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.

Advancing the pipeline of cystic fibrosis clinical trials: a new roadmap with a global trial network perspective.

The growing use of modulator therapies aimed at restoring cystic fibrosis transmembrane conductance regulator (CFTR) protein function in people with cystic fibrosis has fundamentally altered clinical trial strategies needed to advance new therapeutics across an orphan disease population that is now divided by CFTR modulator eligibility. The development of a robust pipeline of nucleic acid-based therapies (NABTs)-initially directed towards the estimated 10% of the cystic fibrosis population who are genetically ineligible for, or intolerant of, CFTR modulators-is dependent on the optimisation of restricted trial participant resources across multiple development programmes, a challenge that will preclude the use of gold standard placebo-controlled trials. Advancement of a full pipeline of symptomatic therapies across the entire cystic fibrosis population will be challenged by smaller effect sizes and uncertainty regarding their clinical importance in a growing modulator-treated population with more mild and stable pulmonary disease. In this Series paper, we aim to lay the foundation for clinical trial strategy and community partnership that must deviate from established and familiar precedent to advance the future pipeline of cystic fibrosis therapeutics.

Severe respiratory viral infections in children with history of asymptomatic or mild COVID-19.

IMPORTANCE: The spectrum of complications of COVID-19 in children, including the effect of COVID-19 on later viral infection, is not known. OBJECTIVE: To examine the features of children hospitalized for respiratory illness with history of prior COVID-19. DESIGN: Retrospective observational case series at a single pediatric quaternary medical center in New York City. Data were obtained from review of medical records. PARTICIPANTS: Children with prior mild or asymptomatic COVID-19 and no known risk factors for severe respiratory disease, who were hospitalized at our center for acute respiratory illness from October 2020 to May 2021, were reviewed. MAIN OUTCOMES AND MEASURES: Co-morbidities, history of prior COVID-19 symptoms, respiratory viral panel findings, acuity of illness, degree of respiratory decompensation based on support and interventions required, duration of hospitalization, and overall clinical course were assessed from the medical record. RESULTS: This study included 5 patients (median age, 4 years; age range: 0.8-9 years; 4 [80%] male). All had positive COVID-19 serology, 1 (20%) had mild symptoms, while the others had no symptoms of prior Sars-CoV-2 infection, 3 (60%) had asthma, and the remaining had no co-morbidities. All were admitted between April and May 2021. Two were re-admitted for respiratory symptoms in the subsequent 3 months. CONCLUSIONS AND RELEVANCE: This case series describes a possible association between severe lower respiratory tract infection and prior mild COVID-19 in children. Larger cohort studies describing the respiratory effects of prior COVID-19 in children are needed.

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.

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.

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.

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.

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.

Cystic fibrosis pulmonary guidelines: pulmonary complications: hemoptysis and pneumothorax.

RATIONALE: Cystic fibrosis (CF) is a recessive genetic disease characterized by dehydration of the airway surface liquid and impaired mucociliary clearance. As a result, individuals with the disease have difficulty clearing pathogens from the lung and experience chronic pulmonary infections and inflammation. There may be intermittent pulmonary exacerbations or acute worsening of infection and obstruction, which require more intensive therapies. Hemoptysis and pneumothorax are complications commonly reported in patients with cystic fibrosis. OBJECTIVES: This document presents the CF Foundation's Pulmonary Therapies Committee recommendations for the treatment of hemoptysis and pneumothorax. METHODS: The committee recognized that insufficient data exist to develop evidence-based recommendations and so used the Delphi technique to formalize an expert panel's consensus process and develop explicit care recommendations. MEASUREMENTS AND MAIN RESULTS: The expert panel completed the survey twice, allowing refinement of recommendations. Numeric responses to the questions were summarized and applied to a priori definitions to determine levels of consensus. Recommendations were then developed to practical treatment questions based upon the median scores and the degree of consensus. CONCLUSIONS: These recommendations for the management of the patient with CF with hemoptysis and pneumothorax are designed for general use in most individuals but should be adapted to meet specific needs as determined by the individuals, their families, and their health care providers. It is hoped that the guidelines provided in this manuscript will facilitate the appropriate application of these treatments to improve and extend the lives of all individuals 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.

Respiratory microbiology of patients with cystic fibrosis in the United States, 1995 to 2005.

BACKGROUND: Numerous improvements in diagnostic and therapeutic strategies for patients with cystic fibrosis (CF) have occurred during the past 2 decades. We hypothesized that these changes could impact trends in respiratory microbiology. METHODS: Data from the Cystic Fibrosis Foundation Patient Registry were used to examine trends in the incidence and prevalence of bacterial pathogens isolated from patients with CF in the United States from 1995 to 2005. RESULTS: The number of patients with CF in the patient registry increased from 19,735 in 1995 to 23,347 in 2005. During the study period, the reported annual prevalence of Pseudomonas aeruginosa significantly declined from 60.4% in 1995 to 56.1% in 2005 (p < 0.001). The decline was most marked in children 6 to 10 years old (48.2 to 36.1%) and adolescents 11 to 17 years old (68.9 to 55.5%). Both the incidence (21.7% in 1995 and 33.2% in 2005) and prevalence (37.0% in 1995 and 52.4% in 2005) of methicillin-susceptible Staphylococcus aureus significantly increased and the age-specific prevalence was highest in patients 6 to 17 years old. The prevalence of methicillin-resistant S aureus increased from 0.1% in 1995 to 17.2% in 2005 and from 2002 to 2005 was highest in adolescents 11 to 17 years old. Both the prevalence and incidence of Burkholderia cepacia complex declined, while the prevalence of Haemophilus influenzae, Stenotrophomonas maltophilia, and Alcaligenes xylosoxidans increased. CONCLUSIONS: Data from the patient registry suggest that the epidemiology of bacterial pathogens in patients with CF changed during the study period. Future studies should continue to monitor changing trends and define the association between these trends and care practices in CF.

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.

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.

Staphylococcus aureus nasal colonization among pediatric cystic fibrosis patients and their household contacts.

BACKGROUND: Little is known about the prevalence of Staphylococcus aureus nasal colonization and the epidemiology of methicillin-susceptible and methicillin-resistant S. aureus (MRSA) among cystic fibrosis (CF) patients and their household members. OBJECTIVES: We sought to determine the epidemiology of S. aureus among children and adolescents with CF and their household members. METHODS: Three CF centers enrolled case subjects with at least 1 MRSA-positive respiratory tract culture from 2001 to 2006 and control subjects with MRSA-negative cultures. S. aureus isolates from the anterior nares of CF subjects and their household members were assessed for staphylococcal chromosomal cassette (SCC) mec type. Strain similarity was determined by pulsed-field gel electrophoresis. RESULTS: S. aureus nasal colonization occurred in 52.4% (22/42), 27.0% (17/63), and 25.0% (72/288) of case, control, and household participants, respectively. Case subjects and their contacts were more likely to harbor MRSA in their nares and be from a multipatient CF family. Of 31 MRSA strains, 10 (32.3%) were SCCmec type IVa, associated with community-acquisition. Overall, 27.6% of 98 households had > or =2 members colonized with closely related isolates. Household members were equally likely to be colonized with closely related strains of MRSA (20/31, 65%) versus MSSA (38/80, 48%). CONCLUSIONS: This study demonstrated that household members of CF children harbor both MSSA and MRSA, including CA-MRSA, and that S. aureus is transmitted within CF households. Carriage of S. aureus by household members of CF children may have implications for infection control and treatment strategies. Future studies should monitor the distribution and virulence of SCCmecA types in patients with CF.

Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health.

RATIONALE: Cystic fibrosis is a recessive genetic disease characterized by dehydration of the airway surface liquid and impaired mucociliary clearance. As a result, individuals with the disease have difficulty clearing pathogens from the lung and experience chronic pulmonary infections and inflammation. Death is usually a result of respiratory failure. Newly introduced therapies and aggressive management of the lung disease have resulted in great improvements in length and quality of life, with the result that the median expected survival age has reached 36 years. However, as the number of treatments expands, the medical regimen becomes increasingly burdensome in time, money, and health resources. Hence, it is important that treatments should be recommended on the basis of available evidence of efficacy and safety. OBJECTIVES: The Cystic Fibrosis Foundation therefore established a committee to examine the clinical evidence for each therapy and to provide guidance for the prescription of these therapies. METHODS: The committee members developed and refined a series of questions related to drug therapies used in the maintenance of pulmonary function. We addressed the questions in one of three ways, based on available evidence: (1) commissioned systematic review, (2) modified systematic review, or (3) summary of existing Cochrane reviews. CONCLUSIONS: It is hoped that the guidelines provided in this article will facilitate the appropriate application of these treatments to improve and extend the lives of all individuals with cystic fibrosis.