The Childhood Asthma Management Program (CAMP)

Design Paper The Childhood Asthma Management Program (CAMP): Design, Rationale, and Methods Childhood Asthma Management Program Research Group NHLBI/Division of Lung Diseases

ABSTRACT: The Childhood Asthma Management Program (CAMP) is a multicenter, randomized, double-masked clinical trial designed to determine the long-term effects of three inhaled treatments for mild to moderate childhood asthma: budesonide (a glucocorticoid used daily) and albuterol (a short-acting b-agonist bronchodilator used as needed); nedocromil (a nonsteroid anti-inflammatory agent used daily) and albuterol; and placebo and albuterol. One thousand forty-one children (32% from ethnic minority groups), aged 5 to 12 years at screening, are currently participating. The primary outcome measure is lung growth as indicated by postbronchodilator forced expiratory volume in 1 second (FEV1) percent of predicted, observed over 5- to 6-year period. The trial also assesses differences between treatment groups with respect to airway responsiveness, morbidity, physical growth and development, and psychological growth and development. This report describes the design of the trial, the rationale for the design choices made, and the methods used to carry out the trial. Controlled Clin Trials 1999;20: 91–120  Elsevier Science Inc. 1999 KEY WORDS: Albuterol, allergens, anti-inflammatory agents, atopy, bronchial provocation test, bronchodilator agents, budesonide, childhood asthma, clinical trials, environmental exposure, glucocorticoids, growth, inhaled bronchodilator, nedocromil, psychological test, spirometry

INTRODUCTION Asthma, the most common chronic respiratory disease of childhood, is characterized by airway obstruction that is at least partially reversible, by airway inflammation, and by increased airway responsiveness to a variety of stimuli [1]. Ten million children under the age of 16 in the United States have asthma [2]. Both its prevalence and the frequency of hospitalizations it necessitates are increasing among children [3–5]. Asthma appears to have a strong inverse effect on lung growth in childhood [6]. The maximal level of lung function attained in early adulthood may be an important predictor of the rate of decline of lung function [7], which, in turn, may lead to the development of chronic obstructive lung disease. Address requests to: CAMP Coordinating Center, The Johns Hopkins Center for Clinical Trials, 615 North Wolfe Street, Room 5010, Baltimore, MD 21205. Received September 12, 1997; accepted July 19, 1998. Controlled Clinical Trials 20:91–120 (1999)  Elsevier Science Inc. 1999 655 Avenue of the Americas, New York, NY 10010

0197-2456/99/$–see front matter PII S0197-2456(98)00044-0

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Therapy for asthma focuses on prevention and/or treatment of airway inflammation, as well as relief of symptoms. Studies have found inhaled corticosteroids to relieve bronchial responsiveness and increase lung function [8–10]. Nonsteroid anti-inflammatory medications have also been found effective in a substantial proportion of patients [11–13]. Bronchodilators (such as inhaled b-agonists, inhaled anticholinergic agents, and oral theophylline) work quickly to relieve symptoms by relaxing the smooth muscles in the walls of the airways. Asthma episodes that do not respond sufficiently to bronchodilators may be treated with short courses (several days) of oral steroids. Concerns remain, however, about the long-term use of steroids in children, as they may decrease or delay somatic growth and sexual and bone maturation [14–25]. Repeated use of oral steroids to control acute exacerbations carries other side effects, such as adrenal suppression, osteoporosis, and cataracts [26–28]. The concerns about side effects, uncertainty about the relative effectiveness of steroid versus nonsteroid antiasthma medication, and questions about the need for chronic medication for mild asthma pose a dilemma for clinicians. With these issues in mind, the National Heart, Lung, and Blood Institute (NHLBI) released a Request for Proposal (RFP) for the Childhood Asthma Management Program (CAMP) in November 1990. The RFP called for proposals for a trial comparing regular use of two classes of anti-inflammatory medications (inhaled corticosteroids or cromolyn sodium) to regular bronchodilator medication. The NHLBI awarded contracts for the clinics and coordinating center in September 1991. The investigators, the sponsor, and the trial’s Data and Safety Monitoring Board (DSMB) approved a protocol for a randomized, controlled clinical trial designed to determine the long-term efficacy and safety of three treatment strategies for mild to moderate asthma in children aged 5 to 12 years at enrollment [29, 30]. Budesonide (Pulmicort, Astra USA, Inc.), an inhaled glucocorticoid, and nedocromil (Tilade, Rhone-Poulenc Rorer), an inhaled nonsteroid anti-inflammatory medication, are each being compared with placebo. Every patient uses albuterol (Ventolin, Glaxo Inc.), an inhaled short-acting b-agonist bronchodilator, as needed for asthma symptoms and signs or as a precaution prior to exercise. The planned follow-up period of 5 to 6 years allows most participants to initiate or complete their pubertal growth spurts, thus permitting assessment of the effects of treatments on growth and development. Randomization of patients began in December 1993 and concluded in September 1995; follow-up continues currently. This report describes the design of the trial, the rationale for the design choices, and the methods of the trial. DESIGN AND RATIONALE Study Medications Until the late 1980s, oral theophylline, a bronchodilator that is used daily, was considered a first-line asthma therapy. Its use declined dramatically as the anti-inflammatory properties of inhaled glucocorticoids came to light. Concern over serious adverse side effects in children, the requirement for periodic blood sampling to help minimize the risk of overdose, and the risk of drug interactions

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with commonly prescribed medications precluded selection of theophylline as a study medication [31, 32]. At the time CAMP began, salmeterol, a b-agonist with bronchodilator and bronchoprotective properties lasting as long as 12 hours, was pending regulatory approval. Several investigators had concern, however, that b-agonist used as regularly scheduled (daily) monotherapy could potentially be more harmful than helpful in controlling asthma [33, 34] and that there was no evidence of its efficacy in reducing inflammatory cells. Therefore, CAMP did not select a long-acting b-agonist as a study treatment. The investigators felt it imperative for the study medications to include an inhaled glucocorticoid, a nonsteroid anti-inflammatory therapy, and a shortacting bronchodilator medication for use by all patients as a rescue therapy for asthma symptoms and signs. Investigators also believed that the study medications should have uniform dosing schedules to minimize confusion and that the doses should have demonstrated safety and efficacy, be adequate for a wide range of ages, and be effective over time. Last, dosing regimens had to be convenient, interfering minimally with school activity. CAMP considered a twice-a-day regimen ideal for adherence and for administration at home. Inhaled glucocorticoid. The investigators had four inhaled glucocorticoids from which to choose: beclomethasone dipropionate, budesonide, flunisolide, and triamcinolone acetonide. Given the length of the follow-up period, investigators had to take account of the likely availability of the inhaled glucocorticoid at the close of the trial as well as its efficacy and safety. At the beginning of the trial, budesonide and the Turbuhaler delivery system were available in most countries and under evaluation for approval in the United States. Information, although limited, suggested that budesonide had a higher topical to systemic ratio of effect than the three inhaled glucocorticoid medications approved for use in the United States [35]. Also, it was anticipated that the three inhaled glucocorticoids available in the United States would have to delete chlorofluorocarbons from their delivery systems, which might have jeopardized their availability throughout follow-up. Studies supported the use of budesonide for twice-daily administration in a dose of 400 mg/day, divided equally into two daily doses [13, 36]. Consequently, CAMP selected budesonide, delivered by the dry-powder, breath-actuated delivery system (Turbuhaler), as a study treatment. Alternative anti-inflammatory therapy. At the time the trial began, the future of cromolyn in its available delivery system was unclear. The impending availability of nedocromil through the same pharmaceutical firm also raised concerns about the continued availability of cromolyn. Nedocromil, also a nonsteroid anti-inflammatory medication, has properties similar to cromolyn, but has the advantages of being effective on a wider array of inflammatory cells [37–39] and having a sustained effect on reducing airway responsiveness [40–42]. Previous studies supported the use of nedocromil for twice-daily administration [43–44]. Therefore, CAMP selected nedocromil as the nonsteroid anti-inflammatory medication, with a daily dose of 16 mg, divided equally in two doses. CAMP requires use of a spacer (AeroChamber) for administration of nedocromil. Rescue therapy. Investigators considered it important for the rescue medication to be rapid-acting with a duration of action sufficient to relieve symptoms

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of acute bronchospasm in children. The trial group chose albuterol (90 mg per puff, two puffs by a metered-dose inhaler [MDI]) over the other medications available, such as terbutaline and pirbuterol, because it was the most frequently prescribed rescue medication in children and its continued availability throughout the trial seemed certain. Masking Because the delivery devices for budesonide (a Turbuhaler) and nedocromil (an MDI) are different, CAMP uses two types of placebo. One half of the patients assigned to placebo use a placebo Turbuhaler matched to budesonide; the other half use a placebo MDI matched to nedocromil (with an AeroChamber spacer). The placebo budesonide consists of lactose; the placebo nedocromil consists of sorbitan triolate and a propellant. Masking thus applies to the comparison of active medication to placebo, but not to the class of medication used. Masking patients and clinic staff to the class of medication would have required each patient to use three devices: a Turbuhaler for the study medication; an MDI for the study medication; and an MDI for albuterol. CAMP deemed management of these multiple medications too confusing for young children and too complicated for sustained adherence over the period of follow-up. Investigators recognized, however, that biases from knowledge of the class of medication could affect compliance by patients and physicians. Fear of perceived or real side effects of steroid medications could reduce compliance, whereas faith in the efficacy of steroid medications could increase it. CAMP tries to minimize speculation by staff and patients about treatment assignments and to ensure that the staff members who perform pulmonary function testing not be the same ones who dispense medication and monitor diary cards. Following the start of randomization, CAMP encountered difficulties in maintaining the mask on study medications. The colors of nedocromil and its placebo differ, as do the weights of the active and placebo medications in both treatment groups. Differences in taste and in side effects can also compromise the mask’s effectiveness. CAMP strongly discourages the unmasking of study drug identity before the end of the trial and, to date, has not required it. Discontinuing the drug has sufficed in the case of patients with reported adverse events. CAMP requires that if a study drug needs to be unmasked, the center director must obtain consent from the coordinating center principal investigator or the NHLBI project officer. Sample Size and Power Calculations The design variable used to determine the CAMP sample size is the change, measured from baseline to 5 years of follow-up, in postbronchodilator forced expiratory volume in 1 second (FEV1) percent of predicted (i.e., change in the ratio 100 3 [FEV1/predicted FEV1 after administration of two puffs of albuterol via MDI]; predicted FEV1 is based on age, gender, race, and height). CAMP calculated the sample size of 960 patients (288 patients in each test treatment group and 192 patients in each placebo group) assuming a 3.5%

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detectable difference in mean change between either of the two test treatment groups versus the placebo group and a 3.8% detectable difference in mean change for the budesonide versus nedocromil groups, a two-sided type I error rate 5 0.01, power 5 0.90, a within-group standard deviation (SD) of 11% for the 5-year change from baseline in FEV1 percent of predicted, and a loss-tofollow-up rate of 10% owing to deaths or dropouts. Determinations of sample size and the minimum detectable mean differences were based on a t test for comparing means of the individual changes from baseline [45]. The SD (11%) assumed for within-group change in FEV1 percent of predicted (measured from baseline to 5 years of follow-up) was approximated from Van Essen-Zandvliet et al. [46] (baseline vs. determinations at an average of 22 months) and the Childhood Asthma Study (baseline vs. 6-month FEV1 determinations [Adkinson, 1992, personal communication]). CAMP carried out additional calculations keeping the two different types of placebos as distinct groups. The same assumptions as above resulted in a 4.6% detectable difference in mean change between the two placebo groups and a 4.2% detectable difference between either test treatment group and its matching placebo group. The sample size calculations did not account for the attenuation of effects due to noncompliance, nor did CAMP include formal adjustments for multiplicity (multiple comparisons, interim assessments, or multiple outcomes), although it chose a lower type I error rate of 0.01 (rather than 0.05) out of concern for these issues. Furthermore, the trial’s primary outcome is long-term change in lung growth; interim assessments of the data are for consideration of safety only. The sample size calculations did not take account of enrollment of siblings, who were independently randomized. We can put the clinical significance of the detectable effect sizes derived for CAMP into perspective by using data from Weiss et al. [6] and Adkinson (personal communication, 1992: Childhood Asthma Study, 106 asthmatic children followed from 6 to 60 months), which both yielded an approximate 1%/ year worsening in FEV1 percent of predicted in children with asthma. Also, Van Essen-Zandvliet et al. [46] reported a highly significant difference (11%, 95% confidence limits 7% to 15%) in the change in FEV1 percent of predicted over a 22-month period following treatment with a bronchodilator (salbutamol) plus budesonide compared with a bronchodilator plus placebo in a study of 116 asthmatic children. Patients in the budesonide plus bronchodilator group had a change in FEV1 percent of predicted in this period of 17%, whereas patients in the placebo plus bronchodilator group had a change in FEV1 percent of predicted of 24%. In contrast to the sample size calculations, which use only a baseline determination and a single measure after 5 years of follow-up, analyses for treatment effects will compare averages of individual slopes (change in percent of predicted per year) based on FEV1 measures made at baseline and at all available follow-up visits (three visits/year) during the 5 to 6 years of follow-up. The within-group SD for individual slopes derived for children in the Childhood Asthma Study followed from 6 to 60 months was 6% per year. Using this value for CAMP, we find that detectable differences in mean slopes (under the assumptions just stated) are 1.9%/year for test treatment versus placebo groups

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and 2.1%/year for the test treatments versus each other in the difference in mean change in FEV1 percent of predicted. Given a sample size of 960 patients, CAMP calculated detectable effects for other outcome measures to be 0.32 SD (within-group SD of the outcome measure) for comparing a test treatment group with its placebo group, and 0.34 SD for comparing the test treatment groups with each other. The sample size achieved was 1041 patients (324 of whom are from minority ethnic groups) assigned to treatment groups as follows: budesonide, 311; nedocromil, 312; placebo budesonide, 208; placebo nedocromil, 210. Fifty-nine sets of siblings are participating in CAMP (57 pairs and two sets of three siblings). METHODS Screening and Data Collection CAMP designed selection criteria (Table 1) to enroll patients with mild to moderate asthma and to exclude patients who could not comply with the protocol. Eligibility assessment included medical history, spirometry, successful completion of a 28-day screening period with daily recording of asthma symptoms (Table 2), and measurement of airway responsiveness. Data collected for baseline measurements not directly related to eligibility assessment included a physical examination, allergen skin testing, hematology, and measurements of neurocognitive and psychosocial functioning. Screening, baseline data collection, and randomization took place over five visits completed in a period ranging from 5 weeks to a maximum of 4 months (Table 3). Each child’s parent or guardian signed a consent statement approved by the clinic’s institutional review board (IRB). The clinics also obtained each child’s assent. Beginning with the first screening visit (S1), patients and their parents or guardians took part in an educational program consisting of written handbooks, videos, and individual teaching sessions on asthma signs, performance of spirometry, use of an MDI, and use of a peak flow meter [47]. At the close of the second screening visit (S2), clinics required each patient to stop all asthma medications except prn (as needed) albuterol (prednisone could be used if needed for asthma exacerbations). The clinics presented an action plan based on the presence of symptoms and the peak flow levels compared with a “personal best” value for the child to each family to provide for appropriate management while the child was on prn albuterol only and to facilitate communication with the clinic staff concerning symptoms. Clinics provided albuterol MDIs to patients for use with or without an AeroChamber spacer, in line with patients’ preferences. Also, at this time (visit S2), each patient was asked to begin keeping a daily diary of asthma signs and symptoms, use of medications for asthma, days missed from school because of asthma, and contact with physicians for asthma (Table 2). At least 28 days had to elapse between the second screening visit (S2) and the third (S3). At the start of the third visit (S3), clinics reviewed the experiences of each patient during the preceding 28 days. Patients who had needed a course of treatment with prednisone during this time had to restart the 28day screening once the course of treatment was over, or were dropped from screening. CAMP assessed the diary data for the 28-day period for completeness

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Table 1 Criteria for Selection Criteria for inclusion • Aged 5 to 12 years at time of screening • Chronic asthma as evidenced by one or more of the following historical findings for at least 6 months in the year prior to interview: —asthma symptoms at least two times per week —at least two usages per week of an inhaled broncholilator —daily asthma medication • Completion of a screening period (28 days) providing evidence of mild to moderate asthma as defined by criteria (see Table 2) • Methacholine reactivity: FEV1 PC20 no greater than 12.5 mg/mL • Consent of parent or guardian • Assent of child • Ability to comply with trial for 5 to 6 years Criteria for exclusion • Severe asthma as evidenced by one or more of the following historical findings: —two or more hospitalizations for asthma in the year prior to screening —six or more steroid bursts in the year prior to screening —intubation for asthma at any time in the past • Presence of one or more of the following confounding or complicating conditions: —other active pulmonary disease —pulmonary function suggesting a ventilatory defect or evidence of irreversible lung disease —severe chronic sinusitis or nasal polyposis —introduction of, or a change in, allergen immunotherapy in the month prior to interview —use of more than four sprays of nasal steroids daily (only beclomethasone allowed) at the time of randomization —current use of cimetidine, metoclopramide, ranitidine, or other treatment for gastroesophageal reflux —participation in another pharmaceutical, immunotherapy, respiratory, or asthma study —pregnancy • Inability to perform acceptable spirometry • Inability to complete the methacholine challenge • Evidence that the patient or family might be noncompliant or might move from the clinic area before completion of follow-up

(as a measure of compliance) and for indications of too-mild or too-severe asthma (Table 2). CAMP defined “personal best” peak flow initially as the highest of three postbronchodilator peak flows obtained with an acceptable technique at the second screening visit (S2). CAMP redetermined this value for the eligibility check made at the start of the third visit (S3) using the diary card peak flow data from the 28-day screening period as well as the three postbronchodilator peak flow values obtained at the second visit. The personal best value was the maximum peak flow in this pool of values if the second highest value was .90% of the maximum value. If the second highest value was 90% of the maximum value or less, CAMP considered the second highest peak flow as the best value. This value remained the child’s personal best peak flow for the duration of follow-up until the child obtained a larger postbronchodilator peak flow value with an acceptable technique at a regularly scheduled clinic visit. Once CAMP determined that the 28-day screening period eligibility criteria

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Table 2 Selection Criteria for 28-day Screening Period Days included • 28 days immediately prior to the screening methacholine challenge • Two weeks of data per card Data collected • Three postbronchodilator peak-flow values at visit S2 • Diary card data (night awakenings, morning and evening peak flows, albuterol for symptoms or signs, physician contact for asthma, absence from school for asthma, prednisone for asthma, asthma symptom code) Inclusion criteria relating to 28-day screening period • Sufficient amount of diary data —at least 24 days for which diary showed a recorded asthma code —of the 24 to 28 days with recorded asthma codes, no more than 4 days with both morning and evening peak flows missing Exclusion criteria relating to data from 28-day screening period • Too severe asthma —proportion of days (with data) with night awakenings greater than 0.214 (if all 28 days have data, children with more than five night awakenings will be excluded) —use of 9 or more puffs of albuterol for asthma symptoms or signs on each of 3 consecutive days —mean asthma code .2 —need for antiasthma medication other than albuterol • Too mild asthma —fewer than 8 days with asthma code at least 1, morning peak flow less than 80% personal best, or evening peak flow less than 80% personal best Definition of asthma symptom codes in diary cards • An asthma episode is a single period of one or more asthma “stop signs,” such as wheezing, coughing, chest tightness, or shortness of breath • 0: No asthma episodes • 1: One to three asthma episodes, each lasting 2 hours or less, all mild • 2: Four or more mild asthma episodes, or one or more asthma episodes that temporarily interfere with activity, play, school, or sleep • 3: One or more asthma episodes that last longer than 2 hours or result in shortened normal activity, seeing a doctor for acute care, or going to a hospital for acute care

had been met, the other procedures scheduled for the third screening visit (S3) were carried out. During the screening visits, staff administered questionnaires to elicit data on demographics, history of asthma symptoms and severity, treatment for asthma including hospitalizations and medication use, allergy history, features of the home environment, and relevant family history. CAMP evaluated each child’s neurocognitive functioning and the psychological functioning of the child and family at the fourth screening visit (S4; Table 4). Compliance with diaries, the likelihood of adherence, willingness to participate in the trial, and understanding of the trial protocol and the responsibilities of participation were also judged during the screening period. Follow-up visits occurred at 2 months and 4 months after randomization to treatment and continue at 4-month intervals thereafter for the duration of follow-up (Table 5).

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Table 3 Schedule for Collection of Screening Data Screening Visit

Ideal Time From Randomization

S1

27 weeks

S2

26 weeks

S3

22 weeks

S4

21 week

RZ

0 weeks

Activities/Procedures Eligibility interview; asthma history; education Medical history; height measurement; spirometry before and after BD; peak flow before and after BD; home environment questionnaire; education 28-day screening review; methacholine challenge; height and weight measurement; waist and hip measurement; Tanner staging; other physical exam; skin testing; hematology; bone densitometry Neurocognitive assessment; individual and family functioning assessment Diary card review; height and weight measurement; spirometry before and after BD; peak flow before and after BD; randomization

Recruitment Two of the eight clinical centers participating in CAMP (see credit roster) are located in health maintenance organizations associated with academic institutions; the other six are located in specialty practices within academic or research institutions. Clinics followed an array of strategies to recruit the required numbers of patients, including collaboration with primary care pediatricians and radio, television, and newspaper advertising. Table 4 Neurocognitive and Behavioral Measures Test Name

Time Required (in Minutes)

Completed by child WPPSI-R (age 5) [48] or WISC-III (ages 6 to 18) [49]) Woodcock–Johnson Achievement Battery [50] Wide Range Assessment of Memory & Learning [51] Gordon Diagnostic System [52] Children’s Manifest Anxiety Scale—Revised [53] Children’s Depression Inventory [54] Social Anxiety Scale for Children [55, 56] Youth Self-Report (age 11 and older) [57]

20 30 20 30 10 10 5 15

Completed by parent/guardian Child Behavior Checklist [58] Family Environment Scale [59] Impact on Family Scale [60] MOS Social Support Survey [61]

30 25 12 5

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Table 5 Schedule for Collection of Follow-Up Data Follow-Up Time From RZ or Its Yearly Anniversary 2 months (first year of follow-up only)

4 months (annually)

8 months (annually)

12 months (annually)

Activities/Procedures Interim history; diary card review; height and weight measurement; spirometry before and after BD; peak flow before and after BD; house dust collection Interim history; diary card review; height and weight measurement; spirometry before and after BD; peak flow before and after BD Interim history; diary card review; height and weight measurement; methacholine challenge; peak flow before and after BD Interim history; diary card review; height and weight measurement; waist and hip measurement; Tanner staging; other physical exam; spirometry before and after BD; peak flow before and after BD; home environment questionnaire; environmental counseling; individual and family functioning assessment; neurocognitive assessment (years 3 and 5); house dust collection (year 3); hematology (year 5); skin testing (year 5)

The primary consideration in the decision to allow recruitment of siblings was the undesirability of forcing a parent to choose which child to enroll. CAMP judged that the negative consequences of requiring such a decision would outweigh all other considerations. Furthermore, CAMP had to address the issue of siblings with asthma regardless of whether siblings were enrolled. CAMP judged that the best strategy was to emphasize that medications, supplies, and materials are prescribed for specific patients and should not be shared with siblings who also have asthma. Diaries, peak flow meters, and medications are color-coded and labeled for the specific patient. In discussions at visits, staff emphasize the need for children to use their own medications and supplies. Visits for enrolled siblings may occur on separate days, back to back, or simultaneously (with different staff), according to the clinic schedule and family preference, but the clinic deals with the siblings individually and interviews the parent about each child separately. Randomization The randomization schedule for the trial consists of eight strata, one stratum per clinic. CAMP did not select other baseline covariates for added stratification. Given the sample size for the trial, the gain in statistical precision from stratification is virtually nil compared with the use of multiple-regression techniques

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to adjust for imbalance in the composition of the treatment groups with respect to covariates [62]. CAMP released treatment assignments in a masked fashion by defining treatment assignment as assignment to one of 40 medication bins. Each stratum of the randomization schedule consisted of a series of assignments to a medication bin (numbered 11 through 50): 12 of the bins contained budesonide; 12 nedocromil; 8 placebo budesonide; and 8 placebo nedocromil. The coordinating center used a pseudo-random-number generator to generate the assignments in permuted blocks of varying lengths within each clinic stratum, so that assignment to the four medication groups was balanced over time with respect to the desired ratio. The assignments were also simultaneously balanced so that no more than five patients were assigned to any one bin and so that all bins were used when enrollment was complete. A schedule of treatment assignments was prepared for each clinic, encrypted, and installed on the clinic’s CAMP data system. The assignment for a patient was revealed only after all required baseline data were collected, recorded, keyed, and checked for conformance with the eligibility criteria via computer program. Rescue Therapy Clinics teach each patient and caregiver to recognize an asthma exacerbation by symptoms or by a decrease in the patient’s peak flow to ,80% personal best. Rescue treatment is administered in the form of albuterol 90 mg per puff, two puffs by MDI. Clinics provide instructions for additional albuterol treatment and for notifying a physician or seeking immediate medical care in the case of acute exacerbation. If nebulized albuterol is used, 0.25 mL of albuterol is considered equivalent to two puffs by MDI. The treating physician prescribes oral prednisone if the patient uses more than 12 puffs of albuterol in 24 hours and has symptom code 3 (Table 2) or peak flow of ,70% of personal best before each treatment, or if the patient has symptom code 3 for 48 hours or longer, or if peak flow drops to ,50% of personal best despite albuterol therapy. For acute exacerbations, CAMP recommends a prednisone dose of 2 mg/kg per day (maximum 60 mg) as a single morning dose for 2 days, followed by 1 mg/kg per day (maximum 30 mg) as a single morning dose for 2 days. The physician then decides on an extended course on the basis of clinical response. Adjustment of Treatment To accommodate spontaneous remission of asthma and to reduce the risk of adverse effects, CAMP established criteria for tapering study medication in two steps (Table 6). A decision to halve the study medication dose in the case of a particular patient is based on data recorded on the diary cards completed by the patient, the course of the treatment for asthma, pulmonary function at the visit when the decision is made, and judgment by the study physician. For study medication to discontinue subsequently, the patient must meet similar criteria after 8 months of using it at half the original dosage (Table 6). CAMP

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Table 6 Adjustment of Treatment Criteria for tapering study medication to half-dose (all must be met) • Patient has been on full-dose study medication for at least 7.5 months • At least 75% of the diary days in the previous 6 months have at least one value recorded • Prebronchodilator FEV1 > 85% of predicted at current visit • Prebronchodilator FEV1/FVC ratio > 85% at current visit • Patient has taken no more than four puffs of albuterol in each 7-day period in the preceding 6 months, excluding preventive use before exercise, as documented on the diary cards • There has been no more than 1 day with asthma symptoms that prevented the patient from full participation in his/her usual daily activities for each 30day period in the preceding 6 months, as documented on the diary cards • Study physician judges that the asthma is sufficiently controlled to warrant reduction of study medication Criteria for tapering study medication from half-dose to 0 dose (all must be met) • Patient does not meet any of the criteria for resumption of full-dose study medication • Patient has been on half-dose study medication for at least 7.5 months • At least 75% of the diary days in the previous 6 months have at least one value recorded • Physician believes missing diary data reflect well-being • Prebronchodilator FEV1 > 85% of predicted at current visit • Prebronchodilator FEV1/FVC ratio > 85% at current visit • Patient has taken no more than four puffs albuterol in each 30-day period in the preceding 6 months, excluding preventive use before exercise, as documented on the diary cards • There has been no more than 1 day with asthma symptoms that prevented the patient from full participation in his/her usual daily activities for each 30day period in the preceding 6 months and less than 5 days total, as documented on the diary cards • Study physician judges that the asthma is sufficiently controlled to warrant withdrawal of study medication Criteria for resumption of full-dose study medication from a tapered dose (any one is sufficient) • Prebronchodilator FEV1 , 90% of previous best value or , 85% of predicted at current visit • Prebronchodilator FEV1/FVC ratio , 85% at current visit • There have been >8 days during any 28-day period since the previous followup visit with asthma symptoms that prevented the patient from full participation in his/her usual daily activities or mean (morning and evening) peak flow ,80% of the personal best peak-flow value at the previous visit, as documented on the diary cards • Patient has taken >32 puffs of albuterol during any 28-day period since the taper began, excluding preventive use of albuterol prior to exercise, as documented on the diary cards • Patient has been hospitalized for asthma since the taper began • Patient has been prescribed antiasthma medication other than study drug and albuterol since the taper began • Study physician judges that resumption of full-dose study medication is warranted (continued)

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Table 6 (continued) Criteria for adding four puffs of beclomethasone BID (2 times per day) to full-dose study medication (any one is sufficient) • Patient has had at least six courses of prednisone or >31 days of prednisone • Patient has had at least two hospitalizations for asthma • Patient has used .1200 puffs albuterol/120 days (excluding preventive use before exercise), and study physician judges that the use is excessive and warrants addition of beclomethasone • Asthma worsens otherwise so as to warrant addition of beclomethasone These criteria are assessed over the previous year or over the interval since the patient last started full-dose study medication alone, whichever is shorter Criteria for withdrawing four puffs beclomethasone BID (all must be met) • Patient has been on beclomethasone and full-dose study drug for 3.5 months • Patient has been prescribed antiasthma medication other than the assigned study drug, albuterol, beclomethasone, and prednisone • Patient has had no hospitalizations for asthma • Patient uses <300 puffs albuterol/30 days (excluding preventive use before exercise) • Study physician judges that asthma is under control These criteria are assessed over the previous year or over the interval since the patient last added beclomethasone, whichever is shorter Criteria for treatment at discretion of study physician when full-dose study medication and four puffs beclomethasone BID are inadequate to control asthma (any one is sufficient) • Patient has been prescribed antiasthma medication other than assigned study medication, beclomethasone, albuterol, and prednisone • Patient has been hospitalized for asthma • Patient uses .300 puffs of albuterol/30 days (excluding preventive use before exercise) • Asthma worsens otherwise so as to warrant treatment at study physician’s discretion. These criteria are assessed over the interval since the patient last added beclomethasone

also established criteria for resumption of full dosage for patients who did not achieve well-being while on the tapered dosage (Table 6). Four puffs (42 mg/inhalation) of beclomethasone dipropionate (Vanceril, Schering-Plough) taken twice daily are added to the study medication if the patient demonstrates inadequate control of asthma while on the study medication alone (Table 6). The total glucocorticoid dose when the patient taking the full study dose of budesonide has beclomethasone added is 736 mg, less than the 800 mg/day thought to be a risk factor for steroid side effects [63]. CAMP also specified criteria for withdrawal of beclomethasone after 3.5 months of treatment (Table 6). Treatment is prescribed at the discretion of the study physician (or a private physician acting in collaboration with the study physician) if the patient’s asthma is inadequately controlled by the addition of beclomethasone to fulldose study medication or if the patient becomes pregnant, experiences an adverse reaction to study medication judged to warrant its discontinuation, requires assisted ventilation, or is otherwise judged to be best treated by other therapy (Table 6).

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Acquisition, Labeling, and Shipment of Study Medication Investigational new drug (IND) applications were made to the Food and Drug Administration (FDA) in 1993 for the use of budesonide and nedocromil. The NHLBI project officer holds the INDs for both budesonide and nedocromil. CAMP receives the study medications, albuterol, and beclomethasone free of charge from their respective manufacturers (see credit roster), which ship the medications to the drug distribution center for the trial. The drug distribution center retains samples from each lot of medication in long-term storage in case questions about a particular lot arise. Study medications and the placebo are shipped unlabeled. When a clinic requests a supply of study medication, staff at the drug distribution center label each drug with the appropriate medication bin number and content specification (“budesonide or placebo” or “nedocromil or placebo”). Clinic staff place patient identification labels and dose instruction labels on each Turbuhaler and MDI when issuing medication to the patient. Adverse Events As holder of the INDs, the NHLBI project officer is responsible for filing reports to the FDA regarding adverse events and deaths. Adverse events reportable to the FDA according to the Code of Federal Regulations include any serious or life-threatening unexpected event or death judged to be associated with study medication. Each center director must forward a copy of each adverse event report to their local IRB. Education of Patients A principal objective of the educational component of the protocol is to maximize adherence to CAMP’s treatment and evaluation regimens. Clinics emphasize appreciation of and commitment to the purposes of the trial; foster the bonding of participants to the trial, its staff, and the sponsoring institution; issue certificates and small rewards for accomplishments; monitor adherence; respond promptly and individually to indications of waning adherence; initiate group activities to enhance bonding among participants; and reinforce education through a variety of activities. The Patient Education Center (PEC) designs, develops, and distributes educational materials relevant to the trial and provides direction to clinic staff on teaching techniques [47]. Methods of education include both group and individual components. The CAMP-certified clinic coordinator/educator at each site oversees the application of curriculum items. The PEC provides educational materials in written and audiovisual formats. It developed handbooks for the educators [64], parents/caregivers [65], children in kindergarten through grade 3 [66], and children in grades 4 through 6 [67]. The materials cover the use and administration of medications, peak flow monitoring, action plans for dealing with symptoms and deterioration in pulmonary function, and measures for environmental control. “Booster” education materials to review and reinforce management skills are distributed to patients periodically throughout follow-up.

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Spirometry and Peak Flow Measurement Spirometry is carried out by CAMP-certified pulmonary function technicians with a volume-displacement spirometer interfaced to a computer. The equipment specifications and the testing protocol meet or exceed American Thoracic Society standards [68]. Spirometry is performed at least 4 hours after the last use of a short-acting bronchodilator and 24 hours after the last use of a longacting bronchodilator (if one is used under physician-discretion treatment). Technicians take pre- and postbronchodilator measurements (two puffs albuterol by MDI) at each spirometry session. After the bronchodilator is administered at least 15 minutes must elapse before the postbronchodilator tests are performed. Each patient in CAMP receives an Assess peak flow meter, low range or standard as appropriate. Peak flow meters are replaced yearly. Staff teach children to stand and blow out hard and fast and monitor them for acceptable technique. Personal best peak flow is re-established when a patient switches from the low-range meter to the standard-range meter. Patients bring their peak flow meters to the clinic at each visit, where staff obtain three pre- and three postbronchodilator peak flow measurements. Each child also obtains three peak flow measurements in the morning and three in the evening (bedtime) daily, before using medication. Each child records the highest of the three morning values and the highest of the three evening values on the CAMP diary card. Airway Responsiveness Clinics determine airway responsiveness by the decrease in FEV1 after they administer increasing concentrations of methacholine using the Wright nebulizer–tidal breathing technique. A CAMP-certified pulmonary function technician performs the test in accordance with protocol [69] at least 4 hours after the last use of a short-acting bronchodilator and at least 24 hours after the last use of a long-acting bronchodilator (if one is used under physician-discretion treatment). To minimize the effects of factors other than the study medication and the course of the asthma, staff do not determine airway responsiveness within 4 weeks of an upper respiratory tract infection or use of oral steroids, or if the FEV1 at baseline is ,70% of predicted. The methacholine solutions are prepared quarterly by the University of Iowa School of Pharmacy in line with protocol [69] and then are shipped to the drug distribution center, which in turn sends them to the clinics. The Immunology Complement Laboratory of the National Jewish Medical and Research Center samples the solutions to confirm their stated concentration and their stability over time. Control of Asthma Diary cards help clinics monitor the control of asthma on a daily basis (Table 2). Diary card completion begins at the second screening visit (S2) and continues throughout follow-up. After randomization, patients also record their use of study medication (budesonide, nedocromil, or placebo) on these cards. They

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mail the cards at the end of each 2-week period to the clinic staff, who monitor adherence and intervene with appropriate action, if necessary, before the next scheduled visit. For the younger enrollees, CAMP expects and encourages parents to supervise administration of study medication and completion of diary cards. As the children approach and enter adolescence, the coordinators and educators at the clinic make it a priority to teach them to keep the diaries themselves and to take increasing responsibility for their medication. Parental involvement is still needed, but clinics start emphasizing partnerships to create environments in which the children can carry out the responsibility. Somatic Growth and Development CAMP established a protocol for measuring somatic growth and development to help standardize these assessments [70]. Staff measure standing height and weight every 4 months; measure sitting height, waist and hip circumferences, and bone density of the spine annually; and assess sexual maturation (Tanner staging) annually. Clinics measure standing and sitting height with the Harpenden stadiometer, calibrating the stadiometer prior to each measurement session. They measure weight with the Detecto scale with the child wearing light clothing and socks or going barefoot. Staff reset the scale to 0 before each measurement. Waist and hip measurements are made over the child’s underwear; staff use a Seritex linen tape measure. Except for assessment of testicular volume, Tanner staging assessments involve only visual inspection of each child. Staff use the Holtain orchidometer to assess testicular volume. Clinics try to provide each child with an assessor of the same gender. Psychological Growth and Development The psychological and psychosocial tests selected for use in CAMP (Table 4) assess: (1) intellectual and academic skills; (2) cognitive skills potentially affected by asthma medications; (3) the presence of psychological disorders, including anxiety and depression; (4) social adjustment; (5) physical activity level; (6) impact of the child’s asthma on the family; and (7) family functioning. Staff members assess neurocognitive functioning at screening and at 3 and 5 years after randomization; they assess individual and family functioning at screening and annually thereafter. CAMP-certified psychologists or psychometrists administer tests in accordance with CAMP protocol [71]. Although the battery was not designed to provide a diagnostic assessment of the child’s psychological health, procedures were defined for identification of responses or values indicative of a potential problem for an individual patient and for counseling of the patient or family regarding further assessment. Hematology Clinics collect two blood samples during screening and will collect them again at the 5-year follow-up visit. One sample is processed locally for total

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eosinophil count, hemoglobin, and white blood cell count (total and differential). The second goes to the Dust and Serum Laboratory for IgE assessment and storage [72]. Allergy Skin Testing Clinics perform skin-prick testing during screening and will repeat it at the 5-year follow-up visit. Testing is performed by CAMP-certified personnel in accordance with protocol [73]. Tests are administered on the back and read 15 minutes after initiation. A test is considered positive if the result is a wheal with mean diameter (mean of maximum and 908 midpoint diameters) of at least 3 mm or if the result is a flare with mean diameter (mean of maximum and 908 midpoint diameters) of 10 mm or more. Staff members test each child to a core battery of allergens (Dermatophagoides pteronyssinus, Dermatophagoides farinae, cat, dog, American cockroach, German cockroach, penicillium mix, aspergillus mix, Timothy grass, and short ragweed) and a clinic-specific battery of locally relevant allergens. Environmental Control Recommendations for environmental controls based on local environmental allergens, the patient’s history of home exposures, and demonstrated allergenskin-test reactivity are provided at baseline and reinforced over follow-up. At clinics in locations where the dust mite is endemic, all study patients receive mite-retardant mattress and pillow covers regardless of their allergen-skintest reactivity. Clinics also provide instructions for animal allergen control, recommending preferentially that pets be removed from the home regardless of skin-test sensitivity. When there is a smoker in the home, staff members advise cessation and refer the family to smoking cessation programs. After making individual recommendations to families during screening and allowing time for compliance with environmental control measures, clinics schedule a home visit for each patient. During the visit, a CAMP-certified technician uses a vacuum cleaner fitted with a filter to collect a dust sample from the upper part of the patient’s mattress cover, bedroom floor or carpet, family room floor or carpet, the kitchen floor, and a major item of upholstered furniture [72]. The technician also completes an observational survey of the home. The specimen is sieved for fine dust, and analyzed quantitatively at the study’s Dust and IgE Laboratories for presence of major allergens of Dermatophagoides pteronyssinus, Dermatophagoides farinae, cat, dog, and cockroach. An agar plate is streaked for enumeration of fungus colonies, which are not further identified. A technician obtains an additional house dust specimen (and observational survey) after a move into a new home and between 3 and 4 years after randomization [72]. Data Management CAMP maintains its database using a distributed data management system that comprises two computer systems: the clinic data system [74] and the clinic spirometric system [68]. Each clinic data system consists of an IBM PS/2 Model

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56 microcomputer with a 200-MB hard disk, two 150-MB Bernoulli disk drives, and one 2.88-MB diskette drive. The system operates under a Windows 3.1 operating system with DOS 6.2. Software written in SAS 6.08 AF/SCL was developed for data inventory, entry, editing, transfer, back-up, patient randomization, and a variety of patient management tasks. The same technician keys each data form twice in immediate succession. The data entry programs include range checks, consistency checks on responses within a form, and a limited number of cross-form consistency checks. More extensive checks are performed by batch-editing programs run bimonthly at the coordinating center. These include a check for consistency between the information collected on patient data forms at the spirometric sessions and the data collected by the spirometric system. The spirometric system used in CAMP is a Survey III Dry-Seal Spirometer (W. E. Collins, Braintree, MA) with a Stead-Wells bell. The spirometer connects to a Dell Model 450M computer equipped with two 150-MB Bernoulli drives and a LaserJet IIIP printer with a Proprinter emulation cartridge. The software for the spirometric system was developed for CAMP by the S&M Instrument Company (Doylestown, PA). Each clinic’s database (including information from keyed forms and spirometric data) is collected monthly via the mailed transfer of two 150-MB Bernoulli cartridges. After this database is copied to the coordinating center’s central database, the coordinating center generates a clinic-specific report and sends it to the clinic with the Bernoulli cartridges. This report includes information on completion of visits, a list of data forms that are due from those visits, a report on receipt of diaries for each patient, and a list of patients due for a visit in the next month. Organization The operational units of the trial consist of eight clinical centers, ten resource centers, and four standing committees (see credit roster). The Steering Committee (SC) is the primary decisionmaking body of the CAMP Research Group (RG). The SC, with input from the RG, designs and executes the trial. The Executive Committee (EC), a subcommittee of the SC, is empowered to make interim decisions between SC meetings. The Publications Committee (PC), also a subcommittee of the SC, organizes, nurtures, and monitors the manuscripts produced by CAMP. The Data and Safety Monitoring Board (DSMB) reviews accumulating data related to performance and treatment effects (including adverse experiences) and makes recommendations concerning continuation of the trial. Appointed by the NHLBI, members of the DSMB are independent of the CAMP investigators and their institutions. The DSMB submits its recommendations to the director of the NHLBI for approval. Only coordinating center staff, the designated staff in the NHLBI project office, and DSMB members have access to data by treatment group. Representatives of the pharmaceutical suppliers for CAMP provided advice to the SC during the design phase. They are kept informed of CAMP’s activities and progress through inclusion in study mailings and invitation to RG meetings.

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Conflict-of-Interest Disclosures Principal investigators, coinvestigators, and members of the EC are asked yearly to report in writing to the coordinating center director, any relationships (including work or consulting activities) that they consider, or believe might be considered, to represent a conflict of interest. The EC is charged with reviewing the letters and making recommendations concerning resolution of any reported relationships that they view as representing such a conflict. None of the activities or relationships reported thus far have been so viewed. Quality Assurance Before opening for enrollment, each clinic must complete requirements for staff and site certification and enroll two start-up patients. Staff are certified for the following positions: clinic coordinator, data entry technician, dust technician, pharmacist, psychologist, psychometrist, pulmonary function technician, allergen skin tester, and study physician. Specific requirements for certification vary by function but generally include reading of study manuals, practice in completing procedures, completion of a written test of knowledge about study protocol, and signature of a statement indicating understanding of the requirements for accuracy and integrity in data collection. Only CAMP-certified staff may collect and record study data. The two start-up patients had to complete screening and randomization to treatment before the clinic could enroll patients in the trial proper. Whereas CAMP follows the start-up patients for the duration of the trial, it does not combine their data with data from the patients in the trial proper. These criteria helped ensure that clinic staff were trained in, equipped for, and experienced in study procedures before screening patients on an unlimited basis. Under the leadership of the EC, visits to participating centers (clinics and resource centers) are made periodically for review of activities and performance. Site visit teams usually include representatives from the DSMB, project office, coordinating center, EC, and clinics. Visiting begins shortly prior to the start of data collection and continues throughout the follow-up period. The coordinating center sends a study performance report monthly to the clinics, DSMB, and sponsor. During the recruitment phase the reports focus on the number of patients completing the screening visits, as well as the number randomized. During follow-up the reports include numbers of completed, missed, pending, and future visits; numbers of returned, completed, and expected diary cards; and a cumulative list of reported adverse events. CAMP audits keyed forms monthly. Coordinating center staff collect photocopies of 24 to 30 forms for randomized patients from each clinic and compare the forms to the keyed records. Staff report any noted discrepancies between the forms and the database to the clinic for resolution. Software designed for the trial reads the electronic data from each spirometric and methacholine testing session and generates assessments of the quality of each session with respect to the number of efforts, the duration of efforts, conformance with the protocol, and other aspects of performance. A technician at the coordinating center reviews each session to check agreement with the software assessment and to provide additional comments to the pulmonary

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function technician. A paper report generated for each session shows the data and tracings for the session, the performance assessment, and comments from the technician. A pulmonary physician at the coordinating center reviews these reports and sends them to the pulmonary function technician to provide direct and timely feedback on his/her performance. Ancillary Studies Any member of the RG may propose an ancillary study. The member submits the research plan to the SC for consideration of the possible impact of the proposed study on the participation of patients in the trial and on data collection for the outcome measures of the trial. The SC and the local IRB of each participating center must approve the protocol for the ancillary study. Ancillary studies have provided a way for investigators to examine secondary objectives of CAMP and have been useful in stimulating and maintaining the interest of RG participants. Data Analysis The responsibility for monitoring the accumulating data for evidence of adverse or beneficial effects rests with the DSMB. Interim analyses assess patient safety, protocol integrity, and data quality and determine whether the trial objectives are being met. The DSMB meets twice each year to monitor the emerging results and to assess the risks and benefits of each mode of therapy. The primary data analyses compare the treatment groups to identify adverse or beneficial effects that might be attributable to the treatment. CAMP will carry out its primary analyses by intention-to-treat. The trial will compare the treatment groups with respect to lung function (postbronchodilator FEV1), as well as to airway responsiveness (FEV1 PC20) to methacholine, frequency of self-reported asthma symptoms, days of limited activity, and days lost from school. Physical growth and development (growth rate and bone density), psychological growth and development (neurocognitive functioning and social adjustment), and side effects of treatment will also be compared. CAMP will pool patients assigned to Turbuhaler placebos with those assigned to MDI placebos only after checking that, after adjustment for baseline characteristics, the outcome measures are comparable between the two placebo types. If a clinically significant difference emerges between the two types of placebos (e.g., mean changes in postbronchodilator FEV1 percent of predicted differ by .5%), or if the difference between the placebo groups is numerically larger than either of the test treatments versus its matching placebo, CAMP will limit comparisons to each test treatment versus its matching placebo. The analysis for treatment effects will focus on contrasts in estimated rates of change in FEV1 percent of predicted, determined by regression analysis of individual slopes (obtained by fitting a straight line to each patient’s serial FEV1 measures [including baseline] vs. time) on treatment group and baseline covariates (age at entry, height, ethnic group, gender, and clinic), using robust variance estimation [75] to account for the differences in variance of slope for each patient. In addition, longitudinal data analysis [75] will help CAMP develop models comparing the treatment groups with respect to FEV1 percent of

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predicted and other continuous or discrete responses. CAMP will assess the fit of resulting models using residual plots and other measures of fit [76]. The use of antiasthma medications other than the study medications is inevitable and will complicate the analyses for treatment effects. Although such use blurs the distinctions between the treatment groups, it is an outcome by which CAMP may compare the treatment groups. Secondary analyses can include treatment received as a time-dependent covariate or can consider treatment received as an outcome. CAMP considers the use of prednisone to indicate significant breakdown in asthma control. The analysis will include a comparison of the three study groups (four, if the placebo is considered as two separate groups) in regard to numbers of days on which the child needed prednisone, the number of courses of prednisone needed per year, and the total dose of prednisone required, all normalized for the days the patients are on study treatment. In addition, CAMP will compare study groups in regard to the proportions of patients who required at least one course of prednisone and more than four courses of prednisone. DISCUSSION CAMP is designed to determine the long-term efficacy and safety of three treatment strategies for mild to moderate asthma in children aged 5 to 12 years at enrollment. The trial aims to answer questions about the long-term growth and development of children with mild to moderate disease. This focus dictated the choice of postbronchodilator FEV1 as the primary outcome measure. Use of postbronchodilator FEV1 rather than the prebronchodilator measure minimizes fluctuations due to diurnal variation and day-to-day variability of airway tone. FEV1 is a reasonable surrogate for lung growth because it is the primary determinant of the development of disease outcomes and mortality. In addition, FEV1 is correlated with vital capacity, the spirometric measure of maximal size of the lungs. The true measure of lung growth is total lung capacity. Total lung capacity, however, can only be measured by body plethysmography, which has not been used in clinical investigations and does not show a clear track record as a predictor of disease outcome. Discussions about medication were the most controversial aspect of CAMP’s design. The recognition that twice-a-day therapy was necessary to enhance adherence led to the ultimate choice of budesonide and nedocromil as the two anti-inflammatory treatments. Because of the complex disease model, the length of follow-up planned, and the choice of medications, CAMP recognized the necessity for algorithms to add or withdraw medication as needed and for a treatment protocol for acute exacerbations. These considerations greatly complicated the protocol compared with protocols designed to study chronic diseases without acute exacerbations. There was, however, a strong consensus that these modifications to the protocol for treatment with study medication not only enhanced the generalizability of the trial, but also were likely to improve the retention of patients and the compliance of physicians. Considerable controversy also occurred over the definition of mild to moderate asthma. Indeed, the definition of mild, moderate, and severe asthma remains empiric today. It tends to be primarily symptom-based, with relatively little input from peak flow or formal pulmonary function testing. This trial required

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patients to have a minimum of eight symptomatic or low-peak flow days during a 28-day screening period while on prn b-agonist only. CAMP excluded individuals who had more than one hospitalization for asthma in the year prior to screening or more than five treatments with oral steroids for asthma in the year prior to randomization, or if evidence from the 28-day screening period indicated that a given patient was unlikely to be satisfactorily managed with albuterol alone (Table 2). Empirically, CAMP found that these screening criteria were relatively stringent, excluding a large number of patients as too mild or too severe. Objective definition of asthma severity will require further research to enhance generalizability of clinical trial results. Although it is extremely labor-intensive, the extensive screening of prospective trial candidates allowed selection of more appropriate participants and enhanced education prior to randomization. This period was probably the most important aspect of the trial to ensure minimal variability across clinics. A very strong educational component enhanced the quality of the data and the compliance and retention of patients. The educational component was a major source of attraction for many parents. Psychologists were very involved in designing the trial, as the psychological functioning of the child and family is important in the overall management of this chronic disease [77–79]. The SC believes that the trial is a unique opportunity to investigate psychosocial aspects of asthma. The screening requirement of five visits over a minimum of 5 weeks undoubtedly selected children for motivation and ability to comply with complex regimens. This selection was part intentional, because of the 5- to 6-year duration of CAMP and its focus on children who, in most cases, were not incapacitated by their disease. From a design perspective, a differential dropout rate based on disease severity was highly undesirable, and CAMP believes that this “hurdles” method of selecting patients helped create a population that will provide a high completion rate. A counterbalancing concern is that such selection for compliance may restrict generalizability of study results. Because this study provides several indirect measures of individual patient adherence, and an ancillary study has been mounted in three clinics to define compliance with the medication regimens precisely, it should be possible to estimate, within reasonable limits, the average amount of each medication taken in achieving whatever biological outcomes are observed. Furthermore, such a large sample size will make it possible to use regression techniques to establish a relationship between the dose taken and the effect size. Thus, we will be able to estimate reliably the potential generalizability of results to other populations. Generalizability to less compliant populations would be of greater concern if the primary objective of the study were to evaluate a practical treatment regimen rather than to define pharmacological effects. Most children with asthma receive less education and medical attention than the participants in CAMP. The extent to which this degree of medical attention and education will affect compliance with medications and hence the study’s outcome is unknown. Because they are offered equally to all participants their effect should not confound the primary exposure of interest, treatment, and its influence on FEV1. While some differential effect of education by treatment group may possibly exist, we can examine the degree to which the use of diary

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cards, peak flow meters, and so on varies by treatment group and, if we note differential use, we can adjust for it. CAMP relies heavily on peak flow monitoring as a means of enhancing asthma care. This was also an extremely controversial issue: Although the guidelines of the National Asthma Education Program recommend peak flow monitoring [80], there is no evidence suggesting that it is any more effective in mild to moderate childhood disease than monitoring diaries for scores on symptoms. Data collected in CAMP will provide information needed for evaluation of the usefulness of peak flow monitoring in mild to moderate asthma. In summary, we have presented an overview of the largest, longest, and most comprehensive multicenter treatment trial for childhood asthma ever attempted in the United States. The study database, which includes data on pulmonary function, airway responsiveness, atopy, home environment, medical and family history, and neurocognitive and psychosocial functioning, both at entry and over follow-up on an ethnically diverse population, provides an important resource for investigation of many aspects of asthma and its treatment. At the end of the trial, we shall address whether anti-inflammatory therapy alters the course of lung growth and development, whether inhaled glucocorticoid therapy subjects children to significant risks of adverse effects, and whether inhaled glucocorticoids are more effective than nonsteroid antiasthma medications, specifically nedocromil. This trial may serve as a prototype for others attempting to investigate clinical aspects of asthma. The Childhood Asthma Management Program is supported by Contracts NO1-HR-16044, 16045, 16046, 16047, 16048, 16049, 16050, 16051, and 16052 with the National Heart, Lung, and Blood Institute.

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31. Weinberger M, Hendeles L. Theophylline. In: Middleton E, Reed CE, Ellis EF, et al, eds. Allergy: Principles and Practice. St. Louis, MO: Mosby; 1993. 32. Szefler SJ, Bender BG, Jusko WJ, et al. Evolving role of theophylline for treatment of chronic childhood asthma. J Pediatr 1995;127:176–185. 33. Sears MR, Taylor RD, Print CG, et al. Regular inhaled beta-agonist treatment in bronchial asthma. Lancet 1990;336:1391–1396. 34. Spitzer WO, Suissa S, Ernst P, et al. The use of beta-agonists and the risk of death and near death from asthma. N Engl J Med 1992;326:501–506. 35. Brattsand R, Thalen A, Roempke K, et al. Development of new glucocorticosteroids with a very high ratio between topical and systemic activities. Eur J Respir Dis 1982;63(suppl 122):62–73. 36. Nyholm E, Frame MH, Cayton RM. Therapeutic advantages of twice-daily over four-time daily inhalation budesonide in the treatment of chronic asthma. Eur J Respir Dis 1984;65:339–345. 37. Bruijnzeel PLB, Warrings RAJ, Kok PTM, et al. Effects of nedocromil sodium on in vitro induced migration, activation and mediator release from human granulocytes. J Allergy Clin Immunol 1993;92:159–164. 38. Joseph M, Tsicopoulos A, Tonnel AB, Capron A. Modulation by nedocromil sodium of immunologic and nonimmunologic activation of monocytes, macrophages, and platelets. J Allergy Clin Immunol 1993;92:165–170. 39. Pearce FL. Effect of nedocromil sodium on mediator release from mast cells. J Allergy Clin Immunol 1993;92:155–158. 40. del Bufalo C, Fasano L, Patalano F, Gonella G. Inhibition of fog-induced bronchoconstriction by nedocromil sodium and sodium cromoglycate in intrinsic asthma: a double-blind, placebo-controlled study. Respiration 1989;55:181–185. 41. Orefice U, Struzzo P, Dorigo R, Peratoner A. Long-term treatment with sodium cromoglycate, nedocromil sodium and beclomethasone dipropionate reduces bronchial hyperresponsiveness in asthmatic subjects. Respiraton 1992;59:97–101. 42. Sont JK, Bel ER, Dijkman JH, Sterk PJ. The long-term effect of nedocromil sodium on the maximal degree of airway narrowing to methacholine in atopic asthmatic subjects. Clin Exp Allergy 1992;22:554–560. 43. Callaghan B, Teo NC, Clancy L. Effects of the addition of nedocromil sodium to maintenance bronchodilator therapy in the management of chronic asthma. Chest 1992;101:787–892. 44. Schwartz HJ, Kemp JP, Blanco S, et al. Highlights of the nedocromil sodium clinical study presentations. J Allergy Clin Immunol 1993;92:204–209. 45. Dupont WD, Plummer WD Jr. Power and sample size calculations: a review and computer program. Controlled Clin Trials 1990;11:116–128. 46. Van Essen-Zandvliet EE, Hughes MD, Waalkens JK, et al. Effects of 22 months of treatment with inhaled corticosteroids and/or beta-2-agonists on lung function, airway responsiveness and symptoms in children with asthma. Am Rev Respir Dis 1992;146:547–554. 47. Childhood Asthma Management Program Research Group. Design and implementation of a patient education center for the Childhood Asthma Management Program. Ann Allergy Asthma Immunol (in press). 48. Wechsler D. Manual for the Preschool and Primary Scale of Intelligence (Revised). San Antonio, TX: Psychological Corporation; 1989. 49. Wechsler D. Manual for the Wechsler Intelligence Scale for Children 3rd ed. San Antonio, TX: Psychological Corporation; 1991. 50. Woodcock RW, Johnson MB. Manual for the Woodcock–Johnson Psycho-Educational Battery Tests of Achievement (Revised). Allen, TX: Teaching Resources; 1990. 51. Adams W, Sheslow D. Manual for the Wide Range of Assessment of Memory and Learning. Wilmington, DE: Jastak Associates; 1990.

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52. Gordon M, Mettelman BB. Technical Guide to the Gordon Diagnostic System Model III-R. DeWitt, NY: Gordon Systems; 1987. 53. Reynolds CR, Richmond BO. Revised Children Manifest Anxiety Scale (RCMAS). Los Angeles: Western Psychological Services; 1985. 54. Kovacs M. Rating scales to assess depression in school-aged children. Acta Paedopsychiatrica 1981;46:305–315. 55. La Greca AM, Dandes SK, Wick P, Shaw K, Stone WL. The development of the Social Anxiety Scale for Children (SASC): reliability and concurrent validity. J Clin Child Psychol 1988;17:84–91. 56. La Greca AM, Stone WL. The Social Anxiety Scale for Children—Revised: factor structure concurrent validity. J Pediatr Psychol 1993;15:87–305. 57. Achenbach T. Manual for Youth Self Report and 1991 Profile. Burlington, VT: University of Vermont Department of Psychiatry; 1991. 58. Achenbach T. Manual for the Child Behavior Checklist/4-18 and 1991 Profile. Burlington, VT: University of Vermont Department of Psychiatry; 1991. 59. Moos RH, Moos BS. Family Environment Scale (FES) Manual. Palo Alto, CA: Consulting Psychologists Press; 1981. 60. Stein REK, Riessman CK. The development of an Impact-on-Family scale: Preliminary findings. Med Care 1980;18:465–472. 61. Sherbourne CD, Stewart AL. The MOS social support survey. Soc Sci Med 1991;32:705–714. 62. Grizzle JE. A note on stratifying versus complete random assignment in clinical trials. Controlled Clin Trials 1982;3:365–368. 63. Barnes PJ, Pedersen S. Efficacy and safety of inhaled corticosteroids in asthma. Am Rev Respir Dis 1993;148(suppl):S1–S26. 64. Childhood Asthma Management Program Research Group. Childhood Asthma Management Program Educator’s Manual (Accession No. PB97-134563). Springfield, VA: National Technical Information Service; 1997. 65. Childhood Asthma Management Program Research Group. Childhood Asthma Management Program Patient Education Notebook (Parent Version) (Accession No. PB95137147). Springfield, VA: National Technical Information Service; 1994. 66. Childhood Asthma Management Program Research Group. Childhood Asthma Management Program Patient Education Notebook (Kindergarten Through Third Grade Version) (Accession No. PB95-137139). Springfield, VA: National Technical Information; 1994. 67. Childhood Asthma Management Program Research Group. Childhood Asthma Management Program Patient Education Notebook (Fourth Through Sixth Grade Version) (Accession No. PB95-137121). Springfield, VA: National Technical Information Service; 1994. 68. Childhood Asthma Management Program Research Group. Childhood Asthma Management Program Spirometry Manual, Version 3.0 (Accession No. PB95-137113). Springfield, VA: National Technical Information Service; 1994. 69. Childhood Asthma Management Program Research Group. Childhood Asthma Management Program Manual for Methacholine Challenge Testing, Version 3.0 (Accession No. PB95-137154) Springfield, VA: National Technical Information Service; 1994. 70. Childhood Asthma Management Program Research Group. Childhood Asthma Management Program Somatic Growth Measures Manual, Version 1.0 (Accession No. PB95137170). Springfield, VA: National Technical Information Service; 1994. 71. Childhood Asthma Management Program Behavioral Scientists Group. Childhood Asthma Management Program Behavioral Scientists Group Test Administration and Scoring Manual, Version 4.0 (Accession No. PB95-137196). Springfield, VA: National Technical Information Service; 1994.

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APPENDIX The members of the CAMP Research Group as of February 1998 are as follows. Clinical Centers ASTHMA, Inc., Seattle, Washington: Gail G. Shapiro, MD (Director); Thomas R. DuHamel, PhD (Codirector); Timothy G. Wighton, PhD (Codirector); Tamara Chinn, RN (Coordinator); C. Warren Bierman, MD; Clifton T. Furukawa, MD; Leonard C. Altman, MD; Frank S. Virant, MD; Paul V. Williams, MD; Dominick A. Minotti, MD; Michael S. Kennedy, MD; Jonathan W. Becker, MD; Chris Reagan; Heather Eliassen; Dan Crawford, RN; Babi Hammond; Grace Strodtbeck; Marian Sharpe, RN (1992–1994). Brigham & Women’s Hospital, Boston, Massachusetts: Scott Weiss, MD, MS (Director); Dirk Greineder, MD (Codirector); Walter Torda, MD (Codirector); Martha Tata, RN (Coordinator); Peter Barrant, MD; Anthony DeFilippo; Mary Grace, RN (1993–1996); Stephanie Haynes; Margaret Higham, MD; Susan Kelleher (1993–1997); Jay Koslof, PhD (1993–1995); Nancy Madden, RN; Dana Mandel; Agnes Martinez (1994–1997); Jean McAuliffe (1994–1995); Paola Pacella; Paula Parks (1993–1995); Anne Plunkett, RN; Kay Seligsohn, PhD; June Traylor, MSN, RN; Melissa Van Horn, PhD; Janice Ware, PhD; Carolyn Wells, RN (1993–1995); Ann Whitman, RN (1994–1996). The Hospital for Sick Children, Toronto, Ontario, Canada: Joe Reisman, MD, FRCP(C) (Director); Ian MacLusky, MD, FRCP(C) (Codirector); Henry Levison, MD, FRCP(C) (former Director); Anita Hall, RN (Coordinator); Yola Benedet;

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Jennifer Chay; Michelle Collinson, RN; Jane Finlayson-Kulchin, RN; Kenneth Gore, MA; Melody Miki, RN; Rene´e Sananes, PhD. Johns Hopkins Asthma & Allergy Center, Balitmore, Maryland: N. Franklin Adkinson, Jr., MD (Director); Peyton Eggleston, MD (Codirector); Karen Huss, DNSc (Coinvestigator); Leslie Plotnick, MD (Coinvestigator); Margaret Pulsifer, PhD (Coinvestigator); Cynthia Rand, PhD (Coinvestigator); Barbara Wheeler, RN, BSN (Coordinator); Nancy Bollers, RN; Kimberly Hyatt; Betsy Leritz; Mildred Pessaro; Stephanie Philips, RN. National Jewish Medical and Research Center, Denver, Colorado: Stanley Szefler, MD (Director); Harold S. Nelson, MD (Codirector); D Sundstro¨m (Coordinator); Bruce Bender, PhD; Kristin Brelsford; Melanie Gleason, PA-C; Joseph Hassell; Caroline Hendrickson, RN (Coordinator, 1995–1997); Charles G. Irvin, PhD; Tara Junk; Andrew Liu, MD; Joseph Spahn, MD; Michael P. White; Jeryl Feeley, MA (Coordinator, 1992–1995); Jessyca Bridges (1995–1997); Jody Ciacco (1993– 1996); Michael Eltz (1994–1995); Michael Flynn (1995–1996); Marcia Hefner (1992–1994); Daniel Hettleman (1995–1996); 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 (1996–1997). University of California, San Diego, California: Robert Zeiger, MD, PhD (Director); Anthony Horner, MD (Codirector); Noah Friedman, MD (Coinvestigator); Al Jalowayski, PhD (Coinvestigator); Alan Lincoln, PhD (Coinvestigator); Michael H. Mellon, MD (Coinvestigator); Michael Schatz, MD (Coinvestigator); Kathleen Harden, RN (Coordinator); Linda L. Galbreath; Ellen Hanson; Elaine M. Jenson; Shirley King, MSW; Brian Lopez; Michaela Magiari, MA; Catherine A. Nelle, RN; Senia Pizzo, PhD; Eva Rodriquez; James G. Easton, MD (Codirector, 1993–1994); Kathleen Mostafa, RN (1994–1995); Avraham Moscona (1994– 1996); Karen Sandoval (1995–1996). University of New Mexico, Albuquerque, New Mexico: Bennie McWilliams, MD (Director); Robert Annett, PhD (Coinvestigator); H. William Kelly, PharmD (Coinvestigator); Mary Spicher, RN (Coordinator); Diane Becker; Selda Bereket; Marisa Braun; Shannon Bush; David Hunt; Margaret Moreshead; Barbara Ortega. Washington University, St. Louis, Missouri: Robert C. Strunk, MD (Director); Gordon R. Bloomberg, MD (Coinvestigator); James M. Corry, MD (Coinvestigator); Thomas F. Smith, MD (Coinvestigator); Ellen Albers, RNC, MSN (Coordinator); Bernadette Davantes; Gregg Belle; Marisa Dolinsky; Edwin B. Fisher, PhD; Stephen J. Gaioni, PhD; Emily Glynn, CPNP, MSN; Cathy Herman; Debra Kemp, RN, BSN; Claire Lawhon; Sharon Meltzer; Cynthia Moseid; Tina OliverWelker, CRTT; Denise Rodgers, RPFT; Carl Turner; Deborah K. White; Mary Caesar, MPH (Coordinator, 1993–1996); Diana S. Richardson (1994–1997); Elizabeth Ryan (1994–1996); Susan C. Sylvia (1994–1996). Resource Centers Chair’s Office, National Jewish Medical and Research Center, Denver, Colorado: Reuben Cherniack, MD (Study Chair).

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Coordinating Center, The Johns Hopkins University, Baltimore, Maryland: James Tonascia, PhD (Director); Curtis Meinert, PhD (Codirector); Debra AmendLibercci; Patricia Belt; Karen Collins; Betty Collison; Christopher Dawson; John Dodge; Michele Donithan, MHS; Dawn Easton; Vera Edmonds; Cathleen Ewing; Judith Harle; Robert Huffman; Kung-Yee Liang, PhD; Jill Meinert; Deborah Nowakowski; Rosetta Owens; Michael Smith; Alice Sternberg, ScM; Mark Van Natta, MHS; Robert Wise, MD. Drug Distribution Center, McKesson BioServices Corporation, Rockville, Maryland: Robert Rice, PhD, DVM (Director of Pharmaceutical Services Division Operations); Bob Hughes (Director of Pharmaceutical Repository); Tom Lynch (Repository Technician); Sarma Vadlamani, RPh. Dermatology, Allergy and Clinical Immunology (DACI) Reference Laboratory, Johns Hopkins University School of Medicine, Asthma and Allergy Center, Baltimore, Maryland: Robert G. Hamilton, PhD, D ABMLI (Director); Carol Schatz (Business Office Manager); Jack Wisenauer, MT (Laboratory Supervisor). Immunology and Complement Laboratory, National Jewish Medical and Research Center, Denver, Colorado: Ronald J. Harbeck, PhD, D ABMLI (Director); Rhonda Emerick; Brian Watson. Patient Education Center, National Jewish Medical and Research Center, Denver, Colorado: Stanley Szefler, MD (Director); Bruce Bender, PhD; Harold Nelson, MD; Cindi Culkin MEd (Coordinator, 1996–1997); Jeryl Feeley, MA (Coordinator, 1992–1995); Sarah Oliver, MPH (Cocoordinator, 1992–1996); Colleen Lum Lung, RN (1992–1994); Ann Mullen, RN (1994–1996). Project Office, National Heart, Lung, and Blood Institute, Bethesda, Maryland: Virginia Taggart, MPH (Project Officer); Pamela Randall (Contracting Officer); Paul Albert, PhD; Suzanne Hurd, PhD; James Kiley, PhD; Margaret Wu, PhD; Sydney Parker PhD (1991–1994). S&M Instrument Company, Doylestown, Pennsylvania: William Letvenko (President); William Repko. Serum Repository, DACI Reference Laboratory, Johns Hopkins Asthma & Allergy Center, Baltimore, Maryland: Robert Hamilton, PhD, D ABMLI (Director); N. Franklin Adkinson, MD (Codirector). The University of Iowa, College of Pharmacy, Division of Pharmaceutical Services, Iowa City, Iowa: Rolland Poust, PhD (Director); David Herold, RPh; Dennis Elbert, RPh. Pharmaceutical Suppliers Astra USA, Inc., Westborough, Massachusetts; Glaxo, Inc., Research Institute, Research Triangle Park, North Carolina; Rhone-Poulenc Rorer, Collegeville, Pennsylvania; Schering-Plough, Kenilworth, New Jersey. Committees Data and Safety Monitoring Board: Howard Eigen, MD (Chair); Michelle Cloutier, MD; John Connett, PhD; Leona Cuttler, MD; Clarence E. Davis, PhD; David Evans, PhD; Meyer Kattan, MD; Sanford Leikin, MD; Rogelio Menendez, MD; F. Estelle R. Simons, MD.

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Executive Committee: Reuben Cherniack, MD; Curtis Meinert, PhD; Robert Strunk, MD; Stanley Szefler, MD; Virginia Taggart, MPH; James Tonascia, PhD. Steering Committee: Reuben Cherniack, MD (Chair); Robert Strunk, MD (ViceChair); N. Franklin Adkinson, MD; Robert Annett, PhD (1992–1995, 1997–1998); Bruce Bender, PhD (1992–1994, 1997–1998); Mary Caesar, MPH (1994–1996); Thomas R. DuHamel, PhD (1992–1994, 1996–1997); Henry Levison, MD (1992– 1996); Alan Lincoln, PhD (1994–1995); Bennie McWilliams, MD; Curtis L. Meinert, PhD; Sydney Parker, PhD (1991–1994); Joe Reisman, MD, FRCP(C); Kay Seligsohn, PhD (1996–1997); Gail G. Shapiro, MD; Marian Sharpe (1993–1994); 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. Writing Committee for this manuscript: Reuben Cherniack, MD (Chair); N. Franklin Adkinson, MD; Robert Strunk, MD; Stanley Szefler, MD; James Tonascia, PhD; Scott Weiss, MD, MS.