Long-Term Budesonide or Nedocromil Treatment, Once Discontinued, Does Not Alter the Course of Mild to Moderate Asthma in Children and Adolescents
Article Outline
Objectives
To determine whether long-term, continuous use of inhaled anti-inflammatory medications affects asthma outcomes in children with mild to moderate asthma after use is discontinued.
Study design
Of the 1041 participants in the Childhood Asthma Management Program randomized clinical trial, 941 (90%) were followed to determine whether 4.3 years of twice-daily budesonide or nedocromil administration (each compared with placebo) affected subsequent asthma outcomes during a 4.8-year posttrial period in which treatment was managed by the participants' physicians.
Results
The groups treated continuously during the trial with either budesonide or nedocromil did not differ from the group given placebo in terms of lung function, control of asthma, or psychological status at the end of 4.8 years of posttrial follow-up. However, the decreased mean height in the budesonide group relative to the placebo group at the end of the trial (1.1 cm; P = .005) remained statistically significant (0.9 cm; P = .01) after an additional 4.8 years and was more pronounced in girls (1.7 cm; P = .001) than in boys (0.3 cm; P = .49). Participants in all groups used inhaled corticosteroids during 30% of the posttrial period.
Conclusions
Clinically meaningful improvements in the control of asthma and in airway responsiveness achieved during continuous treatment with inhaled corticosteroids do not persist after continuous treatment is discontinued.
Abbreviations: BMD, Bone mineral density, CAMP, Childhood Asthma Management Program, FEV1, Forced expiratory volume in one second, FVC, Forced vital capacity, ICS, Inhaled corticosteroids, NAEPP, National Asthma Education and Prevention Program, RR, Relative risk
Asthma is a disease of chronic airway inflammation characterized by reversible airway obstruction and increased airway responsiveness.1, 2 Inhaled anti-inflammatory therapy provides improved asthma symptom control and pulmonary function.1, 3, 4 Inhaled corticosteroids (ICS) have been shown to be the most effective form of anti-inflammatory therapy, with benefits for periods of more than 1 year reported in controlled clinical trials.5, 6 The Childhood Asthma Management Program (CAMP) was a randomized clinical trial comparing 3 treatments for mild to moderate asthma.5, 7 CAMP demonstrated that budesonide 200 μg twice daily led to significantly lower airway responsiveness to methacholine, fewer hospitalizations, fewer urgent care visits, greater reduction in the need for albuterol to reduce symptoms, fewer courses of prednisone, and a smaller percentage of days in which additional asthma medications were needed, compared with placebo over a 4.3-year period.5 The CAMP trial also found that nedocromil 8 mg twice daily significantly reduced urgent care visits and courses of prednisone compared with placebo but did not affect airway responsiveness, symptoms, or hospitalizations.5 Budesonide increased forced expiratory volume in 1 second (FEV1) after bronchodilator use in the first year of the trial, but neither budesonide nor nedocromil had an impact on this measure of lung function at the end of the trial.5 Side effects of budesonide were limited to a small reduction in height; neither treatment had a detrimental impact on bone density, fracture rate, or psychological measures.5
Although asthma control was improved in the patients treated with anti-inflammatory medications during the 4.3 years of the CAMP trial, the long-term benefits and safety of these medications, particularly ICS, remained to be determined. Consequently, patients enrolled in the CAMP trial were reenrolled in an observational posttrial follow-up study to determine whether the 4.3 years of regular anti-inflammatory treatment, once discontinued, had an influence on asthma control, pulmonary function as measured by prebronchodilator and postbronchodilator spirometry, airway lability, physical growth, bone density, and psychological status.
Methods
Children age 5 to 12 years with mild to moderate asthma, defined by the presence of symptoms or by the use of an inhaled bronchodilator at least twice weekly or daily medication for asthma, enrolled in the CAMP trial between December 1993 and September 1995.7 At the time of enrollment, each child's airway responsiveness to methacholine, as indicated by the concentration of the drug that caused a 20% decrease in the FEV1, was ≤ 12.5 mg/mL.7
Follow-Up After Study Medication Discontinuation
At the end of the CAMP trial, study medication (budesonide Turbuhaler [AstraZeneca, Westborough, Massachusetts] 200 μg twice daily or nedocromil 8 mg twice daily vs matching placebos) was discontinued, and participants were followed by the CAMP investigators during a washout period for 8 calendar months (March through October 1999). Although the goal was to treat all patients with albuterol alone during this washout period, patients who were using open-label asthma medications in addition to the study medication continued on those medications, and patients whose asthma was judged too severe to tolerate albuterol alone were prescribed open-label asthma medication according to National Asthma Education and Prevention Program (NAEPP) guidelines. Each participant was seen twice during the washout period, once for a methacholine challenge and once for prebronchodilator and postbronchodilator spirometry. Initiation of medication for asthma, prednisone use, urgent care use, and hospitalizations were reported by the participants or their parents to clinic staff during the washout period. At the end of the washout period, the participants were invited to enroll in a 4.5-year posttrial follow-up study, during which care was advised based on NAEPP guidelines1, 8 in communications to the primary care physicians. Each participant's parent or guardian signed a written informed consent approved by the local institutional review board, with reconsent provided by the participant himself or herself at age 18 years.
During the posttrial follow-up study initiated in November 1999, participants were seen twice yearly in a CAMP clinic and were interviewed by telephone twice yearly (between clinic visits). One of the annual clinic visits included prebronchodilator and postbronchodilator spirometry; this visit was timed to occur on the participant's randomization anniversary. The second annual visit included prebronchodilator spirometry and a methacholine challenge (a challenge was not performed within 28 days of an upper respiratory tract infection or the use of prednisone for exacerbation of asthma), timed to occur about 6 months from the participant's randomization anniversary. At each visit, the study coordinator queried the participant (or the parents, depending on the participant's age) about health history since the previous contact, reviewed medicines used for asthma in the preceding 7 days, and asked about the number of courses of oral corticosteroids used since the last contact. Height (measured with a Harpenden stadiometer [Holtain Limited, Crosswell, Crymych, Pembrokeshire, UK]) and weight were measured at each visit. Sexual maturation was assessed by Tanner staging annually up to age 18 years, or until Tanner stage 5 in all parameters was measured on 2 consecutive examinations.
The telephone interviews used the same interim health history and medication use questionnaire used during the twice-yearly clinic visits, giving a total of 4 interviews per year. Medication use over the preceding 7 days was assumed to represent use in the 3 months since the last contact.
Bone density (total bone mineral density [BMD] of the spine from L1 to L4, in g/cm2) was measured at 7 and 9 years after randomization by dual-energy X-ray absorptiometry using a Hologic or a Lunar scanner with either a fan or pencil beam (Hologic; Bedford, Massachusetts, and Lunar Corporation; Madison, Wisconsin). The Lunar measures were standardized to the Hologic measures by the following equation: Hologic BMD = 0.885 × Lunar BMD.9 As patients grow taller, the pencil and fan beam values deviate from one another, necessitating further correction.9 Pencil beam values for participants of height ≥ 1.4 m were standardized to fan beam values by the following equation: fan beam BMD = pencil beam BMD + 0.0549.10 These corrections were sufficient for pooling the Hologic and Lunar values, except for the Lunar values from the Denver clinic; no amount of adjustment allowed the pooling of those values with the others.
The Child Behavior Checklist11 was completed annually by a parent for participants under age 18 years. The Pediatric Asthma Quality of Life questionnaire12 was completed annually by participants.
Information obtained during each visit, including spirometry, symptoms, and medication requirements, was used to recommend treatment in accordance with the NAEPP guidelines1, 8 in a letter to the participant's primary care provider after each clinic visit.
Statistical Analysis
The outcome measures and statistical methods parallel the measures and methods used in the report of the primary results,5 but with outcome measures defined during the 4.8 years of posttrial follow-up after discontinuation of continuous use of study medication according to the trial protocol. Each participant was included in the treatment group assigned at randomization regardless of the course of subsequent treatment for asthma (intention-to-treat analysis). The mean differences between the budesonide or nedocromil group and the placebo group in terms of age, duration of follow-up, and percentage of time receiving asthma treatment during the posttrial period were assessed using t-tests. Rates of morbidity outcomes (ie, prednisone courses, urgent care visits due to asthma, hospitalizations due to asthma, fractures) during the posttrial period were calculated as the number of outcome events occurring during the posttrial period divided by the number of person-years of posttrial follow-up. Relative risks (RRs) of each morbid outcome, comparing the budesonide or nedocromil group with the placebo group, were calculated using multivariate Poisson regression with an offset for the person-years of follow-up.13 Differences in means of continuous outcomes, comparing the budesonide or nedocromil group with the placebo group, measured at the end of the posttrial period (ie, prebronchodilator and postbronchodilator lung function, airway lability, physical growth, psychological, and quality-of-life measures) were determined from multivariate linear regression models for each continuous outcome. The multivariate Poisson and linear regression models included 2 binary variables to indicate the budesonide or nedocromil treatment group, along with the following 8 covariates: the value of the outcome measure at randomization (continuous outcomes only), age at randomization, race or ethnic group (African American, Hispanic, or other; 2 indicator variables), sex, clinic (7 indicator variables), duration of asthma at randomization (at least 7 years, less than 3 years, or other; 2 indicator variables), severity of asthma at randomization (moderate vs mild), and skin test reactivity at randomization (any reactivity vs none). Adjusted means for each continuous posttrial outcome measure in each treatment group were derived from the regression model using mean values for all covariates except treatment group indicators.14 The statistical significance of differential treatment effects on height in males and females, comparing the budesonide or nedocromil group with the placebo group, was assessed by adding a sex-by–treatment group interaction term to the multivariate regression model for posttrial mean height. Adjusted mean values for each measure of morbidity, lung function after the use of a bronchodilator, and bronchodilator reversibility during the 9 years of follow-up after randomization to the budesonide, nedocromil, or placebo group were derived from the regression model using mean values for all covariates except treatment group indicators and replacing the treatment group indicators with indicator variables for each treatment by follow-up assessment time combination.
The P values presented for all analyses are 2-sided and are not adjusted for multiple comparisons. The multivariate Poisson regression analyses were performed using Stata release 9 (StataCorp, College Station, Texas); all other analyses were performed using SAS version 6.12 (SAS Institute Inc, Cary, North Carolina).
Results
Study Population and Completion of Follow-Up
Approximately 90% of the original CAMP cohort (941 of 1041) enrolled in the posttrial follow-up study. The enrollees were similar to the nonenrollees in all aspects except with respect to clinic; the percentage of enrollment of participants at the various clinics ranged from 78% to 99% (P < .001) (Table I; available at www.jpeds.com). Despite the 10% nonenrollment across the original cohort, the participants in the budesonide, nedocromil, and placebo groups who enrolled in the follow-up study were similar with respect to characteristics at CAMP randomization (Table II; available at www.jpeds.com). At the end of the posttrial follow-up period, age and duration of follow-up were similar in the 3 groups (Table III; available at www.jpeds.com). The percentage of scheduled visits completed during the posttrial follow-up period exceeded 96% in each group. The mean duration of follow-up in the posttrial period was 4.8 ± 0.5 years.
Table I. Comparison of nonenrollees and enrollees in the posttrial follow-up study, as of entry into the CAMP trial
| Nonenrollees | Enrollees | |||
|---|---|---|---|---|
| n | (n = 99)⁎ | (n = 941) | P value† | |
| Total | 1040⁎ | 9.5% | 90.5% | |
| Treatment group in CAMP trial | ||||
 Budesonide | 311 | 27.3% | 30.2% | .55 |
| Nedocromil | 311 | 34.3% | 29.4% | |
| Placebo budesonide | 208 | 22.2% | 19.8% | |
| Placebo nedocromil | 210 | 16.2% | 20.6% | |
| Clinic | ||||
| Albuquerque | 121 | 16.2% | 11.2% | <.001 |
| Baltimore | 128 | 3.0% | 13.3% | |
| Boston | 124 | 9.1% | 12.2% | |
| Denver | 143 | 32.3% | 11.8% | |
| San Diego | 122 | 12.1% | 11.7% | |
| Seattle | 144 | 14.1% | 13.8% | |
| St Louis | 133 | 2.0% | 13.9% | |
| Toronto | 125 | 11.1% | 12.1% | |
| Age at randomization, years | ||||
| 5 to 6 | 233 | 20.2% | 22.6% | .16 |
| 7 to 9 | 456 | 37.4% | 44.5% | |
| 10 to 13 | 351 | 42.4% | 32.8% | |
| Race or ethnic group | ||||
| Caucasian or other | 804 | 79.8% | 77.1% | .09 |
| African American | 138 | 7.1% | 13.9% | |
| Hispanic | 98 | 13.1% | 9.0% | |
| Sex | ||||
| Female | 419 | 45.5% | 39.7% | .28 |
| Male | 621 | 54.5% | 60.3% | |
| Severity of asthma | ||||
| Mild | 498 | 48.5% | 47.8% | .90 |
| Moderate | 542 | 51.5% | 52.2% | |
| FEV1 % of predicted‡ | ||||
| Prebronchodilator | — | 98.8±18.0 | 97.2±17.2 | .38 |
| Postbronchodilator | — | 108.3±16.1 | 106.8±16.3 | .38 |
| FVC % of predicted‡ | ||||
| Prebronchodilator | — | 106.5±15.2 | 104.2±14.4 | .14 |
| Postbronchodilator | — | 110.1±15.0 | 106.6±13.8 | .02 |
| FEV1/FVC (%) | ||||
| Prebronchodilator | — | 80.2±8.6 | 79.7±8.3 | .53 |
| Postbronchodilator | — | 85.1±6.7 | 85.5±6.5 | .52 |
| Time since doctor diagnosis of asthma | ||||
| Less than 3 years | 264 | 29.3% | 25.1% | .04 |
| At least 3 but less than 7 years | 519 | 38.4% | 51.4% | |
| At least 7 years | 251 | 32.3% | 23.4% | |
| Enrollment cohort | ||||
| December 1993 to June 1994 | 235 | 32.3% | 21.6% | .09 |
| July to December 1994 | 373 | 30.3% | 36.5% | |
| January to June 1995 | 368 | 33.3% | 35.6% | |
| July to September 1995 | 64 | 4.0% | 6.4% |
⁎Excludes 1 participant who died during the CAMP trial. |
†P value for homogeneity among groups. |
Table II. Characteristics of participants in the posttrial follow-up study as of entry into the CAMP trial (n = 941), by treatment group in the CAMP trial
| Treatment group in the CAMP trial | |||
|---|---|---|---|
| Bud | Ned | Placebo | |
| (n = 284) | (n = 277) | (n = 380) | |
| Age at randomization, years | 9.0±2.0 | 8.8±2.1 | 8.9±2.2 |
| Race or ethnic group, n (%) | |||
| Non-Hispanic white | 186(65.5) | 197(71.1) | 266(70.0) |
| Non-Hispanic black | 44(15.5) | 33(11.9) | 54(14.2) |
| Hispanic | 29(10.2) | 24(8.7) | 32(8.4) |
| Other | 25(8.8) | 23(8.3) | 28(7.4) |
| Sex, n (%) | |||
| Female | 115(40.5) | 95(34.3) | 164(43.2) |
| Male | 169(59.5) | 182(65.7) | 216(56.8) |
| Age at onset of asthma symptoms, years | 3.1±2.3 | 3.1±2.4 | 3.0±2.5 |
| Time since doctor diagnosis of asthma, years | 5.2±2.5 | 5.0±2.6 | 5.0±2.7 |
| Treatments in the 6 months before enrollment, n (%) | |||
| Cromolyn or nedocromil | 125(44.0) | 135(48.7) | 154(40.5) |
| ICS | 116(41.4) | 103(37.3) | 139(36.8) |
| Oral corticosteroid | 98(34.9) | 88(31.9) | 149(39.3) |
| Severity of asthma, n (%) | |||
| Mild | 134(47.2) | 134(48.4) | 182(47.9) |
| Moderate | 150(52.8) | 143(51.6) | 198(52.1) |
| Hospitalizations for asthma in year before enrollment, n/100 person-years | 7.0 | 5.1 | 6.8 |
| Recordings on daily diary card | |||
| Episode-free days,⁎ n/month | 9.5±7.5 | 9.4±7.6 | 9.3±7.2 |
| Use of albuterol for symptoms, puffs/week | 10.6±9.9 | 10.6±9.8 | 10.2±9.7 |
| Night awakenings, n/month | 0.9±1.7 | 1.0±1.8 | 0.8±1.5 |
| Days with symptoms interfering with daily Activity, n/month | 2.4±4.5 | 2.2±3.3 | 1.9±2.9 |
| Prebronchodilator lung function | |||
| FEV1 % of predicted† | 96.6±16.8 | 97.2±17.4 | 97.7±17.4 |
| FVC % of predicted† | 104.1±14.1 | 104.1±14.2 | 104.3±14.8 |
| FEV1/FVC (%) | 79.4±8.3 | 79.4±7.9 | 80.1±8.7 |
| Postbronchodilator lung function | |||
| FEV1 % of predicted† | 106.3±16.2 | 106.6±16.3 | 107.3±16.4 |
| FVC % of predicted† | 106.6±14.0 | 106.3±13.4 | 106.8±14.0 |
| FEV1/FVC (%) | 85.4±6.5 | 85.3±6.3 | 85.8±6.7 |
| Airway lability | |||
| Bronchodilator reversibility, %‡ | 11.0±10.1 | 10.4±9.9 | 10.7±10.0 |
| FEV1PC20 methacholine, mg/mL§ | 1.08±3.22 | 1.12±3.31 | 1.06±3.13 |
| Physical growth | |||
| Females | |||
| Height, cm | 134.8±13.6 | 132.4±13.8 | 133.5±13.3 |
| Tanner breast stage, n (%) | |||
| 1 | 80(69.6) | 71(74.7) | 114(69.5) |
| 2 or higher | 35(30.4) | 24(25.3) | 50(30.5) |
| Number | 115 | 95 | 164 |
| Bone density, g/cm2¶ | 0.68±0.12 | 0.66±0.13 | 0.65±0.10 |
| Number | 98 | 84 | 141 |
| Males | |||
| Height, cm | 134.0±13.0 | 133.1±14.0 | 133.1±14.5 |
| Tanner genital stage, n (%) | |||
| 1 | 122(73.1) | 131(72.8) | 165(76.7) |
| 2 or higher | 45(26.6) | 49(26.9) | 50(23.1) |
| Number | 169 | 182 | 216 |
| Bone density, g/cm2¶ | 0.65±0.10 | 0.63±0.09 | 0.64±0.09 |
| Number | 151 | 162 | 192 |
| Overall | |||
| Height, cm | 134.3±13.2 | 132.8±13.9 | 133.3±14.0 |
| Bone density, g/cm2¶ | 0.66±0.11 | 0.64±0.10 | 0.64±0.09 |
| Number | 249 | 246 | 333 |
| Child Behavior Checklist questionnaire⁎⁎ | |||
| Total problem T-score | 50.9±10.6 | 51.2±10.0 | 51.7±9.7 |
| Externalizing T-score | 49.5±9.8 | 50.0±9.2 | 50.4±9.3 |
| Internalizing T-score | 52.5±10.2 | 52.6±10.2 | 53.0±10.0 |
⁎An episode-free day is defined as a day with no night awakenings, albuterol, prednisone, school absence, or physician contact due to asthma; morning and evening peak flow ≥ 80% of personal best; and no episode of wheezing, coughing, chest tightness, or shortness of breath. |
‡((Postbronchodilator value - prebronchodilator value)/prebronchodilator value) × 100. |
§Values are geometric means |
¶Bone density means do not include patients enrolled at Denver, because of incompatibilities with scanner values from other CAMP sites. |
⁎⁎The Child Behavior Checklist is a 118-item questionnaire completed by the parent about the child age 17 and under. The total problem score (range, 1 to 100) produces a composite index of behavior problems; the externalizing T-score (range, 1 to 100) measures fearful, shy, anxious, and inhibited behavior; and the internalizing T-score (range, 1 to 100) measures aggressive, antisocial, and undercontrolled behavior. |
Table III. Age, follow-up, asthma treatment, morbidity, lung function, airway lability, physical growth, psychological measures, and quality-of-life measures of participants in the posttrial follow-up study, by treatment group in the CAMP trial
| Treatment group in CAMP trial | P value | ||||
|---|---|---|---|---|---|
| Bud | Ned | Placebo | Bud vs | Ned vs | |
| (n = 284) | (n = 277) | (n = 380) | placebo | placebo | |
| Age and follow-up | |||||
| Age at end of trial, years | 13.4 | 13.2 | 13.3 | .60 | .33 |
| Age at end of posttrial, years | 18.2 | 18.0 | 18.2 | .61 | .54 |
| Duration of posttrial, years | 4.8 | 4.9 | 4.8 | .89 | .02 |
| % of scheduled visits completed during posttrial | 96.3% | 98.3% | 96.8% | .54 | .04 |
| Asthma treatment | |||||
| % of time on ICS during trial | 96.8% | 14.1% | 18.0% | <.001 | .09 |
| % of time on ICS posttrial | 31.3% | 30.9% | 30.2% | .69 | .80 |
| % of time on nedocromil during trial | 0.13% | 94.5% | 0.03% | .37 | <.001 |
| % of time on nedocromil posttrial | 0.04% | 0.90% | 0.07% | .75 | .007 |
| % of time on long-acting bronchodilator posttrial | 12.3% | 16.5% | 16.5% | .05 | <.99 |
| % of time on leukotriene modifier posttrial | 14.5% | 13.3% | 13.2% | .53 | .93 |
| % of time on albuterol only posttrial | 20.5% | 22.5% | 21.7% | .50 | .67 |
| % of time not reporting any medication for asthma posttrial | 45.2% | 42.4% | 45.4% | .96 | .31 |
| Morbidity during posttrial | |||||
| Prednisone courses for asthma | |||||
| Number | 247 | 277 | 462 | ||
| Number/person-year⁎ | 0.17 | 0.19 | 0.23 | ||
| RR versus placebo⁎ | 0.71 | 0.83 | 1.00 | .05 | .28 |
| Urgent care visits due to asthma | |||||
| Number | 96 | 109 | 203 | ||
| Number/person-year⁎ | 0.06 | 0.07 | 0.09 | ||
| RR versus placebo⁎ | 0.64 | 0.81 | 1.00 | .05 | .33 |
| Hospitalizations due to asthma | |||||
| Number | 20 | 22 | 19 | ||
| Number/person-year⁎ | 0.008 | 0.010 | 0.006 | ||
| RR versus placebo⁎ | 1.39 | 1.70 | 1.00 | .31 | .09 |
| Fractures† | |||||
| Number | 73 | 97 | 88 | ||
| Number/person-year⁎ | 0.052 | 0.066 | 0.046 | ||
| RR versus placebo⁎ | 1.12 | 1.42 | 1.00 | .56 | .04 |
| Prebronchodilator lung function at end of posttrial‡ | |||||
| FEV1 % of predicted§ | 93.7 | 93.5 | 92.7 | .25 | .35 |
| FVC % of predicted§ | 103.5 | 102.2 | 103.2 | .75 | .18 |
| FEV1/FVC (%) | 78.3 | 79.1 | 77.7 | .28 | .02 |
| Postbronchodilator lung function at end of posttrial‡ | |||||
| FEV1 % of predicted§ | 100.1 | 100.2 | 99.3 | .31 | .28 |
| FVC % of predicted§ | 104.0 | 103.7 | 104.0 | .93 | .66 |
| FEV1/FVC (%) | 83.2 | 83.5 | 82.6 | .21 | .06 |
| Airway lability at end of posttrial‡ | |||||
| Bronchodilator reversibility (%)¶ | 7.3 | 8.0 | 8.1 | .17 | .86 |
| FEV1PC20 methacholine (mg/mL)⁎⁎ | 4.43 | 4.07 | 4.27 | .74 | .67 |
| Physical growth at end of posttrial‡ | |||||
| Females | |||||
| Height, cm | 162.4 | 163.5 | 164.1 | .001 | .29 |
| Tanner breast stage | 4.8 | 4.8 | 4.8 | .92 | .39 |
| Number | 115 | 95 | 164 | ||
| Bone density, g/cm2†† | 1.06 | 1.05 | 1.05 | .45 | .81 |
| Number | 98 | 84 | 141 | ||
| Males | |||||
| Height, cm | 175.2 | 175.9 | 175.5 | .49 | .39 |
| Tanner genital stage (males) | 4.8 | 4.8 | 4.8 | .17 | .60 |
| Number | 169 | 182 | 216 | ||
| Bone density, g/cm2†† | 1.02 | 1.01 | 1.02 | .75 | .80 |
| Number | 151 | 162 | 192 | ||
| Overall | |||||
| Height, cm | 170.1 | 171.1 | 171.0 | .01 | .94 |
| Interaction, females versus males | .03 | .23 | |||
| Bone density, g/cm2†† | 1.03 | 1.03 | 1.03 | .59 | .94 |
| Psychological measures at end of posttrial‡ | |||||
| Children=s Behavior Checklist | |||||
| Total problem T-score | 42.5 | 43.3 | 42.6 | .89 | .59 |
| Externalizing T-score | 47.2 | 47.5 | 47.0 | .87 | .66 |
| Internalizing T-score | 47.6 | 47.6 | 47.7 | .92 | .93 |
| Quality-of-life measures at end of posttrial‡ | |||||
| Pediatric Asthma Quality-of-Life Questionnaire | |||||
| Activity limitations domain score | 6.2 | 6.3 | 6.3 | .33 | .70 |
| Symptoms domain score | 6.3 | 6.3 | 6.4 | .65 | .28 |
| Emotional function domain score | 6.7 | 6.7 | 6.7 | .72 | .97 |
⁎Rate has been adjusted for age at randomization (continuous), race or ethnic group (African American, Hispanic, or other), sex, clinic, duration of asthma at randomization (< 3 years, at least 7 years, or other), severity of asthma at randomization (moderate or mild), and skin test reactivity at randomization (any reactivity or none). |
†Defined as a fractured, broken, or cracked bone. |
‡Outcome (value at end of posttrial follow-up) has been adjusted for age at randomization (continuous), race/ethnicity (African American, Hispanic, or other; 2 indicator variables), sex, clinic (7 indicator variables), duration of asthma at randomization (< 3 years, at least 7 years, other; 2 indicator variables), severity of asthma at randomization (moderate vs mild), skin test reactivity at randomization (any reactivity vs none), and the value of the outcome measure at randomization (continuous). The Pediatric Asthma Quality-of-Life outcomes are not adjusted for the value of the outcome measure at randomization, because the questionnaire was not obtained at randomization. |
¶(Postbronchodilator value - prebronchodilator value)/prebronchodilator value] × 100. |
⁎⁎Ratio of follow-up value to baseline value. |
††Analyses do not include values for patients randomized at Denver, because of incompatibilities with scanner values from other CAMP sites. |
Treatment for Asthma During the Posttrial Follow-Up Period
Treatment for asthma reported by the participants in the posttrial follow-up period was similar in the budesonide, nedocromil, and placebo groups (Table III). The mean percentage of time using ICS was approximately 30% in each group. The mean percentage of time using no medication for asthma ranged from 42% to 45% in the 3 groups.
Asthma Morbidity
During the posttrial follow-up period, the budesonide group had 29% fewer prednisone courses (P = .05) and 36% fewer urgent care visits (P = .05) compared with the placebo group (Table III; Figure). However, 15 and 32 participants, respectively, would need to be treated with budesonide regularly for 4.3 years to prevent 1 prednisone course per year and 1 urgent care visit per year after discontinuation of treatment.
Figure.
Mean values for measures of morbidity, lung function after the use of a bronchodilator, and bronchodilator reversibility during 9 years of follow-up after randomization to the budesonide, nedocromil, and placebo groups. A, Annual prednisone course rate. B, Annual urgent care visit rate. C, Postbronchodilator FEV1 % of predicted. D, Postbronchodilator FVC % of predicted. E, Postbronchodilator FEV1/FVC. F, Bronchodilator reversibility. All data to the left of the vertical line on each graph were obtained during the trial when participants were treated regularly with budesonide 200 μg twice daily, nedocromil 8 mg twice daily, or placebo. All data to the right of the vertical line on each graph were obtained during the posttrial follow-up period after regular treatment with study medications was discontinued.
Budesonide; 
Nedocromil; 
Placebo.
Prednisone courses and urgent care visits did not differ significantly between the nedocromil and placebo groups (Table III; Figure). Twenty-six and 59 participants, respectively, would need to be treated with nedocromil regularly for 4.3 years to prevent 1 prednisone course per year or 1 urgent care visit per year after discontinuation.
Spirometry
No differences between either the budesonide or nedocromil group and the placebo group were seen in FEV1 % of predicted or forced vital capacity (FVC) % of predicted both before and after bronchodilator use at the end of the posttrial follow-up (Table III; Figure). FEV1/FVC was significantly higher in the nedocromil group before (P = .02), but not after (P = .06), bronchodilator treatment compared with the placebo group.
Airway Lability
No differences between either the budesonide or nedocromil group and placebo were seen in bronchodilator reversibility at the end of the posttrial follow-up (Table III). Methacholine responsiveness in the budesonide group returned to placebo level by the end of washout5 and remained similar to placebo at the end of the posttrial follow-up (Table III). There was no difference in methacholine responsiveness between the nedocromil and placebo groups.
Possible Medication Side Effects
The statistically significant decreased height in the budesonide group relative to the placebo group observed at the end of the trial (1.1 cm; P = .005) persisted, with a decrease of 0.9 cm (P = .01) at end of posttrial follow-up. This height decrease was observed in girls (1.7 cm; P = .001) but not in boys (0.3 cm; P = .49; interaction, P = .03). Some 25% of the girls and 54% of the boys had not yet achieved adult height by the end of the posttrial follow-up. There were no differences during posttrial follow-up between either the budesonide or nedocromil group and the placebo group in rate of fractures, development of sexual maturation, or any of the psychological or asthma-specific quality-of-life measures examined (Table III).
Discussion
Compared with placebo, regular use of budesonide and, to a limited extent, nedocromil improved clinical measures of asthma control during the 4.3-year CAMP treatment period.5 But after the study medications were discontinued and treatment was managed by the participants' primary care physicians, asthma morbidity (including prednisone courses and urgent care use) and asthma medication use were not appreciably affected by earlier long-term treatment with either medication. The 29% reduction in prednisone courses and 36% reduction in urgent care visits after study medication discontinuation in the budesonide group relative to the placebo group must be considered in the context of the very low rates of these events in all groups during the posttrial follow-up period (Figure). Furthermore, although the reductions in prednisone use and urgent care visits reached the .05 level of statistical significance, these reductions likely are not clinically relevant, because 15 and 32 patients, respectively, would have had to be treated with budesonide for 4.3 years to prevent 1 prednisone course and 1 urgent care visit per year during the posttrial follow-up. In contrast, only 2 and 10 patients, respectively, needed to be treated with budesonide to prevent 1 prednisone course per year and urgent care visit per year during treatment in the CAMP clinical trial.5 Perception of symptoms and activity restrictions were similar across all 3 groups during the posttrial follow-up (Table III).
Characterizing the treatment regimen subsequent to the CAMP trial as a discontinuation of regular treatment is supported by the reduction in ICS use in the budesonide group during the posttrial compared with the trial (31.3% of the time during the posttrial vs 96.8% of the time during the trial), the similar proportion of posttrial follow-up time receiving ICS in all 3 groups, the low rate of nedocromil use across all 3 groups (< 1% of the time in all groups), and the similar proportion of follow-up time not using asthma medication across all 3 groups (Table III).
During treatment in the CAMP trial, regular use of budesonide resulted in significantly improved prebronchodilator, but not postbronchodilator, FEV1 and FEV1/FVC compared with placebo; these effects were not seen in the nedocromil group during the CAMP trial.5 At the end of the posttrial follow-up, participants treated earlier with budesonide or nedocromil exhibited no improvement in any lung function parameter except for a small (but statistically significant), 1.4% higher prebronchodilator FEV1/FVC % at the end of follow-up achieved in the nedocromil group compared with placebo. Given that nedocromil had no effect on either prebronchodilator or postbronchodilator FEV1/FVC during active treatment, the effect of nedocromil on prebronchodilator FEV1/FVC seen at the end of the posttrial follow-up likely is spurious.
The reductions in prednisone courses and urgent care visit rates seen as the participants were followed from mean age 8.9 years to mean age 18.1 years (Figure) are a particularly notable finding of this study. These reductions are consistent with the known improvement in the clinical course of asthma that occurs as children reach adolescence.16 The reductions also could be related in part to a reluctance of the treating physicians to prescribe prednisone during acute exacerbations compared with the protocol-mandated use of prednisone for exacerbations during the trial. The reductions are not likely due to incomplete data collection, because there were 4 contacts each year (2 clinic visits and 2 telephone visits), with careful questioning about prednisone use and urgent care at each contact.
The inability of long-term treatment with either an inhaled corticosteroid or a mast cell stabilizer to modify the course of asthma after their discontinuation was observed against the background of the overall decrease in asthma morbidity. Results of regular treatment with anti-inflammatory medication, especially ICS, were most notably different from placebo early in the course of the trial, when symptoms and morbidity were most apparent. In the second year of regular treatment, the effects on spirometry began to wane, and by the end of the trial, levels returned toward those seen in the placebo group (Figure). Outcomes of bronchodilator reversibility, annual prednisone course rate, and annual urgent care visit rate in the ICS-treated group were returning toward placebo levels by the end of the trial but were still different at that point (Figure). The return toward placebo levels during the trial is unlikely to be due to reductions or discontinuation of use of ICS; the difference in methacholine responsiveness between the ICS and placebo groups persisted throughout the trial, with a rapid return of responsiveness in ICS-treated participants to placebo levels within 0.3 years after discontinuation.5
The data obtained during the CAMP trial support the current guidelines recommending regular treatment with ICS for patients with at least mild persistent asthma.4 At the end of the first year of treatment, symptoms, exacerbations, airway responsiveness, and FEV1 were all improved.5 At the end of 4 to 6 years of treatment, symptoms, exacerbations, and airway responsiveness were still improved, but FEV1 had returned to levels seen in placebo-treated participants.5 These results are similar to those from other studies of long-term ICS treatment in young children with recurrent wheeze,17 school-age children with moderate asthma,18 and school-age children and adults with recent-onset asthma.6, 19
The follow-up of the CAMP participants after discontinuation of regular anti-inflammatory medication indicates that continued benefit of these medications likely requires continued use. This is similar to studies of young children with recurrent wheeze treated with ICS for 2 years17 and school-age children with asthma treated with ICS for 28 to 36 months,20 in which discontinuation of ICS was associated with a return to placebo levels for episode days and exacerbations requiring oral steroids17 and increases in symptoms, additional bronchodilator use, and airway responsiveness20 within several months, suggesting no long-term effect of treatment.
Questions remain about the long-term safety of inhaled anti-inflammatory agents, especially ICS. Results obtained during the 4.3 years of regular treatment with budesonide revealed a small decrease in height of 1.1 cm compared with placebo. At the last visit of the posttrial follow-up (mean time since randomization, 9.1 years), the reduction in growth in the budesonide group relative to placebo was less, but still noticeable, at 0.9 cm (P = .01). This height decrease was seen only in girls. It should be noted, however, that 25% of the girls and 54% of the boys still had not achieved final adult height at the end of the posttrial period. These findings are in contrast to those of Tinkelman et al,21 who observed more pronounced growth suppression in boys than girls treated with beclomethasone, but treatment was for only 1 year in that study. There were no effects of nedocromil treatment on growth. There were no differences between either budesonide or nedocromil and placebo in terms of bone density, fracture rate, psychological status, or asthma-specific quality-of-life at the end of the posttrial period.
More than 90% of the participants in the CAMP trial enrolled in the posttrial follow-up study. Despite differential enrollment among clinics, the participants in the follow-up study were similar at CAMP trial baseline to the nonparticipants; thus, the results of the follow-up study are not biased by incomplete enrollment.
Budesonide 200 μg twice daily, and considerably less so nedocromil 8 mg twice daily, improved multiple dimensions of asthma control compared with placebo in children with mild to moderate asthma during the CAMP trial. But neither treatment had a clinically meaningful modifying effect on the course of asthma (clinical course, pulmonary function, or airway lability) during follow-up after regular use was discontinued and the participants received care from their primary care physicians based on NAEPP guidelines. ICS at doses used in the CAMP trial are generally safe and effective in controlling asthma for the long-term, but do have a small and significant effect on growth and do not have a durable effect on the course of asthma after discontinuation of continuous treatment. Selection of patients who would experience long-term benefit from regular use of anti-inflammatory medications is an ongoing clinical challenge that will likely require determination of individual asthma/allergy phenotypes and/or genotypes along with such factors as age, ongoing symptoms, and recent morbidity.
Appendix
Childhood Asthma Management Program Research Group
Clinical Centers
ASTHMA, Inc, Seattle, Washington: Gail G. Shapiro, MD (Director), Thomas R. DuHamel, PhD (Co-Director), Mary V. Lasley, MD (Co-Director), Tamara Chinn, MSN, ARNP (Coordinator), Michele Hinatsu, MSN, ARNP, Clifton T. Furukawa, MD, Leonard C. Altman, MD, Frank S. Virant, MD, Paul V. Williams, MD, Michael S. Kennedy, MD, Jonathan W. Becker, MD, Grace White, C. Warren Bierman, MD (1992-1997), Dan Crawford, RN (1996-2002), Heather Eliassen, BA (1996-1999), Babi Hammond (1996-1999), Dominick A. Minotti, MD (1992-2003), Chris Reagan (1992-2003), Marian Sharpe, RN (1992-1994), Timothy G. Wighton, PhD (1994-1998).
Brigham & Women's Hospital, Boston, Massachusetts: Scott Weiss, MD, MS (Director), Anne Fuhlbrigge, MD (Principal Investigator), Anne Plunkett, NP, MS (Coordinator), Nancy Madden, RN, BSN, Peter Barrant, MD, Christine Darcy, Kelly Thompson, MD, Walter Torda, MD (Co-Investigator Director, 1993-2003), Martha Tata, RN (1993-2002), Sally Babigian, RN (1997-1999), Linda Benson (1998-2004), Jose Caicedo (1998-1999), Tatum Calder (1998-2001), Anthony DeFilippo (1994-2000), Cindy Dorsainvil (1998-2001), Julie Erickson (1998-1999), Phoebe Fulton (1997), Mary Grace, RN (1994-1996), Jennifer Gilbert (1997-1998), Dirk Greineder, MD (1993-2000), Stephanie Haynes (1993-1998), Margaret Higham, MD (1996-1998), Deborah Jakubowski (1999), Susan Kelleher (1993-1997), Jay Koslof, PhD (1993-1995), Dana Mandel (1996-1998), Patricia Martin (2001-2003), Agnes Martinez (1994-1997), Jean McAuliffe (1994-1995), Erika Nakamoto (2002-2004), Paola Pacella (1993-1998), Paula Parks (1993-1995), Johanna Sagarin (1998-1999), Kay Seligsohn, PhD (1995-2004), Susan Swords (2003-2005), Meghan Syring (1998-2001), June Traylor, MSN, RN (1996-1998), Melissa Van Horn, PhD (1996-1999), Carolyn Wells, RN (1993-1995), Ann Whitman, RN (1994-1996).
The Hospital for Sick Children, Toronto, Ontario, Canada: Ian MacLusky, MD, FRCP(C) (Director), Joe Reisman, MD, FRCP(C), MBA (Director, 1996-1999), Henry Levison, MD, FRCP(C) (Director, 1992-1996), Anita Hall, RN (Coordinator), Jennifer Chay, Melody Miki, RN, BScN, Renée Sananes, PhD, Yola Benedet (1994-1999), Susan Carpenter, RN (1998-2001), Michelle Collinson, RN (1994-1998), Jane Finlayson-Kulchin, RN (1994-1998), Kenneth Gore, MA (1993-1999), Noreen Holmes, RRT (1998-1999), Sharon Klassen, MA (1999-2000), Joseé Quenneville, MSc (1993-1995), Christine Wasson, PhD (1999).
Johns Hopkins Asthma & Allergy Center, Baltimore, Maryland: N. Franklin Adkinson, Jr, MD (Director), Peyton Eggleston, MD (Co-Director), Elizabeth H. Aylward, PhD, Karen Huss, DNSc (Co-Investigator), Leslie Plotnick, MD (Co-Investigator), Margaret Pulsifer, PhD (Co-Investigator), Cynthia Rand, PhD (Co-Investigator), Nancy Bollers, RN (Coordinator), Deborah Bull, LPN, Robert Hamilton, PhD, Kimberly Hyatt, Susan Limb, MD, Mildred Pessaro, Stephanie Philips, RN, Barbara Wheeler, RN, BSN.
National Jewish Medical and Research Center, Denver, Colorado: Stanley Szefler, MD (Director), Harold S. Nelson, MD (Co-Director), Bruce Bender, PhD (Co-Investigator), Ronina Covar, MD (Co-Investigator), Andrew Liu, MD (Co-Investigator), Joseph Spahn, MD (Co-Investigator), D Sundström (Coordinator), Melanie Phillips, Michael P. White, Kristin Brelsford (1997-1999), Jessyca Bridges (1995-1997), Jody Ciacco (1993-1996), Michael Eltz (1994-1995), Jeryl Feeley, MA (Coordinator, 1992-1995), Michael Flynn (1995-1996), Melanie Gleason, PA-C (1992-1999), Tara Junk-Blanchard (1997-2000), Joseph Hassell (1992-1998), Marcia Hefner (1992-1994), Caroline Hendrickson, RN (1995-1998, Coordinator, 1995-1997), Daniel Hettleman, MA (1995-1996), Charles G. Irvin, PhD (1992-1998), Jeffrey Jacobs, MD (1996-1997), Alan Kamada, PharmD (1994-1997), Sai Nimmagadda, MD (1993-1996), Kendra Sandoval (1995-1997), Jessica Sheridan (1994-1995), Trella Washington (1993-1997), Eric Willcutt, MA (1996-1997). We also thank the pediatric allergy and immunology fellows for their participation (Kirstin Carel, MD, Neal Jain, MD, Harvey Leo, MD, Beth Macomber, MD, Chris Mjaanes, MD, Lora Stewart, MD, Ben Song, MD).
University of California, San Diego and Kaiser Permanente Southern California Region, San Diego, California: Robert S. Zeiger, MD, PhD (Director), Noah Friedman, MD (Co-Investigator), Michael H. Mellon, MD (Co-Investigator), Michael Schatz, MD (Co-Investigator), Kathleen Harden, RN (Coordinator), Elaine M. Jenson, Serena Panzlau, Eva Rodriguez, RRT, James G. Easton, MD (Co-Director, 1993-1994), M. Feinberg (1997-1998), Linda L. Galbreath (1991-2002), Jennifer Gulczynski (1998-1999), Ellen Hansen (1995-1997), Al Jalowayski, PhD (Co-Investigator, 1991-2005), Alan Lincoln, PhD (Co-Investigator, 1991-2003), Jennie Kaufman (1994), Shirley King, MSW (1992-1999), Brian Lopez (1997-1998), Michaela Magiari-Ene, MA (1994-1998), Kathleen Mostafa, RN (1994-1995), Avraham Moscona (1994-1996), Catherine A. Nelle, RN (1991-2005), Jennifer Powers (2001-2003), Karen Sandoval (1995-1996), Nevin W. Wilson, MD (Co-Director, 1991-1993).
University of New Mexico, Albuquerque, New Mexico: H. William Kelly, PharmD (Director), Aaron Jacobs (Co-Investigator), Mary Spicher, RN (Coordinator), Hengameh H. Raissy, Robert Annett, PhD (Co-Investigator, 1993-2004), Teresa Archibeque (1994-1999), Naim Bashir, MD (Co-Investigator, 1998-2005), H. Selda Bereket (1995-1998), Marisa Braun (1996-1999), Shannon Bush (2002-2006), Michael Clayton, MD (Co-Investigator, 1999-2001), Angel Colon-Semidey, MD (Co-Investigator, 1997-2000), Sara Devault (1993-1997), Roni Grad, MD (Co-Investigator, 1993-1995), David Hunt, RRT (1995-2004), Jeanne Larsson, RN (1995-1996), Sandra McClelland, RN (Coordinator, 1993-1995), Bennie McWilliams, MD (Co-Investigator, Director, 1992-1998), Elisha Montoya (1997-2000), Margaret Moreshead (1996-1999), Shirley Murphy, MD (Co-Investigator, 1992-1994), Barbara Ortega, RRT (1993-1999), David Weers (1997-1998), Jose Zayas (1995-1996).
Washington University, St Louis, Missouri: Robert C. Strunk, MD (Director), Leonard Bacharier, MD (Co-Investigator), Gordon R. Bloomberg, MD (Co-Investigator), James M. Corry, MD (Co-Investigator), Denise Rodgers, RFPT (Coordinator), Lila Kertz, MSN, RN, CPNP, Valerie Morgan, RRT, Tina Oliver-Welker, CRTT, Deborah K. White, RPFT, RRT.
Resource Centers
Chair's Office, National Jewish Medical and Research Center, Denver, Colorado: Reuben Cherniack, MD (Study Chair).
Coordinating Center, The Johns Hopkins University, Baltimore, Maryland: James Tonascia, PhD (Director), Curtis Meinert, PhD (Co-Director), Patricia Belt, Karen Collins, Betty Collison, Ryan Colvin, MPH, John Dodge, Michele Donithan, MHS, Judith Harle, Rosetta Jackson, Hope Livingston, Jill Meinert, Kapreena Owens, Michael Smith, Alice Sternberg, ScM, Mark Van Natta, MHS, Margaret Wild, Laura Wilson, ScM, Robert Wise, MD, Katherine Yates, ScM.
Project Office, National Heart, Lung, and Blood Institute, Bethesda, Maryland: Virginia Taggart, MPH (Project Officer), Lois Eggers, James Kiley, PhD, Gang Zheng, PhD, Paul Albert, PhD (1991-1999), Suzanne Hurd, PhD (1991-1999), Sydney Parker, PhD (1991-1994), Pamela Randall (1992-2003), Margaret Wu, PhD (1991-2001).
Committees
Data and Safety Monitoring Board: Howard Eigen, MD (Chair), Michelle Cloutier, MD, John Connett, PhD, Leona Cuttler, MD, David Evans, PhD, Meyer Kattan, MD, Rogelio Menendez, MD, F. Estelle R. Simons, MD, Clarence E. Davis, PhD (1993-2003), Sanford Leikin, MD (1993-1999).
Executive Committee: Reuben Cherniack, MD (Chair), Robert Strunk, MD, Stanley Szefler, MD, Virginia Taggart, MPH, James Tonascia, PhD, Curtis Meinert, PhD (1992-2003).
Steering Committee: Reuben Cherniack, MD (Chair), Robert Strunk, MD (Vice-Chair), N. Franklin Adkinson, MD, Robert Annett, PhD (1992-1995, 1997-1999), Bruce Bender, PhD (1992-1994, 1997-1999), Mary Caesar, MHS (1994-1996), Thomas R. DuHamel, PhD (1992-1994, 1996-1999), H. William Kelly, PharmD, Henry Levison, MD (1992-1996), Alan Lincoln, PhD (1994-1995), Ian MacLusky, MD, Bennie McWilliams, MD (1992-1998), Curtis L. Meinert, PhD, Sydney Parker, PhD (1991-1994), Joe Reisman, MD, FRCP(C), MBA (1991-1999), Denise Rodgers (2003-2005), Kay Seligsohn, PhD (1996-1997), Gail G. Shapiro, MD, Marian Sharpe (1993-1994), D Sundström (1998-1999), Stanley Szefler, MD, Virginia Taggart, MPH, Martha Tata, RN (1996-1998), James Tonascia, PhD, Scott Weiss, MD, MS, Barbara Wheeler, RN, BSN (1993-1994), Robert Wise, MD, Robert Zeiger, MD, PhD.
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The Childhood Asthma Management Program is supported by the National Heart, Lung, and Blood Institute (contracts NO1-HR-16044, -16045, -16046, -16047, -16048, -16049, -16050, -16051, and -16052) and the National Center for Research Resources (General Clinical Research Center grants M01RR00051, M01RR0099718-24, M01RR02719-14, and RR00036). The authors declare no conflicts of interest.
No reprints are available from the authors.
PII: S0022-3476(08)01034-2
doi:10.1016/j.jpeds.2008.11.036
© 2009 Mosby, Inc. All rights reserved.
