Clinical trial NCT02979431: Dose Ranging Study of ALX-0171 in Infants Hospitalized for Respiratory Syncytial Virus Lower Respiratory Tract Infection
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Respiratory Syncytial Virus Lower Respiratory Tract Infection
Keywords: RSV, Lower Respiratory Tract Infection, pediattric patients
Lead sponsor: Ablynx, a Sanofi company
Sponsor class: INDUSTRY
First posted: 2016-12-01
Enrollment: 180
Sex: ALL
Minimum age (years): 28
Maximum age (years): 2
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Male or female infant or young child aged 28 days to \< 2 years with gestational age ≥ 33 weeks at screening.
2. Subject weighed between ≥ 3.0 kg and \< 15.0 kg at screening.
3. 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.
4. Subject had a positive RSV diagnostic test at screening.
5. Subject was expected to have to stay in the hospital for at least 24 hours (according to the Investigator's judgment at screening).
6. 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.
7. 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
8. Normal psychomotor development.

Exclusion Criteria:

1. 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.
2. 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.
3. Subject was known to be immunocompromised.
4. 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.
5. Subject had significant oral and/or maxillofacial malformations that would prevent proper positioning of the face mask.
6. Subject received invasive mechanical ventilation or non-invasive respiratory support (i.e., continuous or bilevel positive airway pressure) in the 4 weeks prior to screening.
7. During the 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).
8. 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)

Primary outcomes:
measure: Time for Viral Load to Drop Below Assay Quantification Limit (BQL) (Plaque Assay Analysis)
timeFrame: Overall Study Period (i.e., approximately 28 days)
Secondary outcomes:
measure: Change From Baseline in Global Severity Score on Day 2 (5 Hours Post-dose)
timeFrame: from Baseline untill Day 2 (5 hours post-dose)
measure: Time-to-Clinical Response
timeFrame: Overall Study Period (i.e., approximately 28 days)
measure: Time-to-BQL (RT-qPCR)
timeFrame: Overall Study Period (i.e., approximately 28 days)
measure: Time-to-undetectable Viral Load (Plaque Assay Analysis)
timeFrame: Overall Study Period (i.e., approximately 28 days)
measure: Viral Load Changes From Baseline (Plaque Assay Analysis)
timeFrame: From Baseline until Day 14 (Follow-up) (Baseline; Day 1, 5 hours post-dose; Day 3, 2 hours post-dose; and Follow-up reported)
measure: Viral Load Changes From Baseline (RT-qPCR Analysis)
timeFrame: From Baseline until Day 14 (Follow-up) (Baseline; Day 1, 5 hours post-dose; Day 3, 2 hours post-dose; and Follow-up reported)
measure: Viral Load Time-weighted Average Changes From Baseline (Plaque Assay Analysis)
timeFrame: From Baseline until Day 14 (Follow-up) (Baseline, Day 3, and Follow-up reported)
measure: Viral Load Time-weighted Average Changes From Baseline (RT-qPCR Analysis)
timeFrame: From Baseline until Day 14 (Follow-up) (Baseline, Day 3, and Follow-up reported)
measure: Immunogenicity; Number of Subjects With Treatment-emergent Anti-drug Antibodies
timeFrame: Overall Study Period (i.e., approximately 28 days)
measure: Immunogenicity; Number of Subjects With Treatment-emergent Neutralizing Antibodies
timeFrame: Overall Study Period (i.e., approximately 28 days)
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: Investigator site 2
city: Brussels
country: Belgium
facility: Investigator site
city: Edegem
country: Belgium
facility: Investigator Site
city: Leuven
country: Belgium
facility: Investigator Site
city: Roeselare
country: Belgium
facility: Investigator site
city: Kozloduy
country: Bulgaria
facility: Investigator Site
city: Plovdiv
country: Bulgaria
facility: Investigator Site
city: Ruse
country: Bulgaria
facility: Investigator Site
city: Sofia
country: Bulgaria
facility: Investigator Site
city: Stara Zagora
country: Bulgaria
facility: Investigator Site
city: Santiago
country: Chile
facility: Investigator Site
city: Valdivia
country: Chile
facility: Investigator site
city: Cali
country: Colombia
facility: Investigator site
city: Floridablanca
country: Colombia
facility: Investigator Site
city: Medellín
country: Colombia
facility: Investigator Site 1
city: Medellín
country: Colombia
facility: Investigator site 2
city: Cakovec
country: Croatia
facility: Investigator site
city: Osijek
country: Croatia
facility: Investigator site
city: Slavonski Brod
country: Croatia
facility: Investigator site
city: Varaždin
country: Croatia
facility: Investigator site
city: Zagreb
country: Croatia
facility: Investigator site 1
city: Zagreb
country: Croatia
facility: Investigator site 2
city: Zagreb
country: Croatia
facility: Investigator site 3
city: Zagreb
country: Croatia
facility: Investigator site 4
city: Hradec Králové
country: Czechia
facility: Investigator site
city: Tartu
country: Estonia
facility: Investigator Site
city: Bochum
country: Germany
facility: Investigator site
city: Dresden
country: Germany
facility: Investigator site
city: Sankt Augustin
country: Germany
facility: Investigator Site
city: Wuppertal
country: Germany
facility: Investigator Site
city: Balassagyarmat
country: Hungary
facility: Investigator Site
city: Budapest
country: Hungary
facility: Investigator site 1
city: Budapest
country: Hungary
facility: Investigator Site 2
city: Budapest
country: Hungary
facility: Investigator Site 3
city: Budapest
country: Hungary
facility: Investigator Site 4
city: Debrecen
country: Hungary
facility: Investigator site
city: Szeged
country: Hungary
facility: Investigator Site
city: Szekesfehervar
country: Hungary
facility: Investigator site
city: Veszprém
country: Hungary
facility: Investigator Site
city: Beer sheva
country: Israel
facility: Investigator site
city: Haifa
country: Israel
facility: Investigator site
city: Petah tikva
country: Israel
facility: Investigator site
city: Daugavpils
country: Latvia
facility: Investigator Site
city: Riga
country: Latvia
facility: Investigator Site
city: George Town
country: Malaysia
facility: Investigator site
city: Kuala Lumpur
country: Malaysia
facility: Investigator Site
city: Seremban
country: Malaysia
facility: Investigator Site
city: Sibu
country: Malaysia
facility: Investigator Site
city: Alabang
country: Philippines
facility: Investigator Site
city: Manila
country: Philippines
facility: Investigator site
city: Quezon City
country: Philippines
facility: Investigator Site 1
city: Quezon City
country: Philippines
facility: Investigator Site 2
city: Lublin
country: Poland
facility: Investigator site
city: Trzebnica
country: Poland
facility: Investigator site
city: Banská Bystrica
country: Slovakia
facility: Investigator site
city: Bratislava
country: Slovakia
facility: Investigator site
city: Košice
country: Slovakia
facility: Investigator site
city: Poprad
country: Slovakia
facility: Investigator Site
city: Barcelona
country: Spain
facility: Investigator Site 1
city: Barcelona
country: Spain
facility: Investigator Site 2
city: Barcelona
country: Spain
facility: Investigator Site 3
city: Bilbao
country: Spain
facility: Investigator Site
city: El Palmar
country: Spain
facility: Investigator Site
city: Madrid
country: Spain
facility: Investigator site 1
city: Madrid
country: Spain
facility: Investigator Site 2
city: Málaga
country: Spain
facility: Investigator Site
city: Santiago de Compostela
country: Spain
facility: Investigator site
city: Sevilla
country: Spain
facility: Investigator site
city: Valencia
country: Spain
facility: Investigator Site
city: Bangkok
country: Thailand
facility: Investigator Site 1
city: Bangkok
country: Thailand
facility: Investigator site 2
city: Chiang Mai
country: Thailand
facility: Investigator Site
city: Hat Yai
country: Thailand
facility: Investigator site
city: Khon Kaen
country: Thailand
facility: Investigator Site
Study officials:
affiliation: Ablynx, a Sanofi company
name: Ablynx Clinical Department
role: STUDY_DIRECTOR
References: