Need help?

800-5315-2751 Hours: 8am-5pm PST M-Th;  8am-4pm PST Fri
Medicine Lakex

Early anti-pseudomonal acquisition in young patients with cystic fibrosis: rationale and design of the epic clinical trial and observational study,

Contemporary Clinical Trials 30 (2009) 256–268 Contents lists available at Contemporary Clinical Trials Early anti-pseudomonal acquisition in young patients with cystic fibrosis:Rationale and design of the EPIC clinical trial and observational study Miriam M. Treggiari Margaret Rosenfeld Nicole Mayer-Hamblett , George Retsch-Bogart Ronald L. Gibson Judy Williams Julia Emerson Richard A . Kronmal Bonnie W. Ramsey a Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, WA, USAb Cystic Fibrosis Therapeutics Development Network, Cystic Fibrosis Foundation, Seattle, WA, USAc Department of Pediatrics, University of Washington, Children's Hospital and Medical Regional Center, Seattle, WA, USAd Department of Pediatrics, University of North Carolina, Chapel Hill, NC, USAe Department of Biostatistics, School of Public Health and Community Medicine, University of Washington, Seattle, WA, USA Background: The primary cause of morbidity and mortality in patients with cystic fibrosis (CF) Received 7 August 2008 is progressive obstructive pulmonary disease due to chronic endobronchial infection, Accepted 6 January 2009 particularly with Pseudomonas aeruginosa (Pa). Risk factors for and clinical impact of early Painfection in young CF patients are less well understood.
Purpose: The present studies are designed to evaluate risk factors and outcomes associated with early Pa acquisition, and the benefits and harms of four anti-pseudomonal treatment regimens Inhaled tobramycin in young CF patients initiated after the first Pa positive respiratory culture.
Methods: The Early Pseudomonas Infection Control (EPIC) program consists of two studies, a Pseudomonas aeruginosa randomized multicenter trial in CF patients ages 1–12 years at first isolation of Pa from a respiratory culture, and a longitudinal cohort study enrolling Pa-negative patients. Using a factorial design, trial participants are assigned for 18 months to either anti-pseudomonal treatment on a scheduledquarterly basis (cycled therapy) or based on recovery of Pa from quarterly respiratory cultures(culture-based therapy). The study drugs include inhaled tobramycin (300 mg BID) for 28 days,combined with either oral ciprofloxacin (15–20 mg/kg BID) or oral placebo for 14 days. The primaryendpoints of the trial are the time to pulmonary exacerbation requiring IV antibiotics orhospitalization for respiratory symptoms, and the proportion of patients with new Pa-positiverespiratory cultures during the study. The broad goals of the observational study are to describe therisk factors and outcomes associated with early acquisition of Pa. 306 patients were randomized inthe clinical trial and 1787 were enrolled in the cohort study.
Conclusions: These companion studies will provide valuable epidemiological and microbiologicalinformation on early CF lung disease and Pa acquisition, and safety and clinical efficacy data on anti-pseudomonal treatment strategies for early Pa infections in the airways of young children with CF.
2009 Elsevier Inc. All rights reserved.
☆ Financial support: The research for this article was supported in part by the Cystic Fibrosis Foundation grants number EPIC0K0 and OBSERV04K0, the National Heart Lung and Blood Institute (NHLBI) and National Institute for Digestive Disorders and Kidney (NIDDK) grant number U01-HL080310, and the National Centerfor Research Resources (NCRR) grant number ULI-RR2501401. Study drugs and devices were supplied free of charges by Novartis Pharmaceutical Corp. (inhaledtobramycin) and Bayer Healthcare AG (oral ciprofloxacin and oral placebo), compressors and nebulizers were provided by PARI Respiratory Equipment Inc.
☆☆ numbers: NCT00676169; NCT00097773.
⁎ Corresponding author. Department of Anesthesiology and Pain Medicine, Box 359724, Harborview Anesthesiology Research Center, Harborview Medical Center — University of Washington, 325 Ninth Avenue — Seattle, WA 98104, USA. Tel.: +1 206 744 3059; fax: +1 206 744 8090.
E-mail address: (M.M. Treggiari).
1 Participating clinical sites and investigators are listed in Appendix A.
1551-7144/$ – see front matter 2009 Elsevier Inc. All rights reserved.
doi: M.M. Treggiari et al. / Contemporary Clinical Trials 30 (2009) 256–268 which enrolled young Pa-negative patients and clinical trialparticipants. The goal of the observational study is to 1.1. Study rationale determine improved strategies for prevention and treatmentof early Pa infection.
Cystic fibrosis (CF), an autosomal recessive disease lacking a curative therapy, has a current median survival of over 1.2. Study overview 36 years, and affects approximately 25,000–30,000 indivi-duals in the United States and 70,000 people worldwide .
In order to assess the clinical and microbiologic efficacy of The primary cause of morbidity and mortality in patients with early anti-pseudomonal therapy, and more thoroughly CF is progressive obstructive pulmonary disease associated address issues of safety and antimicrobial resistance, the with chronic Pseudomonas aeruginosa (Pa) endobronchial Early Pseudomonas Infection Control multi-center clinical trial bacterial infection and an intense neutrophil-dominated host (EPIC-CT) and an observational study (EPIC-OBS) target inflammatory response . Pa, a ubiquitous environmental children with CF younger than 12 years of age.
bacterium, is the most important pathogen in CF lung disease.
The EPIC-OBS serves both as a freestanding epidemiologic Pa infection can begin very early in life, and the prevalence of study of risk factors associated with early Pa airway infection, Pa in respiratory cultures increases with age, from 10–30% at and as an adjunct to the EPIC-CT by providing pre-study data ages 0–5 years to 80% at ages ≥18 years . Unlike established on risk factors potentially affecting response to the trial Pa infection, features of early Pa infection, including suscept- regimens and post-enrollment follow-up for the clinical trial ibility to antibiotics, non-mucoid phenotype, and low bacterial participants for up to five years ).
density, appear to provide a "window of opportunity" during The EPIC-CT was designed to allow the randomized which time anti-pseudomonal therapy may be effective in controlled evaluation of early intervention with inhaled and eradicating Pa Over time, the distinct microenviron- oral anti-pseudomonal therapy in young patients with CF at ment in the CF airways allows selection of Pa uniquely adapted first isolation of Pa from respiratory cultures. Participants for chronic, persistent infection. These organisms are mucoid, meeting the eligibility criteria were offered the opportunity to form biofilms, become increasingly antibiotic-resistant, are be enrolled in the clinical trial and initiate or continue present at high density, and are virtually impossible to simultaneous participation in the observational study. The eradicate. Chronic Pa infection is clearly associated with clinical trial assigned children to two different antimicrobial poorer clinical outcomes among patients with CF The treatment strategies: (1) Cycled antibiotic therapy, i.e., risk factors for and clinical impact of early Pa infection are treatment provided in quarterly cycles regardless of findings even less understood, yet are of great import to clinicians from respiratory cultures obtained quarterly, and (2) anti- caring for young patients with CF. Preliminary data suggest a biotic therapy based upon cultures, i.e., treatment based on favorable effect of aggressive treatment at first isolation of Pa recovery of Pa from respiratory cultures obtained at sched- from respiratory cultures, but data from large randomized uled quarterly intervals throughout the 18-month study trials are lacking .
Thus, we designed a randomized trial in children with CF To summarize, the overall objectives of the clinical trial are to investigate the benefits and harms of aggressive, early anti- to compare the clinical and microbiological efficacy and safety pseudomonal interventions with the goal of delaying or of cycled therapy versus culture-based therapy, initiated at preventing chronic Pa infection and its clinical consequences.
the time of early Pa infection of the respiratory tract and given Companion to this clinical trial is the first large, multicenter, over an 18-month study period. Because a true placebo group longitudinal observational study of early lung disease in CF, receiving no anti-pseudomonal antibiotic therapy was not Fig. 1. EPIC study diagram and overlap between the clinical trial and the observational study.

M.M. Treggiari et al. / Contemporary Clinical Trials 30 (2009) 256–268 Fig. 2. Randomization assignment of participants enrolling in the clinical trial component of EPIC. ⁎Patients with culture positive for Pa at the end of 28 days ofinhaled therapy will receive a second 28-day treatment course for the first cycle only.
feasible at the time of study initiation in 2004, clinical trial associated with isolation of Staphylococcus aureus (S. aureus) participants will be also compared with two external controls, from respiratory cultures, and with emergence of methicillin- a concurrent cohort (derived from the EPIC Observational resistant S. aureus (MRSA) will also be evaluated. DNA study) that will allow the evaluation of the generalizability of samples extracted from whole blood are being collected and the clinical trial results, and a historical group that will allow banked from participants and their parents of origin for a the evaluation of low versus high intensity exposure to separate planned evaluation of genetic factors that may be antipseudomonal antibiotics. This historical group, derived associated with CF pathogenesis, disease progression, and from an existing patient registry and covering a period clinical outcomes. Finally, Pa isolates and serum samples from ranging from 1997–1999, had significantly less exposure to observational participants are banked for future studies to inhaled tobramycin prior to the commercial product's (TOBI) enhance the understanding of microbiological aspects of early FDA approval in 1998. Children in the historical group will be CF lung disease.
matched 2:1 for age and gender to each EPIC-CT participant.
For subjects who enroll in the EPIC-CT, the observational study provides pre-enrollment data to allow examination of 2. The observational study component the association between risk factors prior to trial enrollment,particularly Pa serology and Pa phenotype (mucoid versus 2.1. Objectives and aims of EPIC-OBS non-mucoid), and response to trial regimens. Moreover, theobservational study provides follow-up data on trial end- The primary aim of EPIC-OBS is the identification of risk points after completion of trial participation to allow factors associated with early age at first isolation of Pa from assessment of the long-term effects of trial regimens respiratory cultures and with the early emergence of mucoid (The observational study will also allow characteriza- and antibiotic-resistant strains of Pa, in particular, modifiable tion of patients who declined enrollment in the clinical trial to exposures, such as environmental tobacco smoke, breastfeed- estimate the presence of potential selection bias and to ing and daycare. The EPIC-OBS also aims to describe the evaluate the effect of non-protocol based antimicrobial longitudinal changes in clinical endpoints (e.g., lung function, approaches on the clinical, microbiology, and serology end- growth, exacerbation frequency) associated with initial points of interest in the clinical trial.
acquisition of Pa, as well as changes in clinical endpointsassociated with emergence of mucoid Pa and antibiotic- 2.2. Study design of EPIC-OBS resistant Pa. Among subjects not enrolled in the clinical trial,the effect of type and length of anti-pseudomonal therapy on The EPIC-OBS is an ongoing prospective, observational clinical endpoints, subsequent Pa serology, Pa antimicrobial cohort study. The size of the original cohort was 1787 resistance, Pa genotype, and emergence of other pathogens participants at 59 CF centers. CF patients ≤12 years of age will be examined. The longitudinal relationships between at the time of enrollment were eligible if they had no prior anti-pseudomonal serology, isolation of Pa from respiratory isolation of Pa from respiratory cultures, or if prior history of cultures, and evolving clinical signs and symptoms during isolation of Pa from respiratory cultures, at least a two-year early CF lung disease will be described. Clinical outcomes period with Pa negative cultures (documented by at least 1 M.M. Treggiari et al. / Contemporary Clinical Trials 30 (2009) 256–268 culture annually) or were concurrently enrolled in the EPIC- on statistics from the 2000 CFF National Patient Registry CT. The study was approved by the Institutional Review Board and questionnaire data from prospective sites participating in at each participating site, and all participants or their the EPIC studies. Combining the information from both surrogates provided written informed consent.
sources indicated that at approximately 60 sites, a sample of The EPIC-OBS involves prospective data and specimen about 2000 total Pa negative patients age 12 and younger was collection (Clinical care and monitoring is not affected available. The sample size justification was based on the by study participation. The Cystic Fibrosis Foundation (CFF) primary EPIC-OBS aim, i.e., to define risk factors for early age maintains a National Patient Registry containing a wide array of at first isolation of Pa. We hypothesized that environmental demographic, clinical, and actuarial data on all patients seen at tobacco smoke exposure and other modifiable exposures CF care centers. Registry data entry is encounter-based and would have an effect on age at first isolation of Pa at least as submitted via a secure web site ). The EPIC- great as that of other known risk factors evaluated in prior OBS study is made possible by the existence of this resource: studies, such as aerosol use, mother's education, and delta data collection occurs at each encounter and via an annual F508 homozygous status . The prevalence of smoking family survey utilizing an augmented version of the CFF among parents of children with CF ranges from 15 to 40% Registry containing the standard Registry data collection nationally. The minimum detectable hazard ratios, varying forms as well as additional, study-specific forms. The EPIC- the underlying prevalence of the risk factor from 0.2 to 0.5, OBS annual family survey is a parent/family questionnaire on and as a function of study power, ranged from 1.32 to 1.25 for potential risk factors for Pa acquisition, such as environmental a power of 0.8. These detectable hazard ratios are within the tobacco smoke and daycare attendance. Study sites are also range of risk estimates reported in prior studies. All calcula- queried annually regarding issues such as infection control tions were based on the log-rank statistic, assumed a two- practices and use of standardized monitoring and treatment sided .05 significance level and the occurrence of 650 events regimens in young CF patients.
(conversions to Pa positive status during the study period) EPIC-OBS participants have a serum sample collected and uniform accrual of the study participants over the two annually for evaluation of Pa serology and for banking. After year enrollment period.
the first isolation of Pa from respiratory culture at the local provides the projected number of patients site laboratory, an annual respiratory specimen is sent to the converting to Pa-positive during the study period. The Coordinating Center Core Microbiology Laboratory for semi- following assumptions were made to estimate duration of quantitative culture, evaluation of Pa mucoidy and banking. If enrollment in EPIC-OBS at the participating sites: 1. An available, initial Pa isolates from the local site laboratory are enrollment rate of 70% of eligible patients; 2. 15% annual rate also shipped to the Core Microbiology Laboratory for banking.
of conversion to Pa-positive; 3. 40% of Pa positive patients A single whole blood sample is collected from participants would enroll in EPIC-CT; and 4. 10% of enrolled subjects would and a whole blood sample or buccal swab is collected from drop-out or be lost to follow-up by the end of the study. Based parents of origin for DNA extraction and banking.
on these assumptions, enrollment into the EPIC-OBS wasneeded for the first two years of the study to achieve a sample 2.3. Sample size and power for EPIC-OBS of approximately 1400 Pa negative patients, of whom 650participants were expected to convert to Pa positive before The sample size, number of sites for both the EPIC-OBS and completion of the observation period, from which approxi- EPIC-CT, and duration of enrollment were determined based mately 300 were expected to enroll in the EPIC-CT.
Table 1EPIC-OBS data and sample collection schedule.
Quarterly encounter Hospitalization or IV antibiotic EPIC-OBS enrollment form Registry clinical encounter form EPIC-OBS clinical encounter form a Registry year-end survey EPIC-OBS year-end survey b Registry hospitalization/IV history Results of respiratory culture (local site lab) c Results of outpatient complete blood count d Serum for serology and banking Respiratory specimen sent to Core Microbiology Lab e a The EPIC-OBS clinical encounter form collects information about the following characteristics: use of oral and inhaled antibiotics since the previous visit, presence of crackles or wheezes on chest auscultation, cough frequency, cold symptoms, physical activity level, and activity limitations due to respiratorysymptoms.
b The EPIC-OBS year-end survey collects information about the following exposures: influenza and pneumococcal vaccines; environmental tobacco smoke; wood-burning stoves; hot tubs; swimming pools; attendance at social events with individuals who have CF; playing with other children who have CF; otherhousehold members with CF; daycare attendance; Synagis® prophylaxis; breast-feeding; mother's education; and annual household income.
c Culture results from routine clinical cultures performed at the local site laboratory are recorded in the Registry clinical encounter forms.
d Result of outpatient complete blood counts are recorded on the EPIC-OBS clinical encounter form.
e After the first isolation of Pa from a respiratory culture at the local site laboratory, annual respiratory specimens (OP swab or sputum) are shipped to and processed at the Cystic Fibrosis Foundation Therapeutics Development (TDN) Core Microbiology Laboratory. If possible, initial Pa isolates from the local sitelaboratory will also be shipped to the TDN Core Microbiology Laboratory.
M.M. Treggiari et al. / Contemporary Clinical Trials 30 (2009) 256–268 3.2. Choice of interventions in the EPIC-CT Estimated annual number of eligible patients among 60 U.S. CF centers in2000 based on the CFF National Patient Registry.
In young patients in whom Pa is isolated for the first time, the goal of treatment is maintaining sustained eradication rate of first Pa rather than controlling a chronic infection. The main con- siderations that were taken into account in the treatment selection process were the following: (1) a group receiving no active anti-pseudomonal antibiotics was not deemed feasible in consideration of current clinical practice, (2) 28-day therapy seemed appropriate based on previous literature concerning cycled inhaled tobramycin , and (3) a quarterly cycle would allow sufficient time off antibiotics tolimit exposure to antimicrobials.
Enrollment rates exceeded expectations, and the observa- The proposed regimens were discussed among a panel of tional study actually enrolled 1787 rather than 1400 experts from the CF community convened by the study principal investigators and the CFF to develop the optimalrange of therapeutic approaches that would ensure adequate 3. The clinical trial component microbial coverage for all subjects and preserve clinicalequipoise in the CF community.
3.1. Objectives of EPIC-CT A systematic review of the literature was prepared for the panel to assist in selection of the most effective and safest The primary objectives of the clinical trial are to anti-pseudomonal agents for administration in this young age investigate if an intensive quarterly anti-pseudomonal strat- group. Aminoglycosides are the drug class with the largest egy (cycled therapy) reduces pulmonary exacerbations and amount of information available about sputum–antibiotic the isolation of Pa from respiratory cultures, compared with a interactions in patients with CF. It was the general agreement strategy of anti-pseudomonal administration solely based that tobramycin for inhalation was a logical prototypical agent upon recovery of positive respiratory cultures collected for trials of early intervention in CF, as its safety and efficacy in quarterly (culture-based therapy). The specific primary aim patients six years and older is the most thoroughly docu- is twofold and includes a clinical and a microbiological mented of all inhaled antibiotics. It is the only FDA approved endpoint. The clinical endpoint is the time to first pulmonary inhaled antibiotic for the treatment of Pa infection in patients exacerbation (requiring intravenous antibiotics or with CF. There have been several studies in children less than hospital admission during the 18 month study period. The six years old demonstrating at least transient Pa eradication microbiological endpoint is the proportion of Pa-positive from upper and/or lower airways with inhaled tobramycin respiratory cultures among quarterly cultures obtained after randomization. Secondary independent clinical efficacy end- The recommended dosage of preservative-free inhaled points include: (1) time to pulmonary exacerbation not tobramycin for adults and children ≥6 years of age is 300 mg.
requiring intravenous antibiotic usage or hospitalization, (2) This dose was demonstrated to attain sputum levels adequate to frequencies of pulmonary exacerbations, hospitalizations, anduse of concomitant oral, inhaled, and intravenous antibiotics, Table 3Definition of pulmonary exacerbation — minimal criteria for treatment with (3) anthropometric measures (linear growth, weight gain), (4) pulmonary function tests including FVC, FEF25%–75%, andFEV The presence of a pulmonary exacerbation is established by the following: 1 (patients 4 years of age and older, able to reproducibly One of the major criteria alone or two of the minor signs/symptoms and perform spirometry), and (5) total hospitalization days.
fulfillment of symptom duration.
Secondary microbiological endpoints include the micro- Major criteria: (one finding alone establishes the presence of a pulmonary biologic profile of Pa isolates from respiratory cultures as indicated by: (1) changes in antibiotic susceptibility patterns (1) Decrease in FEV1 of ≥10% from best baseline within past 6 months, (minimal inhibitory concentrations of 12 antibiotics), (2) unresponsive to albuterol (in participants able to reproducibly performspirometry) colony morphology, and (3) the presence of mucoid isolates (2) Oxygen saturation b90% on room air or ≥5% decline from previous from baseline to the end of the study. The emergence of intrinsically aminoglycoside- and ciprofloxacin-resistant non- (3) New lobar infiltrate(s) or atelectasi(e)s on chest radiograph pseudomonal organisms is also evaluated (e.g., B. cepacia, A.
(4) Hemoptysis (more than streaks on more than one occasion in past week)Minor signs/symptoms: (two minor signs/symptoms are required with duration xylosoxidans, and S. maltophilia).
criteria in the absence of major criteria) Study participants are also followed with respect to the (1) Increased work of breathing or respiratory rate serologic response against selected Pa surface and secretory (2) New or increased adventitial sounds on lung exam antigens and changes in inflammatory markers (white blood (3) Weight loss ≥5% of body weight or decrease across 1 major percentile in count with differential and C reactive protein).
weight percentile for age in past 6 months (4) Increased cough The comparison of the safety profiles between the two (5) Decreased exercise tolerance or level of activity groups include the emergence of organ toxicities detected by (6) Increased chest congestion or change in sputum serial evaluation of articular/skeletal symptoms, renal func- Signs/symptom duration: (required with two minor signs/symptoms in absence tion, hearing acuity, liver function, hematological profile, and of major criteria) (1) Duration of sign/symptoms ≥5 days or significant symptom severity adverse events.
M.M. Treggiari et al. / Contemporary Clinical Trials 30 (2009) 256–268 overcome potential sputum antagonism . Inhaled tobramycin groups could receive an additional 28-day course of inhaled has also been shown to be safe and to achieve therapeutic tobramycin at the end of the first treatment cycle if their concentrations in the lower airway of patients b6 years of age respiratory cultures sampled after three weeks of the first . Dose adjustments for age or weight are not required.
anti-pseudomonal cycle continued to be positive for Pa. They Studies in patients chronically colonized with Pa support did not receive a second course of ciprofloxacin or placebo.
the use of inhaled tobramycin twice a day for cycles of 28 days Following this initial antibiotic regimen, participants receiving drug, followed by 1 month not receiving drug. In randomized to the cycled therapy group (n = 153) received colonized patients, data suggested that the effect of a 28-day therapy administrated in quarterly cycles for five additional cycle persists at least 56 days in over half of the patients, quarters, while participants randomized to the culture-based indicating that a 28-day cycle followed by 56 days off therapy therapy group (n = 153) received a course of therapy only when may be appropriate . This discontinuous dosing has the quarterly respiratory cultures, from either the central or the theoretical advantages of minimizing emergence of resistance local laboratory, were found positive for Pa for the same study and of reducing drug exposure. Therefore, quarterly therapy duration. The same anti-pseudomonal antibiotics, inhaled was selected for this young population.
tobramycin twice-daily for 28 days and oral ciprofloxacin or The consensus panel supported a combination of an placebo twice-daily for 14 days, were used in both groups. The inhaled antibiotic with an oral fluoroquinolone such as inhaled tobramycin therapy was not blinded. The ciprofloxacin ciprofloxacin for initial eradication. There are several pre- was administered as a pill to older children taking 250 mg or sumed advantages to this approach. First, oral fluoroquino- higher dose and placebo tablets were provided by Bayer.
lones are distributed systemically providing access to the Younger children received ciprofloxacin suspension or taste sinuses and upper airway, a potential reservoir for re- masked placebo suspension provided by Bayer.
infection . Second, they are bactericidal agents which Overall, the study follows a factorial design and partici- have a broad spectrum of antimicrobial activity with excellent pants were allocated to the treatment regimens as displayed in vitro activity against Pa strains from CF patients and in . Once patients were assigned to a treatment group, documented in vitro synergism with tobramycin . Third, patients and treating physicians had to adhere to the assigned they are well tolerated and easily administered. Fourth, the regimen for the 18-month study period. Except for the initial risk of emergence of resistance can be minimized by short- two study visits, patients were seen on a quarterly basis in term administration . The pharmacokinetic profile of oral conjunction with their routine clinic visits. Irrespective of and intravenous ciprofloxacin was examined in 150 pediatric randomization assignment, participants in each of these patients ages 0.3–17 years, including 28 children with CF. On groups were allowed to receive necessary antibiotic therapy average, the most frequently used dose of ciprofloxacin in for treatment of a pulmonary exacerbation in addition to their children is twice daily 15–20 mg/kg/dose up to a maximum assigned treatment regimen. An operational definition of of 750 mg/dose, for a two-week course .
pulmonary exacerbation was developed for the purpose of thestudy ). Participants presenting in a stable condition 3.3. Study design at the time of randomization were assigned to one of thestudy regimens immediately. Study participants presenting This clinical trial is a multicenter, randomized study of with new onset of a pulmonary exacerbation requiring IV young children with CF. Fifty seven clinical centers throughout antibiotics or hospital admission were treated at the discre- the US participated and the enrollment goal of 300 partici- tion of the investigator and then randomized at the following pants was met in 2.5 years ). Participating sites are listed quarter if they continued to meet the study eligibility criteria.
in Appendix A. All participating centers obtained IRB approvalfrom their respective institutions. After obtaining informed consent/assent, 306 participants have been equally rando-mized to one of two early anti-pseudomonal treatment Inhaled tobramycin was provided in an open label fashion, algorithms (cycled or culture-based therapy groups). The while oral ciprofloxacin was provided in a double-blinded duration of study participation for each subject is 18 months, fashion. To minimize potential bias due to the lack of blinding, during which time each participant receives up to six we developed an objective and rigorous operational definition treatment cycles. In combination with inhaled tobramycin of pulmonary exacerbation (and we verified all the (Novartis Pharmaceutical Corp), patients were randomized to hospitalization records to ensure that the reason of hospitaliza- receive either oral ciprofloxacin or oral placebo (Bayer tion was a pulmonary exacerbation. A patient diary was Healthcare AG).
maintained as a corroborating mechanism to ensure the active Randomization was carried out by permuted blocks, and reporting of any and all respiratory symptoms. A review performed using a computer generated sequence. The committee is devoted to the quality control of this endpoint randomization blocks did not account for clinical site since in a blinded fashion. Further, all of the secondary endpoints are we assumed that the potential clustering effect of clinical site objective measures. Additional measures to minimize bias would be mitigated by the large number of sites (i.e., large included an extensive ongoing training of both physicians and number of clusters of small size).
research coordinators by quarterly newsletters, teleconferences At study enrollment, participants received an initial course and annual study meetings. Educational tools for families and of anti-pseudomonal antibiotic therapy consisting of 28 days primary care physicians who might also be involved in the care of inhaled tobramycin with 14 days of oral ciprofloxacin or of the study participants have also been provided. All protocol placebo. To promote initial eradication of Pa at the beginning deviations and violations have been evaluated on a case-by- of the study, participants randomized to any of the study M.M. Treggiari et al. / Contemporary Clinical Trials 30 (2009) 256–268 Table 4EPIC-CT study visit schedule.
Medical history review b Interim medical history b Concomitant medication review Complete physical exam c Oropharyngeal or sputum culture f CBC with differential C-reactive protein Chest X-ray (PA and lateral) g Adverse event monitoring Additional plasma aliquot a If needed, for pulmonary exacerbation (PE) or follow up of adverse events (AE), including musculo-skeletal, articular or neurological symptoms.
b Neurological side effects based on medical history; if abnormalities are reported, patient is referred to the facility enrolling study subjects.
c Complete physical exam, including standard articular/skeletal muscle exam.
d Height/length and weight must be measured by same equipment throughout study period. Participants initiating study with length measurements must continue with length throughout study.
e Spirometry in participants ≥4 years of age.
f MICs at Week 0, Week 22, Week 46, and Week 70.
g Chest X-ray must not be prior to 6 months prior to inclusion in the study.
h Annual audiology at the sites is recommended. If abnormal results are found, a confirmatory audiology will be repeated four weeks later.
3.5. Choice of study population or other methyl-xanthines within 30 days of the time ofenrollment, administration of more than one course of Male and female subjects ≥1 year and ≤12 years of age with intravenous anti-pseudomonal antibiotics (defined as at least a diagnosis of CF with a documented new onset of orophar- 10 days of therapy) in the 2 years prior to baseline or more than yngeal, sputum or lower respiratory tract culture positive for Pa one course (at least 28 continuous days of therapy) of inhaled within six months prior to study entry were eligible for anti-pseudomonal antibiotics within two years prior to study participation in this study. For study purposes, first isolation entry, and chronic macrolides use (more than 3-month of Pa was defined as the first lifetime documented respiratory duration) within 3 months of baseline; presence of a condition culture positive for Pa or as a positive Pa culture after at least or abnormality that in the opinion of the Investigator would two-year absence of Pa growth (minimum of one documented compromise the safety of the patient or the quality of the data.
negative Pa culture per year). For participants ages 12 to Intravenous or inhaled anti-pseudomonal antibiotics needed to 15 months, at least one Pa positive respiratory culture since be completed more than 30 days prior to baseline.
birth was required. Children below the age of 1 year were notconsidered for enrollment because oral ciprofloxacin could not 3.6. Study subject screening and follow up strategies be administered for safety concerns regarding potentialarthropathy Other eligibility criteria included: Diag- Potential study participants were screened at the participat- nosis of CF clinically stable with no evidence of any ing sites whether or not they were previously enrolled in the significant respiratory symptoms at screening that would observational study. Patients meeting the criteria for the EPIC- require administration of intravenous antipseudomonal anti- CT were enrolled and randomization assignment was made biotics, oxygen supplementation and/or hospitalization; signed centrally via an interactive voice response system. informed consent by parent or legal guardian.
shows the content of the baseline encounter and subsequent Patients were excluded from the study if they had a history quarterly study visits for the 18 month study duration. Patients of aminoglycoside hypersensitivity or adverse reaction to had microbiology samples from oropharyngeal swab cultures at inhaled aminoglycoside, history of hypersensitivity or adverse every quarterly visit. Anthropometric measures and nutritional event associated with ciprofloxacin or other fluoroquinolones, assessment included length (children ≤18 months) or height, abnormal renal function (serum creatinine N1.5 times the and weight. Spirometry data were collected in subjects 4 years upper limit of normal for age), clinically documented chronic of age or older, according to the guidelines stipulated in the hearing loss, serum transaminase levels at the screening visit 1994 American Thoracic Society Guidelines with modified N2 times the upper limit of normal range, administration of any criteria for children investigational drug within 30 days prior to enrollment, chronic EPIC-CT participants, who were not previously enrolled in administration of loop diuretics, administration of theophylline the observational study, had the option to enroll in EPIC-OBS M.M. Treggiari et al. / Contemporary Clinical Trials 30 (2009) 256–268 prior to completion of the clinical trial in order to collect long- consisted of parent recall at quarterly visits and review of parent term clinical and safety follow-up data.
diary. The diary collected data on daily drug consumption, any Due to potential for aminoglycoside ototoxicity, audio- changes in patient health or new onset of symptoms, medica- metry utilizing age appropriate testing with tympa- tion use, and encounters with other health-care providers. The nometry to detect the presence of fluid in the middle ear was diary was maintained to ensure, among other things, an active performed at study enrollment, at the end of the first year and mechanism to capture the possible occurrence of new at study completion. Abnormal hearing was defined as an respiratory symptoms that could qualify as a study defined auditory threshold ≥25 dB at any frequency (500–8000 Hz) in either ear. If abnormal results were found during the studyperiod, confirmatory audiometry was repeated four weeks 3.8. Microbiology methods and specimen collection later. Children with abnormal audiologic findings had atympanometry performed, and if both were abnormal, they Oropharyngeal specimens were obtained at all study were referred to the study investigator or medically-qualified visits. Specimens were collected with a cotton-tipped swab sub-investigator for an ear examination. Audiometry was not from the posterior oropharyngeal wall and tonsillar pillars.
collected on all participants because some sites did not have Participants were encouraged to cough prior to collection of the capability to perform audiometric testing in this age the OP specimen. With the exception of the specimen group and some children were unable to comply with the obtained at the end of the first treatment cycle (which was testing procedure or had uninterpretable results due to processed at the site laboratory), all specimens were pneumatic equalizing tube placement.
processed at the core microbiology laboratory at Children's Blood samples were obtained for assessment of clinical Hospital and Regional Medical Center in Seattle, WA.
status and included blood chemistry (creatinine, blood urea Oropharyngeal swab specimens were sent on wet ice by nitrogen, and liver function tests including hepatic transami- overnight express shipment to the core microbiology labora- nases [AST and ALT] and γGT, and C reactive protein), and a tory, and needed to be received and cultured within 2 complete blood count (hemoglobin, hematocrit, red blood calendar days of collection. Bacterial culture techniques cell count, white blood cell count, and white blood cell were performed according to core microbiology laboratory differential count). After baseline, blood samples were standard procedures using a semi-quantitative bacterial obtained twice a year and at the end of the study. Blood culture technique All organisms were identified sampling also included serum banking for Pa serology assays.
using standard techniques, including standard biochemical For this purpose, the blood sample was centrifuged, the serum testing and PCR techniques . All Pa isolates were assessed extracted, and the specimen stored at −70 °C.
for mucoid phenotype. Minimal inhibitory concentrations Chronic use of azithromycin was not permitted. All (MIC) for Pa of 12 antibiotics were determined using a semi- participants were encouraged to remain on the same medica- automated microbroth dilution (Sensititre, AccuMed, Wes- tions throughout the entire study period, as medically feasible.
tlake, OH), according to standard National Committee on Study participants maintained a diary while on the study and Clinical Laboratory Standards methods. MICs for any Pa the information recorded in the patient diary was abstracted at isolate were performed at baseline and every six months.
every clinic visit. The diary collected data among others on We conducted quality control procedures to ensure that the treatment adherence and changes in concomitant medications.
sample shipment and processing methods would yield accurateresults. For this purpose we spiked 50 samples with inoculums 3.7. Drug distribution and adherence to treatment regimen of known micro-organism species (Pa, Stenotrophomonasmaltophilia, Achromobacter xylosoxidans, and "no organism") Within seven days of the study visit participants were and density (103 to 105 CFU) that were sent blindly to the core contacted to report the microbiology results and to review the microbiology laboratory. The specificity for Pa identification treatment plan. If participants required study medication based was excellent (100%), as there were no instances of Pa mis- on group assignment, the drug was prescribed at this time. Study identification. There was a single instance of the laboratory drugs (tobramycin solution for inhalation, ciprofloxacin suspen- finding no isolates from a Pa positive sample, yielding a sion or tablets, or a matched oral placebo) were distributed by a sensitivity for Pa isolation of 97%. To further evaluate measure- central pharmacy and mailed to the study participants' domicile ment error due to sampling, manipulation, and transport, data within 48 h of prescription. At the first treatment cycle patients were collected from the clinical site microbiology laboratory to were also provided with a nebulizer (PARI-Proneb® Ultra evaluate concordance between results for those participants compressors and PARI LC Plus® reusable nebulizers, PARI who had two simultaneous or sequential oropharyngeal Respiratory Equipment Inc., Midlothian, VA). Participants were cultures collected at the same study visit.
contacted within 48 h of prescription of the study drugs to verifydrug receipt, and were instructed to initiate treatment upon 3.9. Sample size and power of EPIC-CT receipt of the study drugs. Subsequently, participants werecontacted within 14 days of the clinic visit to identify occurrence By design, the primary study endpoint for which the study is of adverse events including a musculoskeletal assessment powered is the clinical efficacy endpoint, time to first exacer- survey, and to discuss study medication adherence. All partici- bation requiring intravenous antibiotics and/or hospitalization, pants were again contacted within 6 weeks of the clinic visit to which will be compared between treatment groups using a evaluate possible changes in health status.
hazard ratio as an estimate of the relative risk. The primary Further monitoring for patient adherence to prescribed analysis will compare the more aggressive treatment group, treatment regimen (cycled and culture-based treatment arms) cycled therapy, to the less aggressive treatment group, culture- M.M. Treggiari et al. / Contemporary Clinical Trials 30 (2009) 256–268 based therapy to evaluate the relative reduction in pulmonary tial interactions between the tobramycin and ciprofloxacin exacerbations achieved by the more aggressive therapy. To regimens. These analyses will involve comparing smaller determine the statistical power and sample size for this clinical subgroups of participants in each of the four relevant efficacy endpoint, we first obtained expected rates of exacer- subgroups (approximately 75 participants per group).
bation in this patient population.
A modified intent-to-treat (ITT) population was defined as all To determine a reasonable relative risk size for which to randomized participants who received at least one dose of study power this clinical efficacy endpoint, we estimated the annual exacerbation event rate using data on over 40,000 person-yearsrepresented in the CFF National Patient Registry during 1985– 3.11. Statistical analysis plan 2000 All patients born in 1985 or later and who werebetween the ages of 1 and 12 were classified into three mutually By design, the primary study endpoint for which the study exclusive groups at each calendar year: (i) patients with no is powered is the clinical efficacy endpoint, time to first positive Pa culture since birth; (ii) patients who had the first protocol-defined pulmonary exacerbation requiring intrave- positive culture during that year, and (iii) patients with at least nous antibiotics and/or hospitalization. The censored failure one positive culture in previous years. Based on the percentages time will be taken as the diagnosis date of the pulmonary of patients experiencing at least one exacerbation related event exacerbation, or the end of follow-up if no exacerbation during a calendar year, we estimated that the annual incidence meeting these criteria has occurred. End of follow-up is rate of exacerbations was 0.17 in group (i), 0.36 in group (ii), defined as the date of the last study visit completed by the and 0.37 in group (iii). These rates appeared to be consistent participant. Time will be measured in number of days post across age categories within each group. We assumed that an Day 0, the first day study therapy was started. The null aggressive early antibiotic therapy could potentially reduce the hypothesis is that there is no difference between the cycled risk of exacerbation by as much as 50% when comparing group therapy and culture-based therapy groups in terms of the (ii) to group (i). Based on the annual exacerbation incidence time to first protocol-defined exacerbation requiring intrave- rates estimated in the registry, an 18-month study with 300 nous antibiotics and/or hospitalization.
patients had 80% power to detect a relative risk of approxi- A Kaplan–Meier plot will be used to graphically display mately 0.6 or lower, equivalent to detecting a 40% or greater estimates of the survivor function in terms of the proportion of reduction in risk of pulmonary exacerbations. The primary participants who were exacerbation free over time for both the microbiologic analysis of the proportion of Pa positive cultures cycled and culture-based groups. Relative risk due to treatment in the 18-month study period will also compare the cycled will be estimated using a Cox proportional hazards regression therapy arm to the culture-based therapy arm. For this model, with covariate adjustment for baseline age group (1–3, objective, a sample size of 300 subjects provides 80% power N3–6, and N6 years). The significance of the treatment group to detect an odds ratio 0.6 or smaller for Pa-positive respiratory variable will be tested by the likelihood ratio test at a two-sided cultures between the two treatment strategies.
0.05 level of significance. The relative risk due to treatment fromthis model and corresponding 95% confidence interval will be 3.10. Factorial aspects of sample size and power the primary measure of treatment effect. Secondary analyseswill evaluate the interaction between the inhaled and oral The design of this study makes it possible to perform treatment groups within the context of this model, and similar separate evaluations of (1) the effect of two different models will be used to investigate differences between tobramycin treatment strategies and (2) the effect of oral treatment groups with respect to an important secondary ciprofloxacin versus oral placebo, each based on comparing endpoint, time to pulmonary exacerbation requiring any two groups of 150 study participants. The first evaluation antibiotics (inhaled, oral, or IV) and/or hospitalization. The would compare the cycled versus the culture-based group, following covariates will be considered for adjustment in and the second evaluation would compare the group assigned exploratory models for these endpoints: gender, enrollment to receive oral ciprofloxacin (regardless of tobramycin regi- season, Pa status at enrollment, and/or geographic region.
men) with the group assigned to receive oral placebo. The The microbiology endpoint is the proportion of Pa-positive secondary analysis will explore the main effect of ciproflox- respiratory cultures among the seven respiratory cultures taken acin by comparing all participants randomized to oral during the 18 months of the follow-up. The respiratory culture ciprofloxacin to all participants randomized to placebo.
results obtained from oropharyngeal cultures or expectorated Since the sample size in each of these groups is the same as sputum cultures obtained at weeks 3, 10, 22, 34, 46, 58, and 70 for the primary comparison, the study will have the same will be used in this analysis. The response will be binary power for this analysis as the primary analysis. Assuming lack (positive or negative culture). In the rare event that both an of interaction between cycled therapy and ciprofloxacin, the oropharyngeal culture and an expectorated sputum culture are factorial structure of the study will allow performing two available at a given visit and produce discordant results, a independent comparisons with adequate power, by spending positive result will be used in the analysis for this visit. The ITT only one degree of freedom on each comparison. The study population will be used for this longitudinal analysis and would have reduced power for finding an effect if there is a missing data will not be included. A generalized estimating negative interaction between cycled therapy and ciproflox- equation (GEE) model using a logit link will be used to model acin which is thought to be unlikely. However, we could also this data with an independence working correlation matrix. The gain power if there was a positive synergistic effect between significance of the treatment group variable will be tested by the cycled therapy and ciprofloxacin. Importantly, further the Wald test using a two-sided 0.05 level of significance. The exploratory analyses will be performed to investigate poten- treatment associated odds ratio from this model and

M.M. Treggiari et al. / Contemporary Clinical Trials 30 (2009) 256–268 corresponding 95% confidence interval will be the primary Each adverse event is entered into the case report form and measure of treatment effect. The estimated treatment effect will evaluated with respect to intensity, seriousness, causality be interpreted as the marginal odds ratio of Pa-positive (relationship to treatment) and actions taken. A summary of respiratory cultures during the 18 months.
potential trends or unexpected events is provided to the Data Sensitivity analyses will be performed in order to evaluate the Safety Monitoring Board for further review and evaluation.
robustness of the primary microbiologic results to missingculture data, which by virtue of study design should be minimal.
3.13. Data and Safety Monitoring Board (DSMB) Specifically, we will perform three additional analyses for theprimary microbiologic endpoint: (1) an analysis which imputes Safety is monitored on an ongoing basis throughout the trial missing respiratory culture data using the Last Observation by a Data and Safety Monitoring Board (DSMB) appointed by the Carried Forward (LOCF) method, (2) an analysis which assumes National Heart Lung and Blood Institute (NHLBI). The DSMB all missing culture data is negative for Pa, and (3) an analysis convenes at fixed times during the study in open and closed which assumes all missing culture data is positive for Pa. A meetings at approximately 6 month intervals, including an further analysis will investigate the sensitivity of the results to the annual in-person meeting. At each meeting, the DSMB reviews augmentation of core laboratory results with available results safety data, enrollment data, protocol violations, and overall from individual site microbiology laboratories. In some instances, study progress. Descriptions of serious adverse events are participants were double-swabbed and one swab was sent to the communicated to the DSMB Chair within 24 h of their occurrence.
core lab and one to the site lab. In instances for which the site lab There are no pre-specified stopping rules for efficacy or result was positive for Pa and the core lab was negative, the final futility. If the data from this study are unable to support the result will be treated as positive. Additional secondary endpoints superiority of the cycled based treatment regimen to the culture including longitudinal changes in anthropometric measures and based therapy in terms of both clinical and microbiologic spirometry will be modeled using the GEE framework to test for efficacy, this would be an important result that could influence differences in the 18-month change in each endpoint. Adverse clinical care. In particular, there would be no supportive data to events will be descriptively summarized by MEDRA system suggest that newly colonized CF patients be aggressively treated organ class and preferred term. Colony morphology will be regardless of their culture positivity. If the two regimens are summarized by the eradication and incidence patterns during equal in terms of efficacy, the secondary endpoints regarding the follow up period as compared to baseline for each of the safety and microbiologic resistance become even more impor- following bacterial organisms: P. aeruginosa, A. xylosoxidan, B.
tant for determining which regimen is superior and these must cepacia, S. aureus and S. maltophilia. This analysis will primarily be evaluated for the entire duration of the study. The DSMB be descriptive, and the proportion of patients who have follows the safety (quarterly) and efficacy (semi-annually) eradicated or newly acquired the organism by the end of the endpoints on a regular basis and could stop the study at any study will be summarized with corresponding 95% confidence time if they felt it was ethically necessary.
3.14. Study enrollment 3.12. Adverse event monitoring During the 2.5 years enrollment period, from December In the case of a serious adverse event (as defined by the FDA 20, 2004 to February 7, 2008, the actual accrual was excellent 21 CFR 312.32) the site investigator notifies the Coordinating due to excellent participation by all sites, closely overlapping Center within 24 h of learning of the event.
the projected figures (Clinical site performance is Fig. 3. EPIC clinical trial enrollment by month. Solid line indicates actual enrollment, dotted line indicates projected enrollment.
M.M. Treggiari et al. / Contemporary Clinical Trials 30 (2009) 256–268 monitored on an ongoing basis and, if deficiencies are dosing, safety, and efficacy in this young population. A site survey identified, these are addressed in a timely fashion.
was also distributed to confirm that the proposed strategies wereacceptable in the context of the local practices and in equipoise with current treatments in use at each participating institution.
This process ensured that the proposed strategies would be well The major objective of EPIC-CT is to help define a safe, accepted by the CF community and facilitated successful effective and systematic approach to the treatment of first enrollment throughout the study period.
isolation of Pa from young CF patients. These young patients In an effort to minimize the burden of a long term trial on potentially have the most to gain from aggressive early participants and their families, we scheduled the clinical trial intervention, but also the most to lose in terms of cumulative study visits to coincide with routine clinic visits and study drug toxicities and acquisition of resistant pathogens. If the drugs were shipped directly to the participant's residence.
study demonstrates both a microbiologic effect and clinical Because of frequent microbiology sampling, the study also efficacy of aggressive therapy without significant adverse avoided the use of invasive sampling procedures and ensured events or high rates of acquisition of resistant organisms, then that sampling occurred in conjunction with procedures there would be a strong rationale for aggressive early interven- performed (blood draws and oropharyngeal swabs) for tion. If the two treatment approaches are not different then the routine care. Although Pa monitoring via oropharyngeal use of aggressive cycled antibiotic therapy must be reassessed.
cultures is suboptimal, more invasive approaches were not The major objectives of the EPIC-OBS study are 1) to feasible in a study of this size and in the age range of the study provide a closely-monitored cohort of young children prior to participants. Results of study oropharyngeal cultures were potential EPIC-CT entry, 2) to provide long-term follow-up of provided to the sites to allow continued clinical care.
the treatment regimens for the subset of randomized This study did not examine patient/family reported patients, and 3) to establish a large, multi-center, well- outcomes due to the lack of availability of validated instru- characterized cohort of young children with CF to obtain more ments for participants of ages 6 years or younger . Future generalizable data on the risk factors for and impact of Pa studies should consider collecting age-appropriate quality of acquisition and infection. The ultimate goal is for this cohort life measures to evaluate the effect of long term interventions to be closely monitored for at least 10 years with both study- on treatment burden and health related quality of life.
specific data collection and ongoing use of the CF Patient The emphasis placed on engaging the clinical sites in the Registry. We anticipate that this longitudinal study will be early phase of study development and designing the study to informative on both risks factors for and clinical outcomes of meet the needs of both the sites and the participant's families initial, chronic, and mucoid Pa infection, and will explore the likely contributed to the excellent enrollment rate that impact of polymicrobial infections (interaction of S. aureus exceeded projections by 6 months. In addition, the attrition and Pa) in children with CF. The banked serum will provide a rate has remained at less than 10% easily meeting expectations.
rich resource for the analyses of serologic markers of early and In conclusion, this study will provide valuable clinical and chronic Pa infection, and other potential biomarkers of early microbiologic efficacy and safety data regarding the optimal CF lung disease. The DNA bank from whole blood of EPIC-OBS use of antipseudomonal therapy in young children with CF, participants will provide a unique resource for the evaluation and the long-term follow-up of this unique cohort of children of genetic modifiers of early CF disease.
will supply important data on the effect of Pa infection on This initiative represents the largest cohort and therapeu- subsequent health status, and the linked serum and DNA tic study ever conducted in children with CF and provides a banks will contribute valuable information on surrogate model of how to conduct a phase 3 trial in a population of markers and genetic modifiers of early CF lung disease.
young children. The project was made possible under theauspices of the Cystic Fibrosis Foundation and the National Heart, Lung and Blood Institute who joined forces to create acooperative program, along with the support of industry who The research for this article was supported in part by the donated study drugs and supplies. The studies made use of Cystic Fibrosis Foundation grants number EPIC0K0 and existing resources both during the planning and implementa- OBSERV04K0, the National Heart Lung and Blood Institute tion phase as provided by the linkage to the National CFF (NHLBI) and National Institute for Digestive Disorders and Kidney Registry. Similar to the design of the Women's Health Initiative (NIDDK) grant number U01-HL080310, and the National Center that combined a cohort study and a clinical trial, the for Research Resources (NCRR) grant number ULI-RR2501401.
observational cohort study not only serves as a free-standing Study drugs and devices were supplied free of charges by epidemiologic study of early CF lung disease, but also provides Novartis Pharmaceutical Corp. (inhaled tobramycin) and Bayer a pool of potential clinical trial participants and provides long Healthcare AG (oral ciprofloxacin and oral placebo), compressors term follow-up data on clinical trial participants. These and nebulizers were provided by PARI Respiratory Equipment Inc.
features should provide an ideal setting for the interpretation The Sponsors had no role in designing the study, in the of the clinical trial findings and their generalizability. A large data collection, or in the writing of the manuscript. They have number of sites were recruited to ensure timely enrollment no access to the study data.
and provide a broad geographic distribution and to ensure theinclusion of a representative sample of the population.
Appendix A. — Epic investigators In the trial planning stage, a consensus process among experts in the CF field was used to ensure that the study treatment Program Office: National Institute of Health: Susan Banks- strategies were optimal in terms of administration schedule, Schlegel, PhD, National Heart, Lung and Blood Institute, Project M.M. Treggiari et al. / Contemporary Clinical Trials 30 (2009) 256–268 Director; Gail Weinman, MD, National Heart, Lung and Blood College, Westchester Medical Center, Valhalla, NY, Allen Institute, Executive Secretary; Cystic Fibrosis Foundation Ther- Dozor, MD and Nikhil Amin, MD; Northern California Kaiser apeutics: Robert J. Beall, Ph.D., Preston W. Campbell III, MD, Bruce CF Center, Kaiser Permenente Medical Center, Oakland, CA, C. Marshall, MD.
Greg Shay, MD and Albin Leong, MD; Oregon Health Sciences Data and Safety Monitoring Board: Lynne Quittell, MD (Chair) University, Portland, OR, Michael Wall, MD; Penn State Milton Columbia University; William Clarke, PhD, University of Iowa; S. Hershey Medical Center, Hershey, PA, Gavin Graff, MD; Mary Jane Kennedy, PharmD, Kosair Charities Pediatric Clinical Rainbow Babies & Childrens Hospital, Cleveland, OH, Michael Research Unit, Louisville; Robert Nelson, MD, PhD, University of W. Konstan, MD; Rhode Island Hospital, Providence, RI, Mary Pennsylvania; Kenneth N. Oliver, MD, MPH, National Institute of Ann Passero (EPIC-OBS only); Riley Hospital, Indiana Uni- Allergy and Infectious Disease; Ronald Rubenstein, MD, PhD, versity, Indianapolis, IN, Michelle Howenstine, MD; Schneider Children's Hospital of Philadelphia; O. Dale Williams, PhD, Children's Hospital, New Hyde Park, NY, Joan DeCelie- University of Alabama at Birmingham; Gail Weinman, MD, Germana, MD; Spectrum Health Hospitals – DeVos Children's National Heart, Lung and Blood Institute; Susan Banks-Schlegel, Butterworth Hospital, Grand Rapids, MI, Susan Millard, MD; St.
PhD, National Heart, Lung and Blood Institute; Jungman Joo, PhD, Christopher's Hospital for Children, Philadelphia, PA, Laurie National Heart, Lung and Blood Institute.
Varlotta, MD; Stanford University, Packard Children's Hosp., Coordinating Center: Study monitors: Amanda Bailey, Palo Alto, CA, Richard Moss, MD; SUNY Upstate Medical Molly Andrina, Amy Feldman, Robin Hill, Tamara Potter, University, Upstate Medical Center, Syracuse, NY, Ran D. Anbar, Deborah Chambers, Shirley Desmon; Data Management: MD; Texas Children's Hospital, Houston, TX, Peter Hiatt, MD; Barbara Mathewson, MS, David Escobar, MPH; Biostatistical Tulane University School of Medicine, New Orleans, LA, Scott Unit: Umer Khan, MS, Kelli Joubran, MS; Microbiology Core H. Davis, MD; University of Alabama at Birmingham, Birming- Lab: Jane Burns, MD, Jenny Stapp, Anne Marie Buccatt, Griffith ham, AL, Hector H. Gutierrez, MD; University of California, San Adam; Medical Monitor: Christopher Goss, MD, MSc.
Francisco, San Francisco, CA, Dennis Nielson, MD; University of Clinical Centers: Albany Medical College, Albany, NY, Paul Florida College of Medicine, Gainesville, FL, Terry Spencer, MD; Comber, MD, PhD; All Children's Hospital CF Center, St.
University of Iowa, Iowa City, IA, Richard C. Ahrens, MD; Petersburg, FL, Magdalen Gondor, MD; Cardinal Glennon University of Kentucky, Lexington, KY, Jamshed F. Kanga, MD; Children's Hospital — St. Louis University, St. Louis, MO, University of Mass Memorial Health Care, Worcester, MA, Blakeslee E. Noyes, MD; Nationwide Children's Hospital, Brian P. O'Sullivan, MD; University of Michigan, Ann Arbor, MI, Columbus, OH, Karen McCoy, MD; Children's Hospital & Samya Nasr, MD; University of Mississippi Medical Center, Regional Medical Center, Seattle, WA, Ronald L. Gibson, MD, Jackson, MS, Alicia DePaula, MD and Fadel Ruiz, MD; PhD (EPIC-CT), Margaret Rosenfeld, MD, MPH (EPIC-OBS); University of Nebraska, Omaha, NE, John L. Colombo, MD; Denver Children's Hospital, Denver, CO, Frank Accurso, MD University of New Mexico, Albuquerque, NM, L. Francine and Jeffrey Wagener, MD; Children's Hospital Medical Center Caffey, MD; University of North Carolina, Chapel Hill, Chapel of Akron, Akron, OH, Greg Omlor, MD; Children's Hospital of Hill, NC, George Retsch-Bogart, MD; University of Rochester, Michigan, Detroit, MI, Debbie Toder, MD; Children's Hospital Rochester, NY, Clement L. Ren, MD; University of Utah, Salt of Pittsburgh, Pittsburgh, PA, David Orenstein, MD; Children's Lake City, UT, Barbara A. Chatfield, MD; University of Virginia, Hospital of Wisconsin, Milwaukee, WI, William M. Gershan, Charlottesville, VA, Deborah K. Froh, MD; University of MD; Children's Hospital, Boston, Boston, MA, Terry Spencer, Wisconsin Hospital and Clinics, Madison, WI, Michael Rock, MD, Thomas Martin, MD, and David Waltz, MD; Children's MD; Vanderbilt University Medical Center, Nashville, TN, Hospitals & Clinics, Minneapolis, MN, John McNamara, MD; Elizabeth Perkett, MD and Christopher Harris, MD; Vermont Children's Medical Center of Dayton, Dayton, OH, Robert J.
Children's Hospital at Fletcher Allen Health Care, Burlington, Fink, MD; Children's Memorial Hospital, Chicago, IL, Adrienne VT, Thomas Lahiri, MD; Washington University School of Prestridge, MD; Children's Mercy Hospital, Kansas City, MO, Medicine, St. Louis Children's Hospital, St. Louis, MO, Thomas Philip Black, MD; Cook Children's Medical Center, Ft. Worth, Ferkol, MD; Women & Children's Hosp of Buffalo, Children's TX, Maynard Dyson, MD; Dartmouth-Hitchcock Medical Hospital of Buffalo, Buffalo, NY, Daniel Sheehan, MD; Chil- Center, New Hampshire CF Center, Lebanon, NH, H. Worth dren's Hospital of Los Angeles, USC Medical School, Los Parker, MD and Dennis Stokes, MD; duPont Hospital for Angeles, CA, Marlyn Woo, MD.
Children, A.I. duPont Inst. Med. Center, Wilmington, DE, AaronChidekel, MD; Emory University CF Center, Atlanta, GA,Michael Schecter, MD, Lawrence McKean, MD and Daniel Caplan, MD; Johns Hopkins University, Baltimore, MD, PeterMogayzel, MD, PhD; LeBonheur Children's Medical Center, [1] Cystic Fibrosis Foundation. Patient Registry 2004 annual data report.
Memphis, TN, Robert A. Schoumacher, MD; Maine Medical Bethesda, Maryland: Cystic Fibrosis Foundation; 2005.
Center, Portland, ME, Anne Marie Cairns, DO; Massachusetts [2] IACFA Newsl 1999(Issue 56):8.
[3] Kosorok MR, Wei WH, Farrell PM. The incidence of cystic fibrosis. Stat General Hospital, Boston, MA, Allen Lapey, MD, and Henry L.
Dorkin, MD; Medical College of Georgia, Augusta, GA, [4] Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of Margaret F. Guill, MD; Miller Children's Hospital, Memorial pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med2003;168:918–51.
Miller Children's Hosp, University of California, Irvine, Long [5] Gibson RL, Emerson J, McNamara S, Burns JL, Rosenfeld M, Yunker A, et al.
Beach, CA, Felice Adler-Shohet, MD and Jay Lieberman, MD; Significant microbiological effect of inhaled tobramycin in young Monmouth Medical Center, Long Branch, NJ, Robert L. Zanni, children with cystic fibrosis. Am J Respir Crit Care Med 2003;167:841–9.
[6] Rosenfeld M, Gibson RL, McNamara S, Emerson J, Burns JL, Castile R, et al.
MD; Nemours Children's Clinic, Jacksonville, FL, David Schaef- Early pulmonary infection, inflammation, and clinical outcomes in fer, MD and Kathryn Blake, PharmD; New York Medical infants with cystic fibrosis. Pediatr Pulmonol 2001;32:356–66.
M.M. Treggiari et al. / Contemporary Clinical Trials 30 (2009) 256–268 [7] Burns JL, Gibson RL, McNamara S, Yim D, Emerson J, Rosenfeld M, et al.
[23] Haller I. Comprehensive evaluation of ciprofloxacin–aminoglycoside Longitudinal assessment of Pseudomonas aeruginosa in young children combinations against Enterobacteriaceae and Pseudomonas aeruginosa with cystic fibrosis. J Infect Dis 2001;183:444–52.
strains. Antimicrob Agents Chemother 1985;28:663–6.
[8] Dakin CJ, Numa AH, Wang H, Morton JR, Vertzyas CC, Henry RL.
[24] Ball P. Emergent resistance to ciprofloxacin amongst Pseudomonas Inflammation, infection, and pulmonary function in infants and young aeruginosa and Staphylococcus aureus: clinical significance and ther- children with cystic fibrosis. Am J Respir Crit Care Med 2002;165:904–10.
apeutic approaches. J Antimicrob Chemother 1990;26:165–79 Suppl F.
[9] Demko CA, Byard PJ, Davis PB. Gender differences in cystic fibrosis: [25] Bosso JA. Use of ciprofloxacin in cystic fibrosis patients. Am J Med Pseudomonas aeruginosa infection. J Clin Epidemiol 1995;48:1041–9.
[10] Proesmans M, Balinska-Miskiewicz W, Dupont L, Bossuyt X, Verhaegen J, [26] Burkhardt JE, Hill MA, Carlton WW, Kesterson JW. Histologic and Hoiby N, et al. Evaluating the "Leeds criteria" for Pseudomonas aeruginosa histochemical changes in articular cartilages of immature beagle dogs infection in a cystic fibrosis centre. Eur Respir J 2006;27:937–43.
dosed with difloxacin, a fluoroquinolone. Vet Pathol 1990;27:162–70.
[11] Lee TW, Brownlee KG, Conway SP, Denton M, Littlewood JM. Evaluation [27] Chysky V, Kapila K, Hullmann R, Arcieri G, Schacht P, Echols R. Safety of of a new definition for chronic Pseudomonas aeruginosa infection in ciprofloxacin in children: worldwide clinical experience based on compas- cystic fibrosis patients. J Cyst Fibros 2003;2:29–34.
sionate use. Emphasis on joint evaluation. Infection 1991;19:289–96.
[12] Valerius NH, Koch C, Hoiby N. Prevention of chronic Pseudomonas [28] Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus aeruginosa colonisation in cystic fibrosis by early treatment. Lancet statement. Cystic Fibrosis Foundation Consensus Panel. J Pediatr [13] Taccetti G, Campana S, Festini F, Mascherini M, Doring G. Early [29] De Boeck K, Wilschanski M, Castellani C, Taylor C, Cuppens H, Dodge J, et al.
eradication therapy against Pseudomonas aeruginosa in cystic fibrosis Cystic fibrosis: terminology and diagnostic algorithms. Thorax patients. Eur Respir J 2005;26:458–61.
[14] Frederiksen B, Koch C, Hoiby N. Antibiotic treatment of initial [30] Standardization of spirometry, 1994 update. American Thoracic Society.
colonization with Pseudomonas aeruginosa postpones chronic infection Am J Respir Crit Care Med 1995;152:1107–36.
and prevents deterioration of pulmonary function in cystic fibrosis.
[31] Beydon N, Davis SD, Lombardi E, Allen JL, Arets HG, Aurora P, et al. An Pediatr Pulmonol 1997;23:330–5.
official American Thoracic Society/European Respiratory Society state- [15] Kosorok MR, Jalaluddin M, Farrell PM, Shen G, Colby CE, Laxova A, et al.
ment: pulmonary function testing in preschool children. Am J Respir Comprehensive analysis of risk factors for acquisition of Pseudomonas Crit Care Med 2007;175:1304–45.
aeruginosa in young children with cystic fibrosis. Pediatr Pulmonol [32] Thompson G, Wilson WR. Clinical application of visual reinforcement audiometry. Semin Hear 1984;5:85–99.
[16] Maselli JH, Sontag MK, Norris JM, MacKenzie T, Wagener JS, Accurso FJ.
[33] Gravel GS. Behavioral assessment of auditory function. Semin Hear Risk factors for initial acquisition of Pseudomonas aeruginosa in children with cystic fibrosis identified by newborn screening. Pediatr Pulmonol [34] Burns JL, Emerson J, Stapp JR, Yim DL, Krzewinski J, Louden L, et al.
Microbiology of sputum from patients at cystic fibrosis centers in the [17] Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB, Williams- United States. Clin Infect Dis 1998;27:158–63.
Warren J, et al. Intermittent administration of inhaled tobramycin in [35] Burns JL, Van Dalfsen JM, Shawar RM, Otto KL, Garber RL, Quan JM, et al.
patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Effect of chronic intermittent administration of inhaled tobramycin on Group. N Engl J Med 1999;340:23–30.
respiratory microbial flora in patients with cystic fibrosis. J Infect Dis [18] Ratjen F, Doring G, Nikolaizik WH. Effect of inhaled tobramycin on early Pseudomonas aeruginosa colonisation in patients with cystic fibrosis.
[36] Qin X, Emerson J, Stapp J, Stapp L, Abe P, Burns JL. Use of real-time PCR with multiple targets to identify Pseudomonas aeruginosa and other [19] Wiesemann HG, Steinkamp G, Ratjen F, Bauernfeind A, Przyklenk B, nonfermenting gram-negative bacilli from patients with cystic fibrosis.
Doring G, et al. Placebo-controlled, double-blind, randomized study of J Clin Microbiol 2003;41:4312–7.
aerosolized tobramycin for early treatment of Pseudomonas aeruginosa [37] Cystic Fibrosis Foundation. Patient Registry 2002 annual data report.
colonization in cystic fibrosis. Pediatr Pulmonol 1998;25:88–92.
Bethesda, Maryland: Cystic Fibrosis Foundation; 2003.
[20] Rosenfeld M, Gibson R, McNamara S, Emerson J, McCoyd KS, Shell R, et al.
[38] Design of the Women's Health Initiative clinical trial and observational Serum and lower respiratory tract drug concentrations after tobramycin study. The Women's Health Initiative Study Group. Control Clin Trials inhalation in young children with cystic fibrosis. J Pediatr 2001;139:572–7.
[21] Smith MJ, White LO, Bowyer H, Willis J, Hodson ME, Batten JC.
[39] Modi AC, Quittner AL. Validation of a disease-specific measure of Pharmacokinetics and sputum penetration of ciprofloxacin in patients health-related quality of life for children with cystic fibrosis. J Pediatr with cystic fibrosis. Antimicrob Agents Chemother 1986;30:614–6.
[22] Klinger JD, Aronoff SC. In-vitro activity of ciprofloxacin and other antibacterial agents against Pseudomonas aeruginosa and Pseudomonas cepacia from cysticfibrosis patients. J Antimicrob Chemother 1985;15:679–84.


Carotid endarterectomy—An evidence-based review: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology S. Chaturvedi, A. Bruno, T. Feasby, R. Holloway, O. Benavente, S. N. Cohen, R. Cote, D. Hess, J. Saver, J. D. Spence, B. Stern and J. Wilterdink Neurology 2005;65;794-801 DOI: 10.1212/01.wnl.0000176036.07558.82


Journal of Anxiety Disorders 23 (2009) 563–574 Contents lists available at Journal of Anxiety Disorders The use of virtual reality in acrophobia research and treatment Carlos M. Coelho ,Allison M. Waters , Trevor J. Hine Guy Wallis a School of Human Movement Studies, University of Queensland, Level 5, Building 26, St. Lucia, QLD 4072, Australiab Griffith Institute of Health and Medical Research and School of Psychology, Griffith University, Brisbane, Australiac Queensland Brain Institute, University of Queensland, Brisbane, Australia