More than 85% of patients with cystic fibrosis (CF) have severe exocrine pancreatic insufficiency (EPI) (1) and need lifelong treatment with pancreatic enzyme replacement therapy (PERT) to enable them to digest and thus absorb nutrients and to maintain adequate nutrition and age-appropriate growth and weight gain (2,3). Relatively few improvements have been made in the composition of PERT products, which are porcine-derived extracts of lipase, protease, and amylase but also contain other proteins and purines, and have the potential to be contaminated with porcine viruses (4). Microencapsulated PERTs with >20,000 US Pharmacopoeia [USP] units of lipase per capsule were introduced in the early 1990s without upper limits on dosing, but were voluntarily withdrawn from the market soon after being associated, in a dose-dependent manner, with a newly identified serious complication of CF termed fibrosing colonopathy (5–7). In this context, the US Cystic Fibrosis Foundation (CFF) in conjunction with the US Food and Drug Administration (FDA) convened a consensus conference that recommended weight-based (as opposed to symptom-based) PERT dosing guidelines (8,9).
In view of concerns about the significant variations in bioavailability among porcine pancreatic enzyme dosage forms, batch-to-batch variation in enzyme activity, susceptibility to loss of activity over time (which led to the routine practice of overfilling, within limits set by the USP (10)), and consequent instances of serious under- and overdosing (6–8,11–15), particularly in association with the common practice of “generic” substitution (16,17), the FDA required all companies manufacturing PERTs to submit new drug applications and comply with strict new bioavailability regulations, including a curb on the practice of overfilling and more attention to the issue of viral contamination (18–20).
Liprotamase is a novel nonporcine PERT, containing a proprietary biotechnology-derived formulation of cross-linked crystalline lipase, crystalline protease, and amorphous amylase with broad substrate specificity, that has been designed for purity (no viral contamination), precise dose standardization, resistance against proteolysis without polymeric coating, and stability in acid pH for reliable potency of activity in the proximal small intestine (21–24). A preliminary phase I study with liprotamase demonstrated good safety and clinical activity in patients with CF with EPI (25); a phase II dose-finding study showed positive effects with a midrange fixed dose at each meal and snack (26); and a rigorously controlled phase III multicenter efficacy trial demonstrated that single-capsule dosing at the same fixed dose was well tolerated compared with placebo and was associated with significant improvements in coefficient of fat absorption (CFA) and other absorption/nutritional parameters (27). We report the results of the first ever 12-month open-label trial of the safety, tolerability, and clinical activity of a PERT for chronic use by patients with CF with EPI.
The phase III 12-month open-label trial was conducted between June 2007 and April 2009 at 33 sites in the United States and 11 sites outside the United States with expertise in treating patients with CF. The study protocol and informed consent form were approved by the institutional review board/independent ethics committee at each site, and all of the subjects or their legal representatives provided written consent and, in the case of subjects younger than 18 years of age, assent. Safety data, including reports of serious adverse events (SAEs), were monitored by a study-specific committee of the CFF data safety monitoring board.
Study Subjects and Design
Boys and girls 7 years old and older were eligible for the trial if they had documented evidence of the diagnosis of CF (2 clinical features consistent with CF and either genotype with 2 identifiable mutations consistent with CF or sweat chloride >60 mEq/L by quantitative pilocarpine iontophoresis), had EPI as defined by a fecal elastase (1) ≤100 μg/g stool measured at screening visit, had no evidence of acute upper or lower respiratory tract infection, were able to take PERTs in the form of capsules, and were able to undergo the testing and procedures designated in the study protocol. All of the eligible subjects were long-term or lifetime users of porcine PERTs and were required to discontinue these therapies before enrollment in the trial.
Subjects were excluded if they were pregnant, breast-feeding, or of childbearing potential and not willing to use birth control during the study. Subjects were also excluded for history of fibrosing colonopathy, organ transplantation, significant bowel resection, any acute or chronic diarrheal illness unrelated to EPI, baseline elevation of liver transaminases >5 times the upper limit of normal (ULN) or of bilirubin >1.5 times ULN, inability to discontinue enteral tube feedings during the study, known hypersensitivity to food additives, or pancreatic sufficiency (baseline CFA >93%) during the phase III liprotamase efficacy trial.
Subjects previously enrolled in the phase III efficacy trial were eligible for enrollment in this trial, along with subjects who had never received liprotamase (de novo subjects). De novo subjects were screened within 4 weeks of the trial baseline (Fig. 1), discontinued their previously prescribed PERTs, and began liprotamase treatment for an intended period of 12 months.
Subjects who completed the phase III efficacy trial and who elected to enroll in this long-term safety trial entered at week 6 of the present study. Subjects who had discontinued from the phase III efficacy trial either because of invalid baseline stool collection or baseline CFA >80% (ie, subjects who had been studied in that trial as part of a safety population but not part of the efficacy evaluation), and who remained eligible and elected to participate in the long-term safety trial, entered the trial at week 4 (Fig. 1). It was presumed that, if possible, these subjects enrolling at week 4 or week 6 would be doing so directly following their participation in the efficacy trial and thus would have no interruption in liprotamase treatment. This would also allow them to match the duration of exposure to liprotamase of de novo subjects who were not previously treated with liprotamase. Subjects who had interruption of liprotamase treatment of >7 days following their participation in the efficacy trial were considered ineligible to enroll in the safety trial. Subjects who were enrolled in this long-term safety trial after participating in the liprotamase efficacy trial were to be treated in this trial for a term of 10.5 to 11 months; safety data collected during their participation in the efficacy trial were incorporated into the present analysis to yield up to 12 months of exposure and follow-up for all of the trial subjects.
During the first 2 months of treatment in this trial, subjects were evaluated clinically and with anthropometric and laboratory testing and assessment of nutrient intake, adverse events, and concomitant medication usage at weeks 1, 2, 4, 6, and 8; subjects were then evaluated at months 3, 4, 6, 8, 10, and 12 and at a final follow-up visit 2 weeks after completing the trial (Fig. 1). Study drug compliance was assessed throughout the trial by means of capsule counts and regular review of mandatory study drug and vitamin diaries.
Study Drug and Dosage
Liprotamase is a nonporcine PERT containing highly purified biotechnology-derived enzymes (lipase, protease, and amylase). The lipase and protease are crystallized, and the crystallized lipase is cross-linked to increase shelf life and stability under harsh conditions such as low pH and exposure to proteolytic enzymes. The amylase is amorphous. The enzymes do not require polymeric coating for protection against acid hydrolysis or proteolysis. The lipase is active against a wide range of triglyceride substrates. Each lot of the individual drug substances is tested to ensure compliance with specifications, including biologic purity and activity. The 3 drug substances are blended together with pharmaceutical-grade excipients and dispensed into a size 2 gelatin capsule at a fixed ratio of lipase:protease:amylase activities of 1.3:1:0.15. Each liprotamase capsule used in the trial contained 32,500 USP units lipase activity, 25,000 USP units protease activity, and 3750 USP units amylase activity. The rationale for the dosing proportions has been described (26). The acid-resistant and proteolysis-resistant product does not require polymeric coating because this resistance is an inherent property of the individual enzymes composing the drug.
All of the subjects were initially prescribed 1 capsule of liprotamase orally in the middle of each of 3 meals and 2 snacks per day. The single-capsule fixed liprotamase dosing represented the midrange effective dose identified in the phase II dose-finding study of liprotamase and confirmed as efficacious in the phase III efficacy trial. Subjects were then allowed to increase to 2 capsules per meal (with no increase allowed for snacks) based on specific criteria defined in the protocol (related to steatorrhea, weight loss, or lack of weight gain for pediatric patients) under the guidance of the medical monitor. This study is the first time in the liprotamase development program that dose adjustment was allowed based on considerations similar to those used in clinical practice. Subjects rolled over from the liprotamase phase III efficacy trial had not previously undergone such dosage increases because the dose was fixed at 1 capsule per meal and snack in that trial.
A CF-specific multivitamin enriched with vitamins A, D, E, and K was provided to all of the subjects in the United States. Subjects outside the United States were encouraged to take fat-soluble vitamins, but such vitamins were not supplied by the trial sponsor. If fat-soluble vitamin deficiencies were identified during the trial, the need for increased supplementation was determined by the study investigators.
Study Endpoints and Statistical Methods
The primary objective of the trial was to evaluate the long-term safety and tolerability of liprotamase treatment in subjects with CF-related EPI. As part of this safety analysis, the trial also assessed the effect of liprotamase treatment on the nutritional status of subjects with CF-related EPI, through serial measurement of height, weight, body mass index (BMI), and lung function by forced expiratory volume in 1 second (FEV1) among other parameters. Weight loss >5% of baseline body weight was considered to be significant.
The objective of the trial was for 100 subjects to complete 12 months of treatment. Based on prior experience reported in other long-term CF studies (28), it was anticipated that the withdrawal rate would be 20% during the first 6 months and that an additional 20% would withdraw during the second 6 months. The target enrollment for this study was therefore set at 200 subjects. It was expected that approximately 160 subjects would complete 6 months of treatment and that 128 subjects would complete the full 12 months.
The safety population was defined as all subjects who took at least 1 dose of liprotamase. Adverse events were coded using MedDRA version 10 (Northrop Grumman, Falls Church, VA) and treatment-emergent adverse events (TEAEs), occurring after the first exposure to the study drug, were summarized overall and by severity and causality. SAEs were required to be reported and adjudicated. Adverse events and actual values and changes from baseline in clinical laboratory parameters and vital signs were analyzed descriptively. Shift and outlier analyses were conducted on laboratory parameters and vital signs. Clinical activity relative to height, weight, and BMI, and z scores for these parameters was evaluated at each time point using descriptive statistics. Height, weight, and BMI z scores were determined with reference to year 2000 growth charts from the Centers for Disease Control (CDC), which take into account age and sex differences and allow translation of any given height, weight, and BMI data point into the standard measures based on subject age and sex. Data were tabulated using observed values with last observation carried forward (LOCF) methodology for imputation of missing values following early withdrawal from the study. Maintenance/gain/loss of weight (>5% decrease or increase) was assessed over time after week 8 of the trial, which was chosen as a baseline for this calculation to allow time for adjustment to enzyme.
Data management was performed by Quintiles (Livingston, GA), and the data management system built with InForm (validated for version 4.5; Oracle, Redwood Shores, CA). Study database analyses were conducted and reported using the Cognos Reporting Tool and SAS version 9.2 (SAS Institute, Cary, NC).
Subject Disposition and Demographics
The study was performed at 44 centers in the United States (n = 33), Argentina (n = 1), Italy (n = 2), Israel (n = 1), Poland (n = 3), Serbia (n = 1), and Slovakia (n = 3). A total of 248 subjects were screened; 215 were enrolled, including 127 de novo subjects and 88 subjects who rolled over from the liprotamase efficacy trial. Among the 88 rollover subjects, 80 had been randomized in the previous trial, 36 to liprotamase and 44 to placebo; 8 (7 with coefficient of fat absorption [CFA] >80%) had not met the trial criteria for randomization in that trial. All of the 88 subjects who rolled over had received liprotamase during the open-label phase of the efficacy trial. With the exclusion of 1 de novo subject who was not treated with liprotamase, the safety population for the present trial consisted of 214 subjects who received at least 1 dose of liprotamase. Of the 214 subjects, 112 (52.3%) were enrolled at US sites, whereas 102 (47.7%) were enrolled at sites outside the United States. The mean and median numbers of capsules taken per day during the whole study period for the entire safety population were 5.5 and 5.4, respectively. The maximum average number of capsules per day was 8.8, 9.9, and 10.6 for patients 7 to younger than 12 years, 12 to younger than 17 years, and 17 years old or older, respectively. Most of the dose increases occurred in the first 2 to 3 months of the trial (Fig. 2). A total of 161 (75.2%) of the 214 subjects were treated for at least 6 months, and 145 (67.8%) completed the trial.
The median age of subjects was 16.5 years (range 7–62 years). Baseline demographic characteristics by age subgroup and for the overall trial safety population are presented in Table 1. Baseline nutritional measures indicate that subjects in this study had worse nutritional status compared with subjects in the CFF Patient Registry for 2008 (28). The median BMI z score of –0.373 in subjects younger than 20 years corresponds to the 35.5th percentile, which is well below the 47.7th percentile average reported for subjects 2 to 20 years old in the 2008 CFF Patient Registry (29). Mean height, weight, and BMI z scores for the safety population were –0.490, –0.607, and –0.493, respectively, indicating that subjects were approximately half a standard deviation below the 50th percentile relative to the norm for these characteristics in the general US population. Mean baseline FEV1 was 76.4% for the safety population and decreased across increasing age subgroups. About half (50.9%) of the subjects were receiving acid suppression therapy (Table 1).
Overall, 211 (98.6%) of the 214 subjects in the safety population experienced at least 1 TEAE during the course of the trial. The most commonly reported TEAEs were abdominal pain (42.5%), respiratory tract infection (38.3%), cough (36.4%), diarrhea (35.5%), flatulence (30.4%), upper abdominal pain (28.5%), and frequent bowel movements (28.0%). The vast majority of TEAEs were assessed as mild to moderate in intensity. There was a marked reduction in gastrointestinal (GI) TEAEs during the first 8 weeks coinciding with the dose adjustment by some subjects during this period, whereas the incidence did not vary substantially over time for pulmonary-related TEAEs (Fig. 2). In general, there were no clinically meaningful differences in the types or incidences of TEAEs reported across patient subgroups—according to age, sex, or geographic location—that suggested an effect of liprotamase as opposed to the underlying disease condition.
A 25-year-old man died at 11 months into the trial of CF-related respiratory failure, which was assessed as unrelated to study treatment. SAEs occurred in 61 (28.5%) of the 214 subjects; the most common SAE was respiratory tract infection, in 39 subjects (18.2%). Only 4 of the 61 SAEs were judged to be related to the study drug: 1 episode of distal intestinal obstruction syndrome that resolved easily, 2 episodes of abdominal pain, and 1 episode of gastritis and duodenitis (unexpected) identified on endoscopy conducted in a patient who developed abdominal pain following a rugby injury.
A total of 36 (16.8%) of the 214 subjects discontinued treatment because of a TEAE. The most common events leading to withdrawal from treatment (not mutually exclusive) were GI, including steatorrhea (4.7%), flatulence (4.2%), frequent bowel movements (3.3%), upper abdominal pain (2.8%), diarrhea (2.8%), and decreased weight (2.8%). Most withdrawals occurred during the first 3 months of the study (data on file). The other 33 withdrawals were for a range of reasons unrelated to study drug.
There were no clinically meaningful changes in clinical chemistry, hematology, coagulation parameters, urinalysis, or spirometry (FEV1) over time on treatment that suggested an effect of liprotamase. Mean changes from baseline were small for all parameters, and no trends were apparent over time or across patient subgroups. Specifically, there were no decreases in albumin, prealbumin, fasting triglycerides, or total cholesterol. Uric acid levels were unchanged during the study period as was expected of a PERT that lacks purines.
There were no obvious trends for increases in liver function tests over time or across patient subgroups that would suggest a relation to long-term exposure to liprotamase. A total of 6 (3%) of the 214 subjects had treatment-emergent alanine aminotransferase (ALT) values >5 times ULN (grade 3), mostly transient. None of the subjects with >5 times ULN elevations had concurrent elevations in total bilirubin >1.5 times ULN, and no subject had an elevation >10 times ULN in ALT. No subject met the definition of drug-induced liver injury (Hy Law) of >3 times ULN of ALT or AST with a serum bilirubin >2 times ULN.
Only US subjects were given vitamin supplements as part of the study protocol and thus had vitamin levels measured. Modest changes from baseline were noted over time for vitamins A, D, E, and K (Fig. 3), with mean and mean-change data highly variable. The majority of US subjects enrolled in the winter months, with low levels of vitamin D; the levels then increased in the summer months and returned to just below the normal range in the subsequent winter (investigator observation).
After an initial transition period during the first 2 months of treatment—when most withdrawals occurred and dosage adjustment took place for some patients—height, weight, and BMI z scores were relatively stable over the remaining treatment period, with similar results regardless of the analysis conducted (based on the observed data over time [Fig. 4]), LOCF with imputation for missing data after withdrawal, and data for subjects who completed the study), in all age groups. Mean (SD) BMI z scores for the safety populations were –0.493 (0.994) at baseline, –0.682 (1.013) at 3 months, –0.733 (1.031) at 6 months, and –0.681 (1.054) at 12 months. From 3 to 12 months on study, mean BMI z scores stayed within a narrow range between the 23rd and 25th percentiles based on the CDC growth charts for the normal US population. Results were similar for the 211 subjects included in the LOCF analysis and the 145 subjects who completed the study. Pulmonary function as measured by FEV1 was also maintained during the course of the study. Mean FEV1 was 76.4% at baseline and remained stable at 75.9% at 6 months and at 76.5% at 12 months.
BMI z scores were stable in the subgroups on and off acid suppressant use (H2 blockers and/or proton pump inhibitors) and within different geographic regions (United States or outside the United States; data not shown), although subjects outside the United States had a lower mean baseline BMI (18.3 kg/m2) ± (3.00 SD) compared to subjects in the United States (20.5 kg/m2) ± (4.93 SD). In subgroup analyses of the subjects who rolled over from the previous liprotamase efficacy trial, the changes in weight and BMI z scores during the present trial were evaluated overall (Fig. 5) and according to terciles of CFA measurements made 2 to 6 weeks earlier in the efficacy trial (Table 2) (30). The mean changes in weight and BMI z scores between month 3 and month 12 were not significantly different among subgroups stratified by previous CFA tercile—either at baseline in the efficacy trial (n = 87) or after randomization in that trial to liprotamase (n = 36) (Table 2) (30).
Age-appropriate gains in height and weight (indicated by stable z scores) were seen in children (Fig. 6). By month 12, in the age group of 7 to younger than 12 years, none of the subjects had lost >5% of body weight while 67.5% had gained >5%; in the age group of 12 to younger than 17 years, again none of the subjects had lost >5% of body weight while 62.8% had gained >5%. Of the 8 subjects who had sustained loss of weight >5% during the study period, all were 17 years old or older, and 7 were below the 25th percentile in weight at baseline. Three of the 8 had FEV1 <35% of predicted at baseline.
This landmark trial was the first ever conducted to evaluate the long-term safety and tolerability of any PERT in “all comers” adult and pediatric subjects 7 years and older with CF-related EPI. Subjects were not excluded based on nutritional or functional parameters, such as low BMI or FEV1. Our open-label prospective design enabled us to evaluate growth, lung function, and micronutrient outcomes in a large international population and sets a new standard for PERT trials. Maintenance of nutritional status and lung function is a highly relevant clinical outcome. Our study population was more malnourished than patients in the 2008 CFF Patient Registry, likely because of our inclusion of subjects from countries where there may have been less focus on quality improvement in care delivery processes focused on nutritional outcomes. There may also have been some selection bias, with investigators or coordinators steering patients with more GI complaints toward this study of a new form of PERT. Despite this bias, patients maintained stable height, weight, and BMI z scores during the study after a period of physiologic adaptation and dose increase when needed.
z Scores were used for measurement of clinical activity because the age of the subjects ranged from 7 to 62 years and the population included peripubertal children. z Scores allow normalization of growth percentiles and comparison of subjects of different ages when there are different rates of growth. Specifically, z scores indicate how many standard deviations any given data point is above or below the population mean. For example, a z score of –1.96 represents the 2.5th percentile, and a z score of 0 represents the 50th percentile. A z score that does not change over time indicates growth at the expected rate for the subject's age and baseline nutritional status. This study also demonstrated that after the adjustment period, subjects in the actively growing years were able to maintain age-appropriate growth and weight gain while taking liprotamase. z Scores for all parameters appear to drop initially but then remain stable throughout the study period. Given that the subjects enrolled in this study had a mean weight z score of −0.607 at entry (including 73 subjects with z scores <−1, 16 of whom had a z score <−2), it is likely that some portion of these subjects were declining during the year before study entry and then may have subsequently stabilized on liprotamase. Although not formally assessed, the principal investigator noted that the subjects who dropped out early tended to be older and heavier. It is possible that heavier subjects ate a higher-fat diet but that dose adjustment was not accomplished early enough to account for the increased substrate. Many patients with CF have colons filled with sticky mucofeculent material (31) and nearly half of patients with CF have excess fecal load (32). The initial period of symptom and weight adjustment may represent clearance of colonic contents. No measures of body composition were used; thus, this explanation remains speculative.
Subjects were to initiate treatment with 1 capsule of liprotamase with each meal and snack, representing the midrange effective dose identified in the phase II liprotamase dose-finding study (26) and confirmed for efficacy in the phase III multicenter efficacy trial (27). This was the first study of liprotamase in which subjects were permitted to receive increased doses of liprotamase based on protocol-specified criteria if the initial dosing regimen was insufficient to control signs or symptoms consistent with pancreatic insufficiency. For the entire trial population, the mean number of capsules taken per day (5.5) remained close to the fixed dosing in the efficacy trial. This finding is important in the context of the adherence issue associated with the burden of needing to take numerous porcine PERT capsules many times per day for a lifetime. In 1 study of treatment adherence for children with CF, the rates of adherence to prescribed PERTs ranged from 27% to 46% (33). The potential with liprotamase to take close to 1 capsule of PERT with each meal and snack is likely to improve adherence even outside of the context of a research study.
CFA was not measured in this safety study; however, 80 subjects who had been randomized in the liprotamase efficacy study in which CFA was measured rolled over into this safety study, and thus a measure of the amount of improvement in fat absorption on liprotamase was available from that previous trial. It is striking that these subjects maintained stable BMI values over time in the present trial regardless of baseline off-enzyme CFA or the amount of improvement in fat absorption, as measured by CFA. This finding contrasts CFA (a short-term measurement of fat digestion and absorption useful for short-term efficacy studies) with growth and nutritional status as clinically relevant outcomes that were measured during a period of up to 1 full year in this study. Other indirect measures of nutrient absorption indicated that liprotamase supported nutritional status. Values for albumin and transthyretin (also known as prealbumin), 2 indirect measures of protein status (34,35), were essentially the same at the end of the study as they were at the start. The same was true for fasting triglycerides and cholesterol. Because lysophosphatidylcholine is essential for the transport of triglycerides from the enterocyte into the blood and unhydrolyzed phospholipids impair the absorption of cholesterol, unchanged triglyceride and cholesterol levels imply indirectly that liprotamase effectively mediates phospholipid hydrolysis in the gut without the need for cofactors (36). Levels of the fat-soluble vitamins A, E, D, and K were fairly stable during the study period, indicating that liprotamase supports absorption of these micelle-dependent micronutrients.
Some of our subjects had an early decline in weight and BMI z scores during the initial adjustment period, followed by a period of stabilization (ie, achievement of a normal rate of growth). Those subjects who dropped out as a result of weight loss or GI symptoms mostly did so during the first 2 to 3 months of the trial. It was also during this initial period of the study that some patients adjusted their doses. There was a marked decline in the incidence of GI symptoms as patients acclimated to the new treatment. Most SAEs and transient elevations of ALT seen were likely caused by the underlying disease.
Children with CF are at high risk for growth failure during the peripubertal period. Weight percentiles steadily decline in prepubertal children with CF in the United States (29), and the rate of height growth during puberty, the timing of puberty, and the ultimate height achieved are negatively affected for those with lower weight percentiles (CFF Patient Registry, unpublished data). There is a strong association between nutritional status and lung function (FEV1) in patients with CF (37). Our finding of normal rates of height, weight, and BMI gain and stable percent predicted FEV1 in peripubertal children indicates that liprotamase supports appropriate nutritional status, including age-appropriate growth and weight gain, during this metabolically demanding period of life.
In summary, treatment with a mean of 5.5 capsules of liprotamase daily with meals and snacks for up to 12 months was shown to be safe and well tolerated in subjects with CF-related EPI. There was no signal of increased risk for liver enzyme elevations with chronic treatment. Overall, subjects in this study were able to maintain and/or gain weight and maintain their BMI z scores. In particular, young subjects who are at the most risk for poor nutritional status exhibited age-appropriate growth and weight gain while taking liprotamase. This 12-month open-label trial, the only large study of PERT ever conducted, demonstrated that chronic treatment with liprotamase was well tolerated and resulted in maintenance of pulmonary function and age-appropriate growth and weight gain.
APPENDIX: LIPROTAMASE 767 STUDY GROUP
Javeed Akhter (Advocate Hope Children's Hospital, Oak Lawn, IL); Ran Anbar (Upstate Medical University Hospital, Syracuse, NY); Mykola Aryayev (Odessa SMU, Regional Pediatric Clinical Hospital, Odessa, Ukraine); Steven Boas (Chicago CF Care Specialists, Glenview, IL); Barbara Chatfield (University of Utah Medical Center, Salt Lake City, UT; UL1-RR025764); Marco Cipolli (Cystic Fibrosis Center, Ospedale Civile Maggiore, Verona, Italy); Anna Feketeova (Centrum pre cysticku fibrozu, I. KDD DFN Kosice, Slovak Republic); Robert J. Fink (The Children's Medical Center of Dayton, Dayton, OH); Deborah Froh (University of Virginia Health System, Charlottesville, VA); Stuart Gordon (Dartmouth-Hitchcock Medical Center, Lebanon, NH); Margaret Guill and Kathleen McKie (Medical College of Georgia, Atlanta, GA); Leslie Hendeles (University of Florida, Gainesville, FL, RR17568); Douglas Homnick (Jasper Clinic, Kalamazoo, MI); Michelle Howenstine (James Whitcomb Riley Hospital for Children, Indianapolis, IN); Patricia Joseph (University of Cincinnati Medical Center, Cincinnati, OH); Hana Kayserova (FNsP Bratislava, Bratislava, Slovak Republic); Dana Kissner (Harper University Hospital, Detroit, MI); Tetyana Kobets (Simf. Cent. District Clinical Hospital, Simferopol, Ukraine); Nathan Kraynack (Children's Hospital Medical Center of Akron, Akron, OH); Tadeusz Latos (Centrum Alergologii i Chorob, Karpacz, Poland); Michael Light (University of Miami School of Medicine, Miami, FL); Vincenzina Lucidi (Ospedale Bambino Gesù, Rome, Italy); Carlos Macri and Omar Pivetta (Hospital Universitario Austral, Buenos Aires, Argentina); Susanna McColley (Children's Memorial Hospital, Chicago, IL; UL1 RR025741); Henryk Mazurek (Instytut Gruzlicy i Chorob Pluc, Rabka Zdroj, Poland); Susan Millard (Helen DeVos Children's Hospital & Spectrum Health Hospitals, Grand Rapids, MI); Suzanne Miller (University of Mississippi Medical Center, Jackson, MS); Predrag Minic (Mother and Child Health Care Institute, Belgrade, Serbia); Kathryn Moffett (West Virginia University, Morgantown, WV); Muthiah P. Muthiah (University of Tennessee Health Sciences Center, Memphis, TN); Samya Nasr (University of Michigan Medical Center, Ann Arbor, MI; M01-RR000042); Jerry Nick (National Jewish Health, Denver, CO); Christopher Oermann (Texas Children's Hospital, Houston, TX); Adupa Rao (University of Southern California CF Center, Los Angeles, CA); James Royall (Oklahoma University Health Sciences Center, Oklahoma City, OK); Dorota Sands (Instytut Matki i Dziecka, Warsaw, Poland); Aruna Sannuti (Indiana University School of Medicine, Indianapolis, IN); David Schaeffer (Nemours Children's Clinic, Jacksonville, FL); Michael Schechter (Emory University, Atlanta, GA; UL1 RR025008); Howard Schmidt (Virginia Commonwealth University, Richmond, VA); Robert Schoumacher (Le Bonheur Childrens Medical Center, Memphis, TN); Gregory Shay (Kaiser Permanente, Oakland, CA); Daniel Sheehan (Women's & Children's Hospital of Buffalo, Buffalo, NY); Leonard Sicilian (Massachusetts General Hospital, Boston, MA); Arvey Stone (North Suburban Pulmonary and Critical Care Consultants, Niles, IL); Branko Takac (Centrum pre cysticku fibrozu, Banska Bystrica, Slovak Republic); Heather Thomas (University of Nebraska Medical Center, Omaha, NE); Henry Thompson (Idaho Pediatric Gastroenterology, Boise, ID); Debbie Toder (Children's Hospital of Michigan, Detroit, MI); Maria Trawinska-Bartnicka (Specjalistyczny ZOZ nad Matka i dzieckiem) Gdansk, Poland; Michael Wall (Oregon Health and Science University, Portland, OR); James Wallace (Sanford Clinic, Sioux Falls, SD); Laurie Whittaker Leclair (University of Vermont, Burlington, VT); Michael Wilschanski (Hadassah University Hospital–Mount Scopus, Jerusalem, Israel); Robert Zanni (Monmouth Medical Center, Long Branch, NJ)
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