Respiratory Syncytial Virus Lower Respiratory Tract Infection
Conditions
Brief summary
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.
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.
Interventions
BIOLOGICALALX-0171 1.5 mg/kg
ALX-0171 1.5 mg/kg was administered via a single inhalation once daily for 3 consecutive days.
OTHERPlacebo
Placebo was administered via a single inhalation once daily for 3 consecutive days.
Sponsors
Ablynx, a Sanofi company
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
28 Days to 2 Years
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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). | From the subject's first study drug administration until completion of the subject's last visit, an average of 4 weeks | 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. |
| Safety and Tolerability of Inhaled ALX-0171 1.5 mg/kg as Measured by the Number of Serious and Non-serious TEAEs. | From the subject's first study drug administration until completion of the subject's last visit, an average of 4 weeks | Number of serious and non-serious TEAEs reported in the ALX-0171 1.5 mg/kg treatment group and placebo treatment group. |
Countries
Japan
Participant flow
Recruitment details
Sixteen subjects were screened for Cohort 1. Of these, 15 subjects were randomized. There was 1 screen failure due to consent withdrawal. For Cohort 2, 1 subject was screened but considered a screen failure (consent withdrawal). Consent was obtained from the first subject on 1 March 2018; last subject completed the final visit on 19 October 2018
Pre-assignment details
All randomized subjects received at least 1 administration of study drug and were included in the Safety Population.
Participants by arm
| Arm | Count |
|---|---|
| ALX-0171 1.5 mg/kg Single inhalation of ALX-0171 1.5 mg/kg once daily for 3 consecutive days. | 12 |
| Placebo Single inhalation of placebo once daily for 3 consecutive days. | 3 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Consent withdrawn by legal guardian | 1 | 0 |
Baseline characteristics
| Characteristic | ALX-0171 1.5 mg/kg | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 7.4 months STANDARD_DEVIATION 4.65 | 3.5 months STANDARD_DEVIATION 3.04 | 6.6 months STANDARD_DEVIATION 4.58 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 12 Participants | 3 Participants | 15 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 5 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Male | 7 Participants | 1 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 3 |
| other Total, other adverse events | 8 / 12 | 1 / 3 |
| serious Total, serious adverse events | 1 / 12 | 0 / 3 |
Outcome results
Primary
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.
Time frame: From the subject's first study drug administration until completion of the subject's last visit, an average of 4 weeks
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ALX-0171 1.5 mg/kg | Safety and Tolerability of Inhaled ALX-0171 1.5 mg/kg as Measured by the Number of Serious and Non-serious TEAEs. | Serious TEAE | 2 TEAE |
| ALX-0171 1.5 mg/kg | Safety and Tolerability of Inhaled ALX-0171 1.5 mg/kg as Measured by the Number of Serious and Non-serious TEAEs. | Non-Serious TEAE | 18 TEAE |
| Placebo | Safety and Tolerability of Inhaled ALX-0171 1.5 mg/kg as Measured by the Number of Serious and Non-serious TEAEs. | Serious TEAE | 0 TEAE |
| Placebo | Safety and Tolerability of Inhaled ALX-0171 1.5 mg/kg as Measured by the Number of Serious and Non-serious TEAEs. | Non-Serious TEAE | 1 TEAE |
Primary
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.
Time frame: From the subject's first study drug administration until completion of the subject's last visit, an average of 4 weeks
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ALX-0171 1.5 mg/kg | 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). | At least one serious TEAE | 1 participants |
| ALX-0171 1.5 mg/kg | 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). | At least one non-serious TEAE | 8 participants |
| Placebo | 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). | At least one serious TEAE | 0 participants |
| Placebo | 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). | At least one non-serious TEAE | 1 participants |