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

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Two 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

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power 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

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Table 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.

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Asthma 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.

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Comparisons 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-

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Table 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.

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steps. 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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