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`Comparable Efficacy of Administration with
`Face Mask or Mouthpiece of Nebulized Budesonide
`Inhalation Suspension for Infants and Young
`Children with Persistent Asthma
`MICHAEL MELLON, JEFFREY LEFLEIN, KAREN WALTON-BOWEN, MARIO CRUZ-RIVERA, SHERAHE FITZPATRICK,
`and JOSEPH A. SMITH
`
`Allergy Department, Kaiser Permanente Medical Offices, San Diego, California; Allergy and Immunology Associates of Ann Arbor,
`Ypsilanti, Michigan; and AstraZeneca, Wayne, Pennsylvania
`
`A randomized, double-blind, placebo-controlled, parallel-group study
`including 481 children at 37 centers in the United States demon-
`strated the efficacy and safety of budesonide inhalation suspension in
`doses of 0.25 mg once daily, 0.25 mg twice daily, 0.5 mg twice
`daily, and 1.0 mg daily in infants and young children with persis-
`tent asthma. The retrospective analysis presented here compares the
`efficacy of treatment with the suspension administered through a
`face mask or mouthpiece. All patients receiving budesonide inhalation
`suspension via face mask or mouthpiece showed clinical improve-
`ments in nighttime and daytime asthma symptoms as compared with
`administration of a placebo. The improvements were of similar
`magnitude as those observed in an analysis of all patients treated.
`Improvements in nighttime asthma symptoms were statistically
`5
`significant with budesonide at 0.25 mg daily (p
` 0.040), 0.25 mg
`5
`5
`twice daily (p
` 0.008), and 0.5 mg twice daily (p
` 0.046) deliv-
`ered by face mask. In patients using mouthpieces, nighttime asthma
`5
`symptoms improved significantly in the 0.25-mg twice-daily (p
`5
`0.005) and 1.0-mg daily (p
` 0.035) groups. Patients receiving
`budesonide at 0.5 mg twice daily via a face mask improved signifi-
`5
`cantly in daytime asthma symptoms (p
` 0.009). The use of break-
`through medication was reduced in patients receiving budesonide
`via face masks or mouthpieces relative to placebo, and treatment was
`well tolerated in all study groups. This retrospective analysis suggests
`that nebulized budesonide inhalation suspension can be administered
`effectively by either face mask or mouthpiece to young children with
`persistent asthma.
`
`Asthma causes significant morbidity and mortality in children,
`affecting an estimated 4.8-million children in the United States
`(1, 2). Although asthma is now recognized as an inflammatory
`disease, antiinflammatory agents are underutilized in its treat-
`ment (3). Until recently, asthma therapy for infants and young
`children was limited to oral and nebulized formulations of
`bronchodilators, cromolyn sodium, and oral corticosteroids.
`Recent evidence suggests that the duration of asthma in children
`may be associated with a lower level of lung function and more
`asthma symptomatology (4), and that early intervention with anti-
`inflammatory medications, including inhaled glucocorticosteroids,
`may prevent the development of irreversible airway obstruction
`(5–7). A recent study by Clough and colleagues (8) identified
`factors predictive of persistence of wheezing in infants; these
`findings will contribute to studies of early intervention strategies.
`Furthermore, recent guidelines for asthma treatment from the
`National Heart, Lung, and Blood Institute (NHLBI) and the
`
`(Received in original form September 8, 1999 and in revised form February 11, 2000
`
`Supported by AstraZeneca, Inc.
`Correspondence and requests for reprints should be addressed to Michael Mel-
`lon, M.D., Kaiser Permanente Medical Offices, Allergy Department, 5th Floor,
`7060 Clairemont Mesa Boulevard, San Diego, CA 92111.
`Am J Respir Crit Care Med Vol 162. pp 593–598, 2000
`Internet address: www.atsjournals.org
`
`)
`
`pediatric initiative of the American Academy of Allergy,
`Asthma, and Immunology recommend inhaled antiinflammatory
`agents for all but the mildest cases of asthma (1, 9).
`An estimated 80% of children with asthma present with
`symptoms within the first 2 yr of life (10). The efficacy of in-
`haled budesonide in alleviating symptoms of asthma has been
`demonstrated in numerous trials in children under 4 yr of age
`with a pressurized metered-dose inhaler (pMDI) with a spacer
`and face mask (11–13).
`Large-volume pMDIs with a spacer device and face mask
`are usually recommended initially for young children (1), but
`may require the assistance of more than one adult for drug ad-
`ministration (14). Use of smaller-volume pMDIs may improve
`ease of handling, but a decline in performance has been ob-
`served (15). Generally, children under 4 yr of age lack the co-
`ordination necessary to use pMDI devices (1, 16), and in one
`study, nearly one-third of pediatric patients experienced some
`difficulty in accepting a metered-dose inhaler with a spacer
`(13). Nebulizer treatment, however, permits drug delivery to
`young children through passive inhalation (1). Currently,
`there are no approved inhaled corticosteroids available in the
`United States for nebulization or for use in children under 4 yr
`of age.
`Budesonide inhalation suspension (Pulmicort Respules;
`AstraZeneca, Wayne, PA) is a novel nebulized corticosteroid
`that will soon be available in the United States for use in in-
`fants and children 1 to 8 yr of age who have persistent asthma.
`A number of small trials or individual case studies have shown
`that nebulized budesonide reduces asthma symptoms in in-
`fants and children (17–21). In a recent series of randomized,
`double-blind, placebo-controlled trials, the efficacy and safety
`of budesonide inhalation suspension were demonstrated at
`various doses and with various administration schedules for
`the treatment of mild to moderate asthma in infants and
`young children with disease meeting well-defined criteria (22–
`24). This report presents the results of a retrospective analysis
`of one of these randomized trials (22). This retrospective anal-
`ysis compared the efficacy of nebulized budesonide adminis-
`tered via face mask with that administered via a mouthpiece.
`
`METHODS
`Patients
`A parallel-group, double-blind, placebo-controlled study involving
`481 randomized patients was conducted at 37 centers in the United
`States. Children 6 mo to 8 yr of age who had moderate, persistent
`asthma diagnosed according to the NHLBI criteria (25) were enrolled
`in the study. Patients were required to have a 6-mo history of recur-
`rent exacerbations of cough and/or wheezing (which could include
`nighttime symptoms), with infrequent severe exacerbations. Other el-
`igibility criteria included the presence of asthma symptoms (with an
`overall daytime or nighttime severity score of 1, 2, or 3) on five or
`
`
`
`Liquidia's Exhibit 1131
`Page 1
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`

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`594
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`AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 162 2000
`
`more of the 7 d immediately preceding randomization, daily use of at
`least one chronic asthma medication (e.g., an inhaled corticosteroid,
`cromolyn sodium, or theophylline) for at least 3 mo before screening,
`and the periodic use of rescue bronchodilator therapy for break-
`through asthma symptoms. Patients who were capable of consistently
`performing pulmonary function tests (PFTs) were required to demon-
`>
`>
`
`50% predicted (26) and a reversibility of
`15%
`strate a baseline FEV
`1
`6
` 5 min after a standard dose of inhaled albuterol.
`at 15
`Patients were excluded from the study for any of the following rea-
`sons: history of severe and/or unstable asthma, long-term use of systemic
`corticosteroids within 12 wk of screening, or a history of intermittent
`use of systemic corticosteroids within 30 d of screening. Prior use of an in-
`haled corticosteroid was permitted if it was used daily for at least 2 mo at
`a stable dose before screening. Patients with other concomitant lung
`diseases and patients hospitalized for treatment of airway obstruction
`within 30 d of screening were excluded, as were patients with upper or
`lower respiratory tract infections within 14 d of screening.
`
`Study Design
`Informed consent was obtained from the patient and/or parent or
`guardian at the initial screening visit. A 2- to 3-wk baseline period
`preceded the 12-wk treatment period. Patients visited their respective
`study sites six times: at screening, at randomization, and after 2, 4, 8,
`and 12 wk of study therapy. Each clinic visit included a brief physical
`examination and a review of daily diary records; spirometry was done
`in the subset of patients who were capable of consistently performing
`the necessary maneuvers. Diary cards were used to record the severity
`of nighttime and daytime asthma symptoms, morning and evening
`peak expiratory flow rates (PEFRs), and bronchodilator use for break-
`through symptoms. A four-point asthma symptom score scale was
`5
` no symptoms of asthma,
`used to determine asthma severity, on which 0
`5
` mild symptoms (awareness of asthma symptoms and/or signs that
`1
`5
` moderate symptoms (asthma symptoms and/
`are easily tolerated), 2
`or signs with some discomfort, causing some interference with daily
`5
` severe symptoms (incapacitating asthma
`activities or sleep), and 3
`symptoms or signs with inability to perform daily activities or to
`sleep). Morning and evening PEFRs were measured with a peak flow
`meter (Vitalograph, Inc., Lenexa, KS) in the subset of patients capa-
`ble of consistently performing peak flow measurement maneuvers.
`After the baseline period, eligible patients discontinued their chronic
`asthma medications and were randomized to receive nebulized pla-
`cebo or one of the following nebulized treatment regimens: budes-
`onide in a dose of 0.25 mg daily, 0.25 mg twice daily, 0.5 mg twice
`daily, or 1.0 mg daily. Budesonide inhalation suspension and placebo
`were supplied in identical 2.0-ml white polyethylene ampules, and a
`Pari LC-Jet Plus nebulizer with a mouthpiece or face mask and Pari
`Master compressor (Pari Respiratory Equipment, Inc., Richmond,
`VA) were used to deliver the medication. Face masks and mouthpieces
`were issued to patients on the basis of their demonstrated ability to use
`them. The time for complete nebulization was approximately 5 min. Vi-
`talograph peak flow meters were issued to the subset of children who
`could perform this test, and these patients and their parents or guard-
`ians were instructed about the meter’s use and care.
`The incidence and severity of adverse events (AEs) were recorded
`during the study. AEs were defined as any unintended, unfavorable
`clinical signs, symptoms, medical complaints, or clinically relevant
`changes in laboratory test values. Assessment was conducted by means
`of standard questioning of patients and/or legal guardians, and by re-
`view of clinical and laboratory test results. AEs were classified by the
`patients’ parents or legal guardians as mild (easily tolerated symp-
`toms), moderate (enough discomfort to interfere with daily life/usual
`activities), or severe (incapacitating, such as the inability to attend day
`care/school or to take part in normal activities). Safety variables in-
`cluded changes in physical examination findings, vital signs, and clinical
`laboratory tests. Changes in adrenocorticotropic hormone-stimulated
`plasma cortisol levels from baseline to the end of the 12-wk study period
`were measured in a subset of patients at selected study sites to assess
`adrenal function. These data are reported elsewhere (22).
`
`Data Analysis
`Changes from baseline values (mean of the last 7 d preceding the ran-
`domization visit) to values found in the double-blind phase of the
`
`study (mean over Weeks 0 to 12) were analyzed for all efficacy vari-
`ables (except spirometry measurements, for which mean values over
`Weeks 2 to 12 were calculated). Data were included from all patients
`who received at least one dose of medication during the treatment
`phase and who had at least one observation while receiving study
`medication. Data were carried forward for patients who discontinued
`study participation or had missing observations. The primary efficacy
`variables were changes from baseline in nighttime and daytime asthma
`symptom scores. Secondary efficacy variables included the change
`from baseline in number of days per 2-wk interval on which rescue
`medications were used, morning and evening PEFRs and spirometric
`test results (in the subset of patients who could perform the tests), and
`the proportion of patients who were withdrawn from the study. The
`proportion of patients withdrawn from the study was evaluated with
`Fisher’s exact test; all other efficacy variables were evaluated through
`analysis of variance (ANOVA) techniques. The statistical analysis
`presented here to compare the efficacy of face mask versus mouth-
`piece administration of budesonide was a retrospective analysis. The
`continuing demand for safe, cost-effective medical treatments has
`brought an increased reliance on different types of clinical data, in-
`cluding retrospective analyses of previous clinical trial data or data
`from small-scale case or cohort studies (27). Retrospective analyses
`may be useful in identifying unsuspected findings or associations, de-
`velopment of new hypotheses, or addition of constructive input into
`prospective studies (27). However, limitations may be present in mea-
`surement capabilities, as in our analysis, in which study groups were
`further stratified after the study period was completed. The sample
`size of the original study design provided power to detect differences
`in efficacy for the different budesonide dose groups versus placebo.
`For this analysis, emphasis was placed on the magnitude of differ-
`ences in each of the study variables in the group using face masks and
`that using mouthpieces. The Statistical Analysis Systems (SAS) statis-
`tical software package version 6.11 (SAS Institute, Inc., Cary, NC)
`was used for statistical analysis.
`
`RESULTS
`Four hundred seventy-one patients were included in the all-
`patients-treated analysis; a face mask was used in the treat-
`ment of 211 patients and a mouthpiece was used in the treat-
`ment of 260 patients. Baseline demographic characteristics
`and baseline asthma symptoms and pulmonary function for
`children who received budesonide inhalation suspension and
`placebo are listed in Tables 1 and 2. As expected, most of the
`younger patients used face masks during nebulization. The
`mean age of face mask users was 36.4 mo and that of mouth-
`,
`4 yr of age,
`piece users was 70.0 mo. Among the 214 patients
`161 (75%) used a face mask and 53 (25%) used a mouthpiece;
`>
`4 yr of age used a face mask (19%) and
`50 of 257 patients
`207 (81%) used a mouthpiece. Other differences between the
`study groups in baseline characteristics were consistent with
`the older age of patients who used a mouthpiece; differences
`included duration of asthma and fraction of children capable
`of consistently performing PFTs. The average duration of
`asthma in patients using face masks was 24.3 mo and that in
`patients using mouthpieces was 42.0 mo. Only 13 of 211 pa-
`tients (6.2%) treated with face masks were capable of per-
`forming consistent PFTs, as compared with 148 of 260 patients
`(56.9%) using mouthpieces.
`Baseline nighttime and daytime asthma symptom scores
`were well balanced between the groups of children who re-
`ceived treatment with face masks and those using mouth-
`pieces. The average nighttime asthma symptom score was 1.21
`for patients who used face masks and 1.22 for patients who
`used mouthpieces. Similarly, patients who received treatment
`with face masks had an average daytime symptom score of
`1.31 as compared with an average score of 1.26 among patients
`using mouthpieces.
`Of the 211 patients receiving treatment with face masks,
`149 (71%) completed the study, including 19 (54%) patients in
`
`
`
`Liquidia's Exhibit 1131
`Page 2
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`Mellon, Leflein, Walton-Bowen,
`
`
`
`et al.: Budesonide Inhalation Suspension
`
`595
`
`TABLE 1
`BASELINE DEMOGRAPHICS OF STUDY POPULATION
`
`Face Mask
`Budesonide Inhalation Suspension
`
`Mouthpiece
`Budesonide Inhalation Suspension
`
`Characteristic
`
`Placebo
`5
`(
`n
`
`
`35
`)
`
`0.25 mg
`Daily
`5
`n
`
`
` 49
`
`)
`
`(
`
`0.25 mg
`Twice Daily
`5
`(
`n
`
`
`
` 43)
`
`0.5 mg
`Twice Daily
`5
`
`(n
`
`
`
`44)
`
`1.0 mg
`Daily
`5
`n
`
`
`
`
`40)
`
`(
`
`Placebo
`5
`(
`
`n
`
` 57
`)
`
`0.25 mg
`Daily
`5
`n
`
`
`
`
` 44)
`
`(
`
`0.25 mg
`Twice Daily
`5
`
`(n
`
`
`
` 54)
`
`0.5 mg
`Twice Daily
`5
`
`
`(n
`
`
` 52)
`
`1.0 mg
`Daily
`5
`(n
`
`
`
`
`53)
`
`
`
`25 (71.4%)
`10 (28.6%)
`
`36 (73.5%)
`13 (26.5%)
`
`24 (55.8%)
`19 (44.2%)
`
`34 (77.3%) 27 (67.5%) 32 (56.1%)
`10 (22.7%) 13 (32.5%) 25 (43.9%)
`
`22 (50.0%)
`22 (50.0%)
`
`37 (68.5%)
`17 (31.5%)
`
`33 (63.5%) 34 (64.2%)
`19 (36.5%) 19 (35.8%)
`
`6
`6
`6
`6
`6
`6
`6
`6
`6
`6
` 24.1 71.9
` 20.3 67.8
` 20.9 70.3
` 22.1 71.3
` 20.5 35.5
` 17.5 34.5
`39.7
` 22.8 38.9
` 16.8 33.7
` 17.4 68.9
` 21.7
`11–89
`8–83
`7–95
`9–86
`8–71
`19–100
`34–107
`22–105
`10–107
`17–108
`
`35 (79.5%) 30 (75.0%) 48 (84.2%)
`8 (18.2%)
`7 (17.5%)
`4 (7.0%)
`—
`2 (5.0%)
`3 (5.3%)
`—
`—
`1 (1.8%)
`1 (2.3%)
`1 (2.5%)
`1 (1.8%)
`
`35 (79.5%)
`7 (15.9%)
`2 (4.5%)
`—
`—
`
`44 (81.5%)
`6 (11.1%)
`2 (3.7%)
`—
`2 (3.7%)
`
`45 (86.5%) 46 (86.8%)
`3 (5.8%)
`2 (3.8%)
`3 (5.8%)
`3 (5.7%)
`—
`1 (1.9%)
`1 (1.9%)
`1 (1.9%)
`
`Sex, n (%)
`Male
`Female
`Age, mo
`6
`Mean
` SD
`Range
`Race, n (%)
`White
`Black
`Hispanic
`Asian
`Other
`Duration of asthma, mo
`6
`Mean
` SD
`Range
`
`31 (88.6%)
`3 (8.6%)
`1 (2.9%)
`—
`—
`
`37 (75.5%)
`10 (20.4%)
`1 (2.0%)
`—
`1 (2.0%)
`
`31 (72.1%)
`11 (25.6%)
`1 (2.3%)
`—
`—
`
`6
`6
`6
`6
`6
` 19.0 22.2
` 15.7 23.0
`28.9
` 20.7 24.8
` 14.0 23.5
` 13.8
`6–78
`5–68
`4–83
`5–65
`6–60
`
`6
`40
` 23.7
`5–90
`
`6
`6
`6
`6
` 23.5 43.3
` 24.1 39.6
`43.4
` 24.2 44.2
` 26.4
`2–91
`4–96
`7–88
`8–98
`
`the placebo group, 38 (78%) patients in the group given budes-
`onide at 0.25 mg daily, 33 (77%) patients in the group given
`budesonide at 0.25 mg twice daily, 35 (80%) patients in the
`group given budesonide at 0.5 mg twice daily, and 24 (60%)
`patients in the group given budesonide at 1.0 mg daily. Among
`the patients who used mouthpieces, 206 of 260 (79%) completed
`the study, including 39 (68%) patients in the placebo group, 36
`(82%) patients in the group given budesonide at 0.25 mg daily,
`45 (83%) patients in the group given budesonide at 0.25 mg
`twice daily, 44 (85%) patients in the group given budesonide
`at 0.5 mg twice daily, and 42 (79%) patients in the group given
`budesonide at 1.0 mg daily. Differences in the proportions of
`mouthpiece users and face mask users who completed the
`
`study were not statistically significant. Among face mask users,
`reasons for study discontinuation included nonprotocol use of
`,
`1%),
`medications (23%), AEs (2%), disease deterioration (
`,
`1%), withdrawal of con-
`noncompliance with study procedures (
`,
`,
`,
`1%), ineligibility (
`1%), and loss to follow-up (
`1%).
`sent (
`Among mouthpiece users, reasons for study discontinuation
`included nonprotocol use of medications (15%), disease de-
`terioration (3%), noncompliance with study procedures (1%),
`,
`,
`1%), withdrawal of consent (
`1%), and ineligibility
`AEs (
`,
`1%). The proportion of treatment discontinuations caused
`(
`by worsening asthma did not differ significantly between the
`placebo group and any of the budesonide inhalation suspension
`treatment groups. In addition, no significant differences were
`
`TABLE 2
`BASELINE ASTHMA SYMPTOMS AND PULMONARY FUNCTION OF STUDY POPULATION
`
`Face Mask
`Budesonide Inhalation Suspension
`
`Placebo
`5
`(
`n
`
`
`
`35)
`
`0.25 mg
`Daily
`5
`(
`n
`
`
` 49
`
`)
`
`0.25 mg
`Twice Daily
`5
`(
`
`n
`
` 43
`)
`
`0.5 mg
`Twice Daily
`5
`(
`n
`
`
`44
`)
`
`1.0 mg
`Daily
`5
`n
`
`
` 40
`
`)
`
`(
`
`Mouthpiece
`Budesonide Inhalation Suspension
`
`0.25 mg
`Twice Daily
`5
`(
`n
`
`
`54
`)
`
`0.5 mg
`Twice Daily
`5
`(
`n
`
`
`
`52)
`
`1.0 mg
`Daily
`5
`(
`n
`
`
`53
`
`)
`
`0.25 mg
`Daily
`5
`n
`
`
`44
`
`(
`
`)
`
`Placebo
`5
`(
`n
`
`
` 57
`)
`
`35
`6
`1.16
`
`49
`43
`6
`6
` 0.69 1.18
` 0.60 1.33
`
`40
`44
`6
`6
` 0.67 1.19
` 0.64 1.22
`
`57
`6
` 0.65 1.17
`
`44
`6
` 0.61 1.08
`
`54
`6
` 0.53 1.33
`
`52
`53
`6
`6
` 0.62 1.22
` 0.61 1.27
`
` 0.62
`
`Variable
`
`Nighttime asthma
`symptom scores*
`
`n
`6
` SD
`Mean
`Daytime asthma
`symptom scores*
`
`6
` SD
`
`35
`48
`43
`40
`44
`57
`44
`54
`52
`53
`6
`6
`6
`6
`6
`6
`6
`6
`6
`6
`1.33
` 0.52 1.27
` 0.53 1.32
` 0.48 1.39
` 0.52 1.24
` 0.57 1.24
` 0.48 1.16
` 0.34 1.30
` 0.50 1.29
` 0.52 1.31
`
` 0.57
`
`1
`90.0
`1
`40.0
`
`1
`170.0
`
`1
`162.9
`
`3
`29
`28
`31
`28
`32
`6
`6
`
`6 15.8 83.1 6 20.6 81.6 6 18.0 78.8 6 13.5
`75.3
` 27.6 80.0
` 16.5 80.1
`3
`29
`28
`32
`28
`32
`25.3 6 9.3
`29.4 6 19.0 28.1 6 15.3 31.2 6 16.8 29.7 6 19.4 26.8 6 12.2
`
`31
`28
`32
`28
`29
`3
`119.1 6 36.6 163.4 6 37.1 175.6 6 52.2 167.5 6 33.1 176.9 6 54.5 170.8 6 33.4
`
`29
`3
`107.9 6 42.1 158.2 6 38
`
`31
`28
`32
`28
`169.7 6 55.0 156.6 6 32.2 167.0 6 49.7 161.4 6 37.9
`
`n
`Mean
`, L
`FEV
`1
`2
`n
`6
`6
`% predicted
`3
`n
`% reversibility 6 SD 26.7 6 3.8
`Evening PEFR, L/min
`n
`Mean 6 SD
`Morning PEFR, L/min
`n
`Mean 6 SD
`
`†
` SD
`
`65.0
`
`4
`2
`6
`6
` 25.5 72.3
` 24.3 82.5
`4
`2
`33.0 6 18.9 19.0 6 4.2
`
` 23.3
`
`2
`4
`3
`135.2 6 32.4 129.4 6 23.5 187.5 6 95.5
`
`2
`4
`3
`133.6 6 34.7 125.3 6 18.7 166.2 6 71.4
`
`* Asthma symptom score scale of 0 to 3 (0 5 no symptoms, 1 5 mild symptoms, 2 5 moderate symptoms, 3 5 severe symptoms).
`† Percent of predicted value for age, height, and sex.
`
`
`
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`

`

`596
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`
`observed in any treatment group between patients who received
`treatment with face masks and those treated with mouthpieces.
`
`Efficacy
`Adjusted mean changes in nighttime and daytime asthma symp-
`tom scores from baseline to the 12-wk treatment period are
`shown in Figures 1 and 2. Overall, mean changes in nighttime
`or daytime asthma symptom scores with face mask use were
`numerically similar to those observed with use of a mouthpiece.
`The improvements also were of similar magnitude to those ob-
`served in the total patient population (22). In the retrospective
`analysis, the improvements in nighttime asthma symptoms
`were statistically significant with budesonide delivered by face
`mask at 0.25 mg daily (p 5 0.040), 0.25 mg twice daily (p 5
`0.008), and 0.5 mg twice daily (p 5 0.046) (Figure 1). Among
`mouthpiece users, significant differences from placebo in night-
`time asthma symptoms were observed in patients who received
`nebulized budesonide at 0.25 mg twice daily (p 5 0.005) and
`1.0 mg daily (p 5 0.035). Significant differences in changes in
`
`daytime symptom scores versus placebo were observed in the
`group of face mask users who received budesonide at 0.5 mg
`twice daily (p 5 0.009) (Figure 2).
`Differences in changes in nighttime asthma symptom scores
`over the 12-wk study period for patients using mouthpieces
`relative to those using face masks were 0.22 6 0.16 for the placebo
`group, 0.04 6 0.12 for the group treated with budesonide at
`0.25 mg daily, 0.02 6 0.13 for the group treated with budesonide
`at 0.25 mg twice daily, 0.01 6 0.14 for the group treated with
`budesonide at 0.5 mg twice daily, and 0.06 6 0.13 for the group
`treated with budesonide at 1.0 mg daily. The corresponding
`differences in changes in daytime asthma symptom scores for
`mouthpiece users relative to face mask users were 0.12 6 0.13
`in the placebo group, 0.08 6 0.12 in the group treated with
`budesonide at 0.25 mg daily, 20.02 6 0.12 in the group treated
`with budesonide at 0.25 mg twice daily, 0.10 6 0.13 in the group
`treated with budesonide at 0.5 mg twice daily, and 20.03 6 0.13 in
`the group treated with budesonide at 1.0 mg daily. Therefore,
`the overall changes in symptom scores were very similar among
`face mask users and mouthpiece users.
`An overall reduction in the use of breakthrough medica-
`tions was observed in all budesonide inhalation suspension
`treatment groups for both face mask and mouthpiece users.
`
`Figure 1. Adjusted mean changes from baseline in nighttime asthma
`symptom scores for patients using face masks (A) and mouthpieces
`(B). *p 5 0.04 for budesonide at 0.25 mg daily versus placebo; †p 5
`0.008 for budesonide at 0.25 mg twice daily versus placebo; ‡p 5
`0.046 for budesonide at 0.5 mg twice daily versus placebo; §p 5 0.005
`for budesonide at 1.0 mg daily versus placebo; ||p 5 0.035 for budes-
`onide at 0.25 mg twice daily versus placebo.
`
`Figure 2. Adjusted mean changes from baseline in daytime asthma
`symptom scores for patients using face masks (A) and mouthpieces
`(B). *p 5 0.009 for budesonide at 0.5 mg twice daily versus placebo.
`
`
`
`Liquidia's Exhibit 1131
`Page 4
`
`

`

`Mellon, Leflein, Walton-Bowen, et al.: Budesonide Inhalation Suspension
`
`597
`
`The number of days of breakthrough medication use per 2-wk
`interval decreased significantly in patients treated with budes-
`onide inhalation suspension taken by mouthpiece as com-
`pared with those who received placebo (p < 0.008 for all dose
`groups). Among mouthpiece users, differences in changes in
`days per 2-wk interval on which patients took breakthrough
`medications relative to placebo were 23.09 d (p 5 0.008) for
`the group treated with budesonide at 0.25 mg daily, 23.78 d
`(p 5 0.001) for the group treated with budesonide at 0.25 mg
`twice daily, 24.26 d (p , 0.001) for the group treated with
`budesonide at 0.5 mg twice daily, and 23.55 d (p 5 0.001) for
`the group treated with budesonide at 1.0 mg daily (Figure 3).
`Patients who received budesonide through face masks also re-
`ported use of less breakthrough medication per 2-wk interval
`than did those who received placebo, with differences of 21.17 d
`in the group given budesonide at 0.25 mg daily, 21.29 d in the
`group given budesonide at 0.25 mg twice daily, 20.87 d in the
`group given budesonide at 0.5 mg twice daily, and 20.35 d in
`the group given budesonide at 1.0 mg daily. These reductions
`were not statistically significant, which may be explained by
`the small sample size and by the fact that this group of pa-
`tients generally was younger and perhaps less likely to request
`breakthrough medications. When the number of days of use
`per 2-wk interval of breakthrough medications by mouthpiece
`users was compared with that by face mask users within each
`dose group, however, there were no statistically significant dif-
`ferences between these patient groups.
`Most patients who received treatment with face masks were
`unable to reproducibly perform PFTs. Consequently, these ad-
`ditional measures of efficacy were meaningful only in patients
`who used mouthpieces. Clinically significant improvements in
`PFTs were observed in patients who used mouthpieces for nebu-
`lization; improvements in FEV1, FVC, and evening PEFR
`achieved statistical significance (p 5 0.039, p 5 0.005, and p 5
`0.023, respectively) in the group treated with budesonide at
`0.5 mg twice daily as compared with the placebo group.
`
`Safety
`The overall incidence, type, and severity of non-asthma–related
`AEs were similar in the placebo and budesonide inhalation
`suspension treatment groups (Table 3). The most frequently
`reported AEs among all treatment groups were respiratory in-
`fection, fever, sinusitis, otitis media, and rhinitis. No clinically
`significant differences were observed between the budesonide
`
`Figure 3. Adjusted mean changes from baseline in days per 2-wk inter-
`val of breakthrough medication use. *p 5 0.0008 for budesonide at
`0.25 mg daily versus placebo; †p < 0.001 for budesonide at 0.25 mg
`twice daily, 0.5 mg twice daily, and 1.0 mg daily versus placebo.
`
`TABLE 3
`ADVERSE EVENTS EXPERIENCED BY > 5% OF PATIENTS
`IN PLACEBO VERSUS ALL TREATMENT GROUPS
`FOR FACE MASK AND MOUTHPIECE USERS
`
`Face Mask
`
`Mouthpiece
`
`Placebo
`(n 5 35)
`n (%)
`
`BIS
`(n 5 176)
`n (%)
`
`Placebo
`(n 5 57)
`n (%)
`
`BIS
`(n 5 203)
`n (%)
`
`11 (31)
`6 (17)
`4 (11)
`8 (23)
`3 (9)
`—
`1 (3)
`4 (11)
`1 (3)
`3 (9)
`3 (9)
`—
`2 (6)
`—
`2 (6)
`1 (3)
`1 (3)
`—
`
`73 (41)
`48 (27)
`30 (17)
`32 (18)
`24 (14)
`5 (3)
`9 (5)
`10 (6)
`13 (7)
`9 (5)
`7 (4)
`12 (7)
`2 (1)
`4 (2)
`8 (5)
`11 (6)
`11 (6)
`8 (5)
`
`16 (28)
`13 (23)
`14 (25)
`7 (12)
`6 (11)
`7 (12)
`7 (12)
`5 (9)
`6 (11)
`4 (7)
`3 (5)
`2 (4)
`3 (5)
`3 (5)
`1 (2)
`1 (2)
`2 (4)
`1 (2)
`
`62 (31)
`22 (11)
`25 (12)
`17 (8)
`15 (7)
`7 (3)
`10 (5)
`5 (2)
`16 (8)
`14 (7)
`16 (8)
`6 (3)
`13 (6)
`2 (1)
`10 (5)
`4 (2)
`7 (3)
`3 (1)
`
`Adverse Event
`
`Respiratory infection
`Fever
`Sinusitis
`Otitis media
`Rhinitis
`Bronchitis
`Headache
`Bronchospasm
`Accident and/or injury
`Coughing
`Gastroenteritis
`Moniliasis
`Pharyngitis
`Pneumonia
`Viral infection
`Vomiting
`Ear infection NOS
`Diarrhea
`
`Definition of abbreviations: BIS 5 Budesonide inhalation suspension; NOS 5 not oth-
`erwise specified.
`
`inhalation suspension and placebo groups in vital signs, physical
`examination findings, or laboratory tests (including nasal or
`oral fungal cultures) during the course of the study. The overall
`incidence of any AEs among budesonide-treated patients was
`slightly higher in patients who received treatment with face
`masks (85%) than in those who received treatment with mouth-
`pieces (78%).
`
`DISCUSSION
`This study showed that budesonide inhalation suspension at
`0.25 mg twice daily, 0.5 mg twice daily, and 1.0 mg daily re-
`sulted in improvements in all efficacy parameters in infants
`and young children with moderate persistent asthma (22). The
`retrospective analysis presented here compared face mask versus
`mouthpiece administration of budesonide, and evaluated efficacy
`on the basis of symptom scores and breakthrough medication
`use. This analysis indicated that treatment at the foregoing dose
`levels of budesonide inhalation suspension alleviated nighttime
`and daytime asthma symptoms and reduced the use of break-
`through medication in both children using face masks and in
`those using mouthpieces. The mode of administration apparently
`does not affect the efficacy of budesonide treatment.
`Young children with asthma may be unable to use dry
`powder or pMDI administration devices; for these patients,
`nebulization may be the preferred route of inhaled drug ad-
`ministration. Zainudin and colleagues (28) compared various
`methods of administration and found that the amount of an in-
`haled bronchodilator deposited in the lungs by a pMDI device
`was not significantly different from the amount deposited by a
`nebulizer. Three randomized, placebo-controlled studies de-
`termined that administration of budesonide by nebulizer is ef-
`fective in the treatment of infants and young children with
`asthma (22–24).
`Nebulizer treatment with a face mask is a reliable means of
`delivering aerosols. In two small studies of b2-agonists in asth-
`matic patients, no difference in response to treatment was
`found between mouthpiece and face mask users (29, 30). Simi-
`
`
`
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`
`lar results were observed in a larger, randomized trial in-
`cluding 64 children 6 to 19 yr of age with acute asthma (31);
`overall, both methods of delivery were found to be equally ef-
`fective. Thus, the clinical decision to use either a face mask or a
`mouthpiece for nebulizer-driven budesonide inhalation sus-
`pension therapy should be based on the individual patient’s
`ability to use the respective devices.
`Administration of nebulized bronchodilators is sometimes
`done with a “blow by” technique in which the face mask is
`waved in front of a child who is anxious or resistant to the use
`of normal procedures. This method is less efficient, reducing
`the amount of drug delivered by approximately 50% when the
`face mask is held at a distance of 2 to 3 cm from the face (32).
`In addition, parents observing this technique may assume that
`it is appropriate for medication delivery and continue this in-
`correct method at home.
`In the present retrospective analysis, patients who received
`nebulized budesonide therapy by either face mask or mouth-
`piece achieved a response that appeared to be independent of the
`mode of budesonide administration, as suggested by changes in
`asthma symptom scores and in the use of breakthrough medi-
`cation. Studies with larger treatment groups would be necessary
`to confirm that the delivery devices investigated in the present
`study have equivalent efficacy. Patients may benefit from
`nebulized budesonide inhalation suspension whether it is ad-
`ministered via face mask or mouthpiece, extending valuable
`treatment options to young children with persistent asthma.
`
`References
`1. National Asthma Education and Prevention Program. 1997. Expert panel
`report 2: guidelines for the diagnosis and management of asthma. Na-
`tional Heart, Lung, and Blood Institute, National Institutes of Health
`(NIH), Bethesda, MD. Publication No. 97-4051.
`2. Centers for Disease Control and Prevention. 1995. Ast