Dose Ranging Study of ALX-0171 in Infants Hospitalized for Respiratory Syncytial Virus Lower Respiratory Tract Infection

Study Overview
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Brief Summary
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The primary objective is to evaluate the anti-viral effect and safety of different doses of inhaled ALX-0171 in subjects hospitalized for Respiratory Syncytial Virus Lower Respiratory Tract Infection (RSV LRTI). The secondary objective is to evaluate the clinical activity, pharmacokinetic (PK) properties, pharmacodynamic (PD) effect and immunogenicity of different doses of inhaled ALX-0171.

Detailed Description
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This was a Phase 2b, randomized, double-blind, placebo-controlled, international, multicenter dose-ranging study in infants and toddlers hospitalized for RSV LRTI. The study evaluated 3 dose levels of ALX-0171 in a sequential part (safety Cohorts 1-3) followed by a parallel part (Cohort 4). An Independent Data Monitoring Committee (IDMC) was assigned to review study data and provide recommendations on proceeding to the next safety cohort and on which dose levels could be taken forward in the parallel part. Three dose levels of ALX-0171 were evaluated: Dose 1: target dose of 3.0 mg/kg Dose 2: target dose of 6.0 mg/kg Dose 3: target dose of 9.0 mg/kg The study drug was administered by inhalation once daily for 3 consecutive days along with standard of care treatment, which was determined by the Investigator (or his/her designee) according to institutional practice.

Official Title
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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

Conditions
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Respiratory Syncytial Virus Lower Respiratory Tract Infection

Intervention / Treatment
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* Biological: ALX-0171 3.0 mg/kg
* Biological: ALX-0171 6.0 mg/kg
* Biological: ALX-0171 9.0 mg/kg
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female infant or young child aged 28 days to < 2 years with gestational age ≥ 33 weeks at screening. Subject weighed between ≥ 3.0 kg and < 15.0 kg at screening. Subject is otherwise healthy but was hospitalized for and clinically diagnosed with RSV LRTI (bronchiolitis or broncho-pneumonia), i.e., showing typical clinical signs and symptoms such as tachypnea, wheezing, cough, crackles, use of accessory muscles and/or nasal flaring. Subject had a positive RSV diagnostic test at screening. Subject was expected to have to stay in the hospital for at least 24 hours (according to the Investigator's judgment at screening). Symptoms were likely related to RSV infection (i.e., the symptoms present needed to be probably linked to the current RSV infection according to Investigator's judgment) had appeared within 4 days of screening and were not yet improving at screening and randomization. Subject fulfilled at least 2 of the following RSV disease severity criteria at screening and randomization: Inadequate oral feeding that required feeding support (i.e., nasogastric tube or intravenous [i.v.] line) Inadequate oxygen saturation defined as: Oxygen saturation (peripheral capillary oxygen saturation [SpO2]) ≤ 92% on room air or Requiring oxygen supplementation to maintain oxygen saturation > 90% with documented pre-supplementation value ≤ 92% Signs of respiratory distress defined as: Respiratory rate ≥ 50 per minute in infants up to 12 months of age, and ≥ 40 per minute in children above 12 months and/or Moderate or marked respiratory muscle retractions Normal psychomotor development. Exclusion Criteria: Subject was known to have significant comorbidities including: Genetic disorders (e.g., trisomy 21, cystic fibrosis), Hemodynamically significant congenital heart disease (e.g., needing corrective therapy or inotropic support), Bronchopulmonary dysplasia, Any hereditary or acquired metabolic (bone) diseases, Hematologic or other malignancy. Subject was known to be human immunodeficiency virus (HIV)-positive. If the subject was < 6 months of age, a known HIV-positivity of the mother was also exclusionary. Subject was known to be immunocompromised. Subject had or was suspected to have an active, clinically relevant concurrent infection (e.g., bacterial pneumonia, urinary tract infection). Concurrent acute otitis media was not exclusionary. Subject had significant oral and/or maxillofacial malformations that would prevent proper positioning of the face mask. Subject received invasive mechanical ventilation or non-invasive respiratory support (i.e., continuous or bilevel positive airway pressure) in the 4 weeks prior to screening. During the admission, the subject was initially hospitalized in an intensive care unit (ICU) setting and/or had received invasive mechanical ventilation or non-invasive respiratory support (i.e., continuous or bilevel positive airway pressure). Subject was critically ill and/or was expected to require invasive mechanical ventilation, non invasive respiratory support (i.e., continuous or bilevel positive airway pressure), or High Flow oxygen therapy (HFOT) at levels not enabling nebulization therapy according to the Investigator's judgment. High Flow oxygen, with a maximum flow of 2 L/kg/min, was permitted under the following conditions: used as Standard of Care outside ICU setting could be removed for study drug administration (Note: oxygen flow at 2 L/min could be provided)

Ages Eligible for Study
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Minimum Age: 28 Days
Maximum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ALX-0171 3.0 mg/kg<br>Inhalation of ALX-0171 3.0 mg/kg once daily for 3 consecutive days | Biological: ALX-0171 3.0 mg/kg<br> <br> |
| Experimental: ALX-0171 6.0 mg/kg<br>Inhalation of ALX-0171 6.0 mg/kg once daily for 3 consecutive days | Biological: ALX-0171 6.0 mg/kg<br> <br> |
| Experimental: ALX-0171 Dose 9.0mg/kg<br>Inhalation of ALX-0171 9.0 mg/kg once daily for 3 consecutive days | Biological: ALX-0171 9.0 mg/kg<br> <br> |
| Placebo Comparator: Placebo<br>Inhalation of Placebo once daily for 3 consecutive days | Other: Placebo<br> <br> * Other names: Matching Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time for Viral Load to Drop Below Assay Quantification Limit (BQL) (Plaque Assay Analysis) | 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 logrank 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/kg vs Placebo, followed by ALX-0171 6mg/kg vs Placebo, ALX-0171 3mg/kg vs Placebo. | Overall Study Period (i.e., approximately 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Global Severity Score on Day 2 (5 Hours Post-dose) | 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 9.0 mg/kg versus placebo; 6.0mg/kg versus placebo; 3.0 mg/kg versus placebo). Evolution over time in Global Severity Score. The maximum total score is 20 (minimum:0 to manimum:20); higher score indicates more severe disease. | from Baseline untill Day 2 (5 hours post-dose) | 
| Time-to-Clinical Response | The time-to-clinical response was defined as the time between the first study drug administration and the time of achieving adequate oxygen saturation (defined as SpO2 > 92% over a period of at least 4 hours) and adequate oral feeding (which is sufficient to maintain sufficient hydration, in the judgment of the Investigator). | Overall Study Period (i.e., approximately 28 days) | 
| Time-to-BQL (RT-qPCR) | As secondary endpoint, the time-to-BQL using RT-qPCR was summarized using Kaplan Meier (KM) estimates. No p-values were calculated. For RSV load by RT-qPCR, the lower limit of quantification (LLOQ) was 2.4 log10 copies/mL. The upper limit confidence interval (CI) could not be calculated; Values of the 25 percentile are reported here. | Overall Study Period (i.e., approximately 28 days) | 
| Time-to-undetectable Viral Load (Plaque Assay Analysis) | The time-to-undetectability (hours), defined as the time from the first study drug administration to the first occurrence of viral titer below the lower limit of quantification (LLOQ), and target not detected provided the next measured value was also below the quantification limit and undetected, were summarized using KM estimates, based on the plaque assay. The time-to-event for subjects with missing data and/or subjects who did not reach undetectability during the trial were censored at the last non-missing viral load assessment. For RSV load by plaque assay the LLOQ was 1.7 log10 pfu/mL. | Overall Study Period (i.e., approximately 28 days) | 
| Viral Load Changes From Baseline (Plaque Assay Analysis) | Change from Baseline in RSV Load measured by Plaque Assay (RSV Infected Population) | From Baseline until Day 14 (Follow-up) (Baseline; Day 1, 5 hours post-dose; Day 3, 2 hours post-dose; and Follow-up reported) | 
| Viral Load Changes From Baseline (RT-qPCR Analysis) | Change from Baseline in RSV Load measured by RT-qPCR (RSV Infected Population) | From Baseline until Day 14 (Follow-up) (Baseline; Day 1, 5 hours post-dose; Day 3, 2 hours post-dose; and Follow-up reported) | 
| Viral Load Time-weighted Average Changes From Baseline (Plaque Assay Analysis) | The time-weighted average change from baseline to Day x was defined as (AUCx - x* viral load at baseline) /x, where AUCx denotes the AUC between baseline and Day x. For subjects who only had data up to Day t (t<x), the endpoint was defined as (AUCt - t*viral load at baseline) / t. | From Baseline until Day 14 (Follow-up) (Baseline, Day 3, and Follow-up reported) | 
| Viral Load Time-weighted Average Changes From Baseline (RT-qPCR Analysis) | The time-weighted average change from baseline to Day x was defined as (AUCx - x* viral load at baseline) /x, where AUCx denotes the AUC between baseline and Day x. For subjects who only had data up to Day t (t<x), the endpoint was defined as (AUCt - t*viral load at baseline) / t. | From Baseline until Day 14 (Follow-up) (Baseline, Day 3, and Follow-up reported) | 
| Immunogenicity; Number of Subjects With Treatment-emergent Anti-drug Antibodies | The number of subjects with treatment-emergent (TE) anti-drug antibodies (ADA; TE ADA) based on ADA assay by treatment group for the Safety Population. Blood samples for immunogenicity assessments were collected at Baseline and on Day 14. Immunogenicity data were analyzed using the Safety Population. This population differs from the ITT and mITT Populations as 2 subjects who were originally randomized to placebo, received active treatment once; one subject received ALX-0171 6.0 mg/kg and one subject ALX-0171 9.0 mg/kg. | Overall Study Period (i.e., approximately 28 days) | 
| Immunogenicity; Number of Subjects With Treatment-emergent Neutralizing Antibodies | Number of subjects with 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. Immunogenicity data were analyzed using the Safety Population. This population differs from the ITT and mITT Populations as 2 subjects who were originally randomized to placebo, received active treatment once; one subject received ALX-0171 6.0 mg/kg and one subject ALX-0171 9.0 mg/kg. | Overall Study Period (i.e., approximately 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RSV, Lower Respiratory Tract Infection, pediattric patients