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. 2021 Nov 16;2021(11):CD013757. doi: 10.1002/14651858.CD013757.pub2

Feltes 2003.

Study characteristics
Methods Study design: randomised, double‐blind, placebo‐controlled trial.
Study dates: during 4 RSV seasons, 1998 until 2002. Randomisation from 1 November until 31 December each year between 1998 and 2001. 
Setting: multicentre, multinational, outpatient
Country: the study was conducted at 76 centres in the United States (47), Canada (6), Sweden (3), Germany (4), Poland (6), France (4) and the United Kingdom (6).
Participants Inclusion criteria:

  • Children ≤ 24 months old at the time of randomisation with documented haemodynamically significant CHD determined by the investigator and had unoperated or partially corrected CHD


Exclusion criteria:

  • Children with unstable cardiac or respiratory status, including cardiac defects so severe that survival was not expected or for which cardiac transplantation was planned or anticipated

  • Hospitalised children, unless discharge was anticipated within 21 days

  • Children with anticipated cardiac surgery within 2 weeks of randomisation

  • Children requiring mechanical ventilation, extracorporeal membrane oxygenation, continuous positive airway pressure, or other mechanical respiratory or cardiac support

  • Children with associated non‐cardiac anomalies or end‐organ dysfunction resulting in anticipated survival of < 6 months or unstable abnormalities of end‐organ function

  • Known HIV infection

  • Acute RSV or other acute infection or illness

  • Previous receipt of palivizumab or other monoclonal antibody

  • Receipt of investigational agents within the previous 3 months (other than investigational agents commonly used during cardiac surgery or the immediate postoperative period, i.e. nitric oxide)

  • Current participation in other investigational protocols of drugs or biological agents

  • Receipt of intravenous immune globulin (IGIV), including RSV‐IGIV (RespiGam, MedImmune, Inc, Gaithersburg, MD, USA), within 3 months before random assignment or anticipated use of IGIV, RSV‐IGIV, or open‐label palivizumab during the study period


Sample size: 1287 participants
Group 1 (n = 639): palivizumab
Age (mean ± SE): 6.8 ± 0.2 months
Sex n (%): male: 349 (54.6), female: 290 (45.4)
Race/ethnicity, n (%): 

  • White: 453 (70.9)

  • Hispanic: 77 (12.1)

  • Black: 52 (8.1)

  • Other: 57 (8.9)


Multiple birth, n (%): 27 (4.2)
Weight at entry (mean ± SE): 6.1 ± 0.1 kg
Gestational age (mean ± SE): 38.5 ± 0.1 weeks
RSV risk factors:

  • Number of people in home (mean ± SE): 4.4 ± 0.1

  • RSV neutralising antibody titre ≥ 1:200 at baseline, n (%): 170 (31.4)

  • Child in daycare, n (%): 76 (11.9)

  • Other children in daycare, n (%): 100 (15.6)

  • Smoker in household, n (%): 211 (33.0)

  • Family history of asthma, n (%): 172 (27.7)


Characteristics of CHD at study entry: 

  • Cyanotic stratum, n (%): 339 (53.1)

  • Previous cardiac surgery or interventional catheterisation, n (%): 396 (62.0)

  • Hypercyanotic episode, n (%): 73 (11.4)

  • Receiving cardiac medications, n (%): 484 (75.7)

  • Congestive heart failure, n (%): 401 (62.8)

  • Pulmonary hypertension, n (%): 152 (23.8)

  • Increased pulmonary blood flow, n (%): 237 (37.1)

  • Children with cyanotic lesions, single ventricle including hypoplastic left or right heart and tetralogy of fallot, n (%): 140 (21.9)

  • Children with acyanotic lesions, ventricular defect and atrioventricular defect, n (%): 115 (18.0)


Group 2 (n = 648): placebo
Age (mean ± SE): 6.5 ± 0.2 months
Sex n (%): male: 344 (53.1), female: 304 (46.9)
Race/ethnicity, n (%): 

  • White: 459 (70.8)

  • Hispanic: 66 (10.2)

  • Black: 61 (9.4)

  • Other: 62 (9.6)


Multiple births, n (%): 23 (3.5)
Weight at entry (mean ± SE): 6.0 ± 0.1 kg
Gestational age (mean ± SE): 38.5 ± 0.1 weeks
RSV risk factors:

  • Number of people in home (mean ± SE): 4.4 ± 0.1

  • RSV neutralising antibody titre ≥ 1:200 at baseline, n (%): 173 (30.5)

  • Child in daycare, n (%):  69 (10.6)

  • Other children in daycare, n (%):  115 (17.7)

  • Smoker in household, n (%): 223 (34.4)

  • Family history of asthma, n (%): 191 (29.7)


Characteristics of CHD at study entry: 

  • Cyanotic stratum, n (%): 343 (52.9)

  • Previous cardiac surgery or interventional catheterisation, n (%): 391 (60.3)

  • Hypercyanotic episode, n (%): 84 (13.0)

  • Receiving cardiac medications, n (%): 491 (75.8)

  • Congestive heart failure, n (%): 428 (66.0)

  • Pulmonary hypertension, n (%): 164 (25.3)

  • Increased pulmonary blood flow, n (%): 253 (39.0)

  • Children with cyanotic lesions, single ventricle including hypoplastic left or right heart and tetralogy of fallot, n (%): 74 (11.4)

  • Children with acyanotic lesions, ventricular defect and atrioventricular defect, n (%): 47 (7.2)
Interventions Group 1 (n = 639): palivizumab 15 mg/kg, intramuscular injection every 30 days for a total of 5 doses.
Group 2 (n = 648): placebo (same formulation as palivizumab without antibody and with 0.02% Tween‐80 added), intramuscular injection every 30 days for a total of 5 doses.
Co‐interventions: palivizumab and placebo were supplied as lyophillised product in coded vials that were reconstituted by the pharmacist with sterile water for injection (final concentration of palivizumab is 100 mg/mL) and dispensed in a syringe that did not identify the contents.
Outcomes Hospitalisation due to respiratory‐related illness
How measured: number of children with cardiorespiratory hospitalisation, n (%)
Time points measured: throughout the study
Time points reported: throughout the study
Group 1: 321 (50.2)
Group 2: 359 (55.4)
Mortality
How measured: number of deaths (associated with RSV), n. Total number of deaths, n (%)
Time points measured: throughout the study
Time points reported: throughout the study
Number of deaths (associated with RSV), n:
Group 1: 2
Group 2: 4
Total number of deaths, n (%).
Group 1: 21 (3.3)
Group 2: 27 (4.2)
( P = 0.463)
Adverse events
How measured: reported as total number of adverse events, total number of children (n) with adverse event (%), total number of children (n) with related adverse event, total number of children (n) with serious adverse event (%) and total number of children (n) with related serious event (%). Treatment groups were compared for adverse events (COSTART coded terms) by evaluating the number of children in each group with at least 1 event by body system and the distribution of severity and relatedness of these events. Any adverse change from a child’s medical condition at entry was reported as an adverse event, graded for severity, and assessed by the blinded investigator as to potential relation to study drug. Serious adverse events were those that resulted in death; were life‐threatening; resulted in hospitalisation or prolonged hospitalisation; resulted in significant disability; or were another important medical event that required intervention to prevent 1 of the above outcomes.
Time points measured: children were followed for 150 days from random assignment (30 days after the last scheduled study injection) for the occurrence of adverse events.
Time points reported: children were followed for 150 days from random assignment (30 days after the last scheduled study injection) for the occurrence of adverse events.
Total number of adverse events, n: 
Group 1: 4169
Group 2: 4518
Total number of children with adverse event, n (%):
Group 1: 611 (95.6)
Group 2: 625 (96.5)
(P = 0.477)
Total number of children with adverse event coding to cardiovascular system, n (%): 
Group 1: 286 (44.8)
Group 2: 315 (48.6)
(P = 0.180)
Total number of children with adverse event coding to respiratory system, n (%): 
Group 1: 525 (82.2)
Group 2: 547 (84.4)
(P = 0.296)
Total number of children with adverse event requiring medical intervention, n (%): 
Group 1: 588 (92.0)
Group 2: 605 (93.4)
(P = 0.392) 
Total number of children with related adverse event, n (%):
Group 1: 46 (7.2)
Group 2: 45 (6.9)
(P = 0.914)
Total number of children with related adverse event resulting in permanent discontinuation, n (%):
Group 1: 0 (0.0)
Group 2: 0 (0.0)
Total number of children with serious adverse event, n (%): 
Group 1: 354 (55.4)
Group 2: 409 (63.1)
(P = 0.005)
Total number of children with related serious event, n (%):
Group 1: 0 (0.0)
Group 2: 3 (0.5)
(P = 0.249)
Subgroups:
Incidence of serious adverse of events, (%):
Group 1:
Cyanotic stratum: 59.9
“Other” stratum: 50.3
Group 2: 
Cyanotic stratum: 67.1
“Other” stratum: 58.7
Days of supplemental oxygen
How measured: total RSV hospital days with increased oxygen requirement, n (total days per 100 children). Also reported as relative reduction (%). 
Time points measured: throughout the study.
Time points reported: throughout the study.
Group 1: 178 (27.9)
Group 2: 658 (101.5)
Reduction: 73 (P = 0.014)
Intensive care unit length of stay
How measured: total days of RSV‐associated intensive care, n (total days per 100 children). Also reported as relative reduction (%).  
Time points measured: throughout the study.
Time points reported: throughout the study.
Group 1: 101 (15.9)
Group 2: 461 (71.2)
Reduction: 78
(P = 0.080)
Mechanical ventilation days
How measured: total days of RSV‐associated mechanical ventilation, n (total days per 100 children). Also reported as relative reduction (%). 
Time points measured: throughout the study
Time points reported: throughout the study
Group 1: 42 (6.5) 
Group 2: 354 (54.7)
Reduction: 41
(P = 0.224)
Hospitalisation due to RSV infection
How measured: incidence of RSV hospitalisation, n (%). Also reported as total days of RSV hospitalisation, D (total days per 100 children). In addition, reported as relative reduction of RSV hospitalisation rate, % and relative reduction of total days of RSV hospitalisation, %. 
Time points measured: throughout the study
Time points reported: throughout the study
Group 1: 34 (5.3), D: 367 (57.4)
Group 2: 63 (9.7), D: 836 (129.0)
Reduction (rate): 45
Reduction (days): 56
(P = 0.003)
Notes Overall, 93.0% of children in the palivizumab group and 91.8% in the placebo group received all 5 planned injections; 95.6% in the palivizumab group and 95.5% in the placebo group completed the study. No child had study drug discontinued for a related adverse event. A total of 48 children died during the study: 21 (3.3%) in the palivizumab group and 27 (4.2%) in the placebo group. No deaths were attributed to study drug. Deaths associated with RSV infection occurred in 2 children in the palivizumab group and 4 children in the placebo group.