A Randomized clinical Trial of Inhaled Ciclesonide for Acute Asthma

Demétrius Tierno Martins Universidade Federal de Sao Paulo Escola Paulista de Medicina Karla Carlos (  ka.carlos1@hotmail.com ) Universidade Federal de Sao Paulo Escola Paulista de Medicina https://orcid.org/0000-0002-66004587 Luciane BC Carvalho Universidade Federal de Sao Paulo Escola Paulista de Medicina Lucila Bizari Prado Universidade Federal de Sao Paulo Escola Paulista de Medicina Carolina Fransolin Universidade Federal de Sao Paulo Escola Paulista de Medicina Gilmar F Prado Universidade Federal de Sao Paulo Escola Paulista de Medicina

because they avoid the need for venipuncture, which is sometimes di cult 2,3,4 .These drugs exert vasoconstrictor effects on the mucosa by reducing neuronal reuptake of noradrenaline at the neuromuscular junctions of mucosal vessels, thus reducing secretions and facilitating the delivery of beta-2 agonists to their target receptors; onset of action is rapid, with peak vasoconstriction occurring in 30 minutes and lasting up to 90 minutes after inhalation 5,6 .
Ciclesonide is a prodrug which is activated at the site of action (bronchial cells and lining uid of bronchus) by bronchial esterases, converting ciclesonide to desisobutyryl ciclesonide, which has 100-fold greater a nity for the glucocorticoid receptor than ciclesonide itself 7 . Because of this peculiar property, common side effects such as hoarseness, dysphonia, oral candidiasis, and suppression of the hypothalamic-pituitary-adrenal axis are much less frequent with ciclesonide than with other high-dose inhaled corticosteroids, as it is inactive outside the lung 7,8,9,10,11 .
The anti-in ammatory action of intravenous corticosteroids occurs via a genomic mechanism, reducing expression of proin ammatory mediators such as interleukins 12 and upregulating expression of betaadrenoceptors in bronchial smooth muscle. This effect is also shared by inhaled corticosteroids and begins 4 to 6 hours after administration 13 , although some studies have shown that systemic corticosteroids administered up to 1 hour after emergency department admission in severely ill patients yields clinical bene ts, such as reduced hospitalization rate and shorter length of emergency department stay 14,15 .
Data from double-blind randomized controlled trials suggest that, compared to systemic corticosteroids, inhaled corticosteroids can decrease admission rates and allow earlier discharge from the emergency department. Peak ow levels and FEV1 also rise more quickly in patients given inhaled corticosteroids 16,17,18,19 .
To the best of our knowledge, this is the rst double-blind randomized clinical trial to compare high-dose inhaled ciclesonide versus injectable hydrocortisone for acute asthma management in the emergency setting. This trial is justi ed by the expected potential for fewer side with inhaled ciclesonide, supposed bene t of its rapid onset of action, and need for more inhaled drugs available for clinicians dealing with asthma exacerbation in the emergency department.

Methods
Population and setting. We studied patients with asthma aged 13 years or older, of both sexes, in the city of São Paulo, Brazil. Patients were recruited from the emergency department of Hospital São Paulo (a teaching hospital of the Federal University of São Paulo) and from two public freestanding urgent care centers a liated with the hospital: AMA Santa Cruz and AMA Sacomã.
We included patients with a previous diagnosis of asthma (dyspnea, cough, wheezing, chest tightness, associated with allergen exposure or cold air) 20,21 who received follow-up at outpatient clinics within the catchment area of the Hospital São Paulo emergency department and had a peak ow <50% of predicted.
All participants had a longstanding history of asthma, with repeated exacerbations and emergency room visits. Our included patients had at least 2 years of moderate or severe asthma, with a mean peak ow immediately before intervention of 163 L/min. We excluded patients with body temperature ≥37.8°C, smokers, pregnant women, patients undergoing psychiatric treatment, patients with a history of heart, liver, kidney, or other disease that might contraindicate corticosteroid therapy, patients who had undergone lung resection, patients undergoing treatment for tuberculosis or mycotic infections of the lung, and patients with tracheotomy or mechanical obstruction of the trachea. We also excluded patients with myopathies or neurological conditions (such as sequelae of stroke or encephalopathies), as well as patients with BMI >40 kg/m². Ethical Aspects. This study was approved by the Research Ethics Committee of the Federal University of São Paulo (judgment number 364240). All patients provided written informed consent for participation in accordance with international regulations for human subject research. When patients were underage, consent was obtained from their parents or legal guardians.
This study is registered in the Brazilian Registry of Clinical Trials (http://www.ensaiosclinicos.gov.br/ ) under accession number RBR-6XWC26.
Sample. We studied 31 patients in the ciclesonide group and 27 patients in the hydrocortisone group. We calculated sample size according to Greenberg 22 , considering a FEV1 improvement of 0.37±0.85 L after intervention, resulting in 65 patients for each group.
Study design. This is a double-blind, placebo-controlled, randomized clinical trial designed to compare the e cacy of inhaled ciclesonide versus intravenous hydrocortisone in the management of moderate or severe acute asthma in an emergency department setting.
Blinding. Both blinding and randomization were done centrally at Neuro-Sono Sleep Center, São Paulo, Brazil. Blinding of active ingredients and their respective placebos was achieved by random allocation of four letters -A, B, C, and D -to each of the following products: hydrocortisone, ciclesonide, hydrocortisone-identical placebo, and ciclesonide-identical placebo. After random allocation of letters to designate each product, we de ned two product pairs, Inhaled Active Ingredient + Intravenous Placebo and Intravenous Active Ingredient + Inhaled Placebo, in a random combination that enhanced the safety of blinding. Both the intravenous placebo and the inhaled placebo were identical to their active counterparts.
Information about the intervention that each patient randomized to the study would receive was distributed in opaque, numbered envelopes, which were only opened at the time of use. The nursing staff prepared the medications for administration as instructed in the numbered envelopes. The staff who prepared the medications, the providers who administered them, and all researchers involved were blinded to the active pharmaceutical ingredients of interest.
Randomization. Patients included in the sample were recorded consecutively in a logbook and assigned a serial number.
The 58 patients were divided into 2 groups: study (Ciclesonide) and control (Hydrocortisone), according to two computer-generated random number tables. Each table contained an ascending sequence of numbers. Patients were allocated to one or the other according to the serial number attributed at the time of enrollment, which ensured that neither staff nor patients were aware of the intervention to which each patient would be allocated.
Ciclesonide Group. Patients received ciclesonide at a dose of 160 mcg/puff. The rst dose was administered 5 minutes after inclusion in the trial, and consisted of 3 puffs (480 mcg); the second dose at 20 minutes (480 mcg); and the third dose at 40 minutes (480 mcg), for a total of 1440 mcg. Patients in this group also received hydrocortisone-identical placebo at 5 minutes.
Hydrocortisone Group. Patients in this group received 500mg of hydrocortisone intravenously and ciclesonide-identical placebo at 5, 20, and 40 minutes.
Measures. We adopted as a primary outcome measure the spirometric variables FEV1 and peak expiratory ow (PEF), as well as the clinical variables dyspnea, wheezing, and accessory muscle use during breathing (assessed by observation of the sternocleidomastoid muscle). As secondary outcomes, we evaluated the heart rate, respiratory rate, blood pressure, and pulse oximetry.
These parameters were measured every 30 minutes from the time of patient admission until the second hour and every 60 minutes thereafter until the fourth hour in the emergency department, for a total of 7 measurements, ensuring rigorous monitoring throughout the patient observation period. For the purposes of this study, we analyzed data from baseline and the fourth hour, as we felt these assessments were su cient to represent the patients' course among the 7 measurements obtained.
Procedures. The emergency room nurse applied the Manchester Triage System and measured oxygen saturation, blood pressure, and breathing pattern. The emergency room physician then con rmed the diagnosis of asthma exacerbation and noti ed the investigators, who performed an initial assessment by measuring peak ow and explaining the study to the patient. Patients with a peak ow less than 50% of predicted were invited to participate in the study (Figure 1), as the sample was designed to include only severe patients.
Once the patient was included, the investigators worked with the emergency department staff to provide all necessary care and perform the measurements required for the study.
Spirometric parameters were measured in an Easy One model 2009 spirometer (ndd Medizintechnik AG, Zurich, Switzerland). The best of three successive expiratory curves was considered valid and used for analysis, as recommended by the American Thoracic Society. Peak ow was estimated with the Mini-Wright Peak Flow meter (Clement Clarke, Hanlon, United Kingdom). Again, the highest of three measurements was considered for analysis. Dyspnea was assessed subjectively as perceived shortness of breath, using the Borg scale, a visual analogue scale of 0 to 10 where 0 is absence of dyspnea and 10 is maximal dyspnea. During the initial assessment and at each time point of reassessment, we evaluated wheezing and accessory muscle use. Wheezing was assessed through pulmonary auscultation and ranked from 0 to 3 on an ascending scale of severity (0: no wheezing; 1: slight wheezing; 2: moderate wheezing; 3: severe wheezing). Accessory muscle use was also measured on a scale of increasing intensity (0: no accessory muscle activity: 1: slight activity; 2: moderate activity; 3: marked accessory muscle activity). When there was little wheezing or a silent chest plus marked accessory muscle use or signs of muscle fatigue, dyspnea was classi ed as severe. Individual and pooled analyses were performed for all parameters.
Criteria for Improvement. Patients were evaluated for improvement at all time points of assessment, to ensure patient safety and detect possible need for additional interventions other than those provided for in the study protocol. For the purposes of this study, we considered the following de nitions of improvement: 1) FEV1 and PEF ≥70% predicted for age, sex, weight, and height; 2) Improvement of dyspnea: a) Borg score <2 23 ; b) reduction of wheezing severity from baseline; and c) no accessory muscle use, as determined by observation of the sternocleidomastoid muscles.
Interim Analysis. We planned an interim analysis for when the number of patients included had reached approximately half the predicted sample size, to decide whether to continue or terminate inclusion. This analysis was carried out at the randomization and blinding center (Neuro-Sono Sleep Center) by a committee established speci cally for this purpose. After inclusion of 58 patients, the Interim Analysis Committee suggested that the study be interrupted, since no difference between treatments was detected.
Adverse Events. We actively evaluated the more frequent adverse events, such as dry mouth, tremor, palpitations, anxiety, headache, and recorded any other patient-reported events 24,25 . These variables were evaluated by intention to treat (ITT).
Statistical Analysis. The sample size was calculated considering a change in FEV1 of 0.37 L, after treatment, as an indicator of improvement; a standard deviation of 0.85 L; a signi cance level of 5%; and a statistical power of 80% 16,22 , resulting in a sample size of n=130 patients, i.e., 65 patients in each group. As noted above, interim analyses were carried out as planned after enrollment of 30 patients in each group; at this time, in view of the results, the interim analysis committee recommended termination of enrollment.
Quantitative variables were expressed as mean ± SD, and categorical variables, as n (%). We used Student's t-test for independent samples for normally distributed data, the Mann-Whitney U test for asymmetrically distributed data, and Pearson's chi-square test or Fisher's exact test for categorical data 26,27 . Outcomes were assessed by ITT, considering the worst scenario, i.e., losses in the study group were considered treatment failures and losses in the control group as successful treatment. P-values < 0.05 were considered statistically signi cant.
Availability of Data and Materials. All data generated and analysed during this study are included in this published article (supplementary information les).

Results
Thirty-one patients in the ciclesonide group and 27 patients in the hydrocortisone group were analyzed by ITT.
Demographic Data. The ciclesonide and hydrocortisone groups ( Table 1) were similar in age, systolic blood pressure (SBP), diastolic blood pressure (DBP), and proportion of smoking, hypertension (HTN), diabetes (DM), and alcohol use. There were more women in the ciclesonide group (p < 0.001). The ciclesonide and hydrocortisone groups did not differ regarding vital signs and pulse oximetry ( Table 2). On within-group assessment, as expected, HR and RR were lower at hour 4, which is consistent with the clinical improvement observed in both groups. On between-group analysis, pulse oximetry and vital signs were not different at hour 4. Clinical Variables. All clinical parameters evaluated in this study showed improvement at hour 4 as compared with hour 1 (baseline). There was also no difference between the effects of ciclesonide and those of hydrocortisone at hour 4, i.e., both treatments were equally effective in improving respiratory effort, accessory muscle use, wheezing, and Borg Dyspnea Scale scores (Table 3). increased signi cantly from baseline to hour 4 (p < 0.001) in both groups, and both treatments were equally effective when compared head-to-head at hour 4 (Table 4). Adverse Events. More patients in the hydrocortisone group complained of dry mouth, but there was no statistically signi cant difference in frequency of any adverse effect between groups (Table 5). There was no signi cant difference between groups; dry mouth was the only complaint more prevalent in the hydrocortisone group.
Hospitalization, Losses, and exclusions. Two patients in the ciclesonide group developed worsening bronchospasm and severe desaturation still early in the course of treatment (having received only one dose of medication), and ultimately required ventilatory support.

Discussion
To the best of our knowledge, this was the rst double-blind randomized clinical trial to test high-dose inhaled ciclesonide for the management of acute asthma in the emergency department. Our ndings suggest that high-dose inhaled ciclesonide is as effective as intravenous hydrocortisone for this purpose.
In this study, we tested ciclesonide as the intervention because it is a prodrug with high potency and minimal potential for side effects inhaled corticosteroid, which is particularly important for use in acute exacerbations of asthma, a setting in which high doses of inhaled corticosteroids must be administered 12 .
Studies have shown that inhaled and systemic corticosteroids can decrease the length of emergency department stay and hospitalization rate when administered the rst hour of an acute asthma exacerbation 16 , but the optimal agent, dosage, and duration of observation in the emergency department are still unknown 20,28 .
Both drugs reduced expiratory effort, wheezing, and accessory muscle use (Table 3); however, among the spirometric parameters analyzed, only PEF had improved signi cantly from baseline at hour 4 in both groups (Table 4). Adverse events, such as dry mouth, palpitations, tremor, headache, and anxiety, did not differ between the two groups ( Table 5).
Clinical studies using high doses of inhaled corticosteroids such as uticasone 16 , unisolide 17 , and beclometasone 11 also found these agents to be effective in increasing peak ow.
Although we did not enroll a large number of patients, the groups did not differ in terms of demographic characteristics, except for the higher proportion of women in the ciclesonide group (Table 1). Two patients in the ciclesonide group, both with peak ow < 30% of predicted, developed worsening bronchospasm and severe desaturation still early in the course of treatment (having received only one dose of medication), and ultimately required invasive ventilation. Given the small sample, the likelihood of between-group differences is very high, and we judge these events to be attributable to chance.
Clinical parameters (Table 3) and vital signs ( Table 2) were similar at baseline and at hour 4. Only DBP was higher in the hydrocortisone group, possibly due to the systemic effects of the corticosteroid 3 .
FVC and FEV1 remained unchanged from baseline to hour 4, and did not differ between the two groups.
Previous studies of uticasone 16 and unisolide 17 reported improvement in these parameters. In our study, we observed an increase in PEF despite no increase in FEV1. This is consistent with the well-known mismatch between FEV1 and PEF in acute severe asthma 29,30,31 , a condition in which FEV1 is underestimated and does not correlate adequately with rises in peak ow.
A Cochrane review noted the higher cost of inhaled versus systemic corticosteroids as an obstacle to use of the former 28 . However, this was not an issue in our study, where 9 puffs of ciclesonide (total dose used in the emergency department) had an estimated cost of US$2.47, while a single 500-mg dose of hydrocortisone had a cost of US$3.18, making ciclesonide more cost-effective. In the United States, the average cost of treatment 30 days after a severe asthmatic exacerbation is US$1368. 32. Still regarding the cost and utility of inhaled corticosteroids, the FourFold Asthma Study (FAST) showed that it is clinically safe for a patient to simply quadruple their usual dose of inhaled corticosteroids at home upon deterioration, thus aborting a severe asthma attack and obviating the need forhospitalization 33 .
Limitations of our study included the lack of follow-up (to assess for recurrence) and the small sample size, which, for instance, prevented us from determining whether dry mouth was truly more prevalent in the hydrocortisone group. Some strengths of our study include its design and external validity, since we included adult patients from general population with no restriction regarding to age, gender or ethnic group; rigorous evaluation of clinical and spirometric parameters; appropriate masking and blinding; and close, rigorous monitoring of patients for a 4-hour period during the study protocol.

Conclusion
In summary, our study suggests that high-dose inhaled ciclesonide is as effective as injectable hydrocortisone for the management of acute severe asthma and had a similarly favorable adverse-event pro le, with the advantage of being a prodrug that exerts topical anti-in ammatory effects while reducing