A Prospective Open Randomized Clinical Trial of Non-invasive Ventilation Versus Standard Therapy for Children Hospitalized With an Acute Exacerbation of Asthma.
Phase: NA
Conditions: Asthma Acute, Asthma in Children
Sponsor: University of British Columbia

 
 
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Study Protocol and  
Statistical Analysis Plan 
 
 
 
 
 
 
 
A Prospective Open Randomized Clinical Trial of Non-
invasive Ventilation Versus Standard Therapy for Children 
Hospitalized With an Acute Exacerbation of Asthma 
 
NCT03296579  
Protocol ID: H17-02008 
 
 
 
September 27, 2017 

 
 
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A prospective open randomized clinical trial of non-invasive ventilation versus 
standard therapy for children hospitalized with an acute exacerbation of asthma. 
 
 
 
 
 
 
PRINCIPAL INVESTIGATORS : 
 
Dr Mike Seear,  
Clinical Professor, 
Head, Division of Respirology, 
BC’s Children’s Hospital, 
UBC Department of Pediatrics, 
 
Dr Joseph Mathew, 
Assistant Professor, 
Department of Pediatrics, 
Post-Graduate Institute of Medical Research,  
Chandigarh 
 
 
 
CO INVESTIGATORS: 
 
Dr Mandeep Wallia. 
DR Jayshree Muralidharan. 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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RESEARCH PROTOCOL 
 
Hypothesis and aims. 
 
Acute asthma produces greatly increased work of breathing and increased oxygen 
requirement secondary to bronchial narrowing and airway obstruction by inflammatory 
secretions. There is growing evidence that non-invasive ventilation can reverse these 
processes more efficiently than conventional asthma therapy. Surprisingly, there have not 
yet been any large scale prospective controlled studies to investigate this hypothesis, 
(either in adults or children).  Consequently, the aim of this study is to determine if the use 
of non-invasive positive airway pressure, for children admitted to hospital with an acute 
exacerbation of asthma, reduces their work of breathing, need for adjunctive medications, 
and shortens the length of hospital stay, compared to current standard therapy.  
 
Study background. 
 
Asthma is a common, chronic disorder of reversible airway obstruction caused by a triad 
of airway inflammation, bronchial smooth muscle contraction and increased airway 
secretions [1]. While there have been huge advances in the control of chronic childhood 
asthma, acute exacerbations remain common, particularly during the viral season. Acute 
asthma has a low mortality rate but the condition is so common that it imposes a very 
high health care burden. Studies by our own group [2] and others [3] have shown that 
asthma exacerbations remain a major cause of emergency room visits and a leading 
cause of hospitalization in children. The patient burden at Children’s Hospital in 
Vancouver, is similar to published studies showing that asthma accounts for 3% to 7% of 
all pediatric ED visits with a mortality rate of 2 to 3 per million children in North America 
[3]. Any therapy that could improve the outcome in acute asthma would have significant 
medical and economic benefits. 
 
There are two types of non invasive ventilation (NIV).[4] The first is continuous positive 
airway pressure (CPAP) where the patient breathes against a constant pressure delivered 
by face mask. The second is BiPAP – here the patient’s breathing is assisted by cycling 
between high and low pressures at a pre-set rate. It is analogous to traditional ventilation 
but without the need for intubation. After its introduction around 1990, NIV rapidly gained 
acceptance in the treatment of a wide range of respiratory conditions[5]. Machines are 
relatively cheap and the non-invasive pressure delivery minimizes side effects compared 
to traditional ventilators. NIV is now the commonest form of ventilatory support used in 
intensive care units.  
 
The standard therapy for acute asthma is based on oral or intravenous corticosteroids to 
control the acute inflammation plus a range of bronchodilators to reverse airway 
narrowing – the commonest of these is the beta agonist salbutamol. Most children 
admitted to hospital with acute asthma will improve with this well-established clinical 
framework [6]. A few children do not respond 

 
 
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However, a minority will not respond adequately to such management and require 
adjunctive medications, usually requiring admission to the ward, and sometimes to the 
ICU.  Medical treatments commonly used in addition to beta agonists, include intravenous 
magnesium sulfate, inhaled anticholinergics and aminophylline. The evidence base for 
the efficacy of such treatments is limited and inconsistent, and adverse side effects are 
common [7]. 
 
There is growing evidence that positive airway pressure delivered by a non-invasive face 
mask, can reduce airway obstruction and also improve ventilation-perfusion mismatch. 
The resulting decrease in respiratory work and reduced need for added oxygen, shortens 
hospital stay and minimizes exposure to multiple medications [8]. In recent years the use 
of non-invasive positive pressure ventilation for management of a range of acute 
respiratory pathologies has become increasingly common. Results from studies in this 
area are encouraging, however most studies to date have been small and retrospective 
[9]. There is very little prospective controlled research to guide clinical practice concerning 
non-invasive ventilation in asthma. In view of the limited information available in the 
published literature, we believe that a prospective controlled trial of the value of BiPAP in 
acute asthma would provide a valuable evidence base to guide the management of this 
common clinical problem.  
 
Literature Review: 
 
Although non-invasive ventilation is increasingly used for treatment of asthma in 
emergency medicine[10], there is surprisingly little relevant research literature. Recent 
literature reviews [9,11], including a Cochrane review based on only 5 studies[12], all 
conclude that the therapy is promising but that there is an urgent need for large controlled 
studies.  Meduri, in adults[13] and Williams in children[14] published retrospective reviews 
of their clinical experience with non-invasive ventilation in acute asthma. Both claimed 
that non-invasive ventilation (NIV) was at least safe, and likely effective but neither 
included controls. 
 
From a physiological point of view, there is good theoretical support for the use of NIV in 
acute asthma. The administration of positive pressure ventilation leads to bronchial 
distention and enables maintenance of small airway patency. This decreases airway 
resistance, recruits areas of atelectasis and facilitates clearance of secretions[15].  
 
As noted, there have been very few prospective studies of NIV in the management of 
acute asthma. The addition of NIV to conventional therapy, in a small prospective adult 
study, showed significantly shorter ICU and hospital stays in the treatment arm[15].  
A prospective randomized crossover study of 20 children with lower airway bstruction[16], 
reported a significant improvement in respiratory rate and clinical asthma score when 
receiving non-invasive ventilation, which worsened on conversion to standard medical 
treatment. A recent prospective randomized controlled pilot study [17] compared NIV to 
standard management in 20 patients with status asthmaticus. The study identified 

 
 
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significant improvements in respiratory rate and clinical asthma scores in the NIV 
treatment arm.  
 
 Research Methods: 
 
Overview of study design:  
 
The aim of the study is to determine if the use of NIV, for children admitted to hospital 
with an acute exacerbation of asthma, reduces their work of breathing, need for 
adjunctive medication, length of hospital stay, and need for intubation and mechanical 
ventilation. Study design will be prospective, randomized and controlled. The tightly fitting 
face mask necessary for NIV makes it impossible to make this a blinded study.  
 
The principal enrollment criteria will be children over 2 years of age presenting to the ER 
with acute asthma. After diagnosis, all children are treated with standard therapy 
(systemic steroids plus 3 doses of inhaled salbutamol and 1 dose of inhaled ipratropium 
over a 1 hour period then hourly salbutamol). The principal decision between discharge 
track and admission track will be made at 2 hours after first steroid dose. Admission 
criteria are based on sequential PRAM scores.  
 
After initial asthma treatment and observation in the emergency room, to determine which 
patients can be discharged home, those who need admission will be asked to join the 
study, then consented and randomized. There will be three treatment groups:  
 
 BiPAP: standard steroid dose, hourly salbutamol and BiPAP at 15/5 cm H2O by 
face mask with rate 10 to 15/min, oxygen as needed. 
 CPAP: standard steroid dose, hourly salbutamol and 8 to 10 cm H2O constant 
pressure by face mask, oxygen as needed.  
 Conventional therapy: standard steroid dose plus hourly nebulized salbutamol, 
nebulized ipratropium q 6 hrly, magnesium sulphate 50 mg/kg IV (4 doses q 6 
hrly), loading dose of aminophylline 6 mg/kg IV if no progress, oxygen as needed. 
 
All children will be admitted to a small 3 bed respiratory unit. They will be closely  
monitored and objectively scored every 4 hours using the PRAM asthma clinical severity 
score (Pediatric Respiratory Assessment Measure)[18]. End points will be: time to reach 
room air, time to reach  PRAM score <3, numbers requiring intubation and mechanical 
ventilation and medication use. Those children older than 5 or 6 yrs, will also perform lung 
function tests twice daily. Projected patient enrollment will be at least 30 in each arm. 
Estimated study duration is 6 months.   
 
Inclusion criteria:  

 
 
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In order to avoid confusion with viral bronchiolitis, the study is open to all children over 24 
months old who present to the emergency department diagnosed with an acute asthmatic 
attack severe enough to require hospital admission. 
 
Diagnostic criteria:   
The biggest challenge in asthma research is determining an unambiguous clinical 
definition that allows one coughing/wheezing child to be distinguished from another. Our 
group has recently published a large study of the best diagnostic indicators in tachypneic 
children[20]. Based on that work,our diagnosis of asthma will depend on respiratory rate 
greater than WHO’s age-dependent criteria, a history of similar previous episodes and 
wheezing heard on auscultation by an experienced physician.  These criteria provide a 
diagnostic sensitivity and specificity of 85%[20]. 
 
Exclusion criteria: 
 Clinical suspicion of bacterial pneumonia: focal crackles or bronchial breathing, 
and/or major chest x-ray findings. 
 Impending respiratory failure at presentation requiring direct PICU admission 
 Any contraindication to BiPAP use including altered mental status, recent bowel 
surgery, intractable vomiting, inability to protect airway, pneumothorax.  
 Receiving maintenance dose of oral steroid at time of hospital admission  
 History of serious unrelated illness such as congenital heart disease or 
bronchopulmonary dysplasia. 
 
Measured Outcomes: 
 Length of time to reach a PRAM score of ≤ 3 
 Time to room air. 
 Total medication use per 12 hr period. 
 Numbers failing treatment and transferred to ICU. 
 Numbers in each group requiring hospital readmission within 48 hours of discharge 
 Time to reach FEV1 >80% predicted in those children able to perform PFTs. 
 
Study summary:  
 Identify patients aged ≥ 2 years attending the Emergency Department with a 
significant acute asthma exacerbation (using criteria above).  
 Begin steroids and initial protocolised standard bronchodilator therapy. Observe in 
ER and score PRAM hourly. 
 Research coordinator is informed and provides parents and child with study 
information to read during the child’s period of observation in the ED. 
 A decision about study inclusion should be made 2 hours post-steroid 
administration in children with PRAM of 8 or more.  
 Once admission decision has been made, child is eligible for the study. Obtain 
consent from the parents and assent from child where possible. If the child is too 
unstable, assent will be explained and collected when the child is capable. 

 
 
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 After consent, participants will be randomized to one of the three treatment arms in 
blocks of six, using consecutively numbered opaque envelopes stored in the ED. 
 
Management of treatment groups: 
Participants will be randomized into one of three treatment arms – BiPAP, CPAP, 
conventional therapy. In addition to standard therapy, the three treatments will consist of: 
 BiPAP group (Trilogy device) to be started in the ER after randomization, 
pressures 16/5 cm H2O, with rate of 10 to 15 / minute plus hourly salbutamol.  
 CPAP group (Trilogy device) to be started in ER after randomization. Starting 
pressure 8 cm H2O, increased to 10 cm H2O if no clinical response and hourly 
salbutamol.  
 Conventional therapy, hourly nebulized salbutamol, nebulized ipratropium q 6 hrly, 
magnesium sulphate 50 mg/kg IV (4 doses q 6 hrly), loading dose of aminophylline 
6 mg/kg IV if no progress. 
 
General care for all three groups: 
All three treatment arms will receive the following standard care: 
 Oxygen to keep saturations ≥ 92% for all three groups. 
 Standard course of oral steroid: dexamethasone 0.3mg/kg/dose once daily for 4 
consecutive days,  
 On-call research coordinator to assess the patients and record data. 
 If a patient in any of the treatment groups  deteriorates, they will be managed in the 
usual way with medical review and admission to ICU as required.  
 
Criteria for study termination: 
 Failure to tolerate BiPAP (persistent agitation and tachycardia, refusal to wear 
mask) resulting in the need for its discontinuation despite appropriate 
administration of sedation. 
 Signs of impending respiratory failure in either study arm should immediately 
prompt discussion with the ICU team and discontinuation of study participation 
 
Study enrolment: 
Parents will be approached while their child is receiving initial asthma therapy in the 
Emergency Room of the Post Graduate Institute of Paediatric Medical Research in 
Chandigarh, India. Parents will be approached by one of the two local study coordinators 
(both are qualified paediatricians), during the child’s 2 hour observation period in the 
Emergency Department. At that time parents will be given the invitation letter, written in 
local language (Hindi) and the research coordinator will answer any questions they have. 
If they cannot read, the information will be read to them in a private room. If the child fails 
to improve and requires hospital admission, consent for study participation will be sought 
once the decision to admit has been made. This will not delay treatment in any way. 
Children will only be eligible to enroll in the study whilst they are in the Emergency 

 
 
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department. Previously admitted ward patients are not eligible. All study information and 
consent documents are attached in section 9. 
 
Randomization: 
Once consent has been obtained, treatment selection will be decided using consecutively 
numbered envelopes randomized in groups of six. These envelopes will be stored in a 
box in the Emergency Department.  Once consent has been obtained, an envelope will be 
selected in numerical sequence to determine the child’s allocated treatment group. The 
envelope will then be stapled to the consent form to enable the investigator to know each 
patient’s subject study number. 
 
Safety Monitoring: 
Although there are decades of experience confirming the safety of NIV in children, this 
study represents a significant change to well-established conventional therapy so extra 
levels of observation of the treatment groups have been included in the study design: 
 The study hospital has agreed to set aside a 3 bed ward dedicated to the duration 
of the study. It will be staffed by 4 nurses and 2 qualified pediatricians who will 
provide continuous 24 hr a day coverage for the study participants. Staff salaries 
for the study will be covered by study funds. 
 Since this is an open study, we plan to perform an interim review of adverse events 
after 10 patients have been enrolled in each treatment arm. The clinical reviewer 
will be Dr Skippen and the statistical reviewer will be Boris Kuzeljevic  - both from 
Children’s Hospital, Vancouver. 
 The head of ER at PGIMER, Chandigarh, has agreed to be the local external 
monitor. The research coordinators will be the most likely people to pick up 
adverse events.  All RCs will be trained in the study protocol, including the 
reporting process in the event of an adverse event. Nursing staff are also aware of 
the need for extra monitoring and the need to report potential problems. 
 
Sample size calculation. 
In order to have an impact on common practice, we would define a significant treatment 
effect as a 25% reduction in time to PRAM of 3. In order to demonstrate this effect with a 
power of 80% and a 5% chance of a type 1 error, we need an estimate of mean time to 
PRAM of 3 plus standard deviation from previous published work. Unfortunately, there is 
very little published information to act as a guide. The only published pediatric study that 
provides relevant data is a pilot study by Basnet et al.[17] Using only 10 patients in each 
arm, they showed BiPAP reduced time in ICU (48+/- 16 hrs vs. 36+/-14 hrs). They used a 
clinical score to guide management but it was different to the PRAM. If we take the higher 
of these standard deviations as a rough guide to the average ICU admission time and 
combine it with a power of 80% and type 1 error risk of 5%, we will need 26 patients in 
each arm to detect a 25% reduction in time to PRAM of 3. It must be emphasized that the 
shortage of relevant literature makes this only a rough estimate. 
 

 
 
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Statistical analysis. 
Outcomes in the two treatment arms of the study (BiPAP and CPAP), will be compared to 
those in the control group (conventional acute paediatric asthma treatment). The principal 
end points will be analysed in the following ways: 
1. Changes in asthma score over time.  
     The PRAM respiratory distres score is based on objective and subjective observations 
so the final values are non-parametric. Multiple comparisons over time, between 
treatment group and control, will be made with the Kruskal-Wallace test with Dunn’s post-
hoc test. 
2. Time to reach asthma score <3. 
     The value will be measured in hours after starting treatment so the values will be 
parametric. Comparison between treatment and control values will be made using t test.  
3. Total number of pharmacological treatments per day. 
     The total number of drug treatments will be calculated for each 12 hour period. These 
are parametric values. Comparisons between control and treated group of repeat 
measures over time, will be made by analysis of variance with Tukey's post-hoc test. 
4. Lung function tests. 
     Standard spirometry and flow-volume loops will be performed with portable equipment 
in children old enough to cooperate. The main measured end point for analysis will be the 
change in Forced Expiratory Volume in 1 second (FEV1) over time. These values are 
parametric. Multiple comparisons between control and treated groups will be made by 
analysis of variance with Tukey's post-hoc test. 
 
References 
 
1. Martinez, et al. Asthma. Lancet 2013;382:1360-72. 
2. Seear et al(a). Fifty years of pediatric asthma in developed countries. Ped Pulm 
2012;47: 211-219. 
3. CDC. Asthma surveillance data, 2014. Retrieved from: 
http://www.cdc.gov/asthma/asthmadata.htm. 
4. Nava S et al. Non-invasive ventilation in acute respiratory failure. Lancet 
2009;374:250-259. 
5. British Thoracic Society. Non-invasive ventilation in acute respiratory failure. 
Thorax 2002;57:192-211. 
6. Nievas I, et al. Severe acute asthma exacerbation in children: a stepwise approach 
to escalating therapy in a pediatric ICU. J Pediatr Pharmacol Ther 2013;18:88-104. 
7. Papiris et al. Acute severe asthma: new approaches to assessment and treatment. 
Drugs 2009;69:2363-91. 
8. Green E, et al. Noninvasive ventilation for acute exacerbations of asthma: a 
systematic review of the literature. Aust crit Care 2017. Epub ahead of print. 
DOI:10.1016/j.aucc.2017.01.003. 
9. Soroksky et al. Noninvasive positive pressure ventilation in acute asthmatic attack. 
Eur Resp Rev 2010;19:39-45. 

 
 
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10. Abramo T, et al. Pediatric ED BiPAP continuous quality improvement programme 
with patient analysis: 2005-2013. BMJ Open 2017;7:1-13. 
11. Pallin M, et al. Is non-invasive ventilation safe in acute severe asthma? 
Respirology 2015;20:251-257 
12. Lim W, et al. Non-invasive positive pressure ventilation for treatment of respiratory 
failure due to severe acute exacerbations of asthma. Cochrane Database Syst Rev 
2012;12:CD004360. 
13. Meduri et al. Noninvasive positive pressure ventilation in status asthmaticus. Chest 
1996;110:767-74. 
14. Williams A, et al. Safety and clinical findings of BiPAP utilization in children 20 kg 
or less for asthma exacerbations. Intens Care Med 2011;37:1338-1343. 
15. Gupta, et al. A prospective randomized controlled trial on the efficacy of 
noninvasive ventilation in severe acute asthma. Respire Care 2010;55:536-543. 
16. Thill et al. Noninvasive positive pressure ventilation in children with lower airway 
obstruction. Pediatr Crit Care Med 2004;5:337-42. 
17. Basnet et al. Safety, efficacy and tolerability of early NIV in children admitted with 
status asthmaticus. Pediatr Crit Care Med 2012; 13:393-8. 
18. Ducharme et al. The Pediatric Respiratory Assessment Measure. J Pediatr 2008; 
152:476-80. 
19. Friedman, J et al. Bronchiolitis: recommendations for diagnosis, monitoring and 
management of children one to 24 months of age. Pediatr Child Health 
2014;19:485-491. 
20. Seear et al. Can we distinguish pneumonia from wheezy diseases in tachypneic 
children? Arch Dis Child 2014;99;889-906. 
 
Appendix. 
 
PRAM score (Ducharme, 2008) 
 
Signs 
0 
1 
2 
3 
Suprasternal 
retractions 
Absent 
Absent 
Present 
Present 
Scalene 
contractions 
Absent 
Absent 
Present 
Present 
Air entry 
Absent 
Decreased at 
bases 
Widespread 
decrease 
Widespread 
decrease 
Wheezing 
Absent 
Expiratory only 
Inspiratory and 
expiratory 
Audible 
O2 saturation 
in room air 
>95 
92-94% 
90-92% 
<92 
 
Severity categories: 
Mild: 
0 – 3  
Moderate 
4 – 7  
Severe: 
≥ 8