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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, multicenter dose ranging study of ALX-0171 in infants and young children hospitalized for respiratory syncytial virus lower respiratory tract infection

    Summary
    EudraCT number
    		 2016-001651-49
    Trial protocol
    		 GB   DE   LV   HU   ES   EE   LT   SK   BE   BG   CZ   Outside EU/EEA   PL   HR  
    Global end of trial date
    25 May 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    13 Jun 2019
    First version publication date
    25 Apr 2019
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    The record will be updated to bring the EU clinical trials record in line with the clinicaltrials.gov results record (e.g., additional data on immunogenicity will be added).

    Trial information

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    Trial identification
    Sponsor protocol code
    ALX0171-C201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02979431
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ablynx NV
    Sponsor organisation address
    Technologie Park 21, Zwijnaarde, Belgium, 9052
    Public contact
    clinicaltrials@ablynx.com, Ablynx NV, +32 (0)9262 00 00, clinicaltrials@ablynx.com
    Scientific contact
    clinicaltrials@ablynx.com, Ablynx NV, +32 (0)9262 00 00, clinicaltrials@ablynx.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001553-PIP01-13
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 Sep 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 May 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    25 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the anti-viral effect and safety of different doses of inhaled ALX-0171 in subjects hospitalized for respiratory syncytial virus (RSV) lower respiratory tract infection.
    Protection of trial subjects
    Written informed consent was obtained according to local requirements after the nature of the study was fully explained to the parent/ legal representative and before performance of any study-related activity. The informed consent form (ICF) was approved by both the Sponsor and the reviewing IEC/IRB. The ICF was in accordance with principles that originated in the Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory requirements, and Sponsor policy. Before undertaking any study-related procedure, the Investigator or an authorized member of the investigational staff explained to the parents/legal representatives of potential subjects the aims, methods, objectives, potential lack of clinical benefit, and potential hazards of the study, and any discomfort participation in the study would entail. The parents/ legal representatives were informed that their participation was voluntary and that they could refuse to participate or withdraw from the study at any time, without penalty or loss of benefits to which the subject was otherwise entitled to and that all data collected up to the point of withdrawal would be used and reported in an anonymous way. Only subjects who met all the study inclusion criteria and none of the exclusion criteria were to be randomized to study treatment. Close monitoring of all subjects was to be adhered to throughout the study.
    Background therapy
    		 The treatment and care provided to each subject were 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 (2014), could also be followed. Permitted treatment/ medications included (but were not limited to) the following: -O2 supplementation through nasal cannula, via face mask or headbox. The initiation, monitoring and weaning of oxygen supplementation followed local practice. It should be removed for the nebulized study drug administration, during which air or oxygen flow of 2 L/min was provided -Fluid/food supplementation (i.v. or via nasogastric tube, if applicable) -Antipyretics and/or nonsteroidal anti-inflammatory medication -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
    Evidence for comparator
    		 Not applicable. This was a placebo-controlled study; the placebo group served as comparator group for the 3 ALX-0171 treatment groups (ALX-0171 target concentrations: 3.0mg/kg, 6.0mg/kg, and 9.0mg/kg).
    Actual start date of recruitment
    11 Jan 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 13
    Country: Number of subjects enrolled
    Slovakia: 4
    Country: Number of subjects enrolled
    Spain: 16
    Country: Number of subjects enrolled
    Croatia: 23
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Bulgaria: 33
    Country: Number of subjects enrolled
    Czech Republic: 1
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Hungary: 27
    Country: Number of subjects enrolled
    Latvia: 10
    Country: Number of subjects enrolled
    Chile: 4
    Country: Number of subjects enrolled
    Philippines: 5
    Country: Number of subjects enrolled
    Thailand: 10
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Malaysia: 14
    Country: Number of subjects enrolled
    Colombia: 1
    Worldwide total number of subjects
    180
    EEA total number of subjects
    142
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    180
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 First Subject First Visit: 11 January 2017, Last Subject Last Visit: 25 May 2018 Subjects were enrolled in 50 sites in 16 countries: Belgium, Bulgaria,Chile, Colombia, Croatia, Czech Republic, Germany, Hungary, Israel, Latvia, Malaysia, Philippines, Poland, Slovakia, Spain, and Thailand.

    Pre-assignment
    Screening details
    		 A total of 301 subjects were screened. 180 subjects were randomized to study drug treatment. Five subjects were randomized but not treated with study drug. Of those, 2 subjects discontinued as the parent/guardian withdrew consent, 2 subjects were randomized in error without receiving study drug, and 1 subject discontinued due to an AE of dyspnoea.

    Period 1
    Period 1 title
    Overall Study Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer
    Blinding implementation details
    To ensure blinding across dose groups, study drug was administered via inhalation using 2 consecutive nebulizations; 2X ALX-0171 nebulizations, or 1X ALX-0171 and 1X placebo, or x2 placebo depending on the assigned treatment group. To protect the integrity of the data, treatment assignment was kept blinded for investigative sites, parent(s)/legal guardian(s) and caregiver(s), site monitors, other study team members until the final database lock. No unblinding by the site occurred for the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Matching placebo was administered via inhalation using the FOX-Flamingo inhalation system (using 2 consecutive nebulizations), once daily for 3 consecutive days. The formulation 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.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Matching placebo was administered via inhalation using the FOX-Flamingo inhalation system (using 2 consecutive nebulizations), once daily for 3 consecutive days.

    Arm title
    		 ALX-0171 3.0mg/kg
    Arm description
    		 Subjects in this arm received a target ALX-0171 dose of 3.0mg/kg. ALX-0171 was administered via inhalation using the FOX-Flamingo inhalation system (using 2 consecutive nebulizations), once daily for 3 consecutive days. The formulation of ALX-0171 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ALX-0171
    Investigational medicinal product code
    Other name
    ALX-0171 Nanobody
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    ALX-0171 at target concentration of 3.0mg/kg was administered via inhalation using the FOX-Flamingo inhalation system (using 2 consecutive nebulizations), once daily for 3 consecutive days. To achieve double-blinding across the different groups, each dose was administered as 2 consecutive nebulizations (i.e., 2 nebulizations of ALX-0171, or one nebulization of ALX-0171 and one of placebo, or 2 nebulizations of placebo depending on the treatment group assigned).

    Arm title
    		 ALX-0171 6.0mg/kg
    Arm description
    		 Subjects in this arm received a target ALX-0171 dose of 6.0mg/kg. ALX-0171 was administered via inhalation using the FOX-Flamingo inhalation system (using 2 consecutive nebulizations), once daily for 3 consecutive days. The formulation of ALX-0171 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ALX-0171
    Investigational medicinal product code
    Other name
    ALX-0171 Nanobody
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    ALX-0171 at target concentration of 6.0mg/kg was administered via inhalation using the FOX-Flamingo inhalation system (using 2 consecutive nebulizations), once daily for 3 consecutive days. To achieve double-blinding across the different groups, each dose was administered as 2 consecutive nebulizations (i.e., 2 nebulizations of ALX-0171, or one nebulization of ALX-0171 and one of placebo, or 2 nebulizations of placebo depending on the treatment group assigned).

    Arm title
    		 ALX-0171 9.0mg/kg
    Arm description
    		 Subjects in this arm received a target ALX-0171 dose of 9.0mg/kg. ALX-0171 was administered via inhalation using the FOX-Flamingo inhalation system (using 2 consecutive nebulizations), once daily for 3 consecutive days. The formulation of ALX-0171 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ALX-0171
    Investigational medicinal product code
    Other name
    ALX-0171 Nanobody
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    ALX-0171 at target concentration of 9.0mg/kg was administered via inhalation using the FOX-Flamingo inhalation system (using 2 consecutive nebulizations), once daily for 3 consecutive days. To achieve double-blinding across the different groups, each dose was administered as 2 consecutive nebulizations (i.e., 2 nebulizations of ALX-0171, or one nebulization of ALX-0171 and one of placebo, or 2 nebulizations of placebo depending on the treatment group assigned).

    Number of subjects in period 1 [1]
    		Placebo ALX-0171 3.0mg/kg ALX-0171 6.0mg/kg ALX-0171 9.0mg/kg
    Started
    42
    45
    43
    45
    Included in the mITT Population
    42
    45
    43
    45
    Completed
    40
    44
    43
    44
    Not completed
    2
    1
    0
    1
         Other
    1
    -
    -
    -
         Withdrawal by parent/guardian
    1
    1
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 301 subjects were screened. Of those, 121 subjects (40.2%) were considered screening failures. A total of 180 subjects were randomized in the study (placebo: 44 subjects; ALX-0171 3.0 mg/kg: 46; 6.0 mg/kg: 45; 9.0 mg/kg: 45). Five subjects were randomized but they were not treated with study drug. Demography and Baseline Disease characteristics are reported for the mITT Population. Therefore, the number of subjects/group shown are those in the mITT Population.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo was administered via inhalation using the FOX-Flamingo inhalation system (using 2 consecutive nebulizations), once daily for 3 consecutive days. The formulation 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.

    Reporting group title
    ALX-0171 3.0mg/kg
    Reporting group description
    		 Subjects in this arm received a target ALX-0171 dose of 3.0mg/kg. ALX-0171 was administered via inhalation using the FOX-Flamingo inhalation system (using 2 consecutive nebulizations), once daily for 3 consecutive days. The formulation of ALX-0171 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.

    Reporting group title
    ALX-0171 6.0mg/kg
    Reporting group description
    		 Subjects in this arm received a target ALX-0171 dose of 6.0mg/kg. ALX-0171 was administered via inhalation using the FOX-Flamingo inhalation system (using 2 consecutive nebulizations), once daily for 3 consecutive days. The formulation of ALX-0171 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.

    Reporting group title
    ALX-0171 9.0mg/kg
    Reporting group description
    		 Subjects in this arm received a target ALX-0171 dose of 9.0mg/kg. ALX-0171 was administered via inhalation using the FOX-Flamingo inhalation system (using 2 consecutive nebulizations), once daily for 3 consecutive days. The formulation of ALX-0171 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.

    Reporting group values
    		 Placebo ALX-0171 3.0mg/kg ALX-0171 6.0mg/kg ALX-0171 9.0mg/kg Total
    Number of subjects
    		 42 45 43 45 175
    Age categorical
    The numbers shown are of subjects included in the mITT Population (placebo N=42; ALX-0171 3.0mg/kg N=45; 6.0mg/kg N=43; 9.0mg/kg N=45).
    Units: Subjects
        < 6 months
    		 24 23 27 25 99
        ≥ 6 months and < 12 months
    		 8 13 7 12 40
        ≥ 12 months
    		 10 9 9 8 36
    Age continuous
    The numbers shown are of subjects included in the mITT Population (placebo N=42; ALX-0171 3.0mg/kg N=45; 6.0mg/kg N=43; 9.0mg/kg N=45). The age reported is the age at the time of informed consent signing.
    Units: months
        arithmetic mean (standard deviation)
    		 6.964 ( 6.0668 ) 6.933 ( 5.8827 ) 6.657 ( 6.2605 ) 7.022 ( 5.6884 ) -
    Gender categorical
    The numbers shown are of subjects included in the mITT Population (placebo N=42; ALX-0171 3.0mg/kg N=45; 6.0mg/kg N=43; 9.0mg/kg N=45).
    Units: Subjects
        Female
    		 24 15 19 17 75
        Male
    		 18 30 24 28 100
    Race
    The numbers shown are of subjects included in the mITT Population (placebo N=42; ALX-0171 3.0mg/kg N=45; 6.0mg/kg N=43; 9.0mg/kg N=45).
    Units: Subjects
        Asian
    		 7 7 3 10 27
        Black or African American
    		 0 0 1 0 1
        Multiple
    		 0 0 2 0 2
        Other
    		 0 0 1 3 4
        White
    		 35 38 36 32 141
    Ethnicity
    The numbers shown are of subjects included in the mITT Population (placebo N=42; ALX-0171 3.0mg/kg N=45; 6.0mg/kg N=43; 9.0mg/kg N=45).
    Units: Subjects
        Hispanic or Latino
    		 4 4 5 5 18
        Not Hispanic or Latino
    		 38 41 38 40 157
    Weight category
    The numbers shown are of subjects included in the mITT Population (placebo N=42; ALX-0171 3.0mg/kg N=45; 6.0mg/kg N=43; 9.0mg/kg N=45).
    Units: Subjects
        ≥ 3.0 kg and < 4.0 kg
    		 1 2 0 2 5
        ≥ 4.0 kg and < 5.0 kg
    		 8 6 13 7 34
        ≥ 5.0 kg and < 7.0 kg
    		 15 15 11 14 55
        ≥ 7.0 kg and < 10.0 kg
    		 11 17 12 19 59
        ≥ 10.0 kg and < 12.0 kg
    		 6 4 7 1 18
        ≥ 12.0 kg and < 15.0 kg
    		 1 1 0 2 4
    Gestational age
    The numbers shown are of subjects included in the mITT Population (placebo N=42; ALX-0171 3.0mg/kg N=45; 6.0mg/kg N=43; 9.0mg/kg N=45).
    Units: Weeks
        arithmetic mean (standard deviation)
    		 38.5 ( 1.78 ) 38.6 ( 1.99 ) 38.6 ( 1.62 ) 38.3 ( 1.54 ) -
    Weight
    The numbers shown are of subjects included in the mITT Population (placebo N=42; ALX-0171 3.0mg/kg N=45; 6.0mg/kg N=43; 9.0mg/kg N=45).
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 7.065 ( 2.4193 ) 7.188 ( 2.2278 ) 6.988 ( 2.4084 ) 7.020 ( 2.2474 ) -
    Height
    The numbers shown are of subjects included in the mITT Population (placebo N=42; ALX-0171 3.0mg/kg N=45; 6.0mg/kg N=43; 9.0mg/kg N=45).
    Units: centimeter
        arithmetic mean (standard deviation)
    		 65.84 ( 9.997 ) 65.71 ( 10.210 ) 65.25 ( 10.190 ) 66.55 ( 9.580 ) -
    RSV titers at Baseline by plaque assay
    The numbers shown are of subjects included in the mITT Population (placebo N=42; ALX-0171 3.0mg/kg N=45; 6.0mg/kg N=43; 9.0mg/kg N=45).
    Units: Log10 PFU/mL
        arithmetic mean (standard deviation)
    		 3.155 ( 0.2531 ) 3.078 ( 0.2259 ) 3.023 ( 0.2438 ) 2.140 ( 0.2286 ) -
    RSV titers at Baseline by RT-qPCR
    The numbers shown are of subjects included in the mITT Population (placebo N=42; ALX-0171 3.0mg/kg N=45; 6.0mg/kg N=43; 9.0mg/kg N=45).
    Units: Log10 copies/mL
        arithmetic mean (standard deviation)
    		 4.731 ( 0.3266 ) 4.623 ( 0.2519 ) 5.040 ( 0.2250 ) 4.008 ( 0.3070 ) -
    Number of days between symptom onset and first dose of study drug
    The numbers shown are of subjects included in the mITT Population (placebo N=42; ALX-0171 3.0mg/kg N=45; 6.0mg/kg N=43; 9.0mg/kg N=45).
    Units: days
        arithmetic mean (standard deviation)
    		 3.16 ( 1.207 ) 3.34 ( 1.144 ) 3.23 ( 0.845 ) 3.25 ( 1.149 ) -
    Global Severity Score
    The numbers shown are of subjects included in the mITT Population (placebo N=42; ALX-0171 3.0mg/kg N=45; 6.0mg/kg N=43; 9.0mg/kg N=45).
    Units: score
        arithmetic mean (standard deviation)
    		 9.1 ( 2.44 ) 9.2 ( 2.00 ) 9.3 ( 2.09 ) 9.4 ( 2.41 ) -
    RDAI score
    The numbers shown are of subjects included in the mITT Population (placebo N=42; ALX-0171 3.0mg/kg N=45; 6.0mg/kg N=43; 9.0mg/kg N=45).
    Units: score
        arithmetic mean (standard deviation)
    		 8.5 ( 3.74 ) 8.41 ( 4.07 ) 8.74 ( 3.19 ) 8.11 ( 3.80 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo was administered via inhalation using the FOX-Flamingo inhalation system (using 2 consecutive nebulizations), once daily for 3 consecutive days. The formulation 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.

    Reporting group title
    ALX-0171 3.0mg/kg
    Reporting group description
    		 Subjects in this arm received a target ALX-0171 dose of 3.0mg/kg. ALX-0171 was administered via inhalation using the FOX-Flamingo inhalation system (using 2 consecutive nebulizations), once daily for 3 consecutive days. The formulation of ALX-0171 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.

    Reporting group title
    ALX-0171 6.0mg/kg
    Reporting group description
    		 Subjects in this arm received a target ALX-0171 dose of 6.0mg/kg. ALX-0171 was administered via inhalation using the FOX-Flamingo inhalation system (using 2 consecutive nebulizations), once daily for 3 consecutive days. The formulation of ALX-0171 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.

    Reporting group title
    ALX-0171 9.0mg/kg
    Reporting group description
    		 Subjects in this arm received a target ALX-0171 dose of 9.0mg/kg. ALX-0171 was administered via inhalation using the FOX-Flamingo inhalation system (using 2 consecutive nebulizations), once daily for 3 consecutive days. The formulation of ALX-0171 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.

    Subject analysis set title
    Intent-to-treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population consisted of all randomized subjects.

    Subject analysis set title
    modified Intent-to-Treat (mITT)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The modified ITT (mITT) population consisted of all randomized subjects who received at least 1 administration of study drug. When using this population, the subjects were classified as randomized (i.e., using the treatment to which the subject was randomized). This was the primary study population for the analysis of baseline characteristics, efficacy and pharmacodynamic data.

    Subject analysis set title
    RSV-Infected Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    RSV-Infected population (confirmed in central laboratory by RT-qPCR): Although a positive local RSV test was required for eligibility assessment, a central RSV test was used for defining the RSV-Infected population. The RSV-Infected population consisted of all randomized subjects with RSV infection, as confirmed by RT-qPCR (hVIVO quantitative PCR assay) on Day 1 (pre- or post-dose), who received at least 1 administration of study drug. Subjects were classified as randomized when using this population. Dedicated outputs on the RSV-Infected population were created only if this population differed from the mITT population.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population consisted of all subjects who received at least 1 administration of study drug. When using this population, the subjects were classified as treated (i.e., using the treatment that the subject actually received). This was the primary population for the analysis of prior/concomitant medications, exposure, safety and immunogenicity data.

    Primary: Time-to-below quantification limit (BQL) (plaque assay analysis)

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    End point title
    		 Time-to-below quantification limit (BQL) (plaque assay analysis)
    End point description
    The primary endpoint for this trial was the time needed for the viral load to drop below the quantification limit (time-to-BQL) of the plaque assay in nasal mid-turbinate swab specimens. Time-to-BQL was defined as the time from the first study drug administration to the first occurrence of a value below the quantification limit (BQL), provided the next measured value was also below the limit of quantification. The time to BQL for subjects with missing data and/or who did not reach BQL during the trial were censored at the last non-missing viral load assessment. The primary endpoint was analysed using log-rank test to compare time-to-BQL between each of the ALX-0171 treatment groups and the combined placebo group. The tests were performed in a sequential way to preserve the family-wise error rate at 0.05. The comparisons were performed in the following order: ALX-0171 9 mg vs Placebo, followed by ALX-0171 6mg vs Placebo, ALX-0171 3mg/kg vs Placebo.
    End point type
    Primary
    End point timeframe
    Overall Study Period
    End point values
    		 Placebo ALX-0171 3.0mg/kg ALX-0171 6.0mg/kg ALX-0171 9.0mg/kg
    Number of subjects analysed
    42 [1]
    45 [2]
    43 [3]
    45 [4]
    Units: hours
        median (confidence interval 95%)
    46.1 (29.33 to 94.42)
    14.2 (5.17 to 26.28)
    5.1 (4.78 to 24.72)
    5.1 (4.97 to 5.17)
    Notes
    [1] - mITT Population
    [2] - mITT Population
    [3] - mITT Population
    [4] - mITT Population
    Statistical analysis title
    		 ALX-0171 9.0mg/kg versus placebo
    Statistical analysis description
    The primary endpoint was analysed using log-rank test to compare time-to-BQL between each of the ALX-0171 treatment groups and the combined placebo group. The tests were performed in a sequential way to preserve the family-wise error rate at 0.05.
    Comparison groups
    Placebo v ALX-0171 9.0mg/kg
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.001
    Method
    		 Logrank
    Parameter type
    		 Median time-to-BQL
    Confidence interval
    Notes
    [5] - Survival Analysis using lon-rank test
    Statistical analysis title
    		 ALX-0171 6.0mg/kg versus placebo
    Statistical analysis description
    The primary endpoint was analysed using log-rank test to compare time-to-BQL between each of the ALX-0171 treatment groups and the combined placebo group. The tests were performed in a sequential way to preserve the family-wise error rate at 0.05.
    Comparison groups
    Placebo v ALX-0171 6.0mg/kg
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.001
    Method
    		 Logrank
    Parameter type
    		 Median time-to-BQL
    Confidence interval
    Notes
    [6] - Survival analysis using log-rank test
    Statistical analysis title
    		 ALX-0171 3.0mg/kg versus placebo
    Statistical analysis description
    The primary endpoint was analysed using log-rank test to compare time-to-BQL between each of the ALX-0171 treatment groups and the combined placebo group. The tests were performed in a sequential way to preserve the family-wise error rate at 0.05.
    Comparison groups
    ALX-0171 3.0mg/kg v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.001
    Method
    		 Logrank
    Parameter type
    		 Median time-to-BQL
    Confidence interval
    Notes
    [7] - Survival analysis using log-rank test

    Secondary: Change from Baseline in Global Severity Score on Day 2 (5 hours post-dose)

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    End point title
    		 Change from Baseline in Global Severity Score on Day 2 (5 hours post-dose)
    End point description
    A formal comparison for change from Baseline in GSS to Day 2, 5 hours post-dose was performed using a contrast analysis on a longitudinal mixed model with random factor subject and fixed effects baseline value, treatment group and timepoint, including the treatment-by-timepoint interaction term. All data up to and including Day 3 were used in the longitudinal mixed model. The Kenward-Roger approximation of degrees of freedom was used. The model was fitted using an unstructured variance-covariance matrix. The individual pair-wise comparisons were reported (comparison in least square [LS] means for 3.0 mg/kg versus placebo; 6.0mg/kg versus placebo; 9.0 mg/kg versus placebo).
    End point type
    Secondary
    End point timeframe
    Day 2 (5 hours post-dose)
    End point values
    		 Placebo ALX-0171 3.0mg/kg ALX-0171 6.0mg/kg ALX-0171 9.0mg/kg
    Number of subjects analysed
    42 [8]
    45 [9]
    43 [10]
    45 [11]
    Units: score
        least squares mean (standard error)
    -3.6392 ( 0.4160 )
    -3.8548 ( 0.4103 )
    -4.1296 ( 0.4129 )
    -4.2844 ( 0.4099 )
    Notes
    [8] - mITT Population
    [9] - mITT Population
    [10] - mITT Population
    [11] - mITT Population
    Statistical analysis title
    		 GSS;9.0mg/kg vs placebo comparison
    Statistical analysis description
    A comparison for change from Baseline in GSS to Day 2, 5 hours post-dose was performed using a contrast analysis on a longitudinal mixed model with random factor subject and fixed effects baseline value, treatment group and timepoint, including the treatment-by-timepoint interaction term. All data up to + including Day 3 were used in the longitudinal mixed model. The Kenward-Roger approximation of degrees of freedom was used.The model was fitted using an unstructured variance-covariance matrix.
    Comparison groups
    Placebo v ALX-0171 9.0mg/kg
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.271
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in LS means
    Confidence interval
    Notes
    [12] - Contrast analysis using a longitudinal mixed model
    Statistical analysis title
    		 GSS;6.0mg/kg vs placebo comparison
    Statistical analysis description
    A comparison for change from Baseline in GSS to Day 2, 5 hours post-dose was performed using a contrast analysis on a longitudinal mixed model with random factor subject and fixed effects baseline value, treatment group and timepoint, including the treatment-by-timepoint interaction term. All data up to + including Day 3 were used in the longitudinal mixed model. The Kenward-Roger approximation of degrees of freedom was used.The model was fitted using an unstructured variance-covariance matrix.
    Comparison groups
    Placebo v ALX-0171 6.0mg/kg
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.404
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in LS means
    Confidence interval
    Notes
    [13] - Contrast analysis using a longitudinal mixed model
    Statistical analysis title
    		 GSS;3.0mg/kg vs placebo comparison
    Statistical analysis description
    A comparison for change from Baseline in GSS to Day 2, 5 hours post-dose was performed using a contrast analysis on a longitudinal mixed model with random factor subject and fixed effects baseline value, treatment group and timepoint, including the treatment-by-timepoint interaction term. All data up to + including Day 3 were used in the longitudinal mixed model. The Kenward-Roger approximation of degrees of freedom was used.The model was fitted using an unstructured variance-covariance matrix.
    Comparison groups
    Placebo v ALX-0171 3.0mg/kg
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.713
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in LS means
    Confidence interval
    Notes
    [14] - Contrast analysis using a longitudinal mixed model

    Secondary: Time-to-clinical response

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    End point title
    		 Time-to-clinical response
    End point description
    The time-to-clinical response was defined as the time between the first study drug administration and the time of achieving adequate oxygen saturation and adequate oral feeding.
    End point type
    Secondary
    End point timeframe
    Overall Study Period
    End point values
    		 Placebo ALX-0171 3.0mg/kg ALX-0171 6.0mg/kg ALX-0171 9.0mg/kg
    Number of subjects analysed
    42 [15]
    45 [16]
    43 [17]
    45 [18]
    Units: hours
    median (confidence interval 95%)
        Time-to-clinical response
    47.9 (29.17 to 64.08)
    44.1 (28.33 to 51.20)
    27.9 (21.08 to 43.68)
    46.3 (38.00 to 50.38)
        Time-to adequate oral feeding
    43.7 (22.50 to 47.58)
    44.0 (25.92 to 52.00)
    17.6 (6.50 to 25.85)
    23.8 (17.17 to 38.00)
        Time-to-adequate oxygen saturation
    53.4 (28.70 to 71.78)
    38.5 (24.75 to 61.93)
    29.5 (20.75 to 47.43)
    46.5 (42.15 to 48.25)
    Notes
    [15] - mITT Population
    [16] - mITT Population
    [17] - mITT Population
    [18] - mITT Population
    No statistical analyses for this end point

    Secondary: Time-to-BQL (RT-qPCR)

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    End point title
    		 Time-to-BQL (RT-qPCR)
    End point description
    The upper limit of CI could not be calculated; Values of the 25% percentile are reported here.
    End point type
    Secondary
    End point timeframe
    Overall Study Period
    End point values
    		 Placebo ALX-0171 3.0mg/kg ALX-0171 6.0mg/kg ALX-0171 9.0mg/kg
    Number of subjects analysed
    42 [19]
    45 [20]
    43 [21]
    45 [22]
    Units: hours
        median (confidence interval 95%)
    26.7 (5.00 to 49.92)
    26.8 (5.17 to 44.62)
    28.9 (18.25 to 49.25)
    6.3 (4.97 to 25.25)
    Notes
    [19] - mITT Population
    [20] - mITT Population
    [21] - mITT Population
    [22] - mITT Population
    No statistical analyses for this end point

    Secondary: Time-to-undetectable viral load

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    End point title
    		 Time-to-undetectable viral load
    End point description
    End point type
    Secondary
    End point timeframe
    Overall Study Period
    End point values
    		 Placebo ALX-0171 3.0mg/kg ALX-0171 6.0mg/kg ALX-0171 9.0mg/kg
    Number of subjects analysed
    35 [23]
    40 [24]
    40 [25]
    38 [26]
    Units: hours
    median (confidence interval 95%)
        plaque assay analysis
    95.9 (47.23 to 121.82)
    26.3 (20.25 to 28.92)
    21.0 (4.88 to 28.25)
    5.1 (5.00 to 5.87)
    Attachments
    		 Time to undetectable viral load (RT-qPCR)
    Time to undetectable viral load (plaque assay)
    Notes
    [23] - RSV-Infected Population
    [24] - RSV-Infected Population
    [25] - RSV-Infected Population
    [26] - RSV-Infected Population
    No statistical analyses for this end point

    Secondary: Viral load changes from Baseline (plaque assay analysis)

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    End point title
    		 Viral load changes from Baseline (plaque assay analysis)
    End point description
    Change from Baseline in RSV Load measured by Plaque Assay (RSV Infected Population)
    End point type
    Secondary
    End point timeframe
    Overall Study Period
    End point values
    		 Placebo ALX-0171 3.0mg/kg ALX-0171 6.0mg/kg ALX-0171 9.0mg/kg
    Number of subjects analysed
    35 [27]
    40 [28]
    40 [29]
    38 [30]
    Units: log10 pfu/mL
    arithmetic mean (standard error)
        Baseline
    3.494 ( 0.2396 )
    3.312 ( 0.2165 )
    3.135 ( 0.2430 )
    2.385 ( 0.2526 )
        Day 1, 5 hours post-dose
    -0.270 ( 0.1607 )
    -2.173 ( 0.2123 )
    -2.189 ( 0.2676 )
    -1.535 ( 0.2526 )
        Day 3, 2 hours post-dose
    -1.936 ( 0.2317 )
    -2.396 ( 0.2234 )
    -2.134 ( 0.2525 )
    -1.516 ( 0.2558 )
        Follow-up
    -2.368 ( 0.2946 )
    -2.431 ( 0.2202 )
    -2.279 ( 0.2576 )
    -1.416 ( 0.2821 )
    Notes
    [27] - RSV-InfectedPopulation;Evaluable subjects BSL n=34; D1(5h post-dose)n=30;D3(2h post-dose)n=29;FUn=30
    [28] - RSV-InfectedPopulation;Evaluable subjects BSL n=38; D1(5h post-dose)n=33;D3(2h post-dose)n=36;FUn=37
    [29] - RSV-InfectedPopulation;Evaluable subjects BSL n=39; D1(5h post-dose)n=38;D3(2h post-dose)n=33;FUn=35
    [30] - RSV-InfectedPopulation;Evaluable subjects BSL n=37; D1(5h post-dose)n=37;D3(2h post-dose)n=35;FUn=32
    No statistical analyses for this end point

    Secondary: Viral load changes from Baseline (RT-qPCR)

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    End point title
    		 Viral load changes from Baseline (RT-qPCR)
    End point description
    Viral load changes from baseline measured by RT-qPCR in the RSV-infected Population. The RSV-Infected Population comprised subjects with positive RSV test by central laboratory. Although a positive local RSV test was required for eligibility assessment, a central RSV test was used for defining the RSV-Infected population. For the RT-qPCR data, the median change from Baseline could not be estimated and thus values are entered where possible.
    End point type
    Secondary
    End point timeframe
    Overall Study Period
    End point values
    		 Placebo ALX-0171 3.0mg/kg ALX-0171 6.0mg/kg ALX-0171 9.0mg/kg
    Number of subjects analysed
    35 [31]
    40 [32]
    40 [33]
    38 [34]
    Units: log10 copies/mL
    arithmetic mean (standard error)
        Baseline
    5.236 ( 0.2827 )
    4.966 ( 0.2095 )
    5.232 ( 0.1899 )
    4.525 ( 0.2937 )
        Day 1, 5 hours post-dose
    -0.221 ( 0.1601 )
    -0.544 ( 0.1286 )
    -0.241 ( 0.2031 )
    -0.449 ( 0.1883 )
        Day 3, 2 hours post-dose
    -2.156 ( 0.2454 )
    -2.589 ( 0.2138 )
    -2.310 ( 0.2797 )
    -2.025 ( 0.2840 )
        Follow-up
    -3.413 ( 0.3715 )
    -3.665 ( 0.2203 )
    -3.972 ( 0.2032 )
    -3.033 ( 0.3252 )
    Notes
    [31] - RSV-InfectedPopulation;Evaluable subjects BSL n=35; D1(5h post-dose)n=34;D3(2h post-dose)n=34;FUn=33
    [32] - RSV-InfectedPopulation;Evaluable subjects BSL n=40; D1(5h post-dose)n=40;D3(2h post-dose)n=38;FUn=39
    [33] - RSV-InfectedPopulation;Evaluable subjects BSL n=40; D1(5h post-dose)n=40;D3(2h post-dose)n=38;FUn=38
    [34] - RSV-InfectedPopulation;Evaluable subjects BSL n=38; D1(5h post-dose)n=38;D3(2h post-dose)n=36;FUn=33
    No statistical analyses for this end point

    Secondary: Viral Load Time-weighted Average Changes from Baseline (plaque assay analysis)

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    End point title
    		 Viral Load Time-weighted Average Changes from Baseline (plaque assay analysis)
    End point description
    End point type
    Secondary
    End point timeframe
    Overall Study Period
    End point values
    		 Placebo ALX-0171 3.0mg/kg ALX-0171 6.0mg/kg ALX-0171 9.0mg/kg
    Number of subjects analysed
    35 [35]
    40 [36]
    40 [37]
    38 [38]
    Units: log10 pfu/mL
    arithmetic mean (standard error)
        Baseline
    3.494 ( 0.2396 )
    3.312 ( 0.2165 )
    3.135 ( 0.2430 )
    2.385 ( 0.2526 )
        Day 3
    -1.014 ( 0.1540 )
    -1.924 ( 0.1659 )
    -1.804 ( 0.2098 )
    -1.330 ( 0.2434 )
        Day 14 (Follow-Up)
    -2.096 ( 0.2443 )
    -2.295 ( 0.2116 )
    -2.028 ( 0.2217 )
    -1.419 ( 0.2488 )
    Notes
    [35] - RSV-Infected Population; Baseline n=34; Day3 n=33;Day14 (FU) n=33, where n=evaluable subjects/group
    [36] - RSV-Infected Population; Baseline n=38; Day3 n=37;Day14 (FU) n=37, where n=evaluable subjects/group
    [37] - RSV-Infected Population; Baseline n=39; Day3 n=38;Day14 (FU) n=38, where n=evaluable subjects/group
    [38] - RSV-Infected Population; Baseline n=37; Day3 n=37;Day14 (FU) n=37, where n=evaluable subjects/group
    No statistical analyses for this end point

    Secondary: Viral Load Time-weighted Average Changes from Baseline (RT-qPCR analysis)

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    End point title
    		 Viral Load Time-weighted Average Changes from Baseline (RT-qPCR analysis)
    End point description
    End point type
    Secondary
    End point timeframe
    Overall Study Period
    End point values
    		 Placebo ALX-0171 3.0mg/kg ALX-0171 6.0mg/kg ALX-0171 9.0mg/kg
    Number of subjects analysed
    35 [39]
    40 [40]
    40 [41]
    38 [42]
    Units: log10 copies/mL
    arithmetic mean (standard error)
        Baseline
    5.236 ( 0.2827 )
    4.966 ( 0.2095 )
    5.232 ( 0.1899 )
    4.525 ( 0.2937 )
        Day 3
    -0.933 ( 0.1421 )
    -1.209 ( 0.1301 )
    -1.113 ( 0.1932 )
    -0.842 ( 0.1842 )
        Day 14 (Follow-up)
    -2.684 ( 0.2263 )
    -2.828 ( 0.2099 )
    -2.756 ( 0.1831 )
    -2.292 ( 0.2581 )
    Notes
    [39] - RSV-Infected Population
    [40] - RSV-Infected Population
    [41] - RSV-Infected Population
    [42] - RSV-Infected Population
    No statistical analyses for this end point

    Secondary: Immunogenicity: Incidence of of Treatment-emergent Anti-drug Antibodies

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    End point title
    		 Immunogenicity: Incidence of of Treatment-emergent Anti-drug Antibodies
    End point description
    The incidence of treatment-emergent anti-drug antibodies (TE ADA) and ADA status based on ADA assay by treatment group - safety population. Blood samples were collected at Baseline and on Day 14. The results are categorized as follows: - Total TE ADA positive: Post-dose sample ADA positive or in case pre-dose sample is ADA positive, post-dose sample ADA positive and significant increase in titer post-dose versus pre-dose. The increase of the log10titer post-dose versus pre-dose should be > log10(Minimum Significant Ratio). - Total TE ADA negative: Post-dose sample ADA negative. - TE ADA equivocal: Pre -and post-dose sample ADA positive and no significant increase in titer post-dose versus pre-dose. - TE ADA inconclusive: No pre-dose or post-dose sample available. The Safety Population consisted of all subjects who received at least 1 administration of study drug. Number of subjects with non-missing ADA results were: placebo: 39; ALX-0171 3.0mg/kg: 45; 6.0mg/kg: 44; 9.0mg/kg: 46
    End point type
    Secondary
    End point timeframe
    Overall Study Period
    End point values
    		 Placebo ALX-0171 3.0mg/kg ALX-0171 6.0mg/kg ALX-0171 9.0mg/kg
    Number of subjects analysed
    39 [43]
    45 [44]
    43 [45]
    45 [46]
    Units: percentage
    number (not applicable)
        Total TE ADA positive
    25.6
    33.3
    36.4
    32.6
        Total TE ADA negative
    41.0
    37.8
    31.8
    28.3
        TE ADA equivocal
    30.8
    26.7
    29.5
    30.4
        TE ADA inconclusive
    2.6
    2.2
    2.3
    8.7
    Notes
    [43] - Safety Population N=40; The denominator in the placebo group for the ADA results is N=39
    [44] - Safety Population N=45
    [45] - Safety Population N=44
    [46] - Safety Population N=46
    No statistical analyses for this end point

    Secondary: Immunogenicity: Incidence of of Treatment-emergent Neutralizing Antibodies

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    End point title
    		 Immunogenicity: Incidence of of Treatment-emergent Neutralizing Antibodies
    End point description
    Incidence of treatment-emergent neutralizing antibodies (TE NAb) as detected with the competitive ligand binding NAb assay. Blood samples for immunogenicity assessments were collected at Baseline and on Day 14. The Safety Population consisted of all subjects who received at least 1 administration of study drug. When using this population, the subjects were classified as treated (i.e., using the treatment that the subject actually received). Number of subjects with non-missing ADA results were: placebo: 39; ALX-0171 3.0mg/kg: 45; 6.0mg/kg: 44; 9.0mg/kg: 46.
    End point type
    Secondary
    End point timeframe
    Overall Study Period
    End point values
    		 Placebo ALX-0171 3.0mg/kg ALX-0171 6.0mg/kg ALX-0171 9.0mg/kg
    Number of subjects analysed
    39 [47]
    45 [48]
    43 [49]
    45 [50]
    Units: percentage
    number (not applicable)
        Post-dose Positive
    5.1
    24.4
    40.9
    26.1
        Post-dose Negative
    92.3
    73.3
    59.1
    67.4
        Post-dose Missing
    2.6
    2.2
    0
    6.5
    Notes
    [47] - Safety Population N=40; The denominator in the placebo group for the ADA results is N=39
    [48] - Safety Population N=45
    [49] - Safety Population N=44
    [50] - Safety Population N=46
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events (AEs) were reported from the time of a signed/dated ICF until the completion of the subject’s last visit.
    Adverse event reporting additional description
    A treatment-emergent AE (TEAE) was defined as any AE starting or worsening in severity (for pre-existing conditions) from the start of study drug administration, until completion of the subject’s last visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Includes the number of subjects in the placebo group included in the Safety Population.

    Reporting group title
    ALX-0171 3.0 mg/kg
    Reporting group description
    		 Subjects included in ALX-0171 3.0mg/kg teatment group in the Safety Population.

    Reporting group title
    ALX-0171 6.0 mg/kg
    Reporting group description
    		 Subject included in the ALX-0171 6.0 mg/kg treatment group in the Safety Population

    Reporting group title
    ALX-0171 9.0 mg/kg
    Reporting group description
    		 Subjects included in the ALX-0171 9.0mg/kg treatment group in the Safety Population.

    Serious adverse events
    		 Placebo ALX-0171 3.0 mg/kg ALX-0171 6.0 mg/kg ALX-0171 9.0 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 40 (12.50%)
    4 / 45 (8.89%)
    3 / 44 (6.82%)
    3 / 46 (6.52%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    General disorders and administration site conditions
    Vessel puncture site phlebitis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 45 (0.00%)
    1 / 44 (2.27%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 45 (0.00%)
    1 / 44 (2.27%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia bacterial
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 45 (0.00%)
    1 / 44 (2.27%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 45 (2.22%)
    0 / 44 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 45 (2.22%)
    0 / 44 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 45 (2.22%)
    0 / 44 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumococcal bacteraemia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 45 (2.22%)
    0 / 44 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo ALX-0171 3.0 mg/kg ALX-0171 6.0 mg/kg ALX-0171 9.0 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 40 (42.50%)
    23 / 45 (51.11%)
    21 / 44 (47.73%)
    15 / 46 (32.61%)
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 45 (4.44%)
    4 / 44 (9.09%)
    0 / 46 (0.00%)
         occurrences all number
    1
    3
    4
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 45 (0.00%)
    1 / 44 (2.27%)
    0 / 46 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 40 (5.00%)
    1 / 45 (2.22%)
    0 / 44 (0.00%)
    0 / 46 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea
         subjects affected / exposed
    1 / 40 (2.50%)
    6 / 45 (13.33%)
    3 / 44 (6.82%)
    2 / 46 (4.35%)
         occurrences all number
    1
    7
    3
    2
    Cough
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 45 (4.44%)
    3 / 44 (6.82%)
    2 / 46 (4.35%)
         occurrences all number
    1
    2
    3
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
    0 / 46 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 40 (7.50%)
    3 / 45 (6.67%)
    3 / 44 (6.82%)
    2 / 46 (4.35%)
         occurrences all number
    3
    3
    4
    2
    Conjunctivitis
         subjects affected / exposed
    2 / 40 (5.00%)
    2 / 45 (4.44%)
    1 / 44 (2.27%)
    1 / 46 (2.17%)
         occurrences all number
    2
    2
    1
    1
    Rhinitis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 45 (0.00%)
    1 / 44 (2.27%)
    3 / 46 (6.52%)
         occurrences all number
    0
    0
    1
    3
    Otitis media
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 45 (0.00%)
    0 / 44 (0.00%)
    0 / 46 (0.00%)
         occurrences all number
    3
    0
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Oct 2016
    -Criteria for stopping dose escalation during the sequential part of the study, as well as specifications for which doses could be used in the parallel part of the study, were added. The individual discontinuation criteria were updated to ensure consistency with the dose-escalation stopping criteria. -Inclusion criterion 2 was updated to allow inclusion of subjects weighing up to < 15.0 kg. -For clarity, the exclusion criterion on HIV positivity was reworded and an additional criterion was added to exclude subjects with a known hypersensitivity to the study drug or any excipient of the study drug from the study. -Instructions for dosing were updated with additional weight bands and safety margin calculation was updated accordingly. -Detailed guidance on early detection and treatment of the potential risks of airway hyperreponsiveness and immediate or delayed adverse drug reactions were added.
    30 Oct 2017
    1. The non-interventional, Follow-up Study ALX-0171 C202 was deleted, as it will not be conducted; following interactions between the Sponsor and the European Medicines Agency’s Paediatric Committee, the study was removed from the product’s Paediatric Investigation Plan. 2. The age range for study population was updated for consistency (age range reads: 28 days to < 2 years). 3. The Schedule of Assessments underwent changes for clarity and easier flow in the assessments to be performed: - On Day 1, the time window before study drug administration was extended to 3 hour - Time windows of 0.5 hours before and after the 2-hour post-dose assessments were added to allow additional time for the site staff to perform the assessments. - To enhance the overview, the randomization row was moved. - Additional guidance was added on the footnote referring to the documentation of sleep disturbance due to night-time coughing. 4. A clarification was added that, at a minimum, the SpO2, feeding, respiratory muscle retractions, and respiratory rate should be evaluated on Day 1 before randomization, unless these assessments were already performed within the last 3 hours before randomization. 5. The method of stratified randomization per cohort was corrected.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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