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    Clinical Trial Results:
    A Phase I/IIa Multicentre Study in Otherwise Healthy Infants and Toddlers Hospitalised For and Diagnosed With Respiratory Syncytial Virus Lower Respiratory Tract Infection, Consisting of an Open-label Lead in Part Followed by a Double-blind, Placebo-controlled Part, to Evaluate the Safety, Tolerability, and Clinical Activity of ALX-0171, Administered Via Inhalation, in Addition to Standard of Care

    Summary
    EudraCT number
    		 2014-002841-23
    Trial protocol
    		 GB   HU   SK   BE   ES   EE   LV   BG   PL  
    Global end of trial date
    17 Feb 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Aug 2016
    First version publication date
    18 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ALX0171-C104
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02309320
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ablynx
    Sponsor organisation address
    Technologiepark 21, Zwijnaarde, Belgium, 9052
    Public contact
    clinicaltrials@ablynx.com, Ablynx NV, +32 (0)9 262 0000, clinicaltrials@ablynx.com
    Scientific contact
    clinicaltrials@ablynx.com, Ablynx NV, +32 (0)9 262 0000, 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
    17 Feb 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Feb 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the safety and tolerability of multiple doses of ALX-0171
    Protection of trial subjects
    Only subjects who met all the study inclusion and none of the exclusion criteria were to be randomized to trial treatment. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Randomized patients were required to stay in the hospital during the treatment period. The Investigator informed each subject’s parent(s) or legal guardian(s) of the nature of the study (objectives, methods, potential hazards and benefits, and any discomfort that subjects might have during participation in the study) and the procedures involved, using the information in the main ICF. After given sufficient time to understand the information and to ask questions, subject’s parent(s) or legal guardian(s) provided written informed consent before enrolment of their child in this study and before any protocol specified procedures were performed. No additional safety evaluations requiring additional consent procedures have become necessary in this study. If this was not standard practice at the site, an additional short ICF could be signed by the subject’s parent(s)/legal guardian for performing a Sponsor-provided respiratory syncytial virus (RSV) diagnostic test.
    Background therapy
    		 The standard of care during hospitalization for RSV LRTI, as defined for this study, included (but was not limited to) the following: • Oxygen supplementation (via simple face mask up to 6 L/min, nasal cannula up to 2 L/min, or headbox oxygen) • Fluid/food supplementation (administered intravenously or via nasogastric tube, if applicable) • Short-acting β2 agonists • Antibiotics (in case of secondary bacterial infection [superinfection] during hospitalization) • Epinephrine (but not within 1 hour before study drug administration) • Anticholinergics • Antipyretics and/or nonsteroidal anti inflammatory medication The treatment and care provided to each subject were determined by the Investigator (or designee) according to institutional practice. The recommendations on the diagnosis and management of bronchiolitis in subjects under 2 years of age, as described by the American Academy of Pediatrics (2006), could be followed in addition to the institutional practice. Other concomitant medications were allowed, apart from those listed under the prohibited therapies (see below), at the Investigator’s discretion (based on medical need). The following treatments were prohibited during the study: • Ribavirin • Hypertonic saline • Heliox • Leukotriene receptor antagonists (e.g., montelukast) • Exogenous surfactant • Corticosteroids • Mucolytics • Ventilation other than oxygen supplementation via simple face mask, nasal cannula, or headbox • Intravenous immunoglobulin and palivizumab (subjects who required RSV prophylaxis were not eligible for inclusion in the study) After the end of the study, each subject was to be treated according to standard clinical practice.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Dec 2014
    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
    Israel: 7
    Country: Number of subjects enrolled
    Malaysia: 8
    Country: Number of subjects enrolled
    Philippines: 3
    Country: Number of subjects enrolled
    Thailand: 5
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Slovakia: 3
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Bulgaria: 2
    Country: Number of subjects enrolled
    Hungary: 5
    Worldwide total number of subjects
    51
    EEA total number of subjects
    28
    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)
    51
    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
    		 Subjects were enrolled in 27 study centers in Asia (Malaysia, Philippines, Thailand and Israel) and in Europe (Belgium, Bulgaria, Hungary, Poland, Slovakia, Spain and the United Kingdom) between 18 Dec 2014 and 17 Feb 2016. The study started with an open-label lead-in part (5 subjects) and was then continued double-blind.

    Pre-assignment
    Screening details
    		 - 57 subj screened, 53 randomized, 51 completed study visits (Safety population) - 1 subj discontinued due to a SAE before receiving study drug (excl. from Safety population) - 1 subj discontinued from the study prior to dosing on Day 3 (withdrawal consent) - 1 subj did not receive study drug (protocol violation - excl. from Safety population)

    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, Data analyst, Carer, Assessor
    Blinding implementation details
    The study started with an open-label lead-in part: 5 subjects received ALX-0171. After positive recommendation of the DMC, the remainder of the study was double-blind. All subject’s parent(s)/legal guardian(s), Investigators (+ designees) and all study personnel involved in the study were blinded to treatment assignment. One unblinded, independent statistician was assigned to prepare summaries for the DMC members but did not otherwise participate in the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ALX-0171
    Arm description
    		 A total of 51 subjects completed the study visits: 35 subjects received ALX-0171 and 16 subjects received placebo in the study, 32 subjects completed study treatment in the ALX-0171 arm, all subjects completed study treatment in the placebo arm.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ALX-0171
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Eligible subjects received ALX-0171 (open-label lead in part, 5 subjects) or were randomly assigned to receive ALX-0171 via inhalation with a FOX Flamingo Inhalation System once daily for 3 consecutive days. The dose administered was based on body weight. Study drug was administered following a 2-hour baseline monitoring period and administration of the short-acting β2-agonist salbutamol.

    Arm title
    		 Placebo
    Arm description
    		 A total of 51 subjects completed the study visits: 35 subjects received ALX-0171 and 16 subjects received placebo in the study, 32 subjects completed study treatment in the ALX-0171 arm, all subjects completed study treatment in the placebo arm.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Eligible subjects were randomly assigned to receive placebo (after open-label lead-in part) via inhalation with a FOX Flamingo Inhalation System once daily for 3 consecutive days. Study drug was administered following a 2 hour baseline monitoring period and administration of the short-acting β2-agonist salbutamol.

    Number of subjects in period 1
    		ALX-0171 Placebo
    Started
    35
    16
    Completed
    32
    16
    Not completed
    3
    0
         Consent withdrawn by subject
    1
    -
         Adverse event, non-fatal
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ALX-0171
    Reporting group description
    		 A total of 51 subjects completed the study visits: 35 subjects received ALX-0171 and 16 subjects received placebo in the study, 32 subjects completed study treatment in the ALX-0171 arm, all subjects completed study treatment in the placebo arm.

    Reporting group title
    Placebo
    Reporting group description
    		 A total of 51 subjects completed the study visits: 35 subjects received ALX-0171 and 16 subjects received placebo in the study, 32 subjects completed study treatment in the ALX-0171 arm, all subjects completed study treatment in the placebo arm.

    Reporting group values
    		 ALX-0171 Placebo Total
    Number of subjects
    		 35 16 51
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 35 16 51
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    		 7.76 ± 5.561 8.17 ± 6.052 -
    Gender categorical
    Units: Subjects
        Female
    		 9 6 15
        Male
    		 26 10 36

    End points

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    End points reporting groups
    Reporting group title
    ALX-0171
    Reporting group description
    		 A total of 51 subjects completed the study visits: 35 subjects received ALX-0171 and 16 subjects received placebo in the study, 32 subjects completed study treatment in the ALX-0171 arm, all subjects completed study treatment in the placebo arm.

    Reporting group title
    Placebo
    Reporting group description
    		 A total of 51 subjects completed the study visits: 35 subjects received ALX-0171 and 16 subjects received placebo in the study, 32 subjects completed study treatment in the ALX-0171 arm, all subjects completed study treatment in the placebo arm.

    Primary: 1. Subjects with treatment-emergent adverse events (TEAEs)

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    End point title
    		 1. Subjects with treatment-emergent adverse events (TEAEs) [1]
    End point description
    The summary table for the treatment-emergent adverse events is presented (safety population). One subject experienced 2 severe non-treatment related TEAEs (hypotonia and hyporesponsiveness). The events were considered serious.
    End point type
    Primary
    End point timeframe
    From screening until last follow-up visit
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only number of subjects with TEAEs are provided
    End point values
    		 ALX-0171 Placebo
    Number of subjects analysed
    35 [2]
    16 [3]
    Units: number of subjects with TEAEs
        Subjects w AEs leading to death
    0
    0
        Subjects w SAEs
    4
    0
        Subjects w AEs leading to treatm discontinuation
    2
    0
        Subjects w AEs leading to withdrawal
    0
    0
        Subjects w severe TEAEs
    1
    0
        Subjects w possibly rel. TEAEs (judged by invest)
    3
    0
        Possibly related TEAE: cough
    1
    0
        Possibly related TEAE: rhinorrhea
    1
    0
        Possibly related TEAE: pyrexia
    1
    0
    Notes
    [2] - safety population
    [3] - safety population
    No statistical analyses for this end point

    Secondary: 2. Immunogenicity

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    End point title
    		 2. Immunogenicity
    End point description
    The number of subjects with treatment-emergent anti-drug antibodies is presented.
    End point type
    Secondary
    End point timeframe
    at Day 14
    End point values
    		 ALX-0171 Placebo
    Number of subjects analysed
    35 [4]
    16 [5]
    Units: Subjects
    8
    1
    Notes
    [4] - safety population
    [5] - safety population
    No statistical analyses for this end point

    Other pre-specified: 3. Viral loads from nasal swabs

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    End point title
    		 3. Viral loads from nasal swabs
    End point description
    Data on mean viral loads in the course of the study are presented (plague assay). The first ALX-0171 dose reduced mean cultivatable virus titers to below the quantification limit within 6 hours which was not the case for placebo treated subjects (mean change from baseline of ‑0.879 log10 PFUs/mL for ALX-0171 versus -0.434 log10 PFUs/mL for placebo following the first dose) although baseline values were lower in the ALX-0171 group than in the placebo group. Subsequent mean cultivatable virus titers were maintained below the quantification limit in the ALX-0171 treated subjects whereas for subjects in the placebo group, mean cultivatable virus titers only dropped below the quantification limit after the second dose. For these samples a numerical value half the lower limit of quantification (LLOQ) was imputed.
    End point type
    Other pre-specified
    End point timeframe
    Day 1: pre-dose, post-dose Day 2, Day 3: pre-dose at discharge
    End point values
    		 ALX-0171 Placebo
    Number of subjects analysed
    35 [6]
    16 [7]
    Units: log10 PFU/mL
    arithmetic mean (standard deviation)
        Day 1, 2 h pre-dose
    2.047 ± 1.4702
    2.396 ± 1.4651
        Day 1, 6 h post-dose
    1.159 ± 0.8861
    1.962 ± 1.2688
        Day 2, 2 h pre-dose
    1.189 ± 0.8813
    1.768 ± 1.0745
        Day 3, 2 h pre-dose
    1.14 ± 0.8238
    1.261 ± 0.8087
        at discharge
    0.957 ± 0.4649
    1.109 ± 0.7186
    Notes
    [6] - safety population (not all data available for all subjects at all time points)
    [7] - safety population
    No statistical analyses for this end point

    Post-hoc: 4. Global severity score (GSS)

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    End point title
    		 4. Global severity score (GSS)
    End point description
    A post-hoc analysis was performed to assess comprehensively the collected clinical activity data which resulted in the Global Severity Score (GSS). The GSS is derived from the ReSVinet scale which is a validated clinical scoring system that allows objective categorization of infants with respiratory infections based on feeding intolerance, medical intervention, respiratory difficulty, respiratory frequency, apnea, general condition, fever. A decrease in the GSS indicates an improvement. Mean GSS scores are presented at different time points for the modified safety population, excluding the 5 subjects participating to the open-label part of the study and excluding 5 subjects without detectable RSV. The resulting GSS showed decreases in mean scores over the course of the study for both treatment groups with improvements being more pronounced in the ALX-0171 group compared to the placebo group starting at Day 1, which suggested faster recovery with ALX-0171 treatment versus placebo.
    End point type
    Post-hoc
    End point timeframe
    Day 1: 2 h pre-dose, 6 h post-dose Day 2: 2 h pre-dose, 6 h post-dose Day 3: 2 h pre-dose, 6 h post-dose
    End point values
    		 ALX-0171 Placebo
    Number of subjects analysed
    26 [8]
    15 [9]
    Units: Global Severity Score
    arithmetic mean (standard deviation)
        Day 1, 2 h pre-dose
    7.7 ± 2.42
    7.4 ± 3.2
        Day 1, 6 h post-dose
    5.8 ± 3.27
    6.5 ± 4.03
        Day 2, 2 h pre-dose
    5.1 ± 2.77
    6.4 ± 2.97
        Day 2, 6 h post-dose
    4.4 ± 2.94
    6.1 ± 3.63
        Day 3, 2 h pre-dose
    3.5 ± 2.3
    4.3 ± 3.33
        Day 3, 6 h post-dose
    3.2 ± 2.11
    3.8 ± 3.13
    Notes
    [8] - Modified safety population
    [9] - Modified safety population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From screening until last follow-up visit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    ALX-0171
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 ALX-0171 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 35 (11.43%)
    0 / 16 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Hyporesponsive to stimuli
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotonia
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ALX-0171 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 35 (31.43%)
    4 / 16 (25.00%)
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 16 (6.25%)
         occurrences all number
    2
    1
    Crying
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    Rhinorrhoea
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 16 (6.25%)
         occurrences all number
    1
    1
    Erythema
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Rash maculo-papular
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Jul 2014
    Protocol version 2.0: (The initial version of the protocol, Protocol version 1.0 was not submitted due to an administrative error in the Schedule of Assessments.) A minor correction was included in the Schedule of Assessments (timing of nasal swab assessments) prior to initiating the clinical trial applications.
    23 Dec 2014
    Protocol v3.0: The inclusion criterion that specified the duration of symptoms prior to screening was updated to include subjects with appearance of symptoms that are likely related to respiratory syncytial virus infection within ≤ 7 days (instead of ≤ 4 days) at the time of screening, based on the Investigator’s judgement. The age of inclusion for the double-blind, placebo controlled part of the trial was updated from 5 months to potentially 3 months, dependent on a positive recommendation from the independent data monitoring committee after completion of Part A. These changes were included to increase Protocol flexibility with regards to recruitment. Other minor clarifications and updates were incorporated as well.
    11 Aug 2015
    Protocol v4.0: The age of inclusion for the double blind, placebo controlled part of the trial was updated from 3 months to potentially 28 days, dependent on a positive recommendation from the independent data monitoring committee (after 15 subjects had completed study treatment in Part B). The design of the study was updated: once all subjects in Part B had completed the study drug treatment period, up to 18 additional subjects aged 28 days to < 5 months were to be enrolled in an expansion cohort (Part C). These changes were included to allow the Sponsor to obtain additional data in an extended and highly relevant population. Other minor clarifications and updates were incorporated as well.

    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.
    This First-in-Infant trial was primarily focused on safety and tolerability and no formal statistical analysis was prespecified.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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