A Controlled Trial of Chlorofluorocarbon-Free Triamcinolone Acetonide Inhalation Aerosol in the Treatment of Adult Patients With Persistent Asthma
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A Controlled Trial of
Chlorofluorocarbon-Free Triamcinolone
Acetonide Inhalation Aerosol in the
Treatment of Adult Patients With
Persistent Asthma*
Michael Welch, MD; David Bernstein, MD; Gary Gross, MD;
Robert E. Kane, MS; Donald Banerji, MD; and the Azmacort HFA Study
Group†
Study objective: To compare the dose response, efficacy, and safety of inhaled triamcinolone
acetonide (TAA) with a hydrofluoroalkane (HFA) propellant (75 mg/puff), TAA with a chlorofluo-
rocarbon propellant (dichlorodifluoromethane [P-12]; 75 mg/puff), and placebo in adult patients
with persistent asthma.
Design: Multicenter, randomized, double-blind, placebo-controlled, parallel-group study of 514
adult patients with persistent asthma.
Interventions and measurements: Patients received 8 weeks of treatment with 150, 300, or 600
mg/d of TAA HFA, the same doses of TAA P-12, or placebo following a 5- to 21-day baseline
period. Efficacy was assessed by spirometry, and by daily recordings of albuterol use, peak
expiratory flow (PEF), asthma symptom ratings, and nighttime awakenings throughout the study.
Results: Linear trend analysis showed that both formulations of TAA at all doses produced
statistically significant improvements compared with placebo in spirometry, asthma symptom
scores, albuterol use, and PEF. Significant improvement was seen as early as 24 h for morning
PEF and as early as 1 week for FEV1 (TAA HFA, 600 mg/d; TAA P-12, 300 and 600 mg/d) and
albuterol use (all doses of both formulations). The P-12 and HFA formulations had comparable
efficacy. A dose response showing greater improvement with higher doses was evident for the
majority of parameters for both formulations. The incidences of adverse events were similar
across all treatment groups with no dose-related trends.
Conclusion: HFA and P-12 formulations of TAA inhalation aerosol were therapeutically equiva-
lent and showed comparable safety and dose-related efficacy in the treatment of patients with
persistent asthma. (CHEST 1999; 116:1304 –1312)
Key words: asthma; chlorofluorocarbon; dichlorodifluoromethane; hydrofluoroalkane-134a; inhaled corticosteroids;
triamcinolone acetonide
Abbreviations: ANOVA 5 analysis of variance; CFC 5 chlorofluorocarbon; FEF25–75% 5 forced expiratory flow in the
middle half of the FVC; HFA 5 hydrofluoroalkane-134a; MDI 5 metered-dose inhaler; P-12 5 dichlorodifluorometh-
ane; PEF 5 peak expiratory flow; TAA 5 triamcinolone acetonide
T hetonideinhaled corticosteroid triamcinolone ace-
(TAA) has been available since 1984 in
supplied as a metered-dose inhaler (MDI) with an
integrated spacer device using the chlorofluorocar-
the United States for the treatment of chronic bon (CFC) propellant dichlorodifluoromethane (P-
asthma in adults and children aged $ 6 years.1–5 It is 12). Approximately 20% of asthma patients use
inhaled corticosteroids, and TAA accounts for a
*From the Allergy & Asthma Medical Group & Research Center significant proportion of that use. In recent years,
(Dr. Welch), San Diego, CA; Bernstein Clinical Research Center CFCs including P-12 have been implicated in the
(Dr. Bernstein), Cincinnati, OH; Pharmaceutical Research &
Consulting, Inc. (Dr. Gross), Dallas, TX; and Rhône-Poulenc destruction of the stratospheric ozone layer; conse-
Rorer (Mr. Kane and Dr. Banerji), Collegeville, PA. quently, many nations including the United States
†A complete list of participants is located in the Appendix. have agreed to replace CFCs in medicinal aerosols
This trial was supported by contracts between Rhône-Poulenc
Rorer Pharmaceuticals, Inc., Collegeville, PA, and the individual with more environmentally friendly propellants.6 –9
clinical investigators or their institutions. An alternative propellant is hydrofluoroalkane-134a
Manuscript received March 12, 1999; revision accepted June 10, 1999. (1,1,1,2-tetrafluoroethane; HFA), which has little
Correspondence to: Michael Welch, MD, Allergy & Asthma
Medical Group & Research Center, 9610 Granite Ridge Dr, Suite potential for ozone destruction and has been shown
B, San Diego, CA 92123; e-mail: mwelch@pol.net to have a favorable short-term toxicity profile.10
1304 Clinical Investigations
Downloaded From: http://publications.chestnet.org/ on 02/07/2015Two new formulations of TAA (75 mg and 225 mg screening visit, a 5- to 21-day pretreatment baseline period, and
dosing strengths) using HFA as a propellant (TAA an 8-week treatment period. Patients discontinued their previ-
ously used inhaled corticosteroid and received single-blind pla-
HFA) have been developed as MDIs. The TAA HFA cebo inhaler treatment during the baseline period. At visit one,
formulations were developed to match the P-12 informed consent was obtained and medical, medication, and
formulation in dose delivery and particle size distri- asthma history were recorded. Pulmonary function tests and a
bution, and use the same integrated spacer device. physical examination including measurement of height and
The present study utilized the 75-mg TAA HFA weight were performed. All spirometry measurements were
performed after withholding albuterol for $ 6 h. For patients to
formulation, which is the same strength as the enter the baseline period, FEV1 must have been within 50 to 90%
marketed P-12 formulation. The current method for of predicted. Blood and urine samples were collected after an 8-h
determination of unit spray content using the new fast for hematology, blood chemistry, and urinalysis. Eligible
United States Pharmacopoeia-tested device11 shows patients were required to demonstrate the proper use of an MDI,
that both formulations deliver approximately 75 mg and were instructed in the use of a Mini-Wright peak flow meter
(Clement Clarke International; Harlow, Essex, UK). They were
of TAA per actuation from the mouthpiece (com- also provided with diaries, an albuterol inhaler for use only as
pared with 100 mg using the old methodology). This needed to control asthma symptoms, and placebo inhalers (HFA
investigation was designed to compare the efficacy propellant) with instructions to take one puff bid for the duration
and tolerability of TAA HFA with those of placebo of the baseline period. During baseline, patients measured and
and TAA P-12 using three different daily doses (150, recorded morning and evening peak expiratory flow (PEF) and
recorded use of baseline study medication (placebo inhaler),
300, and 600 mg) in patients with moderate asthma. albuterol, and other concomitant medication. Patients also re-
corded the number of nighttime awakenings due to asthma,
daytime and nighttime asthma symptoms, and any adverse
Materials and Methods events. At the end of the baseline period, the following criteria
were required for randomization: FEV1 between 50% and 80% of
predicted, $ 24 inhalations of albuterol during the last 4 days,
Patient Selection and a total symptom score of $ 20 points (see “Efficacy and
Safety Variables”) during the last 5 days of the baseline period.
Eligible outpatients were aged $ 18 years, had chronic asthma
During the 8-week treatment period, patients continued to
for $ 2 years, had required daily therapy with inhaled cortico-
record PEF, symptom scores, nighttime awakenings, medication
steroids for $ 30 days, and had an FEV1 of between 50% and
use, and adverse events. Patients returned to the clinic every 14
90% of the predicted value with 15% reversibility following two
days for mouth and throat examination, assessment of pulmonary
puffs of albuterol. Patients who were current smokers or who had
function, and review of diary cards. At the final visit, patients
a smoking history of $ 10 pack-years, life-threatening asthma,
underwent a posttreatment physical examination, and blood and
upper respiratory infection within 30 days, acute exacerbation of
urine were collected for laboratory analysis.
asthma, fungal infection, or other significant coexisting disease
were excluded. Women who were pregnant, lactating, or of
childbearing potential but not practicing an adequate method of Efficacy and Safety Variables
birth control were also excluded. The study protocol and in-
formed consent were reviewed and approved by an independent The primary efficacy variables were mean change from base-
central institutional review board and by boards associated with line to end point in FEV1 (% change) and albuterol use (puffs per
selected sites. Written informed consent was obtained from all day). Other efficacy variables were as follows: mean change from
patients. baseline to end point in forced expiratory flow in the middle half
of the FVC (FEF25–75%); morning and evening PEF; daytime,
nighttime, and 24-h symptom scores; and nighttime awakenings.
Study Medications
Asthma symptoms were rated on a 7-point scale (0 5 no symp-
During the double-blind treatment period, patients were ran- toms to 6 5 incapacitating symptoms requiring physician inter-
domly assigned to receive 1, 2, or 4 inhalations of HFA or P-12 vention). Baseline was the last value before study drug treatment,
formulations of TAA bid (150, 300, or 600 mg/dl), or to receive 1, and end point was the last double-blind visit for FEV1 and
2, or 4 inhalations of HFA-containing placebo bid. All patients FEF25–75%. For diary variables, baseline was the average of
received single-blind HFA placebo treatment during the baseline values in the last 5 days of the baseline period (4 days for
period. Albuterol inhalers were supplied for use as needed to albuterol use), and end point was the average over the last 7 days
control asthma symptoms throughout the study. of double-blind treatment. Mean changes from baseline to each
Patients were not permitted to use any asthma medications visit or each week were also determined.
other than the study drug and albuterol inhaler. Patients who Safety variables included adverse events recorded or reported
required additional asthma medications or used more than 12 by patients, and changes in laboratory test results, vital signs, and
puffs of albuterol on 2 consecutive days were considered treat- physical examination findings. In addition, all patients remained
ment failures. Patients taking a stable regimen were allowed to in the clinic for a minimum of 30 min after inhalation of the first
continue immunotherapy. Patients were also permitted to receive dose of double-blind medication to be watched for any irritant
treatment with intranasal corticosteroids, intranasal cromolyn effects on the airways.
sodium, antibiotics, and antihistamines.
Statistical Analysis
Study Design
The primary intent-to-treat analysis was the comparison of
This was a double-blind, placebo-controlled study conducted at active treatment with placebo within each formulation. A sample
39 centers in the United States. The study consisted of a size of 78 patients per group was chosen to achieve an overall
CHEST / 116 / 5 / NOVEMBER, 1999 1305
Downloaded From: http://publications.chestnet.org/ on 02/07/2015power of $ 90% (a 5 0.05, two-sided) for the placebo vs active FEV1 was 2.2 L (65% of predicted) at the end of the
treatment comparison with regards to FEV1. The difference in baseline period. The full 8-week treatment period
the mean percent change in FEV1 values for the active and
placebo treatments was assumed to be 10% with an SD of 15%.
was completed by 419 of the 514 patients (81.5%).
Analysis of variance (ANOVA), with treatment and center as Thirty-four of the 95 patients (35.8%) who failed to
main effects, was used to assess center by treatment interaction complete the study were in the placebo group. The
for all efficacy variables. In all cases, it was determined that reason for discontinuation was ineffectiveness of the
treatment-by-center interaction was not significant, and a one- test drug in 75 patients, of whom 30 were in the
way ANOVA was used to determine treatment main effect for all
variables, for baseline to end point as well as for weekly analyses.
placebo group, 19 in the TAA P-12 150-mg group,
Dose response was assessed by using a one-sided linear trend and between 3 and 8 in each of the other P-12 and
test, and by pairwise comparisons between doses within each HFA groups (Table 2). Fourteen patients were lost
treatment. Early onset of efficacy for each group was assessed to follow-up. A total of six patients discontinued
using two-sided paired t tests to compare the last morning PEF study participation because of adverse events (three
prior to randomization with PEF values 24 h and 48 h h after the
first dose of treatment. Onset of effect was similarly determined
placebo, two TAA P-12 300 mg, and one TAA HFA
for daily albuterol use on the second day after the beginning of 600 mg).
treatment.
Three sets of analyses were performed to evaluate the compa- Pulmonary Function
rability of the HFA and P-12 formulations regarding five efficacy
variables (FEV1, albuterol use, morning PEF, number of night- Patients taking both formulations of TAA at doses
time awakenings, and 24-h symptom scores). The first analyses
of 150, 300, and 600 mg/d showed significantly
determined whether 90% or 95% confidence intervals fell within
predetermined therapeutic equivalence intervals to establish the greater improvement in FEV1 compared with those
therapeutic equivalence of the same dose of the two formula- taking placebo (Fig 1). The mean increase in FEV1
tions. A one-way ANOVA model was used to compare all at the end of the treatment period ranged from 12.3
treatments, including placebo. Because this analysis showed to 22.0% for the HFA groups and from 14.4 to 24.8%
statistically significant differences between active drug and pla-
for P-12.
cebo, averages (linear combination) across the doses of the two
formulations were tested to determine the overall significance of The results of the analyses of the pulmonary
comparisons between the two formulations. The incidence of function variables other than FEV1 are shown in
adverse events was analyzed using a likelihood ratio test. Table 3. Morning PEF improved significantly in the
Clinical adverse events were summarized and analyzed based HFA 150-, 300-, and 600-mg/d groups (by 9 L/min,
on incidence. All laboratory tests were analyzed based on base-
36 L/min, and 45 L/min, respectively), compared
line-to-end point data. Vital signs (respiration, BP, and pulse),
weight, and physical examination findings were summarized with a decrease of 12 L/min in the placebo group.
descriptively. Evening PEF also significantly increased by 9 to 33
L/min in the HFA groups, compared with a decrease
of about 8 L/min for placebo. Changes in morning
Results and evening PEF were similar in the HFA and P-12
groups, with all doses showing statistically signifi-
Demographics
cant differences from placebo. The increase in
Five hundred fourteen patients (315 women, 199 FEF25–75% was significantly greater for only the
men; mean age, 39 years) were randomized and 600-mg/d dosage of TAA HFA, and for all doses of
treated with double-blind study medication. The the P-12 formulation, compared with placebo.
seven groups were well matched for demographics, Changes in FEV1 at each visit are shown in Figure
baseline FEV1, and albuterol usage (Table 1). Mean 2. Statistically significant improvement vs placebo
Table 1—Baseline Demographic Data, Spirometry, and Albuterol Use in 514 Patients
TAA P-12, mg/d TAA HFA, mg/d
Demographics Placebo 150 300 600 150 300 600
No. of patients 76 71 71 70 74 77 75
Mean age, yr 41.0 39.3 39.2 39.9 37.7 39.3 41.7
Range 19–75 19–74 18–78 22–74 19–69 20–72 18–72
Women, No., % 51 (67) 46 (65) 40 (56) 42 (60) 41 (55) 47 (61) 48 (64)
Mean height, cm 168.3 167.4 169.1 169.7 170.2 168.1 167.7
Mean weight, kg 78.0 79.0 79.6 79.0 77.0 79.0 76.9
Mean FEV1 prebaseline, % predicted 74.6 73.2 73.3 74.2 71.9 74.7 70.9
Mean FEV1 at end of baseline, % predicted 65.7 64.6 64.3 65.3 63.8 67.5 63.2
Mean albuterol use during baseline period, 7.4 7.5 7.1 7.6 7.1 7.4 7.3
puffs/d
1306 Clinical Investigations
Downloaded From: http://publications.chestnet.org/ on 02/07/2015Table 2—Patient Completion Status
Patients, No.
HFA, mg/d P-12, mg/d
Totals Placebo 150 300 600 150 300 600
Randomized 514 76 74 77 75 71 71 70
Completed 419 42 64 68 68 50 61 66
Discontinued 95 34 10 9 7 21 10 4
Inefficacy 75 30 8 6 3 19 6 3
Adverse event 6 3 0 0 1 0 2 0
was seen at week 1 in the 600-mg/d HFA group Bronchodilator Use
(p , 0.005) and was maintained at all visits (Fig 2,
top). The 300-mg/d group was significantly better Statistically significant reductions (p , 0.005) in
than the placebo group at week 2, but not at the rescue albuterol use were seen for all TAA HFA and
other visits (because the analysis was a linear trend P-12 groups compared with placebo (Fig 3). The
test, the significance test for the 150-mg group was reduction from baseline to end point ranged from
not done if the 300-mg group was not significantly 1.8 to 3.4 puffs/d for the HFA groups, and from 1.7
different from the placebo group). The FEV1 to 3.4 puffs/d for P-12; in the placebo group, there
changes were significantly greater with 300 mg/d and was a small decrease of 0.4 puffs/d.
600 mg/d of P-12 than with placebo at all visits (Fig Changes in albuterol use after 48 h were not
2, Bottom). statistically significant for any of the TAA groups,
Morning PEF showed significant improvement as whereas mean albuterol consumption in the placebo
early as 24 h after the beginning of treatment with group increased by 1.3 puffs/d (p , 0.001). By the
TAA HFA or TAA P-12 (Table 4). In the HFA end of week 1, albuterol use decreased significantly
groups, mean PEF increased by 8.6 to 20.2 L/min at in all dose groups of both formulations compared
24 h and by 12.9 to 23.0 L/min at 48 h; the changes with placebo (Fig 4). Albuterol use decreased further
were statistically significant for the 300- and 600-mg during week 2 and trended downward for the re-
groups. The 150- and 600-mg P-12 groups showed mainder of the study. The reductions were greater in
significant increases in morning PEF at these times, the 300- and 600-mg/d groups; in those groups, the
but the small increase in the 300-mg group was not decreases were significantly greater compared with
statistically significant. The placebo group showed placebo during each week of the study. The 150-
small decreases in morning PEF at both 24 h and mg/d groups were significantly different from pla-
48 h. cebo only during weeks 1 to 3 (HFA) or weeks 1 and
3 (P-12), but not during subsequent weeks when the
placebo group showed a decline in mean albuterol
use, probably attributable to the discontinuation of
treatment failures.
Table 3—Changes in Pulmonary Function From
Baseline to End Point: Comparisons Between TAA and
Placebo in 514 Patients*
Morning PEF, Evening PEF, FEF25–75%,
L/min L/min % Change
Placebo 212.1 (6.4) 27.9 (6.6) 6.8 (5.3)
TAA HFA 150 mg/d 9.2† (6.6) 8.9† (6.7) 31.3 (5.4)
TAA HFA 300 mg/d 36.4† (6.4) 27.1† (6.6) 15.9 (5.2)
TAA HFA 600 mg/d 44.9† (6.6) 33.5† (6.8) 32.5† (5.3)
TAA P-12 150 mg/d 24.3† (7.0) 7.7† (6.7) 25.3† (6.0)
TAA P-12 300 mg/d 23.4† (7.0) 19.7† (6.7) 33.7† (6.0)
TAA P-12 600 mg/d 33.7† (7.0) 24.4† (6.7) 42.5† (6.0)
Figure 1. Mean percent change in FEV1 from baseline to end of *Data expressed as mean 6 SEM.
treatment. *p , 0.05 vs placebo; **p , 0.001 vs placebo. †p , 0.05, one-sided linear trend test, TAA vs placebo.
CHEST / 116 / 5 / NOVEMBER, 1999 1307
Downloaded From: http://publications.chestnet.org/ on 02/07/2015Asthma Symptoms Table 4 —Changes in Morning PEF 24 and 48 h After
the Beginning of Treatment in 514 Patients*
Daytime, evening, and 24-h asthma severity scores
Change at 24 h, Change at 48 h,
improved significantly at the end of treatment
L/min L/min
(p , 0.05) in all groups treated with TAA HFA
compared with the placebo group (Table 5). Noctur- Placebo 22.5 (6.6) 23.5 (6.7)
TAA HFA 150 mg/d 8.6 (6.0) 12.9 (6.6)
nal awakenings were also significantly decreased
TAA HFA 300 mg/d 20.2† (7.2) 20.9† (5.8)
across all treatment groups. The P-12 groups showed TAA HFA 600 mg/d 11.5† (5.5) 23.0† (6.7)
very similar results, except that the change in day- TAA P-12 150 mg/d 20.6† (8.2) 18.7† (6.5)
time symptom score was not statistically significant TAA P-12 300 mg/d 4.3 (4.9) 4.9 (6.6)
for the 150-mg/d group. TAA P-12 600 mg/d 23.6† (6.6) 28.9† (7.3)
*Data expressed as mean 6 SEM.
†p , 0.05, two-sided paired test compared with baseline.
Dose Response
Linear trend test results showed dose-response
trends for TAA HFA and TAA P-12. All doses were
significantly different from placebo, with greater daytime, nighttime, and 24-h asthma symptom score;
improvement at higher doses for most efficacy vari- and nighttime awakenings (Table 5).
ables, including morning and evening PEF (Table 3); The results of pairwise comparisons also demon-
strate dose response for both formulations (Table 6).
The HFA 600-mg/d group showed significantly
greater improvement than the 150-mg/d group in all
efficacy variables except FEV1 and FEF25–75%. Dif-
ferences between the 600- and 300-mg/d dosages
were significant for FEV1, FEF25–75%, and daytime
symptom scores, and the 300- and 150-mg/d dosages
were significantly different for morning and evening
PEF, albuterol use, and nighttime awakenings. The
pairwise comparisons between P-12 groups showed
similar results, with the high and low doses showing
significant differences for most variables. The me-
dium and low doses of P-12 were significantly dif-
ferent for three of the nine comparisons, but no
statistically significant differences were found be-
tween the 600- and 300-mg/d dosages of P-12.
Figure 3. Mean change in albuterol use from baseline to end of
Figure 2. Mean percent change in FEV1 at each visit with TAA treatment. *p , 0.05 vs placebo; **p , 0.001 vs placebo.
HFA (top) and TAA P-12 (bottom). *p , 0.05 vs placebo.
1308 Clinical Investigations
Downloaded From: http://publications.chestnet.org/ on 02/07/2015Comparisons Between Formulations
The three methods used to compare the HFA and
P-12 formulations show results supporting equiva-
lence. The analyses based on 95% confidence inter-
vals showed that the two formulations were thera-
peutically equivalent at all three doses with regard to
albuterol use (therapeutic interval, 6 2 puffs) and
nighttime awakenings (therapeutic interval, 6 0.5
awakenings/night). Using the same analysis, thera-
peutic equivalence could not be demonstrated for
FEV1 (therapeutic interval, 6 5%); morning PEF
(therapeutic interval, 6 20 L/min); and 24-h symp-
tom scores (therapeutic interval, 6 0.5 U), although
mean changes were similar in both formulations, and
confidence intervals overlapped zero difference in all
cases.
No significant differences between formulations
Figure 5. Change in morning PEF after 24 and 48 h of
treatment with TAA HFA. *p , 0.05 vs placebo; **p , 0.001 vs
placebo.
were found using the ANOVA model, while the
overall difference between active treatments and
placebo was highly significant (p , 0.001) for all five
outcome measures examined. The linear regression
model showed similarity between formulations in
FEV1, albuterol use, and morning PEF, with parallel
regression lines and overlapping 95% confidence
bands across all dose levels. For 24-h symptom
scores, the confidence bands overlapped at the two
lower doses but not at the 600-mg dose.
Tolerability
Overall, the incidence of adverse events in the
combined TAA groups (P-12 and HFA) were com-
parable (53.8% and 56.6%, respectively), but slightly
higher than in the placebo group (48.7%). Because
of a higher dropout rate in the placebo group, the
extent of exposure was less for the placebo group
than for any of the TAA groups. There were no
trends toward increasing adverse event incidence
with increasing dose level of either formulation. In
fact, for TAA HFA, the lowest incidence of adverse
events (49%) was at the 600-mg dose.
The incidence of adverse events related to the
mouth and throat was low in all groups. “Pharyngi-
tis,” which includes events such as “sore throat” and
“strep throat,” was reported in four placebo patients,
and between two and five patients in each of the
Figure 4. Weekly change in albuterol use for TAA HFA (top)
and TAA P-12 (bottom). *p , 0.05 vs placebo; **p , 0.001 vs active groups. Three cases of oral monilia were
placebo. reported— one each in the P-12 150-mg, P-12 600-
CHEST / 116 / 5 / NOVEMBER, 1999 1309
Downloaded From: http://publications.chestnet.org/ on 02/07/2015Table 5—Changes in Asthma Symptoms From Baseline to End Point:
Comparisons Between TAA and Placebo in 514 Patients*
Daytime Asthma Nighttime Asthma 24-h Symptom
Symptom Score Symptom Score Score Nighttime Awakenings, No./d
Placebo 20.31 (0.11) 20.37 (0.11) 20.73 (0.20) 0.04 (0.10)
TAA HFA 150 mg/d 20.76† (0.11) 20.75† (0.11) 21.52† (0.21) 20.27† (0.10)
TAA HFA 300 mg/d 20.98† (0.11) 21.03† (0.11) 22.03† (0.20) 20.58† (0.10)
TAA HFA 600 mg/d 21.29† (0.11) 21.28† (0.11) 22.57† (0.21) 20.75† (0.10)
TAA P-12 150 mg/d 20.55 (0.11) 20.68† (0.13) 21.27† (0.23) 20.37† (0.09)
TAA P-12 300 mg/d 21.00† (0.11) 21.01† (0.13) 22.01† (0.23) 20.43† (0.09)
TAA P-12 600 mg/d 21.18† (0.11) 21.13† (0.13) 22.34† (0.24) 20.57† (0.09)
*Data expressed as mean 6 SEM.
†p , 0.05, one-sided linear trend test, TAA vs placebo.
mg, and HFA 600-mg groups. Voice alterations were cantly more effective than placebo in improving lung
reported in 10 patients—5 each in the P-12 and HFA function and decreasing asthma symptoms. FEV1
groups. Five patients reported adverse events during and morning and evening PEF showed statistically
the 30-min observation period after the first dose of significant improvements in the active groups com-
study drug. The events were mild dry mouth (P-12 pared with the placebo group at all three dosing
150 mg and HFA 150 mg), moderate nasal congestion levels. Asthma symptom scores and nighttime awak-
(placebo), mild tingling sensation in tongue (HFA enings also showed consistent, statistically significant
600 mg), and mild vertigo (HFA 300 mg). improvement compared with placebo, along with
Six patients withdrew from the study because of decreased use of albuterol in the TAA groups.
adverse events. Four of these were respiratory The TAA HFA 75 mg product was formulated
events: pneumonia and asthma exacerbation (P-12 specifically to replace the CFC-containing product.
300 mg); chest congestion and raspy throat (placebo); The HFA and P-12 formulations of TAA appear to
upper respiratory infection (placebo); and cough be comparable based on the results of this study.
(HFA 600 mg). One patient (P-12 300 mg) withdrew Comparisons across formulations incorporating all
because of a range of symptoms including head- treatment groups indicated no statistically significant
aches, generalized edema, anxiety, and insomnia. or clinically significant efficacy differences between
The sixth patient (placebo) withdrew because of the two formulations. In particular, therapeutic
poison ivy. None of these adverse events were equivalence was demonstrated across formulations
thought to be related to the study medication. There for albuterol use and nighttime awakenings. The
were two serious adverse events: anxiety (P-12 300 relatively stringent therapeutic intervals chosen
mg) and acute exacerbation of asthma (HFA 300 mg). partly explain the failure to show equivalence for the
Both serious adverse events were considered unre- other variables. The results of regression analyses
lated to the study drug. were consistent with those of the other two analyses,
No clinically significant changes in laboratory val- ie, both formulations were comparable at all doses.
ues, vital signs, or physical examination fingings were It is well known that it is difficult to demonstrate
observed in any of the treatment groups. clear dose-response effects for improvement in lung
function with inhaled corticosteroids. The review by
Discussion Pedersen and O’Byrne12 pointed out that 9 of 10
published efficacy studies of inhaled corticosteroids
The results of this study showed that both the have failed to show statistically significant differ-
HFA and P-12 formulations of TAA were signifi- ences between the clinical effects of adjacent dose
Table 6 —Dose Response: Pairwise Comparisons Between Doses in 514 Patients*
Treatment Morning Evening Albuterol Daytime Nighttime 24-h Sx Nighttime
Comparisons FEV1 FEF25–75% PEF PEF Use Sx Scores Sx Scores Scores Awakenings
HFA-600 vs HFA-300 0.007 0.023 NS NS NS 0.044 NS NS NS
HFA-600 vs HFA-150 NS NS ,0.001 0.007 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001
HFA-300 vs HFA-150 NS NS 0.001 0.031 0.002 NS NS NS 0.022
P-12-600 vs P-12-300 NS NS NS NS NS NS NS NS NS
P-12-600 vs P-12-150 0.012 NS NS 0.038 ,0.001 ,0.001 0.014 0.001 NS
P-12-300 vs P-12-150 NS NS NS NS 0.002 0.010 NS 0.029 NS
*Sx 5 symptom; NS 5 not statistically significant (p . 0.05). The higher dose showed greater improvement for all statistically significant
differences.
1310 Clinical Investigations
Downloaded From: http://publications.chestnet.org/ on 02/07/2015steps. The reasons for failure to demonstrate signif- HFA are in accord with previous studies of intranasal
icant dose response in previous studies could depend TAA in patients with allergic rhinitis.20 –22
on a number of factors, such as severity of the Both treatments were well tolerated: the minimal
disease itself, prior treatment with inhaled steroids, occurrences of adverse events in the active groups
length of treatment period, or small patient sample were not clinically different from placebo. There was
size. In this study, however, a dose response was no evidence of increased incidence of adverse events
evident for both formulations, with the high dosage with increasing dose of either formulation of TAA.
(600 mg/d) showing significantly greater improve- This study was not designed to assess the relative
ment than the low dosage (150 mg/d) for the majority systemic effects of the HFA and CFC formulations.
of parameters. Statistically significant dose-response A previous study in asthmatic adults showed very
differences were also demonstrated between adja- small decreases in cosyntropin stimulation test re-
cent doses of TAA HFA for several variables. The sults after 6 or 12 months of treatment with TAA
same was true for the low and middle doses of TAA HFA.23 Another study in children treated with TAA
P-12, but no significant differences in any of the HFA or TAA CFC for 6 weeks showed no difference
variables were found between the 300-mg and in response to cosyntropin between the two formu-
600-mg doses. Similar results were reported in an lations.24 These results and those of the current
earlier study of TAA P-12, with significant differ- study lead us to conclude that the formulation of
ences between doses for albuterol use but not for TAA inhalation aerosol using HFA-134a as propel-
FEV1 or symptom scores.13 Significant differences in lant is as efficacious and safe in the treatment of
response between different doses have also been persistent asthma as the marketed CFC formulation.
reported in studies of budesonide and fluticasone
propionate.14,15
The significant differences in FEV1 and Appendix
FEF25–75% between the 300- and 600-mg doses of
TAA HFA are notable because the 150- and The Azmacort HFA Study Group consisted of 39 clinical research
600-mg doses did not significantly differ for these centers in the United States. The principal investigators at the 39
centers are as follows: Donald Aaronson, MD, Des Plaines, IL;
variables. These unexpected findings are probably Howard Offenberg, MD, Gainesville, FL; Donald Auerbach,
attributable to the fact that FEV1 and FEF25–75% MD, Cherry Hill, NJ; John Oppenheimer, MD, Morristown, NJ;
increased more in the 150-mg group than in the Thomas Bell, MD, Missoula, MT; Peter Petroff, MD, San
300-mg group, which in turn may have been due to Antonio, TX; George Bensch, MD, Stockton, CA; Frank Picone,
the fact that baseline values for both parameters MD, Tinton Falls, NJ; William Berger, MD, Mission Viejo, CA;
Stephen Pollard, MD, Louisville, KY; David Bernstein, MD,
were higher in the 300-mg group than in any of the Cincinnati, OH; Gordon Raphael, MD, Bethesda, MD; Jacques
other groups. This higher baseline did not allow Caldwell, MD, Daytona Beach, FL; Robert Rhodes, MD, Mar-
for as large an improvement for the 300-mg group. tinez, GA; Robert Cohen, MD, Lawrenceville, GA; Richard
Lung function improvement as measured by Rosenthal, MD, Fairfax, VA; Leonard Cosmo, MD, Tampa, FL;
morning and evening PEF, on the other hand, was Eric Schenkel, MD, Easton, PA; Frank Demarco, Jr., MD,
Wheat Ridge, CO; Nathan Segall, MD, Atlanta, GA; Thomas
significantly greater in the 300-mg group than in Edwards, MD, Albany, NY; Guy Settipane, MD, Providence, RI;
the 150-mg TAA group, just the opposite of the Stanley Fineman, MD, Marietta, GA; William Silvers, MD,
result seen for FEV1 and FEF25–75%. Englewood, CO; Marc Goldstein, MD, Mt. Laurel, NJ; Tommy
Inhaled corticosteroids must be taken regularly to Sim, MD, Galveston, TX; Gary Gross, MD, Dallas, TX; William
effectively control asthma,16 and for that reason the Sokol, MD, Newport Beach, CA; Dan Henry, MD, Salt Lake
City, UT; Sheldon Spector, MD, Los Angeles, CA; Robert
effects of inhaled corticosteroids are generally Jacobs, MD. San Antonio, TX; Paul Steinberg, MD, Minneapolis,
thought to occur gradually over a period of weeks or MN; Michael Kraemer, MD, Spokane, WA; William Stricker,
months.17 In the current study, both formulations MD, Rolla, MO; Craig LaForce, MD, Raleigh, NC; Michael
showed statistically significant improvement in FEV1 Wein, MD, Vero Beach, FL; Bruce Martin, DO, San Antonio,
as early as the first return visit, 1 week after the start TX; Michael Welch, MD, San Diego, CA; Michael Noonan, MD,
Portland, OR.
of treatment. Albuterol use was significantly de-
creased as well by the end of 1 week at all doses of
TAA. Even earlier onset of effect was evident by the
significant improvement in morning PEF at 24 h and References
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1312 Clinical Investigations
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