Evaluation of ALX-0171 in Japanese Children Hospitalized for Respiratory Syncytial Virus Lower Respiratory Tract Infection

A Randomized, Double-blind, Multicenter, Multiple-dose Study of ALX-0171 Versus Placebo Along With Standard of Care in Japanese Infants and Young Children Hospitalized for Respiratory Syncytial Virus Lower Respiratory Tract Infection

This was a randomized, double-blind, multicenter, Phase II study (NCT03418571) designed to support the selection of an optimal dose of inhaled ALX-0171 for further clinical development, taking ethnicity into consideration.

Based on the results of the Phase IIb dose-ranging study ALX0171-C201 (RESPIRE), the Sponsor decided to discontinue ALX-0171 development in infants and to early terminate the ALX0171-C203 study.

Study Overview

• Status: Terminated
• Conditions: Respiratory Syncytial Virus Lower Respiratory Tract Infection
• Intervention / Treatment: Biological: ALX-0171 1.5 mg/kg; Other: Placebo

Detailed Description

Four dose levels were planned to be evaluated in four consecutive cohorts consisting of Japanese infants and young children aged 28 days to <2 years with a gestational age ≥33 weeks who were hospitalized for and diagnosed with respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI):

• Dose level 1: target dose of 1.5 mg/kg
• Dose level 2: target dose of 3.0 mg/kg
• Dose level 3: target dose of 6.0 mg/kg
• Dose level 4: target dose of 9.0 mg/kg

Each cohort was planned to consist of 15 subjects enrolled and randomly assigned to receive ALX-0171 or placebo, in an allocation ratio of 4:1 (N = 12 active versus N = 3 placebo per cohort).

Due to early termination of the trial, only enrollment of Cohort 1 could be completed as planned. For Cohort 2, only 1 subject was screened but did not meet the eligibility criteria and was considered a screen failure. Therefore, data were not available for treatment groups ALX-0171 3.0 mg/kg, 6.0 mg/kg, and 9.0 mg/kg.

Of note, in line with applicable guidelines, an Independent Data Monitoring Committee (IDMC) was assigned to monitor the study. Upon completing of Cohort 1, the IDMC reviewed the available unblinded safety data and unanimously recommended to continue the study with no changes to the protocol.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2

Contacts and Locations

Study Locations

• Japan
  • Aoi-ku, Japan
    • Investigator site
  • Asahikawa, Japan
    • Investigator site
  • Fuchu-shi, Japan
    • Investigator site
  • Fukuyama-shi, Japan
    • Investigator site
  • Funabashi, Japan
    • Investigator site
  • Gifu, Japan
    • Investigator site
  • Isesaki, Japan
    • Investigator site
  • Kawasaki, Japan
    • Investigator site
  • Koga, Japan
    • Investigator site
  • Kurashiki, Japan
    • Investigator site
  • Kurume-shi, Japan
    • Investigator site
  • Meguro-ku, Japan
    • Investigator site
  • Minami-ku, Japan
    • Investigator site
  • Nagano-shi, Japan
    • Investigator site
  • Saitama-shi, Japan
    • Investigator site
  • Shimotsuke-shi, Japan
    • Investigator site
  • Takatsuki, Japan
    • Investigator site
  • Toshima-ku, Japan
    • Investigator site
  • Toyohira, Japan
    • Investigator site
  • Ueda, Japan
    • Investigator site
  • Wako, Japan
    • Investigator site
  • Yachiyo, Japan
    • Investigator site
  • Yokosuka, Japan
    • Investigator Site 1
  • Yokosuka, Japan
    • Investigator Site 2
  • Ōmura, Japan
    • Investigator site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 weeks to 2 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Main inclusion criteria:

1. Subject was a Japanese male or female infant or young child aged 28 days to <2 years with gestational age ≥33 weeks at screening.
2. Subject was of Japanese descent, i.e., born in Japan to Japanese parents and had Japanese maternal and paternal grandparents.
3. Subject weighed between ≥3.0 kg and <15.0 kg at screening.
4. Subject was 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.
5. Subject had a positive RSV diagnostic test within 4 days of screening.
6. Subject was expected to have to stay in the hospital for at least 24 hours (according to the Investigator's judgment at screening).
7. Symptoms 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.

8. Subject fulfilled at least two of the following RSV disease severity criteria at screening and randomization:

   • Inadequate oral feeding that required feeding support (i.e., nasogastric tube or i.v. line),

   • Inadequate oxygen saturation defined as:

     • Peripheral capillary oxygen saturation (SpO2) <95% on room air, or
     • Requiring oxygen supplementation to maintain adequate oxygen saturation with documented pre-supplementation value <95%

   • Signs of respiratory distress defined as:

     • Respiratory rate ≥50 breaths per minute in infants up to 12 months of age, and ≥40 breaths per minute in children above 12 months, and/ or
     • Moderate or marked respiratory muscle retractions
9. Subject had normal psychomotor development.

Others as defined in the protocol

Main 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, 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 which would have prevented 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 current admission, subject was initially hospitalized in an Intensive Care Unit (ICU) setting and/or 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/minute could be provided through the nebulizer)
9. Subject had received 1 or more doses of palivizumab or treatment or prophylaxis with any RSV antiviral compound (e.g., ribavirin, i.v. immunoglobulin, or any investigational drug or vaccine for RSV [including subject's mother who had been vaccinated against RSV]) at any time prior to screening.
10. Subject was required to continue or start systemic corticosteroid therapy. Subject on a maintenance therapy of inhaled corticosteroids could continue this treatment at the usual dose. Topical corticosteroids for skin disorders were permitted.
11. Subject had clinically meaningful abnormalities on a 12-lead electrocardiogram (ECG), which according to the Investigor's judgement did not allow participation of the subject in the study. A 12-lead ECG performed within 4 days of screening was acceptable. If not available, the 12-lead ECG could be performed at the time of screening.

Others as defined in the protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Other: Placebo; Placebo was administered via a single inhalation once daily for 3 consecutive days.
Experimental: ALX-0171 1.5 mg/kg	Biological: ALX-0171 1.5 mg/kg; ALX-0171 1.5 mg/kg was administered via a single inhalation once daily for 3 consecutive days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability of Inhaled ALX-0171 1.5 mg/kg as Measured by the Number of Subjects With at Least 1 Serious or Non-Serious Treatment-emergent Adverse Event (TEAE).	Number of subjects reported with at least 1 serious or non-serious TEAEs in the ALX-0171 1.5 mg/kg treatment group and placebo treatment group.	From the subject's first study drug administration until completion of the subject's last visit, an average of 4 weeks
Safety and Tolerability of Inhaled ALX-0171 1.5 mg/kg as Measured by the Number of Serious and Non-serious TEAEs.	Number of serious and non-serious TEAEs reported in the ALX-0171 1.5 mg/kg treatment group and placebo treatment group.	From the subject's first study drug administration until completion of the subject's last visit, an average of 4 weeks

Collaborators and Investigators

• Sponsor: Ablynx
• Investigators: Study Director: Medical Monitor, Ablynx NV

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2018
• Primary Completion (Actual): October 24, 2018
• Study Completion (Actual): October 24, 2018

Study Registration Dates

• First Submitted: January 26, 2018
• First Submitted That Met QC Criteria: January 26, 2018
• First Posted (Actual): February 1, 2018

Study Record Updates

• Last Update Posted (Actual): July 30, 2019
• Last Update Submitted That Met QC Criteria: July 17, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Disease Attributes; Infections; Communicable Diseases; Respiratory Tract Infections; Anti-Infective Agents; Antiviral Agents; Gontivimab
• Other Study ID Numbers: ALX0171-C203

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No