A model for oversight of rare disease studies: The 25-year experience of the cystic fibrosis foundation data safety monitoring board.

This manuscript addresses the development and operating procedures of the Cystic Fibrosis Foundation Data Safety Monitoring Board (CFF-DSMB) and its role in the development and approval of new therapies through complex clinical trials with an emphasis on ensuring patient safety and study integrity. The authors describe the processes that have been developed over the last 25 years including the development of educational curricula for DSMB members and patient representation on DSMBs. The experience and success of the CFF-DSMB can serve as a model for providing high quality oversight of clinical trials for other groups who are dedicated to developing treatments for rare and complex diseases.

Adherence with tobramycin inhaled solution and health care utilization.

BACKGROUND: Adherence with tobramycin inhalation solution (TIS) during routine cystic fibrosis (CF) care may differ from recommended guidelines and affect health care utilization. METHODS: We analyzed 2001-2006 healthcare claims data from 45 large employers. Study subjects had diagnoses of CF and at least 1 prescription for TIS. We measured adherence as the number of TIS therapy cycles completed during the year and categorized overall adherence as: low ≤ 2 cycles, medium >2 to <4 cycles, and high ≥ 4 cycles per year. Interquartile ranges (IQR) were created for health care utilization and logistic regression analysis of hospitalization risk was conducted by TIS adherence categories. RESULTS: Among 804 individuals identified with CF and a prescription for TIS, only 7% (n = 54) received ≥ 4 cycles of TIS per year. High adherence with TIS was associated with a decreased risk of hospitalization when compared to individuals receiving ≤ 2 cycles (adjusted odds ratio 0.40; 95% confidence interval 0.19-0.84). High adherence with TIS was also associated with lower outpatient service costs (IQR: $2,159-$8444 vs. $2,410-$14,423) and higher outpatient prescription drug costs (IQR: $35,125-$60,969 vs. $10,353-$46,768). CONCLUSIONS: Use of TIS did not reflect recommended guidelines and may impact other health care utilization.

Impact of colonizing organism in the respiratory tract on the incidence, duration, and time between subsequent hospitalizations among patients with cystic fibrosis.

BACKGROUND: This study aimed to examine the association between colonizing respiratory tract organism and frequency, duration, and time between subsequent hospitalizations among hospitalized patients with cystic fibrosis (CF). METHODS: This retrospective cohort study of 312 CF patients from 2 New York City hospitals (2006-2016) examined the effects of colonization with Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus aureus (MSSA) or methicillin-resistant S aureus (MRSA), co-colonization on incidence of hospitalization, time to next hospitalization, and total length of stay (LOS). RESULTS: Annual rate of subsequent hospitalizations was highest in patients with P aeruginosa: adjusted incidence rate ratios (aIRRs) were 2.75 (95% confidence interval [CI], 1.72-4.41) for P aeruginosa versus MSSA, 2.57 (95% CI, 1.52-4.31) for co-colonization versus MSSA, and 1.77 (95% CI, 1.04-3.01) for P aeruginosa versus MRSA. Time to readmission was shortest for P aeruginosa: aIRRs were 1.75 (95% CI, 1.05-2.94) for MRSA versus P aeruginosa, 1.64 (95% CI, 1.03-2.59) for MSSA versus P aeruginosa, and 1.61 (95% CI, 1.04-2.47) for co-colonization versus P aeruginosa. LOS was longest for P aeruginosa: aIRRs were 3.41 (95% CI, 2.19-5.32) for P aeruginosa versus MSSA, 1.66 (95% CI, 1.01-2.75) for co-colonization versus MSSA, 2.50 (95% CI, 1.58-3.93) for P aeruginosa versus MRSA, and 2.05 (95% CI, 1.32-3.18) for P aeruginosa versus co-colonization. CONCLUSIONS: CF patients with P aeruginosa alone experienced more hospitalizations, longer LOS, and shorter time to readmission versus patients with S aureus or both organisms.

Perceptions of safety monitoring in CF clinical studies and potential impact on future study participation.

BACKGROUND: Individuals with CF and their parents cite safety concerns as barriers to participating in clinical studies. We assessed whether a brochure/infographic describing patient safety monitoring processes could reduce knowledge and attitude barriers regarding safety monitoring. We also identified factors associated with likely participation in future CF studies. METHODS: Respondents from three CF centers in the U.S. were randomly assigned to receive the safety monitoring brochure/infographic or an unrelated brochure. Fifty parents of children with CF <16, 50 adolescents with CF 16-21, and 50 adults with CF ≥22 years old were recruited to complete the study survey. Factors associated with survey responses and with reported likelihood of participating in future studies were assessed. RESULTS: Overall the safety monitoring brochure/infographic was associated with increased likelihood of future participation in non-drug studies (aOR 2.30, CI95 1.01-5.28), but not in drug studies. Non-Hispanic respondents reported greater likelihood of participating in a future drug study than Hispanic respondents (aOR 3.18, CI95 1.30-7.74). Adults with CF (aOR 2.62, CI95 1.05-6.51) and parents (aOR 4.49, CI95 1.66-12.15) were more likely than adolescents to report they would ask their care team about clinical trials. Confidence in safety monitoring was associated with reported likelihood of future participation in drug studies. CONCLUSIONS: Potential future participation in CF drug and/or non-drug studies was associated with respondent age and ethnicity, receiving the safety monitoring brochure/infographic, and confidence in safety monitoring. Our findings underscore the need for education about safety monitoring, with targeted approaches for the Hispanic CF population and adolescents.

Understanding of safety monitoring in clinical trials by individuals with CF or their parents: A qualitative analysis.

BACKGROUND: Recruiting both pediatric and adult participants for clinical trials in CF is currently of paramount importance as numerous new therapies are being developed. However, recruitment is challenging as parents of children with CF and adults with CF cite safety concerns as a principal barrier to enrollment. In conjunction with the CF Foundation (CFF) Data Safety Monitoring Board (DSMB), a pilot brochure was developed to inform patients and parents of the multiple levels of safety monitoring; the CFF simultaneously created an infographic representing the safety monitoring process. This study explores the attitudes and beliefs of CF patients and families regarding safety monitoring and clinical trial participation, and elicits feedback regarding the educational materials. METHODS: Semi-structured interviews were conducted using a pre-tested interview guide and audio-recorded during routine CF clinic visits. Participants included 5 parents of children with CF <16years old; 5 adolescents and young adults with CF 16-21years old; and 5 adults with CF ≥22years old from pediatric and adult CF centers. The study team performed systematic text condensation analysis of the recorded interviews using an iterative process. RESULTS: Four major thematic categories with subthemes emerged as supported by exemplar quotations: attitudes toward clinical trials, safety values, conceptualizing the safety monitoring process, and priorities for delivery of patient education. Participant feedback was used to revise the pilot brochure; text was shortened, unfamiliar words clarified (e.g., "pipeline"), abbreviations eliminated, and redundancy avoided. CONCLUSIONS: Qualitative analysis of CF patient and family interviews provided insights into barriers to participation in clinical trials, safety concerns, perspectives on safety monitoring and educational priorities. We plan a multicenter study to determine if the revised brochure reduces knowledge, attitude and practice barriers regarding participation in CF clinical trials.

Infection control knowledge, attitudes, and practices among cystic fibrosis patients and their families.

BACKGROUND: In 2003, the Cystic Fibrosis (CF) Foundation in the United States published evidence-based infection control guidelines and distributed these to CF care centers. However, it is unclear how well the guidelines have been disseminated to patients and families, how well patients and families understand the principles of infection control, and what barriers they experience implementing the guidelines. METHODS: We assessed infection control knowledge, attitudes, and practices among CF patients and their families at 17 randomly selected CF centers. Anonymous surveys were completed by CF patients (≥16 years old) or their family members (patients <16 years old). To adjust for similarities of patients within each center, generalized estimating equations regression was used. RESULTS: From January 2007 to May 2009, 1,399 respondents completed surveys of whom 38% were patients and 62% were family members (overall mean age of patients = 14 years). Overall, 65% of respondents were aware of the CF infection control guidelines, but only 30% had discussed them more than once with their CF care team. More than one discussion was associated with increased knowledge of infection control, including routes of pathogen transmission; the importance of avoiding close contact with other CF patients; increased confidence in practicing infection control; and increased belief in the health benefits of infection control. CONCLUSIONS: This study revealed that many CF patients and families are aware of the infection control guidelines, but that few had discussed them more than once with their CF teams. These findings underscore the importance of engaging patients and their families in regular discussions about infection control that address questions and concerns including the potential impact of infection control on health and well-being. Further strategies are needed to overcome barriers to implementing these guidelines.

Facial palsy and idiopathic intracranial hypertension in twins with cystic fibrosis and hypovitaminosis A.

Facial nerve palsies are uncommon in infants. We report on 10-week-old monozygotic twins, diagnosed with cystic fibrosis by newborn screening, who developed facial palsy and increased intracranial pressure. Cranial imaging and cerebrospinal fluid analysis produced normal results. Levels of serum vitamin A were below normal range. Low levels of vitamin A are associated with facial nerve paralysis, and are at least partly implicated in the development of increased intracranial pressure in infants with cystic fibrosis.

Cell phone intervention to improve adherence: cystic fibrosis care team, patient, and parent perspectives.

BACKGROUND: Treatment regimens for patients with cystic fibrosis (CF) are time-consuming and complex, resulting in consistently low adherence rates. To date, few studies have evaluated innovative technologies to improve adherence in this population. Current infection control guidelines for patients with CF seek to minimize patient-to-patient transmission of potential pathogens. Thus, interventions must avoid face-to-face contact and be delivered individually, limiting opportunities for peer support. This study aimed to develop and assess a web-enabled cell phone, CFFONE, designed to provide CF information and social support to improve adherence in adolescents with CF. METHODS: The acceptability, feasibility, and utility of CFFONE were evaluated with health care professionals (n = 17) adolescents with CF aged 11-18 years old (n = 12), adults with CF aged 21-36 years old (n = 6), parents of adolescents with CF (n = 12), and technology experts (n = 8). Adolescents also tested a prototype of CFFONE (n = 9). Qualitative and quantitative data were collected. RESULTS: Focus group data with health care professionals indicated a need for this intervention, and indicated that CFFONE would be likely to improve knowledge and social support, and somewhat likely to improve adherence. Adolescent, adults, and parents all rated CFFONE as likely to improve adherence. Technology experts rated the prototype design and format as appropriate. CONCLUSIONS: The current study provided some support from key stakeholders for this intervention to improve adherence in adolescents with CF. Next steps include a multi-center trial of the efficacy and safety of CFFONE.

Defective CFTR increases synthesis and mass of sphingolipids that modulate membrane composition and lipid signaling.

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) that affect protein structure and channel function. CFTR, localized in the apical membrane within cholesterol and sphingomyelin rich regions, is an ABC transporter that functions as a chloride channel. Here, we report that expression of defective CFTR (DeltaF508CFTR or decreased CFTR) in human lung epithelial cell lines increases sphingolipid synthesis and mass of sphinganine, sphingosine, four long-chain saturated ceramide species, C16 dihydroceramide, C22, C24, C26-ceramide, and sphingomyelin, and decreases mass of C18 and unsaturated C18:1 ceramide species. Decreased expression of CFTR is associated with increased expression of long-chain base subunit 1 of serine-palmitoyl CoA, the rate-limiting enzyme of de novo sphingolipid synthesis and increased sphingolipid synthesis. Overexpression of DeltaF508CFTR in bronchoalveolar cells that do not express CFTR increases sphingolipid synthesis and mass, whereas overexpression of wild-type CFTR, but not of an unrelated ABC transporter, ABCA7, decreases sphingolipid synthesis and mass. The data are consistent with a model in which CFTR functions within a feedback system that affects sphingolipid synthesis and in which increased sphingolipid synthesis could reflect a physiological response to sequestration of sphingolipids or altered membrane structure.

Quantitative analysis of longitudinal response to aerosolized granulocyte-macrophage colony-stimulating factor in two adolescents with autoimmune pulmonary alveolar proteinosis.

BACKGROUND: Autoimmune pulmonary alveolar proteinosis (APAP) is characterized by autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF) in blood and tissues, resulting in alveolar surfactant protein accumulation. Patients with APAP present with ground-glass opacities (GGOs) and interlobular septal thickening on thin-slice chest CT scans. Aerosolized GM-CSF therapy (aeroGM-SCF) has qualitatively improved the clinical condition of patients with APAP. This report details quantitative chest CT responses to aeroGM-CSF. METHODS: Two adolescent patients (aged 16 and 19 years) with APAP were treated with aeroGM-CSF. Clinical parameters, including pulmonary function tests and chest CT scans, were obtained before and after aeroGM-CSF therapy. To evaluate the effect of the therapy, serial chest CT scans were analyzed using a novel approach permitting quantitative assessment of improvement in GGOs, lung weight, and gas volume. RESULTS: In association with GM-CSF treatment, nutritional status and pulmonary function improved. Quantitative analysis of the CT scans demonstrated reduction in GGOs and lung weight, concomitant with an increase in airspace volume and lung inflation. The findings were consistent with a qualitative reduction in GGOs on chest CT imaging. CONCLUSIONS: Quantitative analysis of CT holds promise as a sensitive diagnostic tool permitting longitudinal and objective analysis of the therapeutic response to aeroGM-CSF in patients with APAP.