Design and powering of cystic fibrosis clinical trials using rate of FEV(1) decline as an efficacy endpoint.

BACKGROUND: Rate of lung function decline (RLFD) (as FEV(1) percent predicted/yr) is a robust measure of CF therapeutic efficacy rarely used as a study endpoint, in part due to uncertainty of sample size requirements. METHODS: Sample size requirements for 1:1 randomizations to detect RLFD treatment effects from 20% to 80% were assessed in Epidemiologic Study of CF (ESCF) patients. Effects of measuring FEV(1) 1-4 times per year in studies of 1- to 4-year durations were assessed in 399 patients age ≥ 6 years with FEV(1) ≥ 70%. Impacts of inclusion/exclusion based on risk factors in 2369 ESCF patients were assessed over 1.5 years using semi-annual FEV(1) measures. RESULTS: Increasing study duration and exclusion of lower risk patients (e.g., no P. aeruginosa infection) both substantially reduced requirements. CONCLUSIONS: CF RLFD studies of 1.5 years in duration appear feasible provided that investigators account for the beneficial effects of subject inclusion/exclusion based on risk factors in power estimates.

Ultrase MT12 and Ultrase MT20 in the treatment of exocrine pancreatic insufficiency in cystic fibrosis: safety and efficacy.

BACKGROUND: Cystic fibrosis causes exocrine pancreatic insufficiency, leading to malabsorption. Supplemental pancreatic enzyme therapy alleviates the concomitant malnutrition experienced by cystic fibrosis patients. It is recognized that patients experience variations in clinical response to different brands of enzymes. This has prompted the US Food and Drug Administration to require that enzyme supplements be subjected to New Drug Applications. AIM: To investigate the safety and efficacy of supplemental pancreatic enzyme therapy in cystic fibrosis subjects. METHODS: We compared two doses of one formulation of enteric-coated pancreatic enzymes: Ultrase MT12 (12,000 lipase units per capsule) and Ultrase MT20 (20,000 lipase units per capsule), to placebo in two separate safety and efficacy studies. RESULTS: Mean total fat, protein and carbohydrate intake did not differ significantly between the groups. A significant difference in both fat and protein absorption occurred with the enzyme therapy groups. The Ultrase MT12 and Ultrase MT20 groups experienced a mean fat and protein absorption 79.4% and 83.8%, and 87.3% and 88.6%, respectively. No adverse events related to study drug were reported. CONCLUSIONS: This study further supports the use of enzymes to treat pancreatic insufficiency in cystic fibrosis. Excellent fat and protein absorption was achieved with minimal adverse events and safe doses.

Beclomethasone diproprionate reduced airway inflammation without adrenal suppression in young children with cystic fibrosis: a pilot study.

Inhaled corticosteroids are commonly used in cystic fibrosis (CF), but there are few studies evaluating their safety in young children. We, therefore, prospectively administered beclomethasone diproprionate (BDP) to 12 clinically stable young children with CF to examine the safety of this therapy with respect to adrenal suppression and airway infection. To determine potential mechanisms of corticosteroid action in CF, we also examined airway markers of inflammation before and after inhaled steroid treatment. BDP 210 microg twice a day was given via spacer for 2 months. Twelve-hour serum and urine cortisols and response to low-dose synthetic ACTH cortisol stimulation were assessed. Bronchoalveolar lavage fluid (BALF) was examined pre- and posttreatment with BDP by quantitative bacteriology and indices of airway inflammation, including levels of total neutrophils, neutrophil elastase-alpha-1 antiprotease complexes (NEAP), CA 19-9 mucin-associated antigen, interleukin-8 (IL-8), and macrophage IL-8 mRNA. Following 2 months of treatment, serum and urine cortisol levels were unchanged. Response to low-dose ACTH cortisol stimulation was not significantly decreased at 30 min. Posttreatment BALF bacterial density was not statistically different from pretreatment; however, one patient who was initially culture negative became culture-positive with Hemophilus influenzae. BALF total neutrophil counts, corrected for epithelial lining fluid dilution, were decreased to approximately one third of pretreatment values (P = 0.03). NEAP and CA 19-9 mucin-associated antigen demonstrated similar decreases. BALF IL-8 levels and macrophage IL-8 mRNA levels were not statistically changed. These findings suggest that treatment with BDP 420 microg per day for 2 months in young children with CF does not affect urine and blood cortisol, causes no decrease in adrenal reserve, and does not result in a clinically significant increase in airway infection. In addition, the fall in bronchoalveolar lavage fluid inflammatory markers following BDP suggests possible modulation of neutrophil influx into the CF airway and provides justification for further studies of inhaled corticosteroids in CF.

A comparison of the efficacy and tolerance of pancrelipase and placebo in the treatment of steatorrhea in cystic fibrosis patients with clinical exocrine pancreatic insufficiency.

OBJECTIVE: The safety and efficacy of Minimicrospheres, which are enteric-coated, delayed-release pancrelipase capsules, on fat absorption in pediatric/adolescent and adult cystic fibrosis (CF) patients was assessed. Exocrine pancreatic insufficiency, common in CF patients, causes steatorrhea due to insufficient release of pancreatic enzymes. METHODS: In the open-label phase, 97 CF patients with pancreatic insufficiency and steatorrhea were stabilized on a high-fat diet and administered pancrelipase. Seventy-four patients with >80% coefficient of fat absorption received placebo or pancrelipase in the double-blind phase. Fat intake and excretion, stool frequency and consistency, and clinical global improvement were recorded. RESULTS: Average daily fat intake was comparable between treatment groups within each age group (adults vs pediatric/adolescent), but placebo patients had a significant (p < 0.001) mean decrease in coefficient of fat absorption (adult, 36.9 percentage points; pediatric/adolescent, 34.9 percentage points) from open-label to double-blind treatment compared to pancrelipase patients (adult, 2 percentage points; pediatric/adolescent, 3.25 percentage points); this difference was caused by a greater (p < or = 0.001) increase in mean fecal fat excretion (grams per day) in the placebo groups compared to pancrelipase groups (adult: 61.9 vs 2.3; pediatric/adolescent: 45.4 vs 4.1). Change in mean stool frequency from open-label to double-blind phases was significantly different (p < or = 0.002) between treatment groups, with increases in placebo groups and no difference (adult) or decrease (pediatric/adolescent) in pancrelipase groups. Pancrelipase patients' stool consistency remained about the same from open-label to double-blind. Placebo patients' stool consistency decreased (became softer) from open-label pancrelipase to double-blind placebo. Clinical global improvement data showed that > or =83% of pancrelipase patients improved or remained unchanged. CONCLUSIONS: Enteric-coated, delayed-release (Minimicrospheres) pancrelipase capsules are an effective treatment for steatorrhea associated with pancreatic insufficiency in patients with cystic fibrosis.

Prospective, long-term study of fat-soluble vitamin status in children with cystic fibrosis identified by newborn screen.

OBJECTIVE: To prospectively evaluate the biochemical status of vitamins A, D, and E in children with cystic fibrosis (CF). SUBJECTS: A total of 127 infants identified by the Colorado CF newborn screening program. DESIGN: Vitamin status (serum retinol, 25-hydroxy vitamin D, ratio of alpha-tocopherol/total lipids) and serum albumin were assessed at diagnosis (4 to 8 weeks), ages 6 months, 12 months, and yearly thereafter, to age 10 years. RESULTS: Deficiency of 1 or more vitamins was present in 44 (45.8%) of 96 patients at age 4 to 8 weeks as follows: vitamin A 29.0%, vitamin D 22.5%, and vitamin E 22.8%. Of these patients with initial deficiency, the percent that was deficient at 1 or more subsequent time points, despite supplementation, was vitamin A 11.1%, vitamin D 12.5%, and vitamin E 57.1%. Of the initial patients with vitamin sufficiency, the percent who became deficient at any time during the 10-year period was as follows: vitamin A 4.5%, vitamin D 14.4%, and vitamin E 11.8%. The percent of patients deficient for 1 or more vitamins ranged from 4% to 45% for any given year. CONCLUSIONS: Despite supplementation with standard multivitamins and pancreatic enzymes, the sporadic occurrence of fat-soluble vitamin deficiency and persistent deficiency is relatively common. Frequent and serial monitoring of the serum concentrations of these vitamins is therefore essential in children with CF.

Aerosol delivery and safety of recombinant human deoxyribonuclease in young children with cystic fibrosis: a bronchoscopic study. Pulmozyme Pediatric Broncoscopy Study Group.

The purpose of this study was to assess the delivery to the lungs and the short-term safety of recombinant human deoxyribonuclease (rhDNase, Pulmozyme) in children with cystic fibrosis younger than 5 years of age compared with older children. Patients between the ages of 3 months and 10 years had bronchoscopic examination with bronchoalveolar lavage (BAL) after administration of an aerosol dose of 2.5 mg of rhDNase. After recovery from the procedure, patients were discharged home for an additional 13 days of rhDNase therapy. During this time adverse events were recorded to assess short-term safety. A total of 98 patients were enrolled, 65 (66%) aged 3 months to 5 years and 33 (34%) aged 5 years to 10 years. Deoxyribonuclease concentrations in BAL fluid were variable (interquartile range, 752 to 3943 micrograms/mL epithelial lining fluid [ELF]) and did not depend on patient age, weight, or height or differ when delivered through a mouthpiece or mask. The median value for the BAL DNA concentration in the younger group was 432 micrograms/mL ELF compared with 703 micrograms/mL ELF in the older patients. This study demonstrates the value of bronchoscopy and BAL for assessing nebulized medication delivery in young children and shows that aerosolized medications can be delivered to and are present in comparable amounts in the lower airways of younger and older children. Exposure to rhDNase appears to be safe over 2 weeks in infants and young children with cystic fibrosis.

The diagnostic value of bronchoalveolar lavage in immunocompetent children with chronic diffuse pulmonary infiltrates.

We have investigated the diagnostic value of (BAL) in 29 immunocompetent children (ages 1 month to 18 years) with chronic diffuse pulmonary infiltrates on chest radiograph who presented for evaluation over a 3-year period. The median age at the time of the BAL was 20 months with a range of 1-210 months. Positive results (1) diagnostic of a primary disorder; (2) consistent with a diagnosis; or (3) diagnostic of a secondary disorder, were obtained in 20/29 patients (13 with a single positive BAL finding and 7 with more than one finding). BAL was diagnostic of a primary disorder in only 5 patients (17%) with aspiration detected in 3 and infection in 2. The differential diagnosis was narrowed in 15 patients by the presence of lymphocytosis, neutrophilia, or eosinophilia. A secondary disorder was uncovered in 8 patients. Negative results were obtained in 9 additional patients. We conclude that BAL provided useful information in children with chronic diffuse infiltrates, but its ability to determine the primary cause was limited.

Increased DNA levels in bronchoalveolar lavage fluid obtained from infants with cystic fibrosis.

Airway inflammation in children younger than 5 yr of age is difficult to assess, particularly in patients with cystic fibrosis (CF). Furthermore, determining responses to therapies is often subjective in infants, especially those with CF. To determine whether airway DNA levels could be used as an index of airway inflammation, we measured DNA levels in bronchoalveolar lavage fluid (BALF), using a Hoechst dye-binding assay. BALF DNA levels and neutrophils from 16 infants with CF were compared with levels obtained from seven older CF patients and nine control children who underwent bronchoalveolar lavage for evaluation of other pulmonary diseases. BALF DNA was increased in both infants (3.2 +/- 0.7 microg/ml) and older patients with CF (5.4 +/- 0.9 microg/ml) compared with the controls (0.7 +/- 0.2 microg/ml) (mean +/- SEM). BALF DNA levels were not significantly different between infants and older patients with CF. BALF neutrophil counts in CF patients were significantly higher than in controls. Furthermore, BALF DNA levels and total neutrophil counts in infants with CF correlated positively with one another. We conclude that: (1) DNA levels were easily quantifiable in BALF of young children; (2) DNA levels in BALF from CF patients were greater than in a group of children with other pulmonary diseases, and that in some infants with CF, BALF DNA levels were equivalent to those of much older patients with CF; (3) DNA levels in BALF correlate with BALF neutrophil number, an index of inflammation; and (4) some infants with CF have increased levels of DNA in BALF, which may justify a clinical trial of aerosolized rhDNase in this population.

Short-term effects of postural drainage with clapping vs autogenic drainage on oxygen saturation and sputum recovery in patients with cystic fibrosis.

To compare the short-term effects of postural drainage with clapping (PD) and autogenic drainage (AD) on oxygen saturation, pulmonary function, and sputum recovery, we studied ten patients with cystic fibrosis (CF) randomly treated with PD or AD on separate days. Pulse oximetry was monitored and sputum was collected during and for 1 h following each treatment. Pulmonary function was measured before and then 1, 15, and 60 min after each treatment. There was no significant difference in the amount of sputum recovered with AD (14.0 +/- 3.5 g) vs PD (10.4 +/- 3.0 g) and no significant differences in pulmonary function occurred. Oxygen saturation during PD fell from 93.3 +/- 0.7% to 91.2 +/- 0.8% (p < 0.01) and required 15 min following treatment to return to baseline. Oxygen saturation did not fall during AD and increased to 94.5 +/- 0.7% by 1 h following treatment (baseline, 93.3 +/- 0.8%; p < 0.01). We conclude that AD is less likely to produce oxygen desaturation and may be better tolerated by patients with CF, while producing similar benefits in sputum clearance.

Anti-inflammatory therapy for children with asthma.

Anti-inflammatory therapy has become the mainstay of chronic asthma therapy in children. Which medication should become the "first-line" choice of physicians depends on each medication's anti-inflammatory effectiveness, side effects, techniques required for administration, and ability to modify disease progression. Additionally, certain medications may be more effective than others for treating specific clinical conditions. Improved understanding of the inflammatory response in asthma suggests that none of the currently available medications are ideal and that new, less toxic, yet more effective therapies are needed to control inflammation.

Early pulmonary inflammation in infants with cystic fibrosis.

The mechanisms underlying the initiation of lung disease and early respiratory morbidity in cystic fibrosis (CF) are poorly understood. By identifying infants with CF through a statewide neonatal screening program, we investigated whether airway inflammation was present in these infants, with the goal of furthering our understanding of the early events in this lung disease. Bronchoalveolar lavage fluid (BALF) from 16 infants with CF (mean age, 6 mo) and 11 disease control infants (mean age, 12 mo) was examined for the following inflammatory parameters: (1) neutrophil count; (2) activity of free neutrophil elastase; (3) elastase/alpha 1-antiprotease inhibitor complexes; and (4) the level of interleukin-8 (IL-8). We also quantified the spontaneous level of expression of IL-8 mRNA transcripts by airway macrophages. Each index of airway inflammation was increased in the BALF of infants with CF as compared with control infants. In addition, both the number of neutrophils and IL-8 levels were increased in infants with CF who had negative cultures (n = 7) for common bacterial CF-related pathogens, as well as for common respiratory viruses and fungi at the time of bronchoalveolar lavage (BAL). These findings suggest that airway inflammation is already present in infants with CF who are as young as 4 wks. Furthermore, although many different cell types (e.g., epithelial cells) may express IL-8, airway macrophages appear to be a source of this chemokine, and may thus play a prominent role in early neutrophil influx into the lung.

Relationship of genotype to early pulmonary function in infants with cystic fibrosis identified through neonatal screening.

To determine whether pulmonary function in infants with asymptomatic cystic fibrosis is related to genotype, we studied 18 infants with cystic fibrosis identified through neonatal screening and 18 healthy control infants. Infants with cystic fibrosis (mean age, 2.0 months; range, 1.0 to 4.6 months) were identified from June 1990 to September 1991 through a statewide screening program based on elevated immunoreactive trypsinogen concentrations. Pulmonary function testing was done before and after inhalation of albuterol. There were no differences in pulmonary function between the cystic fibrosis group and the control infants (mean age, 2.7 months; range, 0.9 to 4.5 months). However, infants homozygous for the delta F508 deletion (n = 10) differed from infants with other genotypic variants of cystic fibrosis and control infants with respect to respiratory system resistance (79.4 +/- 11.5 vs 52.0 +/- 3.8 vs 55.5 +/- 5.0 cm H2O/L per second, respectively; p = 0.04) and specific conductance (0.15 +/- 0.02 vs 0.21 +/- 0.02 vs 0.21 +/- 0.02 cm H2O-1 sec-1, respectively; p = 0.02). Infants homozygous for the delta F508 deletion, but not other infants, responded to albuterol with a decrease in respiratory system resistance. We conclude that infants with asymptomatic cystic fibrosis homozygous for the delta F508 deletion have early evidence of airways obstruction and may need early respiratory treatment.

Bronchoscopy with bronchoalveolar lavage in the evaluation of pulmonary complications of bone marrow transplantation in children.

Pulmonary complications are a frequent cause of morbidity and mortality following bone marrow transplantation. We examined the results of flexible bronchoscopy (FB) and bronchoalveolar lavage (BAL) in 27 pediatric bone marrow transplant (BMT) recipients with 29 episodes of pulmonary complications. Bone marrow transplant was performed for a variety of malignancies and hematologic disorders. Median age of BMT was 10.3 years (range, 1.7-17.6 years). Median time of FB following BMT was 60 days (range, 11-1,026 days). Routine cytologic and culture techniques were utilized to detect malignant cells, viruses, fungi, bacteria, and protozoa. Positive results were found in 15 (52%) with cytomegalovirus (CMV), the most common positive finding. In 14 (48%) episodes the results were negative. Fourteen patients had follow-up autopsy or open lung biopsy (OLB). Based on autopsy/OLB results, there were two false negatives and no false positives, giving a diagnostic sensitivity of 75% and specificity of 100%. There was one possible complication of FB and BAL. Survival of both positive and negative patients was poor, only seven patients being alive 90 days post-FB with BAL. We conclude that FB with BAL is a safe and accurate procedure for the diagnosis of pulmonary complications of BMT.

Pulmonary mechanics in healthy term neonates: variability in measurements obtained with a computerized system.

Using a commercially available computer-based analysis of ventilation and esophageal pressure (PeDs), we studied 11 healthy term neonates with serial pulmonary mechanics measurements during the first 3 days of life to determine the intrasubject variability of repeated measurements. Three consecutive pulmonary function tests were obtained before and after repositioning of the esophageal catheter, for a total of six measurements per day in each subject. The daily coefficient of variation for these 11 subjects ranged from 6% to 32% for respiratory rate; 6% to 27% for tidal volume; 3% to 28% for specific dynamic compliance, and 11% to 69% for pulmonary resistance. Repositioning the esophageal catheter did not produce significant differences in measurements of pulmonary mechanics (p greater than 0.05). We conclude that within a given subject, the maximum variability (mean + 2 SD) was 28% for specific dynamic compliance and 56% for pulmonary resistance. These intrasubject variability limits are important when one is interpreting pulmonary mechanics measurements in neonates before and after specific treatment, such as bronchodilators, diuretics, surfactant, or steroids.