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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 180
- 试验地点
- 74
- 主要终点
- Time for Viral Load to Drop Below Assay Quantification Limit (BQL) (Plaque Assay Analysis)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 28 Days 至 2 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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)
研究组 & 干预措施
ALX-0171 3.0 mg/kg
Inhalation of ALX-0171 3.0 mg/kg once daily for 3 consecutive days
干预措施: ALX-0171 3.0 mg/kg (Biological)
ALX-0171 6.0 mg/kg
Inhalation of ALX-0171 6.0 mg/kg once daily for 3 consecutive days
干预措施: ALX-0171 6.0 mg/kg (Biological)
ALX-0171 Dose 9.0mg/kg
Inhalation of ALX-0171 9.0 mg/kg once daily for 3 consecutive days
干预措施: ALX-0171 9.0 mg/kg (Biological)
Placebo
Inhalation of Placebo once daily for 3 consecutive days
干预措施: Placebo (Other)
结局指标
主要结局
Time for Viral Load to Drop Below Assay Quantification Limit (BQL) (Plaque Assay Analysis)
时间窗: Overall Study Period (i.e., approximately 28 days)
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.
次要结局
- Change From Baseline in Global Severity Score on Day 2 (5 Hours Post-dose)(from Baseline untill Day 2 (5 hours post-dose))
- Time-to-Clinical Response(Overall Study Period (i.e., approximately 28 days))
- Time-to-BQL (RT-qPCR)(Overall Study Period (i.e., approximately 28 days))
- Time-to-undetectable Viral Load (Plaque Assay Analysis)(Overall Study Period (i.e., approximately 28 days))
- Viral Load Changes From Baseline (Plaque Assay Analysis)(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)(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)(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)(From Baseline until Day 14 (Follow-up) (Baseline, Day 3, and Follow-up reported))
- Immunogenicity; Number of Subjects With Treatment-emergent Anti-drug Antibodies(Overall Study Period (i.e., approximately 28 days))
- Immunogenicity; Number of Subjects With Treatment-emergent Neutralizing Antibodies(Overall Study Period (i.e., approximately 28 days))