Motavizumab Treatment of Infants Hospitalized With RSV
This was a phase 2, randomized, double-blind, placebo-controlled, multicenter study (ClinicalTrials.gov Identifier: NCT00421304). The study was conducted at multiple sites in the Northern and Southern Hemispheres during the 2006–2007 and 2007–2008 RSV seasons. Eligible participants were previously healthy infants of ≥36 weeks gestational age who were ≤12 months of age at randomization and hospitalized for LRTI with a documented positive RSV test within 48 hours before randomization. Exclusion criteria included antiviral treatment for the current RSV infection before randomization; use of steroids within 30 days of randomization; medically significant underlying illness; intubation for ventilatory support at randomization, previous supplemental oxygen use or mechanical ventilation and receipt of palivizumab or other immunoglobulin products during the 2 months before randomization.
Eligible subjects were randomized 1:1:1 using an interactive voice response system to receive a single IV dose of motavizumab (30 or 100 mg/kg) or placebo to be administered as soon as possible after the decision to hospitalize a child with RSV illness was made and no later than 12 hours after admission. The interactive voice response system was also used for assignment of patient identification number and assignment of blinded study drug kits. Subjects' parents/guardians, clinical site staff and protocol-associated personnel were blinded to group assignment. Because the 100 mg/kg dose of motavizumab was larger than had been studied previously, subjects were initially randomized 1:1:1 in a stepwise fashion into cohorts of 15. After three 15 subject cohorts had been randomized and followed up for 30 days for safety without concern, the remaining subjects were randomized and received motavizumab or placebo. All subjects were followed up for safety assessments for 90 days after dosing.
Written informed consent was obtained from each parent or legal guardian before conduct of any protocol-specific activity or study entry. This study was conducted in accordance with the principles of the Declaration of Helsinki, the International Conference on Harmonisation Guidance for Good Clinical Practice, any applicable laws and requirements and any conditions required by a regulatory authority. The study was approved by the institutional review boards of each participant site.
For the determination of RSV load, nasal wash samples were collected on study days 0, 1, 2, 3, 4 through 6 (if still hospitalized), 7, 30, 90 and 180. All study sites were given detailed instructions on the collection and handling of nasal specimens. Nasal wash specimens were obtained using a nasal wash collection kit that was provided to the sites. An aliquot of 1.5 mL of saline was instilled into each nostril and aspirated using a suction catheter into a reservoir (specimen trap). The same suction catheter was then used to aspirate 3 mL of viral transport media into the reservoir with the nasal wash sample. The samples were stored in freezers at −70°C or below at the sites and then shipped on dry ice to the MedImmune collection and storage facility. Once samples were received at the facility, they were placed in a freezer at −70°C or below and held until distributed for testing. Samples remained frozen until immediately before analysis.
Clinical outcomes data collected included the duration of hospitalization, the need for supplemental oxygen and mechanical ventilation and admission to and length of stay in the intensive care unit (ICU). The incidence of ≥1 or ≥3 medically attended wheezing episodes through 12 months after randomization was measured by documented events evaluated by the healthcare provider. Follow-up visits for subjects discharged from the hospital were conducted on study days 3, 7, 30, 90, 180, 270 and 360; phone contact was made every 2 weeks.
At a central laboratory, personnel who were blinded to treatment assignment tested nasal specimens for RSV A and RSV B using validated quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR) assays. Nasal wash samples for determination of motavizumab concentrations in the upper airway were obtained on study days 0, 1, 2, 7 and 30 and measured using an enzyme-linked immunosorbent assay. Serum for determination of motavizumab concentrations was obtained on study days 1, 7, 90, 180 and 360 and measured using an enzyme-linked immunosorbent assay. Serum for antimotavizumab antibodies was collected on study days 0, 180 and 360 and measured using an electrochemiluminescent assay. Respiratory status was assessed using the respiratory distress assessment instrument score, a 17-point scale that measures the degree of severity of wheezing and retractions.
Data regarding adverse events (AEs) and serious AEs (SAEs) were collected from the time of administration of study drug through study day 90. An AE was any change from the patient's baseline status. SAEs were events that resulted in a significant disability (a substantial impairment of baseline function) or death, required or prolonged hospitalization or otherwise were considered an important medical event. Site investigators assessed the severity of AEs and SAEs [level 1 (mild), level 2 (moderate), level 3 (severe) and level 4 (life threatening)] and relationship to study drug (none, remote, possible, probable and definite).
A sample size of 50 per treatment group was planned to allow detection of a 1 log10 decrease in RSV quantitation with approximately 98% power, assuming a standard deviation of 1.1 (log10 plaque-forming unit equivalents per mL). Enrollment was halted at 118 subjects because of slow accrual over 4 RSV seasons in the Northern and Southern Hemispheres. Analysis populations included the intent-to-treat (all subjects randomized) and safety (subjects who received any study drug) populations, the evaluable population for pharmacokinetics/antidrug antibodies (subjects who received a full dose of study drug) and the RSV evaluable population (subjects who were positive at study day 0 as measured by RT-PCR).
The Wilcoxon rank sum test was used to compare treatment groups for real-time RT-PCR results and the Kruskal-Wallis test was used for the overall comparison. Duration of RSV hospitalization from randomization to discharge was summarized. The incidence of ≥1 or ≥3 medically attended wheezing episodes was summarized by treatment group.
Median trough serum concentrations of motavizumab at each time point were summarized using descriptive statistics. The number and percentages of subjects with antimotavizumab antibodies were summarized. Detection of antimotavizumab immune reactivity was defined as a titer ≥1:30. The Fisher's exact test was used for comparisons among treatment groups for number of subjects with motavizumab in nasal wash samples.
Materials and Methods
Study Design
This was a phase 2, randomized, double-blind, placebo-controlled, multicenter study (ClinicalTrials.gov Identifier: NCT00421304). The study was conducted at multiple sites in the Northern and Southern Hemispheres during the 2006–2007 and 2007–2008 RSV seasons. Eligible participants were previously healthy infants of ≥36 weeks gestational age who were ≤12 months of age at randomization and hospitalized for LRTI with a documented positive RSV test within 48 hours before randomization. Exclusion criteria included antiviral treatment for the current RSV infection before randomization; use of steroids within 30 days of randomization; medically significant underlying illness; intubation for ventilatory support at randomization, previous supplemental oxygen use or mechanical ventilation and receipt of palivizumab or other immunoglobulin products during the 2 months before randomization.
Eligible subjects were randomized 1:1:1 using an interactive voice response system to receive a single IV dose of motavizumab (30 or 100 mg/kg) or placebo to be administered as soon as possible after the decision to hospitalize a child with RSV illness was made and no later than 12 hours after admission. The interactive voice response system was also used for assignment of patient identification number and assignment of blinded study drug kits. Subjects' parents/guardians, clinical site staff and protocol-associated personnel were blinded to group assignment. Because the 100 mg/kg dose of motavizumab was larger than had been studied previously, subjects were initially randomized 1:1:1 in a stepwise fashion into cohorts of 15. After three 15 subject cohorts had been randomized and followed up for 30 days for safety without concern, the remaining subjects were randomized and received motavizumab or placebo. All subjects were followed up for safety assessments for 90 days after dosing.
Written informed consent was obtained from each parent or legal guardian before conduct of any protocol-specific activity or study entry. This study was conducted in accordance with the principles of the Declaration of Helsinki, the International Conference on Harmonisation Guidance for Good Clinical Practice, any applicable laws and requirements and any conditions required by a regulatory authority. The study was approved by the institutional review boards of each participant site.
Study Endpoints
For the determination of RSV load, nasal wash samples were collected on study days 0, 1, 2, 3, 4 through 6 (if still hospitalized), 7, 30, 90 and 180. All study sites were given detailed instructions on the collection and handling of nasal specimens. Nasal wash specimens were obtained using a nasal wash collection kit that was provided to the sites. An aliquot of 1.5 mL of saline was instilled into each nostril and aspirated using a suction catheter into a reservoir (specimen trap). The same suction catheter was then used to aspirate 3 mL of viral transport media into the reservoir with the nasal wash sample. The samples were stored in freezers at −70°C or below at the sites and then shipped on dry ice to the MedImmune collection and storage facility. Once samples were received at the facility, they were placed in a freezer at −70°C or below and held until distributed for testing. Samples remained frozen until immediately before analysis.
Clinical outcomes data collected included the duration of hospitalization, the need for supplemental oxygen and mechanical ventilation and admission to and length of stay in the intensive care unit (ICU). The incidence of ≥1 or ≥3 medically attended wheezing episodes through 12 months after randomization was measured by documented events evaluated by the healthcare provider. Follow-up visits for subjects discharged from the hospital were conducted on study days 3, 7, 30, 90, 180, 270 and 360; phone contact was made every 2 weeks.
Assessments
At a central laboratory, personnel who were blinded to treatment assignment tested nasal specimens for RSV A and RSV B using validated quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR) assays. Nasal wash samples for determination of motavizumab concentrations in the upper airway were obtained on study days 0, 1, 2, 7 and 30 and measured using an enzyme-linked immunosorbent assay. Serum for determination of motavizumab concentrations was obtained on study days 1, 7, 90, 180 and 360 and measured using an enzyme-linked immunosorbent assay. Serum for antimotavizumab antibodies was collected on study days 0, 180 and 360 and measured using an electrochemiluminescent assay. Respiratory status was assessed using the respiratory distress assessment instrument score, a 17-point scale that measures the degree of severity of wheezing and retractions.
Safety
Data regarding adverse events (AEs) and serious AEs (SAEs) were collected from the time of administration of study drug through study day 90. An AE was any change from the patient's baseline status. SAEs were events that resulted in a significant disability (a substantial impairment of baseline function) or death, required or prolonged hospitalization or otherwise were considered an important medical event. Site investigators assessed the severity of AEs and SAEs [level 1 (mild), level 2 (moderate), level 3 (severe) and level 4 (life threatening)] and relationship to study drug (none, remote, possible, probable and definite).
Statistical Methods
A sample size of 50 per treatment group was planned to allow detection of a 1 log10 decrease in RSV quantitation with approximately 98% power, assuming a standard deviation of 1.1 (log10 plaque-forming unit equivalents per mL). Enrollment was halted at 118 subjects because of slow accrual over 4 RSV seasons in the Northern and Southern Hemispheres. Analysis populations included the intent-to-treat (all subjects randomized) and safety (subjects who received any study drug) populations, the evaluable population for pharmacokinetics/antidrug antibodies (subjects who received a full dose of study drug) and the RSV evaluable population (subjects who were positive at study day 0 as measured by RT-PCR).
The Wilcoxon rank sum test was used to compare treatment groups for real-time RT-PCR results and the Kruskal-Wallis test was used for the overall comparison. Duration of RSV hospitalization from randomization to discharge was summarized. The incidence of ≥1 or ≥3 medically attended wheezing episodes was summarized by treatment group.
Median trough serum concentrations of motavizumab at each time point were summarized using descriptive statistics. The number and percentages of subjects with antimotavizumab antibodies were summarized. Detection of antimotavizumab immune reactivity was defined as a titer ≥1:30. The Fisher's exact test was used for comparisons among treatment groups for number of subjects with motavizumab in nasal wash samples.