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
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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
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Results information
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Results version number |
v1 |
This version publication date |
25 Apr 2019
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First version publication date |
25 Apr 2019
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Other versions |
v2 |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
ALX0171-C201
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02979431 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Ablynx NV
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Sponsor organisation address |
Technologie Park 21, Zwijnaarde, Belgium, 9052
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Public contact |
clinicaltrials@ablynx.com, Ablynx NV, +32 (0)9262 00 00, clinicaltrials@ablynx.com
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Scientific contact |
clinicaltrials@ablynx.com, Ablynx NV, +32 (0)9262 00 00, clinicaltrials@ablynx.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001553-PIP01-13 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
06 Sep 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
25 May 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
25 May 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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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.
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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.
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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
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Poland: 13
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Country: Number of subjects enrolled |
Slovakia: 4
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Country: Number of subjects enrolled |
Spain: 16
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Country: Number of subjects enrolled |
Croatia: 23
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Country: Number of subjects enrolled |
Belgium: 9
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Country: Number of subjects enrolled |
Bulgaria: 33
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Country: Number of subjects enrolled |
Czech Republic: 1
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Country: Number of subjects enrolled |
Germany: 6
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Country: Number of subjects enrolled |
Hungary: 27
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Country: Number of subjects enrolled |
Latvia: 10
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Country: Number of subjects enrolled |
Chile: 4
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Country: Number of subjects enrolled |
Philippines: 5
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Country: Number of subjects enrolled |
Thailand: 10
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Country: Number of subjects enrolled |
Israel: 4
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Country: Number of subjects enrolled |
Malaysia: 14
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Country: Number of subjects enrolled |
Colombia: 1
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Worldwide total number of subjects |
180
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EEA total number of subjects |
142
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
180
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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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
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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
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Period 1 title |
Overall Study Period (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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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.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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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
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation solution
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Routes of administration |
Inhalation use
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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.
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Arm title
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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
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Investigational medicinal product code |
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Other name |
ALX-0171 Nanobody
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Pharmaceutical forms |
Inhalation solution
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Routes of administration |
Inhalation use
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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).
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Arm title
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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
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Investigational medicinal product code |
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Other name |
ALX-0171 Nanobody
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Pharmaceutical forms |
Inhalation solution
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Routes of administration |
Inhalation use
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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).
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Arm title
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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
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Investigational medicinal product code |
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Other name |
ALX-0171 Nanobody
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Pharmaceutical forms |
Inhalation solution
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Routes of administration |
Inhalation use
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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).
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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. |
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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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
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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
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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
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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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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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
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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
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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
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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
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
The ITT population consisted of all randomized subjects.
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Subject analysis set title |
modified Intent-to-Treat (mITT)
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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.
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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.
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End point type |
Primary
|
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End point timeframe |
Overall Study Period
|
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Notes [1] - mITT Population [2] - mITT Population [3] - mITT Population [4] - mITT Population |
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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.
|
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Comparison groups |
Placebo v ALX-0171 9.0mg/kg
|
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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.
|
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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.
|
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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 |
|
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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).
|
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End point type |
Secondary
|
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End point timeframe |
Day 2 (5 hours post-dose)
|
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|
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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.
|
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Comparison groups |
Placebo v ALX-0171 9.0mg/kg
|
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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 |
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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.
|
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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.
|
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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 |
|
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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.
|
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End point type |
Secondary
|
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End point timeframe |
Overall Study Period
|
|||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||
Notes [15] - mITT Population [16] - mITT Population [17] - mITT Population [18] - mITT Population |
||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
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.
|
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End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Overall Study Period
|
||||||||||||||||||||
|
|||||||||||||||||||||
Notes [19] - mITT Population [20] - mITT Population [21] - mITT Population [22] - mITT Population |
|||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||
End point title |
Time-to-undetectable viral load | |||||||||||||||||||||||||
End point description |
||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||
End point timeframe |
Overall Study Period
|
|||||||||||||||||||||||||
|
||||||||||||||||||||||||||
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 |
|
|||||||||||||||||||||||||||||||||||||||||
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)
|
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End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Overall Study Period
|
||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
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 |
|
|||||||||||||||||||||||||||||||||||||||||
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
|
||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
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 |
|
||||||||||||||||||||||||||||||||||||
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
|
|||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||
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 |
|
||||||||||||||||||||||||||||||||||||
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
|
|||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||
Notes [39] - RSV-Infected Population [40] - RSV-Infected Population [41] - RSV-Infected Population [42] - RSV-Infected Population |
||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||
End point title |
Pharmacodynamics | |||||||||||||||||||||||||||||||||||
End point description |
Serum levels of Krebs von den Lungen 6 (KL-6) biomarker - change from Baseline
|
|||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||
End point timeframe |
Overall Study Period
|
|||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||
Notes [43] - mITT Population; Evaluable subjects: D2 (pre-dose) n=14; D2 (post-dose) n=24; FU n=36 [44] - mITT Population; Evaluable subjects: D2 (pre-dose) n=14; D2 (post-dose) n=28; FU n=41 [45] - mITT Population; Evaluable subjects: D2 (pre-dose) n=14; D2 (post-dose) n=26; FU n=39 [46] - mITT Population; Evaluable subjects: D2 (pre-dose) n=11; D2 (post-dose) n=30; FU n=41 |
||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Immunogenicity | ||||||||||||||||||||||||||||||
End point description |
The incidence of treatment-emergent anti-drug antibodies (TE ADA) and ADA status based on ADA assay by treatment group for the Safety Population.
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
Overall Study Period
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
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 |
|
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Adverse events information
|
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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.
|
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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.
|
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.0
|
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Reporting groups
|
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Reporting group title |
Placebo
|
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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
|
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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
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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
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Reporting group description |
Subjects included in the ALX-0171 9.0mg/kg treatment group in the Safety Population. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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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.
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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. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |