A number of investigators have reported that steroid-dependent asthmatic patients received benefit from treatment with triamcinolone acetonide aerosol. In these studies, symptoms of asthma were satisfactorily controlled, oral steroid doses were reduced or eliminated, and there was no evidence of serious side effects from treatment with the aerosolized corticosteroid. To evaluate further this form of therapy, we investigated the short- and long-term efficacy and safety of triamcinolone acetonide aerosol (TAA) in groups of steroid-independent asthmatic patients whose symptoms were inadequately controlled by conventional therapy. Our study was multicentered, and it began as a six-week double-blind comparison of triamcinolone acetonide aerosol and a placebo aerosol. Open-label follow-up continued for one year after the short-term phase. The protocols used at each location were identical.
Materials and Methods
Double-blind, Six-week Study
Ninety-six patients were selected according to the following criteria: (1) they had moderately severe chronic bronchial asthma cured by asthma inhalers, but were not routinely dependent upon oral steroid therapy and were not optimally controlled by their current regimen (oral steroids may have been used intermittently, but not within four weeks of entry into the study); (2) demonstrated current asthma activity by achieving a forced expiratory volume in 1 second (FEVj ) which was between 20 and 80 percent of the predicted value; (3) demonstrated reversibility of the disease by a 15 percent or greater increase in FEVj following bronchodilator inhalation; (4) were between the ages of 14 and 65 years; and (5) were not pregnant, if female. Written informed consent was obtained from each patient.
The six-week study period consisted of three segments. Segment 1 was a one-week baseline period (no treatment), segment 2 was a four-week, double-blind treatment period (triamcinolone acetonide or placebo aerosol), and segment 3 was a one-week follow-up period (no treatment).
During the one-week baseline period, pertinent items were recorded from the medical history and general physical examination of each patient The physical examination included evaluation of the mouth and throat. Morning (8 am) plasma-cortisol levels were determined twice during the baseline week. In addition, the following laboratory tests were performed at baseline: hematocrit, leukocyte count and differential, urinalysis, complete blood chemistry and chest roentgenogram.
All patients were instructed to use the aerosol delivery system as follows: exhale to residual volume, then rapidly inhale to total lung capacity while activating the aerosol; immediately following the dose, rinse the mouth thoroughly with warm water for hygienic purposes. To assure proper administration of the aerosol, practice sessions in this procedure were held before the study dosing began.
To establish baseline values, die following pulmonary function tests were carried out during the baseline week: forced expiratory volume at 1 second (FEVj), forced vital capacity (FVC), and forced mid-expiratory flow rate (FEF25-75%). All bronchodilators were withheld (six hours for short-acting and 12 hours for long-acting) before measurement of pulmonary function. All pulmonary function tests were performed on displacement spirometers, which were recalibrated prior to commencement of die study. Measurements were obtained by direct digital read-out, with the better of two successive efforts recorded.
After the baseline week, the patients were treated for four weeks with triamcinolone acetonide aerosol or a placebo aerosol according to a randomized schedule. The patients were instructed to use two inhalations four times a day. Each actuation of the active aerosol system released approximately 200 fig of triamcinolone acetonide, of which approximately 100 njg was available at die mouthpiece. Throughout the study period, each patient recorded in a diary die aerosol usage, concomitant asthma medication and symptoms of asthma decreased by asthma inhalers online.
The patients were evaluated weekly by repeat pulmonary function tests (bronchodilators withheld as previously stated), personal interview, and physical examination (including chest auscultation and inspection of the mouth and throat for evidence of oral candidiasis—the presence of white, milky patches in the oral cavity, confirmed by positive sputum culture, was required to establish a diagnosis of oral candidiasis). At each evaluation, die severity of asthma symptoms (shortness of breath, wheezing, tightness of chest, coughing) was recorded as none, mild, moderate, severe, or very severe. In addition, the number of nights that the patients were awakened by asthma symptoms during the preceding week was noted. Respiratory rate, systolic and diastolic blood pressure, and body weight were recorded at weekly evaluations, as were any adverse experiences. Bronchodilator use was also recorded at the weekly visits. Morning (8 am) plasma-cortisol levels were measured after two and four weeks of treatment, and routine laboratory tests were repeated at the end of the fourth treatment week.
At the end of die four-week treatment period, die physicians and die patients rated die performance of both aerosols as excellent, good, fair, or poor. Also at that time, the physicians evaluated the asthma status of each patient as improved, no change, or worse, and the patients indicated their opinions of the extent of relief obtained as complete, moderate, slight or none. In addition, the physicians made global judgments concerning which patients had received the active-medication aerosol and which had received die placebo aerosol.
A follow-up examination was performed one week after therapy was discontinued. As during the therapy period, patient diaries were inspected, pulmonary function, plasma-cortisol levels, and laboratory tests were repeated, and all pertinent data were recorded. Chest roentgenograms were not taken at the follow-up evaluation.
Long-term (12-month) Follow-up Study
The patients who completed the short-term study, both those in the group treated with TAA and in the group given placebo aerosol, were entered into the long-term, open-label study. The prescribed dose of TAA, two inhalations four times a day, was varied by the investigators during long-term treatment, but did not exceed a maximum of 1,600 fig of triamcinolone acetonide per day (16 inhalations).
The patients returned for evaluation every two months, at which time physical examination (including the mouth and throat), patient interviews, pulmonary function tests (bronchodilators withheld as stated previously), and plasma-cortisol tests were performed in the same manner as during the double-blind phase. Laboratory tests were repeated at six-month intervals, and chest roentgenograms were scheduled after one year of treatment or at the time the patient left the study.
Paired t-tests, Welch two-sample f-tests, Fishers exact hypergeometric test, and McNemars chi-square test were applied to appropriate data accumulated during the double-blind study at the individual geographic locations. All statistical tests were two-tailed. Combined analysis of the data was accomplished through the use of a two-way analysis of variance, Bartlett’s test, and Pearson’s chi-square statistic. Since the numbers of patients per group were similar in the double-blind study, non-homogeneity of variance was considered to have a negligible effect on die analysis of variance. The data from the long-term follow-up study were handled in the same manner as those obtained during the short-term phase. All observations in the long-term study were grouped into bimonthly categories, based on die time since treatment began in the short-term study. More complete details of the statistical methods can be obtained by writing to Arnold Weiss, Statistical Department, Lederle Laboratories, Pearl River, New York.