Rationale: Survival in patients with cystic fibrosis (CF) is improving over time. Traditionally, there has been concern about high mortality in individuals with CF requiring invasive mechanical ventilation (IMV) for respiratory failure.Objectives: We hypothesized that mortality has decreased over time in this population because of improvements in disease-specific therapies.Methods: The U.S. Nationwide Healthcare Cost and Utilization Project database was used to identify adult patients with CF undergoing IMV between 2002 and 2014. Patients with nonurgent/nonemergent admissions, pregnancy, and encounters related to lung transplantation were excluded. Demographic, geographic, and comorbidities were analyzed. The Cochran-Armitage trend test was used to examine trends in mortality over time. Multivariate mixed effects logistic regression was used to account for possible differences in hospital mortality patterns.Results: We identified 58,799 CF admissions from 2002 to 2014, with 3,727 (6.3%) undergoing IMV. After exclusions, 1,711 admissions remained. In 762 (44.5%) of adult hospitalizations, the patient died. Annual mortality per hospitalization ranged from 29.9 to 55.3%. The Cochran-Armitage trend test suggested an increased probability of survival over time. Factors significantly associated with mortality in multivariate analysis included female sex (odds ratio [OR], 1.54; 95% confidence interval [CI], 1.14-2.09), acute renal failure (OR, 1.99; 95% CI, 1.32-3.01), and malnutrition (OR, 1.44; 95% CI, 1.01-2.06). IMV greater than 96 hours was associated with increased mortality in univariate analysis (OR, 1.51; 95% CI, 1.14-1.98); however, after adjustment for potential confounders, the association was no longer statistically significant (OR, 1.05; 95% CI, 0.77-1.43).Conclusions: Mortality per hospitalization in adults with CF who are not bridging to lung transplant and require emergent IMV is 44.5%, suggesting IMV is not futile. Furthermore, mortality decreased over the study period. These finding may help providers, families, and patients with CF weigh the risks and benefits of IMV for respiratory failure.

Rationale: Cystic fibrosis (CF) is characterized by dietary antioxidant deficiencies, which may contribute to an oxidant antioxidant imbalance and oxidative stress. Objectives: Evaluate the effects of an oral antioxidant-enriched multivitamin supplement on antioxidant concentrations, markers of inflammation and oxidative stress, and clinical outcomes. Methods: In this investigator-initiated, multicenter, randomized, double-blind, controlled trial, 73 pancreatic-insufficient subjects with CF 10 years of age and older with an FEVI between 40% and 100% predicted were randomized to 16 weeks of an antioxidant-enriched multivitamin or control multivitamin without antioxidant enrichment Endpoints included systemic antioxidant concentrations, markers of inflammation and oxidative stress, clinical outcomes (pulmonary exacerbations, anthropometric measures, pulmonary function), safety, and tolerability. Measurements and Main Results: Change in sputum myeloperoxidase concentration over 16 weeks, the primary efficacy endpoint, was not significantly different between the treated and control groups. Systemic antioxidant ((beta-carotene, coenzyme Q10, gamma-tocopherol, and lutein) concentrations significantly increased in the antioxidant-treated group (P < 0.001 for each), whereas circulating calprotectin and myeloperoxidase decreased in the treated group compared with the control group at Week 4. The treated group had a lower risk of first pulmonary exacerbation requiring antibiotics than the control group (adjusted hazard ratio, 0.50; P = 0.04). Lung function and growth endpoints did not differ between groups. Adverse events and tolerability were similar between groups. Conclusions: Antioxidant supplementation was safe and well tolerated, resulting in increased systemic antioxidant concentrations and modest reductions in systemic inflammation after 4 weeks. Antioxidant treatment was also associated with a lower risk of first pulmonary exacerbation.

SESSION TITLE: Genetic Diseases SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, November 1, 2017 at 01:30 PM - 02:30 PM PURPOSE: Nasal nitric oxide (nNo) is recommended to be used in the diagnostic work-up of primary ciliary dyskinesia (PCD). The objective of the study was to determine whether nNO measurements using the portable, electrochemical device NIOX VERO® could distinguish subjects with PCD from healthy subjects. METHODS: A multi-center, single visit, non-randomized study involved subjects with known PCD vs. age matched healthy controls (HC) conducted in subjects >5 years old. Descriptive data are presented for the 5-11 year old (5-11yo) and 12-17 year old (12-17yo) sub-groups. All subjects attempted nNO measurements first using the Tidal Breathing Method (TB-nNO) followed by the Expiration against Resistance Method (ER-nNO). Two successful measurements from a side were used for analysis if they were within 10% or 25 ppb (whichever was greater). RESULTS: The total population consisted of 157 adult and pediatric subjects. In subjects with two measurements from both nostrils using either breathing method, optimal cut-off values were 171 ppb for TB-nNO (AUC 99.8%; specificity 100%; sensitivity 98.0%) and 356 ppb for ER-nNO (AUC 98.7%; specificity 96.3%; sensitivity 97.8%). There were 104 were children (34 PCD/70 HC) that attempted to perform nNO measurements with either breathing method (whether successful or not). The 5-11yo group (n=59) consisted of 17 subjects with PCD and 42 HC. In subjects with PCD, 14 (82.4%) completed at least two successful nNO measurements from one nostril using either breathing method. There were 15 (88.2%) that completed and two that could not complete at least one successful nNO measurement in both methods. In HC, 100% of the subjects completed at least two successful nNO measurements from one nostril using either breathing method. There were 41 (97.62%) that completed and one that could not complete at least one successful nNO measurement in both methods. Mean nNO with the TB-nNO method in the PCD cohort was 60.7 (SD=72.55) ppb and 528.3 (SD=186.78) ppb for HC. Mean nNO with the ER-nNO method in the PCD cohort was 100.2 (SD=173.71) ppb and 760.4 (SD=302.36) ppb for HC. The 12-17yo group (n=45) consisted of 17 subjects with PCD and 28 HC. In the subjects with PCD, 16 (94.1%) completed at least two successful nNO measurements from one nostril using either breathing method. 100% of subjects completed at least one successful nNO measurement in both methods. In HC, 27 (96.43%) subjects completed at least two successful nNO measurements from one nostril using either breathing method. 100% completed at least one successful nNO measurement in both methods. Mean nNO with the TB-nNO method in the PCD cohort was 50.3 (SD=42.95) ppb and 733.8 (SD=322.87) ppb for HC. Mean nNO with the ER-nNO method in the PCD cohort was 81.1 (SD=79.12) ppb and 1085.1 (SD=402.20) ppb for HC. CONCLUSIONS: Performance of nasal NO measurements with the NIOX VERO® nasal measurement mode can be performed by children as young as 5 years of age and used to differentiate patients with PCD from healthy individuals. CLINICAL IMPLICATIONS: NIOX VERO® nasal measurement mode can be used to measure nasal NO in the pediatric population using two standard breathing methods - Tidal Breathing and Expiration against Resistance as part of the diagnostic work-up of PCD. DISCLOSURE: Kathy Rickard: Employee: salary Margaret Leigh: Grant monies (from industry related sources): contract for study-related tasks Stephanie Davis: Grant monies (from industry related sources): contract for study-related tasks Thomas Ferkol: Grant monies (from industry related sources): contract for study-related tasks Steven Strausbaugh: Grant monies (from industry related sources): contract for study-related tasks Nicole Beydon: Grant monies (from industry related sources): contract for study-related tasks Jane Lucas: Grant monies (from industry related sources): contract for study-related tasks Kim Nielsen: Grant monies (from industry related sources): contract for study-related tasks Claudius Werner: Grant monies (from industry related sources): contract for study-related tasks Ulla Seppala: Employee: salary Margot MacDonald-Berko: Employee: salary At the time of abstract submission, the nasal measurement mode of the NIOX VERO is not CE Marked or cleared by the FDA.

Introduction: Nasal NO is recommended to be used in the diagnostic work-up of PCD. Objective: To determine whether nNO measurements using portable electrochemical device NIOX VERO® could distinguish subjects with PCD from healthy subjects. The primary endpoint was mean nNO measurements in subjects with at least 2 measurements. Method: A multi-center, single visit, non-randomised study involved subjects ≥5 years with known PCD vs. age matched healthy controls (HC). Subjects attempted nNO using both tidal breathing method (TB-nNO) and expiration against resisitance method (ER-nNO). Descriptive analyses were performed, including a Receiver Operating Characteristic curve analysis to assess optimal cut-off values. Results: In this study, 98.1% (49 PCD [mean age 17.5 (SD 11.66)/105 HC 19.4 (SD 14.22)] completed at least one measurement in both methods; 96.8% completed at least two measurements from one nostril using either method. Mean TB-nNO values were 50.7 (SD 50.28) ppb and 575.3 (SD 236.88) ppb in PCD vs HC and mean ER-nNO values were 80.5 (SD 101.73) ppb and 915.9 (SD 391.68) ppb in PCD vs HC. In subjects with two measurements from both nostrils using either method, opitimal cut-off values were 171 ppb (51.3 nL/min) for TB-nNO (AUC 99.8%; specificity 100%; sensitivity 98.0%) and 356 ppb (106.8 nL/min) for ER-nNO (AUC 98.7%; specificity 96.3%; sensitivity 97.8%). Conclusions: The new NIOX VERO® nasal application can be used to differentiate patients with PCD from healthy individuals. The obtained cut-off TB-nNO and ER-nNO values show that both methods in NIOX VERO® can be used in children and adult patients as part of the diagnostic work-up of PCD.

Einleitung: Von einer exokrinen Pankreasinsuffizienz sind mehr als 85% der Patienten mit Mukoviszidose betroffen. NM-BL ist eine neuartige Lipase mikrobiellen Ursprungs in einer flüssigen Formulierung zur Behandlung der exokrinen Pankreasinsuffizienz. Die klinische Wirksamkeit einer Lipase wird mittels des Koeffizienten für die Fettabsorption (CFA) als Surrogatparameter belegt. Für Patienten mit schwerwiegender exokriner Pankreasinsuffizienz und einem CFA < 40% sollte dieser mindestens um 30% verbessert werden.

Objective To evaluate the safety and efficacy of a novel microbial lipase (NM-BL) in a liquid formulation for the treatment of exocrine pancreatic insufficiency (EPI) in patients with cystic fibrosis (CF) in a phase IIa proof-of-concept study.Study design We conducted a double-blind, randomized, placebo controlled crossover study in patients with cystic fibrosis and exocrine pancreatic insufficiency. Adolescent and adult patients with CF were randomized to receive NM-BL or placebo for 1 week as replacement for their usual pancreatic enzyme formulation. They were subsequently crossed-over to the alternate study treatment. The coefficient of fat absorption was evaluated as the primary endpoint. Symptoms and adverse events were evaluated as secondary endpoints.Results A total of 35 patients were randomized into the study and 22 patients completed both treatment periods. During treatment with NM-BL, the coefficient of fat absorption was significantly greater (72.7%) compared with placebo (53.8%) with a difference between groups of 18.8% (P <.001). Subjective assessment of stool fat and stool consistency also improved under treatment with NM-BL. Adverse events were mostly gastrointestinal in nature and were more common in the group receiving NM-BL.Conclusions Currently available pancreatic enzyme products are limited because of the lack of liquid formulations and being largely porcine based. The novel microbial lipase NM-BL was safe and effective in this short term trial. The trial provided clinical proof-of-concept for this novel microbial lipase as a treatment for EPI in CF. A larger phase 2 dose ranging trial is warranted.

The authors regret that during the publication of the above paper Table 3 was published incorrectly, the heading on the right side of the table currently reads “Placebo (N=20)” which is incorrect it should read, “PANCREAZE® (N=20)”. Table 3 is reproduced correctly below:Table 3Other secondary efficacy and safety assessments of the participants.Assessment, n (%)Treatment groupPlacebo (N=20)PANCREAZE® (N=20)n (%)n (%)EPI symptomsaNumber (percent) of patients with ≥1 EPI symptom during treatment.Any11 (55)4 (20)Abdominal pain6 (30)3 (15)Bloating3 (15)1 (5)Diarrhea4 (20)0 (0)Greasy stools3 (15)0 (0)Vomiting0 (0)1 (5)Stool categorybReported at least one during treatment; hard, soft and watery or oily considered abnormal.Abnormal stool18 (90)15 (75)Hard0 (0)4 (20)Soft16 (80)13 (65)Watery or greasy14 (70)2 (10)GAC scorecResponse at end of study.Excellent0 (0)4 (20)Better2 (10)9 (45)Same11 (55)7 (35)Worse7 (35)0 (0)Treatment-emergent adverse eventsAny TEAE12 (60)8 (40)Treatment-related TEAE10 (50)4 (20)Most common TEAEdOccurring in ≥2 participants (≥10%) in either treatment group. Diarrhea4 (20)0 (0) Abdominal pain3 (15)2 (10) Abdominal pain upper3 (15)1 (5) Flatulence3 (15)1 (5) Abnormal feces3 (15)0 (0) Fatigue2 (10)0 (0)EPI: exocrine pancreatic insufficiency; GAC: global assessment of change; TEAE: treatment-emergent adverse event.a Number (percent) of patients with ≥1 EPI symptom during treatment.b Reported at least one during treatment; hard, soft and watery or oily considered abnormal.c Response at end of study.d Occurring in ≥2 participants (≥10%) in either treatment group. Open table in a new tab EPI: exocrine pancreatic insufficiency; GAC: global assessment of change; TEAE: treatment-emergent adverse event. The authors would like to apologise for any inconvenience this may have caused to the readers of the journal. Efficacy and safety of PANCREAZE® for treatment of exocrine pancreatic insufficiency due to cystic fibrosisJournal of Cystic FibrosisVol. 10Issue 5PreviewPancreatic enzyme replacement therapy (PERT) is critical for correction of exocrine pancreatic insufficiency (EPI) in patients with cystic fibrosis (CF). Full-Text PDF Open Archive

BackgroundPancreatic enzyme replacement therapy (PERT) is critical for correction of exocrine pancreatic insufficiency (EPI) in patients with cystic fibrosis (CF).MethodsThis was a randomized, placebo-controlled PERT withdrawal study evaluating the efficacy and safety of PANCREAZE® (pancrelipase) in CF patients with EPI. Participants (n=49) entered an open-label, ≤14day run-in phase, maintained a high-fat diet (100±15g/day), and received PANCREAZE® (10.5 or 21). Participants with a coefficient of fat absorption (CFA)≥80% (n=40) were then randomized (1:1) to receive either PANCREAZE® or placebo during a double-blind, ≤7day withdrawal phase.ResultsPANCREAZE® improved fat absorption as shown by significantly lower mean±SD change in CFA between open-label and double-blind phases for PANCREAZE® (−1.5±5.88%; p<0.001) compared to placebo (−34.1±23.03%). Protein absorption was similarly improved. No unexpected adverse events were reported.ConclusionsThis study demonstrated PANCREAZE® was effective in treating EPI due to CF and was safe and well tolerated.

Background. Pancreatic enzyme replacement therapy is the standard of care for treatment of malabsorption in patients with cystic fibrosis (CF) and exocrine pancreatic insufficiency (PI). Aim. To evaluate efficacy and safety of a new formulation of pancrelipase (Ultrase MT20) in patients with CF and PI. Coefficients of fat absorption (CFA%) and nitrogen absorption (CNA%) were the main efficacy parameters. Safety was evaluated by monitoring laboratory analyses, adverse events (AEs), and overall signs and symptoms. Methods. Patients (n = 31) were randomized in a crossover design comparing this pancrelipase with placebo during 2 inpatient evaluation periods (6-7 days each). Fat and protein/nitrogen ingestion and excretion were measured from food diaries and 72-hour stool collections. CFA% and CNA% were calculated for each period and compared. Results. Twenty-four patients provided analyzable data. This pancrelipase increased mean CFA% and CNA% (+34.7% and +25.7%, resp., P < .0001 for both), reduced stool frequency, and improved stool consistency compared with placebo. Placebo-treated patients reported more AEs, with gastrointestinal symptoms being the most frequently reported AE. Conclusions. This pancrelipase is a safe and effective treatment for malabsorption associated with exocrine PI in patients with CF.