-medication 
is required per protocol, but an inhaled β2-agonist may be administered at the discretion 
of the treating Investigator.  
 During the 3 treatment days, inpatient hospital stay is required.  
 Discharge from the hospital can take place per protocol at the Investigator’s discretion 
from dosing on Day 3 onwards, after all required assessments of the 5 hours (±1 hour) 
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post-dose time point have been completed and provided that the clinical response criteria 
have been met. Subjects who are not discharged from the hospital after completion of 
the treatment period will enter an in-hospital post-treatment period with assessments in 
the morning and evening until discharged. 
 A Follow-Up (FU) visit is scheduled on Day 14 (±2 days), and an End of Study (EOS) visit 
on Day 28 (±2 days).  
 In case a subject is re-hospitalized, or when the Investigator is consulted for a 
respiratory condition occurring after discharge from the hospital, an Unscheduled Visit is 
to be performed. In such cases, a mid-turbinate nasal swab is to be collected and a 
physical examination, including lung auscultation, must be performed. In addition, 
Unscheduled Visits may be conducted to assess or follow-up on AEs or laboratory 
abnormalities. In such cases, the evaluations performed are at the discretion of the 
Investigator. 
 For subjects prematurely withdrawn from the study, a Withdrawal visit is to be performed 
on the day of withdrawal.  
 Subjects who discontinue study drug (for any reason) but remain hospitalized will enter 
the in-hospital post-treatment period and will be followed up twice daily (in the morning 
and the evening) until they are discharged from the hospital. They should also attend the 
FU and EOS visit. 
 
After the end of the subject’s participation in the study, each subject is to be treated 
according to standard clinical practice.  
 
 
*Or withdrawal visit at earlier time point in case of withdrawal 
**Hospital discharge is allowed from Day 3 once all post-dose assessments have been completed and clinical response 
criteria have been met. 
 
 
Study Duration 
 
 The overall study duration is expected to be approximately 12 months.  
 The planned study duration for each subject is approximately 28 days.  
 The maximum study drug treatment duration for each subject is 3 days. 
 The completion of the study is defined as the last visit of the last subject (LSLV) 
participating in the study.  
** 
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Study Population 
 
Japanese infants and young children aged 28 days to <2 years with a gestational age 
≥ 33 weeks, hospitalized for and diagnosed with RSV LRTI (but otherwise healthy). 
 
 
Number of Subjects 
 
A total of 60 subjects will be randomized and treated in the study. 
 
 
Inclusion Criteria 
 
A subject will be eligible for study participation if he/she meets all of the following criteria at 
screening and randomization, unless specified otherwise. 
 
1. 
Subject is a Japanese male or female infant or young child aged 28 days to <2 years 
with gestational age ≥ 33 weeks at screening. 
2. 
Subject is of Japanese descent, i.e., born in Japan to Japanese parents and has 
Japanese maternal and paternal grandparents. 
3. 
Subject weighs between ≥ 3.0 kg and <15.0 kg at screening.  
4. 
Subject is otherwise healthy, but is hospitalized for and clinically diagnosed with RSV 
LRTI (bronchiolitis or broncho-pneumonia), i.e., showing typical clinical signs and 
symptoms such as tachypnea, wheezing, cough, crackles, use of accessory muscles 
and/or nasal flaring.  
5. 
Subject has a positive RSV diagnostic test within 4 days of screening.*  
6. 
Subject is expected to have to stay in the hospital for at least 24 hours (according to 
the Investigator’s judgment at screening).  
7. 
Symptoms likely related to RSV infection (i.e., the symptoms present need to be 
probably linked to the current RSV infection according to Investigator’s judgment) have 
appeared within 4 days of screening and are not yet improving at screening and 
randomization.  
8. 
Subject fulfils at least two of the following RSV disease severity criteria at screening and 
randomization:  
- Inadequate oral feeding that requires feeding support (i.e., nasogastric tube or 
intravenous [i.v.] line),  
- Inadequate oxygen saturation defined as:  
 Oxygen saturation (SpO2) < 95% on room air or  
 Requiring oxygen supplementation to maintain adequate oxygen saturation with 
documented pre-supplementation value < 95%  
- Signs of respiratory distress defined as:  
 Respiratory rate ≥ 50 breaths per minute in infants up to 12 months of age, and 
≥ 40 breaths per minute in children above 12 months and/ or  
 Moderate or marked respiratory muscle retractions  
                                                   
* RSV infection will be confirmed either according to routine site practice (PCR, immunofluorescence or diagnostic 
quick test), or using a Sponsor-provided commercial kit. 
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9. 
Subject has normal psychomotor development.  
10. Parent(s)/legal guardian(s) provide written informed consent in accordance with locally 
approved consent process at screening.  
11. The parent(s)/legal guardian(s) are able and willing to comply with the study protocol 
procedures.  
 
 
Exclusion Criteria 
 
Subjects meeting any of the following criteria at screening or randomization will not be 
eligible for study participation. 
 
1. 
Subject is known to have significant comorbidities including:  
- Genetic disorders (e.g., trisomy 21, cystic fibrosis),  
- Hemodynamically significant congenital heart disease (e.g., needing corrective 
therapy or inotropic support),  
- Bronchopulmonary dysplasia,  
- Any hereditary or acquired metabolic (bone) diseases,  
- Hematologic or other malignancy.  
2. 
Subject is known to be human immunodeficiency virus (HIV)-positive. If the subject is 
< 6 months of age, known HIV-positivity of the mother is also exclusionary.  
3. 
Subject is known to be immunocompromised.  
4. 
Subject has or is suspected to have an active, clinically relevant concurrent infection 
(e.g., bacterial pneumonia, urinary tract infection). Concurrent acute otitis media is not 
exclusionary.  
5. 
Subject has significant oral and/or maxillofacial malformations which would prevent 
proper positioning of the face mask.  
6. 
Subject received invasive mechanical ventilation or non-invasive respiratory support 
(i.e., continuous or bilevel positive airway pressure) in the 4 weeks prior to screening.  
7. 
During the current admission, subject is initially hospitalized in an intensive care unit 
(ICU) setting and/or received invasive mechanical ventilation or non-invasive 
respiratory support (i.e., continuous or bilevel positive airway pressure).  
8. 
Subject is critically ill and/or is expected to require invasive mechanical ventilation, 
non-invasive respiratory support (i.e., continuous or bilevel positive airway pressure), 
or high-flow oxygen therapy (HFOT) at levels not enabling nebulization therapy 
according to the Investigator’s judgment. High Flow oxygen, with a maximum flow of 
2 L/kg/min, is permitted under the following conditions:  
- used as Standard of Care outside ICU setting  
- can be removed for study drug administration (Note: oxygen flow at 2 L/minute can 
be provided through the nebulizer)  
9. 
Subject has received 1 or more doses of palivizumab or treatment or prophylaxis with 
any RSV antiviral compound (e.g., ribavirin, i.v. immunoglobulin, or any investigational 
drug or vaccine for RSV [including subject’s mother who has been vaccinated against 
RSV]) at any time prior to screening.  
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10. Subject is required to continue or start systemic corticosteroid therapy. Subject on a 
maintenance therapy of inhaled corticosteroids will continue this treatment at the usual 
dose. Topical corticosteroids for skin disorders are permitted.  
11. Subject has clinically meaningful abnormalities on a 12-lead ECG, which according to 
the Investigator’s judgement does not allow participation of the subject in the study. A 
12-lead ECG performed within 4 days of screening will be acceptable. If not yet 
available, the 12-lead ECG should be performed at the time of screening. 
12. Subject is a child in care (i.e., a child who has been placed under the control or 
protection of an agency, organization, institution or entity by the courts, the 
government or a government body, acting in accordance with powers conferred on 
them by law or regulation). A child in care can thus include a child cared for by foster 
parents or living in a care home institution, provided that the arrangement falls within 
the definition above, but does not include a child who is adopted or has appointed legal 
representative(s).  
13. Subject is currently participating in any other study with investigational drug or has 
received an investigational drug within 4 weeks or 5 half-lives of the concerned drug 
(whichever is longer) prior to screening.  
14. Subject was previously enrolled in a clinical study of ALX-0171 (including the current 
Study ALX0171-C203).  
15. Subject has a known hypersensitivity to the study drug or any excipient of the study 
drug. 
16. Subject is considered by the Investigator to be ineligible to participate in the trial for 
safety reasons or any other concern. 
 
 
 
Study Medication 
 
Investigational Product 
  
 Name: ALX-0171 (nebulizer solution).  
 Active substance: ALX-0171 Nanobody.  
 Activity: ALX-0171 Nanobody specifically and potently binds to the RSV F protein, 
thereby inhibiting an early step in the viral replication cycle.  
 Composition: 
 
  
 
Reference Product 
  
 Name: Matching placebo (nebulizer solution).  
 Active substance: None.  
 Composition: 
 
  
 
Device 
  
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 Name: FOX-Flamingo inhalation system - CE marked.  
 Main components: re-usable single-patient base unit (containing the electronics), single-
use disposable inhalation set (including pediatric face mask in 2 sizes, mask adapter, 
vibrating mesh nebulizer with reservoir).  
 Description: The FOX-Flamingo inhalation system consists of a battery-operated, 
hand-held device, intended for single-patient use. The device provides an aerosol with 
particle size suitable for the intended study population. The nebulizer is always to be 
used with a flow of 2 L/minute additional air or oxygen.  
 
Standard of Care  
  
 The treatment and care provided to each subject are determined by the Investigator (or 
designee) according to institutional practice (taking into account the prohibited 
medications listed in section 3.3.7). The recommendations on the diagnosis, 
management, and prevention of bronchiolitis as described by the American Academy of 
Pediatrics (2014) [1], may be followed in addition to institutional practice. 
 Treatment may include (but is not limited to) the following:  
- Oxygen supplementation through nasal cannula, via face mask or headbox. The 
initiation, monitoring and weaning of oxygen supplementation will follow local practice. 
It should be removed for the nebulized study drug administration, during which air or 
oxygen flow of 2 L/minute is provided  
- Fluid/food supplementation (i.v. or via nasogastric tube, if applicable)  
- Antipyretics and/or nonsteroidal anti-inflammatory medication  
- Inhalation of hypertonic saline (but not within 4 hours before start or 4 hours after the 
end of study drug administration)  
- Short acting β2-agonists  
- Antibiotics (in case of secondary bacterial infection) 
- Epinephrine  
- Anticholinergics  
 
Concomitant and Prohibited Medications 
  
Apart from those listed under the prohibited therapies, concomitant medications are 
permitted at the Investigator’s discretion (based on medical need).  
 
The following treatments are prohibited up to the FU visit (Day 14 ±2 days):  
 
 Ribavirin, i.v. immunoglobulin and palivizumab  
 Heliox  
 Leukotriene receptor antagonists (LTRAs, i.e. montelukast) and/or sodium cromoglycate; 
initiation of LTRAs and/or sodium cromoglycate is not permitted; infants who are on a 
maintenance therapy at screening are to continue their usual dose during the study 
 Exogenous surfactant   
 Systemic corticosteroids; initiation of inhaled corticosteroids is not permitted; infants who 
are on a maintenance therapy of inhaled corticosteroids at screening are to continue their 
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usual dose during the study. Of note, topical corticosteroids for the treatment of skin 
disorders are permitted.  
 Mucolytics are permitted until screening but their continuation or initiation during the 
study is not allowed.  
 
 
Assessments 
 
Demographic and medical history data (including RSV-related signs and symptoms) will be 
collected at screening. Collected data will include (but are not limited to): month and year 
of birth, age (with indication of week), gender, race and ethnicity. Data on atopy in the 
family, environmental exposure to tobacco and pets, and breastfeeding will also be 
collected. A 12-lead ECG will be performed to assess eligibility. 
 
The mid-turbinate nasal swab sample collected pre-dose on Day 1 will be used to test for 
concurrent viruses and the presence of mycoplasma at baseline. Safety Outcome Measures 
  
 Treatment-emergent adverse events (TEAEs), as noted by healthcare staff and/or 
reported by parents/caregivers. The Investigator (or his/her designee) will review at each 
visit whether AEs/serious adverse events (SAEs) have occurred since the last visit.  
 Heart rate, respiratory rate (measured over a 1-minute interval) and SpO2.  
 Body temperature and body weight. 
 Physical examination including the skin, ears/nose/throat, heart auscultation, lung 
auscultation, and abdomen.  
 Safety lab assessments are planned two times during the study (at screening and at the 
FU visit) and will be performed by the local laboratory in order to allow timely availability 
of the results. The following clinical laboratory test results will be evaluated:  
- 
Clinical chemistry: alanine aminotransferase, aspartate aminotransferase, creatinine, 
sodium, potassium, chloride, C-reactive protein, γ-glutamyl-transferase, blood urea 
nitrogen  
- 
Hematology: hemoglobin, hematocrit, red blood cell count and indices, mean 
corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count 
(or estimate), white blood cell count including differential (lymphocytes, neutrophils, 
monocytes, basophils, eosinophils). 
 
PK Outcome Measures 
  
 The systemic concentration of ALX-0171 will be evaluated in serum.  
 
Antiviral Effect Outcome Measures 
  
 Quantification of viral titers (in mid-turbinate nasal swab samples) over time.  
 
Clinical Activity Outcome Measures†  
                                                   
† The evaluation of several of these parameters will also inform on safety outcome.  
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 Heart rate, respiratory rate (measured over a 1-minute interval) and SpO2.  
 Feeding: type of feeding support, and (time and date of) sufficient feeding to allow for 
hospital discharge, in the opinion of the Investigator (with particular attention to 
hydration and breathing comfort during feeding)  
 Wheezing as assessed during lung auscultation  
 Cough during the night and during the day  
 Respiratory muscle retractions (supraclavicular, intercostal, and subcostal)  
 General appearance: activity, irritation, and responsiveness  
 Body temperature and body weight  
 Occurrence of apnea episodes 
 
Medical Interventions Outcome Measures†  
 
 Length of hospital stay for RSV infection  
 Level, method, and duration of supplemental oxygen therapy  
 Initiation of invasive or non-invasive ventilation (e.g., continuous positive airway 
pressure [cPAP] or HFOT)  
 Level, method and duration of invasive or non-invasive ventilation 
 Transfer to ICU and duration of stay in ICU 
 
The clinical impact of treatment by ALX-0171 in infants and young children will be evaluated 
by changes in clinical symptoms (SpO2, feeding, respiratory rate, wheezing, cough, 
respiratory muscle retractions, and general appearance) and subsequent calculation of 
composite scores (Global Severity Score, Respiratory Distress Assessment Instrument 
[RDAI] score, and Respiratory Assessment Change Score [RACS]), the time needed to 
enable adequate feeding and oxygen saturation (clinical response) to allow for hospital 
discharge, need for medical interventions and length of hospital stay. 
 
Parent/Caregiver Outcome Measures 
   
Parent(s)/caregiver(s) assessment of the clinical condition of the child will be done by daily 
completion of a diary during the hospital stay and up to the EOS (Day 28) visit. This diary 
includes scoring of respiratory symptoms (cough, wheezing, trouble breathing) over the 
preceding 24 hours, evaluating the general health of the child by completing a Visual 
Analogue Scale (VAS), and answering a question as to whether the child has returned to 
his/her normal condition from before the onset the RSV infection. For the period after 
discharge from the hospital, this diary will also allow to capture data on health care 
utilization and use of medication for respiratory symptoms.  
 
Immunogenicity  
  
Systemic presence (serum) of anti-drug antibodies (ADA). 
 
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PD Outcome Measures 
  
Exploratory evaluation of the biomarker Krebs von den Lungen-6 (KL-6) in serum. 
 
Statistics 
 
Sample size 
  
A total of 60 subjects will be randomized and treated in this study. The sample size was 
selected to provide sufficient safety and tolerability experience with ALX-0171 in this 
population, to confirm the safety profile reported in the studies conducted outside of Japan. 
The sample size provides sufficient precision on the PK parameters as described by Wang et 
al., 2012‡, and is expected to be informative on antiviral and clinical activity of ALX-0171 
(descriptive analysis).  
 
Statistical Analysis 
 
Data will be summarized by descriptive statistics as applicable (number of observations, 
mean, standard error, median, minimum and maximum for most continuous data; 
frequencies and percentages of categorical data, as appropriate). For time-to-event 
measures, the number and percentage of subjects achieving the event will be summarized 
by treatment. Kaplan-Meier estimates for the time-to-event will be presented for each 
treatment group.  
 
Analysis of all parameters will be described in a Statistical Analysis Plan (SAP) and a Data 
Analysis Plan (DAP; for PK analysis), which will be finalized prior to database lock, and will 
comprise all methods applied for analysis of the corresponding data. There will be no interim 
analysis performed in this study. 
                                                   
‡ Wang, Y., et al., Clarification on precision criteria to derive sample size when designing pediatric pharmacokinetic 
studies. Journal of clinical pharmacology, 2012. 52(10): p. 1601-6 
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SCHEDULE OF ASSESSMENTS 
Period 
 
Visit 
Screening a b 
Study Drug Treatment Period c 
In-
hospital 
Post-
Treatm. 
Period d 
FU Visit 
(Day 14  
± 2) 
or 
Withdrawal 
Visit 
EOS e 
(Day 
28±2) 
Hospitalized Dosing 
Morning 
and 
Evening 
Day 1 
Day 2 
Day 3 
Time window /  
Study procedure 
-24h to 
randomization 
-3h a 
to dose 
Dose 
2h 
(± 0.5h) 
5h 
(±1h) 
-2h 
to dose 
Dose 
2h 
(± 0.5h) 
5h 
(±1h) 
-2h 
to 
dose 
Dose 
2h 
(±0.5h) 
5h 
(±1h) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RSV diagnosis f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Previous medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalization info. g 
 
Study drug admin. i 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Nasal mid-turbinate swab j 
 
Xj 
 
 
X 
X 
 
 
X 
X 
 
 
X 
 X k 
X 
 
Physical examination l 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
X 
X 
Body weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Body height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body temperature 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
General appearance 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
Lung auscultation o 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
Heart rate 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
SpO2 m 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
Feeding n 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
Respiratory muscle retractions 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
Respiratory rate 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
Randomization 
 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical response  
information h 
 
 
 
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Period 
 
Visit 
Screening a b 
Study Drug Treatment Period c 
In-
hospital 
Post-
Treatm. 
Period d 
FU Visit 
(Day 14  
± 2) 
or 
Withdrawal 
Visit 
EOS e 
(Day 
28±2) 
Hospitalized Dosing 
Morning 
and 
Evening 
Day 1 
Day 2 
Day 3 
Time window /  
Study procedure 
-24h to 
randomization 
-3h a 
to dose 
Dose 
2h 
(± 0.5h) 
5h 
(±1h) 
-2h 
to dose 
Dose 
2h 
(± 0.5h) 
5h 
(±1h) 
-2h 
to 
dose 
Dose 
2h 
(±0.5h) 
5h 
(±1h) 
Daytime coughing 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
Xp 
X 
X 
Sleep disturbance from night-
time coughing q 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Parent/caregiver  
assessment r 
 
Pharmacokinetics  
 
 
 
 
 
X s 
 
s 
      s 
 
 
 
 
 
 
 
Clinical laboratory 
(hematology and clinical 
biochemistry)  
Xt 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xu 
 
Immunogenicity v  
Xw 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xu,x 
 
Concomitant medications 
 
Adverse events y 
 
h=hour; FU=Follow-up; EOS=End of Study 
 
Timing of assessments: Pre-dose time points relate to the start of study drug administration procedure, post-dose time points relate to the end of the study drug 
administration procedure. Throughout the study, study personnel should make every reasonable effort to follow the timing in the schedule of assessments for each subject. 
 
a. At the time of screening, all screening assessments are to be performed. If Day 1 pre-dose timing occurs within 3 hours after screening, the assessments already done 
at screening do not need to be repeated; only the remaining Day 1 (pre-dose assessments) will need to be performed.  
b. At the time of randomization, subjects should be eligible for study participation as defined in the inclusion/exclusion criteria. Therefore, at a minimum, the SpO2, 
feeding, respiratory muscle retractions, and respiratory rate should be evaluated on Day 1 before randomization and dosing, unless these assessments were already 
performed within the last 3 hours before randomization. 
c. Study drug administration should take place within 24 hour intervals (±4 hours) relative to the start of the first dose. For subjects requiring 2 serial nebulizations 
(subjects weighing ≥10 kg in the 9 mg/kg dose group), the timing of study drug administrations should be relative to the start of their first nebulization. Provided that 
the clinical response criteria have been met, discharge from the hospital can take place per protocol at the Investigator’s discretion from dosing on Day 3 onwards after 
all required assessments of the 5 hours (±1 hour) post-dose time point have been completed. Subjects who started study drug dosing, but were discontinued 
prematurely from study drug treatment, should be further monitored according to the in-hospital post-treatment period (if applicable) and should attend the FU and EOS 
visits.  
d. The in-hospital post-treatment assessments are to be performed for subjects who are not discharged from the hospital after the completion or discontinuation of study 
drug treatment.  
e. For subjects who discontinue the study before Day 14, the Withdrawal visit will be conducted on the day of withdrawal as long as there has been no withdrawal of 
consent, subject is lost to follow-up or death. If the Withdrawal visit assessments are performed within 6 hours after the Day 1, Day 2, Day 3, or in-hospital post-
treatment day assessments have been performed, the assessments already done at the prior time point do not need to be repeated and only the additional assessments 
to be performed on the Withdrawal visit will need to be performed. No EOS visit needs to be performed after the Withdrawal visit. In case subjects are hospitalized 
beyond the Day 14 FU visit, the additional assessments (in addition to the in-hospital post-treatment period assessments) of the Day 14 FU visit need to be done on 
Day 14.  
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f. RSV infection will be confirmed either according to routine site practice (polymerase chain reaction [PCR], immunofluorescence or diagnostic quick test), or using a 
Sponsor-provided commercial kit.  
g. Hospitalization information will include occurrence of ICU transfer, apnea episodes, initiation and type of ventilation and hospital/ICU discharge information. 
h. Assessment of Clinical Response will be done with collection of date and time of adequate oral feeding, as well as stable adequate oxygen saturation on room air of 
≥ 95% over a period of at least 4 hours to allow for hospital discharge. 
i. 
Study drug will be administered via nebulization using the study-specific device.  
j. A mid-turbinate nasal swab should be taken using provided kits and following specific instructions. Collection of nasal swab samples from both nostrils is preferred. The 
nasal swab sample collected pre-dose on Day 1 will also be used to test for concurrent viruses and the presence of mycoplasma at baseline. Additionally, mid-turbinate 
nasal swab samples should be taken in case the subject is re-hospitalized or when the Investigator is consulted for a respiratory condition after hospital discharge.  
k. A mid-turbinate nasal swab should be collected during the in-hospital post-treatment period on the day of hospital discharge. A mid-turbinate nasal swab must also be 
taken in case the subject is re-hospitalized or when the Investigator is consulted for a respiratory condition after hospital discharge. Collection of nasal swab samples 
from both nostrils is preferred. 
l. 
Physical examination includes heart auscultation, examination of abdomen, skin and ears/nose/throat. Lung auscultation is listed separately as it is to be assessed more 
frequently.  
m. Continuous monitoring of SpO2 needs to be done until the clinical response criterion for oxygen has been met and/or in case saturation monitoring is to be continued 
according to the Investigator’s judgment.  
n. Type of feeding support, if any, and feasibility of oral feeding.  
o. To assess wheezing, crackles/crepitation and other abnormalities in lung auscultation.  
p. During the in-hospital post-treatment period, daytime coughing should only be recorded in the evening of the same day.  
q. Sleep disturbance from night-time coughing to be documented pre-dose the next day, or in the morning during the in-hospital post-treatment period, at the FU visit, 
EOS or Withdrawal visit, based on feedback from the nursing staff. In case there is no night between screening and study drug administration on Day 1, the Day 1 
assessment should not be performed.  
r. The parent/caregiver assessment should be performed for the first time at screening and afterwards every evening until the EOS visit by completing a diary. 
s. All subjects will undergo PK analysis sampling (3 PK samples per subject), i.e., blood draws on Days 2-3: 1) pre-second dose, 2) between 0.5 hours and 3 hours post-
second dose and at least 1 hour apart from the first sampling, and 3) between 3 hours and 6 hours post-second dose (and at least 1 hour apart from the previous 
sampling). If sufficient serum remains after PK assessment, exploratory biomarker (KL-6) may also be evaluated. 
t. If all hematology and biochemistry blood parameters required for the study are already known from analysis done as a routine assessment upon arrival at the hospital, 
collection of screening clinical laboratory samples does not need to be repeated for the purpose of this study. However, the samples should be analyzed at the same 
local laboratory that will be used for the remainder of the study. 
u. No blood sample needs to be taken in case of premature withdrawal from the study for subjects who did not receive any study drug. 
v. For subjects with a body weight below 5 kg and in case the blood volume needed for local clinical laboratory exceeds 2.5 mL, the sample for analysis of immunogenicity 
should not be collected at screening and on Day 14, but on Day 1 pre-dose and on Day 28, if possible. 
w. If sufficient serum remains after immunogenicity assessment, exploratory biomarker (KL-6) may also be evaluated. In case the blood sample for immunogenicity was 
not taken at screening, the sample should be collected at the Day 1 pre-dose time point, if possible.  
x. If sufficient serum remains after immunogenicity assessment, exploratory biomarker (KL-6) may also be evaluated. In case the blood sample for immunogenicity was 
not taken on Day 14, the sample should be collected at the EOS (Day 28) visit, if possible.  
y. An additional serum sample should be collected (if reasonably feasible) in case a serious and/or severe hypersensitivity reaction judged to be related to study drug 
occurs. 
 
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1. INTRODUCTION 
 
Respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) is a leading cause 
of bronchiolitis in infants and results in over 3 million hospitalizations worldwide per year. 
ALX-0171 is a therapeutic protein (Nanobody) that is currently being developed for the 
treatment of RSV LRTI. 
 
The antiviral effect of ALX-0171 is expected to provide rapid control of the infection, thereby 
reducing the intensity and duration of severe disease. The favorable in vitro potency of 
ALX-0171 Nanobody and the in vivo results obtained in nonclinical studies indicate that 
ALX-0171 may provide an opportunity for therapeutic intervention in established 
RSV infection. This is also supported by an initial clinical study in children hospitalized for 
RSV LRTI, where treatment with inhaled ALX-0171 had an immediate impact on viral 
replication and reduced viral load compared to placebo. 
 
1.1. TREATMENT OF RSV LRTI 
 
Nearly all infants are infected with RSV over the first years of life. RSV LRTI is associated 
with significant morbidity and mortality [1, 2]. RSV infection imposes a significant burden 
on health care infrastructure and there is a high unmet medical need for treatment options. 
Evidence-based guidelines indicate that there are no treatments that shorten the course of 
bronchiolitis or hasten the resolution of symptoms; supportive care (hydration and oxygen 
saturation) remains the cornerstone of clinical management [1, 3, 4]. 
 
1.2. ALX-0171 
 
Nanobodies are a novel class of therapeutic proteins, and are based on the smallest 
functional fragments of single-chain antibodies that occur naturally in the Camelidae family. 
ALX-0171 Nanobody is directed towards the RSV fusion (F) protein, and is intended to 
interfere with viral entry into host cells. ALX-0171 is a trivalent Nanobody, formed by three 
identical building blocks connected via two linkers (Figure 1). All three moieties are capable 
of binding to the homotrimeric RSV F protein. 
 
The F protein is highly conserved between RSV serotypes, and is therefore considered the 
main target for development of viral entry inhibitors. Following activation, the RSV F protein 
causes the membranes of the host cell and the virion to come into close vicinity and fuse 
together, allowing further infection and viral replication. Glycoprotein F also induces fusion 
of infected cells with adjacent, uninfected cells (epithelial cell syncytia), which allows for 
cell-to-cell transmission of the replicated viral RNA and confers additional protection against 
host immune responses [5]. 
 
ALX-0171 Nanobody binds to a well-conserved epitope in antigenic site II of the RSV F 
protein, close to or overlapping with the epitope of the clinical benchmark palivizumab 
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(trade name Synagis®, MedImmune/AstraZeneca). The latter is a humanized monoclonal 
antibody (mAb) indicated for the prevention of serious lower respiratory tract disease in 
high risk children, and is prophylactically administered by monthly intramuscular injections 
throughout the RSV season.  
 
Figure 1: Schematic representation of ALX-0171 Nanobody 
 
 
 
The amino acid (15-GS) linkers connect the C-terminus of the first building block with the N-terminus of the 
second one, and the C-terminus of the second building block with the N-terminus of the third one. The three 
building blocks (designated RSVNMP1A4) are identical, with the only exception of the E1D mutation in the 
first building block, which has been introduced to avoid pyroglutamate formation. 
 
1.2.1. PHARMACEUTICAL PROPERTIES 
 
Since direct delivery and deposition in the respiratory tract is desirable, inhalation was 
considered the preferred route of administration. ALX-0171 was therefore developed as a 
solution for nebulization, containing 50 mg/mL ALX-0171 Nanobody dissolved in a 
formulation buffer suitable for inhalation.  
ALX-0171 solution for nebulization is administered using the handheld FOX-Flamingo 
inhalation system. The FOX-Flamingo is intended for professional use in a clinical 
environment, in spontaneously-breathing subjects from birth up to 3 years. 
 
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1.2.2. NONCLINICAL STUDIES 
 
Pharmacological properties 
 ALX-0171 was characterized using in vitro systems, including assessment of affinity, 
biological activity and specificity. Different cellular systems of RSV replication were used, 
with cell-line adapted virus strains as well as viruses isolated from clinical cases. 
 In vivo efficacy was demonstrated in the RSV infection cotton rat model, a standard 
model used in the field. Intranasal and intratracheal administration and nebulization were 
used to reflect the clinical route of administration.  
 Efficacy and safety were further confirmed in the neonatal lamb model of RSV infection, a 
disease model that allows the assessment of clinical symptoms, histopathology and viral 
titers, and more closely mimics the clinical situation in infants. 
 
Safety pharmacology 
Specific Good Laboratory Practice (GLP) -compliant in vivo studies were designed for the 
evaluation of ALX-0171 effects on respiratory and cardiovascular system, in rats and dogs 
respectively. 
 
Pharmacokinetics 
The objective of the Pharmacokinetic (PK) program was the characterization of plasma and 
local (lung) kinetics of ALX-0171 in nonclinical toxicity studies. Additionally, the impact of 
anti-drug antibodies (ADA) on the PK of ALX-0171 was evaluated. PK parameters were also 
derived from a study in juvenile rats after single or repeated dose inhalation (starting from 
post-natal dose 4), as well as from an efficacy study in neonatal lambs. The latter includes 
information from infected animals.  
 
Toxicology 
Two 14-day repeat-dose toxicity studies in rats, after once-daily administration via 
inhalation 
and 
via 
intravenous 
(i.v.) 
administration 
respectively, 
showed 
no 
treatment-related effects on local tolerance, clinical signs, body weight, food consumption, 
ophthalmic examination, hematology and coagulation, clinical chemistry, urine analysis, 
macropathology, histopathology, or organ weights. 
 
Safety evaluations were included in the studies involving RSV-infected cotton rats and 
neonatal lambs.  
 
The risk of accidental exposure of the face, and particularly of the eyes, during nebulization 
via a face mask, was assessed nonclinically. No local irritant effects of ALX-0171 on bovine 
cornea were observed. Likewise, in a repeated dose PK study in juvenile rats after 
inhalation, no clinical signs indicative of eye irritation or histopathology findings were 
reported. 
 
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1.2.3. EFFECTS IN HUMANS 
 
1.2.3.1. OVERVIEW 
 
At present, three Phase 1 clinical trials have been conducted in adults, to obtain initial 
safety and PK data. Following completion of the adult studies, a first-in-infant clinical study 
was recently completed. A Phase 2b pediatric trial is currently ongoing outside of Japan. 
Please refer to the Investigator’s Brochure (IB) for a detailed overview of each of the 
individual studies: 
 
 First-in-man Phase 1 study ALX-0171-1.1/11 (N=60) evaluated the safety, tolerability 
and PK of ALX-0171, administered by inhalation, in healthy male volunteers. 
 Phase 1 study ALX-0171-1.3/13 (N=44) was performed to obtain additional information 
on local and systemic PK of ALX-0171 in healthy male volunteers.  
 Phase 1 safety study ALX-0171-1.2/13 (N=24) evaluated the potential occurrence, 
reversibility and prevention of bronchoconstriction upon inhalation of ALX-0171 by adults 
with sensitive (hyperresponsive) airways. 
 Study ALX0171-C104 (N=53) was a Phase 1/2a multicenter study in infants and young 
children hospitalized for RSV LRTI, to provide an initial evaluation of the safety, 
tolerability, antiviral and clinical activity of ALX-0171. 
 Phase 2b dose-ranging study ALX0171-C201 (currently ongoing outside of Japan) aims 
primarily to evaluate the antiviral effect of three doses of inhaled ALX-0171, as well as to 
assess the safety and clinical activity, in RSV-infected infants and young children 
hospitalized for RSV LRTI.  
 
1.2.3.2. CLINICAL SAFETY 
 
1.2.3.2.1. 
ADULTS  
 
The completed clinical studies in adults showed that inhaled ALX-0171 was well-tolerated at 
all doses evaluated.  
 
 Treatment-emergent adverse events (TEAEs) resolved quickly without further treatment, 
and were generally of mild to moderate intensity. The most common study drug-related 
TEAEs reported in the Phase 1 studies in adults included headache, rhinitis, 
oropharyngeal pain, cough, chest discomfort, throat irritation and wheezing (the latter in 
adults with hyperresponsive airways), generally of mild intensity.  
 No study drug-related TEAEs leading to withdrawal were reported. Similarly, no study 
drug-related, clinically significant findings were observed with respect to clinical 
laboratory parameters, vital signs, electrocardiogram (ECG), physical examinations, or 
lung auscultations.  
 In the studies in healthy volunteers, no meaningful trends in spirometry parameters were 
observed. The study in adults with hyperresponsive airways demonstrated the 
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reversibility of bronchoconstriction with bronchodilator treatment (β2-agonist) and 
prevention with prophylactic use of bronchodilator. 
 
1.2.3.2.2. 
PEDIATRIC SUBJECTS 
 
In completed study ALX0171-C104, ALX-0171 was also found to be well-tolerated in infants 
and young children hospitalized for RSV LRTI.  
 
 In line with the underlying disease, the most frequent TEAEs in study ALX0171-C104 
were thoracic and mediastinal disorders, infections and infestations, and skin disorders. 
Possibly-related TEAEs occurred in 3 subjects (8.6%) in the ALX-0171 group. These were 
cough, rhinorrhea, and pyrexia. All were mild and resolved. None of the subjects in the 
placebo group showed possibly-related TEAEs. 
 There were no treatment-related serious adverse events (SAEs) in this study. Five SAEs 
were 
reported 
in 
4 subjects 
(11.4%) 
in 
the 
ALX-0171 
group. 
These 
were 
hyporesponsiveness and hypotonia (both in 1 subject), pneumonia (2 subjects), and 
atelectasis. All resolved.  
 Two subjects (5.7%) in the ALX-0171 group were prematurely discontinued from study 
drug (due to SAEs hypotonia and hyporesponsiveness and pneumonia). As noted above, 
all SAEs resolved. None of the subjects in the placebo group discontinued treatment. 
 
1.2.3.3. CLINICAL PHARMACOKINETICS 
 
In adults, the local (epithelial lining fluid) and systemic exposure levels were above the 
target for infants and young children, with good tolerability.  
 
Consistent with lung exposure, inhaled ALX-0171 was quantifiable in the serum of most of 
the infants and young children in study ALX0171-C104.  
 
1.2.3.4. CLINICAL ACTIVITY AND 
PHARMACODYNAMICS 
 
Study ALX0171-C104 provided a first indication of antiviral and clinical activity in a relevant 
clinical setting, i.e., hospitalized infants with RSV LRTI. 
 
 Data on nasal viral load indicates that ALX-0171 treatment rapidly and sustainably 
reduces cultivatable virus titers to below the quantification limit. 
 Post-hoc analysis of a composite of clinical parameters, the Global Severity Score, led to 
an encouraging initial indication of a therapeutic effect for infants treated with ALX-0171. 
 
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1.2.3.5. IMMUNOGENICITY 
 
While immunogenicity has been reported in clinical studies with ALX-0171, no correlation 
with potential immune-related AEs has been established thus far, neither in adults nor in 
RSV-infected children. 
 
 In adults, pre-existing antibodies (pre-Ab§) were found in 7% (ALX-0171-1.1/11) to 18% 
(ALX-0171-1.3/13) of the subjects.  
 In the Phase 1 study ALX0171-1.1/11, no treatment-emergent ADA (TE ADA) responses 
were detected, whereas in the Phase 1 studies ALX-0171-1.3/13 and ALX-0171-1.2/13, 
TE ADA were observed in the serum of 13%-33% of the subjects, respectively. 
 In Study ALX0171-C104, pre-Ab were found in 45% of the subjects, while TE ADA was 
detected in 23% of the infants. Pre-Ab detected in those children may reflect maternal 
antibodies transferred to the infant via the transplacental route during gestation or 
during breastfeeding. As the assay cannot discriminate pre-Ab from drug induced 
TE ADA, it is not clear to what extent the TE ADA detected may represent fluctuating 
levels of pre-Ab. Currently it is not known to what extent pre-Ab can fluctuate within the 
short study period (14 days). No effect of ADA on PK was observed. 
 
TE ADA is not expected to have an impact on PK or efficacy given the short treatment 
duration, as TE ADA do not emerge in considerable amounts within the first 7 days after 
initial drug administration. It is also unlikely that the pre-existing or TE ADA against ALX-
0171 would result in a clinically meaningful safety risk (see section 1.3.2 below). 
 
1.3. SAFETY PROFILE AND BENEFIT-RISK 
ASSESSMENT 
 
The potential benefits and risks for administration of ALX-0171 are assessed from the 
available nonclinical data and the results of the completed Phase 1 clinical studies in adults 
and a Phase 1/2a trial in children hospitalized for RSV LRTI.  
 
1.3.1. NONCLINICAL RESULTS 
 
Detailed nonclinical assessment of systemic toxicity as well as local tolerability and 
respiratory safety revealed no clinically meaningful risks for administration of ALX-0171 to 
pediatric subjects. The results were consistent across the different nonclinical safety and 
toxicology studies.  
 
                                                   
§ Pre-existing antibodies, i.e., ADA present in samples from treatment-naïve subjects, have been commonly 
observed during immunogenicity assessments. 
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1.3.2. CLINICAL SAFETY RESULTS 
 
At present, three Phase 1 clinical studies have been completed in adults. In addition, a 
Phase 1/2a study in children aged 28 days to <2 years hospitalized for RSV LRTI was 
recently completed. ALX-0171 was generally well tolerated in all clinical studies. 
 
1.3.3. POTENTIAL RISKS 
 
ALX-0171 has no endogenous target and no secondary pharmacology was noted throughout 
the pre-clinical development program; potential risks related to the pharmacology or to the 
mechanism of action of the compound are therefore considered unlikely.  
 
More general risks, inherent to administration of inhalation products or therapeutic proteins, 
cannot be excluded. A continuous further evaluation is included during clinical development 
to assess if these potential effects would constitute clinically meaningful risks for 
administration of ALX-0171.  
 
Airway Hyperresponsiveness 
Viral respiratory infections are known to transiently increase bronchial reactivity, potentially 
leading to airway hyperresponsiveness (i.e., an abnormal airway narrowing of the bronchi, 
triggered by various chemical or physical stimuli).  
 
The occurrence, treatment and prevention of potential bronchoconstriction subsequent to 
ALX-0171 inhalation was evaluated in a dedicated Phase 1 study in adults with 
hyper responsive airways (Study ALX-0171-1.2/13). In total, 24 subjects participated in the 
study. 
In 
this 
population, 
10 subjects 
(42%) 
experienced 
a 
mild 
to 
moderate 
bronchoconstriction either during the escalating dose or repeated dose part of the study. All 
events were treated successfully with ß2-agonist (salbutamol). The results of this study 
demonstrated the immediate reversibility of bronchoconstriction with bronchodilator 
treatment (β2-agonist) and prevention with prophylactic use of bronchodilator. 
 
In the first-in-infant Study ALX0171-C104, as a precaution and in order to standardize 
treatment across the sites, an inhaled dose of the short-acting β2-agonist salbutamol was 
administered before each administration of study drug. A review of the safety data and 
respiratory 
parameters 
collected 
in 
the 
first-in-infant 
study 
did 
not 
reveal 
a 
bronchoconstrictive risk after study drug inhalation. Therefore, the requirement for 
prophylactic administration of a β2-agonist is not implemented in the current protocol, but 
the use of bronchodilator treatment is permitted at the Investigator’s discretion. The same 
approach is used in ongoing Phase 2b study ALX0171-C201.  
 
The potential risks of airway hyperresponsiveness and bronchoconstriction will be closely 
monitored in each of the cohorts, including via regular Independent Data Monitoring 
Committee (IDMC) review. 
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Immediate or Delayed Adverse Drug Reactions 
All therapeutic proteins have the potential to elicit antibody or other immune- or 
non-immune-mediated responses, potentially resulting in hypersensitivity or allergic 
reactions such as rash, urticaria, angioedema, serum sickness and anaphylactoid or 
anaphylactic reactions. These responses are complex and could occur following initial or only 
after repeated exposure, and are very difficult to predict.  
 
Within the context of the planned clinical study, immunogenicity-related AEs as a 
consequence of TE ADA are not expected, as TE ADA typically do not emerge in considerable 
amounts earlier than 7 days after first administration of study drug, at times where study 
drug is expected to be cleared, given the short treatment period of 3 days. 
 
While pre-Ab and TE ADA have been reported in clinical studies with ALX-0171, no 
correlation with potential immune-related AEs has been established thus far in adults or in 
RSV-infected children. No immune response-related toxicological findings were reported 
during the nonclinical studies.  
 
 During Study ALX-0171-1.3/13, a possible mild hypersensitivity reaction (unilateral eyelid 
oedema) was noticed in one subject approximately 1 hour after 1 single i.v. dose. No 
pre-Ab or TE ADA were detected in this subject.  
 
 During Study ALX0171-C104, no correlation between immunogenicity (either pre-Ab or 
TE ADA) and safety was seen. One subject with a history of acute urticaria presented 
with a mild exanthema of abdomen, trunk, back and retroauricular area, about 5 hours 
after the second drug administration. The event resolved without medication and was 
considered unlikely/not related to the study drug by the Investigator. This subject was 
pre-Ab positive and TE ADA positive. A possible correlation with immunogenicity (pre-Ab 
and/or TE ADA) cannot be excluded for this subject.  
 
The potential immunogenicity of ALX-0171 has not yet been evaluated in Japanese subjects. 
In line with regulatory and scientific guidance, an immunogenicity risk assessment [6] was 
prepared for administration of ALX-0171, in support of the currently proposed study [7-9]. 
This assessment comprised evaluation of the immunogenic potential of ALX-0171 through 
determination of product-specific, patient- and/or disease-related factors affecting 
immunogenicity. In addition, the available nonclinical and clinical immunogenicity results 
were evaluated to come to an appraisal on the potential consequences on safety, PK and 
efficacy in case immunogenicity would occur in the current pediatric study. The overall risk 
assessment led to a “lower risk class” designation (the lowest category for a therapeutic 
protein) [8], with favorable risk/benefit balance for the current pediatric study. Of note, the 
immunogenicity risk assessment is a dynamic process, with further evaluations and updates 
scheduled as data become available [10]. 
 
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Unintentional Contact/Exposure 
To ensure correct administration of ALX-0171 and handling of the device, detailed 
instructions for use will be provided. During administration by nebulization, caregivers or 
other persons close to the nebulizer may nevertheless come into contact with ALX-0171. 
This may for instance occur due to aerosol escaping through the outlet valves of the 
facemask, or via particles exhaled by the subject. This is not considered to pose a safety 
risk. ALX-0171 is highly specific towards the RSV F protein, and lacks an endogenous 
human target. The in vivo safety pharmacology and toxicology studies revealed no 
meaningful safety risks. As described above, the clinical studies conducted so far showed 
that ALX-0171 was well tolerated at all dose levels and dosing regimens evaluated. In 
addition, no teratogenic or oncogenic properties are expected. As ALX-0171 is a protein 
drug, it is not expected to enter cells and interfere directly with DNA or nuclear proteins. 
 
Furthermore, Investigators, clinical staff, parents, family members or other children in the 
vicinity would only come in contact with ALX-0171 at a negligible dose**. Potential 
deposition of aerosol particles onto surfaces, or unintentional contact by means other than 
inhalation, is not of concern. Similar to other proteins or macromolecules, standard hospital 
or household hygiene procedures are considered sufficient for cleaning of surfaces. There is 
no added risk for contact with skin, since ALX-0171 does not cause irritation, and is not 
prone to transdermal delivery (similar to other macromolecules). Exposure to mucosal 
tissues may be more relevant, but there are no indications that this would be associated 
with additional safety concerns, systemic uptake, or irritative effects. Finally, in case of 
accidental oral intake, ALX-0171 would be rapidly degraded in the digestive tract, similar to 
other proteins.  
 
Routine hygiene conditions and cleaning procedures in the hospital are therefore sufficient 
for administration of ALX-0171. In view of the above, potential risks associated with 
unintentional contact are considered negligible. It should also be noted that, while not 
considered necessary, a standard facemask would be sufficient to further limit unintentional 
contact with ALX-0171 for the person administering study drug.  
 
1.3.4. POTENTIAL BENEFITS 
 
As a respiratory virus, RSV may present as an upper respiratory tract infection (including 
rhinitis, otitis media and pharyngitis), or, as is more often the case in infants and young 
children, as a LRTI, (including acute bronchiolitis and/or broncho-pneumonia). RSV LRTI 
results in hospitalization of about 3% of RSV-infected infants less than 1 year old, and about 
0.5% of RSV-infected children aged between 1 and 2 years [1, 2].  
                                                   
** Calculated “worst case” scenarios (e.g., 1-hour stay after administration of ALX-0171 in an examination room of 
5 m2 with poor ventilation, and assuming that the entire dose filled into the nebulizer is dissipated into the room) 
indicate that inhalation of dissipating aerosol by any person (adult or infant) other than the intended subject 
would result in an ALX-0171 dose at least 100-fold below the nebulized dose. Of note, in case only incomplete or 
inefficient administration is achieved (e.g., because of poor fitting of the face mask, or because of intense crying 
of the subject), nebulization is to be stopped, thereby avoiding unwanted loss of study drug into the room. 
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Since there are no adequate medications available for treatment of RSV infection, the 
standard 
of 
care 
for 
hospitalized infants 
is 
mostly 
supportive 
(e.g., 
fluid/feed 
supplementation, observation, and respiratory support as needed) [1, 3, 4].  
 
ALX-0171 is an antiviral treatment and is intended to neutralize RSV (thereby inhibiting viral 
infectivity). ALX-0171 was shown to be highly effective in nonclinical in vitro and in vivo 
model systems, including RSV-infected cotton rats and neonatal lambs. Results from these 
studies demonstrate a beneficial effect with regard to viral load, inflammatory signs, and/or 
symptoms and signs of RSV infection. The studies in RSV-infected neonatal lambs provided 
proof-of-concept for therapeutic intervention with a 3-day treatment course of ALX-0171.  
 
Analysis of a composite of clinical parameters from the first-in-infant study, the Global 
Severity Score, led to an encouraging initial indication of a therapeutic effect for infants 
treated with ALX-0171 and given its favorable safety profile from clinical studies to date, 
further evaluation of the agent is being pursued. 
 
1.3.5. CONCLUSION 
 
The nonclinical and clinical studies performed so far did not reveal clinically meaningful risks 
for administration of ALX-0171 to pediatric subjects. The results in representative 
nonclinical models, together with those obtained in first-in-infant study ALX0171-C104, 
indicate that ALX-0171 may provide an opportunity for therapeutic intervention in 
established RSV LRTI.  
 
The current Phase 2 study in Japanese infants and young children, study ALX0171-C203, 
will evaluate dose levels investigated in the completed first-in-infant study ALX0171-C104 
and the ongoing Phase 2b, dose-ranging study ALX0171-C201. The doses are estimated to 
achieve concentrations at which antiviral and clinical activity can be expected while 
appropriate safety margins are respected. The dose range is therefore expected to provide a 
potential benefit to the subjects, and is intended to support selection of an optimal dose of 
ALX-0171 for further clinical development, taking ethnicity into consideration.  
 
Regular review of clinical data by the IDMC before initiation of a higher dose, including 
pauses in recruitment, will enable adequate safety follow-up throughout the study. The 
clinical study protocol foresees close monitoring of all subjects, and is considered to provide 
a suitable setting for evaluation of ALX-0171 in infants and young children. 
 
In view of the above, the current benefit/risk assessment is therefore considered favorable 
and supportive of further clinical development.  
 
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2. OBJECTIVES 
 
The objectives of this study are: 
 
 to evaluate the safety, tolerability, and systemic PK of different doses of inhaled 
ALX-0171 in Japanese infants and young children hospitalized for RSV LRTI. 
 to evaluate the antiviral effect, clinical activity, immunogenicity, and PD of different doses 
of inhaled ALX-0171 in Japanese infants and young children hospitalized for RSV LRTI. 
 
3. STUDY DESIGN 
 
3.1. OVERALL STUDY DESIGN 
 
3.1.1. STUDY OVERVIEW 
 
Study ALX0171-C203 is a randomized, double-blind, multicenter, multiple-dose study of 
ALX-0171 versus placebo along with standard of care in Japanese infants and young 
children aged 28 days to <2 years hospitalized for RSV LRTI. A schematic of the study 
design presented in Figure 2.  
 
The overall study duration is expected to be approximately 12 months, with the planned 
study duration for each subject approximately 28 days. 
 
The following dose levels are planned to be evaluated in four consecutive cohorts: 
 
• 
Dose 1: target dose of 1.5 mg/kg 
• 
Dose 2: target dose of 3.0 mg/kg 
• 
Dose 3: target dose of 6.0 mg/kg 
• 
Dose 4: target dose of 9.0 mg/kg 
 
Each cohort will consist of 15 subjects enrolled, randomly assigned to and received 
ALX-0171 or placebo, in an allocation ratio of 4:1 (N=12 active versus N=3 placebo per 
cohort). Study drug will be administered once daily for 3 consecutive days and will be given 
along with standard of care treatment, which will be determined by the Investigator 
according to institutional practice (taking into account the prohibited medications listed in 
section 3.3.7). The 3-day treatment period is expected to bridge the time needed for the 
body to mount an effective immune response. 
 
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Figure 2: ALX0171-C203 – Study Design 
IDMC=Independent Data Monitoring Committee 
 
An overview of the study flow is shown in Figure 3.  
 
 Upon signing of the Informed Consent Form (ICF), subjects will be screened as soon as 
possible after arrival at the hospital/emergency unit. After completion of the screening 
assessments and confirmation of subject’s eligibility, randomization should follow as soon 
as possible but not longer than 24 hours after arrival at the hospital/emergency unit.  
 Study drug administration should start as soon as possible after randomization with a 
maximum time interval of 3 hours following randomization. Subsequent doses of study 
drug will be administered at 24-hour intervals (± 4 hours) relative to the first dose. No 
pre-medication is required per protocol, but an inhaled β2-agonist may be administered at 
the discretion of the treating Investigator.  
 During the 3 treatment days, inpatient hospital stay is required.  
 Discharge from the hospital can take place per protocol at the Investigator’s discretion 
from dosing on Day 3 onwards, after all required assessments of the 5 hours (±1 hour) 
post-dose time point have been completed and provided that the clinical response criteria 
have been met. Subjects who are not discharged from the hospital after completion of 
the treatment period will enter an in-hospital post-treatment period with assessments in 
the morning and evening until discharged. 
 A Follow-Up (FU) visit is scheduled on Day 14 (±2 days), and an End of Study (EOS) visit 
on Day 28 (±2 days).  
 Unscheduled visits may be conducted to assess or follow-up on AEs or laboratory 
abnormalities. In such cases, the evaluations performed are at the discretion of the 
Investigator. 
 An Unscheduled Visit is also to be performed in case a subject is re-hospitalized, or when 
the Investigator is consulted for a respiratory condition occurring after discharge from the 
hospital. In such cases, a mid-turbinate nasal swab is to be collected and a physical 
examination, including lung auscultation, must be performed.  
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 For subjects prematurely withdrawn from the study, a Withdrawal visit is to be performed 
on the day of withdrawal (unless the consent was withdrawn, subject is lost to follow up, 
or died) (see section 3.4). 
 Subjects who discontinue study drug (for any reason) but remain hospitalized will enter 
the in-hospital post-treatment period and will be followed up twice daily (in the morning 
and the evening) until they are discharged from the hospital. They should also attend the 
FU and EOS visit. 
 
After the end of the subject’s participation in the study, each subject is to be treated 
according to standard clinical practice. 
 
Figure 3: ALX0171-C203 - Study Flow 
 
*Or withdrawal visit at earlier time point in case of withdrawal 
**Hospital discharge is allowed from Day 3 once all post-dose assessments have been completed and clinical response 
criteria have been met. 
 
Independent Data Monitoring Committee 
 
In line with applicable guidelines, an IDMC is assigned to monitor the study. The IDMC 
consists of an independent group of clinical experts. The participants, objectives, and roles 
and responsibilities of the IDMC will be described in an IDMC Charter. The IDMC Charter will 
also define and document the content of the safety summaries, and general procedures 
(including communications). The first version of the charter will be finalized prior to the 
initiation of the study. 
After the last subject in a cohort has completed his/her treatment period or has 
discontinued study drug, the IDMC will review the available cumulative unblinded safety 
data (i.e., all available data for all included subjects, including preceding cohorts) and 
advise the Sponsor on proceeding to the subsequent cohort (i.e., the next higher dose). 
Recruitment will be paused during IDMC reviews. 
 
SAE information will be communicated to the IDMC in real time throughout the study, as per 
the IDMC Charter. An ad-hoc meeting can be requested by the IDMC members at any time. 
 
** 
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Dose Escalation Stopping Criteria 
 
 
In addition to the individual discontinuation criteria (see section 3.4), the following criteria 
apply to stopping or pausing recruitment: 
 
1. Should an SAE indicative of acute respiratory distress or an acute systemic 
hypersensitivity reaction be considered by the Investigator to be related to administration 
of ALX-0171, recruitment in that cohort will be stopped and no further dose escalation 
will be done.  
2. The reporting of any other SAE considered by the Investigator to be related to 
administration of ALX-0171 will trigger a pause in recruitment and an immediate review 
by the IDMC. Confirmation of the causality between the administration of ALX-0171 and 
the serious adverse reaction by the IDMC will result in the stopping of recruitment in that 
cohort and no further dose escalation will be done.  
3. In case 2 SAEs considered by the Investigator to be possibly related to administration of 
ALX-0171 occur in the same cohort, recruitment in that cohort will be paused to allow 
further investigation by the IDMC. This includes assessment of the index events as well 
as review of any prior similar events, after which the IDMC will issue a recommendation 
regarding continuation or stopping of the paused cohort. In case recruitment is reinitiated 
based on the IDMC recommendation, the assessment for further dose escalation will be 
performed by the IDMC during the planned pause after completing the cohort, when the 
cumulative dataset is available. 
4. If 2 severe adverse events (AEs) indicative of acute respiratory distress or an acute 
systemic hypersensitivity reaction would occur in a particular cohort and are considered 
by the Investigator to be related to administration of ALX-0171, no further dose 
escalation will be done. 
 
3.1.2. STUDY RATIONALE AND DISCUSSION OF 
STUDY DESIGN 
 
Throughout the clinical program, inhalation of ALX-0171 was shown to be generally well 
tolerated. The encouraging results obtained in Study ALX0171-C104 (first-infant study) 
supported the initiation of a global Phase 2b dose-ranging study in non-Japanese infants 
and young children (aged 28 days to <2 years) hospitalized for RSV LRTI (N=180, study 
ALX0171-C201).  
 
The present study, ALX0171-C203, is a double-blind, multiple-dose study of ALX-0171 
versus placebo along with standard of care in Japanese infants and young children 
hospitalized for RSV LRTI. The RSV infection is confirmed by the Investigator’s assessment 
of clinical criteria, and by virological confirmation (RSV diagnostic test). 
 
The main objective of the study is evaluation of the safety, tolerability and PK of ALX-0171 
compared to placebo. As pharmacologically active doses will be used, the antiviral effect, 
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clinical activity, and PD characteristics of ALX-0171 will also be evaluated, in addition to 
potential immunogenicity. 
 
Study Population 
 
The first-in-infant study ALX0171-C104 provided a first confirmation of safety and 
tolerability of inhaled administration of ALX-0171 in infants and young children hospitalized 
for RSV infection. The children enrolled in this study were, besides their RSV infection, 
otherwise healthy, without significant co-morbidities and with a normal gestational age. 
Based on the reassuring safety profile observed in study ALX0171-C104, the Phase 2 
studies performed with ALX-0171 include the age range from 28 days up to <2 years, which 
is a highly relevant age window for this indication [11].  
 
Considering that the Phase 2 studies are also aimed at defining appropriate dose levels for 
further development, co-morbidities that would confound this assessment (e.g., clinically 
significant heart or pulmonary diseases) are still excluded. The eligible gestational age 
(≥ 33 weeks) allows moderate to late ex-preterm infants to enter the study, which is an 
important subgroup for RSV infection [11]. Based on discussions with clinical experts, these 
infants are expected to behave similarly to the term infants when they have reached 
28 days of age, and no other co-morbidities (which are exclusionary) are present. 
 
The eligibility criteria in the protocol include restrictions on the type and intensity of 
ventilation. Only conventional oxygen supplementation through nasal cannula, head box, or 
face mask is allowed, since these can be continued during study drug administration (the 
FOX-Flamingo provides a 2 L/minute oxygen or air flow). More intense ventilation, typically 
used for more severely distressed infants, is part of the exclusion criteria. Critically ill 
infants in need of invasive ventilation or respiratory support with positive airway pressure 
cannot be enrolled in the study, because a different outcome and safety profile can be 
expected in this more severe subpopulation.  
 
In order to enable the antiviral treatment to provide clinical benefit to the infants, the time 
between the start of the infection and initiation of treatment is kept as short as possible in 
study ALX0171-C203. The inclusion criteria therefore mandate a maximum of 4 days 
between the onset of symptoms of the RSV infection and screening at the hospital.  
 
Ethnic Sensitivity 
 
To ensure that subjects in study ALX0171-C203 are representative of the Japanese 
population, they are required to be born in Japan, to Japanese parents, and to have 
Japanese maternal and paternal grandparents.  
 
Safety, PK/ PD characteristics, or antiviral activity have so far been evaluated in non-
Japanese pediatric patients. The Sponsor expects that the combined dataset of studies 
ALX0171-C104 and ALX0171-C201, together with the results from Japanese study 
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ALX0171-C203, will enable selection of an optimal dose for future development, including in 
Japanese children. 
 
Determination of Sample Size 
 
The planned sample size of 60 randomized and treated subjects was selected to provide 
sufficient safety and tolerability experience with ALX-0171 in this population, to confirm the 
safety profile reported in studies conducted outside of Japan. The sample size also provides 
sufficient precision on the model estimated PK parameters, as described by Wang et al. 
[12], and it is expected to be informative on antiviral and clinical activity of ALX-0171. 
 
The purpose of including placebo (in addition to standard of care) is to assist in the 
interpretation of results, and not for a formal statistical comparison between active and 
control subjects. 
 
Dose Selection Rationale 
 
The study drug will be administered via nebulization once daily for 3 consecutive days, in 
the hospital setting. The 3-day dosing regimen for ALX-0171 was based on the PD and PK 
properties of ALX-0171 and the current knowledge on viral kinetics and clinical management 
of RSV infection. The treatment period is expected to bridge the time needed for the body to 
mount an effective immune response that will clear the virus, and to provide the optimal 
individual benefit/risk balance for the subjects.  
 
The dose range proposed to be studied in ALX0171-C203 was selected based on the results 
of study ALX0171-C104 (Phase 1/2a first-in-infant study), and includes the doses currently 
being evaluated in ongoing study ALX0171-C201 (Phase 2b dose-range finding study 
conducted outside of Japan). Additional details on the dose selection rationale are available 
in section 3.3.2. 
 
Background Therapy 
 
Standard-of-care therapy will be given as background therapy to all subjects in study 
ALX0171-C203, in addition to ALX-0171 or placebo. This is because the management of RSV 
in nearly all settings is supportive, and the approach is consistent with all major pediatric 
societies’ guidelines [1, 13].  
 
Prior or concomitant administration of palivizumab, other investigational compounds for RSV 
infection, or systemic corticosteroids or the initiation of inhaled corticosteroids will not be 
allowed; these treatments could interfere with the evaluation of ALX-0171 and are not in 
line with the endorsed treatments of RSV infection in the target population. 
 
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Study Assessments 
 
The assessments which will be made in this study are standard and generally recognized as 
reliable, accurate, and relevant. 
 
Safety and tolerability will be assessed through AE collection, measurements of vital signs, 
peripheral capillary oxygen saturation (SpO2), physical examination, and laboratory 
parameters. Safety lab assessments are planned two times during the study (at screening 
and at the FU visit) and will be performed by the local laboratory in order to allow timely 
availability of the results. Furthermore, an IDMC will be involved in the regular review of the 
available safety data. 
 
The systemic concentration of ALX-0171 in serum will be evaluated over time, as a 
surrogate for local (lung) concentrations.  
 
Potential immunogenicity will also be assessed systemically (serum), both pre-dose and 
post-dose (14 days post-initial drug administration) and results will be correlated with PK, 
PD and safety findings.  
 
 
Systemic levels of the serum biomarker Krebs von den Lungen-6 (KL-6) will be determined 
in left-over serum samples. Serum KL-6 was shown to indicate disease activity in various 
interstitial lung diseases and is believed to reflect the presence of alveolar damage [14, 15]. 
High serum KL-6 levels in RSV–infected infants correlate with low SpO2 and need for oxygen 
administration [16]. These findings suggest that serum KL-6 is associated with the severity 
of RSV bronchiolitis, and that it may provide additional insight on potential treatment 
benefits.  
 
The intended volume of blood to be withdrawn for each of the assessments is based on the 
minimum required volume for each of the respective analyses, and is in line with the 
volumes allowed per applicable guidelines [17-21].  
 
Viral load will be assessed in samples obtained via nasal swabs collecting a mid-turbinate 
specimen, and will be quantified using plaque cultures (to evaluate replication-competent 
virus) and by RT-qPCR (to evaluate viral mRNA). Based on ALX-0171 mechanism of action, 
plaque cultures best reflects viral neutralization, whereas RT-qPCR is more sensitive, but 
also quantifies ALX-0171 neutralized viral particles that are unable to infect other cells, 
partially assembled virions, and whole and fragmented viral genome. 
 
The clinical impact of treatment by ALX-0171 in infants and young children will be evaluated 
by changes in clinical symptoms (SpO2, feeding, respiratory rate, wheezing, cough, 
respiratory muscle retractions, and general appearance) and subsequent calculation of 
composite scores, the time needed to achieve adequate feeding and oxygen saturation 
(clinical response) allowing for hospital discharge, the need for medical interventions, and 
length of hospital stay.  
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Based on the clinical activity parameters measured during the study, composite scores that 
reflect the clinical status of the subject suffering from RSV will be calculated, including the 
Global Severity Score, Respiratory Distress Assessment Instrument (RDAI) score, and 
Respiratory Assessment Change Score (RACS).  
 
 The Global Severity Score is based on a recent clinical score that allows categorization of 
infants with respiratory infections on 7 different parameters: feeding intolerance, medical 
intervention, respiratory difficulty, respiratory frequency, apnea, general condition and 
fever [22, 23]. It takes into account all clinically relevant aspects of an RSV infected 
subject.  
 The RDAI is a scoring system based on the presence and severity of wheezing and 
respiratory muscle retractions.  
 The RACS is based on the RDAI and adds a standardized score for the change in 
respiratory rate. 
 
Given the importance of timing of the administration of this antiviral compound in the time 
course of the RSV infection, details on the time elapsed between onset of first clinical 
symptoms and start of treatment with study drug will be collected and analyzed. The need 
for medical interventions will be documented through collection of data on the need for and 
level of oxygen supplementation or respiratory support, need for transfer to intensive care 
unit (ICU), duration of stay in ICU and overall hospital stay. 
 
In addition to the assessments performed by healthcare professionals, the study will also 
collect information on how parents or caregivers perceive the clinical condition of the child 
through daily completion of a diary. This diary includes scoring of respiratory symptoms 
(cough, wheezing, trouble breathing) over the preceding 24 hours, evaluating the general 
health of the child by completing a Visual Analogue Scale (VAS), and answering a question 
as to whether the child has returned to his/her normal condition from before the onset the 
RSV infection. For the period after discharge from the hospital, this diary will also capture 
data on health care utilization and use of medication for respiratory symptoms. The diary 
will be completed during hospital stay and daily thereafter up to the EOS (Day 28) visit as 
RSV induced bronchiolitis is often associated with continuing respiratory symptoms following 
hospitalization. 
 
3.1.3. BLINDING 
 
In order to protect the integrity of the data, treatment assignment will be kept blinded for 
investigative sites, subjects, subject’s parent(s)/legal guardian(s) and caregiver(s), site 
monitors, and other members of the study team, until after the final database lock (i.e., 
after the last subject has completed the final [EOS] visit and all data is considered clean).  
Identification of Sponsor and contract research organization (CRO) personnel who will have 
access to unblinded data (e.g., PK sample analysis team) during the course of the study will 
be documented prior to unblinding. The number of Sponsor personnel having access to the 
data will be limited. 
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Emergency unblinding procedure 
 
Code-breaking and unblinding in the event of medical emergencies can be done by the 
Investigator via the Interactive web/voice response system (IWRS/IVRS), which will be 
accessible 24 hours per day/7 days per week. 
 
Unblinding by the Investigator should occur only in the event of an AE for which it is 
necessary to know the study drug allocated to determine an appropriate course of therapy 
for the subject. The Investigator should first discuss options with the Medical Monitor if 
possible with due consideration of the safety of the subject. If the Investigator must identify 
the treatment assignment of an individual subject, the Principal Investigator/sub-
Investigator is to contact the IWRS/IVRS.  
 
Subjects for whom the code has been broken by the Investigator will have to discontinue 
study drug treatment and subjects will be followed up according to the in-hospital 
post-treatment period (if applicable), FU visit and EOS visit. 
 
3.2. SELECTION OF STUDY POPULATION 
 
Japanese infants and young children of both genders diagnosed with and hospitalized for 
RSV LRTI but otherwise healthy, are eligible for this study. A total of 60 subjects are 
planned to be randomized and treated in the study. 
 
3.2.1. INCLUSION CRITERIA 
 
A subject will be eligible for study participation if he/she meets all of the following criteria at 
screening and randomization, unless specified otherwise. 
 
1. 
Subject is a Japanese male or female infant or young child aged 28 days to <2 years 
with gestational age ≥ 33 weeks at screening. 
2. 
Subject is of Japanese descent, i.e., born in Japan to Japanese parents and has 
Japanese maternal and paternal grandparents. 
3. 
Subject weighs between ≥ 3.0 kg and <15.0 kg at screening.  
4. 
Subject is otherwise healthy, but is hospitalized for and clinically diagnosed with RSV 
LRTI (bronchiolitis or broncho-pneumonia), i.e., showing typical clinical signs and 
symptoms such as tachypnea, wheezing, cough, crackles, use of accessory muscles 
and/or nasal flaring.  
5. 
Subject has a positive RSV diagnostic test within 4 days of screening.††  
6. 
Subject is expected to have to stay in the hospital for at least 24 hours (according to 
the Investigator’s judgment at screening).  
7. 
Symptoms likely related to RSV infection (i.e., the symptoms present need to be 
probably linked to the current RSV infection according to Investigator’s judgment) have 
                                                   
†† RSV infection will be confirmed either according to routine site practice (PCR, immunofluorescence or diagnostic 
quick test), or using a Sponsor-provided commercial kit. 
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appeared within 4 days of screening and are not yet improving at screening and 
randomization.  
8. 
Subject fulfils at least two of the following RSV disease severity criteria at screening and 
randomization:  
- Inadequate oral feeding that requires feeding support (i.e., nasogastric tube or i.v. 
line),  
- Inadequate oxygen saturation defined as:  
 Oxygen saturation (SpO2) < 95% on room air or  
 Requiring oxygen supplementation to maintain adequate oxygen saturation with 
documented pre-supplementation value < 95%  
- Signs of respiratory distress defined as:  
 Respiratory rate ≥ 50 breaths per minute in infants up to 12 months of age, and 
≥ 40 breaths per minute in children above 12 months and/ or  
 Moderate or marked respiratory muscle retractions  
9. 
Subject has normal psychomotor development.  
10. Parent(s)/legal guardian(s) provide written informed consent in accordance with locally 
approved consent process at screening.  
11. The parent(s)/legal guardian(s) are able and willing to comply with the study protocol 
procedures.  
 
3.2.2. EXCLUSION CRITERIA 
 
Subjects meeting any of the following criteria at screening or randomization will not be 
eligible for study participation. 
 
1. 
Subject is known to have significant comorbidities including:  
- Genetic disorders (e.g., trisomy 21, cystic fibrosis),  
- Hemodynamically significant congenital heart disease (e.g., needing corrective 
therapy or inotropic support),  
- Bronchopulmonary dysplasia,  
- Any hereditary or acquired metabolic (bone) diseases,  
- Hematologic or other malignancy.  
2. 
Subject is known to be human immunodeficiency virus (HIV)-positive. If the subject is 
< 6 months of age, known HIV-positivity of the mother is also exclusionary.  
3. 
Subject is known to be immunocompromised.  
4. 
Subject has or is suspected to have an active, clinically relevant concurrent infection 
(e.g., bacterial pneumonia, urinary tract infection). Concurrent acute otitis media is not 
exclusionary.  
5. 
Subject has significant oral and/or maxillofacial malformations which would prevent 
proper positioning of the face mask.  
6. 
Subject received invasive mechanical ventilation or non-invasive respiratory support 
(i.e., continuous or bilevel positive airway pressure) in the 4 weeks prior to screening.  
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7. 
During the current admission, subject is initially hospitalized in an ICU setting and/or 
received invasive mechanical ventilation or non-invasive respiratory support (i.e., 
continuous or bilevel positive airway pressure).  
8. 
Subject is critically ill and/or is expected to require invasive mechanical ventilation, 
non-invasive respiratory support (i.e., continuous or bilevel positive airway pressure), 
or high-flow oxygen therapy (HFOT) at levels not enabling nebulization therapy 
according to the Investigator’s judgment. High Flow oxygen, with a maximum flow of 
2 L/kg/min, is permitted under the following conditions:  
- used as Standard of Care outside ICU setting  
- can be removed for study drug administration (Note: oxygen flow at 2 L/minute can 
be provided through the nebulizer)  
9. 
Subject has received 1 or more doses of palivizumab or treatment or prophylaxis with 
any RSV antiviral compound (e.g., ribavirin, i.v. immunoglobulin, or any investigational 
drug or vaccine for RSV [including subject’s mother who has been vaccinated against 
RSV]) at any time prior to screening.  
10. Subject is required to continue or start systemic corticosteroid therapy. Subject on a 
maintenance therapy of inhaled corticosteroids will continue this treatment at the usual 
dose. Topical corticosteroids for skin disorders are permitted.  
11. Subject has clinically meaningful abnormalities on a 12-lead ECG, which according to 
the Investigator’s judgement does not allow participation of the subject in the study. A 
12-lead ECG performed within 4 days of screening will be acceptable. If not yet 
available, the 12-lead ECG should be performed at the time of screening. 
12. Subject is a child in care (i.e., a child who has been placed under the control or 
protection of an agency, organization, institution or entity by the courts, the 
government or a government body, acting in accordance with powers conferred on 
them by law or regulation). A child in care can thus include a child cared for by foster 
parents or living in a care home institution, provided that the arrangement falls within 
the definition above, but does not include a child who is adopted or has appointed legal 
representative(s).  
13. Subject is currently participating in any other study with investigational drug or has 
received an investigational drug within 4 weeks or 5 half-lives of the concerned drug 
(whichever is longer) prior to screening.  
14. Subject was previously enrolled in a clinical study of ALX-0171 (including the current 
Study ALX0171-C203).  
15. Subject has a known hypersensitivity to the study drug or any excipient of the study 
drug. 
16. Subject is considered by the Investigator to be ineligible to participate in the trial for 
safety reasons or any other concern. 
 
 
 
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3.3. TREATMENT OF SUBJECTS 
 
3.3.1. OVERVIEW OF TREATMENTS ADMINISTERED 
 
Eligible subjects will be randomly assigned to one of the following treatment groups: 
 
 ALX-0171 dose level 1: target dose of 1.5 mg/kg  
 ALX-0171 dose level 2: target dose of 3.0 mg/kg  
 ALX-0171 dose level 3: target dose of 6.0 mg/kg  
 ALX-0171 dose level 4: target dose of 9.0 mg/kg  
 Matching Placebo 
 
Study drug will be administered via inhalation, using a dedicated vibrating mesh nebulizer.  
 
• Vibrating mesh type nebulizers are considered the most appropriate technology for 
nebulization of a therapeutic protein such as ALX-0171 Nanobody.  
• The FOX-Flamingo nebulizer (Vectura GmbH, Germany) was developed concurrently with 
the study drug. The nebulizer is a battery-operated, hand-held device, intended for 
single-patient use. The device provides an aerosol with particle size suitable for the 
intended study population (~3 µm).  
• The nebulizer is always to be used with a flow of 2 L/minute additional air or oxygen (to 
be decided by the Investigator based on oxygen need of the subject). 
 
The formulation of ALX-0171 (and matching placebo) was developed specifically as a liquid 
solution for inhalation, to ensure rapid delivery of the study drug to the site of RSV 
infection, and to maintain product quality and stability in combination with the nebulization 
protocol.  
 
• The formulation buffer is comparable to a normal 0.9% saline solution with respect to 
salt content but has additional buffering capacity. The osmolality and ion concentration of 
the (isotonic) solution were chosen to be within the physiological range. The phosphate 
buffer helps to maintain constant pH, and therefore, to guarantee stability of the drug.  
• All excipients comply with the European Pharmacopoeia and the United States 
Pharmacopeia.  
• The formulation contains no antimicrobial preservatives or tension active agents 
(surfactants), and no coloring agents, flavors, or sugars/sweeteners are present. 
Correspondingly, the nebulizer solution does not have a specific taste or odor. 
 
The use of formulation buffer as placebo is considered appropriate, as it is the most 
representative control for the active study drug, while the minute amounts of phosphate 
present in the buffer would not be expected to result in effects different from saline. 
Throughout the clinical studies conducted with ALX-0171 and placebo, there were no 
consistent findings that would suggest a direct effect of the formulation buffer on respiratory 
parameters. 
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Details on initiation, interruptions and completion of study drug administration, will be 
collected in the electronic case report form (eCRF), as will the acceptability of the face mask 
and nebulizer and whether or not correct administration was achieved. 
  
3.3.2. SELECTION OF DOSES IN THE STUDY 
 
The dose range proposed to be studied in ALX0171-C203 was selected based on the results 
of study ALX0171-C104 (Phase 1/2a first-in-infant study), and includes the doses currently 
being evaluated in ongoing study ALX0171-C201 (Phase 2b dose-range finding study 
conducted outside of Japan).  
 
 The starting dose for ALX0171-C203 (target average dose: 1.5 mg/kg ALX-0171) is the 
same as the dose evaluated in the first-in-infant study (target minimal dose 1.2 mg/kg 
ALX-0171). This dose was selected for the first-in-infant study based on a physiologically 
based PK (PBPK) model that bridged nonclinical, human adult and human pediatric PK 
characteristics by taking into account growth and developmental processes such as organ 
maturation, changes in blood flow, body composition, and ontogeny of elimination 
mechanisms [24]. In total, 53 infants and young children hospitalized for RSV LRTI were 
included in study ALX0171-C104. The results indicated that this dose was well tolerated 
in all age groups (28 days to 24 months). Reductions in nasal viral load (obtained from 
nasal swab specimens) were noted, confirming that ALX-0171 exhibits antiviral activity 
when relevant concentrations are achieved.  
 As the ALX-0171 serum concentrations measured in the first-in-infant study were below 
the initial PBPK model predictions, higher doses (mean target doses of 3, 6, and 9 mg/kg 
ALX-0171) were selected for the subsequent dose-range finding study ALX0171-C201, 
aiming to attain higher local (lung) concentrations. The dose selection of study 
ALX0171-C201 was based on data from nonclinical and clinical studies, and maintains 
adequate safety margin compared to nonclinical and clinical studies (see below). Study 
ALX0171-C201 is currently ongoing outside of Japan. 
 
The three higher dose levels for study ALX0171-C203 (3.0, 6.0 and 9.0 mg/kg ALX0171) 
are the same as those evaluated in ALX0171-C201. As shown in Figure 4, the expected 
plasma concentrations (at 6 hours post-dose) in study ALX0171-C203 (and study 
ALX0171-C201) do not exceed those measured previously in studies in adults.  
 
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Figure 4: 
Comparison 
of 
observed 
and 
extrapolated 
ALX-0171 
plasma 
concentration in pediatric population with adult observed Cmax at 
200 mg QD and 105 mg BID repeated dose 
 
 
 
Cmax=peak plasma concentration; BID=twice a day; QD=once a day.  
Boxplots indicating median, upper, and lower quartile. The notches are the estimation of the 95% confidence 
interval. Black dots are 3 outliers reported in study ALX0171-C104. Y-axis is in logarithmic scale. Only 
quantifiable values were considered for the ALX0171-C104 study and the extrapolation of higher doses. 
The difference between the 1.2 mg/kg dose from the ALX0171-C104 study and the 1.5 mg/kg dose in study 
ALX0171-C203 is negligible, as the two dose ranges largely overlap. No separate boxplot was included. 
 
Safety margins were calculated based on results obtained in a pivotal toxicity study 
conducted in Sprague Dawley rats after 14 day repeated administration via inhalation (see 
IB). Supportive information from (i) a PK study in juvenile rats after single or repeated 
inhalation, and (ii) a neonatal lamb study after single dose in uninfected animals and after 
repeated dose in RSV uninfected or RSV-infected animals did not yield unexpected retention 
of ALX-0171 in tissue or plasma. Concentrations in lung in juvenile rats were somewhat 
lower when compared to adult rats, with high variability to be considered in the study. No 
safety signals were detectable in either study in neonatal or juvenile animals. Based on the 
available information, a correction of calculations based on the GLP-generated data in the 
toxicity studies was not considered warranted. 
 
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 For calculating the safety margins, in vitro Sophia anatomical infant nose-throat (SAINT) 
model data was used to predict the ALX-0171 dose that will come into contact with the 
infants. The inhaled dose (i.e., the lung dose and the dose deposited in the 
nasopharyngeal airways) and the dose on the face/oral cavity were taken into 
consideration and were experimentally shown to be 29.1% of the nebulizer filling dose. 
This fraction of the nebulizer filling dose is assumed to be totally deposited in the lungs. 
This was assumed as “maximally expected local exposure”. 
 The maximally expected local exposure in pediatric subjects was compared to the highest 
lung exposure achieved in the pivotal nonclinical toxicity study (the 14-day repeated 
dose toxicity study after daily administration via inhalation in rats; see IB). In this study, 
no AEs were observed, so the highest dose administered (117 mg/kg) was considered 
safe. Assuming 10% lung deposition in rat, the highest local dose achieved was 
11.7 mg/kg or 2.3 mg/g lung (female numbers were used as these were lower than 
males).  
 Local safety margins were calculated taking the 29.1% fraction of the nominal dose in 
the planned clinical study. With a maximal nominal dose of 10.7 mg/kg (see 
section 3.3.4), and assuming a 1.8% lung weight to body weight ratio [25], the 
calculated maximal deposited dose is 0.17 mg/g lung in the planned pediatric population. 
 The corresponding safety margin was calculated as the ratio between maximal achieved 
dose in rat (2.3 mg/g lung) to maximal calculated deposited dose in patients (0.17 mg/g 
lung), which results in a safety margin of ≥ 13.3. 
 
3.3.3. IDENTITY OF STUDY DRUG 
ALX-0171 and matching placebo will be provided in sterile, preservative-free, masked 
depyrogenated single-use DIN 2R glass vials, with injection stoppers and aluminium 
crimped caps. Each vial contains ≥ 2 mL nebulizer solution (target fill volume: 2.2 mL).  
 
ALX-0171  
 
 Formulation: nebulizer solution 
 Route of administration: inhalation (to be administered via the FOX-Flamingo inhalation 
system) 
 Active substance: ALX-0171 Nanobody 
 Activity: ALX-0171 Nanobody specifically and potently binds to the RSV F protein, 
thereby inhibiting an early step in the viral replication cycle.  
 Composition: 
 
  
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Matching placebo  
 
 Formulation: nebulizer solution 
 Route of administration: inhalation (to be administered via the FOX-Flamingo inhalation 
system) 
 Active substance: None 
 Activity: None  
 Composition: 
 
 
 
Device 
 
 Name: FOX-Flamingo inhalation system - CE marked (Figure 5).  
 Main components: re-usable single-patient base unit (containing the electronics), 
disposable inhalation set (including pediatric face mask in 2 sizes, mask adapter, 
vibrating mesh nebulizer reservoir). 
 Description: Vibrating mesh type nebulizers are considered the most appropriate 
technology for nebulization of a therapeutic protein such as ALX-0171 Nanobody. The 
FOX-Flamingo inhalation system consists of a battery-operated, hand-held device, 
intended for single-patient use. The device provides an aerosol with particle size suitable 
for the intended study population. The nebulizer is always to be used with a flow of 
2 L/minute additional air or oxygen. 
 
Instructions for preparation, use and handling of study medication, the appropriate volume 
to be administered and the materials to be used are provided in a manual concerning study 
drug. Instructions for use for the FOX-Flamingo nebulizer are also provided. 
 
Figure 5: Overview of the FOX-Flamingo inhalation system 
 
 
 
 
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3.3.4. STUDY DRUG ADMINISTRATION 
 
Four doses are planned to be evaluated. The precise dose administered depends on the 
subject’s weight: the drug volume filled into the nebulizer (nominal dose range) is 
calculated per weight category range (see Table 1). 
 
• Dose 1: target dose of 1.5 mg/kg (depending on the subject’s weight category, the actual 
nominal dose of 1.5 mg/kg is between 1.3 and 2.0 mg/kg) 
• Dose 2: target dose of 3.0 mg/kg (depending on the subject’s weight category, the actual 
nominal dose is between 2.5 and 3.6 mg/kg) 
• Dose 3: target dose of 6.0 mg/kg (depending on the subject’s weight category, the actual 
nominal dose is between 5.0 and 7.1 mg/kg) 
• Dose 4: target dose of 9.0 mg/kg (depending on the subject’s category, the actual 
nominal dose is between 7.6 and 10.7 mg/kg) 
 
An overview of the appropriate volumes to be filled into the nebulizer, and an indication for 
minimum and maximum nebulization times, is available in Table 1. The administered dose 
of ALX-0171 is standardized for body weight categories. This is supported by adequate 
safety margins (see section 3.3.2), and also takes into account feasibility of accurately 
measuring and filling the appropriate volume into the nebulizer with a graduated syringe.  
 
The study drug will be administered as a single nebulization. However, due to limitations in 
the volume that can be filled into the nebulizer, 2 consecutive nebulizations are necessary 
for the administration of the highest dose (9 mg/kg) in subjects weighing ≥ 10 kg. 
 
Study drug administration should start within 3 hours following randomization. Subsequent 
doses of study drug will be administered at 24-hour intervals (±4 hours) relative to the first 
dose. No pre-medication is required per protocol, but an inhaled β2-agonist may be 
administered at the discretion of the treating Investigator. 
 
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Table 1: 
Study drug nebulizer filling volumes and nebulization times by dose  
Weight 
category 
Fill volume (and approximate nebulization time) 
Dose 1 
(1.5 mg/kg) 
Dose 2 
(3 mg/kg) 
Dose 3 
(6 mg/kg) 
Dose 4 
(9 mg/kg) 
3.0 to <4.0 kg 
0.10 mL 
(~20-40 sec) 
0.20 mL 
(~30-80 sec) 
0.40 mL 
(~65-180 sec) 
0.60 mL 
(~100-290 sec) 
4.0 to <5.0 kg 
0.15 mL 
(~25-60 sec) 
0.25 mL 
(~40-105 sec) 
0.50 mL 
(~80-230 sec) 
0.75 mL 
(~130-380 sec) 
5.0 to <7.0 kg 
0.20 mL 
(~30-80 sec) 
0.35 mL 
(~55-155 sec) 
0.70 mL 
(~120-350 sec) 
1.05 mL 
(~195-580 sec) 
7.0 to <10.0 kg 
0.25 mL 
(~40-105 sec) 
0.50 mL 
(~80-230 sec) 
1.00 mL 
(~180-545 sec) 
1.50 mL 
(~310-930 sec) 
10.0 to <12.0 kg 
0.35 mL 
(~55-155 sec) 
0.65 mL 
(~110-320 sec) 
1.30 mL 
(~255-770 sec) 
1.50 mL 
(~310-930 sec) 
+ 0.45 mL 
(~70-205 sec) 
12.0 to <15.0 kg 
0.40 mL 
(~65-180 sec) 
0.75 mL 
(~130-380 sec) 
1.50 mL 
(~310-930 sec) 
1.50 mL 
(~310-930 sec) 
+ 0.75 mL 
(~130-380 sec) 
Note: Indicative values given as minimum and maximum nebulization times. 
 
 
3.3.4.1. ADMINISTRATION PROCEDURE 
 
The FOX-Flamingo nebulizer features a tubing connector for air or oxygen supply, and is 
always to be used with a fixed 2 L/minute flow of air, or if needed, oxygen (to be decided by 
the Investigator based on oxygen need of the subject).  
 
 During administration, the face mask should always be in contact with the face of the 
subject: a close fit is essential for appropriate dose administration. Hence, administration 
by “blow by” technique (i.e., hovering the face mask in front of the child during 
administration) is not permitted. 
 At the start of each study drug nebulization, the face mask (connected to the nebulizer) 
will be placed on the subject’s face, and must be verified as being in contact with the 
face. If applicable, the subject’s nasal cannula, face mask, or headbox will need to be 
removed immediately before administration of the study drug (air or oxygen are provided 
through the nebulizer). A nasogastric tube, if used, is to remain in place.‡‡  
 
                                                   
‡‡ Presence of the nasogastric tube has a negligible influence on the inhaled dose of study drug. 
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 Once the subject is able to breathe comfortably in the face mask, the nebulization 
procedure should be started.  
 Nebulization should proceed as long as aerosol is visible in the transparent face mask. 
 
3.3.4.2. ADDITIONAL GUIDANCE  
 
If dosing cannot be initiated successfully (e.g., because the subject is so agitated as to 
prevent adequate contact of the face mask with the face, and/or is crying or coughing 
intensely), new attempts should be made within a maximum of 1 hour (60 minutes) of 
nebulizer filling. 
 
• If on Day 1, study drug initiation has not been successful after 60 minutes§§, the subject 
will be withdrawn from the study (see section 3.4).  
• If on Day 2 or Day 3, study drug initiation‡‡ has not been successful after 60 minutes, 
study drug treatment should be discontinued (i.e., in case dose initiation was not 
successful on Day 2, then no dosing on Day 3 should be done). The subjects should 
remain in the study and all per protocol visits should be conducted according to the 
Schedule of Assessments. 
 
The timing of nebulization should be as close to the timeframes specified in the Schedule of 
Assessments as possible.  
 
If the nebulization procedure is started successfully but cannot be continued and needs to 
be interrupted (e.g., because the subject starts crying intensely, or if the face mask loses 
adequate contact with the subject’s face), study drug administration is to be stopped and 
resumed as soon as possible. Study drug administration should be completed within 2 hours 
(120 minutes) from nebulizer filling for this nebulization. Subsequent daily study drug 
administration should continue per protocol.  
 
For subjects weighing ≥ 10 kg in the 9 mg/kg dose group, the second of the 2 serial 
nebulizations should be initiated as soon as possible after the end of the first nebulization 
and should be completed within 2 hours (120 minutes) from nebulizer filling for this 
nebulization. In case the study drug administration of the second nebulization was started 
successfully but could not be completed, appropriate documentation is needed in the 
medical file and eCRF but subsequent daily study drug administration should continue per 
protocol. 
 
The exact times of study drug administration (i.e., initiation and end of each nebulization) 
and number of interruptions, if any, will be recorded in the eCRF. In addition, acceptability 
of the face mask and the nebulizer after each complete or partial administration, and 
                                                   
§§ In case of subjects weighing ≥ 10 kg in the 9 mg/kg dose group, this refers to the first of 2 serial nebulizations.  
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whether or not correct and complete administration could be achieved will be documented in 
the eCRF. 
 
The product-contacting parts of the nebulizer (i.e., the nebulizer mesh/head and fill 
reservoir, mask adapter, and face mask) are to be disposed of after each nebulization; only 
the base unit containing the electronics and the air/oxygen tubing will be reused (per 
subject and per 3-day treatment window). After completing the study drug treatment 
period, the base unit of the nebulizer must be safely disposed in a secured environment for 
further return to the sponsor or designee (e.g., delegated CRO). 
 
3.3.4.3. MANAGEMENT OF OVERDOSE 
 
The intended dose of ALX-0171 should not be exceeded during the study. No antidote is 
available.  
 
Overdoses that occur during the study should be documented and reported to the Sponsor 
or designee whether or not it results in an AE/SAE. Overdoses with signs and symptoms 
need to be reported as an AE/SAE. For information on medication errors, please refer to 
section 4.2.1. 
 
3.3.5. DRUG ACCOUNTABILITY 
 
The 
Pharmacist, 
the 
Investigator 
or 
his/her 
designee 
is 
responsible 
for 
the 
acknowledgement of receipt for each shipment of study drug/inhalation system and will 
verify the condition and quantity of the study drug and other clinical supplies related to 
Investigational Medicinal Product (IMP) administration. 
 
At study site, the study drug will be kept in a locked and secured storage facility accessible 
only to those authorized by the Investigator to dispense the study drug. 
The responsible person will keep an inventory. This will include the quantity of study 
drug/inhalation system received for the study and a record of the materials that are 
dispensed, to whom (subject number) and when. 
 
The pharmacist, the Investigator and/or designated personnel will conduct a final inventory 
of the study drug/inhalation system and will record the results of this inventory. Upon 
Sponsor approval, all study drug and clinical supplies will be returned to the depot, or will 
be destroyed locally according to local regulations and site procedures. 
Instructions for drug/inhalation system accountability are available in the manual 
concerning study drug. 
 
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3.3.6. STUDY DRUG HANDLING 
 
Instructions for study drug receipt, handling, storage and administration are available in the 
manuals concerning study drug and IWRS/IVRS. 
 
Packaging and Labeling 
Final packaging and labeling will comply with the local regulatory requirements. Details on 
packaging and labeling are provided in the study drug manual.  
 
Storage  
Study drug will be provided under refrigerated conditions and must be stored in a secure, 
limited-access location protected from light and under the storage conditions specified by 
the Sponsor.  
 
Study drug must be refrigerated at 2°C to 8°C and should be stored in the secondary 
packaging until administration. It should not be frozen or shaken.  
 
Site storage conditions should be monitored by the site personnel and reviewed by the 
monitor during site visits. Deviations from the storage requirements must be documented 
and reported to the Sponsor, according to the instructions provided in the manual 
concerning study drug.  
 
Dispensing 
The 
Investigator 
or 
qualified 
designee(s) 
will 
dispense 
(via 
IWRS/IVRS) 
study 
drug/inhalation system to subjects who have met the entry criteria. Clinical supplies 
(including study drug) may not be used for any purpose other than that which is stated in 
this protocol. 
 
Product Quality Complaint 
Product quality complaints have to be communicated (written or electronically) to the 
Sponsor. Instructions for product quality complaint handling are available in the manual 
concerning study drug. 
 
For medical device issues see section 4.2.2.   
 
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3.3.7. CONCOMITANT THERAPY 
 
Any 
concomitant 
medication 
(including 
over-the-counter 
medications 
and 
herbal 
supplements) taken during the study (i.e., from signing of the ICF until the subject’s last 
visit), must be recorded in the eCRF. Items to be recorded concerning concomitant 
medication include: dose and units of dose, start and end date, administration frequency, 
route of administration, therapeutic indication, brand name (or generic name if brand name 
is not available). Of note, previous medications relevant for eligibility will also be recorded in 
the eCRF.  
 
3.3.7.1. STANDARD OF CARE TREATMENT 
 
The treatment and care provided to each subject are determined by the Investigator (or 
designee) according to institutional practice. The recommendations on the diagnosis, 
management, and prevention of bronchiolitis, as described by the American Academy of 
Pediatrics [1], may be followed in addition to institutional practice.  
 
Treatment may include (but is not limited to) the following: 
 
 
Oxygen supplementation through nasal cannula, via face mask or headbox. The 
initiation, monitoring and weaning of oxygen supplementation will follow local practice. 
It should be removed for the nebulized study drug administration, during which air or 
oxygen flow of 2 L/minute is provided 
 
Fluid/food supplementation (i.v. or via nasogastric tube, if applicable) 
 
Antipyretics and/or nonsteroidal anti-inflammatory medication 
 
Inhalation of hypertonic saline (but not within 4 hours before start or 4 hours after the 
EOS drug administration) 
 
Short acting β2-agonists 
 
Antibiotics (in case of secondary bacterial infection) 
 
Epinephrine  
 
Anticholinergics 
 
Apart from those listed under the prohibited medications (see below), concomitant 
medications are permitted at the Investigator’s discretion (based on medical need). 
 
3.3.7.2. PROHIBITED MEDICATIONS 
 
The following medications are prohibited up to the FU visit (Day 14 ±2 days): 
 
 Ribavirin, i.v. immunoglobulin and palivizumab Heliox  
 Leukotriene receptor antagonists (LTRAs, i.e. montelukast) and/or sodium cromoglycate; 
initiation of LTRAs and/or sodium cromoglycate is not permitted; infants who are on a 
maintenance therapy at screening are to continue their usual dose during the study. 
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 Exogenous surfactant  
 Systemic corticosteroids; initiation of inhaled corticosteroids is not permitted; infants who 
are on a maintenance therapy of inhaled corticosteroids at screening are to continue their 
usual dose during the study. Of note, topical corticosteroids for the treatment of skin 
disorders are permitted.  
 Mucolytics are permitted until screening but their continuation or initiation during the 
study is not allowed.  
 
Subjects 
whose 
respiratory 
condition 
is 
deteriorating 
(e.g., 
hypercapnia 
with 
pCO2>8 kPa/60 mmHg, 
decreased 
consciousness) 
and 
need 
to 
start 
non-invasive 
respiratory support or invasive ventilation need to discontinue study drug treatment but 
should remain in the study according to the in-hospital post-treatment period as specified in 
the Schedule of Assessments, and should also attend the FU and EOS visits.  
 
Subjects on HFOT as standard of care at inclusion and for whom the flow needs to be 
increased to levels not enabling study drug nebulization and/or above 2 L/kg/minute also 
need to discontinue study drug treatment and be further followed up as described above. 
SAE reporting is required for these subjects with deterioration of the respiratory condition 
requiring above mentioned methods of ventilation. 
 
After the end of the subject’s participation in the study, each subject is to be treated 
according to standard clinical practice. 
 
3.3.8. TREATMENT COMPLIANCE 
 
Study drug will be administered by a health care professional in hospital, ensuring 
treatment compliance. 
 
The exact times of study drug administration (i.e., initiation and end of each nebulization 
and number of interruptions, if any) will be recorded in the eCRF. In addition, acceptability 
of the face mask and the nebulizer after each complete or partial administration, and 
whether or not correct and complete administration could be achieved will be documented in 
the eCRF. Compliance will be further confirmed by bioanalytical assessment of ALX-0171 in 
blood samples, and could be further confirmed by electronic documentation of the 
administration on the nebulizer base unit. 
 
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3.4. WITHDRAWAL AND 
DISCONTINUATION CRITERIA 
 
3.4.1. WITHDRAWAL FROM THE STUDY 
 
Every reasonable attempt should be made by the Investigator (or his/her designee) to keep 
subjects in the study, however, a subject must be withdrawn from the study if: 
 
 Study drug administration cannot be successfully initiated on Day 1 (see section 3.3.4.2). 
 The Investigator considers it, for safety reasons, in the best interest of the subject. 
 The parent(s)/legal guardian(s) withdraw(s) consent. 
 
A subject may be withdrawn from the study if the subject and/or parent(s)/legal 
guardian(s) fail to comply with dosing, evaluations, or other requirements of the study. 
 
In case a subject is withdrawn from the study for any reason other than death, lost to 
follow-up or informed consent withdrawal (including subjects randomized but not dosed), a 
Withdrawal visit should be conducted at the time of withdrawal.  
 
The reason for withdrawal should be recorded in the eCRF. Investigators (or their 
designees) must attempt to contact the parent(s) or legal guardian(s) of subjects who fail to 
attend scheduled visits by telephone or other means, to exclude the possibility of an AE 
being the cause of withdrawal. Should this be the cause, the AE must be documented, 
reported, and followed-up as described in section 4. 
 
If a subject is withdrawn from the study, the study monitor and the Sponsor are to be 
informed immediately.  
 
3.4.2. DISCONTINUATION OF STUDY DRUG  
 
A subject must be discontinued from study drug treatment if: 
 
 The randomization code is broken prematurely by the Investigator or Sub-Investigator. 
 A severe and/or serious hypersensitivity reaction to study drug occurs. 
 A severe and/or serious acute respiratory distress reaction induced by study drug 
administration occurs. 
 The subject needs to start treatment with one of the medications listed as prohibited (see 
section 3.3.7). 
 The subject needs to start non-invasive respiratory support, invasive ventilation or HFOT 
at levels not enabling removal of the cannula for administration of the study drug 
nebulization and/or levels exceeding 2 L/kg/min. The event will be captured as an SAE 
and will be monitored until resolution, as described in section 4.1.4. 
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 If the Investigator or the Sponsor / medical monitor deems it is in the subject’s best 
interest. 
 If on Day 2 or Day 3, study drug initiation*** has not been successful after 60 minutes, 
study drug treatment should be discontinued (i.e., in case dose initiation was not 
successful on Day 2, then no dosing on Day 3 should be done). 
 
A subject may be discontinued from study drug treatment if an SAE occurs (if considered 
necessary or appropriate by the Investigator). 
 
For subjects remaining hospitalized after study drug treatment discontinuation, in-hospital 
post-treatment assessments will be performed in addition as specified in the Schedule of 
Assessments. Subjects who discontinued treatment prematurely (for any reason) should 
also attend the FU and EOS visits. 
 
If a subject is discontinued from the study drug, the study monitor and the Sponsor are to 
be informed immediately. 
 
3.5. STUDY TERMINATION 
 
If the Sponsor decides not to start the study prior to commencement of any protocol 
activities, and/or after Institutional Review Board (IRB) approval have been received, the 
Investigator or Sponsor must notify the IRB by letter outlining the reasons for abandonment 
of the study, as required per national regulations. 
 
At any time during the study, the Sponsor may suspend or terminate the study or part of 
the study for any reason. If the Investigator plans to suspend or terminate participation in 
the study, the Investigator will promptly inform the Sponsor and the IRB and provide them 
with a detailed written explanation.  
 
Upon study completion, the Sponsor will provide the Investigator, IRB with final reports and 
summaries as required by regulations.  
 
In case of suspension or halt due to safety reasons, the IRB will be notified immediately and 
at the latest within the number of days as specified by local regulations after the study is 
halted, clearly explaining the reasons, and describing follow-up measures, if any, taken for 
safety reasons. 
 
The IDMC, consisting of an independent group of clinical experts will review the available 
cumulative safety data (i.e., all data from prior visits of all subjects including preceding 
cohorts). The IDMC will advise the sponsor concerning continuation, modification or 
potential early termination of the study after every meeting (also see section 3.1.1). 
                                                   
*** In case of subjects weighing ≥ 10 kg in the 9 mg/kg dose group, this refers to the first of 2 serial nebulizations.  
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3.6. STUDY ASSESSMENTS 
 
3.6.1. TIMING OF ASSESSMENTS 
 
3.6.1.1. ELIGIBILITY PROCEDURES 
 
Study related procedures will be done after informed consent has been obtained, after 
which each subject will be assigned his/her unique subject identification (ID) number. The 
date of obtaining written informed consent will be recorded in the eCRF. AEs will be 
recorded from time of obtaining written informed consent to the subject’s last visit. 
 
A signed and dated ICF must be obtained from the parent(s)/legal guardian(s) or legally 
acceptable representative(s) before any study-specific procedures are performed.  
 
The screening process begins when written informed consent has been obtained and 
continues until randomization. Subjects must be randomized within 24 hours of arrival at 
the hospital/emergency unit. 
 
3.6.1.2. SCREENING 
 
Screening assessments and procedures should take place within 24 hours prior to 
randomization and as specified in the Schedule of Assessments. 
 
Screening procedures/measurements include: 
 
 Informed consent 
 Inclusion/exclusion criteria 
 RSV diagnosis 
 12-lead ECG 
 Demographics and medical history 
 Previous and concomitant medications 
 Physical examination 
 Body weight, height and temperature 
 Heart rate and SpO2 
 Feeding, general appearance, lung auscultation, respiratory muscle retractions, 
respiratory rate, daytime coughing, night-time coughing,  
 Hospitalization information: ICU transfer, apnea episodes, ventilation information, 
discharge from ICU/hospital  
 Parent(s)/caregiver(s) assessment by completion of a diary including scoring of 
respiratory symptoms and assessing the global condition of the subject 
 Blood sample for clinical laboratory  
 Blood sample for immunogenicity (ADA) 
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Data of all subjects screened will be collected in the eCRF in order to assess the numbers 
and demographic characteristics of the excluded subjects, and the reasons for their 
exclusion, including documentation of AEs. In case an SAE occurs, this needs to be reported 
according to standard process (see section 4.1.4). 
 
The results of the screening procedures needed to evaluate eligibility must be available prior 
to randomization.  
 
3.6.1.3. RANDOMIZATION 
 
After obtaining written informed consent from the parent(s)/legal guardian(s) or legally 
acceptable representative(s) and screening procedures, eligible subjects will be randomized 
to the different treatment groups. Randomization should take place within 24 hours from 
arrival at the hospital/emergency unit. 
 
At the time of randomization, subjects should be eligible for study participation as defined in 
the inclusion/exclusion criteria. Therefore, at a minimum, the SpO2, feeding, respiratory 
muscle retractions, and respiratory rate should be evaluated on Day 1 before randomization 
and dosing, unless these assessments were already performed within the last 3 hours 
before randomization. 
 
At screening, subjects will receive a unique ID number, assigned by IWRS/IVRS. At 
randomization, subjects will be assigned a randomization number by IWRS/IVRS prior to 
study drug administration according to the randomization scheme. 
 
Sequential dose escalation will be used to enable appropriate safety follow-up. Each of the 
4 cohorts will consist of 15 subjects randomized and treated in a 4:1 ratio to receive either 
ALX-0171 or placebo (N=12 active versus N=3 placebo per cohort). After each cohort (the 
last subject in the cohort has completed the treatment period), an IDMC will review the 
available cumulative safety data and advise the Sponsor on proceeding to the subsequent 
cohort (i.e., the next higher dose). 
 
3.6.1.4. STUDY DRUG TREATMENT PERIOD 
 
During the study drug treatment period, assessments should be performed as specified in 
the Schedule of Assessments. 
 
If screening assessments are performed within 3 hours before the first dose on Day 1, the 
Day 1 pre-dose assessments do not need to be repeated; only the remaining assessments 
planned on Day 1 (pre-dose) will need to be performed. 
 
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Subjects will receive once-daily administration of study drug on 3 consecutive days. The 
first dose of study drug is to be administered as soon as possible and within 3 hours after 
randomization. Study drug administration should take place within 24 hour intervals 
(±4 hours) relative to the start of the first nebulization of the first dose. For subjects 
requiring 2 serial nebulizations (subjects weighing ≥10 kg in the 9 mg/kg dose group), the 
timing of study drug administrations should be relative to the start of their first nebulization. 
 
For all subjects, the exact date, start and end time (and number of interruptions, if any) of 
the study drug nebulizations will be collected in the eCRF. 
 
Hospitalization information will be collected throughout the study, including occurrence of 
ICU transfer, apnea episodes, initiation and type of ventilation and hospital/ICU discharge 
information. Assessment of Clinical Response will be done with collection of date and time of 
adequate oral feeding as well as adequate stable oxygen saturation on room air of ≥ 95% 
for at least 4 hours to enable discharge. In case of oxygen supplementation, the level of 
supplementation is to be considered for reduction at least three times per day. Provided 
oxygen saturation is stable, attempts to remove the supplementation will be done at least 
three times a day. 
 
After the 3 days of treatment and provided that the clinical response criteria have been met 
(which are based on adequate oral feeding and oxygen saturation), discharge from the 
hospital can take place per protocol at the Investigator’s discretion from dosing on Day 3 
onwards (after all required post-dose assessments have been completed).  
 
3.6.1.5. IN-HOSPITAL POST-TREATMENT PERIOD 
 
Subjects who are not discharged from the hospital after completion of the treatment period 
or subjects remaining hospitalized after study drug treatment discontinuation will enter an 
in-hospital post-treatment period with assessments in the morning and evening until 
discharged. 
All assessments will be performed as specified in the Schedule of Assessments.  
 
For subjects in the in-hospital post-treatment period, the mid-turbinate nasal swab should 
be collected only on the day of hospital discharge. 
 
3.6.1.6. WITHDRAWAL VISIT 
 
In case a subject is withdrawn from the study for any reason other than death, lost to 
follow-up or informed consent withdrawal (including subjects randomized but not dosed), a 
Withdrawal visit should be conducted at the time of withdrawal. The reason for withdrawal 
should be recorded in the eCRF. 
 
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If the Withdrawal visit assessments are performed within 6 hours after the Day 1, Day 2, 
Day 3, or in-hospital post-treatment day assessments have been performed, the 
assessments already done at the prior time point do not need to be repeated and only the 
additional assessments to be performed on the Withdrawal visit will need to be performed. 
No EOS visit needs to be performed after the Withdrawal visit. 
 
3.6.1.7. FOLLOW-UP AND END-OF-STUDY VISITS 
 
Subjects who have received at least one dose of study medication should complete a FU 
visit on Day 14 (±2 days), and an EOS visit on Day 28 (±2 days). After the end of the 
subject’s participation in the study, each subject is to be treated according to standard 
clinical practice. 
 
3.6.1.8. UNSCHEDULED VISITS 
 
Unscheduled visits may be conducted to assess and follow-up on AEs or laboratory 
abnormalities. In such cases, the evaluations performed are at the discretion of the 
Investigator. Findings during these Unscheduled visits should be reported in the designated 
sections of the eCRF.  
 
In case a subject is re-hospitalized, or when the Investigator is consulted for a respiratory 
condition occurring after discharge from the hospital (up to the EOS [Day 28] visit), an 
Unscheduled Visit is to be performed. In such cases, a mid-turbinate nasal swab is to be 
collected and a physical examination, including lung auscultation, must be performed.  
 
3.6.1.9. MISSED VISITS 
If a subject misses a study visit for any reason, the Medical Monitor should be contacted as 
soon as possible to discuss rescheduling options of the missed visit to be proposed to the 
subject’s parent(s)/legal guardian(s). For subjects who are considered lost to follow-up, 
reasonable attempts must be made (and documented) to obtain information on the subject. 
 
3.6.2. BASELINE CHARACTERISTICS 
 
Demographic and medical history data (including RSV-related signs and symptoms) will be 
collected at screening. 
 
Collected data will include (but are not limited to): month and year of birth, age (with 
indication of week), gender, race and ethnicity. 
 
Data on atopy in the family, environmental exposure to tobacco, pets and breastfeeding will 
also be collected. 
 
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The mid-turbinate nasal swab sample collected pre-dose on Day 1 will be used to test for 
concurrent viruses and the presence of mycoplasma at baseline. 
 
3.6.3. SAFETY ASSESSMENTS 
 
The safety and tolerability profile of ALX-0171 will be collectively assessed with the following 
outcome measures: 
 
 TEAEs as noted by healthcare staff and/or reported by parents/caregivers. The 
Investigator (or his/her designee) will review at each visit whether AEs/SAEs have 
occurred since the last visit.  
 Heart rate, respiratory rate (measured over a 1-minute interval) and SpO2. 
 Body temperature and body weight. 
 Physical examination including the skin, ears/nose/throat, heart auscultation, lung 
auscultation, and abdomen.  
 Clinical laboratory test results 
 
At each of the time points indicated in the Schedule of Assessments, a physical examination 
should be performed, including heart auscultation, examination of abdomen, skin and 
ears/nose/throat. Lung auscultation is to be performed more frequently and is therefore 
listed separately in the Schedule of Assessments. 
 
The parent(s)/legal guardian(s) will receive a subject card, indicating the address and phone 
number of the Investigator and/or other relevant emergency contact details (including e.g., 
subject number, medication number). The subject’s parent(s)/legal guardian(s) will be 
advised to carry this card with them throughout the study so that the appropriate actions 
can be undertaken in case of emergency. They will also be advised to contact the 
Investigator (or his/her designee) with any medical and/or safety concern. 
 
In order to appropriately document possible events after discharge from the hospital, a 
diary will be completed by the parent(s) or caregiver(s) and be brought to the site at the FU 
visit on Day 14 and EOS visit on Day 28. 
 
3.6.3.1. ADVERSE EVENTS 
 
Definitions and general information on evaluation and reporting of AEs/SAEs and adverse 
drug reactions are provided in section 4. 
 
3.6.3.2. HEART RATE AND SPO2 
Continuous monitoring of SpO2 needs to be done during the study drug treatment period 
and the in-hospital post-treatment period until the clinical response criterion for oxygen 
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saturation on room air (SpO2 ≥ 95% for at least 4 hours) has been met and/or in case 
saturation monitoring is to be continued according to the Investigator’s judgment.  
 
The values for these parameters will be regularly captured in the eCRF (together with e.g., 
oxygen flow delivered and method), according to the Schedule of Assessments. In addition, 
the date and time of achieving the clinical response criterion for oxygen will be collected in 
the eCRF (CFR clinical response information collection). 
 
Clinically significant changes from baseline (warnings and measurements) during the pulse 
oximetry monitoring period are to be captured as AEs in the eCRF. 
 
Evolution of the heart rate and oxygen saturation levels can also inform on clinical activity 
outcome. 
 
3.6.3.3. CLINICAL LABORATORY ASSESSMENTS 
 
Blood samples for clinical laboratory analyses will be collected at the time points indicated in 
the Schedule of Assessments.  
 
Safety laboratory assessments are planned two times during the study (at screening and at 
the FU/Withdrawal visit) and will be performed by the local laboratory in order to allow 
timely availability of the results. For local laboratory data, the local normal ranges and 
laboratory accreditation must be collected/provided. 
 
If all hematology and biochemistry blood parameters required for the study are already 
known from analysis done as a routine assessment upon arrival at the hospital, collection of 
screening clinical laboratory samples does not need to be repeated for the purpose of this 
study. However, the samples should be analyzed at the same local laboratory that will be 
used for the remainder of the study. 
 
The blood samples will be collected according to the site’s standard practice. Anesthetic 
cream or spray can be used to minimize the subject’s discomfort and distress.  
 
The following tests will be included in the clinical laboratory analysis: 
 
 Clinical chemistry: alanine aminotransferase, aspartate aminotransferase, creatinine, 
sodium, potassium, chloride, C-reactive protein, γ-glutamyl-transferase, blood urea 
nitrogen 
 Hematology: hemoglobin, hematocrit, red blood cell count and indices, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration, platelet count (or estimate), 
white blood cell count including differential (lymphocytes, neutrophils, monocytes, 
basophils, eosinophils). 
 
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Clinical relevance of values outside the local laboratory’s normal range will be assessed by 
the Investigator. All clinically significant laboratory findings will be recorded as AEs in the 
eCRF. 
 
In the event of unexplained or unexpected clinical laboratory test values, the test(s) may be 
repeated and followed up until the results have returned to the normal range and/or an 
adequate explanation for the abnormality is found. 
 
3.6.3.4. LUNG AUSCULTATION 
At each of the time points indicated in the Schedule of Assessments, a lung auscultation will 
be performed to assess wheezing (assessed during expiration/inspiration, lung fields 
affected), crackles/crepitation and other abnormalities.  
 
A new finding or a change of a finding that is judged as an undesirable medical event shall 
be reported as an AE.  
 
In case a subject is re-hospitalized, or when the Investigator is consulted for a respiratory 
condition occurring after discharge from the hospital, an Unscheduled Visit is to be 
performed. In such cases, a mid-turbinate nasal swab is to be collected and a physical 
examination, including lung auscultation, must be performed.  
 
3.6.3.5. BODY WEIGHT, HEIGHT, AND 
TEMPERATURE 
 
At the time points indicated in the Schedule of Assessments, the following parameters will 
be assessed: body height, body weight, and temperature.  
 
To obtain the actual body weight, subjects must be weighed lightly clothed.  
 
Temperature is to be measured preferably rectal, oral, or tympanic (axillary method less 
preferred). For each individual subject, the same method should be used throughout the 
study, if possible. The method will be recorded in the eCRF. 
 
3.6.3.6. PHYSICAL EXAMINATION 
 
At each of the time points indicated in the Schedule of Assessments, a physical examination 
should be performed, including heart auscultation, examination of abdomen, skin and 
ears/nose/throat.  
 
Physical examination will be recorded as “normal”, “abnormal, not clinically significant” or 
“abnormal, clinically significant” at every assessment. A new finding or a change of a finding 
that is judged as an undesirable medical event (including all findings recorded as “abnormal, 
clinically significant”) shall be reported as an AE. 
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In case a subject is re-hospitalized, or when the Investigator is consulted for a respiratory 
condition occurring after discharge from the hospital, an Unscheduled Visit is to be 
performed. In such cases, a mid-turbinate nasal swab is to be collected and a physical 
examination, including lung auscultation, must be performed.  
 
3.6.3.7. ABNORMAL FINDINGS 
 
Criteria for determining whether an abnormal objective test finding (e.g., laboratory result), 
a complication of a protocol mandated procedure (e.g., blood draw), or a change in physical 
examination findings should be reported as an AE include (see section 4), but are not 
limited to:  
 
1. 
Result/finding is associated with accompanying clinical signs and symptoms (new onset 
or aggravated in severity of frequency from baseline condition), and/or 
2. 
Result/finding requires extra diagnostic testing (other than diagnostic exclusion tests) 
or medical/surgical intervention, and/or 
3. 
Result/finding would require a premature discontinuation from the study drug, 
significant additional concomitant drug treatment or other therapy, and/or 
4. 
Result/finding leads to any of the outcomes included in the definition of an SAE, and/or 
5. 
Result/finding is considered to be an AE by the Investigator. 
 
Any abnormal test result that is determined to be an error and merely repeating an 
abnormal test does not require reporting as an AE. 
 
3.6.3.8. AIRWAY HYPERRESPONSIVENESS AND 
HYPERSENSITIVITY 
Airway hyperresponsiveness and immediate or delayed adverse drug reactions should be 
managed according to the Investigator’s clinical judgment and applicable standard of care.  
 
 If airway hyperresponsiveness would occur, administration of a bronchodilator like the 
short-acting β2-agonist salbutamol may be administered (with an appropriate follow-up 
period) according to the Investigator’s assessment of the particular reaction and subject’s 
characteristics.  
 With regard to immediate or delayed hypersensitivity reactions, measures beyond basic 
supportive care are not considered necessary for subjects with purely local reactions. 
Subjects with suspected systemic hypersensitivity, however, should be admitted or 
treated and observed for a longer period, preferably in the emergency department or 
another close-observation area, depending on the severity of the reaction and its 
hemodynamic impact. 
 
In case of severe and/or serious hypersensitivity reactions judged to be related to study 
drug occurs, an additional serum sample should be collected (if reasonably feasible) as soon 
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as possible after the start of the event (blood volume: 1 mL) to characterize the reaction (if 
deemed required). As described in section 3.4, subjects must be discontinued from study 
drug treatment in case of a severe and/or serious hypersensitivity reaction, a severe and/or 
serious acute respiratory distress reaction induced by study drug, or when a subject needs 
to start non-invasive respiratory support or ventilation. 
 
3.6.4. PHARMACOKINETIC ASSESSMENTS 
 
Systemic (serum) concentrations of ALX-0171 will be used as a surrogate for local (lung) 
concentrations. 
 
A total of 3 blood samples for PK analysis are planned to be taken from each subject at the 
time points specified in the Schedule of Assessments.  
 
 pre-second dose,  
 between 0.5 hours and 3 hours after completion of the second dose and at least 1 hour 
apart from the first sampling, and  
 between 3 hours and 6 hours after completion of the second dose and at least 1 hour 
apart from the previous sampling. 
 
Blood samples for PK analysis do not need to be collected in case study drug was not 
administered on Day 1 and/or Day 2. 
 
The exact dates and times of blood sampling must be recorded. 
If sufficient serum remains after PK assessment, exploratory biomarker (KL-6) may also be 
evaluated. 
 
The blood samples will be collected from a vein, as using capillary blood (e.g., from heel 
pricks) is not allowed for PK assessments. Anesthetic cream or spray can be used to 
minimize the subject’s discomfort and distress. For further details on sample collection, 
shipment, storage and processing, please refer to a separate Laboratory Manual. 
 
Determination of ALX-0171 concentrations in serum will be done by a validated Ligand 
Binding Assay (LBA)-based method at a designated analytical laboratory according to the 
bioanalytical methodology and procedures described in a separate Bioanalytical Analysis 
Plan.  
 
3.6.5. ANTIVIRAL EFFECT ASSESSMENTS 
 
Throughout the study, nasal swabs (mid-turbinate specimen) will be collected for analysis of 
viral load (RSV) according to the time points defined in the Schedule of Assessments.  
 
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The mid-turbinate nasal swab sample collected pre-dose on Day 1 will also be used to test 
for concurrent viruses and the presence of mycoplasma at baseline. Confirmation of RSV 
diagnosis will also be performed at an analytical laboratory using a qPCR assay. 
 
The swabs that will be used are anatomically-designed for the collection of respiratory 
specimens which allows improved patient comfort and efficiency in specimen collection. In 
addition, appropriate training on the nasal swabbing procedure will be provided to the 
clinical sites to enable standardization across the study. Collection of nasal swab samples 
from both nostrils is preferred. 
 
For all subjects, the exact date and time of nasal swab sampling will be collected in the 
eCRF. 
 
Note that a mid-turbinate nasal swab should also be taken in case the subject is 
re-hospitalized or when the Investigator is consulted for a respiratory condition after 
hospital discharge up to the EOS (Day 28) visit. This should be considered for AE reporting 
according to the Investigator’s judgment; however in any case, in addition to the nasal 
swab, a lung auscultation and a physical examination should be performed when a subject 
returns to the hospital or the Investigator is consulted for a respiratory problem. The 
information on health care utilization for a respiratory condition will be collected through the 
diary completed by the parent(s)/caregiver(s).  
 
The viral load will be measured by plaque and qPCR assay. Determination of Log10 plaque 
forming units (PFU)/mL and Log10 viral copies/mL in nasal swabs will be done by validated 
methods at a designated analytical laboratory. Bioanalytical procedures will be described in 
a separate Bioanalytical Analysis plan. 
 
In order to identify the emergence of resistance towards ALX-0171, the virological samples 
from ALX-0171-treated patients who fail to respond to therapy or experience viral rebound 
will be selected and characterized. For these samples, the pre-treatment (baseline) sample 
and the relevant post-treatment sample will be used for genotypic and phenotypic 
characterization, to identify mutations that could contribute to reduced susceptibility to 
ALX-0171. 
 
If permitted by local regulations and only with written informed consent by the subject’s 
parent(s)/legal guardian(s) or the legally acceptable representative(s), nasal swab samples 
that remain after protocol-specific assessments have been performed may be used by the 
Sponsor for further exploratory work in the context of the development of ALX-0171.  
 
All nasal samples, including those for exploratory work in the context of the development of 
ALX-0171 (if applicable), will be kept for up to 5 years after the end of the study. No human 
DNA or RNA analysis will be performed. 
 
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3.6.6. CLINICAL ACTIVITY ASSESSMENTS  
 
The following assessments will provide valuable information to evaluate clinical activity of 
ALX-0171 (in addition to safety): 
 
 Heart rate, respiratory rate (measured over a 1-minute interval) and SpO2.  
 Feeding: type of feeding support, and (time and date of) sufficient feeding to allow for 
hospital discharge, in the opinion of the Investigator (with particular attention to 
hydration and breathing comfort during feeding)  
 Wheezing as assessed during lung auscultation  
 Cough during the night and during the day  
 Respiratory muscle retractions (supraclavicular, intercostal, and subcostal)  
 General appearance: activity, irritation, and responsiveness  
 Body temperature and body weight  
 Occurrence of apnea episodes 
 
Note: Occurrence of episodes of apnea will be captured together with the overall 
hospitalization information and should be reported as an AE (see section 4). As defined by 
the American Academy of Pediatrics [1], apnea is “an unexplained episode of cessation of 
breathing for 20 seconds or longer, or a shorter respiratory pause associated with 
bradycardia, cyanosis, pallor, and/or marked hypotonia.” 
 
The following medical interventions will also be evaluated: 
 
 Length of hospital stay for RSV infection  
 Level, method, and duration of supplemental oxygen therapy  
 Initiation of invasive or non-invasive ventilation (i.e., continuous positive airway pressure 
[cPAP] or HFOT)  
 Level, method and duration of invasive or non-invasive ventilation 
 Transfer to an ICU and duration of stay in ICU 
 
The clinical activity assessments will be used to calculate the following composite scores 
(see also section 5.7): 
 
 RDAI score (Appendix 1) 
 RACS (Appendix 1) 
 Global Severity Score (Appendix 2) 
 Time-to-Clinical Response  
 
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3.6.7. PARENT/CAREGIVER ASSESSMENTS 
 
Parent(s)/Caregiver(s) assessment of the clinical condition of the subject will be done by 
daily completion of a diary during the hospital stay and up to the EOS (Day 28) visit. The 
diary will be used to measure three respiratory symptoms (cough, [audible] wheeze, and 
trouble breathing), to score the general health of the subject and will ask for use of health 
care utilization and medication for respiratory symptoms.  
 
The three respiratory symptoms (cough, trouble breathing and wheezing) will be scored 
from not present over very mild, mild, moderate, and severe up to very severe. 
 
The global rating of the child’s health by the parent(s)/caregiver(s) will be captured by a 
VAS. The parent or caregiver will make a mark between 0 (”very bad”) and 100 mm 
(“perfect”) on the scale to indicate the subject’s current health. In addition, the 
parent(s)/caregiver(s) will indicate when the child was back to his/her condition as before 
the RSV infection started. 
 
3.6.8. IMMUNOGENICITY ASSESSMENTS 
 
Immunogenicity will be assessed by the presence of pre-Ab, TE ADA, and neutralizing 
anti-drug antibodies (NAb) in serum. 
 
To assess systemic immunogenicity of ALX-0171, blood samples will be collected at the time 
points defined in the Schedule of Assessments. If ADA are present, further testing of their 
neutralizing capacity must be performed.  
 
In case no sample was taken at the screening visit, a blood sample for assessment of 
immunogenicity should be collected at the Day 1 pre-dose timepoint, if possible. In case no 
sample was taken at the FU (Day 14) visit, a blood sample for assessment of 
immunogenicity should be collected at the EOS (Day 28) visit, if possible.  
 
The exact date and time of blood sampling will be recorded. 
 
The blood samples will be collected from a vein, as using capillary blood (e.g., from heel 
pricks) is not allowed for ADA assessments. Anesthetic cream or spray can be used to 
minimize the subject’s discomfort and distress. For further details on sample collection, 
shipment, storage and processing, please refer to a separate Laboratory Manual.  
 
Of note, an additional serum sample should be collected (if reasonably feasible) in case a 
serious and/or severe hypersensitivity reaction judged to be related to study drug occurs. 
The sample (blood volume: 1 mL) should be collected as soon as possible after the start of 
the event to allow characterization of the reaction if deemed required (also see 
section 3.6.3.8). 
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Determination of ADA will be done using a validated screening, confirmation and titration 
ADA bridging assay, with further characterization of ADA positive samples by a competitive 
ligand binding neutralizing antibody assay. The immunogenicity data will be processed 
according to a dedicated Bioanalytical Analysis plan.  
 
Bioanalytical procedures for the additional sample in case of serious and/or severe 
hypersensitivity reaction will be described in a separate Bioanalytical Analysis plan. 
 
3.6.9. PHARMACODYNAMIC ASSESSMENTS 
 
PD measurements will include the quantification of the biomarker Krebs von den Lungen-6 
(KL-6) levels in serum. KL-6 will be assessed on the remainder (if any) of the blood samples 
obtained for PK or immunogenicity testing, once the appropriate volume for their intended 
purpose has been extracted. 
 
Exploratory analysis of KL-6 levels will be done according to the time points defined in the 
Schedule of Assessments.  
 
Determination of KL-6 levels in serum will be done by validated methods at the Sponsor. 
Bioanalytical procedures will be described in a separate Bioanalytical Analysis plan. 
 
3.6.10. TOTAL BLOOD VOLUME 
 
Blood samples collected in this study will be used: 
 
i) 
for safety evaluation (clinical laboratory: hematology and clinical biochemistry),  
ii) 
to monitor the systemic concentration of ALX-0171 (as a surrogate measure of the local 
lung concentration), and  
iii) to assess potential immunogenicity (Table 2).  
 
If all hematology and biochemistry blood parameters required for the study are already 
known from analysis done as a routine assessment upon arrival at the hospital, collection of 
screening clinical laboratory samples does not need to be repeated for the purpose of this 
study. However, the samples should be analyzed at the same local laboratory that will be 
used for the remainder of the study. 
 
The blood samples for PK or ADA assessments will be collected from a vein, as using 
capillary blood (e.g., from heel pricks) is not allowed.  
 
The precise assessments that are intended to be performed on each of the blood samples 
are arranged by priority; when insufficient volume is available (e.g., because of difficulties 
in or limits to obtaining blood), only the highest priority (-/ies) will be assessed (see 
Table 2). 
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Table 2: 
Timing, priority and estimated volume of scheduled blood draws  
Sample  
Priority 
Maximal Target volume 
1 blood draw at 
screening a 
1. Clinical laboratory:  
- 
Hematology (whole blood) 
- 
Biochemistry (serum) 
2. Immunogenicity (serum) b 
3. Exploratory biomarker c 
-  whole blood for hematology (volume according to 
local practice) 
- whole blood to be processed into serum for 
biochemistry (volume according to local practice) 
-  1 mL whole blood, to be processed into serum for 
immunogenicity and biomarker b 
  Total: 1 mL whole blood + volume needed for 
clinical laboratory 
3 blood draws on 
Days 2-3 
1. PK (serum) 
2. Exploratory biomarker b 
-  0.5 mL whole blood, to be processed into serum for 
PK and biomarker b  
  Total: 1.5 mL whole blood  
1 blood draw during 
the Day 14 FU visit  
1. Clinical laboratory:  
- 
Hematology (whole blood) 
- 
Biochemistry (serum) 
2. Immunogenicity (serum) b 
3. Exploratory biomarker c  
-  whole blood for hematology (volume according to 
local practice) 
- whole blood to be processed into serum for 
biochemistry (volume according to local practice) 
- 1 mL whole blood, to be processed into serum for 
immunogenicity and biomarker b 
  Total: 1 mL whole blood + volume needed for 
clinical laboratory 
a If all hematology and biochemistry blood parameters required for the study are already known from analysis done 
as a routine assessment upon arrival at the hospital, collection of screening clinical laboratory samples does not 
need to be repeated for the purpose of this study. However, the samples should be analyzed at the same local 
laboratory that will be used for the remainder of the study. 
b For subjects with a body weight below 5 kg and in case the blood volume needed for local clinical laboratory 
exceeds 2.5 mL, the sample for analysis of immunogenicity should not be collected at screening and on Day 14, 
but on Day 1 pre-dose and on Day 28, if possible.  
c Only if sufficient blood volume (serum) is available after analyzing the samples obtained for PK or 
immunogenicity. 
 
Exploratory biomarker will only be assessed on the remainder of the blood samples once the 
appropriate volume for their intended purpose has been extracted. Note that no human DNA 
or RNA analysis will be performed. 
 
An additional serum sample should be collected (if reasonably feasible) in case a serious 
and/or severe hypersensitivity reaction judged to be related to study drug occurs (blood 
volume: 1 mL).  
 
Of note: For subjects with a body weight below 5 kg and in case the blood volume needed 
for local clinical laboratory exceeds 2.5 mL, the sample for analysis of immunogenicity 
should not be collected at screening and on Day 14, but on Day 1 pre-dose and on Day 28, 
if possible. 
 
If permitted by local regulations and only with written informed consent by the subject’s 
parent(s)/legal guardian(s) or the legally acceptable representative(s), blood samples that 
remain after protocol-specific assessments have been performed may be used by the 
Sponsor for further exploratory work in the context of the development of ALX-0171.  
 
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All blood samples, including those for exploratory work in the context of the development of 
ALX-0171 (if applicable), will be kept for up to 5 years after the end of the study. No human 
DNA or RNA analysis will be performed. 
 
3.6.11. APPROPRIATENESS AND TIMING OF 
MEASUREMENTS 
 
The assessments which will be made in this study are standard and generally recognized as 
reliable, accurate, and relevant. 
 
The timing of all assessments is detailed in the Schedule of Assessments. 
 
Throughout the study, study personnel should make every reasonable effort to follow the 
timing of assessments and procedures in the Schedule of Assessments for each subject.  
 
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4. ADVERSE EVENT EVALUATION AND 
REPORTING 
4.1. ADVERSE EVENTS 
 
4.1.1. DEFINITIONS 
 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a subject or clinical investigation in a 
subject administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
Other examples include any occurrence that is new in onset or aggravated in 
severity or frequency from the baseline condition, or abnormal results of 
diagnostic procedures, including laboratory test abnormalities. 
In differentiating between medical history and AEs, the following points will be 
considered: 
 
Conditions that started before signing of informed consent and for which 
no symptoms or treatment are present up to the timing of signing of 
informed consent are recorded as medical history (e.g., seasonal allergy 
without acute complaints). 
 
Conditions that started before signing of informed consent and for which 
symptoms or treatment are present after signing of informed consent, but 
with unchanged severity, are recorded as medical history (e.g., allergic 
pollinosis). 
 
Conditions that started or deteriorated after signing of informed consent 
will be documented as AEs. 
Treatment-
emergent AEs and 
SAEs 
TEAEs or treatment-emergent SAEs are events temporally associated with the 
use of study drug (occurring during or after the first dose of study drug), 
whether considered related to the study drug or not. 
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Term 
Definition 
Adverse Reaction 
An untoward and unintended response in a subject to an IMP, which is related 
to any dose, administered to that subject. 
The phrase "response to an IMP" means that a causal relationship between a 
study medication and an AE is at least a reasonable possibility, i.e., the 
relationship cannot be ruled out. 
All cases judged by either the reporting medically qualified professional or the 
Sponsor as having a reasonable suspected causal relationship to the study 
medication qualify as adverse reactions. 
Serious Adverse 
Events (SAEs) 
An SAE is any untoward medical occurrence (an AE) occurring at any dose of 
the (investigational) medicinal product, comparator or placebo that fulfils one 
or more of the following conditions: 
 
Results in death 
 
Is life-threatening 
NOTE: The term "life-threatening" in the definition of "serious" refers to an 
event in which the subject was at risk of death at the time of the event; it 
does not refer to an event which hypothetically might have caused death if 
it were more severe. 
 
Requires inpatient hospitalization or prolongation of existing 
hospitalization. 
NOTE: An AE associated with a hospitalization or prolongation of 
hospitalization will not be regarded as an SAE, if at least one of the 
following exceptions is met: 
- Routine treatment or monitoring of the studied indication not 
associated with any deterioration in condition  
- Treatment which was elective or pre-planned, for a pre-existing 
condition not associated with any deterioration in condition, e.g., pre-
planned prior to the start of the study hip replacement operation which 
does not lead to further complications. 
-  Hospital stay of less than 12 hours. 
- The admission is not associated with an AE (e.g., social hospitalization 
for purposes of respite care). 
- Any admission to hospital or other institution for general care where 
there was no deterioration in condition. 
- Treatment on an emergency, outpatient basis for an event not fulfilling 
any of the definitions of serious as given above and not resulting in 
hospital admission. 
 
Results in persistent or significant disability/incapacity. 
NOTE: Disability means a substantial disruption of a person’s ability to 
conduct normal life’s functions. 
 
Consists of a congenital anomaly or birth defect (Not relevant 
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Term 
Definition 
to this clinical study in infants)  
Other ‘important medical events’ may also be considered serious if they 
jeopardize the subject or require an intervention to prevent one of the above 
consequences. 
 
For the purposes of the present clinical study, the following will also trigger 
SAE reporting: 1) Transfer to ICU, 2) Initiation of non-invasive respiratory 
support (including start of HFOT or increasing the flow above the allowed 
level) or invasive ventilation. 
 
NOTE: To avoid confusion or misunderstanding of the difference between the 
terms “serious” and “severe”, the following note of clarification is provided: 
“Severe” is often used to describe intensity of a specific event, which may be 
of relatively minor medical significance (e.g., a severe rash is not likely to be 
an SAE, however, mild chest pain may result in a day’s hospitalization and 
thus is an SAE).  
 
“Seriousness” is the regulatory definition supplied above. 
Serious Adverse 
Reaction (SAR) 
An AE that is both serious and, in the opinion of the reporting Investigator, 
believed with reasonable probability to be due to one of the study 
medications, based on the information provided. 
Suspected 
Unexpected 
Serious Adverse 
Reaction (SUSAR) 
A serious adverse reaction, the nature and severity of which is not consistent 
with the reference safety information about the medicinal product in question 
set out in the IB. 
 
4.1.2. RECORDING OF ADVERSE EVENTS 
 
What will be collected 
All AEs 
Responsibility  
Investigator’s responsibility 
Period of collection AEs 
All AEs will be reported from the time a signed and dated ICF is obtained 
until completion of the subject’s last visit. 
How are AEs elicited 
Spontaneous, unsolicited reports: 
- by subject, parents/caregivers and/or healthcare staff,  
- by observation (by the Investigator and/or healthcare staff),  
- by routine open questioning of the subjects (or parents/caregivers) 
or by the Investigator (e.g., “Is there anything new that you wish 
to discuss?”) 
- by reviewing the diary with the subject’s parent(s)/caregiver(s).  
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Where are AEs recorded 
Documented in the source documents and the eCRF 
When are AEs recorded 
Detailed guidance on when to complete AEs is given in the CRF 
completion guidelines document. 
 
4.1.3. AE ASSESSMENTS 
 
The variables to be collected for each AE are shown in the table below. 
 
What needs to be 
assessed for each 
AE? 
For each AE, the Investigator will record his assessment of:  
 
Seriousness 
 
Causal relationship to study drug 
 
Causal relationship to study procedure  
 
Intensity/severity 
 
Action taken with study drug 
 
Outcome 
 
Medication used to treat the event 
Detailed guidance on how to complete AE data is given in the CRF completion 
guidelines document. 
Seriousness 
Based on the definition of SAE above, the Investigator will assess each AE 
into: 
0- Non-serious (does not meet the definition of serious) 
1- Serious (meets the definition of serious) 
If the AE meets the definition of “serious”, the instruction in section 4.1.4 
and section 4.1.5 must be followed. 
Causal relationship 
scale 
The assessment of the causal relationship between an AE and the 
administration of study drug is a clinical decision based on all available 
information at the time of the completion of the eCRF. 
The assessment is based on whether there was a “reasonable causal 
relationship” to the study drug in question. The scale used for relationship to 
study is: 
 
Not related 
 
Unlikely related 
 
Possibly related 
 
Related 
 
Not Applicable 
Detailed guidance on how to complete AE data is given in the CRF completion 
guidelines document. 
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Causal relationship 
to study procedure 
Assessment of causal relationship of any AE to protocol-required procedures 
(e.g., to anemia caused by blood sampling) can be completed with: 
 
Yes (specify) 
 
No 
Intensity/ 
severity scale 
The Investigator will assess the intensity/severity of AEs on a 3-point scale: 
 
Mild (discomfort noticed but no disruption of normal daily activity) 
 
Moderate (discomfort sufficient to reduce or affect normal daily activity or 
requires specific treatment) 
 
Severe (incapacitating, with inability to perform normal activities) 
It is emphasized that the term severe is a measure of intensity: a severe AE 
is not necessarily serious. For example, itching for several days may be rated 
as severe, but may not be clinically serious. 
Action taken with 
study drug 
Action taken with study drug is to be documented as follows:  
 
Dose not changed 
 
Drug interrupted 
 
Drug withdrawn 
 
Not applicable 
Outcome 
The outcome of the AE is to be documented as follows:  
 
Recovered/resolved  
 
Recovering/resolving  
 
Recovered/resolved with sequelae  
 
Not recovered/not resolved  
 
Fatal  
 
Unknown 
Medication used to 
treat the event 
Any medications necessary for the treatment of the AE must be recorded on 
the concomitant medication section of the CRF. The indication should be 
same term used for the AE.  
Follow-up of AEs 
Investigators are responsible for following-up and providing complete 
information on the AEs up to final outcome and for responding to the 
Sponsor’s queries in a timely manner.  
 
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4.1.4. RECORDING OF SAEs 
 
Collection and recording of SAEs by the Investigator 
What will be 
collected 
All SAEs 
Period of 
collection  
 
From signed informed consent to subject’s last visit: All SAEs. 
 
At any time after the subject’s last visit: Only SARs.  
SAEs assessed by the Investigator as causally related to study drug will be 
notified to the Sponsor even after the subject’s completion of his/her 
participation in the Clinical Trial (e.g., delayed onset/long latency SAEs). 
Exemptions from 
SAE process below 
None  
Where are SAEs 
recorded 
In addition to the recording of the AE as described in the section above, 
Serious AE specific information will also be recorded on the SAE form. 
When are SAEs 
recorded 
Within 24 hrs of Investigator/site’s first knowledge (see also section 4.1.5) 
How are SAEs 
recorded 
Indicate whether the report is initial or follow-up. 
Attach supporting documents relevant to the SAE (e.g., hospital reports). The 
subject’s name should be edited-out from any supporting documents. 
Whenever possible, the overall diagnosis or overall syndrome’s name should be 
used as the SAE verbatim. If the diagnosis is not available, use signs and 
symptoms and provide the final diagnoses as follow-up information when 
available. The AE verbatim term and the SAE verbatim term should match and 
must be clinically equivalent.  
Include medical history and concurrent diseases that are relevant to the SAE. 
The SAE must include the Investigator’s assessment of the relationship of the 
event to study drug. 
SAE forms must be signed by the Investigator or delegated person. 
Causal 
relationship scale 
The assessment of the causal relationship between an SAE and the 
administration of study drug is a clinical decision based on all available 
information at the time of the completion of the SAE form. 
The assessment is based on the question of whether there was a “reasonable 
causal relationship” to the study drug.  
The following considerations should be taken into account for this assessment: 
 
Is the Time-to-Onset of the event compatible with a causal relationship? 
Was it “treatment-emergent”? 
 
Is it of common occurrence in the population under study? 
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Collection and recording of SAEs by the Investigator 
 
Did it respond to de-challenge? 
 
Did it recur on re-challenge? 
 
Were there concomitant medications known to cause the event? 
 
Were confirmatory laboratory/other tests done? 
 
Was there a medical history of the same type of events? 
 
Was there a more likely alternative cause or risk factor? 
The criteria: “a causal relationship cannot be ruled out” should not be used, as 
this is hardly ever possible for individual events. The question should be 
whether the study drug is the most likely cause of the event or whether there 
were other more likely causes or risk factors (underlying diseases, concomitant 
medication, etc.). 
-NOT RELATED (there is not a reasonable causal relationship) 
-RELATED (there is a reasonable causal relationship) 
Follow-up SAE 
information 
Investigators are responsible for following-up and providing complete 
information (i.e., lab reports, hospital reports) on the SAEs up to their final 
outcome and responding to the Sponsor’s queries in a timely manner. 
For reported deaths, the Investigator should supply the Sponsor and the IRB 
with any additional requested information (e.g., autopsy reports and final 
medical reports). 
 
4.1.5. NOTIFICATION OF SAES TO SPONSOR 
 
Investigator Notification of SAEs to the Sponsor 
When 
Immediately and always within 24 hrs of Investigator’s/ site’s first knowledge 
How 
Conventional SAE form will be completed and send by e-mail (preferred 
method) or FAX to: 
e-mail: pv@ablynx.com 
FAX: +32 9 262 00 35 
Follow-up SAE 
information 
Collection and notification to the Sponsor will occur in the same manner and 
timelines as for initial SAEs. 
 
 
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4.1.6. SUSAR NOTIFICATION PROCESS 
 
AE reporting, including SUSARs, will be carried out in accordance with applicable local 
regulations. 
 
Expedited 
reporting 
The Sponsor or delegated vendor(s) will expedite SUSAR or SAR reports to the 
regulatory authorities (PMDA), IRB and Investigators where applicable according 
to  the following reporting timelines: 
To PMDA: 
SUSAR: Suspected Unexpected Serious Adverse Reaction 
SAR: Serious Adverse Reaction 
D: Death 
LT: Life threatening 
 
To IRB and Investigators: 
Expedited reporting of SUSARs will be done immediately after the submission to 
PMDA. 
  
Seriousness 
Domestic 
cases  
Foreign cases 
SUSAR 
D/LT 
Within 7 days  
Within 7 days 
Others 
Within 15 days  
Within 15 days 
SAR 
(Expected) 
D/LT 
Within 15 days 
Within 15 days 
Distribution of 
SUSARs to 
Investigators 
The Sponsor or delegated vendor will distribute the SUSARs to Investigators. 
This can be done in the form of individual reports or periodic line listings.  
Submission to 
local IRBs 
Where required by IRB procedure, it is the Principal Investigator’s responsibility 
to notify the IRB of SUSAR reports received from the Sponsor. 
 
 
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4.2. OTHER REPORTABLE INFORMATION 
 
4.2.1. MEDICATION ERRORS 
 
Medication error is defined as an error made in prescribing, dispensing, administration, 
and/or use of an investigational product. 
 
Medication errors include, but are not limited to, the following: 
 
 Administration of the wrong dosage to the subject (i.e., different from the dose 
prescribed by the protocol). 
 Administration of study drug that has not been assigned to the subject. 
 Administration of expired study drug. 
 Administration by a route other than inhalation. 
 Deviations to the study drug storage conditions when administered to the subject. 
 Nasal cannula not removed. 
 Air or oxygen tube not connected to the FOX-Flamingo inhalation system, damaged or 
kinked. 
 Air or oxygen flow to the FOX-Flamingo inhalation system too low or too high. 
 Re-use of inhalation set (i.e., the face mask, mask adapter, and nebulizer mesh/head 
and fill reservoir). 
 
All medication errors that occur during the study should be reported to the Sponsor 
regardless of whether they are a cause of AEs/SAEs.  
 
AE/SAEs resulting from medication errors need to be reported as any other AEs/SAEs (see 
section 4.1.2 and section 4.1.4) indicating the medication error. 
 
For information on management of overdoses, please refer to section 3.3.4.3. 
 
4.2.2. MEDICAL DEVICE ISSUES 
 
All medical device issues that occur during the study should be reported to the Sponsor 
regardless of whether they are a cause of AEs/ SAEs.  
 
AE/SAEs resulting from medical device issues need to be reported as any other AEs/SAEs 
(see section 4.1.2 and section 4.1.4) indicating the medical device issue. 
 
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5. STATISTICS 
 
5.1. STUDY POPULATIONS 
 
The following populations will be considered for analysis: 
 
• Modified Intent-to-treat (mITT) Population: All randomized subjects who received at 
least 1 administration of study drug, as randomized (i.e., using the treatment to which 
the subject was randomized). 
• Safety Population: All subjects who received at least 1 administration of study drug, as 
treated (i.e., using the treatment that the subject actually received). 
• PK population: Subset of the subjects in the safety population for whom the primary PK 
data are considered to be sufficient and interpretable. For this study, this will correspond 
to all subjects in the safety population who received at least 1 administration of 
ALX-0171 and for whom at least three ALX-0171 serum concentrations have been 
determined.  
 
The mITT Population will be the primary study population used for the analysis of efficacy 
data, the Safety Population for the analysis of safety, PD, and immunogenicity data, and the 
PK population for analysis of PK data. 
 
5.2. STATISTICAL AND ANALYTICAL PLAN 
 
Analysis of all parameters will be described in a Statistical Analysis Plan (SAP) and a Data 
Analysis Plan (DAP; for PK analysis) and will comprise all methods applied for analysis of the 
corresponding data. There will be no interim analysis performed in this study. 
 
The SAP and relevant analytical plans for PK, PD and immunogenicity will be generated 
under responsibility of the Sponsor, and will be finalised prior to database lock. Any 
deviations from the reporting and analysis plans will be reported in the Section of “Changes 
in the planned analysis” in the Clinical Study Report (CSR). 
 
5.3. DEMOGRAPHICS AND BASELINE 
CHARACTERISTICS 
 
Baseline characteristics will be summarized using descriptive statistics (including number of 
observations, mean, standard deviation, median, maximum, and minimum) for continuous 
variables and counts and percentages for categorical variables. 
 
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Prior and concomitant medications will be summarized by treatment group, by the number 
and percentage of subjects taking each medication, classified using World Health 
Organization (WHO) Drug Dictionary, anatomical therapeutic chemical (ATC) class and 
preferred term. 
 
5.4. EVALUATION OF SAFETY 
 
Safety and tolerability of ALX-0171 in Japanese infants and young children hospitalized for 
RSV LRTI will be evaluated based on the following:  
 
 AEs will be fully described and coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA) using the latest MedDRA version available at the time of database 
lock.  
 A treatment-emergent analysis of AEs will be done.  
 Frequency of subjects presenting with AEs, AEs leading to withdrawal, adverse drug 
reactions, and SAEs will be tabulated for each treatment group by system organ class 
and preferred term. 
 For laboratory parameters, descriptive statistics (mean, median, standard error, 
minimum, and maximum) will be computed on the actual values and the change from 
baseline for each parameter. All laboratory values will be categorized according to their 
normal ranges as below, within or above normal. 
 Other safety variables, including e.g., heart rate, need for oxygen therapy (and when 
applicable, relevant parameters such as duration of oxygen therapy needed, oxygen 
delivery mode, flow of inspired oxygen), or any significant worsening requiring immediate 
or intensive medical intervention, will be fully depicted using descriptive statistics.  
 
Findings in physical examinations will be listed. Body weight and body temperature results 
will be summarized by descriptive statistics. 
 
5.5. EVALUATION OF PK 
 
Systemic (serum) concentrations of ALX-0171 will be used as a surrogate for local (lung) 
concentrations. 
 
Individual study drug concentrations will be listed, e.g., in summary tables. In addition, a 
listing of the actual sampling times relative to the study drug administration times will be 
presented. If considered meaningful, geometric means and standard deviations will be 
added to the summary tables.  
 
A population PK model (non-linear mixed effect modeling) will be developed based on the 
ALX-0171 serum concentrations from this study. The dataset will be supplemented with 
serum concentration data from Study ALX0171-C201, and any other studies that are 
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considered relevant to support model structure. The covariate analysis will include the 
investigation of ethnicity.  
 
Individual PK parameters will be derived by means of empirical Bayesian estimation. The 
following individual PK parameters will be provided: apparent clearance (CL/F), area under 
the curve (AUC) as nominal (filling) dose divided by CL/F and cumulative AUC over 72 hours 
as an expression of the cumulated exposure during the course of treatment.  
Individual PK parameters will be summarized with sample size, mean, standard deviation 
and coefficient of variation.  
 
The modeling exercise will be described in a separate analysis plan and will be reported in a 
separate report. The main findings will be summarized in the CSR. 
 
5.6. EVALUATION OF ANTIVIRAL EFFECT 
 
The antiviral effect (viral load in samples from nasal swabs) parameters will be analyzed 
using descriptive statistics. The data will be listed and summarized in tabular and/or 
graphical form. 
 
The viral load (as assessed by plaque assay and qPCR) will be characterized through 
parameters 
including 
time-to-below 
the 
limit 
of 
quantification 
(BQL), 
time-to-
undetectability, time-weighted average change from baseline up to Day 3 and Day 14, 
number and percent of subjects with undetectable RSV (from Day 1 to Day 14), number and 
percent of subjects with BQL and change from baseline in viral load.  
 
5.7. EVALUATION OF CLINICAL ACTIVITY  
 
Based on the Clinical Activity Outcome Measures, the following composite scores will be 
calculated and summarized descriptively: 
 
 RDAI score (based on wheezing and respiratory muscle retractions, see Appendix 1),  
 RACS; based on RDAI and change in respiratory rate),  
 Global Severity Score (based on respiratory parameters, medical interventions, feeding, 
general appearance and body temperature).  
 
The feeding and oxygen saturation outcome measures will be used to calculate Time-to-
Clinical Response. Kaplan-Meier estimates will be provided.  
 
Subjects will be considered to have met the Clinical Response criteria when both of the 
following criteria are fulfilled:  
- Stable oxygen saturation on room air, defined as SpO2 ≥ 95% over a period of at 
least 4 hours to allow for hospital discharge.  
- Adequate oral feeding which is sufficient to maintain hydration and to allow for hospital 
discharge, in the judgment of the Investigator.  
 
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5.8. EVALUATION OF IMMUNOGENICITY 
 
Immunogenicity will be evaluated systemically in serum. Individual immunogenicity results 
will be listed, and summarized using descriptive statistics.  
 
Prevalence of pre-Ab and incidence of TE ADA or NAb, as well as titer levels (TE ADA) and 
normalized ratios (NAb) of the antibody responses, will be reported.  
 
Potential correlation between pre-Ab, TE ADA or NAb and safety, PK or efficacy will be 
assessed. 
 
In case of severe and/or serious hypersensitivity reactions judged to be related to study 
drug occurs, a blood sample will be collected to further characterize the hypersensitivity 
reactions (if deemed necessary). Correlation between hypersensitivity reactions and 
immunogenicity results will be assessed. Results will be summarized through listing of the 
individual results. 
 
5.9. EVALUATION OF PD 
 
The PD characteristics (serum levels of KL-6) will be analyzed using descriptive statistics. 
The data will be listed and summarized in tabular and/or graphical form.  
 
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6. DATA QUALITY ASSURANCE AND 
DIRECT ACCESS TO SOURCE 
DATA/DOCUMENTS 
Audits may be conducted to evaluate systems, processes, and expertise for the 
subcontracted activities and to assess compliance with the contractual agreements, the 
protocol, applicable Standard Operating Procedures, and regulatory requirements. During or 
after the conduct of the study, process-related audits may be performed as well. When 
performed, an audit certificate will be provided in appendix of the final study report.  
The clinical research facility will be monitored by the study monitor, to ensure correct 
performance of the study procedures and to ensure that the study is conducted according to 
the relevant regulatory requirements. 
 
Regulatory authorities, the IRB, and/or the Sponsor representative may request access to 
all source documents, eCRFs and other study documentation for study-related monitoring, 
audit, IRB review, and regulatory inspection. Direct access to these documents must be 
guaranteed by the Investigator, who must provide support at all times for these activities. 
 
Quality control principles will be applied throughout the performance of this study. 
 
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7. DATA PROTECTION 
 
During this clinical study, all clinical data will be identified only through an ID number in 
order to protect the rights of the subjects to privacy and to the protection of their personal 
data in compliance with all applicable laws and regulations.  
 
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8. ETHICS 
 
8.1. ETHICAL APPROVAL 
 
The Clinical Study Protocol(s), ICF(s) and any other written information and/or materials to 
be provided to the subjects’ parent(s)/legal guardian(s) or the legally acceptable 
representative(s) will be submitted for review and approval by the IRB prior to the eligibility 
screening/baseline. The composition of the IRB is in accordance with the local regulations 
where the clinical study is conducted.  
 
The Investigator/Sponsor (or CRO on behalf of the sponsor) will keep the IRB informed 
about the progress of the study. All changes in research activities and all unanticipated 
problems involving risks to human subjects will be immediately reported to the responsible 
persons. The study may be suspended pending further review by the IRB, unless suspension 
would jeopardize the subject’s health. The Investigator will take care that all subject’s 
parent(s)/legal guardian(s) or the legally acceptable representative(s) are kept informed.  
 
No substantial amendments will be implemented to the study without prior IRB approval, 
except when required to eliminate apparent immediate hazards to subjects. 
 
Notification of the end of the study will be sent to the IRB, within the number of days as 
specified by local regulations after completion of follow-up for the last subject. In case the 
study is ended prematurely, the IRB will be notified within the number of days as specified 
by local regulations, including the reasons for the premature termination. Results will be 
provided to the IRB according to local requirements for format and timing. 
 
8.2. ETHICAL CONDUCT OF THE STUDY 
 
This study will be conducted in compliance with Japan- and ICH-GCP (including archiving of 
essential study documents), the Declaration of Helsinki, and the Good Clinical Practice for 
Trials on Drugs (Ministry of Health, Labour and Welfare [MHLW] Ordinance No. 28, 27 March 
1997, partially revised by MHLW Ordinance and their related notifications). 
 
ICH-adopted guidelines and other relevant international guidelines, recommendations, and 
requirements will be taken into account as comprehensively as possible, as long as they do 
not violate local laws. 
The Investigator will be responsible for the care of the subjects throughout the study. If the 
Investigator is not present at the study site, he/she will leave instructions for the staff and a 
telephone number where he/she can be reached. 
 
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8.3. SUBJECT INFORMATION AND 
CONSENT 
 
As the potential subjects are infants or young children, subjects’ parent(s), legal guardian(s) 
or the legally acceptable representative(s) must provide their written informed consent 
before enrolment of their child in the clinical study, and before any protocol-specified 
procedures are performed.  
 
Freely given and written informed consent must be obtained according to local requirements 
after the nature of the study has been fully explained. The consent form must be signed 
before performance of any study-related activity. The consent form that is used will be 
approved by both the Sponsor and designee and by the reviewing IRB. The informed 
consent will be in accordance with principles that originated in the Declaration of Helsinki, 
current ICH-GCP guidelines, applicable regulatory requirements, and the Sponsor’s Standard 
Operating Procedure. 
 
Before undertaking any study-related procedure in the study, the Investigator or an 
authorized member of the investigational staff must explain to the subjects’ parent(s), legal 
guardian(s) or the legally acceptable representative(s) the aims, methods, objectives, 
potential clinical benefits, and potential hazards of the study, and any discomfort 
participation in the study may entail.  
 
The subjects’ parent(s), legal guardian(s), or the legally acceptable representative(s) will be 
informed that the participation is voluntary and that they may refuse to participate or 
withdraw from the study, at any time, without penalty or loss of benefits to which the 
subject is otherwise entitled, and that all data collected up to the point of withdrawal will be 
used and reported in an anonymized way. They will be told that the Investigator will 
maintain a subject identification register for the purposes of long-term follow-up, if needed, 
and that the records may be accessed by health authorities, authorized Sponsor staff, and 
Sponsor representative without violating the confidentiality of the subject, to the extent 
permitted by the applicable law(s) or regulations. In addition, insurance coverage provided 
during the study will be explained. 
 
By signing the ICF the subjects’ parent(s), legal guardian(s), or the legally acceptable 
representative(s) is/are authorizing such access, and agrees to allow the study physician to 
recontact 
the 
subjects’ 
parent(s), 
legal 
guardian(s), 
or 
the 
legally 
acceptable 
representative(s) for the purpose of obtaining consent for additional safety evaluations, if 
needed. 
 
If the subjects’ parent(s), legal guardian(s), or the legally acceptable representative(s) 
is/are unable to read, an impartial witness must be present during the entire informed 
consent discussion. Once the written ICF (and any other written information) is read and 
explained to the subjects’ parent(s), legal guardian(s) or the legally acceptable 
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representative(s), and after the subjects’ parent(s), legal guardian(s), or the legally 
acceptable representative(s) has orally consented to the subject’s participation in the study, 
and, if capable of doing so, has signed and personally dated the ICF, the witness must sign 
and personally date the consent form. By signing the consent form, the witness attests that 
the information in the consent form and any other written information was accurately 
explained to, and apparently understood by, the subjects’ parent(s), legal guardian(s) or 
the legally acceptable representative(s), and that informed consent was freely given by the 
subjects’ parent(s), legal guardian(s) or the legally acceptable representative(s). 
 
The language used in the oral and written information about the study, including the ICF, 
will be as nontechnical as practical and should be understandable to the subjects’ parent(s), 
legal guardian(s) or the legally acceptable representative(s). They will be given sufficient 
time to read the ICF and given the opportunity to ask questions. After this explanation and 
before entry into the study, consent will be appropriately recorded by means of the 
subjects’ parent(s), legal guardian(s) or the legally acceptable representative(s) personally 
dated signature(s) and by the Investigator or an authorized member of the investigational 
staff who conducted the ICF discussion.  
 
After having obtained the consent, a copy of the signed ICF will be given to the subject’s 
parent(s)/legal guardian(s) or the legally acceptable representative(s). The original of the 
ICF will be retained by the Investigator in the “Investigator Site File”. 
 
If any new information on the study medication which may influence the decision of the 
subject to continue the study becomes available, the Investigator(s) should inform the 
subjects’ parent(s), legal guardian(s), or the legally acceptable representative(s) of such 
information immediately, record this in a written form, and confirm with the subjects’ 
parent(s), legal guardian(s), or the legally acceptable representative(s) if they concur with 
the subject’s continued participation in the study. In addition, the currently approved ICF 
should be revised immediately. 
 
The Investigator(s) should re-explain the information to the subjects’ parent(s), legal 
guardian(s), or the legally acceptable representative(s) using the updated ICF even though 
the subjects have already been informed of the new information verbally. Written informed 
consent to continue participation in the study should be provided separately. 
 
8.4. PRIVACY 
 
The study is conducted according to the principles of ICH, including the specifications for 
privacy and data protection.  
 
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to investigate the safety, quality, and utility of the 
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investigational study drug(s) used in this study. The collected data are adequate, and not 
excessive in relation to the purposes for which they are collected and processed. 
 
The data are collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration is in 
place. The data will be kept in a form, which does not readily permit identification of the 
subject. Subjects will be identified by his/her assigned unique subject number and his/her 
year of birth. Personal data will only be collected and processed using these unique 
identification items. Only the Investigator and his/her study team keeps a list that makes it 
possible to link unique subject numbers to an individual name. Sponsor personnel whose 
responsibilities require access to personal data have to agree to keep the identity of study 
subjects confidential. 
 
The informed consent obtained from the subject’s parent(s)/legal guardian(s) or the legally 
acceptable representative(s) includes explicit consent for the processing of personal data 
and for the Investigator to allow direct access to his/her original medical records for study-
related monitoring, audit, IRB review, and regulatory inspection. This consent also 
addresses the transfer of the data to other entities and to other countries. 
 
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9. DATA HANDLING AND RECORD 
KEEPING  
 
9.1. DISTRIBUTION OF ACTIVITIES 
 
Contact details of the Sponsor and third parties are available in the “Investigator Site File”. 
 
9.2. DOCUMENTATION 
 
Study documentation required for study start (as specified in the ICH E6 Guideline for GCP 
[CPMP/ICH/135/95]) shall be exchanged between Ablynx NV and the vendor prior to the 
administration of study drug. 
 
9.2.1. CASE REPORT FORM COMPLETION 
Case report forms will be completed for each subject (incl. screen failures in order to assess 
the numbers and demographic characteristics of the excluded subjects, and the reasons for 
their exclusion). 
 
The Investigator (or sub-Investigator) will ensure that data are recorded on the eCRF as 
specified in the Clinical Study Protocol and in accordance with the instructions in the eCRF 
completion guidelines. The Investigator (or sub-Investigator) will ensure the accuracy, 
completeness, legibility, and timeliness of the data recorded in the eCRF, and of the 
provision of answers to data queries according to the Clinical Study Agreement. All eCRF 
entries, corrections, and alterations must be made by the Investigator or other authorized 
study-site personnel. The Investigator (or sub-Investigator) will sign the completed eCRF. A 
copy of the completed eCRF will be archived at the study site. 
 
9.2.2. SOURCE DOCUMENTATION 
 
At a minimum, source documentation must be available for the following: informed consent 
process, medical history, subject identification, eligibility, and study identification; date of 
informed consent; dates of visits; results of all efficacy evaluations; results of safety 
parameters as required by the protocol; record of all AEs along with intensity and causality 
assessments; and follow-up of AEs; prior and concomitant medication; study drug receipt 
records; study drug administration information; any medical notes (original documents, 
data and records, e.g., laboratory data); date of study completion, and reason for early 
discontinuation of study procedures or withdrawal from the study (and information on 
documented attempts to obtain information on the final status of the subject for those who 
are considered lost to follow-up), if applicable.  
 
In addition, the author of an entry in the source documents should be identifiable. 
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At a minimum, the type and level of detail of source data available for a study subject 
should be consistent with that commonly recorded at the site as a basis for standard 
medical care (Patient’s Medical File). 
 
Following the ICH-GCP guidelines, direct access to source documentation (medical records) 
must be allowed. 
 
9.2.3. RECORD RETENTION 
 
The Investigator/Institution will maintain all eCRFs and all source documents that support 
the data collected from each subject, as well as all study documents before, during and 
after the study as specified in ICH/GCP section 8, Essential Documents for the Conduct of a 
Clinical Study, and all study documents as specified by the applicable regulatory 
requirement(s). The Investigator/Institution will take measures to prevent accidental or 
premature destruction of these documents. 
 
Essential documents must be retained until the day on which the investigational product 
provider receives marketing approval of the test drug (or the day 3 years after the date of 
notification in the case of a notification pursuant to Article 26-10, Paragraph 3), or the day 
3 years after the date of premature termination or completion of the clinical study, 
whichever comes later. These documents will be retained for a longer period if required by 
the Sponsor. It is the responsibility of the Sponsor to inform the Investigator/Institution as 
to the period and method of when these documents no longer need to be retained. 
 
If the responsible Investigator retires, relocates or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who 
will accept the responsibility. The Sponsor must be notified in writing of the name and 
address of the new custodian. Under no circumstance shall the Investigator relocate or 
dispose of any study documents before having obtained written approval from the Sponsor. 
 
If it becomes necessary for the Sponsor or the appropriate regulatory authority to review 
any documentation relating to this study, the Investigator/Institution must permit access to 
such essential documents and subject data. 
 
9.2.4. MONITORING 
 
The monitor will perform on-site monitoring visits as specified in a monitoring plan to 
ensure that all aspects of the protocol, contractual agreements and regulatory requirements 
are followed and that subjects’ human rights, safety and well-being are protected. The 
monitor will record dates of monitoring in a study center visit log that will be kept at the 
site. At these visits, the monitor will perform source data verification and check the data 
entered into the eCRF for completeness and accuracy. The nature and location of all source 
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documents will be identified to ensure that all sources of original data required to complete 
the eCRF are known to the Sponsor and investigational staff and are accessible for 
verification by the Sponsor site contact. If electronic records are maintained at the 
investigational site, the method of verification must be discussed with the investigational 
staff.  
 
Direct access to source documentation ([electronic] medical records) must be permitted at 
all times. Findings from this review of captured data will be discussed with the 
investigational staff. The Sponsor expects that, during on-site monitoring visits, the relevant 
investigational staff will be available, the source documentation will be accessible, and a 
suitable environment will be provided for review of study-related documents. The monitor 
will meet with the Investigator on a regular basis during the study to provide feedback on 
the study conduct. The Investigator agrees to cooperate with the monitor to ensure that any 
problems detected in the course of these monitoring visits will be resolved in a timely 
manner. 
 
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10. FINANCING AND INSURANCE 
 
Insurance 
 
Ablynx NV holds and will maintain an adequate insurance policy covering damages arising 
from Ablynx-sponsored clinical research studies. 
 
Ablynx NV will indemnify the Investigator in accordance with the provisions as set in a 
separate written agreement between Ablynx NV (or a vendor on behalf of the Sponsor) and 
the relevant Investigator/clinical site. 
 
Financing 
 
The financial aspects of the study will be documented in an agreement between the Sponsor 
(or a vendor on behalf of the Sponsor) and the Head of Institution. 
 
Reimbursement for reasonable expenses related to the study will be foreseen. 
 
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11. USE OF INFORMATION, REPORTING, 
AND PUBLICATION 
 
By signing this protocol, the Investigator reaffirms to the Sponsor that he or she will 
maintain in confidence all information furnished, or resulting from this study. He/she will 
only divulge such information as may be necessary to the IRB and the members of the staff 
and the parent(s)/legal guardian(s) of subjects who are involved in this study.  
 
All data and records provided by the Sponsor or generated during the study (other than 
subject’s medical records) and all data and inventions covered in the course of conducting 
the study, whether patentable or not, are the sole and exclusive property of the Sponsor. 
 
The Investigator and all other study team members at any service provider involved will 
keep strictly confidential all information provided by the Sponsor related to this study and 
all data and records generated in the course of the study. They will not use the information, 
data, or records for any other purpose than conducting the study without prior written 
approval of the Sponsor.  
 
A Coordinating Investigator will be selected among the study’s Investigators based on the 
number of subjects overseen at the study’s sites, as well as his/her scientific contributions 
during the conduct of the study. The Coordinating Investigator will review and contribute to 
the contents of the CSR prior to its approval.  
 
Publication of any results from this study will be according to the principles of the 
Declaration of Helsinki, and will require prior review and written agreement of the Sponsor. 
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12. REFERENCES 
1. Ralston, S.L., et al., Clinical practice guideline: the diagnosis, management, and 
prevention of bronchiolitis. Pediatrics, 2014. 134(5): p. e1474-502. 
2. National Institute for Health and Care Excellence (NICE), Guideline in development - 
Bronchiolitis: Diagnosis and Management of Bronchiolitis in Children, 2015: London. 
3. Meissner, H.C., Viral Bronchiolitis in Children. The New England journal of medicine, 
2016. 374(1): p. 62-72. 
4. Mazur, N.I., et al., Lower respiratory tract infection caused by respiratory syncytial 
virus: current management and new therapeutics. The Lancet. Respiratory medicine, 
2015. 3(11): p. 888-900. 
5. Black, C.P., Systematic review of the biology and medical management of respiratory 
syncytial virus infection. Respiratory care, 2003. 48(3): p. 209-31; discussion 231-3. 
6. Ablynx Summary Report, Immunogenicity risk assessment ALX-0171. 
7. Chamberlain, P., Addressing immunogenicity-related risks in an integrated manner. 
Informa UK - Dossier Strategy, 2011. 
8. Shankar, G., C. Pendley, and K.E. Stein, A risk-based bioanalytical strategy for the 
assessment 
of 
antibody 
immune 
responses 
against 
biological 
drugs. 
Nature 
biotechnology, 2007. 25(5): p. 555-61. 
9. FDA, Guidance for Industry: Immunogenicity assessment for therapeutic protein 
products. 2014. 
10. Ablynx Report 24_A001701_14_0038, Immunogenicity risk assessment ALX-0171. 
11. Hall, C.B., et al., The burden of respiratory syncytial virus infection in young children. 
The New England journal of medicine, 2009. 360(6): p. 588-98. 
12. Wang, Y., et al., Clarification on precision criteria to derive sample size when designing 
pediatric pharmacokinetic studies. Journal of clinical pharmacology, 2012. 52(10): p. 
1601-6. 
13. Boe, J., et al., European Respiratory Society Guidelines on the use of nebulizers. The 
European respiratory journal, 2001. 18(1): p. 228-42. 
14. Ablynx report 24_A001701_14_0057, Physiologically-based pharmacokinetic (PBPK) 
model to explore ALX-0171 pharmacokinetics in infants following inhalation. 2014. 
15. Justicia-Grande, A.J., et al., Development and Validation of a New Clinical Scale for 
Infants with Acute Respiratory Infection: The ReSVinet Scale. PloS one, 2016. 11(6): p. 
e0157665. 
16. Murray, Measurement of intracellular replicative strand in Respiratory Syncytial Virus 
(RSV) infected human volunteers. Poster presentation at Molecular Med Tri-Con San 
Francisco, CA. 2016. 
17. Howie, S.R., Blood sample volumes in child health research: review of safe limits. 
Bulletin of the World Health Organization, 2011. 89(1): p. 46-53. 
18. WHO, Paediatric clinical trials - guidance for assessors. 2011. 
19. EMA, Recommendations of the ad hoc group for the development of implementing 
guidelines for Directive 2001/20/EC relating to good clinical practice in the conduct of 
clinical trials on medicinal products for human use - Ethical considerations for clinical 
trials on medicinal products conducted with the paediatric population. 2008. 
20. FDA, 21CFR50 - Subpart D: Additional Safeguards for Children in Clinical Investigations. 
2013. 
21. FDA, 45CFR46 - Protection of human subjects. 2013. 
22. Justicia-Grande, A., et al., Development and validation of a new clinical scale for infants 
suffering from acute respiratory infection. Leipzig: 33rd Annual Meeting of the European 
Society for Paediatric Infectious Diaseases, 2015. 
23. Cebey-Lopez, M., et al., Bacteremia in Children Hospitalized with Respiratory Syncytial 
Virus Infection. PloS one, 2016. 11(2): p. e0146599. 
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24. Barrett, J.S., et al., Physiologically based pharmacokinetic (PBPK) modeling in children. 
Clinical pharmacology and therapeutics, 2012. 92(1): p. 40-9. 
25. De Paepe, M.E., et al., Postmortem lung weight/body weight standards for term and 
preterm infants. Pediatric pulmonology, 2005. 40(5): p. 445-8. 
 
 
 
 
 
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13. APPENDICES 
 
13.1. APPENDIX 1: RDAI AND RACS 
 
The Respiratory Distress Assessment Instrument (RDAI) score is a 17-point score based on 
wheezing and retraction. 
 
Variable 
Number of Points 
 
 
0 
1 
2 
3 
4 
Max 
Points 
Wheezing 
  Expiration 
None 
End 
1-2 
3-4 
All 
4 
  Inspiration 
None 
Part 
All 
NA 
NA 
2 
  Location 
None 
Segmental, ≤2-4 lung fields 
Diffuse, ≥3-4 lung fields 
NA 
NA 
2 
Retractions 
  Supraclavicular 
None 
Mild 
Moderate 
Marked 
NA 
3 
  Intercostal 
None 
Mild 
Moderate 
Marked 
NA 
3 
  Subcostal 
None 
Mild 
Moderate 
Marked 
NA 
3 
NA=not applicable 
 
The RDAI score is the sum of the row scores, with total range 0 to 17; higher scores 
indicate more severe disease. 
 
The Respiratory Assessment Change Score (RACS) is the sum of the change in the RDAI 
score and a standardized score for the change in respiratory rate. The change in respiratory 
rate is assigned 1 point per each 10% change in the respiratory rate.  
 
A decrease in the RDAI or in the respiratory rate during the study period is recorded as a 
negative RACS, meaning an improvement. 
 
 
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13.2. APPENDIX 2: GLOBAL SEVERITY 
SCORE 
 
The Global Severity Score is the sum of the scores of the 7 individual items as described 
below; total maximum score is 20 points; higher score indicates more severe disease. 
 
Item 
Number 
of Points 
Description 
Feeding 
0 
Adequate oral feeding 
 
1 
No adequate oral feeding, occasional breaks during feeding 
 
2 
No adequate oral feeding, frequent breaks during feeding 
 
3 
No adequate oral feeding, unable to feed, feeding support 
Medical interventions 
0 
Not hospitalized 
1 
Hospitalization without O2 supplementation 
 
2 
Conventional oxygen supplementation 
 
3 
Non-invasive respiratory support or invasive ventilation 
Respiratory distress 
0 
No wheezing and no retractions 
1-2-3 
Points will be attributed uniformly across the 17 points for RDAI 
Respiratory rate 
0-1-2-3 
Points will be attributed uniformly across the respiratory rate values for each 
age range 
Apnea 
0 
No apnea episode 
 
3 
Apnea episode 
General appearance a 
0 
Active, playing/ content/ interactive and happy 
1 
Less active/ mildly irritable/ less interactive or responsive 
 
2 
Less active/ moderately irritable/ less interactive or responsive 
 
3 
Not active/ Severely irritable/ Not interactive or not responsive 
 
Note: In case worst item is less active and/or less interactive: if both are present: 2 
points; if only one of both is present and the highest: 1 point 
Body Temperature 
0 
<37,0°C: (measured axillary); <37,5°C (measured by other method) 
1 
≥37,0°C but <38°C (measured axillary); ≥37,5°C but <38,5°C (measured by 
other method) 
 
2 
>38°C (measured axillary); >38,5°C (measured by other method) 
a Assessed through activity, irritation and interest in environment (worst of the three items will be used for 
attributing the points) 
 
 
 
 
 
 
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Signature Page 
This is a representation of an electronic record that was signed electronically in Livelink. 
This page is the manifestation of the electronic signature(s) used in compliance with the organizations 
electronic signature policies and procedures. 
 
UserName: 
 
Title:  SENIOR MEDICAL DIRECTOR 
Date: Tuesday, 14 November 2017, 11:45   Romance Daylight Time 
Meaning: Approved 
================================================
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