Original Studies
Motavizumab Treatment of Infants Hospitalized With Respiratory Syncytial Virus Infection Does Not Decrease Viral Load or Severity of Illness Octavio Ramilo, MD,* Rosanna Lagos, MD,† Xavier Sáez-Llorens, MD,‡ JoAnn Suzich, PhD,§ C. Kathy Wang, PhD,§ Kathryn M. Jensen, MS,§ Brian S. Harris, MS,§ Genevieve A. Losonsky, MD,§ and M. Pamela Griffin, MD§ on behalf of the Motavizumab Study Group Background: This study was conducted to determine whether treatment with motavizumab, an anti-respiratory syncytial virus (RSV) monoclonal antibody, would decrease viral load and improve clinical outcomes in previously healthy term infants hospitalized with RSV lower respiratory tract infection. Methods: Infants hospitalized with lower respiratory tract infection and a positive RSV test performed locally were randomized to receive 1 intravenous dose of motavizumab (30 or 100 mg/kg) or placebo. Nasal wash samples were tested by real-time reverse transcriptase polymerase chain reaction at a central laboratory to determine viral load. Clinical data were collected during RSV hospitalization and at 12-month follow up. Results: Of 118 infants, 112 were confirmed RSV positive by real-time reverse transcriptase polymerase chain reaction. In each study group, median (range) RSV load (log10 copies/mL) decreased at a similar rate from baseline to study day 7 [motavizumab 30 mg/kg: 8.35 (2.5–9.5) to 5.03 (2.5–6.8); motavizumab 100 mg/kg: 8.22 (5.5–9.7) to 4.25 (2.5–8.0); placebo: 8.02 (6.7–9.8) to 5.17 (2.5–7.3)]. Median (range) duration of hospitalization was 3.05 (0.8–16.0), 2.99 (1.0–25.0) and 2.88 (0.8–11.7) days for the motavizumab 30 mg/kg, motavizumab 100 mg/kg and placebo groups, respectively. Six (8%) motavizumab and 0 placebo recipients were admitted to the intensive care unit and 4 required mechanical ventilation. The incidence of wheezing episodes during the 12-month follow up was comparable for all 3 groups. Conclusions: Motavizumab had no appreciable effect on RSV viral load measured in the upper respiratory tract of children hospitalized for RSV lower respiratory tract infection. No differences were observed for duration of hospitalization, severity of illness measures or wheezing episodes during 12-month follow up in children treated with motavizumab or placebo. Key Words: RSV, treatment, pediatric, infant, monoclonal antibody (Pediatr Infect Dis J 2014;33:703–709)
Accepted for publication December 5, 2013. From the *Nationwide Children’s Hospital, Ohio State University College of Medicine, Columbus, OH; †Centro Para Vacunas En Desarrollo-Chile, Santiago, Chile; ‡Hospital del Niño, Ciudad de Panamá, Panamá; and §MedImmune, Gaithersburg, MD. Editorial assistance with the development of this article was provided by John E. Fincke, PhD, and Gerard P. Johnson, PhD, of Complete Healthcare Communications, Inc. (Chadds Ford, PA), funded by MedImmune. This study was sponsored by MedImmune. O.R. has functioned as a member of the board for Quidel, was a consultant for Merck and AbbVie, received grants from Abbott Molecular, received payment for educational lectures and symposia for AbbVie and received reimbursement from MedImmune for travel/ accommodations/meeting expenses unrelated to the aforementioned activities. R.L. and X.S.L. have received research funding on their behalf from MedImmune. J.S., C.K.W., K.M.J., B.S.H. and M.P.G. are employees of MedImmune. G.A.L. was an employee of MedImmune at the time of the study and analysis. The authors have no other funding or conflicts of interest to disclose. ClinicalTrials.gov Identifier: NCT00421304 Address for correspondence: Octavio Ramilo, MD, Nationwide Children’s Hospital, Infectious Diseases ED 161, 700 Children’s Dr, Columbus, OH 43215. E-mail: [email protected]. Copyright © 2013 by Lippincott Williams & Wilkins ISSN: 0891-3668/14/3307-0703 DOI: 10.1097/INF.0000000000000240
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espiratory syncytial virus (RSV) is the leading cause of hospitalization in infants.1 In the United States alone, the average estimated annual number of RSV-associated hospitalizations is 126,000.2 In fact, in the infant population, RSV hospitalization rates are 6 times higher than those observed for influenza.3 In addition, RSV lower respiratory tract infection (LRTI) has been associated with an increased risk of subsequent recurrent wheezing.4–7 There are currently no effective vaccines to prevent RSV in children, and prophylaxis is provided only to those high risk infants who are born prematurely, those with chronic lung disease of prematurity or those with hemodynamically significant congenital heart disease. Treatment of infants who are hospitalized with RSV LRTI is generally supportive care. Ribavirin is the only licensed antiviral agent for RSV LRTI in hospitalized infants but has a number of limitations and is not used routinely.8 It is evident that improved modes of therapy are needed for children with serious RSV illness. There have been several treatment studies using antibodies directed against neutralizing epitopes of RSV including RSV immune globulin (RespiGam, MedImmune, Gaithersburg, MD),9 palivizumab (Synagis, MedImmune)10,11 and motavizumab (MEDI-524, MedImmune).12 Those studies demonstrated that treatment with anti-RSV antibodies was well tolerated, and there was no evidence of acute disease enhancement. In a treatment study using palivizumab, Malley et al11 showed that a 15 mg/kg dose of intravenous (IV) palivizumab significantly reduced RSV viral load in the lower, but not upper, respiratory tract of infants who required mechanical ventilation. While the study was not powered to assess clinical outcomes, a corresponding clinical improvement was not observed. A more recent pilot study of motavizumab by Lagos et al12 showed that at day 1 posttreatment, a 30 mg/kg dose of IV motavizumab significantly reduced RSV viral load in nasal wash samples of children hospitalized with RSV LRTI, and by day 7, significantly fewer motavizumab-treated patients had detectable viral RNA compared with placebo-treated patients. In that small study, there were no observed differences in disease severity. With limited findings from the previous studies, this larger study was designed to obtain additional information regarding RSV viral load reduction and clinical outcomes in infants treated with an anti-RSV monoclonal antibody using a higher dose than in previous studies. Specifically, the current study was undertaken in previously healthy term infants hospitalized with RSV LRTI to (1) assess the effect of treatment with motavizumab (30 or 100 mg/kg) on viral load in the upper respiratory tract and (2) evaluate the effect of treatment on disease severity and clinical outcomes during the acute hospitalization and for 12 months subsequent to hospitalization.
MATERIALS AND METHODS Study Design This was a phase 2, randomized, double-blind, p lacebo-controlled, multicenter study (ClinicalTrials.gov I dentifier: NCT00421304). The study was conducted at multiple sites in the
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The Pediatric Infectious Disease Journal • Volume 33, Number 7, July 2014
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.
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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.13 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.14 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.14 Serum for antimotavizumab antibodies was collected on study days 0, 180 and 360 and measured using an electrochemiluminescent assay.14 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.15
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 ≥1:30.14 The Fisher’s exact test was used for comparisons among treatment groups for number of subjects with motavizumab in nasal wash samples.
RESULTS A total of 118 subjects were randomized at 18 sites in 5 countries and 113 subjects received study drug. One hundred and seven subjects completed through study day 90 and 98 subjects completed through study day 360 (Fig. 1). Similar rates of noncompletion were observed among subjects treated with motavizumab or placebo. Overall, demographics and clinical characteristics were similar across the 3 treatment groups (Table 1). © 2013 Lippincott Williams & Wilkins
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Motavizumab and RSV
Enrolled and Randomized N=118
Randomized to motavizumab 30 mg/kg n=39
Randomized to motavizumab 100 mg/kg n=39
Randomized to placebo n=40
Completed study through study day 90 n=37 (95%)
Completed study through study day 90 n=36 (92%)
Completed study through study day 90 n=34 (85%)
Completed study through study day 360 n=35 (90%)
Completed study through study day 360 n=31 (80%)
Completed study through study day 360 n=32 (80%)
Subjects not completing study through study day 360, n=4 Lost to follow-up, n=2 (5%) Withdrawal of consent, n=2 (5%) Other, n=0 (0%)
Subjects not completing study through study day 360, n=8 Lost to follow-up, n=5 (13%) Withdrawal of consent, n=2 (5%) Other, n=1 (3%)
Subjects not completing study through study day 360, n=8 Lost to follow-up, n=5 (13%) Withdrawal of consent, n=2 (5%) Other, n=1 (3%)
FIGURE 1. Disposition of subjects.
TABLE 1. Demographic and Clinical Characteristics at Study Entry* Motavizumab Characteristic Age at enrollment, median (range), mo Weight at enrollment, median (range), kg Boys, n (%) White, n (%) RDAI score,† n Median† (range)
30 mg/kg (n = 39)
100 mg/kg (n = 39)
Placebo (n = 40)
2.0 (0.4–11.2) 5.4 (3.2–10.6) 20 (51) 26 (67) 39 6 (0–17)
2.2 (0.3–11.3) 5.6 (2.1–9.3) 20 (51) 27 (69) 36 6 (0–13)
2.7 (0.5–10.3) 6.2 (3.1–10.0) 29 (73) 26 (65) 37 4 (0–15)
*Intent-to-treat population. †RSV evaluable population. RDAI, respiratory distress assessment instrument.
One hundred and twelve subjects had adequate baseline samples and tested positive for RSV A [63/112 (56%)] or RSV B [49/112 (44%)] by real-time RT-PCR. Median (range) RSV loads in the upper respiratory tract were similar for all 3 treatment groups at enrollment [8.35 (2.5–9.5), 8.22 (5.5–9.7) and 8.02 (6.7–9.8) in the motavizumab 30 mg/kg, motavizumab 100 mg/kg and placebo groups, respectively]. After treatment with motavizumab or placebo, viral loads decreased at a similar rate at all time points with no statistically significant differences (Fig. 2). By study day 7, median (range) viral loads had decreased to 5.03 (2.5–6.8), 4.25 (2.5–8.0) and 5.17 (2.5–7.3) in the motavizumab 30 mg/kg, motavizumab 100 mg/kg and placebo groups, respectively. Parameters for the severity of the acute RSV illness are shown in Table 2. Median (range) duration of hospitalization was 3.05 (0.8–16.0), 2.99 (1.0–25.0) and 2.88 (0.8–11.7) days for the motavizumab 30 mg/kg, motavizumab 100 mg/kg and placebo groups, respectively. At study entry, 53% (40/75) of the combined © 2013 Lippincott Williams & Wilkins
motavizumab recipients (30 and 100 mg/kg) and 41% (15/37) of placebo recipients required supplemental oxygen. During the hospitalization, 80% (59/74) of the combined motavizumab recipients required supplemental oxygen for a median (range) of 3.0 (1.0–21.0) days compared with 65% (24/37) of placebo recipients for a median (range) of 3.0 (1.0–8.0) days. Admission to the ICU for 6 (8%) motavizumab-treated subjects, ranging from 1.1 to 4.2 months of age, occurred on the day of hospital admission to 2 days following admission. Of the 6 motavizumab recipients who were in the ICU, 4 required mechanical ventilation for a median (range) duration of 6.7 (3.0–8.4) days. None of the subjects in the placebo group required ICU admission or mechanical ventilation. However, the numerical differences between treatment groups that were noted for admission to the ICU and mechanical ventilation were not statistically significant. Excluding wheezing events that occurred during the RSV hospitalization, the percentage of subjects who had no wheezing www.pidj.com | 705
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10
Motavizumab 30 mg/kg
RSV Load, log10 copies/mL
Motavizumab 100 mg/kg Placebo
8
6
4
2
0 N= 39 36 37 Day 0
38 36 37
38 36 37
38 32 34
37 36 35
37 34 35
37 34 33
35 32 32
Day 1
Day 2
Day 3
Day 7
Day 30
Day 90
Day 180
FIGURE 2. RSV load (log10 copies/mL), median (range), in the upper respiratory tract as measured by quantitative real-time RT-PCR. TABLE 2. Severity of RSV Illness During Hospitalization* Motavizumab
Hospitalization information available,† n/N (%) Duration of hospitalization,‡ d Supplemental oxygen use, n/N (%) Duration of supplemental oxygen use,§ d Admission to ICU, n/N (%) Duration of ICU stay,§ d Mechanical ventilation, n/N (%) Duration of mechanical ventilation,‡ d
30 mg/kg (n = 39)
100 mg/kg (n = 36)
38/39 (97) 3.1 (0.8–16.0) 30/38 (79) 3.0 (1.0–12.0) 3/38 (8) 10.0 (2.0–10.0) 2/38 (5) 7.8 (7.2–8.4)
36/36 (100) 3.0 (1.0–25.0) 29/36 (81) 3.0 (1.0–21.0) 3/36 (8) 5.0 (1.0–9.0) 2/36 (6) 4.6 (3.0–6.3)
Placebo (n = 37) 37/37 (100) 2.9 (0.8–11.7) 24/37 (65) 3.0 (1.0–8.0) 0/37 (0) N/A 0/37 (0) N/A
*RSV evaluable population: subjects who were positive for RSV at study day 0 by real-time RT-PCR. †Hospitalization information not available for subjects randomized but not dosed because of withdrawal of consent. ‡Duration is calculated from randomization date/time to discharge date/time and presented as median (range). §Duration is calculated from randomization date to discharge date and presented as median (range). N/A, not applicable (no subjects fit this category).
events during the 12-month follow up was similar for all 3 groups (51%, 56% and 54% for the 30 mg/kg motavizumab, 100 mg/kg motavizumab and placebo groups, respectively). Likewise, the incidence of ≥1 (49%, 44% and 46%) and ≥3 (23%, 14% and 16%) medically attended wheezing episodes was comparable for the 30 mg/kg motavizumab, 100 mg/kg motavizumab and placebo groups, respectively. Median (range) peak serum concentrations of motavizumab increased dose proportionally to 295.0 (143.0–527.0) µg/mL and 853.0 (286.0–1410.0) µg/mL after a single IV dose of 30 or 100 mg/kg, respectively (Fig. 3A). All subjects treated with motavizumab had detectable motavizumab concentrations in their nasal wash samples by study day 2, and all but 1 of these subjects had detectable motavizumab levels in nasal wash samples at study day 30. As expected, median concentrations of motavizumab in the upper respiratory tract were statistically significantly higher (all P < 0.05) in subjects treated with 100 mg/kg motavizumab than in subjects treated with 30 mg/kg motavizumab at all times after study day 0 (Fig. 3B). At study day 180, the proportion of subjects with antimotavizumab antibodies was approximately 32% in both motavizumab
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treatment groups, and by study day 360, 60% and 46% of subjects in the 30 and 100 mg/kg groups, respectively, had detectable antimotavizumab antibodies. The presence of antimotavizumab antibodies did not affect motavizumab clearance.
Safety The incidence rates of AEs and SAEs were similar for the 3 groups and are presented in Table 3. The majority of subjects in each treatment group (≥74%) had ≥1 AE. The treatment groups were not different with regard to the rate of related AEs, level 3 or level 4 AEs or SAEs. There were no treatment-related SAEs, AEs leading to discontinuation of study drug before completion of infusion or deaths reported during the study. Additionally, there was no evidence of antidrug antibody-related AEs.
DISCUSSION This study is the largest conducted to date evaluating the effect of treatment with an anti-RSV antibody on viral load and clinical outcomes in children hospitalized with RSV LRTI. © 2013 Lippincott Williams & Wilkins
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Motavizumab and RSV
A
B
FIGURE 3. Concentrations of motavizumab, median (range) after a single IV dose. (A) Serum; lower limit of quantitation = 1.56 µg/mL. (B) Upper respiratory tract; lower limit of quantitation = 20.0 ng/mL. Whereas 2 previous studies have shown a decrease in viral load in the respiratory tract of children who received treatment with an anti-RSV antibody,11,12 the current study showed that treatment with motavizumab at a higher dose than in previous studies had no appreciable effect on RSV viral load in the upper respiratory tract or on clinical outcomes. An earlier treatment study of IV palivizumab in 35 intubated children
Motavizumab Treatment of Infants Hospitalized With Respiratory Syncytial Virus Infection Does Not Decrease Viral Load or Severity of Illness Octavio Ramilo, MD,* Rosanna Lagos, MD,† Xavier Sáez-Llorens, MD,‡ JoAnn Suzich, PhD,§ C. Kathy Wang, PhD,§ Kathryn M. Jensen, MS,§ Brian S. Harris, MS,§ Genevieve A. Losonsky, MD,§ and M. Pamela Griffin, MD§ on behalf of the Motavizumab Study Group Background: This study was conducted to determine whether treatment with motavizumab, an anti-respiratory syncytial virus (RSV) monoclonal antibody, would decrease viral load and improve clinical outcomes in previously healthy term infants hospitalized with RSV lower respiratory tract infection. Methods: Infants hospitalized with lower respiratory tract infection and a positive RSV test performed locally were randomized to receive 1 intravenous dose of motavizumab (30 or 100 mg/kg) or placebo. Nasal wash samples were tested by real-time reverse transcriptase polymerase chain reaction at a central laboratory to determine viral load. Clinical data were collected during RSV hospitalization and at 12-month follow up. Results: Of 118 infants, 112 were confirmed RSV positive by real-time reverse transcriptase polymerase chain reaction. In each study group, median (range) RSV load (log10 copies/mL) decreased at a similar rate from baseline to study day 7 [motavizumab 30 mg/kg: 8.35 (2.5–9.5) to 5.03 (2.5–6.8); motavizumab 100 mg/kg: 8.22 (5.5–9.7) to 4.25 (2.5–8.0); placebo: 8.02 (6.7–9.8) to 5.17 (2.5–7.3)]. Median (range) duration of hospitalization was 3.05 (0.8–16.0), 2.99 (1.0–25.0) and 2.88 (0.8–11.7) days for the motavizumab 30 mg/kg, motavizumab 100 mg/kg and placebo groups, respectively. Six (8%) motavizumab and 0 placebo recipients were admitted to the intensive care unit and 4 required mechanical ventilation. The incidence of wheezing episodes during the 12-month follow up was comparable for all 3 groups. Conclusions: Motavizumab had no appreciable effect on RSV viral load measured in the upper respiratory tract of children hospitalized for RSV lower respiratory tract infection. No differences were observed for duration of hospitalization, severity of illness measures or wheezing episodes during 12-month follow up in children treated with motavizumab or placebo. Key Words: RSV, treatment, pediatric, infant, monoclonal antibody (Pediatr Infect Dis J 2014;33:703–709)
Accepted for publication December 5, 2013. From the *Nationwide Children’s Hospital, Ohio State University College of Medicine, Columbus, OH; †Centro Para Vacunas En Desarrollo-Chile, Santiago, Chile; ‡Hospital del Niño, Ciudad de Panamá, Panamá; and §MedImmune, Gaithersburg, MD. Editorial assistance with the development of this article was provided by John E. Fincke, PhD, and Gerard P. Johnson, PhD, of Complete Healthcare Communications, Inc. (Chadds Ford, PA), funded by MedImmune. This study was sponsored by MedImmune. O.R. has functioned as a member of the board for Quidel, was a consultant for Merck and AbbVie, received grants from Abbott Molecular, received payment for educational lectures and symposia for AbbVie and received reimbursement from MedImmune for travel/ accommodations/meeting expenses unrelated to the aforementioned activities. R.L. and X.S.L. have received research funding on their behalf from MedImmune. J.S., C.K.W., K.M.J., B.S.H. and M.P.G. are employees of MedImmune. G.A.L. was an employee of MedImmune at the time of the study and analysis. The authors have no other funding or conflicts of interest to disclose. ClinicalTrials.gov Identifier: NCT00421304 Address for correspondence: Octavio Ramilo, MD, Nationwide Children’s Hospital, Infectious Diseases ED 161, 700 Children’s Dr, Columbus, OH 43215. E-mail: [email protected]. Copyright © 2013 by Lippincott Williams & Wilkins ISSN: 0891-3668/14/3307-0703 DOI: 10.1097/INF.0000000000000240
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espiratory syncytial virus (RSV) is the leading cause of hospitalization in infants.1 In the United States alone, the average estimated annual number of RSV-associated hospitalizations is 126,000.2 In fact, in the infant population, RSV hospitalization rates are 6 times higher than those observed for influenza.3 In addition, RSV lower respiratory tract infection (LRTI) has been associated with an increased risk of subsequent recurrent wheezing.4–7 There are currently no effective vaccines to prevent RSV in children, and prophylaxis is provided only to those high risk infants who are born prematurely, those with chronic lung disease of prematurity or those with hemodynamically significant congenital heart disease. Treatment of infants who are hospitalized with RSV LRTI is generally supportive care. Ribavirin is the only licensed antiviral agent for RSV LRTI in hospitalized infants but has a number of limitations and is not used routinely.8 It is evident that improved modes of therapy are needed for children with serious RSV illness. There have been several treatment studies using antibodies directed against neutralizing epitopes of RSV including RSV immune globulin (RespiGam, MedImmune, Gaithersburg, MD),9 palivizumab (Synagis, MedImmune)10,11 and motavizumab (MEDI-524, MedImmune).12 Those studies demonstrated that treatment with anti-RSV antibodies was well tolerated, and there was no evidence of acute disease enhancement. In a treatment study using palivizumab, Malley et al11 showed that a 15 mg/kg dose of intravenous (IV) palivizumab significantly reduced RSV viral load in the lower, but not upper, respiratory tract of infants who required mechanical ventilation. While the study was not powered to assess clinical outcomes, a corresponding clinical improvement was not observed. A more recent pilot study of motavizumab by Lagos et al12 showed that at day 1 posttreatment, a 30 mg/kg dose of IV motavizumab significantly reduced RSV viral load in nasal wash samples of children hospitalized with RSV LRTI, and by day 7, significantly fewer motavizumab-treated patients had detectable viral RNA compared with placebo-treated patients. In that small study, there were no observed differences in disease severity. With limited findings from the previous studies, this larger study was designed to obtain additional information regarding RSV viral load reduction and clinical outcomes in infants treated with an anti-RSV monoclonal antibody using a higher dose than in previous studies. Specifically, the current study was undertaken in previously healthy term infants hospitalized with RSV LRTI to (1) assess the effect of treatment with motavizumab (30 or 100 mg/kg) on viral load in the upper respiratory tract and (2) evaluate the effect of treatment on disease severity and clinical outcomes during the acute hospitalization and for 12 months subsequent to hospitalization.
MATERIALS AND METHODS Study Design This was a phase 2, randomized, double-blind, p lacebo-controlled, multicenter study (ClinicalTrials.gov I dentifier: NCT00421304). The study was conducted at multiple sites in the
The Pediatric Infectious Disease Journal • Volume 33, Number 7, July 2014
www.pidj.com | 703
Ramilo et al
The Pediatric Infectious Disease Journal • Volume 33, Number 7, July 2014
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.
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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.13 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.14 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.14 Serum for antimotavizumab antibodies was collected on study days 0, 180 and 360 and measured using an electrochemiluminescent assay.14 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.15
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 ≥1:30.14 The Fisher’s exact test was used for comparisons among treatment groups for number of subjects with motavizumab in nasal wash samples.
RESULTS A total of 118 subjects were randomized at 18 sites in 5 countries and 113 subjects received study drug. One hundred and seven subjects completed through study day 90 and 98 subjects completed through study day 360 (Fig. 1). Similar rates of noncompletion were observed among subjects treated with motavizumab or placebo. Overall, demographics and clinical characteristics were similar across the 3 treatment groups (Table 1). © 2013 Lippincott Williams & Wilkins
The Pediatric Infectious Disease Journal • Volume 33, Number 7, July 2014
Motavizumab and RSV
Enrolled and Randomized N=118
Randomized to motavizumab 30 mg/kg n=39
Randomized to motavizumab 100 mg/kg n=39
Randomized to placebo n=40
Completed study through study day 90 n=37 (95%)
Completed study through study day 90 n=36 (92%)
Completed study through study day 90 n=34 (85%)
Completed study through study day 360 n=35 (90%)
Completed study through study day 360 n=31 (80%)
Completed study through study day 360 n=32 (80%)
Subjects not completing study through study day 360, n=4 Lost to follow-up, n=2 (5%) Withdrawal of consent, n=2 (5%) Other, n=0 (0%)
Subjects not completing study through study day 360, n=8 Lost to follow-up, n=5 (13%) Withdrawal of consent, n=2 (5%) Other, n=1 (3%)
Subjects not completing study through study day 360, n=8 Lost to follow-up, n=5 (13%) Withdrawal of consent, n=2 (5%) Other, n=1 (3%)
FIGURE 1. Disposition of subjects.
TABLE 1. Demographic and Clinical Characteristics at Study Entry* Motavizumab Characteristic Age at enrollment, median (range), mo Weight at enrollment, median (range), kg Boys, n (%) White, n (%) RDAI score,† n Median† (range)
30 mg/kg (n = 39)
100 mg/kg (n = 39)
Placebo (n = 40)
2.0 (0.4–11.2) 5.4 (3.2–10.6) 20 (51) 26 (67) 39 6 (0–17)
2.2 (0.3–11.3) 5.6 (2.1–9.3) 20 (51) 27 (69) 36 6 (0–13)
2.7 (0.5–10.3) 6.2 (3.1–10.0) 29 (73) 26 (65) 37 4 (0–15)
*Intent-to-treat population. †RSV evaluable population. RDAI, respiratory distress assessment instrument.
One hundred and twelve subjects had adequate baseline samples and tested positive for RSV A [63/112 (56%)] or RSV B [49/112 (44%)] by real-time RT-PCR. Median (range) RSV loads in the upper respiratory tract were similar for all 3 treatment groups at enrollment [8.35 (2.5–9.5), 8.22 (5.5–9.7) and 8.02 (6.7–9.8) in the motavizumab 30 mg/kg, motavizumab 100 mg/kg and placebo groups, respectively]. After treatment with motavizumab or placebo, viral loads decreased at a similar rate at all time points with no statistically significant differences (Fig. 2). By study day 7, median (range) viral loads had decreased to 5.03 (2.5–6.8), 4.25 (2.5–8.0) and 5.17 (2.5–7.3) in the motavizumab 30 mg/kg, motavizumab 100 mg/kg and placebo groups, respectively. Parameters for the severity of the acute RSV illness are shown in Table 2. Median (range) duration of hospitalization was 3.05 (0.8–16.0), 2.99 (1.0–25.0) and 2.88 (0.8–11.7) days for the motavizumab 30 mg/kg, motavizumab 100 mg/kg and placebo groups, respectively. At study entry, 53% (40/75) of the combined © 2013 Lippincott Williams & Wilkins
motavizumab recipients (30 and 100 mg/kg) and 41% (15/37) of placebo recipients required supplemental oxygen. During the hospitalization, 80% (59/74) of the combined motavizumab recipients required supplemental oxygen for a median (range) of 3.0 (1.0–21.0) days compared with 65% (24/37) of placebo recipients for a median (range) of 3.0 (1.0–8.0) days. Admission to the ICU for 6 (8%) motavizumab-treated subjects, ranging from 1.1 to 4.2 months of age, occurred on the day of hospital admission to 2 days following admission. Of the 6 motavizumab recipients who were in the ICU, 4 required mechanical ventilation for a median (range) duration of 6.7 (3.0–8.4) days. None of the subjects in the placebo group required ICU admission or mechanical ventilation. However, the numerical differences between treatment groups that were noted for admission to the ICU and mechanical ventilation were not statistically significant. Excluding wheezing events that occurred during the RSV hospitalization, the percentage of subjects who had no wheezing www.pidj.com | 705
The Pediatric Infectious Disease Journal • Volume 33, Number 7, July 2014
Ramilo et al
10
Motavizumab 30 mg/kg
RSV Load, log10 copies/mL
Motavizumab 100 mg/kg Placebo
8
6
4
2
0 N= 39 36 37 Day 0
38 36 37
38 36 37
38 32 34
37 36 35
37 34 35
37 34 33
35 32 32
Day 1
Day 2
Day 3
Day 7
Day 30
Day 90
Day 180
FIGURE 2. RSV load (log10 copies/mL), median (range), in the upper respiratory tract as measured by quantitative real-time RT-PCR. TABLE 2. Severity of RSV Illness During Hospitalization* Motavizumab
Hospitalization information available,† n/N (%) Duration of hospitalization,‡ d Supplemental oxygen use, n/N (%) Duration of supplemental oxygen use,§ d Admission to ICU, n/N (%) Duration of ICU stay,§ d Mechanical ventilation, n/N (%) Duration of mechanical ventilation,‡ d
30 mg/kg (n = 39)
100 mg/kg (n = 36)
38/39 (97) 3.1 (0.8–16.0) 30/38 (79) 3.0 (1.0–12.0) 3/38 (8) 10.0 (2.0–10.0) 2/38 (5) 7.8 (7.2–8.4)
36/36 (100) 3.0 (1.0–25.0) 29/36 (81) 3.0 (1.0–21.0) 3/36 (8) 5.0 (1.0–9.0) 2/36 (6) 4.6 (3.0–6.3)
Placebo (n = 37) 37/37 (100) 2.9 (0.8–11.7) 24/37 (65) 3.0 (1.0–8.0) 0/37 (0) N/A 0/37 (0) N/A
*RSV evaluable population: subjects who were positive for RSV at study day 0 by real-time RT-PCR. †Hospitalization information not available for subjects randomized but not dosed because of withdrawal of consent. ‡Duration is calculated from randomization date/time to discharge date/time and presented as median (range). §Duration is calculated from randomization date to discharge date and presented as median (range). N/A, not applicable (no subjects fit this category).
events during the 12-month follow up was similar for all 3 groups (51%, 56% and 54% for the 30 mg/kg motavizumab, 100 mg/kg motavizumab and placebo groups, respectively). Likewise, the incidence of ≥1 (49%, 44% and 46%) and ≥3 (23%, 14% and 16%) medically attended wheezing episodes was comparable for the 30 mg/kg motavizumab, 100 mg/kg motavizumab and placebo groups, respectively. Median (range) peak serum concentrations of motavizumab increased dose proportionally to 295.0 (143.0–527.0) µg/mL and 853.0 (286.0–1410.0) µg/mL after a single IV dose of 30 or 100 mg/kg, respectively (Fig. 3A). All subjects treated with motavizumab had detectable motavizumab concentrations in their nasal wash samples by study day 2, and all but 1 of these subjects had detectable motavizumab levels in nasal wash samples at study day 30. As expected, median concentrations of motavizumab in the upper respiratory tract were statistically significantly higher (all P < 0.05) in subjects treated with 100 mg/kg motavizumab than in subjects treated with 30 mg/kg motavizumab at all times after study day 0 (Fig. 3B). At study day 180, the proportion of subjects with antimotavizumab antibodies was approximately 32% in both motavizumab
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treatment groups, and by study day 360, 60% and 46% of subjects in the 30 and 100 mg/kg groups, respectively, had detectable antimotavizumab antibodies. The presence of antimotavizumab antibodies did not affect motavizumab clearance.
Safety The incidence rates of AEs and SAEs were similar for the 3 groups and are presented in Table 3. The majority of subjects in each treatment group (≥74%) had ≥1 AE. The treatment groups were not different with regard to the rate of related AEs, level 3 or level 4 AEs or SAEs. There were no treatment-related SAEs, AEs leading to discontinuation of study drug before completion of infusion or deaths reported during the study. Additionally, there was no evidence of antidrug antibody-related AEs.
DISCUSSION This study is the largest conducted to date evaluating the effect of treatment with an anti-RSV antibody on viral load and clinical outcomes in children hospitalized with RSV LRTI. © 2013 Lippincott Williams & Wilkins
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Motavizumab and RSV
A
B
FIGURE 3. Concentrations of motavizumab, median (range) after a single IV dose. (A) Serum; lower limit of quantitation = 1.56 µg/mL. (B) Upper respiratory tract; lower limit of quantitation = 20.0 ng/mL. Whereas 2 previous studies have shown a decrease in viral load in the respiratory tract of children who received treatment with an anti-RSV antibody,11,12 the current study showed that treatment with motavizumab at a higher dose than in previous studies had no appreciable effect on RSV viral load in the upper respiratory tract or on clinical outcomes. An earlier treatment study of IV palivizumab in 35 intubated children
