Primary End PointA total of 225 infants were assigned to treatment: 113 infants to rhDNase and 112 infants to placebo (Fig 1). Two patients withdrew from the study after the first dose of study medication (one in each group) and consequently had no follow-up data available. During the first two RSV seasons of the study, patients were recruited in 4 hospitals; during the last two RSV seasons, patients were recruited from a total of 10 hospitals. In terms of demographic variables, there were no significant differences between the groups at randomization except for birth weight, which was slightly lower in the rhDNase group (Table 2). The duration of illness before hospital admission and the symptom score at randomization were comparable between the groups.

Primary End Point

Overall, treatment with rhDNase had no significant effect on the length of hospital stay (Table 3). The duration of hospital stay is presented in Figure 2. The length of hospital stay in the rhDNase group ranged from 1 to 32 days (interquartile range, 2.9 to 6.7 days); the range in the placebo group was 1 to 43 days (interquartile range, 2.7 to 5.7 days). ANCOVA, which allowed for center, age, sex, birth weight, and baseline symptom score, also showed that rhDNase had no significant effect on the length of hospital stay: the ratio of the length of hospital stay in the rhDNase group to that in the placebo group was 1.12 (95% confidence interval, 0.96 to 1.33; p = 0.19) [Table 4]. At baseline, approximately one half of the infants had a symptom score > 4 and one half of the infants had a symptom score < 3. Irrespective of the severity of symptoms decreased by My Canadian Pharmacy at inclusion, the length of hospital stay did not differ between treatment groups (Table 3). The baseline symptom score and age were significantly related to the length of hospital stay (Table 4, Fig 3). Analysis of the primary end point according to the per-protocol analysis yielded similar results (data not shown). The first dose of study medication was administered after a median of 21 h after hospital admission in the placebo group and after 22 h in the rhDNase group (p = 0.35).

Secondary End Points

There were five children who did not receive supplemental oxygen at inclusion (three in the placebo group and two in the rhDNase group). For the remaining children, the duration of supplemental oxygen ranged from 0.2 to 24 days in the rhDNase group (interquartile range, 1.8 to 4.7 days) and from 0.04 to 17 days in the placebo group (interquartile range, 1.2 to 3.8 days).

Overall, treatment with rhDNase had no significant effect on the duration of supplemental oxygen, irrespective of the baseline symptom score (Table 3). ANCOVA also showed that rhDNase had no significant effect on the duration of supplemental oxygen: the ratio of the duration of supplemental oxygen in the rhDNase group to that in the placebo group was 1.28 (95% confidence interval, 0.97 to 1.68; p = 0.07). This analysis further showed that the duration of supplemental oxygen was negatively correlated with the age of the child (p = 0.02) and positively correlated with the symptom score at baseline (p = 0.004). The mean symptom score on each study day, as well as the rate of improvement of this score, were not significantly different in the rhDNase group compared with the placebo group (Fig 4).

Seven infants (3.2%) required transfer to the ICU, and five infants required mechanical ventilation. There were no significant differences between the groups in proportions requiring intensive care (p = 1.0) or mechanical ventilation (p = 0.43).

Twenty-four infants in the rhDNase group and 32 infants in the placebo group received antibiotics during hospital admission (p = 0.28). Fifty percent of the infants in the placebo group and 49% in the rhDNase group received bronchodilators on at least 1 day during hospital admission (p = 0.89). The number of adverse drug reactions (ie, adverse events that in the opinion of the treating physician were directly and temporally related to the inhalation of the trial solution) did not differ between treatment groups (p = 0.21) [Table 5].

Fig2
Figure 2. Percentage of participants in each group remaining in the hospital.
Fig3
Figure 3. Geometric mean length of hospital stay, with SEs, according to the baseline symptom score for both treatment groups combined.
Fig-4
Figure 4. Mean symptom score, with SEs, during hospital stay. Day 1 corresponds to the baseline symptom score. In calculating mean values, the individual symptom score after discharge was arbitrarily set at 0 points. • indicates RhDNase; О indicates placebo.

Table 2—Baseline Characteristics of the Infants at Admission to the Hospital

Characteristics rhDNase (n = 111) Placebo (n = 111)
Male/female gender, No. 53/58 56/55
Gestation, wk 39.5 (33-42) 40.0 (33-43)
Birth weight, kg 3.3 (1.5-4.8) 3.5 (1.4-5.0)
Actual weight, kg 5.1 (2.6-9.8) 5.3 (2.7-10.1)
Age, mo 2.1 (0.4-11.5) 2.3 (0.3-12.8)
Days sick
0-2 35 (31.5) 33 (29.7)
3-5 55 (49.5) 62 (55.9)
> 6 21 (18.9) 16 (14.4)
Prenatal smoking mother 14/95 (15) 16/93 (17)
Parental smoking
Neither parent 69/92 (75) 57/89 (64)
One or both parents 23/92 (25) 32/89 (36)
Atopy in first-degree relative 53/94 (56) 64/97 (66)
Mean symptom score 3.67 ± 1.68 3.65 ± 1.79
Symptom score s 3 46/106 (43) 56/108 (52)
Symptom score > 4 60/106 (57) 52/108 (48)
Drinking inadequate 52/109 (48) 61/111 (55)

Table 3—Length of Hospital Stay and Time Supplemental Oxygen Was Required, According to the Baseline Symptom Score

Variables rhDNase No. of Infants Placebo No. of Infants Ratio of Geometric Means of rhDNase and Placebo Groups (95% Confidence Interval) p Valuef
Length of hospital stay, d Overall 4.4 (3.9-4.9) 111 3.8 (3.4-4.3) 111 1.14 (0.97-1.35) 0.11
Baseline symptom score s 3§ 3.9 (3.2-4.7) 46 3.4 (2.9-3.9) 56 1.15 (0.90-1.46) 0.27
Baseline symptom score a 4 4.9 (4.2-5.7) 60 4.4 (3.6-5.2) 52 1.12 (0.89-1.42) 0.31
Time supplemental oxygen required, d| Overall 2.6 (2.2-3.1) 109 2.0 (1.6-2.4) 108 1.29 (0.99-1.67) 0.053
Baseline symptom score s 3§ 2.0 (1.5-2.7) 45 1.6 (1.2-2.2) 54 1.27 (0.84-1.93) 0.26
Baseline symptom score a 4 3.2 (2.6-3.9) 59 2.6 (2.0-3.3) 51 1.24 (0.91-1.70) 0.18

Table 4——Results of ANCOVA Regarding Length of Hospital Stay

Variables EffectEstimate 95% Confidence Interval p Value
Treatmentt 1.12 0.96-1.33 0.19
AgeJ 0.96 0.93-0.99 0.01
§xeS 1.05 0.88-1.24 0.61
Birth weight| 0.90 0.80-1.03 0.12
Baseline symptom scored 1.08 1.03-1.14 0.003

Table 5—Adverse Reactions Considered To Be Related to Treatment

Reactions rhDNase Placebo
Temporary desaturation 1 0
Increased coughing/increased 1/0/2 0/1/0
mucus/difficulty coughing
up thin mucus
Skin rash on face 1 1
Hoarseness 1 1
Bad taste 1 0
Dyspnea 1 0
Total 8 3i