Comparison of hypertonic saline and alternate-day or daily recombinant human deoxyribonuclease in children with cystic fibrosis: a randomised trial

doi:10.1016/S0140-6736(01)06412-1

The Lancet

Volume 358, Issue 9290, 20 October 2001, Pages 1316-1321

https://doi.org/10.1016/S0140-6736(01)06412-1 Get rights and content

Summary

Background

Daily recombinant human deoxyribonuclease (rhDNase) is an established but expensive treatment in cystic fibrosis. Alternate-day treatment, if equally effective, would reduce the drug cost. Hypertonic saline improved lung function to the same degree as rhDNase in short-term studies. We compared the effectiveness of daily rhDNase, hypertonic saline, and alternate-day rhDNase in children with cystic fibrosis.

Methods

In an open cross-over trial, 48 children were allocated in random order to 12 weeks of once-daily rhDNase (2·5 mg), alternate-day rhDNase (2·5 mg), and twice-daily 5 mL 7% hypertonic saline. The primary outcome was forced expiratory volume in 1 s (FEV₁). Secondary outcomes were forced vital capacity, number of pulmonary exacerbations, weight gain, quality of life, exercise tolerance, and the total costs of hospital and community care.

Findings

Mean FEV₁ increased by 16% (SD 25%), 14% (22%), and 3% (21%) with daily rhDNase, alternate-day rhDNase, and hypertonic saline, respectively. There was no difference between daily and alternate-day rhDNase (2% [95% CI -4 to 9], p=0·55). However, daily rhDNase showed a significantly greater increase in FEV₁ than hypertonic saline (8% [2 to 14], p=0·01). The average difference in 12- week cost between daily and alternate-day rhDNase was £513 (95% CI -546 to 1510) and that between daily rhDNase and hypertonic saline was £1409 (440 to 2318). None of the secondary clinical outcomes showed significant differences between treatments.

Interpretation

Hypertonic saline, delivered by jet nebuliser, is not as effective as daily rhDNase, although there is variation in individual response. There is no evidence of a difference between daily and alternate-day rhDNase

Introduction

Cystic fibrosis is the most common lethal recessive disorder of white populations. Most of the morbidity and mortality is from pulmonary disease, which is characterised by bronchial and bronchiolar obstruction by thick tenacious secretions that are difficult to clear.¹ Retention of abnormal airway secretions promotes recurrent respiratory infections, cycles of inflammation, and progressive lung damage.

DNA derived from the degeneration of neutrophils is a major contributor to the viscosity of airway secretions and is present in high concentration in the sputum of patients with cystic fibrosis.² The human enzyme deoxyribonuclease I was cloned and sequenced in 1990. Clinical trials of recombinant human deoxyribonuclease (rhDNase) have shown improvements in lung function and a reduction in protocol-defined infective exacerbations.3, 5 The enzyme is believed to work by cleaving extracellular DNA in airway secretions, thus aiding expectoration of sputum.⁶

Daily rhDNase is widely used in the treatment of cystic fibrosis, but there are unresolved issues. Although many patients improve on treatment, there is wide variation in individual response.⁷ The long-term benefit of rhDNase remains uncertain, and its effect on airway inflammation is still not clear.⁸ Moreover, this therapy is expensive, and the long-term cost-effectiveness has not been established. The current dose recommended in children, 2·5 mg once daily, is as effective as two daily doses of 2·5 mg.⁵ There have been no studies on the use of alternate-day rhDNase, which if equally effective would halve the drug cost and treatment time.

Nebulised hypertonic saline is a potential alternative mucolytic therapy for cystic fibrosis. Hypertonic saline has been used for decades as an agent to aid airway clearance and sputum induction in various respiratory disorders. In short-term studies in cystic fibrosis, hypertonic saline seemed to have beneficial effects on lung function, mucociliary clearance, and sputum expectoration,9, 12 similar to those of rhDNase. It is much cheaper than rhDNase, but there have been no medium-term or long-term comparisons between hypertonic saline and rhDNase.

We aimed to test the hypothesis that hypertonic saline and alternate-day rhDNase are as effective as daily rhDNase in improving respiratory function in children with cystic fibrosis.

Section snippets

Study population

Children with cystic fibrosis, previously diagnosed on standard criteria, were enrolled from two institutions (Great Ormond Street Hospital for Children NHS Trust and the Royal Brompton and Harefield NHS Trust, London, UK). Inclusion criteria were age between 5 and 18 years; ability to carry out spirometry; and either current treatment with rhDNase or a forced expiratory volume in 1 s (FEV₁) of less than 70% of predicted.¹³ Exclusion criteria were inability to take the trial medication; known

Results

48 children were randomised, eight to each of the six possible treatment orders. One 14-year-old girl withdrew from the study almost immediately after randomisation without starting the first treatment, owing to what became a prolonged illness. Table 1 gives the characteristics of the remaining 47 children as observed at the baseline assessment. Eight children were unable to complete all three treatment periods (figure 1). Four patients had severe declines in their pulmonary status and required

Discussion

This randomised trial compared the effects of hypertonic saline and rhDNase in cystic fibrosis patients over 12 weeks. This duration was used because the response to rhDNase at 12 weeks is strongly predictive of response at 1 year.⁷ We found that treatment with daily rhDNase results in a significantly greater increase in FEV₁ than hypertonic saline over 12 weeks and that daily and alternate-day rhDNase result in similar increases in FEV₁. The mean difference in cost for 12 weeks' treatment was

References (29)

SC FitzSimmons
The changing epidemiology of cystic fibrosis
J Pediatr
(1993)
C Ranasinha et al.
Efficacy and safety of short-term administration of aerosolised recombinant human DNase 1 in adults with stable stage cystic fibrosis
Lancet
(1993)
DM Geddes et al.
Where we are now with rhDNase?
Lancet
(1999)
DM Orenstein et al.
The quality of well-being in cystic fibrosis
Chest
(1989)
G Smith
A patient's view of cystic fibrosis
J Adolesc Health Care
(1986)
JJ Smith et al.
Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid
Cell
(1996)
WS Chernick et al.
Composition of tracheobronchial secretions in cystic fibrosis of the pancreas and bronchiectasis
Pediatrics
(1959)
BW Ramsey et al.
Efficacy and safety of short-term administration of aerosolized recombinant human deoxyribonuclease in patients with cystic fibrosis
Am Rev Respir Dis
(1993)
H Fuchs et al.
Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis
N Engl J Med
(1994)
S Shak et al.
Recombinant human DNase I reduces the viscosity of cystic fibrosis sputum
Proc Natl Acad Sci USA
(1990)

J Davies et al.

Retrospective review of the effects of rhDNase in children with cystic fibrosis

Pediatr Pulmonol

(1997)

M Robinson et al.

Effect of hypertonic saline, amiloride, and cough on mucociliary clearance in patients with cystic fibrosis

Am J Respir Crit Care Med

(1996)

M Robinson et al.

Effect of increasing doses of hypertonic saline on mucociliary clearance in patients with cystic fibrosis

Thorax

(1997)

J Riedler et al.

Inhaled hypertonic saline increases sputum expectoration in cystic fibrosis

J Paediatr Child Health

(1996)

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Introduction of novel therapies for cystic fibrosis (CF) raises the question of whether traditional treatments can be withdrawn. Nebulized hypertonic saline (HS) potentially could be discontinued in patients receiving dornase alfa (DA).
In the era before modulators, did people with CF who are F508del homozygous (CF_F508del) and who received DA and HS have better preserved lung function than those treated with DA only?
Retrospective analysis of the Cystic Fibrosis Foundation Patient Registry data (2006-2014). Among 13,406 CF_F508del with data for at least 2 consecutive years, 1,241 CF_F508del had spirometry results and were treated with DA for 1 to 5 years without DA or HS during the preceding (baseline) year. Absolute FEV₁ % predicted change while receiving DA and HS, relative to treatment with DA only, was the main outcome. A marginal structural model was applied to assess the effect of 1 to 5 years of HS treatment while controlling for time-dependent confounding.
Of 1,241 CF_F508del, 619 patients (median baseline age, 14.6 years; interquartile range, 6-53 years) received DA only and 622 patients (median baseline age, 14.55 years; interquartile range, 6-48.1 years) were treated with DA and HS for 1 to 5 years. After 1 year, patients receiving DA and HS showed FEV₁ % predicted that averaged 6.60% lower than that in patients treated with DA only (95% CI, –8.54% to –4.66%; P < .001). Lower lung function in the former relative to the latter persisted throughout follow-up, highlighting confounding by indication. After accounting for baseline age, sex, race, DA use duration, baseline and previous year’s FEV₁ % predicted, and time-varying clinical characteristics, patients treated with DA and HS for 1 to 5 years were similar to those treated with DA only regarding FEV₁ % predicted (year 1: mean FEV₁ % predicted change, +0.53% [95% CI, –0.66% to +1.71%; P = .38]; year 5: mean FEV₁ % predicted change, –1.82% [95% CI, –4.01% to +0.36%; P = .10]).
In the era before modulators, CF_F508del showed no significant difference in lung function when nebulized HS was added to DA for 1 to 5 years.
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ArticlesComparison of hypertonic saline and alternate-day or daily recombinant human deoxyribonuclease in children with cystic fibrosis: a randomised trial

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Study population

Results

Discussion

J Pediatr

Lancet

Lancet

Chest

J Adolesc Health Care

Cell

Composition of tracheobronchial secretions in cystic fibrosis of the pancreas and bronchiectasis

Pediatrics

Efficacy and safety of short-term administration of aerosolized recombinant human deoxyribonuclease in patients with cystic fibrosis

Am Rev Respir Dis

Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis

N Engl J Med

Recombinant human DNase I reduces the viscosity of cystic fibrosis sputum

Proc Natl Acad Sci USA